ACUTE PANCREATITIS

Introduction
-Principal function of the pancreas is to make food-digesting enzymes (exocrine) and Insulin (endocrine). The
pancreas, comprising only 0.1% of total body weight, has 13 times the protein-producing capacity of the liver and
reticulo endothelial system combined, which make up 4% of total
body weight.
-Several mechanisms enable the pancreas to avoid digesting itself. First, proteins are translated into an inactive form
called pro enzymes. The pro enzymes are packaged in a para- crystalline arrangement with protease inhibitors
Zymogen granules have an acidic pH and a low calcium concentration, which are factors that guard against
premature activation
-Under various conditions, these protective mechanisms are disrupted, resulting in intracellular enzyme activation
and pancreatic auto digestion, a condition called acute pancreatitis. This condition typically causes abdominal pain,
usually associated with elevated pancreatic enzyme levels in the blood and inflammation of the pancreas.
Mortality/Morbidity:
-The overall mortality rate of patients with acute pancreatitis is 10-15%.
-In patients with severe disease, the mortality rate is approximately 30%.
-In the first week of illness, most deaths result from multiorgan system failure. In subsequent weeks, infection plays
a more significant role, but organ failure still constitutes a major cause of mortality.
Sex:
-In general, acute pancreatitis affects males more often than females.
-The etiology in males is more often related to alcohol; in females, to biliary tract disease.

Causes
-Although pancreatitis has numerous etiologies, alcohol dependence and biliary tract disease cause most cases. In
10-30% of cases, the cause is unknown, and careful evaluation may identify a rare etiology in 10% of cases.
1. Biliary tract disease (approximately 38%)
-The most common cause of acute pancreatitis is gallstones passing into the bile duct and temporarily lodging at the
sphincter of Oddi. The risk of a stone causing pancreatitis is inversely proportional to its size.
-Abnormal anatomy (eg, choledochal cysts, juxtapapillary diverticula) is also associated with acute pancreatitis.
2. Alcohol (approximately 35%)
-Alcohol abuse is a major cause of pancreatitis; evidence shows that alcohol may cause acute pancreatitis in the
absence of chronic disease.
3. Post-ERCP (approximately 4%)
4. Trauma (~1.5%)
-Abdominal trauma causes an elevation of amylase and lipase levels in 17% of cases and clinical pancreatitis in 5%
of cases.
5. Drugs (~1.4%)
-Drug-induced pancreatitis is usually mild.
-Drugs definitely associated with acute pancreatitis include azathioprine, sulfonamides, sulindac, tetracycline,
valproic acid, didanosine, methyldopa, estrogens, furosemide, 6-mercaptopurine, pentamidine, 5-aminosalicylic acid
compounds, corticosteroids, and octreotide.
6. Infection (<1%)
-Viral causes include mumps, Epstein-Barr, coxsackievirus, echovirus, varicella-zoster, and measles.
-Bacterial causes include Mycoplasma pneumoniae, Salmonella, Campylobacter, and Mycobacterium tuberculosis.
-Worldwide, ascariasis is a recognized cause of pancreatitis resulting from the migration of worms in and out of the
duodenal papillae.
-Pancreatitis has been associated with AIDS; however, this may be the result of opportunistic infections, neoplasms,
or drug therapies
7. Hereditary pancreatitis (<1%)
-This type of pancreatitis is an autosomal dominant disorder related to mutations of the cationic trypsinogen gene
8. Hypercalcemia (<1%)
-Hypercalcemia from any cause can lead to acute pancreatitis
9. Developmental abnormalities of the pancreas (<1%)
10. Hypertriglyceridemia (<1%)

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11. Tumor (<1%)
-Obstruction of the pancreatic ductal system by a pancreatic ductal carcinoma, ampullary carcinoma,
cholangiocarcinoma, or metastatic tumor can cause acute pancreatic
Differentials
-Same as acute abdomen
Clinical presentation
History:
-The cardinal symptom of acute pancreatitis is abdominal pain, which is characteristically dull, boring, and steady.
Most often, it is located in the upper abdomen, usually in the epigastric region, but it may be perceived more on the
left or right side, depending on which portion of the pancreas is involved.
-The pain radiates to the back in approximately half of cases.
-The duration of pain varies but typically lasts more than a day.
-The pain may be aggravated by eating or lying supine and it may be alleviated by fasting or lying on the left side
with the knees and hips flexed.
-Associated symptoms (eg, anorexia, nausea, vomiting) are common, and some patients experience diarrhea due to
indigestion.
-Avulsion to fatty foods may be reported.
Physical:
-The following physical examination findings vary with the severity of the disease.
1. Fever (76%) and tachycardia (65%) are common abnormal vital signs.
2. Abdominal tenderness, muscular guarding (68%), and distension (65%) are observed in most patients. Bowel
sounds are often hypoactive.
-A minority of patients exhibit jaundice (28%).
-Some patients experience dyspnea (10%), which may be caused by irritation of the diaphragm (resulting from
inflammation) or by a more serious condition, such as respiratory distress syndrome.
-In severe cases, hemodynamic instability is evident (10%) and hematemesis or melena sometimes develops (5%).
-A few uncommon physical findings are associated with severe necrotizing pancreatitis.
The Cullen sign is a bluish discoloration around the umbilicus resulting from hemoperitoneum.
The Grey-Turner sign is a reddish-brown discoloration along the flanks resulting from retroperitoneal blood
dissecting along tissue planes.
Erythematous skin nodules may result from focal subcutaneous fat necrosis.
 Rarely, abnormalities on funduscopic examination may be seen in severe pancreatitis. Purtscher
retinopathy, this ischemic injury to the retina appears to be caused by activation of complement and
agglutination of blood cells within retinal vessels. It may cause temporary or permanent blindness.
Lab Tests
1. Amylase and lipase
-Serum amylase and lipase levels are typically elevated in persons with acute pancreatitis. However, these elevations
may only indicate pancreatitis.
-Serum amylase determinations are routinely available, but they are not specific for pancreatitis. Elevations can
occur in anyone with small intestinal obstruction, mesenteric ischemia, tuba-ovarian disease, renal insufficiency, or
macroamylasemia.
-Rarely, elevations may reflect parotitis.
2. Liver-associated enzymes
-Determine alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels to
search for evidence of gallstone pancreatitis.
3. Calcium, cholesterol, and triglycerides
-Determine these levels to search for an etiology of pancreatitis (hypercalcemia or hyperlipidemia) or complications
of pancreatitis (hypocalcemia resulting from saponification of fats in the retroperitoneum).
4. Serum electrolytes, BUN, creatinine, and glucose
- Measure these to look for electrolyte imbalances, renal insufficiency, and pancreatic endocrine dysfunction.
5. CBC count
-An admission hematocrit value greater than 47% may predict severe necrotizing pancreatitis.
-Leukocytosis may represent inflammation or infection.
6. C-reactive protein
-Acute reactant not specific to pancreatitis.

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7. Arterial blood gases
-Measure ABGs if a patient is dyspneic.

Imaging
1. Abdominal radiography
-These radiographs are primarily used to detect free air in the abdomen, indicating a perforated viscus.
-The presence of calcifications within the pancreas may indicate chronic pancreatitis.
2. Abdominal ultrasonography
-This is the most useful initial test in determining the etiology of pancreatitis and is the technique of choice for
detecting gallstones.
3. Abdominal CT scanning
-This is generally not indicated for patients with mild pancreatitis unless a pancreatic tumor is suspected (usually in
elderly patients).
-CT scanning is always indicated in patients with severe acute pancreatitis and is the imaging study of choice for
assessing complications.
-Dynamic spiral CT scanning is used to determine the presence and extent of pancreatic necrosis
4. Magnetic resonance cholangiopancreatography
-Magnetic resonance cholangiopancreatography (MRCP) has an emerging role in the diagnosis of suspected biliary
and pancreatic duct obstruction in the setting of pancreatitis.
-MRCP is safer, noninvasive, and fast, and it provides images useful in guiding clinical care decisions.
5. Endoscopic ultrasonography (EUS) is an endoscopic procedure that allows a high-frequency ultrasound
transducer to be inserted into the gastrointestinal tract to visualize the pancreas and the biliary tract.
6. CT-guided needle aspiration
-This procedure is used to differentiate infected necrosis and sterile necrosis in patients with severe necrotizing
pancreatitis
-Various strategies have been used to predict the severity and outcome of acute pancreatitis
-The Ranson criteria are perhaps best known; however, they have several drawbacks.
-First, 11 criteria are used, some of which are evaluated on day 1 and others on day 2.
- The Ranson score is valid only at 48 hours after onset and not at any other time during the disease
-Acute physiology and chronic health evaluation
-The acute physiology and chronic health evaluation (APACHE) score has the advantage of being able to assess the
patient at any point during the illness;

MANAGEMENT
-Severe acute pancreatitis requires intensive care. Within hours to days, a number of complications (eg, shock,
pulmonary failure, renal failure, gastrointestinal bleeding, and multiorgan system failure) may develop.
- The goals of medical management are to provide aggressive supportive care, decrease inflammation, limit infection
or superinfection, and identify and treat complications as appropriate.
1. Fluids
-Patients are kept NPO and require intravenous hydration. Especially in the early phase of the illness, aggressive
fluid resuscitation is critically important.
-Many patients require a nasogastric tube, a Foley catheter, and a central line or Swan-Ganz catheter for the purpose
of monitoring and managing hydration status.
2. Antibiotics
-Imipenem/cilastatin penetrates the pancreatic parenchyma and reduces the risk of intra-abdominal infection.
Metronidazole and levofloxacin may be used.
3. Analgesia
4. ERCP
-If the imaging and laboratory study findings are consistent with severe acute gallstone pancreatitis or ascending
cholangitis, early ERCP with sphincterotomy and stone extraction is indicated
5. Nutrition
-Depending on the situation, total parenteral nutrition, which has been shown to reduce mortality rates, may be
necessary.

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SURGERY
1. Pancreatic duct disruption:
-Damage to the pancreatic ductal system may allow pancreatic juice to leak from the gland
-Percutaneous placement of a drainage tube into the fluid collection under the guidance of ultrasonography or CT
scanning.
-Endoscopic retrograde pancreatography
-Fluid amylase or lipase levels in the ten thousands strongly suggest the presence of a ductal disruption
2. Pseudocysts may be managed endoscopically by transpapillary or transmural techniques.
-Percutaneous drainage serves as a temporizing measure that may later lead to successful endoscopic or surgical
intervention.
-Surgical cyst-enterostomy
-Infected pancreatic necrosis- Surgery is recommended when large areas of the pancreas are necrotic and
percutaneous CT-guided aspiration demonstrates infection based on a positive Gram stain result.
- Antibiotic therapy alone is not sufficient to achieve a cure

ACUTE POST STREPTOCOCCAL GN ( PSAGN)

Definition
--GN Variety of renal diseases in which there inflammation of the glomerulus, manifested by proliferation of
cellular elements secondary to an immunologic mechanism.
-Most incidents of AGN appear to be associated with a post infectious state ie post bacterial, viral and protozoan
infection eg staphylococcal , pneumococcal infections, coxsackievirus B, echovirus type 9, influenza virus, and
mumps.
-PSAGN follows infection with group A beta hemolytic streptococci.
Pathophysiology
-Immune complexes, preformed by the combination of specific antibodies against streptococcal antigens, localize on
the glomerular capillary wall and activate the complement system.
-The immunologic system may also be activated by streptococcal antigens that adhere to the glomerular structures
and act as "planted antigens" or by alterations in endogenous antigens.
-The activation of the complement cascade then generates chemotactic -activated complement 5 (C5a) and platelet-
derived inflammatory mediators.
-Various cytokines and other cellular immunity factors initiate an inflammatory response manifested by cellular
proliferation and edema of the glomerular tuft.
-Only some strains of Grp A strep are nephrotogenic. Some non Grp A e.g. Grp C also cause PSGN.
-At least 2 antigens isolated from nephritogenic streptococci, zymogen (a precursor of exotoxin B) and
glyceraldehyde phosphate dehydrogenase (GAPDH), have been identified and are believed to be capable of
initiating the immunologic response
-Nodular deposits of immunoglobulin G (IgG) and the third component of complement (C3) on the capillary
basement membrane. The finding of C3 in the renal glomerulus is usually associated with decreased serum
concentrations of C3 and total hemolytic complement. C3 levels return to normal in children in 6-8wks in
children.C4 levels usually depressed too inconsistently.
-PSAGN can occur in epidemics or, more commonly, it is be sporadic. The sporadic form is seasonal; is associated
with respiratory infection, and often associated with pyoderma.
Common group A beta hemolytic streptococci associated with nephritis from nasopharyngeal infections is type 12;
type 49 is most often recovered during outbreaks of pyoderma-related PSAGN.
-In individuals with pharyngitis-related AGN, the latent period is approximately 10 days, and more than 80%
of patients exhibit a significant rise in serum titer of antistreptolysin-O (ASO). Latent period is difficult to define in
persons with impetigo-related AGN, and a rise in the titer of ASO only 50% of patient
-Other streptococcal indicators (eg, antihyaluronidase [AH] titer, antideoxyribonuclease B titer [anti-DNase B])
elevated in either pharyngeal or skin infections.
-When a variety of antibody titers is used, almost 95% of patients with PSAGN demonstrate evidence of a prior
streptococcal infection

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Histology:
-The glomerular tufts usually appear enlarged and swollen; proliferation of mesangial and epithelial cells is present.
Polymorphonuclear leukocytes
Immunofluorescent microscopy Granular deposits of IgG and C3; other immunoglobulins (Igs) and fibrinogen
often are observed.
Electron microscopy of renal tissue from patients with PSAGN usually reveals subepithelial electron-dense
deposits (humps)
-Usually, measurable reduction in volume of glomerular filtrate (GF) is present, and the capacity to excrete salt and
water is usually diminished, leading to expansion of the extracellular fluid (ECF) volume. The expanded ECF
volume is responsible for edema and, in part, for hypertension, anemia, circulatory congestion, and encephalopathy.
Mortality/Morbidity:
Generally good prognosis
-Depends largely on the severity of the initial insult.
–In Very few of pts the initial injury is so severe that either persistent renal failure or progression to chronic renal
failure occurs.
-In most patients, histologic regression of the disease occur, and prognosis good.
-Clinical manifestations of the disease rarely recur after the first 3 months, and second episodes of AGN are
uncommon.
-Poorer prognosis in adults, particularly in elderly individuals.
Clinical course predictable:
Edema usually resolves within 5-10 days
 Gross hematuria usually disappears within 1-3 weeks
 BP usually returns to normal within 2-3 weeks though persistence of elevated pressures for as many as 6
weeks is compatible with complete resolution.
 The C3 concentration returns to normal by 6-8 weeks
 Urinary abnormalities resolve at slower pace. Proteinuria may disappear within the first 2-3 months or
may decrease slowly over 6 months. Intermittent or postural proteinuria has been noted in a few patients
for as long as 1-2 years after onset.
 Microscopic hematuria usually disappears after 6 months; however, its presence for as long as 1 year is not
uncommon
-Possibility that the disease has entered a chronic phase if both hematuria and proteinuria persist for more than
12 months
Age:
-Greatest frequency in children aged 4-12 years, with a peak prevalence in individuals aged approximately 5-6
years. Slight male predominance
-Other postinfectious causes of AGN must be considered in the differential diagnosis (eg, Strep pneumoniae, Staph
aureus, Staph epidermidis, Rickettsia rickettsiae, Mycoplasma species, Meningococcus species, and Leptospira
species).viral illnesses causing AGN; most common varicella-zoster virus, cytomegalovirus, and the Epstein-Barr
virus
1. IgA-associated GN
-Urticarial or purpuric rashes, abdominal complaints, and arthritis and/or arthralgia
-HTN and oedema less prominent.
-No evidence of prior strep infection and c3 levels normal.
2. Berger disease or IgA nephropathy presents as an episode of gross hematuria occurring during the early stages
of a respiratory illness; no latent period exists, and hypertension or edema is uncommon.
-Recurence common. Unlike PSGN
3. Mesangiocapillary or membranoproliferative GN (MPGN)
-The initial manifestations are often more serious in persons with MPGN than in those with IgA nephropathy; the
renal function is reduced markedly (ie, large elevation of serum creatinine). No evidence of strep infection, C3
depressed past 6wks, Urinary abn persists past time of resolution for PSGN.
4. Crescentic GN is the term used to describe a histologic picture of severe proliferative GN.
-Synechiae between the glomerular tuft and Bowman capsule.
-Rapidly progressive GN and may be secondary to a number of causes, including an immune-complex mediated
poststreptococcal nephritis.
-The initial clinical picture is generally severe, and resolution appears delayed.

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Clinical Presentation:
-Most patients with acute GN exhibit milder symptoms between 2 extremes;
-Asymptomatic child whose disease is discovered only by examination of the urine.
-Based on surveillance studies of the siblings and/or household contacts of children affected with PSAGN, at least
50% of persons with laboratory evidence of nephritis (ie, abnormal urinalysis) appear to have no symptoms or signs
of clinical illness
- Severe disease manifested by oliguria, edema, hypertension, and azotemia and with proteinuria, hematuria, and
urinary casts (cylindruria).
-Latent period of 7-21 days between onset of the streptococcal infection and development of clinical GN is
characteristic latent period, after pharyngeal infections, averages 10 days
1. Gross hematuria and/or edema
- The most common signs
-Appear abruptly associated with various degrees of malaise, lethargy, anorexia, fever, abdominal pain, and
headache
-Gross hematuria occurs at onset in 30-50% of children; the urine may be smoky, cola colored, tea colored, or rusty
2. Oliguria.
3. Edema
-First involves the periorbital area, but it may be generalized.
-The degree of edema varies and depends on a severity of glomerular involvement, the fluid intake, and the degree
of hypoalbuminemia
- Insidious onset of edema is more indicative of other forms of renal disease
4. Hypertension
- Is the third cardinal feature of PSAGN and is reported in 50-90%
-Multifactorial and related only in part to ECF volume expansion BP systolic pressures greater than 200 mm Hg and
diastolic pressures greater than 120 mm Hg
-Rarely Hypertensive encephalopathy occurs, most serious early complication of this disease.
- Usually HTN is severe and CNS dysfunction signs as headache, vomiting, depressed sensorium, confusion, visual
disturbances, aphasia, memory loss, coma, and convulsions.
5. Circulatory congestion only rarely causes significant early symptoms.
- Dyspnea, orthopnea, and cough may be present. Pulmonary rales are often audible.
-In the patient with an otherwise normal cardiovascular system, cardiac failure is unusual.
6. Pallor is common at onset and is not explained entirely by the anemia.

Investigations:
-Urine output most often is reduced, and urine is concentrated and acidic
a) Urinalysis.
Proteinuria sometimes glycosuria.
-The urine reaction for protein rarely exceeds 3+ by dipstick, corresponding to fewer than 2 g/m 2/d
-Abt 2-5% of children with PSAGN have massive proteinuria and a nephrotic picture.
 Hematuria is the most consistent abnormality
 Polymorphonuclear leukocytes and renal epithelial cells esp. during the early phase of the disease
 Hyaline and/or cellular casts are almost always present.
 RBC casts,
b) Renal Function Tests.
The elevation in the serum concentrations of creatinine
 Elevated blood urea nitrogen (BUN) is usually modest, although some patients may have severe azotemia
at onset
c) Evidence of streptococcal infection in all patients.
Culture of skin or pharynx
 A number of laboratory tests can be used to measure antibodies to a variety of streptococcal antigens (eg,
ASO, AH, anti-DNase B) or to combinations of antigens (eg, streptozyme test). A rise in the titer of the
antibody, measured at an interval of 2-3 weeks, is more meaningful than a single measurement.
d) Hemolytic complement.
-C3 and total hemolytic complement levels re low.C4 levels are most often normal. Serum levels of fifth component
of complement (C5) and properdin are usually decreased.
-The complement levels generally return to normal by 6-8 weeks after onset.

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e) Electrolytes
-Hyperkalemia and metabolic acidosis are only present in patients with significant renal functional impairment.
-The same applies to hyperphosphatemia.
-Total serum calcium, but not ionized calcium levels, may be low in patients who have a nephrotic picture
f) FHG
-A mild anemia (normocytic, normochromic) is common in persons in the early phase of AGN; its degree tends to
parallel the degree of ECF volume expansion.
- Erythropoiesis may decline in the aftermath of AGN, particularly in individuals with severe cases.
-WBC and platelet counts are usually normal, even though an occasional patient exhibits a leukocytosis; rarely, a
mild thrombocytopenia may be present.
-A few patients have hypoproteinemia and hyperlipidemia.
- A nephrotic picture has been reported in approximately 5% of hospitalized patients with PSAGN.

Imaging Studies:
-Renal ultrasonography generally demonstrates normal to slightly enlarged kidneys bilaterally with some evidence
of increased echogenicity.
-Chest radiographs commonly demonstrate central venous congestion in a hilar pattern, the degree of which parallels
the increase in ECF volume.
Management
-Supportive and directed toward the potential complications
1. Severe hypertension
-That associated with signs of cerebral dysfunction, demands immediate attention. Three drugs are commonly cited
as having a high benefit-to-risk ratio:
1. Labetalol (0.5-2 mg/kg/h IV)
2. Diazoxide
3. Nitroprusside (0.5-2 mcg/kg/min)
-The simultaneous intravenous (IV) administration of furosemide at doses of 2 mg/kg may be merited
2. Mild-to- moderate HTN
-Bed rest, fluid restriction. Loop diuretics, such as furosemide (1-3 mg/kg/d PO, administered 1-2 times daily), may
hasten resolution of the hypertension.
-Resistance either hydralazine or nifedipine is indicated.
-ACEI inhibitors are effective, although they have the potential to produce hyperkalemia and usually are not first-
line drugs in AGN.
-Oedema and circulatory congestion also respond to the treatment.
3. Course of penicillin can be administered to avoid contamination of contacts with a nephritogenic strain of
streptococci
4. Steroid therapy is indicated only in patients with severe crescent GN or in those with rapidly progressive GN.

Complications
1. The most common acute complication is hypertension with or without central nervous system
manifestations.
2. Anemia is common early and is due primarily to dilution. Anemia tends to resolve with diuresis. A few
patients may have diminished erythropoiesis in the recovery phase and have some persisting anemia.
3. An occasional patient develops pulmonary edema because of the marked increase in vascular volume that is
present in the early phase of the disease.
4. Congestive heart failure is rare but has been reported. Definite myocarditis also has been documented.
5. Chronic renal failure

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ACUTE RENAL FAILURE
Background:
Acute renal failure (ARF) is defined as an abrupt or rapid decline in renal function. A rise in serum blood urea
nitrogen (BUN) or serum creatinine concentrations, with or without a decrement in urine output, is usually evidence
of ARF. The condition is often transient and completely reversible.
Pathophysiology
Causes: The causes of ARF traditionally are divided into 3 main categories: prerenal, intrarenal, and postrenal.
In prerenal ARF
Perfusion of the kidneys is compromised by the following:
a) Hypotension
b) CHF.
c) Hypovolemia -Renal loss (e.g. due to Addison disease or diabetic ketoacidosis) or extrarenal loss (e.g. Due to
vomiting, diarrhea, pancreatitis, burns, or sweating) may be present.
d) Intense vasoconstriction due to
 Hypercalcemia
 Prostaglandin inhibition [NSAIDs])
 Cyclosporine
 ACE inhibition
 Amphotericin B
 Cocaine use
 Hepatorenal syndrome also results in intense vasoconstriction leading to functional failure
 Renal artery stenosis

-Depressed perfusion eventually leads to ischemia and cell death.

-This initial ischemic insult triggers production of oxygen free radicals and enzymes that continue to cause cell
injury even after restoration of perfusion.
-Tubular cellular damage results in disruption of tight junctions between cells, allowing back leak of glomerular
filtrate and further depressing effective GFR. In addition, dying cells slough off into the tubules, forming obstructing
casts, which further decrease GFR and lead to oliguria.

Intrarenal ARF
Can be grouped into vascular, interstitial, and glomerular factors, as follows:
a) Vascular causes
 Vasculitis involving the small vessels
 Scleroderma
 Atheroembolic renal disease
 Malignant hypertension
 Thrombotic angiopathy.
Although many of these causes can also be grouped under prerenal ARF, more frequently they cause ischemic
tubular necrosis.
b) Interstitial nephritis
 Drugs commonly implicated include penicillins and other antibiotics, NSAIDs, diuretics, cimetidine, and
allopurinol ,aminoglycosides, or radiologic contrast agents
c) Glomerular
 Crescentic glomerulonephritis
 Post infective glomerulonephritis
 Lupus nephritis,
 Vasculitis-associated glomerulonephritides.
Postrenal ARF
-The most common cause of postrenal failure is secondary to bladder outlet obstruction due to prostatic hypertrophy.
-The obstruction must be distal to the bladder or bilateral to cause ARF unless only a single kidney is functioning
properly.
-Renal ultrasound is a quick and noninvasive study that can help detect obstruction
-In prerenal failure, restoration of circulating blood volume is usually sufficient.
-Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction.

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-With intrinsic renal failure, removal of tubular toxins and initiation of therapy for glomerular diseases decreases
renal afferent vasoconstriction.
Mortality/Morbidity
-Most cases of community-acquired ARF are secondary to volume depletion, as many as 90% of cases are estimated
to have a potentially reversible cause.
-Hospital-acquired ARF often is commonly the end result of multiorgan failure or due to drugs.
-The most common causes of death associated with ARF are sepsis, cardiac failure, and pulmonary failure.
-Mortality rates are generally lower for nonoliguric ARF (>400 mL/day) than for oliguric (<400 mL/day) ARF,
reflecting the fact that nonoliguric ARF is usually caused by drug-induced nephrotoxicity and interstitial nephritis,
which have few other systemic complications.
Sex: Males and females are affected equally.
Age: The patient's age has significant implications for the differential diagnosis of ARF.
Newborns and Infants
The most common cause of ARF is prerenal etiologies.
 Perinatal hemorrhage - Twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth
trauma
 Neonatal hemorrhage - Severe intraventricular hemorrhage, adrenal hemorrhage
 Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome) both may result
in preferential blood shunting away from kidneys (ie, prerenal) to central circulation.
Intrinsic ARF
 Acute tubular necrosis (ATN) can occur in the setting of perinatal asphyxia. (aminoglycosides, NSAIDs)
given to the mother perinatally.
 ACE inhibitors can traverse placenta, resulting in a hemodynamically mediated form of ARF.
 Acute GN is result of maternal-fetal transfer of antibodies against the neonate's glomeruli or transfer of
chronic infections (syphilis, cytomegalovirus)
Postrenal ARF: Congenital malformations of urinary collecting systems should be suspected.
Children
The most common cause of ARF is prerenal etiologies.
Prerenal ARF
 Hypovolemia in children is gastroenteritis.
 Congenital and acquired heart diseases
Intrinsic ARF
 HUS common cause of ARF in children. Commonly associated with a diarrheal prodrome caused by
Escherichia coli. Present microangiopathic anemia, thrombocytopenia, colitis, mental status changes, and
renal failure.
 Acute poststreptococcal GN considered in any child who presents with HTN, edema, hematuria, and renal
failure.

Adults
History-below
Clinical presentation
ARF has such a long differential diagnosis, obtain a directed history along the lines of the pathophysiology of ARF
(prerenal, intrinsic renal, postrenal failure).
Prerenal failure
 Hypovolemia- thirst, decreased urine output, dizziness, and orthostatic hypotension.
 History of excessive fluid loss via hemorrhage, GI losses, sweating, or renal sources.
 Cardiac failure –Leading to depressed renal perfusion may present with orthopnea and paroxysmal
nocturnal dyspnea ,swelling of leg
 Restricted fluid access and should be suspected in the elderly and in comatose or sedated patients.
Intrinsic renal failure
Glomerular diseases:
 Nephritic syndrome of hematuria, edema, and HTN-palpitations
 Query about prior throat or skin infections and history of fever.
 Previous similar illness.
 HTN and DM.
Tubular diseases:

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  Period of hypotension secondary to cardiac arrest, hemorrhage, Sepsis, drug overdose, or surgery.
 Exposure to nephrotoxins should include a detailed list of all current medications and any recent radiologic
examinations (ie, exposure to radiologic contrast agents).
 Pigment-induced ARF -rhabdomyolysis (Trauma to muscle, muscle tenderness, seizures, excessive
exercise) or hemolysis (recent blood transfusion, malaria treatment).
Postrenal failure
 Older men with prostatic obstruction.
 History of prior gynecologic surgery or carcinoma esp. cervix in ladies.
 Flank pain and hematuria should raise a concern about renal calculi or papillary necrosis as the source of
urinary obstruction.
 Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methylsergide, propranolol,
hydralazine), urolithiasis, papillary necrosis
 Acyclovir, methotrexate, triamterene, indinavir, or sulfonamides implies the possibility of tubular
obstruction by crystals of these medications.

Physical:
-Facial puffiness, respiratory distress
-BP-Hypotension and tachycardia are obvious clues to decreased renal perfusion.
Evaluation for hypovolemia should include evaluations for orthostatic hypotension, mucosal membrane moisture,
and tissue turgor.
-In Renal failure may present with HTN and edema
-Pulmonary edema-respiratory distress
-LN-Lymphomas or other systemic infections.
-Parlor-Some GN may present with parlor
-Skin
 Livido reticularis, digital ischemia, butterfly rash, palpable purpura - Systemic vasculitis
 Maculopapular rash - Allergic interstitial nephritis
 Track marks (ie, intravenous drug abuse) – Endocarditis
Eyes
 Keratitis, iritis, uveitis, dry conjunctivae - Autoimmune vasculitis
 Band keratopathy (ie, hypercalcemia) - Multiple myeloma
 Jaundice - Liver diseases
 Signs of diabetes mellitus and Signs of hypertension in retina
 Atheroemboli (retinopathy)
Ears
 Hearing loss - Alport disease and aminoglycoside toxicity.
 Mucosal or cartilage ulcerations - Wegener granulomatosis.
Cardiac
 Irregular rhythms (ie, atrial fibrillation) – Atheroemboli
 Murmurs – Endocarditis
 Increased jugulovenous distention, rales, S3 – CHF
 Apex beat-dilated CCF,HTN
 Pericardial rub-patient sits and bends forwards and holds breath in expiration.
Pulmonary
 Rales - Good pasture syndrome, Wegener granulomatosis, pulmonary edema
 Hemoptysis - Wegener granulomatosis
Abdomen
 Pulsatile mass (ie, aneurysm) – Atheroemboli
 Costovertebral angle tenderness - Nephrolithiasis, papillary necrosis
 Pelvic, rectal masses; prostatic hypertrophy; distended bladder - Urinary obstruction
Limb ischemia, tenderness – Rhabdomyolysis

Investigations
1. Urine output: Changes in urine output generally are poorly correlated with changes in GFR.

10
 Approximately 50-60% of all causes of ARF are nonoliguric. However, categories of anuria, oliguria, and
nonoliguria may be useful in differential diagnosis of ARF.
Anuria –No urine production.
Oliguria less than 500 mL/d
Nonoliguria >500 mL/d
ABG’s if patient in distress.
2. Urinalysis:
Microscopic examination of urine is essential in establishing differential diagnosis.
-Granular casts - ATN, glomerulonephritis, interstitial nephritis
-RBC casts - Glomerulonephritis, malignant HTN
-WBC casts - Acute interstitial nephritis, pyelonephritis
-Eosinophiluria - Acute allergic interstitial nephritis, atheroembolism
-Crystalluria - Acyclovir, sulfonamides, methotrexate, ethylene glycol toxicity, radiocontrast agents.
-Hemoglobinuria-Haemolytic anaemia –Malaria, HUS
-Myoglobinuria-Trauma
3. Raised BUN and Raised Serum creatinine is a reflection of creatinine clearance.
4. Uric acid elevated-Multiple myeloma, malignancy, Gouty nephropathy.
5. FBC and PBF plus ESR
-Leukocytosis- post- infectious AGN
-Leukopenia and thrombocytopenia suggest SLE or TTP.
-Anemia- Hematuria, Malaria, HUS, TTP, multiple myeloma, drugs
-ESR elevated- Lymphoma, Parasitic infections, Multiple myeloma.
-Microangiopathic anemia suggests TTP or atheroemboli.
-Eosinophilia suggests allergic interstitial nephritis, polyarteritis nodosa, or atheroemboli.
6. Electrolytes
-Hyperkalemia
-Hypocalcemia (moderate) is common in ARF
7. Blood cultures -suspect sepsis or focus of infections.
8. ASOT-Streptococcal infections causing AGN. Also Anti-DNase
9. Also screen HIV, HBV, and HCV
10. Slide for malaria parasites.
11. Coagulation screen
Coagulation disturbances indicate liver disease or hepatorenal syndrome
12. Creatinine clearance-Correlate with GFR
24 hour volume urine produced.*Plasma creatinine
Urine creatinine
Cockcroft-Gault equation:
GFR mL/min = (140 - age yrs)(Body weight kg)
Serum creatinine mol/L
Multiply by 0.85 if female.
13. Creatine phosphokinase (CPK) elevations are seen in rhabdomyolysis and myocardial infarction
14. ANA –autoimmune diseases. Positive double-stranded DNA antibody-SLE
15. Rheumatoid factor.
16. Complement factors-C3 Low complement level-SLE, Post Strep AGN, Endocarditis.
-Elevated prostate-specific antigen level Prostate hypertrophy, prostate cancer
-Positive antibasement membrane antibody-Good pastures syndrome
-Positive cytoplasmic antineutrophil cytoplasmic antibody ANCA-Wegener's granulomatosis
Urine chemical indices
Differentiation of prerenal azotemia from ATN takes on a special importance in early management of these patients.
Aggressive fluid resuscitation is appropriate in prerenal ARF. However, rapid fluid infusion in a patient with ATN
who is unable to excrete the extra fluid could result in life-threatening volume overload.
Laboratory Values in Acute Renal Failure
Laboratory test Pre-Renal Intra-
Renal
FeNa, percent* <1 >1

11
 BUN to >20 <10-15
creatinine ratio
Urine specific >1.020 <1.020
gravity
Urine >500 <500
osmolality,
mOsm per kg
Urine sodium <15-20 >20
mEq per L
Urine sediment Hyaline Granular
casts cast

Urine/plasma >40 <20

creatinine ratio

Calculation of fractional excretion of sodium (FeNa)

FeNa = (urine Na/plasma Na)/ (urine creatinine/plasma creatinine)
FeNa <1 % = prerenal ARF
FeNa >1% = ATN
Imaging Studies:
Imaging studies in ARF are most important in the emergent workup of suspected post renal azotemia/s of abdomen
and check sate of kidney and urinary system.
CXR-evidence of volume overload.
Findings of lung infiltration can lead to pulmonary/renal syndromes, such as Wegener granulomatosis and
Goodpasture syndrome, or evidence of pulmonary emboli from endocarditis or atheroembolic disease.
ECG: Obtain routine ECGs to look for manifestations of hyperkalemia and arrhythmias, such as atrial fibrillation,
related to atheroemboli.
Plain abdominal x-ray-Nephrolithiasis, urolithiasis.
Procedures:
Renal biopsy
-Reserved for evaluation of ARF when cause cannot be determined
-Especially important when glomerular causes of ARF are suspected
-Often helpful in finding specific cause of renal failure

PRINCIPLES OF MANAGEMENT
1. Withdraw all nephrotoxic drugs.
2. Deal with emergencies
-Pulmonary edema
-Hyperkalemia
-Metabolic acidosis.
3. Establish Euvolemia
-Pre-renal-Fluid/blood transfusion.
-Renal-Diuretics
- Post renal catheterization.
4. Restriction
a) Fluids-Input output chart with fluid restriction. Previous day output plus 500ml.
b) Salt restriction
c) K+ restriction-fruit
d) Protein restricted This balance is achieved best with a protein intake of 0.6 g per kg per day
e) Daily weight
5. Correct electrolytes and acid base imbalances.
-Sodium bicarbonate therapy should be reserved for the treatment of severe metabolic acidosis (i.e., pH below 7.2 or
a bicarbonate level below 10 to 15 mEq per dL [10 to 15 mmol per L]) with or without associated hyperkalemia.
-It is important to note that sodium bicarbonate and sodium polystyrene sulfonate have a large sodium load and may
worsen fluid status in patients with acute renal failure.

12
 6. Dietary considerations-mode of delivery of nutrients.
7. Care for infections.
8. Care for tissue oxygenation
9. Prophylaxis –GIT bleeds and DVT
10. Investigate and treat primary cause.

Indications for dialysis in patients with ARF are as follows:

1. Volume expansion that cannot be managed with diuretics
2. Hyperkalemia >6.5 mmol/L
3. Correction of severe acid-base disturbances
4. Severe azotemia (BUN >100)
5. Symptoms of uremic pericarditis
6-Uraemic gastritis-N/V, Anorexia, GI Bleeds
7-Uraemic encephalopathy
8-Pulmonary oedema
9-Intractable hypertension

AMOEBA
-Amebiasis is an infection caused by the protozoal organism Entamoeba histolytica and includes amebic colitis and
liver abscess.
-Transmission usually occurs by food-borne exposure, particularly when food handlers are shedding cysts or food is
cultivated in feces-contaminated soil, fertilizer, or water.
-Less common means of transmission include contaminated water, oral and anal sexual practices, and direct rectal
inoculation through colonic irrigation devices.
Pathophysiology:
-E histolytica is a pseudopod-forming, nonflagellated protozoal parasite that exerts a lytic effect on tissue, a
characteristic for which the organism is named.
-Host cells are killed via the induction of apoptosis; therefore, the parasite does not kill the host cell but rather
induces its self-destruction.
-Incubation period is 2-26 days with majority 14 days. Infective dose >103 organisms
- Ingestion of the cyst is followed by excystation in the small bowel and trophozoite colonization of the colon. Upon
colonization of the colonic mucosa, the trophozoite may encyst and be excreted in the feces or it may invade the
intestinal mucosal barrier, thereby gaining access to the circulation, resulting in involvement of the liver, lung, and
other sites.
-Whether infection results in colonization or invasion, the E histolytica strain and its interaction with bacterial flora;
host genetic susceptibility; and factors such as malnutrition, sex, age, and immunocompetence may influence the
infection.
Liver involvement occurs following invasion of E histolytica into mesenteric venules. Amoebae then enter the portal
circulation and travel to the liver where they typically form large abscesses. The abscess contains acellular
proteinaceous debris, which is thought to be a consequence of induced apoptosis and is surrounded by a rim of
amebic trophozoites invading the tissue.
-The right lobe of the liver is more commonly affected than the left lobe. This has been attributed to the fact that the
right lobe is supplied predominantly by the superior mesenteric vein, whereas the left lobe is supplied by the splenic
vein.
NB. Patients with amoebic dysentery are not infective-passing trophozoites.
Morbidity
-E.histolytica probably is second only to malaria as a protozoal cause of death.
-Asymptomatic intestinal infection occurs in 90-99% of infected individuals.
- Most infected individuals eliminate the parasite from the gut within 12 months; however, colonization with E
histolytica carries a low but definite risk of developing into invasive amebiasis.
-Amebic colitis is complicated by fulminant or necrotizing colitis with high mortality rate.
-Amebic liver abscess is complicated by intraperitoneal rupture.
Sex:

13
-Amebic liver abscess is 7-12 times more common in men than in women, although the sex distribution is equal in
children.
-Amebic colitis affects both sexes equally.
Age:
-Young children appear to be at higher risk for fulminant invasive disease, resulting in a higher mortality rate
Clinical presentation

History:
Amebic colitis
1. Dysentry
-Mobile dysentery as patients not usually very sick looking as in bacillary dysentery where patients are bed ridded.
2. Fulminant colitis
-Fulminant or necrotizing colitis is the most serious manifestation, has high a mortality rate.
-Predisposing factors for fulminant colitis include Poor nutrition, Pregnancy, corticosteroid use, very young age
3. Chronic post amoebic colitis
-Sclerotic changes in the bowel
-Irritable bowel
-No amoeba in the stool
4. Amoeboma of the colon or rectum
-Can be, mistaken for colorectal cancer but responds well by medical treatment
5. Perforation
-Amoebia peritonitis
-Pericolic abscess
-Internal intestinal fistula.
Amoebic dysentery may present as:
1) Several weeks of abdominal pain, diarrhea, and bloody stools.
2) Fever is uncommon and occurs in approximately 10-30% of patients.
3) Weight loss is a common complaint and may be accompanied by symptoms of volume depletion (eg,
Orthostasis).

Amebic liver abscess

1) Fever and right upper quadrant abdominal pain
-Unlike amebic colitis, amebic liver abscess is associated with fever in 85-90% of patients.
2) Most do not have concomitant colitis, although a history of dysentery may be obtained.
-History of alcohol abuse is common
-Clinically, almost all patients reveal an enlarged liver and tenderness in the right upper quadrant.
-Polymorphonuclear leukocytosis is usually 15,000 to 20,000/mL, and there is moderate anemia

Pleuropulmonary amebiasis
-Rare but serious complication of amebic liver abscess,
-Caused rupture of a superior right upper lobe abscess with erosion through the diaphragm.
-Patients with this complication present with cough, pleuritic chest pain, dyspnea, and, occasionally, necrotic
sputum.
-Right pleural effusion-Serous and straw coloured.
-Rapture of the liver abscess into the pleural space or peritoneal cavity

Intraperitoneal rupture
-From amebic liver abscess occurs.
-These patients can present with a rigid abdomen that may be diagnosed erroneously as a perforated viscus.

Cerebral amebiasis
-Is a rare cause of brain abscess and is characterized by an abrupt onset of mental status change and/or focal
neurologic deficits.
-Progression to death occurs over 12-72 hours without adequate therapy.

14
Physical examination
Amebic colitis
-Fever-some patients
-Weight loss
-Diffuse abdominal tenderness
-Heme-positive stools
-Patients with fulminant colitis are more likely to present with abdominal pain, distension, and rebound tenderness.
Amebic liver abscess
-Fever
-Right upper quadrant abdominal tenderness
-Durban’s sign-intercostal tenderness consistent sign of amoebic dysentery.
-Weight loss
-Tender Hepatomegaly
-Jaundice

DDX
Amoebic colitis
1) Arteriovenous Malformations
2) Campylobacter Infections
3) Diverticulitis
4) Escherichia Coli Infections
5) Inflammatory Bowel Disease
6) Salmonellosis
7) Shigellosis
8) Ischemic colitis
Amoebic liver abscess
9) Hepatocellular Adenoma
10) Echinococcal cyst
11) Pyogenic Hepatic Abscesses
12) Abdominal Abscess

INVESTIGATIONS
LAB
FHG-Leukocytosis with eosinophilia-Amoeboma
-Presence of PMN cells predominant-Liver abscess
-Anemia may occur.
ESR-elevated

Microscopy
-Finding quadrinucleated cysts or trophozoites containing ingested erythrocytes in stool is considered by many to be
diagnostic for amebic colitis.
Antigen detection
-A stool antigen test specific for E histolytica is available
- Monoclonal antibodies specific for the galactose (Gal)/N-acetyl-D-galactosamine (GalNAc) lectin of E histolytica
>95 % sensitive and specific
Serology
-Serum antiamebic antibody tests are an important adjunct to antigen detection, particularly in cases of amebic liver
abscess, in which the parasite is found less commonly in the stool
-However, antibody persists for years after the initial infection; therefore, differentiating between current and
previous infection may be difficult, especially in individuals from endemic areas.

IMAGING
CXR
-Raised right diaphragm and right pleural effusion
Ultrasound:

15
-An amebic liver abscess will appear as a homogenous hypoechoic round lesion.
CT scan
-With contrast, an amebic liver abscess appears as a rounded, low-attenuation lesion with an enhancing rim.
-The abscess may be homogenous or septated, with or without observable fluid levels.

PROCEDURES
Liver aspiration
-If an amebic or pyogenic cause of liver abscess cannot be differentiated on clinical grounds and the patient is not
stable enough to await serology or antigen detection, liver aspiration under CT scan or ultrasound guidance should
be performed.
-Aspiration of an amebic liver abscess yields an odorless yellow-brown liquid that should be sent for microscopic
examination, culture, and antigen detection.
Colonoscopy
-Colonoscopy is recommended if stool and serologic study results are negative in a patient thought to have amebic
colitis.
-A relative contraindication to endoscopy is if the patient is thought to have fulminant colitis, in which an increased
risk of intestinal perforation exists.
-The appearance of amebic colitis may resemble that of inflammatory bowel disease, with a friable and diffusely
ulcerated mucosa.
-In addition, an ameboma may be present in the form of an annular lesion, which usually occurs in the cecum and
ascending colon and often is visually indistinguishable from colonic carcinoma.

Histologic Findings:
-Endoscopically obtained biopsy specimens should be taken from the edge of ulcers and evaluated for motile
trophozoites.
-Pathologic evaluation of colonic lesions may vary from mucosal thickening to flask-shaped ulcerations to necrosis.
-Periodic acid-Schiff stains E histolytica magenta and may increase detection of the parasite in biopsied material.

MANAGEMENT
Medical
-Asymptomatic colonization with E histolytica is a risk factor for future development of invasive disease; therefore,
affected patients should be treated, and a luminal agent (eg, iodoquinol, paromomycin, diloxanide furoate) should
suffice.
-Patients with invasive amebiasis (eg, colitis, liver abscess) should be treated with metronidazole or tinidazole plus
a luminal agent to eradicate colonization.
Amoebic liver abcess
-Metronidazole remains the drug of choice for amebic liver abscess. Metronidazole enters the protozoa by passive
diffusion and is converted to reactive cytotoxic nitro radicals by reduced ferredoxin or flavodoxin.
-Tinidazole is well tolerated by patients, and it may be administered once daily.
-Metronidazole, 750 mg 3 times a day orally for 10 days,. The drug also is available for intravenous administration
for those patients who are unable to take medication by the oral route.
-Chloroquine phosphate may be substituted or added in the event of failure of resolution of clinical symptoms with
metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.
-Chloroquine has the disadvantage of being associated with higher relapse rates than nitroimidazoles. Adverse
effects include gastrointestinal upset, headache, dizziness, and blurred vision. Retinopathy does not occur at the dose
used for amebic liver abscess.
-Luminal amebicidal agent to eradicate the intestinal carriage after the amebic liver abscess has been treated with
one of the above tissue amebicides.
-Failure to use luminal agents can lead to relapse of infection in approximately 10% of patients.
-Luminal agents with proven efficacy include diloxanide furoate, iodoquinol, and paromomycin.
 Diloxanide furoate is free of major adverse effects. The most common adverse effect is flatulence and
occasional gastrointestinal upset. Give 500mg TDS for 10 days
 Iodoquinol (diiodohydroxyquin) rarely causes abdominal pain, diarrhea, or rash. A structurally related
diiodohydroxyquin caused subacute myelopticoneuropathy and is obsolete now.
 Although paromomycin may occasionally cause nausea, abdominal cramps, or diarrhea, it is the preferred
luminal amebicidal

16
-Antibiotics
-The oral tetracyclines indirectly affect luminal amebas by inhibiting the bacterial associates of E histolytica in the
bowel lumen.
- Paromomycin and erythromycin are directly amebicidal. Except for paromomycin (Aminocidine), none of the
antibiotics are highly effective against intestinal organisms and therefore should not be used by themselves in
treatment.
-Parenteral antibiotics have little antiamebic activity in any site.

Surgical care
-Indications for surgery in fulminant amebic colitis include perforation and persistence of abdominal distension and
tenderness despite antiamebic therapy.
-Surgical intervention for intrathoracic or intraperitoneal rupture of an amebic liver abscess rarely is indicated,
except in cases complicated by secondary bacterial infection.
-Consider therapeutic aspiration of amebic liver abscess in the following situations:
(1) High risk of abscess ruptures, as defined by cavity size greater than 5 cm;
(2) Left lobe liver abscess, which is associated with higher mortality and frequency of peritoneal leak or rupture into
the pericardium;
(3) Failure to observe a clinical medical response to therapy within 5-7 days
(4) Cannot differentiate from a pyogenic liver abscess.
-Imaging-guided needle aspiration or catheter drainage is the procedure of choice.
-Simple needle aspiration is less invasive, less expensive, and has the advantage of being able to drain multiple
abscesses in the same session.
-Simple needle aspiration avoids problems related to catheter care

ANAEMIA
Background: Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying
etiology
Anemia is strictly defined as a decrease in red blood cell (RBC) mass. In practice however; anemia is usually
discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and hematocrit
(Hct).In Kenya defined as Hb below 10g/dl.WHO definition Hb below 12g/dl.
Changes in plasma volume. Eg, dehydration elevates these values, and increased plasma volume in pregnancy can
diminish them without affecting the RBC mass.
Pathophysiology:
-Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient
circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to
progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of
differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes.
-Reticulocytes remain in the circulation for approx. 1 day before reticulin is excised by reticuloendothelial cells with
the delivery of the mature erythrocyte into circulation.
-The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by
phagocytic cells of the reticuloendothelial system.
-Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof
and pentose pathways for energy
-Basically, only 3 causes of anemia exist:
1) Blood loss
2) Increased RBC destruction (hemolysis)
3) Decreased production of RBCs.
-Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy.
-Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain
inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring
form in an RBC and produces pan-hemolysis of RBCs of all ages.
Prevalence
Although geographic diseases, such as

17
  sickle cell anemia
 Thalassemia
 malaria
 Hookworm
 Chronic infections, are responsible for a portion of the increase
- Nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the
increased prevalence of anemia.
Populations with little meat in the diet have a high incidence of iron deficiency anemia because heme iron is better
absorbed from food than inorganic iron
Mortality/Morbidity:
-The morbidity and mortality of anemias vary greatly depending on the etiology.
-Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with
bleeding esophageal varices, approximately 1% with benign peptic ulcers).
-Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy.
-Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle
cell disease may remain relatively asymptomatic with a nearly normal lifespan.
-Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo
bone marrow transplantation.
-Hereditary spherocytosis either may present with a severe hemolytic anemia or may be asymptomatic with
compensated hemolysis.
-Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or
exist without anemia until the patient receives an oxidant medication.
-The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to
immunosuppressive therapy.
-In addition, tolerance of anemia is proportional to the anemia's rate of development. Symptoms and mortality
associated with rapidly developing anemia are more profound than in slowly developing anemia.
Sex:
Overall, anemia is twice as prevalent in females as in males.
-This difference is significantly greater during the childbearing years due to pregnancies and menses.
-Approximately 65% of body iron is incorporated into circulating Hb.
-Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-
linked sideroblastic anemias.

Age:
-Severe genetically acquired anemias (eg sickle cell disease, thalassemia, Fanconi syndrome) are more commonly
found in children because they do not survive to adulthood.
-During the childbearing years, women are more likely to become iron deficient.
-Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the
replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. -Use
of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce
gastrointestinal bleeding.

Etiology
First decision whether anemia is due to
 A decreased production of RBCs
 Increased destruction RBC or loss of blood
The reticulocyte count is the most valuable test in answering this question. If the reticulocyte count is low, a failure
in RBC production is indicated. If it is high, hemolysis is suggested.
a) Hypochromic microcytic anemia-cause
1) Iron deficiency
2) Thalassemia
3) Sideroblastic anaemia
4) Lead poisoning.
b) Macrocytic anemia/ Megaloblastic anaemia

18
Causes of Megaloblastic anaemia
1. Vitamin B-12 deficiency
 Nutritional deficiency:-vegetarian diets without milk, cheese, and eggs over a number of years because
depletion of cobalamin reserves stored in the liver takes years.
 Pernicious anemia (PA) in most cases, the loss of functional IF is caused by the autoimmune destruction of
gastric parietal cells. However, some cases of PA can be traced to a hereditary lack of production of IF.
 Gastrectomy: Patients develop PA following gastrectomy because of the lack of a source of IF.
Development of overt megaloblastosis requires approximately 3-5 years following total gastrectomy and
approximately 12 years following partial gastrectomy. The lag is because of the time required to deplete
cobalamin stores.
 Zollinger-Ellison syndrome:, the persistent acidity inactivates pancreatic proteases in the duodenum and
prevents transfer of cobalamin from r-factor to IF. This factor (r-factor) is a cobalamin binder secreted by
salivary glands.
 Severe abnormalities in the terminal ileum due to ileal resection, regional ileitis, lymphoma, TB, Crohns
disease .The terminal ileum is the site of uptake of cobalamin-IF complexes; therefore, these disorders can
lead to cobalamin deficiencies
 Diphyllobothrium latum (ie, fish tapeworm): When the tapeworm is entrenched in the small intestine, it
competes with the host for ingested cobalamin. The organism is most often found in Canada, Alaska, and
the Baltic Sea

 Blind loop syndrome: This syndrome involves bacterial colonization of intestines that are either deformed
because of strictures, surgical blind loops, or anastomoses or abnormal because of scleroderma or
amyloidosis. Bacteria compete with the host for cobalamin

2. Folate deficiency
 Dietary insufficiency, the destruction of folate by excessive heating of diluted foods, or consuming
alternative diets that are low in folate
 Tropical sprue: Tropical sprue has a more severe effect on the distal ileum than nontropical sprue.
Therefore, tropical sprue can lead to cobalamin deficiency and folate deficiencies.
 Others malabsorption causes regional enteritis, intestinal lymphoma, surgical intestinal resection,
amyloidosis, Whipple disease, and scleroderma.
 Increased turnover or requirements: This can occur during pregnancy s and during lactation. Patients with
psoriasis and exfoliative dermatitis require additional folate because of the increased turnover of epidermal
cells.
 Miscellaneous: Folate deficiency can occur during hyperalimentation and hemodialysis because folate is
lost in dialysis fluid. Megaloblastosis in persons with alcoholism is often due to folate deficiency.
3. Drugs that can cause megaloblastic anemia
 Antifolates - Methotrexate, aminopterin
 Purine analogs - 6-Mercaptopurine, 6-thioguanine, acyclovir
 Pyrimidine analogs - 5-Fluorouracil, 5-azacitidine, zidovudine
 Ribonucleotide reductase inhibitors - Hydroxyurea, cytarabine arabinoside
 Anticonvulsants - Phenytoin, phenobarbital, primidone
 Other drugs that can depress folates - Oral contraceptives, glutethimide, cycloserine
 Drugs that affect cobalamin metabolism - p-Aminosalicylic acid, metformin, phenformin, colchicine,
neomycin, biguanides
4. Non –megaloblastic Macrocytic anemia
 Liver disease
 Hypothyroidism
 Chronic alcoholism
 Other inborn errors
 Accelerated erythropoiesis (reticulocytes)
 Hypoplastic and aplastic anemia
 Infiltrated bone marrow

19
Others
-Hereditary orotic aciduria
-Lesch-Nyhan syndrome
-Thiamine-responsive megaloblastic anemia - This condition is an autosomal recessive disorder with features that
include megaloblastic anemia, deafness, and diabetes mellitus. Thiamine uptake into cells is disturbed, and treatment
with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus.
-Neoplastic or viral infections (eg, myelodysplastic syndromes, other clonal neoplastic diseases) and HIV infections
- Can directly affect bone marrow stem cells

c) Normocytic anaemia-2 main groups

i)Primary bone marrow involvement
-Aplastic anemia
-Myelophthisic anemia: accumulation of malignant or reactive cells or cell products. Immature myeloid cells and
nucleated RBCs in the peripheral blood.
The 3 major classes of disorders that can produce myelophthisic anemia are intrinsic bone marrow malignancies (eg,
leukemia, lymphoma, myeloma), metastatic tumors (eg, neuroblastoma, melanoma, cancers that are more prone to
bone marrow metastasis (eg, prostate, breast, lung, stomach, renal carcinomas), and granulomatous disease (eg,
tuberculosis, sarcoidosis).
-Myelofibrois is known as agnogenic myeloid metaplasia and involves gradual bone marrow fibrosis,
extramedullary hematopoiesis, and splenomegaly with no known underlying systemic disorder.
ii)Anemia chronic illness:
Most cases of anemia in the world are secondary to an underlying disease. This type of anemia includes
 Liver cirrhosis
 Uremia
 chronic inflammation
 Hypoendocrine conditions (eg, thyroid, adrenal, pituitary disorders).
iii) Hemolytic anemias
Congenital and Acquired
Congenital cause
a) Erythrocyte membrane abnormalities
 Congenital spherocytosis
 Stomatocytosis
 hereditary elliptocytosis
 Paroxysmal nocturnal hemoglobulinaemia
b) Enzymatic defects
 G6 Phosphate DH deficiency
 Pyruvate kinase deficiency
c) Hemoglobin abnormalities
 Sickle cell anemia
 Thalasaemia
Acquired hemolytic conditions
a) Immune disorders
 Autoimmune hemolytic anaemia-AIHA
 Alloimmune hemolytic anemia-Blood transfusion
 Hemolytic disease of newborn
 Allograft-solid Transplant
b) Toxic chemicals and drugs
Drug-induced immune hemolysis is classified according to three mechanisms of action:
 drug-absorption (hapten-induced)
 Immune complex
 Autoantibody- Production
These IgG- and IgM-mediated disorders produce a positive DAT and are clinically and serologically indistinct from
AIHA.
Drug-absorption (hapten-induced)
-Hemolysis resulting from high-dose penicillin therapy is an example of the drug-absorption mechanism, in which a
medication attached to the red blood membrane stimulates IgG antibody production. When large amounts of drug

20
coat the cell surface, the antibody binds the cell membrane and causes extravascular hemolysis. Others-Ampicillin
Methicillin, Carbenicillin, Cephalothin (Keflin)*
Cephaloridine (Loridine)
Immune complex hemolysis
-Quinine-induced hemolysis is the prototype of the immune complex mechanism, in which the drug induces IgM
antibody production. The drug-antibody complex binds to the red blood cell membrane and initiates complement
activation, resulting in intravascular hemolysis. Others-Phenacetin, Hydrochlorothiazide, Rifampin, Sulfonamides,
Isoniazid
Autoantibody
-Alpha-methyldopa is the classic example of anti-erythrocyte antibody induction. Although the exact mechanism is
unknown, the drug (perhaps by altering a red blood cell membrane protein and rendering it antigenic 13) induces the
production of ant erythrocyte IgG antibodies and causes an extravascular hemolysis. Others Mefenamic acid
(Ponstel), L-dopa, Procainamide
Ibuprofen, Diclofenac), Interferon alfa
c) Physical damage
-MAHA-Microangiopathic anemia is found in patients with disseminated intravascular coagulation (DIC) or
hemolytic uremic syndrome (HUS) and TTP. Fragmented erythrocytes (schistocytes) also occur with defective
prosthetic cardiac valves
-March hemoglobilunuria
d) Infections
-Protozoa-malaria, babesia
-Bacteria-Clostridia welchi
e) Hypersplenism
f) Liver disease-defective fat metabolism which affect the cell membrane.

History:
Primary symptoms result from tissue hypoxia and might include the following:
- Fatigue, weakness, irritability
- Headache, Dizziness, especially postural
- Vertigo ,Tinnitus ,Syncope
- Dyspnea, especially with increased physical activity (exercise intolerance)
- Chest pain, palpitations
- Difficulty sleeping or concentrating
- Thirst ,Anorexia, Decreased urine output/bowel irregularity
- Decreased libido or impotence
-History of prescription of hematinics provides clues that anemia was detected previously.
-Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding
disorders, and abnormal Hbs-sickle cell disease and thalasaemia.
-Patient's occupation
-Drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious
agents. Many drugs and toxins can cause anemia (eg, alcohol, isoniazid, lead)
-Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless
specifically queried.
Blood loss
 Obs/gy-pregnancies,Abortions,menstrual loss
 Peptic ulcer disease
 Hematochizia and melena stool Changes in bowel habits can be useful in uncovering neoplasms of the
colon.
 Hematuria ,hemopytisis,haematemesis
 Any other bleeding disorder-epistaxis, ecchymoses, bleeding from the gums.
-Dietary history-A thorough dietary history is important in a patient who is anemic. This history must include foods
that the patient both eats and avoids as well as an estimate of their quantity. Taking tea after meal impairs iron
absorption
-Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption
or an underlying wasting disease of infectious, metabolic, or neoplastic origin.
-Nutritional deficiencies may be associated with unusual symptoms.

21
  Iron deficiencies frequently eat soil (soil), dysphasia, brittle fingernails, relative impotence, fatigue, and
cramps in the calves on climbing stairs.
 In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of
proprioception are common. Sometimes no anemia is present despite overt neuro psychiatric disease caused
by administration of folic acid to patients with cobalamin deficiency. This partially corrects the anemia, but
not the neuropathy.
 Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia

Physical:
-General Appearance for underdevelopment, malnutrition, or chronic illness.
-Eyes-Pale conjunctiva, Retinal hemorrhages
-Cardiovascular-Tachycardia, Orthostatic hypotension
-Pulmonary-Tachypnea, Rales
-Abdomen-Hepatomegaly and/or splenomegaly, Ascites
Masses, Positive result on Hemoccult test
-The skin and mucous membranes
 Pallor
 abnormal pigmentation, prominent venous pattern on the abdominal wall-liver disease
 icterus, spider nevi, palmar erythema-liver disease
 Petechiae, purpura-bleeding tendency
 Angiomas, ulcerations
 Coarseness of hair
 Puffiness of the face-Renal, hypothyroidism
 Thinning of the lateral aspects of the eyebrows-hypothyroididm.
 Nail defects-Iron deficiency anaemia
-Examine optic fundi carefully but not at the expense of the conjunctivae and the sclera, which can show pallor,
icterus, splinter hemorrhages, petechiae, and comma signs in the conjunctival vessels, or telangiectasia that can be
helpful in planning additional studies.
-Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or Neoplasia.
-Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may
portend lymphatic obstruction due to a malignancy that cannot be observed or palpated.
-: Hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the
firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm,
nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute
infection usually has a palpably softer and tenderer organ.
-A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of
anemia.
-The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial
nerves, and testing for tendon reflexes.
-The heart enlargement may provide evidence of the duration and the severity of the anemia, and murmurs may be
the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.or haemic murmurs.
-Folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea
-Color, bulk, frequency, and odor of stools and whether the feces float -malabsorption. In steatorrhea whether the
toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water
surface after the first flush.
-Fever because infections, neoplasm, and collagen vascular disease can cause anemia.
-Occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other
bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that
coagulopathy is a cause of the anemia because of bleeding
-Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus, paroxysmal cold
hemoglobinuria, and certain macroglobulinemias.
-The relation of dark urine to either physical activity or time of day can be important in March hemoglobinuria and
paroxysmal nocturnal hemoglobinuria.
-Explore the presence or the absence of symptoms suggesting an underlying disease such as cardiac, hepatic, and
renal disease; chronic infection; endocrinopathy; or malignancy.

22
Investigations
I Confirm diagnosis of anaemia
FBC-RBC count (4.6-5.4 x1012/L and Hb
-WBC and differentials
Neutrophils 60-75%,
Lymphocytes 20-45%
Monocytes 1-10%
Eosinophils1-6%
Basophils 0.4-1%-infections
-Platelets-purpura or bleeding problem
II Tests to establish the type of anaemia
1. RBC indices
MCV-Normal 79-96fl
MCH-27-32 picogram
MCHC-32-36%
RDW (red cell distribution width)-upto 9. It is a of measure anisocytosis.
ESR- Male: 1 - 13 mm/hr
Female: 1 - 20 mm/hr
2. Reticulocyte count, erythroblasts and polychromasia
3. PBF evaluation
-Size-Macro or micro, anisocytosis-size variation
-Shape-poikilocytosis-shape variation
-Sickle cells-SCD
-Target cells-IDA, SCD, Thalasaemia, Liver disease
-Ovalocytes-Macrocytic anaemia
-Tear drop-most anaemias
-Spherocytes, elliptocytes
-Acanthocytes (burr cells)-Hemolytic anaemia,
Pyruvate kinase deficiency, Abetalipoproteinaemia
-Colour-Hypochromic-IDA, Thalasaemia, Sideroblastic
-Polychromasia-variation in colour-hemolytic, pts
On hematinics
-Inclusions
Basophilic stippling-Lead poisoning
Parasites-malaria, babesia, trypanosomes

III Tests for etiology of Anaemia-Dependent on the tests II above:

1. Hypochromic anaemia
-Iron studies. -serum ferritin, TIBC, total iron, and percent saturation. Iron stores stain BM aspirate with Prussian
blue.
-Blood loss-Stool for Ova and cyst. Stool for occult blood
-Urinalysis-hematuria
-Upper GI endoscopy or lower GI endoscopy
-Hb electrophoresis-thalasaemia
2. Hemolytic picture-ie
-Reticulocytosis
-PBF
 Sickle cells-SCD
 polychromasia- indicating RBC immaturity
 Ovalocytes-membranopathy
 Spherocytes
 Acanthocytes.
 Schistocytes (fragmented RBCs), suggesting TTP, HUS, or mechanical damage
 hematological malignancy associated with hemolysis (ie, CLL)

Other tests

23
-LDH- Serum LDH is a criterion for hemolysis
-Serum haptoglobin -A low serum haptoglobin is a criterion for moderate-to-severe hemolysis.
-Indirect bilirubin -Unconjugated bilirubin is a criterion for hemolysis
Specific hemolytic screen.
i) Sickling test –with Na metabisulphite or Na dithionate
ii) Hb Electrophoresis-HbSS, HbAS, HbSF, Thalasaemia
iii) Osmotic fragility Test (Mean Corpuscular osmotic fragility)-For congenital spherocytosis. Cells more fragile
with a tail of fragile cells.
iv) G6 phosphate DH test (Dye Reduction Test)-
v) Hams Test-For paroxysmal Nocturnal hemoglobinuria.
vi) Coomb’s test-Immune hemolytic anaemia
vi) MPS for malaria parasites
vii) ABO and Rhesus grouping –Newborns
3. Macrocytic anemia
Suggestive findings
CBC count-Pancytopenia may occur.
RBC indices-Raised MCV>100fl.
Reticulocyte count-Low (normal 0.2-2%)
PBF-Hypersegmented neutrophils contain 5 or more lobes,
While normal neutrophils contain 3-4 lobes.
-Macro Ovalocytes-Macrocytes may contain nuclear remnants
-Erythrocytes with megaloblastic nuclei.
Other tests
LDH and indirect bilirubin high because of intramedullary destruction of megaloblastic red cell precursors.
The LDH level is often extremely high, and, following therapy, the fall in the LDH level is an excellent indication of
response to or failure of therapy
Specific tests
Vit B12
i) Serum vitamin B-12
ii) A Schilling test is a radiometric test of cobalamin absorption. The test is given in 3 parts:
-First part, radioactive cyanocobalamin is given orally. Meanwhile, unlabeled cyanocobalamin is given
intramuscularly to inhibit the uptake of radioactive cobalamin by the liver.
Urinary secretion of radioactive cobalamin is then measured to estimate whether the orally administered cobalamin
has been taken up. Low secretion suggests either PA or an abnormality in the terminal ileum that prevented the
uptake of IF-cobalamin complexes.
-The 2nd phase of the test is performed in the same manner, except that IF is given orally along with radioactive
cyanocobalamin. If IF restores the uptake of ingested radioactive cyanocobalamin, the patient most likely has PA.
However, if IF does not restore uptake, then an abnormality in the terminal ileum is most likely present.

-A 3rd phase can be performed in which the patient is treated with antibiotics prior to administering radioactive
cyanocobalamin. If antibiotics restore cobalamin absorption from the GI tract, the patient most likely has a blind
loop syndrome.
NB.The results of the Schilling test may indicate cobalamin malabsorption in patients who have severe and long-
standing folate deficiencies. This is because of the effect of severe folate deficiency on the ileal mucosa that leads to
a decrease in cobalamin uptake in the terminal ileum.
iii) Methylmalonic aciduria. Urinary excretion is a reliable index of cobalamin deficiency, provided the patient does
not have renal failure.
Serum methylmalonic acid and homocysteine test results are elevated in more than 90% of patients with cobalamin
deficiencies.
iv) Antiparietal cell antibodies .Of patients with PA, 90% are positive for these antibodies. However, antiparietal
cell antibodies are also present in patients with thyroid disease and other autoimmune disorders.
Anti-IF antibodies (type I and II) are highly specific for PA.
Evaluation of Folate deficiency
i) Serum folate levels, and the red cell folate level are
Folate levels respond rapidly to changes in dietary folate. A low folate level reflects dietary intake during the
previous 2-3 days. Conversely, a single meal with normal folate content can restore serum folate levels to normal.

24
Other Tests:
-Cobalamin deficiency – Tests for autoimmune disorders, regional ileitis, fish tapeworm infection, Zollinger-Ellison
syndrome, pancreatitis, and myeloproliferative disorders
-Folate deficiency - Detect and evaluate pregnancy; malnutrition; and other complications of sprue, chronic
hemolysis, and exfoliative dermatitis
Other causes of macrocytosis
i) Liver Function test
ii) Thyroid function studies-hypothyroidism
Confirmation of diagnosis megaloblastosis
-Bone marrow aspiration and biopsy results are useful to confirm the diagnosis, to rule out myelodysplasia, and to
assess the iron stores.
-Marrow is cellular with erythroid hyperplasia. Megaloblastic RBC precursors are abundant, and giant
metamyelocytes are present.
- Megakaryocytes may be large and hyperlobulated. Iron stores vary from being increased before therapy to
decreased if iron is consumed during therapy

MANAGEMENT
Medical Care: The purpose of establishing the etiology of an anemia is to permit selection of a specific and
effective therapy.
-Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients with a
severe and symptomatic anemia. Transfusion is only palliative.
-In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or
reducing transfusions of packed RBCs.
-The appropriate treatment of anemia due to blood loss is correction of the underlying condition and oral
administration of ferrous sulfate for up to 3months after the correction of anemia to replenish stores.
-Relatively few indications exist for the use of parenteral iron therapy, and blood transfusions should be reserved for
the treatment of shock or hypoxia.
-Nutritional therapy is used to treat deficiency of iron, vitamin B-12, and folic acid. Pyridoxine may be useful in the
treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder.
-Corticosteroids are useful in the treatment of autoimmune hemolytic anemia.
-Treatment of aplastic disorders includes removal of the offending agent whenever it can be identified, supportive
therapy for the anemia and thrombocytopenia, and prompt treatment of infection.
Avoid transfusion in patients with a potential bone marrow donor because transfusion worsens the probability of
cure from transplantation. Certain patients seem to develop a salutary response with immunosuppressive therapy (ie,
antithymocyte globulin, cyclosporin).
Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic, marrow so
that transfusion is not necessary, and platelet and granulocyte counts increase to less dangerous levels
-Therapy and medical care vary considerably in the group of hereditary disorders. Splenectomy has been
advantageous in hereditary spherocytosis and hereditary elliptocytosis, in some of the unstable hemoglobinopathies,
and in certain patients with pyruvate kinase deficiency. It has little value in most other hereditary hemolytic
disorders
- Drugs and chemicals capable of producing aplasia or a maturation arrest of erythroid precursors should be
discontinued and avoided. Similarly, diseases known to be associated with anemia should be appropriately treated.

Surgical Care:
-Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the
gastrointestinal tract, the uterus, or the bladder. Patients should be hemodynamically stable before and during
surgery. A blood transfusion may be needed.
-Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary hemolytic
disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvate kinase deficiency).
Improvement in survival rates has been reported in patients with aplastic anemia, but splenectomy is not the
preferential therapy. Leg ulcers have shown improvement in some patients with thalassemia. Prior to splenectomy,
patients should be immunized with polyvalent pneumococcal vaccine. Preferably, this should be administered more
than 1 week prior to surgery.

25
-Bone marrow and stem cell transplantation have been used in patients with leukemia, lymphoma, Hodgkin disease,
multiple myeloma, myelofibrosis, and aplastic disease. Allogeneic bone marrow transplantation successfully
corrected phenotypic expression of sickle cell disease and thalassemia and provided enhanced survival in patients
who survive transplantation.
Specific Treatment.
VIT.B12 and Folate deficiency
In either of the deficiency both cobalamin and folate therapy is admin.
Transfusion therapy should be restricted to patients with severe, uncompensated, and life-threatening anemia.
Because megaloblastic anemia usually develops gradually, most patients have adjusted to low Hgb levels and do not
require transfusions.
-Cobalamin (1000 mcg) should be given parenterally daily for 2 weeks, then weekly until the hematocrit value is
normal, and then monthly for life. This dose is large, but it may be required in some patients. Patients with
neurological complications should receive cobalamin at 1000 mcg (more in some cases) every day for 2 weeks, then
every 2 weeks for 6 months, and monthly for life
-Folate (1-5 mg) should be administered orally.
- Prophylactic folate therapy (1 mg/d) should be administered during
 Pregnancy and the perinatal period to meet the increased demand for folate by the fetus and during
lactation.
 Folate should also be given daily to patients with chronic hemolysis.
 Folate therapy is currently recommended for individuals with high levels of homocysteine who have a
propensity for thromboembolic disease to prevent this complication
 Multivitamins that contain folate have been recommended for elderly persons.

AORTIC REGURGITATION

Background:
-Primary disease of the aortic valve leaflets, the wall of the aortic root, or both may cause aortic regurgitation (AR).

Pathophysiology:
-Chronic AR produces left ventricular (LV) volume overload that leads to a series of compensatory changes,
including LV enlargement and eccentric hypertrophy.
-The enlarged ventricle is more compliant and is well suited to deliver a large stroke volume.
-The dilated left ventricle can accommodate increased end-diastolic volume and deliver a larger stroke volume to
compensate for the regurgitant aortic flow.
-Wall thickness must increase to compensate for the increased ventricular dimensions. These compensatory changes
are necessary to minimize or normalize wall stress according to the Laplace law (ie, wall tension/stress is related to
the product of intraventricular pressure and radius divided by wall thickness).
- Increased wall thickness hypertrophy observed in a volume-overload state usually is eccentric, as opposed to
concentric hypertrophy observed in a pressure-overload state (ie, aortic stenosis).
-The increased myocardial mass in a hypertrophic heart enables individual sarcomeres to shorten to a normal degree.
-As long as LV wall stress is maintained in the normal range, the LV preload reserve, contractility, and ejection
fraction (EF) remain within the normal range. This is the chronic compensated stage. During this phase of the
disease, most patients remain asymptomatic for decades because chronic AR generally is a slow and insidious
disease with very low morbidity during a long asymptomatic phase.
-With time, transition from a compensated to a decompensated state marks the progression of the disease.
Progressive LV enlargement beyond that required by the valvular regurgitation occurs and is associated with a
change of the left ventricle from an elliptical shape to a spherical shape.
-The cause of this pathologic dilatation is not well understood, but loss of the collagen support system that acts as a
skeleton for the heart may play a substantial role. These maladaptive changes in the interstitial of the heart are an
intricate part of the LV hypertrophy process. In addition, diminished coronary flow reserve in this hypertrophied
ventricle is thought to result in chronic subendocardial ischemia, even in the absence of epicardial coronary artery
disease (CAD). Eventually, subendocardial necrosis and fibrosis occur, along with disruption of the collagen support
system, with loss of LV systolic function. The neurohormonal response complicates the disease state further by its
excessive growth stimuli, which are thought to be partially responsible for apoptosis (programmed cell death) of the
remaining functional myocytes.

26
-The vicious cycle continues until the decompensated stage develops over many years. Progressive LV enlargement,
spherical LV shape, increased wall stress, decline in the contractility and EF, increased afterload, and decreased
diastolic compliance with a rise in end-diastolic pressure characterize this stage. Frequently, development of
congestive symptoms heralds this stage, but an insidious deterioration of ventricular function may occur without
overt clinical signs.
-In acute AR, the normal-sized left ventricle poorly tolerates the sudden large volume imposed on it. The left
ventricle poorly accommodates the abrupt increase in end-diastolic volume, and diastolic filling pressure increases
rapidly and dramatically. This leads to an acute decrease in forward stroke volume, and, although tachycardia
develops as a compensatory mechanism to maintain cardiac output, this often is insufficient. The rise in LV filling
pressure is transmitted to the left atrium, pulmonary veins, and pulmonary capillaries, leading to pulmonary edema
and congestion. Acute AR usually is severe and rapidly leads to LV decompensation and/or failure and cardiogenic
shock

Physical signs

 Hemodynamically severe AR causes a widened pulse pressure, often greater than 100 mm Hg, associated
with a low diastolic pressure, often less than 60 mm Hg.
 The de Musset sign is when patients' heads frequently bob with each heartbeat.
 The Corrigan pulse is when patients' pulses are of the water-hammer or collapsing type, with abrupt
distention and quick collapse.
 The Quincke sign is when light transmitted through the patient's fingertip shows capillary pulsations.
 The Hill sign is when popliteal cuff systolic pressure exceeds brachial cuff pressure by more than 60 mm
Hg.
 The Duroziez sign is when a systolic murmur is heard over the femoral artery when compressed
proximally and when a diastolic murmur is heard when the femoral artery is compressed distally.
 The Müller sign is systolic pulsations of the uvula.
 The Traube sign (also called pistol-shot sounds) refers to booming systolic and diastolic sounds heard
over the femoral artery.
 The apical impulse in chronic AR is diffuse, hyperdynamic, and displaced inferiorly and leftward.
 S3 gallop correlates with development of LV dysfunction.

 The typical diastolic murmur of AR has a decrescendo shape. A high-frequency early diastolic murmur
often occurs in mild AR, whereas a rough holodiastolic or decrescendo diastolic murmur occurs more
commonly in severe AR. The volume and velocity of blood across the incompetent aortic valve tapers off
in mid-to-last diastole as the aortic and LV pressures equilibrate. The diastolic murmur of AR is usually
best heard adjacent to the sternum in the second to fourth left intercostal space. A concomitant systolic
ejection murmur is common in moderate-to-severe AR
 The murmur associated with acute AR may not be impressive. If cardiac decompensation is present, the
diastolic murmur of acute AR may be very soft and surprisingly short.
 Antegrade flow across the mitral valve is thought to cause an Austin Flint murmur, which is a mid- and
late-diastolic apical low-frequency murmur or rumble. The rumble occurs during rapid closure of the
mitral valve as flow velocity is increasing across the valve and LV diastolic pressure is rising rapidly
because of severe aortic reflux. Its presence indicates severe AR.

APPROACH TO PATIENT WITH LIVER DISEASE

-The many causes of liver disease present clinically in a few distinct patterns either
a) Hepatocellular diseases-Features of injury, inflammation and necrosis.
b) Cholestatic (obstructive)-Feature of obstruction of bile flow predominate.
-Typical presenting symptoms of liver disease include
-Jaundice
-Generalized Fatigue

27
 -Itching
-Right upper quadrant pain,
-Abdominal distention
-Intestinal bleeding.
-However, some patients with liver disease are found to have abnormalities in biochemical liver tests as a part of a
routine biochemical tests.
-Evaluation of patients with liver disease should be directed at
(1) Establishing the etiologic diagnosis
-Hepatocellular versus cholestatic injury, as well as on the specific etiologic diagnosis
(2) Estimating the disease severity (grading)
-Assessing the severity or activity of disease-active or inactive, and mild, moderate, or severe.
(3) Establishing the disease stage (staging).
-Estimating the place in the course of the natural history of the disease, whether acute or chronic; early or late; pre-
cirrhotic, cirrhotic, or end-stage.
CLINICAL HISTORY
-Follow symptoms of liver disease
Their nature
 Pattern of onset
 Progression
- Liver-specific symptoms of jaundice, dark urine, light stools, itching, abdominal pain, and bloating.
-Itching occur early in obstructive jaundice (from biliary obstruction or drug-induced cholestasis)
-Itching also occurs in chronic liver diseases, typically the cholestatic forms such as primary biliary cirrhosis and
sclerosing cholangitis where it is often the presenting symptom, occurring before the onset of jaundice.
-RUQ pain or ache ("liver pain") occurs in many liver diseases and is usually marked by tenderness over the liver
area.
-The pain arises from stretching or irritation of Glisson's capsule, which surrounds the liver.
-Severe pain is most typical of gall bladder disease, liver abscess, and severe venoocclusive disease but is an
occasional accompaniment of acute hepatitis.
-Jaundice is the hallmark symptom of liver disease.
-Patients usually report darkening of the urine before they notice scleral icterus.
-Rarely detectable with a bilirubin level less than 51 umol/L. With severe cholestasis there will also be lightening of
the color of the stools and steatorrhea. Jaundice without dark urine usually indicates indirect (unconjugated)
hyperbilirubinemia and is typical of hemolytic anemia eg malaria and sickle cell and the genetic disorders of
bilirubin conjugation eg Gilbert's syndrome, Crigler-Najjar syndrome.
Symptoms suggestive of complications of stage of liver disease:
Haematemesis-varices or portal HTN
 Hemoptysis-chronic heart failure and cardiac cirrhosis.
 Any other bleeding diasthesis-liver failure.
 Swelling of legs-low albumin.
 Abnormal behaviour, confusion or drowsiness
-Constitutional symptoms such as fatigue, weakness, nausea, poor appetite, and malaise.
-Nausea - may accompany fatigue or be provoked by odors of food or eating fatty foods.
-Vomiting -rarely persistent or prominent.
-Anorexia with weight loss occurs commonly in acute liver diseases but is rare in chronic disease, except when
cirrhosis is present and advanced.
- Diarrhea -uncommon in liver disease, except with severe jaundice, with malabsorption leading to steatorrhea.

Major risk factors for liver disease

Detailed history of alcohol use- more than two drinks (22 to 30 g) per day in women and three drinks (33
to 45 g) in men. Increased risk. Most patients with alcoholic cirrhosis have a much higher daily intake and
have drunk excessively for 10 years or more before onset of liver disease.
Previous history of yellowness of eyes-viral hepatitis, aflatoxicosis.
 Medications (including herbal compounds, birth control pills, and over-the-counter medications).
 History of pulmonary TB treatment or chronic cough-Disseminated TB .Also adverse effects of anti-TB.

28
  Sexual History- For assessing the risk of viral hepatitis should include life-time number of sexual partners.
Sexual exposure is a common mode of spread of hepatitis B but is rare for hepatitis C
 Methods of grain storage and history of other family members having similar symptoms.
 Exposure to jaundiced or other high-risk persons
A history of injection drug use, even in the remote past, is of great importance in assessing the risk for
hepatitis B and C. Injection drug use is now the single most common risk factor for hepatitis C.
 Recent surgery
Remote or recent transfusion with blood and blood products .Transfusion with blood or blood products
is no longer an important risk factor for acute viral hepatitis. However, blood transfusions received before
the introduction of sensitive enzyme immunoassays for antibody to hepatitis C virus (anti-HCV) in 1992 is
an important risk factor for chronic hepatitis C. Blood transfusion before 1986, when screening for
antibody to hepatitis B core antigen (anti-HBc) was introduced, is also a risk factor for hepatitis B
Occupation-schistosomiasis, chemical exposure
Accidental exposure to blood or needlestick
Familial history of liver disease -Wilson's disease; hemochromatosis and a1-antitrypsin (a1AT)
deficiency
Suggestive of heart failure-orthopnea, paroxysmal nocturnal dyspnea-Cardiac cirrhosis
PHYSICAL EXAMINATION
-In many patients, the physical examination is normal unless the disease is acute or severe and advanced.
-The physical examination can reveal signs that point to a specific diagnosis, either in risk factors or in associated
diseases.
-Typical physical findings in liver disease
-General condition
-The patient may be wasted because of chronic illness, confused-encephalopathy, dehydrated etc
Hands-6 items
-Leuconychia-chronic liver disease with hypoalbuminaemia
-Finger clubbing
-Asterexis
-Dupytrens contracture
-Palmar erythema
-Palmar parlor

Others general exam

-Spider angiomata
-Excoriations
-Jaundice
-Gynecomastia, scrotal atrophy, parotid enlargement
-Edema
-Hepatic fetor

Per Abdomen
-Prominent veins over the abdomen, and caput medusa
-Ascites
-Hepatomegaly- Careful assessment of the liver edge may also demonstrate unusual firmness, irregularity of the
surface, or frank nodules.
-Hepatic tenderness
-Splenomegaly
-Pulsatile liver-Chronic CCF with Tricuspid regurgitation.
-Hepatic bruit-hepatoma, hepatic hemangioma

Signs of advanced disease include

-Dilated abdominal veins
-Asterixis
-Mental confusion
-Stupor or Coma.

29
A helpful measure of hepatic encephalopathy is a careful mental status examination and use of the trail-making test,
which consists of a series of 25 numbered circles that the patient is asked to connect as rapidly as possible using a
pencil. The normal range for the connect-the-dot test is 15 to 30 s; it is considerably delayed in patients with early
hepatic encephalopathy.

-Spider angiomata and palmar erythema occur in both acute and chronic liver disease and may be especially
prominent in persons with cirrhosis, during pregnancy.
-Spider angiomata are superficial, tortuous arterioles and, unlike simple telangiectases, typically fill from the center
outwards.
-Occurs on the arms, face, and upper torso; they can be pulsatile and may be difficult to detect in dark-skinned
individuals.
-Hepatic failure is defined as the occurrence of signs or symptoms of hepatic encephalopathy in a person with
severe acute or chronic liver disease.
-The first signs of hepatic encephalopathy can be subtle and nonspecific-change in sleep patterns, change in
personality, irritability, and mental dullness. Thereafter, confusion, disorientation, stupor, and eventually coma
supervene. Physical findings include asterixis and flapping tremors of the body and tongue.
-Fetor hepaticus refers to the slightly sweet, ammoniacal odor that is common in patients with liver failure,
particularly if there is portal-venous shunting of blood around the liver.
-Other causes of coma and confusion should be excluded, mainly electrolyte imbalances, sedative use, and renal or
respiratory failure.
-Widened pulse pressure and signs of a hyper dynamic circulation can occur in patients with cirrhosis as a result of
fluid and sodium retention, increased cardiac output, and reduced peripheral resistance.
-Patients with long-standing cirrhosis are prone to develop the hepatopulmonary syndrome with hypoxemia due to
pulmonary arteriovenous shunting, characterized by hypoxia that worsens when lying flat.
-Several skin disorders and changes occur commonly in liver disease.
-Hyper pigmentation -chronic cholestatic diseases such as primary biliary cirrhosis and sclerosing cholangitis.
-Xanthelasma and tendon xanthomata occur as a result of retention and high serum levels of lipids and cholesterol. -
A slate-gray pigmentation to the skin also occurs with hemochromatosis if iron levels are high for a prolonged
period.
-Mucocutaneous vasculitis with palpable purpura, especially on the lower extremities, is typical of
cryoglobulinemia of chronic hepatitis C but can also occur in chronic hepatitis B.
-Some physical signs point to specific liver diseases. Kayser-Fleischer rings occur in Wilson's disease and consist of
a golden-brown copper pigment deposited at the periphery of the cornea; they are best seen by slit-lamp
examination.

INVESTIAGTIONS
1. FHG- Anaemia of chronic illness may be seen.
-Lymphocytosis-Viral hepatitis.
2. LFT
-Liver parenchyma- ALT and AST.
-Cholestasis-alkaline phosphatase, γ-glutamyl transpeptidase (GGT) to define whether alkaline phosphatase
elevations are due to liver disease
-Direct and total serum bilirubin
-Synthetic Function of the liver-albumin and prothrombin time.
3. Viral hepatitis serology to define the type of viral hepatitis-Commonly HBV and HCV plus
HIV ELISA
Hepatitis B
-Acute- HBsAg and anti-HBc IgM
-Chronic- HBsAg and HBeAg and/or HBV DNA
Hepatitis C
-Anti-HCV IgG
-HCV RNA
Other hepatitis
-HAV- Anti HAV IgM
-HDV- HBsAg and anti-HDV
-HEV-Anti-HEV IgM

30
4. RFT’s esp. those presenting with ascites
5. Autoimmune markers –If indicated
-Primary biliary cirrhosis (antimitochondrial antibody; AMA, elevated IgM levels, and compatible histology
-Sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody; P-ANCA), cholangiography
-Autoimmune hepatitis – ANA-antinuclear antibodies; SMA-smooth-muscle antibody, elevated IgG levels, and
compatible histology
6. Familial liver diseases
i) α1 Antitrypsin disease- Reduced α1 antitrypsin levels, phenotypes PiZZ or PiSZ
ii) Wilsons disease-Decreased serum ceruloplasmin and increased urinary copper; increased hepatic copper level
iii) Haemachromatosis-Elevated iron saturation and serum ferritin; genetic testing for HFE gene mutations
7. Tumour markers
Elevated α-fetoprotein level >500; ultrasound or CT image of mass

Staging of Liver disease

-Reliable staging system is the modified Child-Pugh classification with a scoring system of 5 to 15:
Scores of 5 and 6 being Child-Pugh class A (consistent with “compensated cirrhosis”),
Scores of 7 to 9 indicating class B
10 to 15 class C
-This scoring system was initially devised to stratify patients into risk groups prior to undergoing portal
decompressive surgery.
-The Child-Pugh score is a reasonably reliable predictor of survival in many liver diseases and predicts the
likelihood of major complications of cirrhosis such as bleeding from varices and spontaneous bacterial peritonitis.
-It was used to assess prognosis in cirrhosis and to provide the standard criteria for listing for liver transplantation
(Child-Pugh class B).
Child Pugh Classification
Factor Score
1. Serum bilirubin µmol/L
<34 1
34–51 2
>51 3
2. Serum albumin g/L
>35 1
30–35 2
<30 3
3. Prothrombin time INR
<1.7 1
1.7–2.3 2
>2.3 3
4. Ascites
None 1
Easily controlled 2
Poorly controlled 3
5. Hepatic encephalopathy
None 1
Minimal 2
Advanced 3

DIAGNOSTIC IMAGING
1. Ultrasonography-have a high sensitivity for detecting biliary duct dilatation and are the first-line options for
investigating the patient with suspected obstructive jaundice.
2. (CT-scan)
3. (MRI)
-CT and MRI are indicated for the identification and evaluation of hepatic masses, staging of liver tumors, and
preoperative assessment.
4. Magnetic resonance cholangiopancreatography (MRCP)

31
5. ERCP
- (MRCP) and (ERCP) are the procedures of choice for visualization of the biliary tree.
-MRCP offers several advantages over ERCP; there is no need for contrast media or ionizing radiation, images can
be acquired faster, it is less operator dependent, and it carries no risk of pancreatitis.
-MRCP is superior to US and CT for detecting choledocholithiasis but less specific.
-It is useful in the diagnosis of bile duct obstruction and congenital biliary abnormalities, but ERCP is more valuable
in evaluating ampullary lesions and primary sclerosing cholangitis.
-ERCP allows for biopsy, direct visualization of the ampulla and common bile duct, and intraductal
ultrasonography.
-It also provides several therapeutic options in patients with obstructive jaundice, such as sphincterotomy, stone
extraction, and placement of nasobiliary catheters and biliary stents.
-Doppler US and MRI are used to assess hepatic vasculature and hemodynamics and to monitor surgically or
radiologically placed vascular shunts such as transjugular intrahepatic portosystemic shunts (TIPS).
- Finally, interventional radiologic techniques allow the biopsy of solitary lesions, insertion of drains into hepatic
abscesses, and creation of vascular shunts in patients with portal hypertension.
Liver biopsy
-Check preparation and the performance of liver biopsy

Long term follow up for liver disease patients

1. Abstinence from alcohol should be encouraged for all patients with alcohol-related liver disease and in patients
with cirrhosis and those receiving interferon-based therapy for hepatitis B or C.
2. Regarding vaccinations, all patients with liver disease should receive hepatitis A vaccine and those with risk
factors should receive hepatitis B vaccination as well. Influenza and pneumococcal vaccination should also be
encouraged.
3. Patients with liver disease should be careful in use of any medications, other than the most necessary. Drug-
induced hepatotoxicity can mimic many forms of liver disease and can cause exacerbations of chronic hepatitis and
cirrhosis; drugs should be suspected in any situation where the cause of exacerbation is unknown.
4. Surveillance for complications of chronic liver disease such as variceal hemorrhage and hepatocellular
carcinoma.
-Upper endoscopy to assess the presence of varices and should be given chronic therapy with beta blockers if large
varices are found.
-Patients with cirrhosis also screening and long-term surveillance for development of hepatocellular carcinoma. Eg
US of the liver at 6- to 12-month intervals.

ARTERIAL PULSE
-A small weak pulse, pulsus parvus, is common in conditions with a diminished left ventricular stroke volume, a
narrow pulse pressure, and increased peripheral vascular resistance.
- A hypokinetic pulse may be due to hypovolemia, to left ventricular failure, to restrictive pericardial disease, or to
mitral valve stenosis.
-pulsus tardus, In aortic valve stenosis, the delayed systolic peak results from obstruction to left ventricular ejection.
-Large, bounding (hyperkinetic) pulse is usually associated with an increased left ventricular stroke volume, a wide
pulse pressure, and a decrease in peripheral vascular resistance. This pattern occurs characteristically in patients with
an elevated stroke volume, as in complete heart block; with hyperkinetic circulation due to anxiety, anemia,
exercise, or fever; or with a rapid runoff of blood from the arterial system (as caused by a patent ductus arteriosus or
peripheral arteriovenous fistula). Patients with mitral regurgitation or a ventricular septal defect may also have a
bounding pulse, since vigorous left ventricular ejection produces a rapid upstroke in the arterial pulse, even though
the duration of systole and the forward stroke volume may be reduced. In aortic regurgitation, the rapidly rising,
bounding arterial pulse results from an increased left ventricular stroke volume and an increased rate of ventricular
ejection.
-The bisferiens pulse, which has two systolic peaks, is characteristic of aortic regurgitation (with or without
accompanying stenosis) and of hypertrophic cardiomyopathy.
-The dicrotic pulse has two palpable waves, one in systole and one in diastole. It usually denotes a very low stroke
volume, particularly in patients with dilated cardiomyopathy.
-Pulsus alternans is a pattern in which there is regular alteration of the pressure pulse amplitude, despite a regular
rhythm (Fig. 225-2). It is due to alternating left ventricular contractile force, usually indicates severe impairment of
left ventricular function, and commonly occurs in patients who also have a loud third heart sound. Pulsus alternans

32
may also occur during or following paroxysmal tachycardia or for several beats following a premature beat in
patients without heart disease

BURKITS LYMPHOMA
Definition
-It is a high-grade B-cell neoplasm and has 2 major forms, the endemic (African) form and the nonendemic
(sporadic) form. Burkitt lymphoma is a childhood tumor but it is observed in adult patients.
- Burkitt lymphoma is one of the fastest growing malignancies in humans, with a very high growth fraction.(22.5hrs
doubling rate).
Pathophysiology:
-Burkitt lymphoma is a monoclonal proliferation of B lymphocytes characterized by small noncleaved cells that are
uniform in appearance and that produce a diffuse pattern of tissue involvement.
-Under the microscope, Burkitt lymphoma is characterized by the presence of a "starry sky" appearance (also
observed in other highly proliferative lymphomas), imparted by scattered macrophages with phagocytes cell debris.
-The African form most often involves the maxilla or mandible. The involvement of abdominal organs, such as the
kidneys, ovaries, or retroperitoneal structures, is slightly less common. In contrast, the sporadic form usually
involves abdominal organs, with the most common involvement of the distal ileum, cecum, or mesentery and less
common involvement of other abdominal organs, pelvic organs, and facial bones.
-Most Burkitt lymphomas carry a translocation of the c-myc oncogene from chromosome 8 to either the
immunoglobulin (Ig) heavy-chain region on chromosome 14 [t(8;14)] or one of the light-chain loci on chromosome
2 (kappa light chain) [t(8;2)] or chromosome 22 (lambda light chain) [t(8;22)].
-The Epstein-Barr virus (EBV) has been implicated strongly in the African form, while the relationship is less clear
in the sporadic form.
-EBV is associated with about 20% of sporadic cases.
-Rare adult cases are associated with immunodeficiency, particularly AIDS.
-The lymphocytes have receptors for EBV and are its specific target.
-In the African form, the hosts are believed to be unable to mount an appropriate immune response to primary EBV
infection, possibly because of coexistent malaria or another infection that is immunosuppressive. Months to years
later, excessive B cell proliferation occurs
Epidemiology
- Burkitt lymphoma is endemic in certain regions of equatorial Africa and other tropical locations between latitudes
10° south and 10° north. Incidence in these areas of endemic disease is 100 per million children.
Mortality/Morbidity:
-With combination chemotherapy and CNS prophylaxis, the survival rate is now at least 60%.
-Patients with limited disease have a survival rate of 90%.
-Patients with bone marrow and CNS involvement have a poor prognosis. Adults with the disease, especially those
in the advanced stage, do more poorly than affected children.
Sex: The male-to-female ratio is 2-3:1.
Age:
-Burkitt lymphoma is most common in children.
-In Africa, the mean age is 7 years.
-Outside Africa, the mean age is 11 years.
Clinical presentation
History:
In the African form
 Most often present with swelling of the affected jaw, other facial bones, loosening of the teeth
 Swelling of the lymph nodes, which are nontender and rapidly growing, in the neck or below the jaw.
 Abdominal presentation is slightly less common
 Wt loss, Night sweat, generalized fatigue.
Sporadic form
 Abdominal tumors causing swelling and pain in the affected area.

33
  Some patients present with symptoms of bowel obstruction secondary to an ileal-cecal intussusception
caused by tumor growth.
-Because of the rapid growth of the Burkitt tumor, patients may quickly manifest significant metabolic derangement
and renal function impairment
-Less common presentations of Burkitt lymphoma include an epidural mass, skin nodules, CNS symptoms, and bone
marrow involvement.
-Rare cases of Burkitt lymphoma can present as acute leukemia (L3-ALL) with fever, anemia, bleeding, and
adenopathy.
Physical:
-Major signs of Burkitt lymphoma include a soft tissue mass associated with the involvement of the jaw or other
facial bones, enlarged cervical lymph nodes, abdominal masses, and ascites.
Investigations
Lab Studies:
1.FBC and ESR
2.Electrolytes-serum levels of sodium, potassium, calcium, phosphorus, magnesium
3.Urea, and creatinine
4.Uric acid levels
5.Liver function tests.
6.Biopsy of suspected lymph nodes or other disease sites, including bone marrow, is essential for the
diagnosis.
7.FNA of the lymph node may also be done.
8.Cerebrospinal fluid (CSF) also should be evaluated in all cases.
8.Cytogenetic studies of peritoneal or pleural fluid, when appropriate, should be performed for diagnostic
or staging purposes.
Imaging Studies:
1. CXR -rule out lung metastasis and mediastinal involvement. Chest CT should be performed if chest x-
ray is abnormal
2.Abdominal U/S
3. Abdominal CT scan -retroperitoneal and mesenteric lymph nodes, liver, kidneys, ovaries, and other
structures.
4.Head or spinal CT scan or MRI is indicated if neurological signs and symptoms are present.
5.Bone scan and plain bone radiographs are needed for patients with symptoms of bone involvement.

Histologic Findings: Lymph node involvement occurs. Burkitt cells are homogeneous in size and shape, with round
to oval nuclei and slightly coarse chromatin, with multiple nucleoli, and with intensely basophilic vacuolated
cytoplasm that contains neutral fat. Frequent mitotic figures usually are observed. A starry sky appearance is
imparted by scattered macrophages with phagocyte cell debris.
Staging
-The most common system of staging for non-Hodgkin's lymphomas in adults, including Burkitt's lymphoma, is the
Ann Arbor system.
Stage I:
- Limited to one group of lymph nodes either above or below the diaphragm,
- Organ or part of the body other than the lymph nodes, but has not spread to other organs or lymph nodes.
Stage II:
- The lymphoma in two or more lymph node groups on the same side of the diaphragm
- only one organ involved and has spread to the lymph nodes near that organ
Stage III:
- The lymphoma is present in groups of lymph nodes on both sides of the diaphragm.
- It may involve an organ or site outside the lymph nodes, the spleen, or both.
Stage IV:
- The lymphoma is disseminated (spread) throughout one or more organs outside the lymph nodes. There
may or may not be involvement of lymph nodes that are remote from the affected organs.
-For each of stages
A -No general symptoms
B- Is used for patients with any of the following:
 Unexplained loss of more than 10% of body weight in the last six months

34
  Unexplained fever
 Drenching night sweats
E - malignancies outside the lymph nodes
Other sites in the body are identified with additional letters, such as D for the skin or H for the liver.
-The most commonly used staging system for NHL in children is that of the St. Jude's Children's
Research Hospital.
(Stage I) -It separates patients with a single tumor or diseased lymph node
(Stage II) -or two or more tumors or diseased lymph nodes on the same side of the diaphragm
(Stage III)- from those with a large chest or abdominal tumor or
(Stage IV) -Involvement of the bone marrow and central nervous system

Treatment.
 -CHOP (NO Procarbazine) + intrathecal Methotrexate and cytosine arabinoside.
 -Curable in early diagnosis and treatment.
 -Remission rates of >90% if acquired early and nil in late acquisition stages.
 -Prognosis worse in non-burkitts NHL.

Complications of treatment
 Renal failure
 Liver failure
 Bone marrow failure
 Tumor lysis syndrome (leads to DIC).

CHRONIC LEG ULCERS

-It is vital that any patient with leg ulceration has a full assessment. Lack of assessment can lead to long
periods of inappropriate and potentially dangerous treatment.
- For example, applying compression bandaging to a limb where the arterial blood supply is compromised
may result in gangrene; withholding compression bandaging where there is venous insufficiency may result
in failure to heal and/or rapid extension of the ulceration.
Etiology
-The most common cause of leg ulceration is tropical ulcers. Damage to valves within the veins results in reflux of
venous blood and consequent high pressures in the smaller vessels. This in turn leads to oedema and leakage of
blood cells and fibrin into the tissues causing discolouration and hardening of the tissues (lipodermatosclerosis).
-These tissues are then prone to injury and once injured slow to heal. However, there are other causes of ulceration
and these should be excluded before treatment is begun.
Other causes
1. Arterial insufficiency to the lower limb
2. Infections (tropical ulcers)
3. Blood disorders (sickle cell anaemia)
4. Neoplasms (squamous cell carcinoma, basal cell carcinoma
5. Trauma
6. Neuropathic (normally associated with diabetes and occurring on the feet)
7. Mixed arterial and venous insufficiency
8. Small vessel disease (associated with diabetes)
9. Vasculitis (associated with rheumatoid arthritis and other auto-immune disorders such as lupus
erythematosus)
10. Gross obesity
11. Hypertension
12. Lymphoedema
13. Factitious injury (rare)
14. Other rare conditions (scleroderma, pyoderma gangrenosum)
ASSESMENT OF LEG ULCERS

35
History
-Ulcer
-Onset, location, number, discharge or bleeding, pain, pruritus, abnormal odour, skin changes around ulcers
-The ulcer healing or enlarging, recurrences and previous history of treatment
-History of trauma at the site
-Associated leg swelling
-Associated fever
-Associated weight loss, fatigue
-Associated chronic cough, past TB treatment or history of contact with person of chronic cough
-Associated loss of sensation on the limb
-History of yellowness of eyes, recurrent pains in limb or abdomen. Any other history suggestive of sickle cell
disease.
-Associated groin swellings
-Hypertension and diabetes mellitus
-History of smoking
-Intake of any drugs
Past medical history
-Vascular history including: history of DVT
Physical examination
Examination of ulcers
Site and number of wounds
 Size
 Shape
 Edges (undermined eg buruli ulcer, overhanging eg malignant ulcer, irregular or regular)
 Depth
 Floor-clean, necrotic tissue, granulation tissue, bleeds
 Base-palpated mobility, tenderness
 Exudates, discharges from the wound and odour
 Surrounding areas eczema, maceration, signs of scratching, blistering
-Leg examination
Oedema
 Prominent varicosities
 Skin discoloration
 Skin condition colour and temperature
 Examine calf-swelling and tender
Other examination
1. Report pulses-dorsalis pedis, popliteal and femoral pulses to rule out arterial insufficiency
-Blood pressure measurement in both arms
2. Lymphadenopathy –inguinal to rule out malignant ulcers especially malignant melanoma.
- Infectious causes
3. Sensory examination of the lower limb to rule out the neuropathic ulcers
Venous disease
• Usually shallow ulcers (situated on the gaiter area of the leg)
• Oedema
• Eczema
• Ankle flare
• Lipodermatosclerosis
• Varicose veins
• Hyper pigmentation
• Atrophie blanche
Arterial disease-Pain, parlour, parasthesia, paralysis
• Ulcers with a ‘punched out’ appearance
• Base of wound poorly perfused and pale
• Cold legs/feet (in a warm environment)
• Shiny, taut skin
• Dependent rubor

36
• Pale or blue feet
• Gangrenous toes

INVESTIGATIONS
1. FHG -Anemia, Infections, leukemia
2. Doppler measurement of ABPI (ankle brachial pressure index) in both feet (essential to rule out arterial disease).
3. Blood or urine screen for diabetes.
4. Swab ulcer for M/C and sensitivity
-Additional blood investigations will depend on the patient‘s clinical history
-Biopsy is indicated where areas of depigmentation and tissue proliferation raise the suspicion of malignant change
-Radiology may be indicated to show bone changes, especially malignant erosion, pathological fracture,
inflammatory changes, or dystrophic calcification.
-Full assessment should be carried out when the patient first presents and should be repeated if the patient fails to
respond to treatment. Foot pulses should be palpated and if not palpable, Doppler examination should be repeated at
regular intervals (at least three monthly as long as compression therapy is being used). Doppler examination should
also be repeated if there is a sudden increase in pain.

MANAGEMENT
-Treatment of uncomplicated chronic tropical ulcer comprises three main aspects;
1-control of infection
2-control of any factors hindering healing
3-provision of robust epithelial cover which will protect against further ulceration and malignant change.
-For control of infection patients require systemic treatment with antibiotics, chosen on the basis of laboratory
determined sensitivities.
-Excision of indolent granulation tissue, areas of dense fibrosis, and severely scarred depigmented skin may be
essential to achieve ultimate healing.
-Contractures and bone deformity will usually need to be corrected before the ulcer is covered. Bone infection must
be controlled.
-Epithelial cover is usually achieved by applying a split-thickness skin graft to the granulating bed of the ulcer or
after excision of the ulcer.
-Management of underlying condition leading to ulceration.

Malignant Transformation
-Rolled up edges, undermined edges, bleeding, irregular edges, rough floor with necrotic debris
The primary carcinoma
-On presentation, most patients have large squamous cell carcinomas with bone attachment or invasion
-Despite advanced local disease, metastatic disease is not common and potentially curable primary lesions should be
treated by surgery in otherwise well patients. Small localized lesions may be treated by wide excision and split-
thickness skin grafting; however, most lesions require more extensive surgery.
-Amputation has been the mainstay of treatment for large lesions showing extensive bone invasion. The associated
morbidity is poorly

CHRONIC LYMPHOCYTIC LEUKEMIA

Background:
Monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes.
It is the most common form of leukemia found in adults Pathophysiology:
The cells of origin in the majority of patients with CLL are clonal B cells(75%) arrested in the B-cell differentiation
pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells
resemble mature lymphocytes.
B-CLL lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD24
monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal
CD5 + B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell CLL is most likely a malignancy of

37
an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural
autoantibodies.
Recent studies have demonstrated that bcl2, a protooncogene, is overexpressed in B-CLL. The protooncogene bcl2
is a known suppresser of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite
the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of
bcl2, such as t(14;18), are not found in patients with CLL.
An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion
of 13q, which occurs in more than 50% of patients. Patients showing 13q14 abnormalities have a relatively benign
disease that usually manifests as stable or slowly progressive isolated lymphocytosis. The presence of trisomy 12,
which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletions of
bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement and
aggressive disease. More sensitive techniques have demonstrated abnormalities of chromosome 12. Approximately
2-5% of patients with CLL exhibit a T-cell phenotype.
CLL also should be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are
morphologically less mature prolymphocyte
Incidence
Occur between 45-75 years
M>F 2:1

History:
-Patients with CLL present with a wide range of symptoms and signs at presentation.
-Onset is insidious, and it is not unusual for this disorder to be discovered incidentally after a blood cell count is
performed for another reason.
 Predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster
 Enlarged lymph nodes
 Early satiety and/or abdominal discomfort related to an enlarged spleen
 Mucocutaneous bleeding and/or petechiae secondary to thrombocytopenia
 Tiredness and fatigue secondary to anemia
Physical:
-Localized or generalized lymphadenopathy
-Splenomegaly (30-40% of cases)
-Hepatomegaly (20% of cases)
-Petechiae
-Pallor
Causes:
-As in the case of most malignancies, the exact cause of CLL is uncertain.
-The proto-oncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell
death) in the affected lymphoid cells.
-CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare
Investigations
CBC count with differential
1-Absolute lymphocytosis with more than 5000 lymphocytes/ m L. Some consider this to be a prerequisite for the
diagnosis of CLL and classify cases that would otherwise meet the criteria as small lymphocytic lymphoma/diffuse
well-differentiated lymphoma.
2-Anemia-normocytic normochromic
3-Thrombocytopenia

PBF
 confirm lymphocytosis
 Presence of smudge cells, which are artifacts due to damaged lymphocytes during the slide preparation.
Flow cytometry
The most valuable test to confirm CLL. It confirms the presence of circulating clonal B-lymphocytes expressing
CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.
T-cell immunotype (CD2, CD3, and CD8)

38
Imaging Studies:
Liver/spleen scan may demonstrate splenomegaly. Computed tomography of chest, abdomen, or pelvis generally is
not required for staging purposes. However, be careful to not miss lesions such as obstructive uropathy or airway
obstruction that are caused by lymph node compression on organs or internal structures.

Procedures:
Bone marrow aspiration and biopsy.
-Increased mature lymphocytes in the bone marrow-normal up to 5% but in CLL up to 4o %
-Decreased myeloid, erythroid and megakaryocytic cells.
-blast transformation may occur but is lymphoid type only unlike CML.
When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome
Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known CLL to assess the
possibility of transformation to a high-grade lymphoma.
Staging:
Two staging systems are in common use, the Rai-Sawitsky in the United States and the Binet in Europe.
Neither is completely satisfactory, and both have been often modified.
The Rai-Sawitsky staging system divides CLL into 5 Stages, 0-IV. Based on lymphocytosis(o), adenopathy(1),
splenomegaly(2) ,anemia(3),
Thrombocytopenia(4)
Stage 0 is lymphocytosis in the blood and marrow only, with a survival of longer than 120 months.
Stage I is lymphocytosis and adenopathy, with a survival of 95 months.
Stage II is lymphocytosis plus splenomegaly and/or hepatomegaly, with a survival of 72 months.
Stage III is lymphocytosis plus anemia (hemoglobin <10 g), with a survival of 30 months.
Stage IV is lymphocytosis plus thrombocytopenia (platelets <100,000), with a survival of 30 months.
The Binet staging system uses 3 stages, A, B, and C. Stage A requires a hemoglobin of greater than or equal to
100 g/L, platelets greater than or equal to 100 X 10 -9 , and fewer than 3 lymph node areas involved (Rai-Sawitsky
stages 0, I, II). Survival is longer than 120 months.
Stage B requires hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved (Rai-
Sawitsky stages I and II). Survival is 61 months.
Stage C is a hemoglobin less than 100 g/L, platelets less than 100 X 10 -9 , or both (Rai-Sawitsky stages III and IV).
Survival is 32 months.
Chemotherapy
At the time of diagnosis, most patients do not need to be treated with chemotherapy unless they have :
 Weight loss of more than 10%
Extreme fatigue
Fever related to leukemia
 Night sweats
Progressive marrow failure
Autoimmune anemia or thrombocytopenia not responding to prednisone
 Progressive splenomegaly
 Massive lymphadenopathy
 Progressive lymphocytosis. Progressive lymphocytosis is defined as an increase of greater than 50% in 2
months or a doubling time of less than 6 months.

Patients at stages 0,1,2 whose disease is stable require only periodic follow-up.
1.Prednisolone
-Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be
useful in patients with autoimmune manifestations of the disease.
2.Nucleoside analogs
-Nucleoside analogs (i.e fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity
against indolent lymphoid malignancies, including CLL.
3.Chlorambucil and prednisone
-Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients.
-Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission
rate.

39
4.Rituxan (rituximab)
-Therapy with monoclonal antibodies eg an antibody directed at CD52.

CHRONIC MYELOCYTIC LEUKEMIA

Background:
-Chronic myelogenous leukemia (CML) is a myelo-proliferative disorder characterized by increased proliferation of
the granulocytic cell line without the loss of their capacity to differentiate.
-Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature
precursors, including occasional blast cells.
Pathophysiology:
-CML is an acquired abnormality that involves the hematopoietic stem cell. -
-The Philadelphia chromosome is characterized by a cytogenetic aberration consisting of a reciprocal translocation
between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22.as
a large portion of 22q is translocated to 9q, and a smaller piece of 9q is moved to 22q.
-This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of
chromosome 22 in the BCR region.
The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The
expression of this protein leads to the development of the CML.
The presence of BCR/ABL rearrangement is the hallmark of CML, although this rearrangement has also been
described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of
CML.
Sex-slight M>F
Frequency
CML accounts for 20% of all leukemia affecting adults. It peaks 40-50 yars. Although uncommon, the disease also
occurs in younger individuals. Increased incidence was reported among individuals exposed to radiationworld wide-
1-1.5 per 100,000
Mortality/Morbidity
Generally, 3 phases of the disease are recognized. The general course of the disease is characterized by an eventual
evolution to a refractory form of acute myelogenous or, occasionally, lymphoblastic leukemia. The median survival
of patients using older forms of therapy was 3-5 years.
a)Chronic phase
-most patients present in this phase characterized by splenomegaly and leukocytosis with generally few symptoms.
-This phase is easily controlled by medication.
-The major goal of treatment during this phase is to control symptoms and complications resulting from anemia,
thrombocytopenia, leukocytosis, and splenomegaly.
-Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.
b)Blast crisis
-After an average of 3-5 years
-Marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft tissue or
skin leukemic infiltrates.
-Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and
failure of the usual medications to control leukocytosis and splenomegaly.
-The manifestations crisis is similar to those of acute leukemia.
-.
Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops
-In approximately two thirds of cases, the blasts are myeloid. One third of patients, the blasts exhibit a lymphoid
phenotype, further evidence of the stem cell nature of the original disease.
-Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional
Philadelphia chromosomes or other translocations.
c) Accelerated phase
-Occurs 3-6 months before the diagnosis of blast crisis.
-Clinical features in this phase are intermediate between the chronic phase and blast crisis
Age
-In general, this disease occurs in the fourth and fifth decades of life.

40
-Younger patients aged 20-29 years may be affected and may present with a more aggressive form, such as in
accelerated phase or blast crisis.
Clinical presentation
History:
-The clinical manifestations of CML are insidious and are often discovered incidentally when an elevated WBC
count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical
examination.
-Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease.
-Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
-Patients often have symptoms related to enlargement of the spleen, liver, or both. The large spleen may encroach on
the stomach and cause early satiety and decreased food intake.
-Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen
may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.
-The enlarged liver may contribute to the patient's weight loss.
-Some patients may have low-grade fever and excessive sweating related to hypermetabolism.
- Rarely, the patient will present with a clinical syndrome related to leukostasis with blurred vision, respiratory
distress, or priapism
The disease has 3 clinical phases
Chronic phase
-Most patients are diagnosed while still in the chronic phase.
-The WBC count is usually controlled with medication (hematologic remission).
-This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with
hydroxyurea (Hydrea) or busulfan therapy, but it has lasted for longer than 9.5 years in patients who respond well to
interferon alfa therapy.
- Imatinib mesylate has dramatically improved the duration of hematologic and indeed cytogenetic remissions.

Transitional or accelerated phase

-Some patients to this phase to which may last for several months.
-The survival of patients diagnosed in this phase is 1-2 years. This phase is characterized by poor control of the
blood counts with myelosuppressive medication and the appearance of
 Peripheral blast cells ( > 15%)
 Promyelocytes ( > 30%) )
 Basophils ( > 20%),
 Platelet counts less than 100,000 cells/ m L unrelated to therapy.
-Usually, the doses of the medications need to be increased. -Splenomegaly may not be controllable by medications,
and anemia can worsen.
-Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase.
Acute phase, or blast crisis
- Is similar to acute leukemia, and survival is 3-6 months at this stage.
-Bone marrow and peripheral blood blasts of 30% or more are characteristic.
-Skin or tissue infiltration also defines blast crisis.
-Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities
such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.
-Bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually
associated with infections.
Physical:
Parlor, wasted or signs of infection
-Massive Splenomegaly is the most common physical finding in patients with CML.
 -Size of the spleen correlates WBC counts, biggest spleens high WBC counts.
 -A very large spleen harbinger of the transformation into an acute blast crisis form of the disease.
-Hepatomegaly -less commonly than splenomegaly.Part of the extramedullary hematopoiesis occurring in the
spleen.
-Sternal tenderness may be present as a sign of marrow overexpansion.
-Leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts,
exceeding 300,000-600,000 cells/ m L.
-Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

41
Causes:
-The initiating factor of CML is still unknown, but exposure to irradiation has been implicated
Other agents, such as benzene, are possible causes
DDX
 Myelofibrosis ,Myelodysplastic Syndrome Myeloproliferative Disease
Polycythemia Vera
Leukemoid reactions from infections (chronic granulomatous, eg, tuberculosis)
 Tumor necrosis
Essential thrombocytosis/thrombocythemia
CLL ,AML

Investigations
FBC
The hallmark of CML is an elevated WBC; the median white blood count at diagnosis is 150,000/uL.
-Moderate aneamia (8-10 g/dl) normocytic normochromic
-Thrombocytosis
-PBF
The peripheral blood is characteristic. The myeloid series is left-shifted, with mature forms dominating and with
cells usually present in proportion to their degree of maturation.
-Blasts are usually less than 5%. In chronic phase
-Basophilia and eosinophilia of granulocytes may be
present.
NB. With progression to the accelerated and blast phases, progressive anemia and thrombocytopenia occur, and the
percentage of blasts in the blood and bone marrow increases.
Cytochemistry
-Leukocyte alkaline phosphatase score is invariably low and is a sign of qualitative abnormalities in neutrophils.
This unlike leukamoid reactions eg infections-TB, leishmania when LAP is elevated.
-Serum vitamin B12 level elevated
-Markedly elevated serum vitamin B-12–binding protein (TC-I). The latter is synthesized by the granulocytes and
reflects the degree of leukocytosis
- Hyperuricemia, which is a reflection of high bone marrow cellular turnover
BMA
Bone marrow is hypercellular, with left-shifted myelopoiesis.
Myeloblasts < 10% of marrow cells in chronic phase
10-30% in the transitional and >30 % in Blast crisis
-Assess Fibrosis-Many patients develop myelofibrosis in later stages of the disease
-Increased myeloid/erythroid ratio
-Increased megakaryocyes
Cytogenetics
Philadelphia chromosomes-t(9,22) abl/bcr fusion gene.
The Philadelphia chromosome may be detected in either the peripheral blood or the bone marrow. The bcr-abl gene
may be reliably found in peripheral blood by molecular techniques.
Usually at the time of diagnosis, the Philadelphia chromosome-positive clone dominates and may be the only one
detected. About 5% of cases Philadelphia chromosome-negative at the level of light microscope cytogenetics,
though molecular studies demonstrate the bcr/abl fusion gene.
Additional chromosomal abnormalities, such as an additional or double Ph-positive chromosome or trisomy 8, 9, 19,
or 21; isochromosome 17; or deletion of the Y chromosome, have been described as the patient enters a transitional
form or accelerated phase of the blast crisis as the Ph chromosome persists.
Other laboratory abnormalities include
- Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts of
higher than 300,000 cells/ m L, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue
infiltration. Leukapheresis usually reduces the WBC count only temporarily and is often combined with
cytoreductive chemotherapy for more lasting effects.
Interferon alfa was the treatment of choice for most patients with CML who are too old for bone marrow
transplantation (BMT) or who do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-
5 million IU/d subcutaneously after hematologic remission with hydroxyurea.

42
BMT should be considered early in young patients ( <55 y) who have a matched sibling donor.

NB
Lymphoid blast crisis (present in one-third of cases) should be identified because chemotherapy is less toxic and
more effective. Therapy with daunorubicin, vincristine, and prednisone (used in treatment of acute lymphoblastic
leukemia) will lead to remission¾usually short-lived¾in 70% of these cases.

Imaging Studies:
Typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan.
Histologic Findings:
Diagnosis is based on the histopathologic findings in the peripheral blood and the Ph1 chromosome in the bone
marrow cells.
is 40-50%.
Medical Care:
The 3-fold goals of treatment of CML
1) they are to achieve a hematologic remission (normal CBC count and physical examination, ie, no
organomegaly)
2) Achieve cytogenetic remission (normal chromosome returns with 0% Ph-positive cells)
3) Most recently, to achieve molecular remission (negative PCR result for the mutational BCR/ABL m-RNA).
–attempt cure and prolongation of patient survival.
A new approach is to directly inhibit the molecular cause of the disease, ie, using a protein-tyrosine kinase inhibitor
that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Ph chromosome
translocation abnormality.
STI571 or ima-tinib mesylate (Gleevec)
-Inhibits -Proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells positive for BCR/ABL and
fresh leukemic cells in CML positive for the Ph chromosome.
-With imatinib at 400 mg/d orally in patients with newly diagnosed Ph-positive CML in the chronic phase, the
complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%. With higher doses of 800
mg/d, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the
complete molecular response rate

Other drugs:
Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent
used to achieve hematologic remission.
The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and
platelet counts.
Most patients achieve hematologic remission within 1-2 months. This medication causes only a short duration of
myelosuppression, so even if the counts go lower than intended, stopping or decreasing doses usually controls the
blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions.
Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts less than 15,000
cells/ m L. However, the myelosuppressive effects may occur much later and persist longer, making maintaining the
numbers within normal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and
prolonged marrow suppression lasting for months.

CHRONIC PANCREATITIS
Introduction
Definition
-Continuing chronic inflammatory process of the pancreas, characterized by irreversible morphological changes.

43
-This chronic inflammation can lead to chronic abdominal pain and/or impairment of endocrine and exocrine
function of the pancreas.
-Chronic pancreatitis usually is envisioned as an atrophic fibrotic gland with dilated ducts and calcifications.
-However, findings on conventional diagnostic studies may be normal in the early stages of chronic pancreatitis, as
the inflammatory changes can be seen only by histologic examination.
-By definition, chronic pancreatitis is a completely different process from acute pancreatitis.
- In acute pancreatitis, the patient presents with acute and severe abdominal pain, nausea, and vomiting. The
pancreas is acutely inflamed (neutrophils and edema), and the serum levels of pancreatic enzymes (amylase and
lipase) are elevated. Full recovery is observed in most patients with acute pancreatitis,
-In chronic pancreatitis, the primary process is a chronic irreversible inflammation (monocyte and lymphocyte) that
leads to fibrosis with calcification.
-The patient with chronic pancreatitis clinically presents with chronic abdominal pain and normal or mildly elevated
pancreatic enzyme levels; when the pancreas lose its endocrine and exocrine function, the patient presents with
diabetes mellitus and steatorrhea

Pathophysiology:
-The proposed pathologic mechanisms of chronic pancreatitis are:
-Intraductal plugging and obstruction (eg, Ethanol abuse, stones, tumors)
-Direct toxins and toxic metabolites: These act on the pancreatic acinar cell to stimulate the release of cytokines,
which stimulate the stellate cell to produce collagen and to establish fibrosis. Cytokines also act to stimulate
inflammation by neutrophils, macrophages, and lymphocytes (eg, ETOH, tropical sprue).
-Oxidative stress (eg, idiopathic pancreatitis)
-Necrosis-fibrosis (recurrent acute pancreatitis that heals with fibrosis)
-Ischemia (from obstruction and fibrosis), which is important in exacerbating or perpetuating disease rather than in
initiating disease
Autoimmune disorders:
-Chronic pancreatitis has been found in association with other autoimmune diseases, such as Sjögren syndrome,
primary biliary cirrhosis, and renal tubular acidosis.
Sex:
-Males are affected more commonly than females (6.7 vs. 3.2 per 100,000 populations.
-Alcohol-induced illness is more prevalent in males, idiopathic and hyperlipidemic-induced pancreatitis is more
prevalent in females, and equal sex ratios are observed in chronic pancreatitis associated with hereditary pancreatitis.
Age:
-In aggregate, the mean age at diagnosis is 46 years, plus or minus 13 years.
- In idiopathic chronic pancreatitis, a bimodal age distribution has been reported, designated as early-onset form
(median age 19.2 y) and late-onset form (median age 56.2 y).
Clinical presentation

History
-For most patients with chronic pancreatitis,
1. Abdominal pain
-Is the presenting symptom in most patients.
- Intermittent attacks of severe pain, often in the mid or left upper abdomen and occasionally radiating in a band like
fashion or localized to the mid back.
-The pain may occur either after meals or independently of meals, and tends to last at least several hours.
- In alcohol-induced disease, eventual cessation of alcohol intake may reduce the severity of pain.
-Variability in the pain pattern contributes to the delay in diagnosis and makes determining the effect of any
therapeutic intervention difficult.
2. Diarrhea
3. Weight loss.
-This may be due either to fear of eating (eg, postprandial exacerbation of pain) or due to pancreatic exocrine
insufficiency and steatorrhea.
-A small percentage of patients (20%) have painless chronic pancreatitis and present with signs or symptoms of
pancreatic exocrine or endocrine insufficiency.
Physical:
-In most instances, the standard physical examination non-revealing

44
-During an attack, patients may assume a characteristic position in an attempt to relieve their abdominal pain (eg,
lying on the left side, flexing the spine and drawing the knees up toward the chest).
-Funduscopic examination may reveal a milky white hue in the retinal blood vessels when hyperlipidemia is present
-Occasionally, a tender fullness or mass may be palpated in the epigastrium, suggesting the presence of a pseudo
cyst or an inflammatory mass in the abdomen.
-Clinical characteristics include:-
Diffuse enlargement of the pancreas
Diffuse and irregular narrowing of the main pancreatic duct
Increased circulating levels of gamma globulin
 The presence of autoantibodies, and a possible association with other autoimmune diseases.
Fibrosis with lymphocytic infiltration is seen on pathology.
-Alcohol is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic and 10% of cases
are due to rare diseases
-Although a linear relationship exists between the amount of alcohol ingested and the risk of developing chronic
pancreatitis, the fact that fewer than 10% of people with alcoholism actually develop the disease is not understood.
-In the affected gland, alcohol appears to increase protein secretion from acinar cells while decreasing fluid and
bicarbonate production from ductal epithelial cells.
-The resulting viscous fluid results in proteinaceous debris becoming inspissated within the lumen, causing ductular
obstruction, upstream acinar atrophy, and fibrosis.
-GP2, which is secreted from the acinar cell and homologous to a protein involved in renal tubular casts, is an
integral component of these ductal plugs.
-Lithostathine (formerly pancreatic stone protein), which also is produced by acinar cells, accounts for about 5% of
secretory protein and inhibits the growth of calcium carbonate crystals. Abnormal lithostathine S1, whether inherited
or acquired through trypsin digestion, appears to play a role in stone formation; it is insoluble at the neutral pH of
pancreatic juice and is the major constituent of pancreatic stones.
-A competing theory suggests that the persistent demands of metabolizing alcohol (and probably other xenobiotics,
such as drugs, tobacco smoke, environmental toxins, and pollution) causes oxidative stress within the pancreas and
may lead to cellular injury and organ damage, especially in the setting of malnutrition.
-Both oxidative and nonoxidative pathways metabolize ethanol. Alcohol dehydrogenase oxidatively metabolizes
ethanol first to acetaldehyde and then to acetate.
-When the alcohol concentration increases, cytochrome P-450 2E1 is induced to meet the metabolic demands.
Although these reactions occur principally in the liver, further increases in ethanol concentration induce pancreatic
cytochrome P-450 2E1, and the level of acetate within the pancreas begins to approach that observed in the liver.
Reactive oxygen species produced by this reaction may overwhelm cellular defenses and damage important cellular
processes.
-Whatever the etiology of chronic pancreatitis, pancreatic fibrogenesis appears to be a typical response to injury.
-Patients with advanced disease (ie, patients with steatorrhea) exhibit decreased subcutaneous fat, temporal wasting,
sunken supraclavicular fossa, and other physical signs of malnutrition.

Causes
-The cause of chronic pancreatitis usually is metabolic in nature.
1. Excessive alcohol consumption is the most common cause
2. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance, accounting for about 1% of
cases.
3. Cystic fibrosis, one of the most common genetic abnormalities, is an autosomal recessive disorder accounting for
a small percent of patients with chronic pancreatitis.
-The cystic fibrosis transmembrane regulator (CFTR) gene transcribes a protein important in regulating chloride
transport across cellular membranes. Can lead to chronic pancreatitis associated with classic pulmonary disease to
chronic pancreatitis associated with relatively normal respiratory function.
4. Hyperlipidemia (usually type I and type V) also may cause chronic pancreatitis; however, it usually presents
with repeated attacks of acute pancreatitis.
5. Hypercalcemia due to hyperparathyroidism now is a rare cause of chronic pancreatitis
6. Nutritional or tropical, chronic pancreatitis
7.Medications are an infrequent, or possibly under recognized, cause of chronic pancreatitis.
8. Idiopathic chronic pancreatitis, which accounts for approximately 30% of cases, has been subdivided into
early-onset and late-onset forms arbitrarily.

45
9. Obstruction of the flow of pancreatic juice can cause chronic pancreatitis. Obstructive forms account for less
than 10% of cases and may be congenital or acquired.
-Congenital abnormalities or Acquired obstructive forms typically result from blunt abdominal trauma or accidents.
10. Autoimmune pancreatitis is uncommon and accounts probably for less than 1% of cases of chronic
pancreatitis.

DDX
1. Ampullary Carcinoma
2. Cholecystitis
3. Crohn Disease
4. Gastritis, Chronic
5. Intestinal Perforation
6. Mesenteric Artery Ischemia
7. Myocardial Infarction
8. Pancreatic Cancer
9. Peptic Ulcer Disease
10. Pneumonia, Community-Acquired

Lab Studies:
1. Serum amylase and lipase levels
-slightly elevated
-high levels are found only during acute attacks of pancreatitis.
NB. Chronic pancreatitis, atrophy of the pancreatic parenchyma can result in normal serum enzyme levels
and low concentrations of serum trypsin
2. Serum calcium and Triglyceride levels.
-This is usually to determine etiology of the chronic pancreatitis
3. Random blood sugar-endocrine insufficiency
-Maldigestion and malabsorption do not occur until more than 90% of the pancreas has been destroyed
-Steatorrhea is a manifestation of advanced chronic pancreatitis, and neither qualitative nor quantitative fecal fat
analysis can detect early disease
4. Pancreatic function tests

Direct tests:
Lundh’s Test
-Most sensitive and can detect chronic pancreatitis early
-Determination in duodenal aspirates
- Intubation of the duodenum with a Dreiling tube with aspiration of gastric and duodenal contents.
-Exogenous secretin with cholecystokinin (CCK) or a test meal (Lundh meal).
-Is used to achieve maximal stimulation of the pancreas.
-The output of pancreatic bicarbonate, protease, amylase, and lipase then is measured in the duodenal aspirates..
Determination in pancreatic juice
-Peformed in conjunction with (ERCP).
-The pancreatic duct is freely cannulated, an exogenous secretagogue is administered as above, and the pancreatic
juice then is aspirated out of the duct as it is produced. The output of pancreatic bicarbonate, protease, amylase, and
lipase are measured.

Indirect tests:
Tests of fat malabsorption
-For a quantitative measurement of fat absorption, a 72-hour fecal fat collection is often performed and is considered
the criterion standard.
-Qualitative tests include the acid steatocrit test and Sudan III stain of stool, but these tests are less reliable.
-Instruct patients to consume a normal amount (80-100 g/d) of fat before and during the collection.
-Based on this intake, fecal fat excretion in healthy individuals should be less than 7 g/d.
Feccal chymotrypsin

46
-One of the simpler screening tests for exocrine pancreatic insufficiency is measurement of stool chymotrypsin
concentration.
-In patients with steatorrhea, a low stool chymotrypsin concentration suggests the likelihood of exocrine
insuficiency

Testing for integrity of mucosa

D-xylose test
-If the 72-hour fecal fat collection results demonstrate fat malabsorption, the D-xylose test is used to document the
integrity of the intestinal mucosa.
-Facilitated diffusion in the proximal intestine primarily absorbs D-xylose.
-Approximately half of the absorbed D-xylose is excreted in urine, unmetabolized. If the absorption of D-xylose is
impaired due to a luminal factor (eg, bacterial overgrowth) or a reduced or damaged mucosal surface area (eg,
surgical resection, celiac disease), urinary excretion is lower than normal.
-Cases of pancreatic insufficiency usually result in normal urinary excretion because the absorption of D-xylose still
is intact.

Tests of carbohydrate absorption

Hydrogen breath test
-Patients are given an oral solution of lactose.
-In cases of lactase deficiency, colonic flora digests the unabsorbed lactose, resulting in elevated hydrogen content
in the expired air.
-Bacterial overgrowth or rapid transit also can cause an early rise in breath hydrogen, necessitating the use of
glucose instead of lactose to make a diagnosis.
-Up to 18% of patients are hydrogen nonexcretors, causing a false-negative test result.

Imaging Studies:
1. Abdominal x-ray:
-Pancreatic calcifications, often considered pathognomonic of chronic pancreatitis, are observed in approximately
30% of cases.
-The calcifications form within the ductal system—initially in the head, and later in the body and tail, of the gland.
Calcium deposition is most common with
Alcoholic pancreatitis
Hereditary pancreatitis
Tropical pancreatitis; however, it is rare in idiopathic pancreatitis.
2. CT-Scan
-Although it excels at depicting the morphologic changes of advanced chronic pancreatitis
-The subtle abnormalities of early-to-moderate chronic pancreatitis are beyond its resolution, and a normal finding
on this study does not rule out chronic pancreatitis.
-Its used for complications of the disease and is useful in planning surgical or endoscopic intervention.
- The sensitivity and the specificity of CT scan are 80% and 85%, respectively.
3. ERCP
-Provides the most accurate visualization of the pancreatic ductal system and has been regarded as the criterion
standard for diagnosing chronic pancreatitis. Limitation of ERCP is that it cannot be used to evaluate the pancreatic
parenchyma.
-Its also invasive, expensive, requires complete opacification of the pancreatic duct to visualize side branches, and
carries a risk (operator-dependent) of pancreatitis.
4. MRCP
-Imaging provides information on the pancreatic parenchyma and adjacent abdominal viscera
- MRCP uses heavily T2-weighted images to visualize the biliary and pancreatic ductal system.
-The use of secretin during the study enhances the quality of the pancreatogram.
-Accuracy is improving, and MRCP is relatively safe, reasonably accurate, noninvasive, fast, and very useful in
planning surgical or endoscopic intervention.
5. Endoscopic U/S
-May be the best test for imaging the pancreas but requires a highly skilled gastroenterologist.

47
The most predictive endosonographic feature is the presence of stones. Other suggestive features include the
following: visible side branches, cysts, lobularity, an irregular main pancreatic duct, hyperechoic foci and strands,
dilation of the main pancreatic duct, and hyperechoic margins of the main pancreatic duct.
-Endoscopic ultrasonography may be as sensitive and specific as tube tests for both mild disease and advanced
disease, especially when combined with fine needle aspiration or trucut biopsy

MANAGEMENT
Medical Care:
1. Behavior modification
-Cessation of alcohol consumption and tobacco smoking are important.
-In early-stage alcohol-induced chronic pancreatitis, lasting pain relief can occur after abstinence from alcohol.
Tobacco smoking is a strong and independent risk factor for chronic alcoholic pancreatitis..
2. Pancreatic healing
-The benefit of antioxidants in the early stages of chronic pancreatitis is still controversial- Glutathione, vitamin A
and C
3. Alleviation of abdominal pain
Causes of pain in chronic pancreatitis.
Acute disease with inflammation and pseudo cyst formation
Obstruction of the pancreatic duct by strictures or stones -increased pressure and pain.
Pancreatic ischemia
-Diagnostic tests necessary to identify an anatomical explanation for the pain and appropriate treatment.
- If no anatomical explanation, medical therapy can be attempted.
-This therapy includes pain control with analgesic agents and a trial of noncoated pancreatic enzymes.
-The impetus for using exogenous pancreatic enzymes to reduce pain begins with the hypothesis that stimulation of
the pancreas by food causes pain. CCK is one of the possible mediators of this response.
-When exogenous pancreatic enzymes are taken with a meal, CCK-releasing factors are degraded and CCK release
in response to a meal is reduced
-This decreases pancreatic stimulation and pain.
-This occurs in nonalcoholic patients with early chronic pancreatitis and requires the use of uncoated preparations.
-Severe, intractable pain, celiac ganglion blockade can be considered.
-CT-guided and EUS-guided celiac axis block may enhance safety and improve the efficacy of treatment in as many
as 40% of cases.
Analgesics
-NSAIDS-Acetaminophen
-Opiods-Tramadol
-Octreotide (Sandostatin) -- An 8-amino acid sequence containing the active portion of somatostatin. Subcutaneous
injection of octreotide at 200 mcg tid provided relief of pain in 66% of patients. Note that 35% of the control group
also experienced pain relief.
-Amitriptyline hydrochloride (Elavil) -- Analgesic for certain chronic and neuropathic pain25-75 mg PO qd
4. Restoration of digestion and absorption
-Although reduced fat intake is often recommended in patients with chronic pancreatitis, the clinical benefit is
unknown.
-Medium chain triglycerides are directly absorbed by the small intestine without a requirement for digestion by
lipase or micellar solubilization.
- To supply both lipids and calories, medium chain triglycerides can be used in patients with severe fat
malabsorption.
- There is occasionally sufficient loss of fat-soluble vitamins to cause disease.
- Enteric-coated preparations protect lipase from inactivation by gastric acid.
-Uncoated preparations are often less costly and adequate to relieve steatorrhea. Reducing gastric acid secretion may
enhance the effectiveness of uncoated preparations. -Some of the recombinant enzymes are resistant to acidic
denaturation.
-To provide adequate mixing with food, enzymes should be ingested during and just after a meal.
-The most serious adverse effects (ie, colonic strictures) were observed with coated preparations that contained high
concentrations of enzymes.
-Cobalamin or vitamin B-12 is absorbed complexed to intrinsic factor in the terminal ileum.

48
-Some vitamin B-12 absorption that is independent of intrinsic factor occurs throughout the small bowel. When
vitamin B-12 enters the stomach, it binds to a protein known as haptocorrin or R-protein. The haptocorrin is
proteolytically degraded in the small intestine by pancreatic enzymes and released vitamin B-12 then binds to
intrinsic factor. In patients with pancreatic insufficiency, vitamin B-12 can remain bound to haptocorrin and is not
available for absorption by the terminal ileum. Although vitamin B-12 malabsorption can be demonstrated in
patients with chronic pancreatitis, it rarely causes clinical vitamin B-12 deficiency.
-Pancrelipase (Cotazym, Zymase) - Assists in digestion of protein, starch, and fat. Used to treat painful chronic
pancreatitis
5. Management of any endocrine insufficiency-DM

SURGICAL CARE
-Anatomical complication that is correctable by a mechanical intervention exists.
 Pancreatic pseudo cyst
Abscess, fistula, ascites
Fixed obstruction of the intrapancreatic portion of the distal common bile duct
 Stenosis of the duodenum with gastric outlet obstruction
Variceal hemorrhage due to splenic vein thrombosis.
-Depending on the individual case, the appropriate intervention may involve endoscopic, radiologic, or surgical
techniques.
Endoscopic treatment of chronic pancreatitis-Decompressing an obstructed pancreatic duct -pain relief
 Papillary stenosis: In a subset of patients with chronic pancreatitis, the papillary sphincter pressure
and pancreatic ductal pressure are increased. A pancreatic duct sphincterotomy will facilitate drainage,
reduce ductal pressures, and may help alleviate pain
Pancreatic duct strictures: pancreatic sphincterotomy, dilating the stricture, and placing a stent.
Pancreatic duct stones: In addition to various endoscopic techniques, extracorporeal shockwave lithotripsy
often is necessary to break up impacted or large stones into smaller pieces suitable for removal.
 Pancreatic pseudo cyst- transpapillary stents, for communicating cysts. Noncommunicating pseudo cysts
that bulge into the foregut and have a mature wall less than 1 cm thick are treatable by endoscopic
transduodenal or transgastric pseudocystostomy
Radiologic treatment of chronic pancreatitis:
-. If a communication exists between the pancreatic ductal system and the pseudo cyst, percutaneous drainage may
create a persistent pancreaticocutaneous fistula, especially if the duct has a stricture downstream from the site of the
disruption.
-If the anatomy of the pseudo cyst does not lend itself to transpapillary, transgastric, or transduodenal endoscopic
drainage, then percutaneous drainage under ultrasound or CT guidance is an option.
Surgical treatment of chronic pancreatitis:
-The choice of operation depends on the clinical problem and preoperative assessment of the abnormality.
- In general, the approach aims either to improve pancreatic duct drainage or to resect the diseased organ.
Pancreatic duct drainage: In patients with a dilated pancreatic duct, a Roux-en-Y side-to-side
pancreaticojejunostomy is indicated.
Pancreatic resection:
-If the disease is limited to the head of the pancreas, a Whipple operation (pancreaticoduodenectomy) can produce
good results. In patients with intractable pain and diffuse disease with nondilated ducts, a subtotal or total
pancreatectomy can be offered; however, pancreatic function and quality of life are impaired after these procedures,
and the operative mortality rate of total pancreatectomy is about 10%. Pain is treated successfully in approximately
70% of cases.

Total pancreatectomy and islet autotransplantation:

In selected patients, the long-term morbidity caused by diabetes following total pancreatectomy can be avoided.
This involves harvesting the islets from the resected pancreas and injecting them into the portal system, which then
lodges them in the liver

CHRONIC RENAL FAILURE

49
Definition
-Chronic renal failure (CRF) is characterized by progressive destruction of renal mass and function due to
irreversible sclerosis and loss of nephrons.
-CRF is reserved more specifically for patients whose GFR is less than 30 cc/min.
-Chronic renal insufficiency (CRI) term for patients with mild-to-moderate renal impairment, whose GFR falls at
30-90 cc/min.
-End-stage renal disease (ESRD), usually with signs and symptoms of uremia, and GFR less than 10 cc/min.
-The Kidney Disease Outcomes -Quality Initiative (K/DOQI) classification of chronic kidney disease
Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)
Stage 2: Mild reduction in GFR (60-89 mL/min)
Stage 3: Moderate reduction in GFR (30-59 mL/min)
Stage 4: Severe reduction in GFR (15-29 mL/min)-CRF
Stage 5: ESRD (GFR <15 mL/min)
Pathophysiology:
-Approximately 1.2 million nephrons are present in each kidney, each contributing to the total GFR.
-The kidney has an innate ability to maintain GFR by hyperfiltration and compensatory hypertrophy of the
remaining healthy nephrons.
- Urea and creatinine start to show significant increases in only after total GFR has decreased to 50%.As the GFR
falls to less than ~20% of normal, symptoms of uremia may begin to occur.
-Nephrons hyperfiltration and hypertrophy, although beneficial, may be a major cause of progressive renal
dysfunction.
-This is due to increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and
segmental glomerulosclerosis and eventually to global glomerulosclerosis.
-Factors that may accelerate glomerular injury
1) Systemic hypertension
2) Acute insults from nephrotoxins or decreased perfusion
3) Proteinuria
4) Increased renal ammonia genesis with interstitial injury
5) Hyperlipidemia
6) Hyperphosphatemia with calcium phosphate deposition
7) Decreased levels of nitrous oxide

Mortality/Morbidity:
The 5-year survival rate for a patient undergoing chronic dialysis approximately 35%.
This is approximately 20% in patients with diabetes.
Age:
In US, the highest incidence of ESRD occurs in those older than 65 years. The elderly population also is the most
rapidly growing ESRD population in the United States.
NB After age 30 years progressive physiological glomerulosclerosis occurs, with GFR (and creatinine clearance
[CrCl) falling linearly at a rate of approximately 8 cc/min/1.73 m2/year from a maximal GFR of 140 cc/min/1.73 m2.
Aging also results in concomitant progressive physiological decrease in muscle mass such that daily urinary
creatinine excretion also decreases; this combination of factors results in constant serum creatinine values over time
in a given individual, despite a decrease in CrCl (and GFR)

Causes of Chronic renal failure

1. Diabetic Nephropathy
2. Hypertensive nephropathy
3. Vascular disease
Renal artery stenosis
 Cytoplasm pattern antineutrophil cytoplasmic antibody (C-ANCA)–positive vasculiditis
 Perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides
 Antineutrophil cytoplasmic antibody (ANCA)–negative vasculitides
 Hypertensive nephrosclerosis
4. Chronic Primary glomerular disease
Membranous nephropathy

50
  Immunoglobulin A (IgA) nephropathy
 Focal and segmental glomerulosclerosis (FSGS)
 Minimal change disease
 Membranoproliferative glomerulonephritis
 Rapidly progressive (crescentic) GN
5. Chronic Secondary glomerular disease
Post infectious glomerulonephritis-endocarditic, hepatitis B and C, syphilis, HIV, parasitic infection, TB.
 Amyloidosis, light chain deposition disease
 Neoplasm-lympomas
 Thrombotic thrombocytopenic purpura (TTP)
 Hemolytic-uremic syndrome (HUS)
 Henoch-Schönlein purpura
 Alport syndrome
 Reflux nephropathy
6. Connective tissue diseases.
Systemic lupus erythematosus
 Rheumatoid arthritis
 Mixed connective tissue disease
 Scleroderma
 Goodpasture syndrome
 Wegener granulomatosis
7. Tubulointerstitial disease
 Drugs (e.g., sulfa, allopurinol), gold, penicillamine, Chronic NSAIDS
 Chronic infection (viral, bacterial, parasitic)
  Sjögren syndrome
  chronic hypokalemia
  chronic hypercalcemia
  Sarcoidosis
  Multiple myeloma cast nephropathy
  Heavy metals
  Radiation nephritis
 Cystinosis
8. Polycystic kidney disease
9. Urinary tract obstruction
Urolithiasis, benign prostatic hypertrophy, tumors, retroperitoneal fibrosis, urethral stricture, neurogenic bladder

Clinical presentation
History:
Complaints referred to the kidneys themselves are often conspicuously absent in CRD, thus high index of suspicion
is required.
-Patient may just complaint of general fatigue, or just feeling ‘unwell’.
Some patients may present with complaints related to the etiology-DM, Reflux disease, and infections
Many patients present with uraemic symptoms
-Of special importance in establishing the etiology of CRD is a history of
 Hypertension
Diabetes
Systemic infectious
 Inflammatory, or metabolic diseases
Exposure to drugs and toxins- esp. NSAIDS (usage frequently underestimated or denied by the patient),
gold, penicillamine, antimicrobials, lithium, and ACE inhibitors.
Family history of renal and urologic disease.
Severity of CRF-Uraemic symptoms
-GIT- appetite, diet, nausea, and vomiting, hiccupping, -
-CVS-shortness of breath, edema, weight change,
-Musculoskeletal-muscle cramps

51
-Skin-pruritus
CNS-mental acuity and activities of daily living are especially helpful.
Resp-pulm edema BELOW

On physical examination
-General condition-sick looking, propped up in bed-pulm edema
-Facial puffiness or wasted or obesity-DM
-Examination for edema
-Uraemic frost, dry skin, hyperpigmentaion, dialysis scars
-Vital signs esp. blood pressure
-Fundoscopy
-CVS exam-precordial examination
-Abdomen-examination of the abdomen for bruits and palpable renal masses
-Neurologic examination for the presence of asterixis, muscle weakness, and neuropathy.
- In addition the evaluation of prostate size in men, and potential pelvic masses in women should be undertaken
-Patients whose renal adaptation maintains a GFR of 70-100 cc/min and those with CRI (GFR >30 cc/min) generally
are entirely asymptomatic and do not experience clinically evident disturbances in water or electrolyte balance or
endocrine/metabolic derangements.
These disturbances generally become clinically manifest through the stages of CRF (GFR <30 cc/min) and ESRD
(GFR <10 cc/min).
Uremic manifestations in patients with ESRD are felt to be secondary to accumulation of toxins

Investigations
Lab Studies:
1. FHG- Norm chromic normocytic anemia
- WBC-chronic infections
2. Elevated serum urea and creatinine
3. Electrolytes-Hyperkalemia, low serum bicarbonate, hypocalcemia, hyperphosphatemia, hyponatremia (in
ESRD with free-water excess)
4. Liver function tests-Hypoalbuminemia in patients who are nephrotic and/or malnourished
5. Urinalysis
 RBC casts, suggests proliferative GN
Pyuria or/and WBC casts -interstitial nephritis (particularly if eosinophiluria is present) or urinary tract
infection.
Dipstick proteinuria may suggest glomerular or a tubulointerstitial problem.
 Total 24-hour urinary protein excretion. A value of greater than 2.0 g is considered to be within glomerular
range, and a value greater than 3.0-3.5 g is within the nephrotic range; less than 2.0 is characteristic of
tubulointerstitial problems.
Persistence of >17 mg albumin per gram of creatinine in adult males and 25 mg albumin per gram of
creatinine in adult females usually signifies chronic renal damage, irrespective of GFR, and can be
followed in monitoring natural history and response to therapy, especially in CRD consequent to diabetes,
hypertension, or glomerulonephritis
6. Serum complement levels - May be depressed with some glomerulonephritides
7. Fasting blood sugar and lipid profiles

Others as indicated:
8. Serum and urine protein electrophoresis to screen for a monoclonal protein possibly representing multiple
myeloma.
Also serum uric acid.
9. Antinuclear antibodies (ANA), double-stranded DNA antibody levels to screen for systemic lupus
erythematosus
10. C-ANCA (screen Wegener granulomatosis) and P-ANCA levels -polyarteritis nodosa or microscopic
polyangiitis
11. Anti–glomerular basement membrane (anti-GBM) antibodies - Highly suggestive of underlying
Goodpasture syndrome

52
 12. Hepatitis B and C, HIV, Venereal Disease Research Laboratory (VDRL) serology - Conditions associated
with some glomerulonephritides.
13. PSA levels-Elderly male and prostatism

Imaging Studies:
1. Plain abdominal x-ray
Particularly useful to look for radio-opaque stones or nephrocalcinosis
2. Renal ultrasound
- Small echogenic kidneys are observed in advanced renal failure. Except in-Diabetic nephropathy, HIVAN,
Polycystic kidney disease, Amyloid kidney, Gauchers
- Kidneys usually are normal in size in advanced diabetic nephropathy, where affected kidneys initially are enlarged
from hyperfiltration.
-This is a useful test to screen for hydronephrosis, which may not be observed in early obstruction, or involvement
of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Retrograde pyelogram may be indicated if a high
index of clinical suspicion for obstruction exists despite a negative study finding.
Renal artery Doppler to check the state of the renal arteries.
3. Intravenous pyelogram - Not commonly used because of potential for intravenous contrast renal toxicity; often
used to diagnose renal stones
4. Voiding cystourethrogram (VCUG) - Criterion standard for diagnosis of vesicoureteral reflux
5. Renal radionuclide scan
Estimate the residual renal function in severe hydronephrosis.
6. CT scan
CT scan is useful to better define renal masses and cysts usually noted on ultrasound. Also, it is the most
sensitive test for identifying renal stones. IV contrast-enhanced CT
scans should be avoided in patients with renal impairment to avoid acute renal failure; this risk significantly
increases in patients with moderate-to-severe CRF. Dehydration also markedly increases this risk.
The Cockcroft-Gault formula
For estimating Creatinine Clearance should be used routinely as a simple means to provide a reliable approximation
of residual renal function in all patients with CRF. The formulas are as follows:
CrCl (male) = ([140-age] X weight in kg)
Serum creatinine
Female GFR = ([140-age] X weight in kg) X0.85
Serum creatinine
Renal Biopsy
Performed most often with ultrasound guidance .It generally is indicated when renal impairment and/or proteinuria
approaching the nephrotic range are present and the diagnosis is unclear after appropriate other workup. It is not
indicated in the setting of small echogenic kidneys on ultrasound because these are severely scarred and represent
chronic irreversible injury. The most common complication of this procedure is bleeding, which can be life
threatening in a minority of occurrences.
Histologic Findings:
Renal histology in CRF reveals findings compatible with the underlying primary renal diagnosis and, generally,
findings of segmental and globally sclerosed glomeruli and tubulointerstitial atrophy, often with tubulointerstitial
mononuclear infiltrates.

Metabolic complications
Fluid overload
-Results from failure of sodium and free water excretion usually at GFR <10-15/min.
-Patients present with peripheral and, not uncommonly, pulmonary edema and hypertension
Normochromic normocytic anemia
-Principally develops from decreased renal synthesis of erythropoietin
-It becomes more severe as GFR progressively decreases with the availability of less viable renal mass.
-No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding is increased from the uremia-
induced platelet dysfunction
Secondary hyperparathyroidism

53
-Develops because of hypocalcaemia, decreased of renal calcitriol and hyperphosphatemia.
-Calcium and calcitriol are primary feedback inhibitors, and the latter is a stimulus, to parathyroid hormone (PTH)
synthesis and secretion.
-Phosphate retention begins in early CRF; when GFR falls, less phosphate is filtered and excreted but serum levels
do not rise initially because of increased PTH secretion, which increases renal excretion.
-As GFR falls into the moderate-to-severe stages of CRF, hyperphosphatemia develops from the inability of the
kidneys to excrete the excess dietary intake. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-
hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 cc/min.
Hypocalcaemia
-Develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels and
possibly from calcium binding to elevated serum levels of phosphate.
-Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently
trigger PTH synthesis and secretion
-The persistently elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.
-If serum levels of PTH remain elevated, a high–bone turnover lesion, known as osteitis fibrosa, develops. This is
one of several bone lesions, which as a group are commonly known as renal osteodystrophy. These lesions develop
in patients with severe CRF and are common in those with ESRD.
Osteomalacia and adynamic bone disease types.
-Osteomalacia is observed primarily from aluminum accumulation, is markedly less common adynamic bone
disease.
-Adynamic bone disease represents the predominant bone lesion in patients on chronic peritoneal dialysis and is
increasing in frequency.
-Dialysis-related amyloidosis from beta2-microglobulin accumulation in patients who have required chronic dialysis
for at least 8-10 years is another form of bone disease that manifests with cysts at the ends of long bones
-Hyperkalemia
Usually develops when GFR falls to less than 20-25 cc/min because of decreased ability of the kidneys to excrete
potassium.
It can be observed sooner in patients
Potassium-rich diet
 Low serum aldosterone levels are low
 Type IV renal tubular acidosis
 Diabetes nephropathy
 ACE inhibitors use.
 NSAIDs use.
Hyperkalemia in CRF can be aggravated by extracellular shift of potassium, such as occurs in the setting of
acidemia or from lack of insulin.
-Metabolic acidosis
often is mixed, non–anion gap and anion gap, the latter observed generally with severe CRF that is approaching or at
ESRD but with the anion gap generally not higher than 20 mEq/L.
In CRF, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the endogenous acid
into the urine in the form of ammonium. In very advanced CRF, accumulation of phosphates, sulphates, and other
organic anions are the cause of the small anion gap.
Other manifestations of uremia in ESRD
Accumulation of urea, hippurates, end products of nucleic acid metabolism, polyamines, myoinositol, phenols,
benzoates, and indoles, among others

a) Pericarditis
Can complicate with cardiac tamponade, possibly resulting in death
ECG abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis may be
accompanied by the accumulation of pericardial fluid that is readily detected by echocardiography and that
sometimes leads to cardiac tamponade. Pericardial fluid in uremic pericarditis is more often hemorrhagic than in
viral pericarditis.
b) Other CVS-CCF, Ischemic heart disease, Hypertensive heart disease, Arterial hypertension, vascular calcification,
atherosclerosis
c) Encephalopathy –
Can progress to coma and death. memory and concentration and sleep disturbance

54
d) Peripheral neuropathy
Initially, sensory nerves are involved more than motor nerves, lower extremities more than upper and distal portions
of the extremities more than proximal.
The “restless legs syndrome” is characterized by ill-defined sensations of discomfort in the legs and feet requiring
frequent leg movement
If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle
weakness and loss of deep tendon reflexes. Accordingly, evidence of peripheral neuropathy is a firm indication for
renal replacement therapy
f) GI symptoms
- Anorexia, nausea, vomiting, diarrhea, Uraemic ulcers.
e) Skin manifestations
-Parlor, hyperpigmentaion, Uraemic frost, dries skin, pruritus and echymosis.
- Skin necrosis can occur as part of the calciphylaxis syndrome, which also includes subcutaneous, vascular, joint,
and visceral calcification in patients with poorly controlled calcium-phosphate product.
f) Musculoskeletal
Fatigue, increased somnolence, failure to thrive- Neuromuscular irritability, including hiccups, cramps, and
fasciculations/twitching of muscles, becomes evident at later stages. Asterixis, myoclonus, and chorea are common
in terminal uremia, which may also be associated with seizures and coma.
g) Malnutrition
h) Reproductive
-Men-Erectile dysfunction, decreased libido, and Women-amenorrhea estrogen levels are low, and amenorrhea and
inability to carry pregnancies to term are common manifestations of uremia. When the GFR has declined by ~30%
i) Haematological
-Prolongation of bleeding time
-decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness
- impaired prothrombin consumption
-abnormal bleeding and bruising;

MANAGEMENT
Medical Care: Medical care of the patients with CRF should focus on the following:
A. Treating pathologic manifestations of CRF
1. Anemia with erythropoietin
-Monitor iron stores by percent transferrin saturation (TSat) and serum ferritin.
-If patient is iron-deficient (TSat <20%; serum ferritin <100 µg/L), administer iron, 50–100 mg IV twice per week
for 5 weeks; if iron indices are still low, repeat the same course.
-Erythropoietin.50–150 units/kg per week IV or SC (once, twice, or three times per week) .Increase Hb by 1–2 g/dL
over 4-week period. Target Hb 11–12 g/dL
2. Hyperphosphatemia with dietary phosphate binders and dietary phosphate restriction
3. Hypocalcemia with calcium supplements +/- calcitriol
4. Hyperparathyroidism with calcitriol or vitamin D analogs
5. Volume overload with loop diuretics or ultrafiltration
6. Metabolic acidosis with oral alkali supplementation
7. Abnormal bleeding times and coagulopathy -desmopressin, cryoprecipitate, conjugated estrogens, and blood
transfusions, as well as EPO.
8. Greater risk for thromboembolic complications and receive appropriate anticoagulant prophylaxis when
indicated. Avoidance or dose adjustment of certain anticoagulants, such as fractionated low-molecular-weight
heparin, is necessary in CRD patients.
9. Uremic manifestations -with chronic renal replacement therapy (hemodialysis, peritoneal dialysis, or renal
transplantation):
Indications include
 Hyperkalemia > 6.5 and rising
 Metabolic acidosis-persistent
 Uraemic Pericarditis
 Encephalopathy
 Peripheral neuropathy
 GFR less than 10 cc/min

55
  Intractable volume overload
 Pulmonary oedema
 Failure to thrive and malnutrition
 Intractable gastrointestinal symptoms.
B. Delaying or halting progression of CRF
Treatment of the underlying condition if possible
1. Diet:
-Protein restriction early in CRF as a means to delay decline in GFR is controversial; however, as the patient
approaches ESRD, this is recommended to delay onset of uremic symptoms.
Patients with CRF who already are predisposed to becoming malnourished are at higher risk for malnutrition with
overly aggressive protein restriction.
-Malnutrition is a well-established predictor of increased morbidity and mortality in the ESRD population and must
be avoided if possible
-Phosphate restriction starting early in CR
-Potassium restriction
-Sodium and water restriction as needed to
Drugs
Phosphate binders
1) Lanthanum carbonates (Fosrenal)
Noncalcium, nonaluminum phosphate binder indicated for reduction of high phosphorus levels in patients with end-
stage renal disease. Directly binds dietary phosphorus in upper GI tract, thereby inhibiting phosphorus absorption
2) Calcium acetate (Calphron, PhosLo)
-Combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces.
3) Calcium carbonate (Caltrate, Oystercal)
-Successfully normalizes phosphate concentrations in patients with CRF
- Combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces.
4. Sevelamer (Renagel)
-. Binds dietary phosphate in the intestine, thus inhibiting its absorption. In patients on hemodialysis, it decreases the
frequency of hypercalcemic episodes relative to patients on calcium acetate treatment.
Control calcium level and PTH
-Calcitriol (Rocaltrol, Calcijex)
Used to suppress parathyroid production and secretion in secondary hyperparathyroidism and for treatment of
hypocalcemia in CRF by increasing intestinal calcium absorption.
Dose o.25 microgram/day
-Doxercalciferol (Hectorol) -- A vitamin D analog (1-alpha-hydroxyergocalciferol) that does not require activation
by the kidneys. Indicated for the treatment of secondary hyperparathyroidism

2. Treatment of hyperlipidemia

3. Aggressive blood pressure control to target value

Use of ACE inhibitors as tolerated, with close monitoring for renal deterioration and for) hyperkalemia (avoid in
advanced renal failure, bilateral renal artery stenosis [RAS], RAS in a solitary kidney

4. Aggressive glycemic control in patients with diabetes

5. Avoidance of nephrotoxins - IV radiocontrast, Drugs-NSAIDS, aminoglycoside

C.Timely planning for chronic renal replacement therapy
1. Early education regarding natural disease progression, different dialytic modalities, renal transplantation, patient
option to refuse or discontinue chronic dialysis

2.Timely placement of permanent vascular access (arrange for surgical creation of primary arteriovenous fistula, if
possible, and preferably at least 6 months in advance of anticipated date of dialysis)

3. Timely elective peritoneal dialysis catheter insertion avoid volume overload

Timely referral for renal transplantation

56
Consultations:
-Early nephrology referral (decreases morbidity and mortality)
-Renal dietitian
Vascular surgery for permanent vascular access
-General surgery for peritoneal catheter placement
Referral to renal transplant center in end-stage renal disease-
CNS DISEASE IN HIV INFECTION
-AIDS patients are susceptible to the same neurologic diseases as patients who do not have HIV infection.
-In addition, other CNS disease can be classified into:-
Opportunistic infection
Complications caused by HIV virus itself
Neoplasms in HIV
D.Drug used in HIV and opportunistic infection management.
A. Opportunistic infectious
1) Bacterial-TBM, atypical Mycobacteria
2) Viral-CMV, Herpes simplex virus, EBV
3) Fungal-Crytoptocococisis, histoplasmosis
4) Protozoa-Toxoplamosis, neurocysticercosis
5) Progressive Multifocal leukoencephalopathy (PML)
B.Complicated related to HIV virus itself.
1) The HIV-1–associated cognitive/motor complex or AIDS dementia complex (ADC),
2) Vacuolar myelopathy
3) Peripheral neuropathies.
4) Aseptic meningitis
C.Neoplasms
1) CNS lymphoma
2) Kaposi sarcoma
D.Drugs
1) Neuropsychiatric manifestation- -EFV
2) Peripheral neuropathy-Didanosine, stavudine, Zalcitabine
Others
1) Cerebrovascular diseases
2) Myopathies
Introduction.
-The manifestations of AIDS and its neurologic complications differ in children, whose immune and nervous
systems are infected at an immature stage, whether in utero, during delivery, or postpartum. CNS complications tend
to progress more rapidly in children, probably because of the inability of their immune systems to mount an
appropriate T-cell, B-cell, or cytokine response to the infection.
-Neurologic involvement in HIV infection is more frequent in children than in adults. It may take the form of a loss
of previously acquired intellectual and motor milestones or of developmental delay.
Pathophysiology
-When immune defenses are impaired, opportunistic infections arise, often from reactivation of previously acquired
organisms.
Other organisms, such as the JC or SV40 viruses that cause PML, may be activated directly by HIV gene products.
-The likelihood of a particular neurologic syndrome correlates with the clinical stage of HIV infection as reflected
by viral load, immune response, and CD4+ lymphocyte counts.
-This, in turn, is related to the severity of immunodeficiency and autoimmunity and to serum and tissue cytokine
levels.
-Manifestations at seroconversion are often subclinical but may include
Meningitis
 Acute encephalopathy with seizures, confusion, and delirium.
 Early peripheral nerve manifestations include isolated acute cranial nerve palsies and Guillain-Barré
syndrome.

TOXOPLASMOSIS

57
Introduction
-Toxoplasmosis is a disease caused by an obligate intracellular protozoan parasite termed Toxoplasma gondii. The
term was derived from the crescent shape of the parasite (toxon is Greek for arc) plus the name of the North African
rodent in which it was first observed, the gondii.
-It infects the nucleated cells of virtually all warm-blooded animals. Some species of felines are the definitive host
for sexual reproduction of the parasite. Asexual reproduction occurs in secondary hosts, such as rodents, livestock,
birds, and humans and culminates in the formation of tissue cysts, which persist for the lifespan of the secondary
host.
Routes of infection
-Human infection usually occurs via the oral or trans-placental route.
Consumption of raw or undercooked meat containing viable tissue cysts (principally lamb and pork), direct
ingestion of oocysts from contaminated soil and water, or consumption of unwashed vegetables has been common
sources of infection. Infection has occurred after drinking unpasteurized goat's milk.
-Transplacental infection occurs if the mother acquires an acute infection or if a latent infection is reactivated during
immunosuppression.

Pathology
-In adults, most T gondii infections are subclinical, but severe infection can occur in patients who are
immunocompromised, such as those with AIDS and malignancies.
-Affected organs include both the gray and white matter of the brain, retinae, alveolar lining of the lungs (where it
may mimic Pneumocystis carinii infection), heart, and skeletal muscle.
-AIDS-associated Toxoplasma encephalitis results from reactivation of chronic latent infection in more than 95% of
patients.
-Congenital toxoplasmosis may be associated with anomalies such as microcephaly, microphthalmia,
hydranencephaly, hydrocephalus secondary to aqueduct stenosis, porencephalic cyst, and periventricular
calcification.

Pathophysiology
-The T gondii organism is related to Plasmodium malariae and Cryptosporidium, Isospora, and Sarcocystis species.
These parasites form a group termed coccidian parasites, which have a characteristic method of host transmission.
The parasite can attach to any host cell in the body (except non-nucleated RBCs), and they can become invaginated,
forming a parasitophorous vacuole in which the organism resides.
-In definitive hosts, such as cats and other members of the feline family, sexual reproduction leads to oocyst
development in the intestinal lining.
-These oocysts are infective.
-They are hardy and can survive in temperate climates in moist soil and without direct sunlight for up to 1 year.
Infection then may occur when a secondary host (all other hosts including humans) ingests the oocysts.
-After intestinal transit, parasitemia and widespread dissemination occur throughout the body. This acute phase is
followed by a latent phase during which encystation occurs in various tissues, particularly in skeletal and cardiac
muscles and in the brain. Once within the host tissue, asexual multiplication ensues. The asexual cycle occurs in 2
forms. In immunocompetent but nonimmune hosts, multiplication of tachyzoites, producing small cysts, is rapid but
replication slows with the development of host immunity. -The bradyzoites, which divide slowly, remain dormant
within the cysts. These cysts are highly infective, and when cats ingest mice with the cysts, the life cycle of the
parasite is completed.
-In immunocompetent hosts, cysts containing live T gondii organisms cause no harm; most patients remain
asymptomatic but seropositive. However, if the immune system of the host declines, the cysts may reactivate,
causing disseminated infection that manifests as encephalitis, myocarditis, or chorioretinitis
-In immunocompromised patients, T gondii infection is potentially fatal. If seronegative, these patients can be
infected via the usual oral route or via transplantation of an organ. More commonly, infection results from
reactivation of latent tissue cysts.

CNS toxoplasmosis
-Patients with AIDS are at particular risk for developing disseminated toxoplasmosis, which more often manifests as
central nervous system (CNS) abnormalities.

58
-As many as 50% of patients with AIDS who are seropositive for T gondii develop encephalitis. Toxoplasmosis is
the most common cause of a focal brain lesion in patients with AIDS. The disease commonly localizes to the basal
ganglia, although other sites in the brain and spinal cord may be affected. A solitary focus may be seen in one third
of patients, but multiple foci are seen more commonly.
-Histologic findings in CNS toxoplasmosis include inflammatory solid or cystic granulomas secondary to glial
mesenchymal reaction with surrounding edema and microinfarcts resulting from focal vasculitis.

Clinical presentation of CNS disease.

History:
-The natural history of CNS toxoplasmosis includes the following:
Initially, constitutional symptoms and headache
 Later, confusion and drowsiness, seizures, focal weakness, and language disturbance
 Without treatment, progression to coma in days to weeks
Physical:
Personality and mental status changes are noted.
 Seizures, hemi paresis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be observed.
 Occasionally, symptoms and signs of a radiculomyelopathy predominate.
DDX
Ring enhancing lesions.
TBM
Cerebral abscesses
Other differentials
-All other opportunistic infections.
-Other CNS manifestations of HIV.
Investigations.
Lab Studies:
Serology
-Rising serum immunoglobulin G (IgG) titers are observed.
-An immunoglobulin M (IgM) antibody response is seen in cases of newly acquired toxoplasmosis-but in severe
immunesuppresion it may not rise.
-Antibody levels may be very low, especially in AIDS patients
Lumbar puncture
-may be contraindicated because of increased intracranial pressure. Cerebrospinal fluid (CSF) findings may include
elevated protein and variable glucose and WBC counts.
- (PCR) may be helpful in the diagnosis.
Imaging Studies:
-CT scan or MRI
-Single or multiple hypodense or hypointense lesions in white matter and basal ganglia with mass effects may be
observed.
-Lesions may enhance in a homogeneous or ring pattern with contrast.
-MRI is more sensitive than CT scan in detecting multiple lesions.
-Single lesions favor the diagnosis of lymphoma over that of toxoplasmosis.
Procedures:
-Indications for brain biopsy include the following:
Single mass lesion and negative serologic results
 No response to 14 days of empiric therapy
 Diagnostic yield of stereotactic biopsies increases with the number of specimens obtained.
Histologic Findings:
Lymphocytic meningitis, individual cyst-containing lesions
 Astroglial and microglial nodules
 Associated lymphocytic vasculitis

Management.
-Decision to treat a patient for CNS toxoplasmosis is usually empiric; standard therapy consists of combination
pyrimethamine, sulfadiazine, and folinic acid, which is often continued for life.
-In patients who cannot tolerate sulfa drugs, clindamycin may be used.

59
Acute therapy- Total duration for acute therapy is at least 6 weeks
Pyrimethamine
-200 mg PO day 1
-Then 50 mg (<60 kg body weight) to 75 mg (>60 kg) PO daily.
Sulfadiazine
-1g (<60 kg) to 1.5 g (>60 kg) PO QID
Leucovorin
-10–20 mg PO daily (can increase>50 mg)

Alternative therapy
a) Pyrimethamine (leucovorin)* and clindamycin 600 mg IV or PO q6h
b) TMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or PO BID
c) Pyrimethamine (leucovorin) plus Atovaquone 1.5g PO BID with meals (or nutritional supplement) and
d) Sulfadiazine 1–1.5g PO q6h Atovaquone 1.5 g PO BID with meals (or nutritional supplement)
e) Pyrimethamine (leucovorin)* and azithromycin 900–1200 mg PO QD

-For severely ill patients who cannot take oral medications TMP-SMX IV and Pyrimethamine PO
-Adjunctive corticosteroids (e.g., dexamethasone) should be administered when clinically indicated for treatment
of mass effect attributed to focal lesions or associated edema and discontinued as soon as clinically feasible
-Anticonvulsants should be administered to patients with a history of seizures

Chronic maintenance therapy (Secondary Prophylaxis)

First choice
• Sulfadiazine 500–1,000 mg PO QID plus pyrimethamine 25–50 mg PO QD plus leucovorin
10–25 mg by mouth daily
Second choice
• Clindamycin 300–450 mg PO every 6–8 hours plus pyrimethamine 25–50 mg PO QD plus leucovorin
10–25 PO QD
• Atovaquone 750 mg PO every 6–12 hours with or without pyrimethamine 25 mg PO QD plus leucovorin
10 mg PO QD

PERIPHERAL NEUROPATHY
DISTAL PAINFUL SENSORIMOTOR POLYNEUROPATHY
-Is the most common type of HIV-1 associated peripheral neuropathy. It usually develops during late HIV infection.

Pathophysiology:
-More than one pathophysiologic mechanism likely exists:
1) HIV may act directly by infecting dorsal root ganglion neurons. A direct relationship between the HIV-RNA load
and the severity of neuropathic pain has been shown
2) These neurons may also be injured by locally infiltrating activated macrophages that secrete neurotoxic cytokines
or other metabolites
3) Other factors may be involved, including nutritional and vitamin deficiencies.
4) Antiretroviral (eg, didanosine, stavudine, zalcitabine, rarely lamivudine)
-Antiretroviral toxic neuropathy (ATN), which occurs in up to 60% of patients and likely results from mitochondrial
dysfunction, has been recognized.
Clinical presentation
History:
Painful feet (including soles) that are sensitive to light touch
 Distal numbness
 Distal weakness in the more advanced stage
 Autonomic symptoms referable to urogenital and intestinal function
 Rare in otherwise healthy seropositive patients
Can be asymptomatic
Physical:
Panmodal distal sensory loss
 Mild distal weakness

60
 
Hyporeflexia or areflexia

Symmetric presentation

Autonomic signs (often can be elicited by careful evaluation)

DDX
Acute Inflammatory Demyelinating Polyradiculoneuropathy

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Diabetic Neuropathy

HIV-1 Associated Multiple Mononeuropathies

Nutritional Neuropathy

Toxic Neuropathy
 Uremic Neuropathy

Vitamin B-12 Associated Neurological Diseases
 Alcoholic neuropathy
Metabolic neuropathy
Paraneoplastic neuropathy
Paraproteinemic neuropathy
Cytomegalovirus (CMV)–related mononeuropathy
Human T-cell leukemia virus type 2 (HTLV-2)–related neuropathy
Vasculitic neuropathy

Lab Studies:
1. Cerebrospinal fluid
-Mildly elevated protein and Mild pleocytosis
2. Consider the following peripheral neuropathy workup depending on the specific clinical situation:
 HIV-RNA viral load
Complete blood count
Fasting blood sugar and 2-hour glucose tolerance test
 Hemoglobin A1C
Antinuclear antibody screen
Extractable nuclear antibody screen
 ESR
 U/E/C
 Paraproteinemia workup
Lyme serology
Thyroid function tests
Hepatitis workup
Vitamin B-12 and folic acid levels - In patients with B-12 levels below 350 pg/mL, homocysteine and
methylmalonic acid levels are more sensitive indicators of a deficiency; intrinsic factor or parietal cell
antibody testing and a Schilling test may be indicated.

3. Electromyography/nerve conduction study

-Symmetric features
-Sensory findings predominate over motor abnormalities
-Greater involvement of lower than upper extremities
-Distal axonal degeneration
-Significantly reduced sensory and motor amplitudes
-Normal-to-mildly reduced sensory and motor conduction velocities
-Normal-to mildly increased sensory and motor distal latencies
Histologic Findings
Histologic findings include the following:
-Axonal degeneration
-Some demyelination
-Prominent perivascular infiltration by T lymphocytes and macrophages
-Mild loss of dorsal root ganglion neurons, some found to harbor HIV by in situ polymerase chain reaction

61
Medical Care:
-Institution of HARTT is the mainstay of management. Avoid the drugs which may cause peripheral neuropathy.
-Treatment options fall into 2 groups: causal and symptomatic.
-Causal treatment
 Avoid neurotoxic medications, if possible.
Correct vitamin B12 and folate deficiency.
Consider thiamine replacement if malnourished

Drug Category:
Tricyclic antidepressants
-TCAs are effective in painful paresthesias. While dosages are similar, drugs in this category vary in their sedative
properties.
-Amitriptyline can be used if the patient suffers from insomnia, while nortriptyline and desipramine are better
choices when sedation becomes a problem.
Anticonvulsants
Gabapentin
-Gabapentin alleviates painful dysesthesias and spasms. It is well tolerated with a wide dose range
-Day 1-3: 300 mg PO qd
-Day 4-6: 300 mg PO bid
-Day 7-9: 300 mg PO tid
Lamotrigene
-Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane
-Monotherapy: 50-100 mg/d PO divided bid initial dose; 100-400 mg/d PO qd or divided bid maintenance; not to
exceed 500 mg/d
Carbamazepine
-Carbamazepine (Tegretol, Carbatrol, Epitol) Has antineuralgic effects; may depress activity of the nucleus
ventralis of the thalamus or decrease synaptic transmission or summation of temporal stimulation by limiting influx
of sodium ions across cell membrane or by other unknown mechanisms.
-Initial dose: 200 mg PO bid; increase gradually prn over 2-wk interval to 200 mg PO tid; target blood serum
concentrations are 4-12 mg/L
-Sustained release dosing: Therapeutic dose bid
Phenytoin

Topical anesthetics
-These agents are used to induce localized analgesia.
i) Lidocaine (Lidoderm 5% patch)
ii)Capsaicin (Dolorac, Zostrix) - Natural chemical derived from plants of Solanaceae family.
- Penetrates deep for temporary relief of minor aches and pains of muscles and joints associated in inflammatory
reactions.
-May render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons.
-Has demonstrated effectiveness in several studies of diabetic neuropathic pain and in other types of neuropathic
pain.

MULTIPLE PERIPHERAL MONONEUROPATHIES.

-Can occur in the setting of HIV-1 disease. The presentation can be similar to multiple mononeuropathies in the non-
HIV population.
Pathophysiology
-These neuropathies are typically inflammatory in nature and may involve single or multiple cranial or peripheral
nerves. EMG and nerve conduction studies show asymmetric multifocal involvement with axonal degeneration, and
CSF will show elevated protein level and pleocytosis.
-They vary with the stage of HIV infection. Early multiple mononeuropathy (MM) is usually self limited. Late MM
in a patient with a CD4 count <50 is usually related to CMV infection and can progress rapidly; PCR for CMV
should be sent if HIV-associated MM is suspected. Anti-CMV therapy must be initiated.
- The practitioner should also consider complications of herpes or lymphoma when treating this disease.
Clinical presentation.
History:

62
-The patient describes multifocal asymmetric sensory and motor complaints in the distribution of cranial nerves,
peripheral nerves, or nerve roots.
Physical:
Physical findings include:-
-Asymmetric weakness and reflex and sensory loss
-More severe involvement suggests CMV.
-Progression may change presentation from multifocal mononeuropathies to a more generalized polyneuropathy.
Causes:
-A limited form (1-2 nerves) presents in HIV-seropositive patients without AIDS and may have an autoimmune
origin.
A more generalized form (>2 nerves) presents in patients with AIDS. While CMV is often shown to be the cause,
the occurrence of clinical CMV in AIDS has declined with the advent of highly active antiretroviral therapy several
years ago

CRYPTOCOCCAL MENINGITIS
Introduction
-Cryptococcus neoformans is encapsulated yeast.
Virulence plays a relatively small role in determining the outcome of an infection varies among strains of
cryptococci.
-The crucial factor is the immune status of the host.
-The most serious infections usually occur in patients with defective cell-mediated immunity.
-For example, patients with:-
 AIDS
undergoing organ transplantation
Reticuloendothelial malignancy,
 Corticosteroid treatment (
Patients with sarcoidosis experience the most serious infections.
-With the global emergence of AIDS, the incidence of cryptococcosis is increasing and now represents a major life-
threatening fungal infection in these patients.
Mycology
-C neoformans has 2 varieties—neoformans and gattii. Worldwide, C neoformans vary neoformans serotype A
causes most cryptococcal infections in patients who are immunocompromised, including patients infected with HIV.
-For unknown reasons, C neoformans vary gattii rarely infects persons with HIV infection and other patients who
are immunosuppressed. Patients infected with C neoformans vary gattii are usually immunocompetent, respond
slowly to treatment, and are at risk for developing intracerebral mass lesions (eg, cryptococcomas).
-large polysaccharide capsule surrounds each cell.
Clinical presentation
-Meningitis and meningoencephalitis are the most common manifestations and are usually subacute or chronic in
nature.
-This form of infection invariably is fatal without appropriate therapy; death may occur from 2 weeks to several
years after the onset of symptoms.
-The clinical presentation and course of cryptococcal meningitis are variable, relating in part to underlying medical
conditions (eg, diabetes, sarcoidosis, glucocorticoid use) and the immune status of the host.
-The most common symptoms are headache and altered mental status, including personality changes, confusion,
lethargy, obtundation, and coma.
-Nausea and vomiting are frequent; fever and stiff neck are less common.
-Some patients who are HIV positive may have minimal or nonspecific symptoms at presentation. Patients are often
afebrile or have a mildly elevated temperature.
-Symptoms, including blurred vision, photophobia, and diplopia, may occur secondary to arachnoiditis, papilledema,
optic nerve neuritis, and chorioretinitis.
-Other findings include hearing defects, seizures, and ataxia, aphasia, and choreoathetoid movements.
-Dementia is potential sequelae and may indicate the presence of hydrocephalus as a late complication.
Investigations
-FHG and ESR
-Even with widespread disease, the routine laboratory tests (eg, leukocyte count, hematocrit, sedimentation rate)
may produce normal results.

63
Lumbar puncture
-CSF examination, which is essential in diagnosing CNS disease.
-Elevated opening pressure is associated with a poor prognosis.
Biochemistry-
-CSF glucose is depressed
-the protein concentration is usually elevated
-leukocyte counts are 20/mL or higher, with lymphocytes generally outnumbering neutrophils.
NB-CSF can be normal at times, which is observed in patients with AIDS who are unable to mount an adequate
inflammatory response or in persons with early asymptomatic infection
Smear and culture
-An India ink preparation
-If performed correctly, 25-50% of patients with cryptococcal meningitis show cryptococci.
Serology-CRAG
-Latex agglutination test to detect cryptococcal polysaccharide in serum or CSF, is an extremely important adjunct
to the diagnosis.
-In patients with meningitis, cryptococcal antigen is positive in more than 90% CSF and serum is positive in
approximately 75%.
-NB. Anticryptococcal antibodies do not have diagnostic significance, and low concentrations develop in a
significant percentage of healthy people.
Culturing
-May be appropriate even when the CSF profile is normal. In patients with an indolent waxing and waning course
-Diagnosis depends on detecting the organism by culture; therefore, always confirm positive smears with cultures.
-Culture centrifuged CSF specimens on 3 or more occasions to increase the yield.

Management
a) Intensive phase / Sterilization phase
-Initially, administer amphotericin B at 0.7-1 mg/kg/d for 2 weeks, with or without 2 weeks of flucytosine at 100
mg/kg/d,
b) Consolidation phase
-followed by fluconazole at 400 mg/d for a minimum of 10 weeks
c) Maintenance therapy
-Maintenance therapy by administering fluconazole at 200mg/d for life. Or until CD4 count greater than 200
Other aspects.
1-CSF pressure should be monitored during the initial phase of therapy, and elevated pressures should be controlled
by therapeutic CSF removal.
2-A repeat lumbar puncture is recommended in all patients 2 weeks after the initiation of therapy to ensure that CSF
cultures are responding ideally by culture. But can do India stain and CRAG
3-HAART should be started in the consolidation phase of therapy

Monitoring Amphotericin B
-Hydration of patient
-Hypokalemia and total body depletion of potassium can occur in patients with normal renal function
-Adjust doses to prevent associated renal failure
-Mild-to-moderate elevations of serum creatinine are common and reversible
-Renal dysfunction is dose dependent
-Monitor
 Renal function
Serum electrolytes (eg, magnesium, potassium)
Liver function
 CBC count and hemoglobin concentrations
-Resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for >7 d; hypoxemia, acute dyspnea,
and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate
time of amphotericin infusion from time of leukocyte transfusion)

64
CNS HIV-1 DISEASE
-Multiform CNS complications accompany HIV infection.
a) CNS disease related to HIV-1 itself.
 cognitive/motor complex or AIDS dementia complex (ADC)
 Aseptic meningitis
 Vacuolar myelopathy
 Peripheral neuropathies
b) Infectious
 Viral-Progressive multifocal leukoencephalopathy (PML) ,CMV encephalitis Herpes encephalitis
 Fungal-Cryptococcal ,coccidioidomycosis, histoplasmosis meningitis
 Bacterial-Tuberculous meningitis
 ProtozoaToxoplasmosis,Neurocysticercosis
c) Autoimmune
d) Neoplastic due to immunodeficiency include CNS lymphoma, Kaposi sarcoma
e) Cerebrovascular diseases
f) Some neurologic conditions are caused by antiretroviral drugs
Other drugs- Medications as causes are often overlooked including nonsteroidal anti-inflammatory drugs
(NSAIDs), trimethoprim/sulfamethoxazole, and intravenous immunoglobulin (IVIG).
g) In addition, AIDS patients are susceptible to the same neurologic diseases as patients who do not have
HIV infection.

Community acquired pneumonia

1. Strep pneumonia
2. Haemophilus influenzae
3. Staphylococcus aureus
4. Klebsiella pneumoniae
5. Occasionally: other gram-negative bacilli and anaerobic mouth organisms

Causes of atypical pnemonia

1. Legionella
2. Mycoplasma pneumoniae
3 Chlamydia pneumoniae
4. Respiratory viruses
5. Tuberculosis
6. Pneumocystis carinii
Hospital acquired pneumonia
1. Klebsiella
2. Enterobacter
3. Serratia
4. Acinetobacter
5. Pseudomonas aeruginosa
6. Staphylococcus aureus

Anti-pseudomonal
1.Ceftazidime,
2. cefepime, and
3. cefoperazone

Causes of recurrent heart failure:

FAILURE
F-Forgotten medication,
A-Arrhythmia/Anaemia,
I-Ischaemia/Infarct/Infection
L-Lifestyle (Na and fluid uptake),

65
 CVS PHYSICAL EXAMINATION.
-Pulse description
 Rate
 Volume
 Character
 Presence of other pulses
 Delay U-
CHARACTER
1.Pulsus parvus
2.Pulsus alterans
3.Collapsing pulse
4.Biesferens pulse
5.Dicrotic pulse
6.Pulsus bigeminus
Pulsus
7.Pulsusalternans
paradoxus
-Is a pattern in which there is regular alteration of the pressure pulse amplitude, despite a regular rhythm.
-It is due to alternating left ventricular contractile force, usually indicates severe impairment of left ventricular
function, and commonly occurs in patients who also have a loud third heart sound
-Pulsus alternans may also occur during or following paroxysmal tachycardia or for several beats following a
premature beat in patients without heart disease.
Pulsus bigeminus
-There is also a regular alteration of pressure pulse amplitude, but it is caused by a premature ventricular contraction
that follows each regular beat.
Pulsus paradoxus
-The decrease in systolic arterial pressure that normally accompanies the reduction in arterial pulse amplitude
during inspiration is accentuated.
-Decrease in systolic arterial pressure frequently exceeds the normal decrease of 10 mmHg and the peripheral pulse
may disappear completely during inspiration
 Pericardial effusion
 Cardiac tamponade
 Airway obstruction
 Superior vena cava obstruction

Upregulation (increased CO in pregnancy, hyperthyroidism),

R-Renal failure
E-Embolus

causes of a bounding pulse

A BAD FAT CHAP

 Aortic regurgitation
 Beri Beri
 Anemia
 Ductus arteriosus
 Fever
 A-V malformation
 Thyrotoxicosis
 Cirrhosis
 Hypercapnia
 Arteriosus (truncus arteriosus)
 Pregnancy and Pagets

Pulsus parvus
-Small weak pulse, is common in conditions with a diminished left ventricular stroke volume, a narrow pulse
pressure, and increased peripheral vascular resistance
may be due to
 Hypovolemia
 Left ventricular failure
 Restrictive pericardial disease
 Mitral valve stenosis.

66
Pulsus tardus
-In aortic valve stenosis, the delayed systolic peak, results from obstruction to left ventricular ejection.
Bounding /collapsing pulse
-Large pulse is usually associated with an increased left ventricular stroke volume, a wide pulse pressure, and a
decrease in peripheral vascular resistance
 Hyperkinetic circulation due to anxiety, anemia, exercise, or fever
 Rapid runoff of blood from the arterial system PDA, VSD or peripheral arteriovenous fistula.
 Mitral regurgitation -left ventricular ejection produces a rapid upstroke in the arterial pulse, even though
the duration of systole and the forward stroke volume may be reduced.
 Aortic regurgitation, the rapidly rising, bounding arterial pulse results from an increased left ventricular
stroke volume and an increased rate of ventricular ejection.
The bisferiens pulse
-Has two systolic peaks, is characteristic of aortic regurgitation (with or without accompanying stenosis) and of
hypertrophic cardiomyopathy.
-In the latter condition, the pulse wave upstroke rises rapidly and forcefully, producing the first systolic peak
("percussion wave").
-A brief decline in pressure follows because of the sudden mid systolic decrease in the rate of left ventricular
ejection, when severe obstruction often develops.
-This pressure trough is followed by a smaller and more slowly rising positive pulse wave ("tidal wave") produced
by continued ventricular ejection and by reflected waves from the periphery.
The dicrotic pulse
-Has two palpable waves, one in systole and one in diastole.
- It usually denotes a very low stroke volume, particularly in patients with dilated cardiomyopathy.
-Simultaneous palpation of the radial and femoral arterial pulses, which normally are virtually coincident, is
important to rule out aortic coarctation, in which the latter pulse is weakened and delayed

DIABETIC KETOACIDOSIS (DKA)

Introduction
-Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes.
-DKA mainly occurs in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes.
Definitions
Clinically
-An acute state of severe uncontrolled diabetes that requires emergency treatment with insulin and intravenous
fluids.
Biochemically
-Serum ketones greater than 5 mEq/L, hyperglycemia (usually glucose20-30 mmol/L) and metabolic acidosis (pH of
less than 7.3, bicarbonate <15mmol/l)
Alberto 1974
-Severe uncontrolled diabetis requiring treatment with continuous infusion of IV-fluids and IV-insulin and with
blood ketones >5 mmol/l (acetoacetate,3-hydroxybutyrate)
Modified Alberto
-Bicorbinate levels<15mmol/L with significant ketosis (urine ketostix ++ or more, blood ketone+ or more.)
Pathophysiology:
-DKA is a complex disordered metabolic state characterized by
Hyperglycemia
 Acidosis
 Ketonaemia and ketonuria
-DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase
in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine).
-This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis.
Hyperglycemia
-Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess
result in severe hyperglycemia.

67
 Increased ketones
-Lipolysis from the adipose tissue increases serum free fatty acids. Reduced insulin levels, in combination with
elevations in catecholamines and growth hormone, lead to an increase in lipolysis and release of free fatty acids.
Normally, these free fatty acids are converted to triglycerides or very low density lipoproteins (VLDL) in the liver,
but in DKA, hyperglucagonemia alters hepatic metabolism to favor ketone body formation
-Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of
acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketones include acetone, beta hydroxybutyrate, and
acetoacetate.
Metabolic Acidosis
-Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia.
Natural body buffers can buffer ketonemia in its early stages.
-NB. Insulin insensitive tissues-Brain, liver and kidney.

Race: Incidence of DKA is higher in whites because of the higher incidence of type 1 diabetes in this racial group.
Sex: Incidence of DKA is slightly more common in females than in males for reasons that are unclear.
Age: DKA is much more common in young children and adolescents than it is in adults with type 1 diabetes

Clinical presentation
History
Presenting complaints
1. Polydipsia, polyuria are the most common early symptoms of DKA.
2. Nausea and vomiting may be associated with diffuse abdominal pain.
3.Generalized weakness and fatigability
4.Altered consciousness in the form of mild disorientation or confusion
-Frank coma is uncommon, may if dehydration or acidosis is severe.
History suggestive of precipitants
a)Infections
 Fever
 Dysuria-UTI
 Coughing-pneumonia
 Malaise
 Arthralgia
b)myocardial infarction
Acute chest pain or palpitation
 Painless infarction is not uncommon in patients with diabetes and should always be suspected in elderly
patients.
c)Failure to comply with insulin therapy
d) History of rapid weight loss is a symptom in patients who are newly diagnosed with type 1 diabetes.
e)Stressful life event event
History of DM complications
-Metabolic-wt loss or weight gain
-Eye
-Renal
-CVS-Heart(MI or Hart failure) and peripheral vascular disease plus CVS risks smoking and alcohol
-Neuropathy-Foot ulcers and changes in sensation
-Autonomic neuropathy-Gastro paresis, diarrhea, gustatory sweating, Dizziness from seated position, erectile
dysfunction, cystopathy
Etiology
-Family history of DM
Diabetic history
-When diagnosed
-Control manner and number of complication experienced over time
-Compliance to medication
-Education on diet and lifestyle modification

Investigations

68
laboratory
1. Blood glucose level usually is higher than 250 mg/dL.
2. Serum ketones >5mmol/l
3. ABG and Anion gap metabolic acidosis-low bicarbonate and low pH (<7.3).
-The anion gap is elevated ([Na + K] - [Cl + HCO3] >13 mEq/L).
4. Complete Urinalysis-
This test is highly positive for glucose and ketones by dipstick testing.
5.Serum electrolytes
-Serum potassium levels initially are high or within the reference range. Total body depletion
-The serum sodium level usually is low.
-The serum chloride levels and phosphorus levels always are low.
-Plasma osmolarity usually is increased (>290 mOsm/L). If plasma osmolarity cannot be directly measured, it
may be calculated with this formula: plasma osmolarity = 2 (Na + K) + BUN/3 + glucose/18. Urine osmolarity
also is increased.
6. FBC-Even in the absence of infection shows increased WBC count.
7. BUN frequently is increased
8. Blood culture -identify any possible infecting organisms.
Frequency of laboratory studies
-Blood tests for glucose should be performed hourly (until patient is stable, then every 6 h).
-Serum electrolyte determinations should be obtained hourly (until patient is stable, then every 6 h).
-BUN should be performed initially
-ABG should be performed initially, followed with bicarbonate as necessary.

Imaging Studies
1. CXR-may reveals signs of pneumonia.
2. Electrocardiogram-signs of acute myocardial infarction that could be painless in patients with diabetes,
particularly in those with autonomic neuropathy.
T-wave changes may produce the first warning sign of disturbed serum potassium levels.
Low T wave and apparent U wave always signify hypokalemia, while peaked T wave is observed in hyperkalemia.

Investigations for long term management

1.HB A1C
2.Fasting lipid profile
3.Renal ultrasound and urinalysis for microalbuminuria

MANAGEMENT-FIKAP
Involves
1.Correction of fluid loss with IV fluids
2.Correction of hyperglycemia with insulin
3.Correction of electrolyte disturbances, particularly potassium loss
4.Correction of acid-base balance
5. Treatment of concurrent infection if present.

Fluid resuscitation
-Correction of fluid loss makes the clinical picture clearer and may be sufficient to correct acidosis.
-The presence of even mild signs of dehydration means that at least 3 liters of fluid already have been lost.
-Initial correction of fluid loss is either by isotonic sodium chloride solution or by lactated Ringer solution.
Administer 1 liter over the first 30 minutes.
Administer 1 liter over the second hour.
Administer 1 liter over the following 2 hours.
 Administer 1 liter every 4 hours, depending on the degree of dehydration and central venous
pressure (CVP) readings.
-NB When the patient becomes euvolemic, make the switch to half the isotonic sodium chloride solution,
particularly if hypernatremia exists.
-When blood sugar decreases to less than 15mmol/L, isotonic sodium chloride solution is replaced with 5%
dextrose and infusion at rate of 250ml/hr to avoid hypoglycemia.

69
Insulin
Rate: 5-10 IU/hr with syringe pump infusion
-Larger volumes may be easier in the absence of an intravenous infusion pump (eg, 50 IU of insulin in 500 cc of
isotonic sodium chloride solution at a rate of 50ml/hr-100ml/hr). OR
-IM insulin bolus of 10 IU in the deltoid then repeated at 5-10 IU/hr depending on the blood sugars.
-When the blood sugars fall below 15mmol/L, set up a GKI drip with 500ml 5% dextrose plus 5-10 IU of
insulin and 20 meq of KCL and run 50-100ml/hr.
-This gives lower insulin of 1-2 IU/hr also supplements glucose and potassium levels.

Complications of DKA

1. Cerebral edema

2. ARDS

3. Thromboembolism

4. Acute RF

5. Rhinocerebral mucomycoses.

6. Rhabdomyplysis

7. Arrythmia

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HYPEROSMOLAR NON-KETOTIC COMA

-An acute metabolic complication of diabetes mellitus (DM) characterized by:

Impaired mental status (MS)

Elevated plasma osmolality



Hyperglycemia.


Absence of significant ketosis.



-Despite the name, coma is present in fewer than 10% of cases.

-In many cases, the clinical features of HONC and diabetic ketoacidosis (DKA) overlap and these may
be observed simultaneously.

Criteria for HONC include

-Serum osmolality > 320 mOsm/kg

-Plasma glucose level greater than >33.3 mmol/L

-Profound dehydration

- PH of 7.3 and HCO3- of about 15 mEq/L

-Absence of severe ketosis.

-HONC is the initial presentation of DM for 30-40% of patients. Most cases of occur in patients with
type 2 DM, characterized by insulin resistance and defective insulin secretion.

-Also occur in type 1 DM, in whom diabetic ketoacidosis (DKA) is more common. Both HNS and DKA
may occur in the same individual, which suggests these 2 states of uncontrolled DM differ only in the
magnitude of dehydration and the severity of acidosis.

Pathophysiology

-Same as DKA. Unlike patients with DKA, patients do not develop ketoacidosis, but the reason for this
is not known.

-Contributing factors include the limitation on ketogenesis by hyperosmolarity, the lower levels of
free fatty acids available for ketogenesis, the availability of insulin in amounts sufficient to inhibit
ketogenesis but not sufficient to prevent hyperglycemia, and the hepatic resistance to glucagons in
these patients.
Morbidity and mortality
-Cerebral edema-With rapid rehydration
-ARDS- ARDS may develop in association with underlying diseases, such as pancreatitis and MI. May also occur
rapid rehydration causing pulmonary edema.
-Vascular complications: The severe dehydration leads to hypotension and hyperviscosity of the blood, both of
which predispose patients to thromboembolic disease of the coronary, cerebral, pulmonary, and mesenteric beds.
-DIC may also occur.
-Low-dose subcutaneous heparin is advisable for all patients without a contraindication.
Age:
-The average age of patients with HNS is 60 years. Underlying comorbidities that prevent adequate hydration,
including immobility, advanced age, debility, dementia, agitation, and restraint use, place these patients at risk. I
-mpaired senses, such as deafness and blindness, may lead to social isolation and also increase the risk of HNS

71
DIABETIC NEPHROPATHY
-Diabetic nephropathy is a clinical syndrome characterized by
Persistent albuminuria (>300 mg/d or >200 mcg/min) on at least 2 occasions 3-6 months apart,
Relentless decline in (GFR)
Hypertension
-Although both type 1 and 2 DM lead to ESRD, the great majority of patients are those with NIDDM.
Pathophysiology:
-The key change in diabetic glomerulopathy is augmentation of extracellular material.
-Earliest morphologic change is the thickening of the basement membrane (GBM) and expansion of the mesangium
due to accumulation of extracellular matrix.
-Large acellular accumulations the Kimmelstiel-Wilson lesions/nodules.
-Glycation of the glomerular basement membrane may interfere with its breakdown and reduce its turnover, thus
promoting its thickening.
- It may similarly predispose to accumulation of mesangial matrix.
-The glomeruli and kidneys are typically normal or increased in size initially, unlike most forms of CRF with
reduced renal size (except renal amyloidosis and polycystic kidney disease).
-The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and
hypertensive arteriosclerosis.
-Glomerular sclerosis causing nodules result from intraglomerular hypertension (induced by renal vasodilatation or
from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli).
-The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia
(causing hyperfiltration and renal injury), advanced glycosylation products, and activation of cytokines.
Risk factors for the development of diabetic nephropathy
Hyperglycemia
 Systemic hypertension and glomerular HTN
 Hyperfiltration
 Proteinuria
 Cigarette smoking
 Hyperlipidemia
Gene polymorphisms affecting the activity of the renin-angiotensin-aldosterone axis.
-For reasons that are unclear, ESRD from diabetic nephropathy is more common in blacks with type 2 DM than in
whites (4:1 ratio), whereas the reverse is true for type 1 DM.
Clinical presentation.
History:
Diabetes
Passing of foamy urine
Otherwise unexplained proteinuria in a patient with diabetes
 Diabetic retinopathy
Fatigue and foot edema secondary to hypoalbuminemia (if nephrotic syndrome is present)

-Other associated disorders such as peripheral vascular occlusive disease, hypertension, or coronary artery disease
Physical:
-Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the
setting of diabetes.
-Patients usually have physical findings associated with long-standing diabetes mellitus.
 Hypertension
Evidence of diabetic retinopathy after funduscopy or fluorescin angiography
Peripheral vascular occlusive disease (decreased peripheral pulses, carotid bruits)
 Evidence for diabetic neuropathy (evidenced by decreased fine sensations, diminished tendon reflexes)
Evidence for fourth heart sound during cardiac auscultation
Nonhealing skin ulcers/osteomyelitis

Staging of diabetic nephropathy

Stage 1 (very early diabetes)
-Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR).

72
Stage 2 (developing diabetes)
-The GFR remains elevated or has returned to normal, but glomerular damage has progressed to significant
microalbuminuria (small but above-normal level of the protein albumin in the urine). Patients in stage 2 excrete
more than 30 mg of albumin in the urine over a 24-hour period.
-Significant microalbuminuria will progress to end-stage renal disease (ESRD). Therefore, all diabetes patients
should be screened for microalbuminuria on a routine (yearly) basis.
Stage 3 (Overt or dipstick-positive diabetes)
-Glomerular damage has progressed to clinical albuminuria. The urine is "dipstick positive," containing more than
300 mg of albumin in a 24-hour period.
-Hypertension (high blood pressure) typically develops during stage 3.
Stage 4 (late-stage diabetes)
-Glomerular damage continues, with increasing amounts of protein albumin in the urine.
-The kidneys’ filtering ability has begun to decline steadily, and blood urea nitrogen (BUN) and creatinine (Cr) has
begun to increase.
-The glomerular filtration rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage
4.
Stage 5 (end-stage renal disease, ESRD)
-GFR has fallen to approximately 10 milliliters per minute (<10 mL/min) and renal replacement therapy (i.e.,
hemodialysis, peritoneal dialysis, kidney transplantation) is needed.

MANAGEMENT
-Treatment for diabetic nephropathy attempts to manage and slow the progression of the disease.
Aggressive blood pressure control
-Is by far the most important factor in protecting kidney function, regardless of the stage of DN. The goal of
treatment is:  120 – 130 mm Hg systolic blood pressure and
- 70 – 80 mm Hg diastolic blood pressure.
-Angiotensin-converting enzyme (ACE) inhibitors protect the kidneys more effectively than other high blood
pressure medications.
- A new class of blood pressure medications known as angiotensin-receptor blockers (ARBs) may offer comparable
protection. Patients who cannot tolerate ACE inhibitors may use an ARB (e.g., losartan, valsartan).
-Maximum doses of an ACE along with an ARB may provide additional renal protection in people who can tolerate
the medications.
-Both ACE inhibitors and ARBs can cause hyperkalemia (abnormally high level of potassium in the blood) in
patients with chronic renal failure.
-Diet-Salt restriction, fat free diet
Strict blood sugar control
-Is important in the protection of kidney function. Intensive blood sugar regulation requires frequent monitoring and
commitment.
Dietary protein restriction
-Is minimally protective. A high-protein diet (e.g., the Atkins diet) can further damage the kidneys in people with
diabetic nephropathy and/or chronic renal failure (CRF). Protein restriction must be cautiously implemented because
of the risk for malnutrition.
-In general, dietary protein intake should be limited to 0.6 to 0.8 grams per kilogram (0.02 – 0.028 oz/lb) of body
weight each day.
Renal Replacement Therapy
-Once patients with DN progress to stage 5 (end-stage renal disease, ESRD), renal replacement therapy (RRT) is
implemented. The RRT options for DN patients include the following:
 Hemodialysis, removal of the blood’s waste products through filtration outside of the body
 Peritoneal dialysis, filtration through the membrane lining the abdominal cavity; fluid is instilled into the
peritoneal space, and then drained
 Kidney transplantation
Others
-This includes modification and/or treatment of associated risk factors such as
Hyperlipidemia-Atovastation
Smoking-Stopped
Protect gut–Omeprazole.

73
Complications:
-Diabetic retinopathy is present in virtually all persons with IDDM who have nephropathy, whereas only 50-60% of
patients with proteinuric NIDDM have retinopathy. An absence of retinopathy requires further investigation for
nondiabetic glomerulopathies. Blindness due to severe proliferative retinopathy or maculopathy is approximately 5
times more common in persons with IDDM or NIDDM and nephropathy than in persons who are
normoalbuminuric.
-Macroangiopathy (eg, stroke, carotid artery stenosis, coronary heart disease, peripheral vascular disease) is 2-5
times more common in patients who are nephropathic.
-Peripheral neuropathy is present in almost all patients with advanced nephropathy. Foot ulcers with associated
sepsis, which leads to amputation, occur frequently (>25%), probably because of a combination of neural and
arterial disease.
-Autonomic neuropathy may be asymptomatic and simply manifest as abnormal cardiovascular reflexes, or it may
result in debilitating symptoms.
-Nearly all patients have grossly abnormal results from autonomic function tests, with more than half the patients
with advanced nephropathy having symptoms of autonomic neuropathy (ie, gustatory sweating, impotence, postural
hypotension, and diarrhea in one study).
-Diabetic cystopathy is also a frequent (>30%) problem in these patients.
-NB: World Health Organization and American Diabetes Association diagnostic criteria are as follows
 Fasting plasma glucose >126 mg/dL (>7.0 mmol/L) or fasting whole-blood glucose level >110 mg/dL
(>6.1 mmol/L), or a 2-hour post-glucose-load plasma glucose >200 mg/dL (>11.1 mmol/L; 180 mg/dL
[10.0 mmol/L] if whole blood), or a random plasma glucose >200 mg/dL (>11.1 mmol/L) on more than 1
occasion
 Prediabetic stage - Fasting plasma glucose 100-126 mg/dL (5.6-7.0 mmol/L) increasingly recognized as a
risk factor for end-organ complications; evidence supports lifestyle interventions to prevent or delay onset

Stage Description GFR Albuminur BP U/E/C Time since

ia Dx
Stage1 Renal Hyper perfusion Elevated Absent Normal Normal At Dx
Stage2 Latency High Absent Normal Normal At Dx
normal
Stage 3 Incipient nephropathy/ Normal <300mg/da Rising within Normal 5-15yrs
microalbuminuria y or above
normal
Stage4 Clinically manifest Decreased >300mg/da Increased Raised 10-15 yrs
nephropathy/Macroalbumin y
uria
Stage 5 ESRD Diminished Massive Increased Raised 15-30 yrs

ECG CHANGES IN CARDIAC DISEASE.

Normal ECG

74
ECG Waves and Intervals:
P wave: the sequential activation (depolarization) of the right and left atria
QRS complex: right and left ventricular depolarization (normally the ventricles are activated
simultaneously)
ST-T wave: ventricular repolarization
U wave: origin for this wave is not clear - but probably represents "afterdepolarizations" in the ventricles
PR interval: time interval from onset of atrial depolarization (P wave) to onset of ventricular depolarization
(QRS complex)
QRS duration: duration of ventricular muscle depolarization
QT interval: duration of ventricular depolarization and repolarization
RR interval: duration of ventricular cardiac cycle (an indicator of ventricular rate)
PP interval: duration of atrial cycle (an indicator of atrial rate)

Orientation of the 12 Lead ECG

Each of the 12 leads represents a particular orientation in space, as indicated below (RA = right arm; LA
= left arm, LF = left foot):

Bipolar limb leads (frontal plane):

Lead I: RA (-) to LA (+) (Right Left, or lateral)
Lead II: RA (-) to LF (+) (Superior Inferior)
Lead III: LA (-) to LF (+) (Superior Inferior)
Augmented unipolar limb leads (frontal plane):
Lead aVR: RA (+) to [LA & LF] (-) (Rightward)
Lead aVL: LA (+) to [RA & LF] (-) (Leftward)
Lead aVF: LF (+) to [RA & LA] (-) (Inferior)
Unipolar (+) chest leads (horizontal plane):
Leads V1, V2, and V3: (Posterior Anterior)
Leads V4, V5, V6 :( Right Left or lateral)

LOCATION OF CHEST ELECTRODES IN 4TH AND 5TH INTERCOSTAL SPACES:

Einthoven's Triangle

75
V1: right parasternal 4th intercostal space
V2: left parasternal 4th intercostal space
V3: halfway between V2 and V4
V4: left 5th intercostal space, mid-clavicular line
V5: horizontal to V4, anterior axillary line
V6: horizontal to V5, mid-axillary line
ECG Interpretation
1) Measurements
2) Rhythm Analysis
3) Conduction Analysis
4) Waveform Description
5) ECG Interpretation
6) Comparison with Previous ECG (if any)
Measurement
1. Heart Rate
In normal sinus rhythm, a resting heart rate of below 60 bpm is called bradycardia and a rate of above 90 bpm is
called tachycardia.

2. PR Interval
(Measured from beginning of P to beginning of QRS in the frontal plane)
Normal: 0.12 - 0.20s
3. QRS Duration
Normal: 0.06 - 0.10s
Prolonged QRS Duration (>0.10s):
Incomplete right or left bundle branch block
Nonspecific intraventricular conduction delay (IVCD)
some cases of left anterior or posterior fascicular block
Complete RBBB or LBBB
Ectopic rhythms originating in the ventricles (e.g., ventricular tachycardia, pacemaker rhythm)
4. QT Interval
(Measured from beginning of QRS to end of T wave in the frontal plane)

76
Short PR: < 0.12s :
i) WPW (Wolff-Parkinson-White) Syndrome:
An accessory pathway (called the "Kent" bundle) connects the right atrium to the right ventricle, and this
permits early activation of the ventricles (delta wave) and a short PR interval.
ii) LGL (Lown Ganong Levine ):
An AV nodal bypass track into the His bundle exists, and this permits early activation of the ventricles without a
delta-wave because the ventricular activation sequence is normal.
iii) AV Junctional Rhythms
-With retrograde atrial activation (inverted P waves in II, III, aVF): Retrograde P waves may occur before
the QRS complex (usually with a short PR interval), in the QRS complex (i.e., hidden from view), or after
the QRS complex (i.e., in the ST segment).

iv) Ectopic atrial rhythms

Originating near the AV node (the PR interval is short because atrial activation originates close to the AV
node; the P wave morphology is different from the sinus P)
iv) Normal variant.

Prolonged PR: >0.20s

First degree AV block
(PR interval usually constant though’ prolonged and all the P’waves conducted)
 Intra-atrial conduction delay –rare
 Slowed conduction in AV node (most common site)
 Slowed conduction in His bundle (rare)
 Slowed conduction in bundle branch (when contralateral bundle is blocked)
Second degree AV block
(PR interval may be normal or prolonged; some P waves do not conduct)
Type I (Wenckebach): Increasing PR until nonconducted P wave occurs
Type II (Mobitz): Fixed PR intervals plus nonconducted P waves
3rd Degree heart Block
AV dissociation:
Some PR's may appear prolonged, but the P waves and QRS complexes are dissociated (i.e., not married, but
strangers passing in the night).
Normal: heart rate dependent (corrected QT = QTc = measured QT ¸ sq-root RR in seconds; upper limit for
QTc = 0.44 sec)
Long QT Syndrome - "LQTS" (based on upper limits for heart rate; QT c > 0.47 sec for males and > 0.48 sec
in females is diagnostic for hereditary LQTS in absence of other causes of increased QT)
This abnormality may have important clinical implications since it usually indicates a state of increased
vulnerability to malignant ventricular arrhythmias, syncope, and sudden death.
-The prototype arrhythmia of the Long QT Interval Syndromes (LQTS) is Torsade-de-pointes, a polymorphic
ventricular tachycardia characterized by varying QRS morphology and amplitude around the isoelectric
baseline.
Causes of LQTS include the following:
1. Drugs
 Antiarrhythmics
 Tricyclics
 Phenothiazines
2.Electrolyte abnormalities
 Hypokalemia
 Hypocalcemia
 hypomagnesaemia
3. CNS disease (especially subarachnoid hemorrhage, stroke, trauma)
4.Hereditary LQTS (e.g., Romano-Ward Syndrome)
5. Coronary Heart Disease (some post-MI patients)

77
Left ventricular hypertrophy
1) Tall R wave (greater than 25mm in V5 or V6), or R at V5 plus S wave at V1greater than 35 mm -Leons
hypothesis
2) A deep S in V1 or V2
3) If there is significant left ventricular 'strain' then there are also inverted T waves in V5 and V6 and
possible ST depression
4) Left axis deviation may also be present
5) QRS may be slightly prolonged

Right ventricular hypertrophy includes:

1) Right axis deviation
2) Predominant R wave in lead V1 - in a normal ECG the S wave is dominant in V1 there will be a deep
S in V6 - in a normal ECG the QRS complex is predominantly upwards in V6
3) Inverted T waves in right praecordial leads - V2, V3 - will be present in severe cases; it is normal to
have inverted T waves in V1
4) Peaked P waves may also occur due to right atrial hypertrophy
5) QRS < 0.12s

HYPERKALEMIA
ECG CHANGES
Serum K+ 5.5-6.5 mEq/L
 Tall, peaked T waves with narrow base, best seen in precordial leads

Serum K+ 6.5-8.0 mEq/L

 Peaked T waves
 Prolonged PR interval
 Widening of QRS, amplified R wave
 Decreased or disappearing P wave

Serum K+ greater than 8.0 mEq/L

 Absence of P wave
 Intraventricular/fascicular/bundle branch blocks
 Progressive widening of QRS (eventually merging with the T wave just before cardiac arrest,
forming the Sine-wave pattern )

Hypokalemia
 Ventricular dysrhythmias
 Prolongation of QT interval
 ST-segment depression
 T-wave flattening
 Appearance of U waves
-During therapy, monitor for changes associated with overcorrection and hyperkalemia, including a
prolonged QRS, peaked T waves, bradyarrhythmia, sinus node dysfunction, and asystole
Hypercalcemia
-QT interval shortening is common, and, in some cases, the PR interval is prolonged.
-At very high levels, the QRS interval may lengthen, T waves may flatten or invert and a variable degree of
heart block may develop. Digoxin effects are amplified.

ECHINOCOCCOSIS
Introduction
-Echinococcosis is an infection of humans caused by the larval stage of

78
a) Echinococcus granulosus- produces unilocular cystic lesions, is prevalent in areas where livestock is raised in
association with dogs
b) E. multilocularis- multilocular alveolar lesions that is locally invasive
c) E. vogeli-causes polycystic hydatid disease
-Like other cestodes, echinococcal species have both intermediate and definitive hosts.
-The definitive hosts are dogs that pass eggs in their feces. Cysts develop in the intermediate hosts¾sheep, cattle,
humans, goats, camels, and horses for E. granulosus and mice and other rodents for E. multilocularis¾after the
ingestion of eggs.
- When a dog ingests beef or lamb containing cysts, the life cycle is completed.
Etiology
-The small (5 mm long) adult E. granulosus worm, which lives in the jejunum of dogs, has only three proglottids-
one immature, one mature, and one gravid.
-The gravid segment splits to release eggs that are morphologically similar to Taenia eggs and are extremely hardy.
-After humans ingest the eggs, embryos escape from the eggs, penetrate the intestinal mucosa, enter the portal
circulation, and are carried to various organs, most commonly the liver and lungs.
-Larvae develop into fluid-filled unilocular hydatid cysts that consist of an external membrane and an inner
germinal layer. Daughter cysts develop from the inner aspect of the germinal layer, as do germinating cystic
structures called brood capsules. New larvae, called protoscolices, develop in large numbers within the brood
capsule. The cysts expand slowly over a period of years.
The life cycle of E. multilocularis is similar except that small rodents serve as the intermediate hosts. The cyst of E.
multilocularis, however, is quite different in that the larval form remains in the proliferative phase, the hydatid cyst
is always multilocular, and vesicles progressively invade the host tissue by peripheral extension of processes from
the germinal layer.
Clinical Manifestations
Slowly enlarging echinococcal cysts generally remain asymptomatic until their expanding size or their space-
occupying effect in an involved organ elicits symptoms.
-The liver and the lungs are the most common sites of these cysts.
- Since a period of years elapses before cysts enlarge sufficiently to cause symptoms, they may be discovered
incidentally on a routine x-ray or ultrasound study.
-Patients with hepatic echinococcosis who are symptomatic most often present with abdominal pain or a palpable
mass in the right upper quadrant. Compression of a bile duct or leakage of cyst fluid into the biliary tree may mimic
recurrent cholelithiasis, and biliary obstruction can result in jaundice.
-Rupture of or episodic leakage from a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or
anaphylaxis.
-Pulmonary hydatid cysts may rupture into the bronchial tree or peritoneal cavity and produce cough, chest pain, or
hemoptysis.
-Rupture of hydatid cysts may lead to multifocal dissemination of protoscolices, which can form additional cysts.
Rupture can occur spontaneously or at surgery.
- Other presentations are due to the
Involvement of bone (invasion of the medullary cavity with slow bone erosion producing pathologic
fractures)
 The central nervous system (space-occupying lesions)
 And the heart (conduction defects, pericarditis).
-The cysts of E. multilocularis characteristically present as a slowly growing hepatic tumor, with progressive
destruction of the liver and extension into vital structures. Patients commonly complain of upper quadrant and
epigastric pain, and obstructive jaundice may be apparent. A minority of patients experience the metastasis of
lesions to the lung and brain.

Physical:
Physical examination findings from patients with echinococcosis are nonspecific. The findings are related to the
effect of the cyst on the anatomy or the function of the affected organ(s) and to an acute allergic reaction.
Skin
-Jaundice could be a sign of biliary obstruction.
-Spider angiomas are a sign of portal hypertension secondary to either biliary cirrhosis or obstruction of the inferior
vena cava
-Urticaria and erythema may be seen.

79
Vital sign
-Fever could be a sign of secondary infection or allergic reaction.
-Hypotension is observed with anaphylaxis secondary to a cyst leak.
Lungs:
-Decreased breath sounds over the affected area are signs of airway obstruction with consolidation of the affected
segment, lobule, lobe, or the whole lung.
Abdomen
-The most common sign is abdominal tenderness
-Hepatomegaly may be present or a mass may be felt.
Tender hepatomegaly is a sign of secondary infection of the cyst, especially when coupled with fever and chills.
-Ascites is rare.
-Splenomegaly can be the result of either splenic echinococcosis or portal hypertension.
Extremities
-Bone involvement can result in tenderness over the affected area and, rarely, a palpable mass.
-Muscle involvement is usually characterized by a palpable mass.
-Peripheral nerve compression can occur, although extremely rarely. It results in nerve-specific sensory and/or
motor deficit.
Brain
-Depend on the area of the brain involved.
-They range from very mild to full coma and cerebral herniation.
Eyes
-Ocular involvement is rare.
-decreased visual acuity, blindness, and exophthalmos

Investigations
Lab Studies:
LFT,s-Liver involvement may be reflected in an elevated bilirubin or alkaline phosphatase level.
FBC-Leukocytosis may suggest infection of the cyst. Eosinophilia is present in 25% of all infected persons, while
hypogammaglobinemia is present in 30%.
Serology
-The indirect hemagglutination test and (ELISA) have a sensitivity of 80% overall (90% in hepatic echinococcosis,
40% in pulmonary echinococcosis) and are the initial screening tests of choice.
-Immunodiffusion and immunoelectrophoresis demonstrate antibodies to antigen 5 and provide specific
confirmation of reactivity.
Imaging Studies:
Plain films
- A thin rim of calcification delineating a cyst is suggestive of an echinococcal cyst.
Ultrasound
-Daughter cysts and hydatid sand are demonstrated plus the fluid filled cyst.
CT scan
-CT scan has an accuracy of 98% and the sensitivity to demonstrate the daughter cysts.
-It is the best test for the differentiation of hydatid from amebic and pyogenic cysts in the liver
MRI:
-Images show the cysts adequately, but MRI offers no real advantage over CT scan.
Other Tests:
Casoni test
-An intradermal skin test (Casoni test) was used and had a sensitivity of 70%.
It is now largely abandoned because of its low sensitivity, low accuracy, and potential for severe local allergic
reaction.
Procedures:
-ERCP- It is both diagnostic and therapeutic in patients with intrabiliary rupture of a hydatid cyst, in whom
sphincterotomy can be performed.

MANAGEMENT
Medical management
-Surgery remains the primary treatment and the only hope for complete cure.

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-Better forms of chemotherapy and newer methods, such as the puncture, aspiration, injection, and reaspiration
(PAIR) technique are now available but need to be tested. Currently, indications for these modes of therapy are
restricted.
-Chemotherapy -Indications
Primary liver or lung cysts that is inoperable (because of location or medical condition)
 Patients with cysts in 2 or more organs
 Peritoneal cysts.
Contraindications:
Early pregnancy
 Bone marrow suppression
 Chronic hepatic disease
 Large cysts with the risk of rupture
Inactive or calcified cysts
A relative contraindication is bone cysts because of the significantly decreased response.
Drugs
Albendazole and mebendazole.
-Albendazole is administered in several 1-month oral doses (10-15 mg/kg/d) separated by 14-day intervals.
-The optimal period of treatment ranges from 3-6 months
-Mebendazole is also administered for 3-6 months orally in dosages of 40-50 mg/kg/d.
Outcome from medical treatment
-Up to 30% had cyst disappearance (cure), 30-50% had a decrease in the size of the cyst (improvement), and 20-
40% had no changes. Also, younger adults responded better

Complications Related to the medical treatment

Hepatotoxicity
 Anemia
 Thrombocytopenia
 Alopecia
 Embryotoxicity
 Teratogenicity
 Spillage and seeding (secondary echinococcosis

Surgical care
-Concomitant treatment with benzimidazoles (albendazole or mebendazole) has been reported to reduce the risk of
secondary echinococcosis. Treatment is started 4 days preoperatively and lasts for 1 month.
-Indications
Large liver cysts with multiple daughter cysts
 Superficially located single liver cysts that may rupture (traumatically or spontaneously)
 Liver cysts with biliary tree communication
 Pressure effects on vital organs or structures
 Infected cysts
Cysts in lungs, brain, kidneys, eyes, bones, and all other organs are indications for surgery.
-Contraindications
General contraindications to surgical procedures (eg, extremes of age, pregnancy, severe preexisting
medical conditions)
 Multiple cysts in multiple organs
 Cysts that is difficult to access
 Dead cysts; calcified cysts
Very small cysts
-Choice of surgical technique:
-Radical surgery (total pericystectomy or partial affected organ resection, if possible)
-conservative surgery (open cystectomy)
- Simple tube drainage for infected and communicating cysts are choices for surgical technique
Description of surgical procedure
-The basic steps of the procedure are eradication of the parasite by mechanical removal, sterilization of the cyst
cavity by injection of a scolicidal agent, and protection of the surrounding tissues and cavities.

81
-Scolicidal agents include formalin, hydrogen peroxide, hypertonic saline, chlorhexidine, absolute alcohol, and
cetrimide
-The surrounding tissues are protected by covering them with cetrimide-soaked pads.
-The cyst is then evacuated using a strong suction device, and cetrimide is injected into the cavity. This procedure is
repeated until the return is completely clear. Cetrimide is instilled and allowed to sit for 10 minutes, after which it is
evacuated, and the cavity is irrigated with isotonic sodium chloride solution. This ensures both mechanical and
chemical evacuation and destruction of all cyst contents.
--During this process, care is taken to ensure no spillage occurs to prevent seeding and secondary infestation.
-The cavity is then filled with isotonic sodium chloride solution and closed.
-In case of infected cysts with biliary communication, closed suction drainage is required.
-Regardless of whether an open or laparoscopic approach is chosen, these basic principles must be followed in order
to ensure the safety of the procedure.

Complications
Related to the parasite
-Recurrence
-Metastasis
-Infection
-Spillage and seeding (secondary echinococcosis)
- Allergic reaction or anaphylactic shock

GASTROESOPAHGEAL REFLUX DISEASE

Background:
-Gastroesophageal reflux is a normal physiological phenomenon experienced intermittently by most people,
particularly after a meal.
-Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the
esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury (ie,
esophagitis).

Pathophysiology:
-The physiological and anatomical factors that prevent the reflux of gastric juice from the stomach and into the
esophagus include the following:
1) The lower esophageal sphincter (LES) must have a normal length and pressure and a normal number of
episodes of transient relaxation (relaxation in the absence of swallowing).
2) Diaphragmatic crura The gastroesophageal junction must be located in the abdomen crura can assist the action
of the LES, thus functioning as an extrinsic sphincter.
-The presence of a hiatal hernia disrupts this synergistic action and can promote reflux.
3) Esophageal clearance must be able to neutralize the acid refluxed through the LES. (Mechanical clearance is
achieved with esophageal peristalsis. Chemical clearance is achieved with saliva.)
4) The angle of His
5) The stomach must empty properly.
-Abnormal gastroesophageal reflux is caused by the abnormalities of one or more of the following protective
mechanisms:
a)-A functional (frequent transient LES relaxation) or mechanical (hypotensive LES) problem of the LES is the
most common cause of GERD.
b)-Drugs and chemicals that can decrease the pressure of the LES.
 Certain foods (eg, coffee, alcohol)
Medications (eg, calcium channel blockers, nitrates, beta-blockers)
Hormones (eg, progesterone)
c) Increased intra-abdominal pressure ie Obesity is a contributing factor in GERD.
-NB-gastric refluxate is made up not only of acid but also of duodenal contents (eg, bile, pancreatic secretions) is
important

Mortality/Morbidity:
-In addition to the typical symptoms (eg, heartburn, regurgitation, dysphagia), abnormal reflux can cause

82
-Atypical symptoms, such as coughing, chest pain, and wheezing.
Additional atypical symptoms from abnormal reflux include damage to the lungs (eg, pneumonia, asthma, idiopathic
pulmonary fibrosis)
-vocal cords (eg, laryngitis, cancer)
-ear (eg, otitis media)
-teeth (eg, enamel decay).

-Approximately 50% of patients with gastric reflux develop esophagitis.

-Esophagitis is classified into the following 4 grades based on its severity:
Grade I – Erythema
Grade II - Linear nonconfluent erosions
Grade III - Circular confluent erosions
Grade IV - Stricture or Barrett esophagus
-Barrett esophagus [grade IV] is thought to be caused by the chronic reflux of gastric juice into the esophagus.
- Barrett esophagus occurs when the squamous epithelium of the esophagus is replaced by the intestinal columnar
epithelium.
-Barrett esophagus is present in 8-15% of patients with GERD and may progress to adenocarcinoma.
Race:
-White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.
Sex:
-No sexual predilection exists.
-M: F esophagitis is 2-3:1
-M: F Barrett esophagus is 10:1.
Age:
-GERD occurs in all age groups.
-The prevalence of GERD increases in people older than 40 years.

Clinical presentation
History:
- GERD can cause typical (esophageal) symptoms or atypical (extraesophageal) symptoms.
-However, a diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.
-Typical (esophageal) symptoms include the following:
 Heartburn is the most common typical symptom of GERD. Heartburn is felt as a retrosternal
sensation of burning or discomfort that usually occurs after eating or when lying down or bending over.
Regurgitation is an effortless return of gastric and/or esophageal contents into the pharynx. Regurgitation
can induce respiratory complications if gastric contents spill into the tracheobronchial tree.
Dysphagia occurs in approximately one third of patients because of a mechanical stricture or a functional
problem (eg, nonobstructive dysphagia secondary to abnormal esophageal peristalsis). Patients with
dysphagia experience a sensation that food is stuck, particularly in the retrosternal area.

-Atypical (extraesophageal) symptoms include the following:

 Coughing and/or wheezing are respiratory symptoms resulting from the aspiration of gastric contents into
the tracheobronchial tree or from the vagal reflex arc producing bronchoconstriction. Approximately 50%
of patients who have GERD-induced asthma do not experience heartburn.
 Hoarseness results from irritation of the vocal cords by gastric refluxate. Hoarseness is often experienced
by patients in the morning.
 Reflux is the most common cause of noncardiac chest pain, accounting for approximately 50% of cases.
Patients can present to the emergency department with pain resembling a myocardial infarction
DDX
1. Achalasia
2. Cholelithiasis
3. Coronary Artery Atherosclerosis
4. Esophageal Cancer
5. Esophageal Spasm
6. Esophagitis
7. Gastritis, Chronic

83
8. Irritable Bowel Syndrome
9. Peptic Ulcer Disease
Investigations

Lab Studies:
-Laboratory tests are seldom useful in establishing a diagnosis of GERD.

Imaging Studies:
1. Barium esophagogram
-Barium esophagogram is particularly important for patients who experience dysphagia.
-Barium esophagogram can show the presence and location of a stricture and the presence and shape of a hiatal
hernia.
2. Esophagogastroduodenoscopy
- (EGD) identifies the presence and severity of esophagitis and the possible presence of Barrett esophagus.
-EGD also excludes the presence of other diseases (eg, peptic ulcer) that can present similarly to GERD.
-Although EGD is frequently performed to help diagnose GERD, it is not the most cost-effective diagnostic study
because esophagitis is present in only 50% of patients with GERD.
Other Tests:
1. Esophageal manometry
-Esophageal manometry defines the function of the LES and the esophageal body (peristalsis).
-Esophageal manometry is essential for correctly positioning the probe for the 24-hour pH monitoring.
2. Ambulatory 24-hour pH monitoring
-Ambulatory 24-hour pH monitoring is the criterion standard in establishing a diagnosis of GERD with a sensitivity
of 96% and a specificity of 95%.
-Ambulatory 24-hour pH monitoring quantifies the gastroesophageal reflux and allows a correlation between the
symptoms of reflux and the episodes of reflux.
-Patients with endoscopically confirmed esophagitis do not need pH monitoring to establish a diagnosis of GERD.
Indications for esophageal manometry and prolonged pH monitoring include the following:
-Persistence of symptoms while taking adequate antisecretory therapy, such as proton pump inhibitor therapy
-Recurrence of symptoms after discontinuation of acid-reducing medications
-Investigation of atypical symptoms, such as chest pain or asthma, in patients without esophagitis
-Confirmation of the diagnosis in preparation for antireflux surgery
3. Radionuclide measurement of gastric emptying
-Although delayed gastric emptying is present in as many as 60% of patients with GERD, this emptying is usually a
minor factor in the pathogenesis of the disease in most patients (except in patients with advanced diabetes mellitus
or connective tissue disorders).
-Patients with delayed gastric emptying typically experience postprandial bloating and fullness in addition to other
symptoms.

MANAGEMENT

Medical Care:
-Treatment is a stepwise approach.
-The goals are to control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or other complications.
-The treatment is based on lifestyle modification and control of gastric acid secretion.
Lifestyle modifications include the following
 Losing weight (if overweight)
Stop smoking
Avoiding alcohol, chocolate, citrus juice, and tomato-based products
 Avoiding large meals
Waiting 3 hours after a meal before lying down
Elevating the head of the bed 8 inche
Pharmacologic therapy

84
1-Antacids were the standard treatment in the 1970s and are still effective in controlling mild symptoms of GERD.
Antacids should be taken after each meal and at bedtime.
2-Histamine H2 receptor antagonists are the first line agents for patients with mild-to-moderate symptoms and
grades I-II esophagitis.
-Histamine H2 receptor antagonists are effective for healing only mild esophagitis in 70-80% of patients with GERD
and for providing maintenance therapy to prevent relapse.
- Tachyphylaxis has been observed, suggesting that pharmacologic tolerance can reduce the long-term efficacy of
these drugs.
-Additional H2 blocker therapy has been reported to be useful in patients with severe disease (particularly those with
Barrett esophagus) who have nocturnal acid breakthrough.
3. Proton pump inhibitors
-Are the most powerful medications available.
-They should be used only when GERD has been objectively documented. Proton pump inhibitors work by blocking
the final step in the H+ ion secretion by the parietal cell.
- They have few adverse effects and are well tolerated for long-term use.
4. Prokinetic agents improve the motility of the esophagus and stomach.
-These agents are somewhat effective but only in patients with mild symptoms; other patients usually require
additional acid-suppressing medications such as proton pump inhibitors.
-Long-term use of prokinetic agents may have serious, even potentially fatal, complications and should be
discouraged.

Surgical Care:
-Approximately 80% of patients have a recurrent but nonprogressive form of GERD that is controlled with
medications.
-Identifying the 20% of patients who have a progressive form of the disease is important because they may develop
severe complications such as strictures or Barrett esophagus.
-For patients who develop complications, surgical treatment should be considered at an earlier stage to avoid the
sequelae of the disease that can have serious consequences.

Indications for fundoplication include the following:

-Patients with symptoms that are not completely controlled by proton pump inhibitor therapy can be considered for
surgery. Surgery can also be considered in patients with well-controlled disease who desire definitive, one-time
treatment.
-The presence of Barrett esophagus is an indication for surgery.
-The presence of extraesophageal manifestations of GERD may indicate the need for surgery.
(1) Respiratory manifestations (eg, cough, wheezing, aspiration);
(2) Ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media);
(3) Dental manifestations (eg, enamel erosion).

Laparoscopic fundoplication
-The essential elements of the operation are as follows:
 Complete mobilization of the fundus of the stomach with division of the short gastric vessels
 Reduction of the hiatal hernia
 Narrowing of the esophageal hiatus
 Creation of a 360° fundoplication over a large intraesophageal dilator (Nissen fundoplication)
-Approximately 92% of patients obtain resolution of symptoms

GULLAIN BARRE SYNDROME

Definition
-Acute, autoimmune demyelinating poly-radiculo-neuropathy mainly presenting as symmetrical ascending
weakness.
Sex: The male-to-female ratio is 1.5:1.
Age: GBS occurs at all ages, but a bimodal distribution with peaks in young adulthood (15-35 y) and elderly persons
(50-75 y) appears to exist. Rare cases have been noted in infants.

85
Antecedent Events
-75% preceded 1 to 3 weeks by an acute infectious process, usually respiratory or gastrointestinal.
-20-30% -Campylobacter jejuni.
-20-30%a -Human herpes virus infection .sometimes CMV or EBV
-Other viruses and Mycoplasma pneumoniae
It occurs more frequently in patients with
a) Lymphoma, including Hodgkin's disease
b) HIV-seropositive individuals
c) SLE

Pathogenesis
-Autoimmune process where immune responses to non-self antigens (infectious agents, vaccines) that misdirect to
host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism
-Both cellular and humoral immune mechanisms contribute to tissue damage.
-M. Fisher syndrome (MFS), which presents as rapidly evolving ataxia and areflexia of limbs without weakness, and
ophthalmoplegia often with pupillary paralysis.
- The MFS variant accounts for ~5% of all GBS cases. Anti-GQ1b antibodies are found in >90% of patients with
MFS (and titers of IgM and IgG are highest early in the course. Anti-GQ1b antibodies are not found in other forms
of GBS unless there is extraocular motor nerve involvement. )
-In the demyelinating forms of GBS, the basis for flaccid paralysis and sensory disturbance is conduction block.
-The axonal connections remain intact. Hence, recovery can take place rapidly as remyelination occurs. In severe
cases of demyelinating GBS, secondary axonal degeneration usually occurs
- More secondary axonal degeneration correlates with a slower rate of recovery and a greater degree of residual
disability.

Clinical presentation
-Rapidly evolving areflexic motor paralysis +/- sensory disturbance.
Motor
-The usual pattern is an ascending paralysis.
-The legs are usually more affected than the arms
-Weakness evolves over hours to a few days.
-Deep tendon reflexes usually disappear within the first few days of onset
-Facial diparesis is present in 50% of affected individuals.
-The lower cranial nerves are also frequently involved, causing bulbar weakness and difficulty with handling
secretions and maintaining an airway.
-Respiratory muscles involvement require ventilator support
Sensory
-Sensory abnormalities less prominent and may include tingling dysesthesias in the extremities.
- Pain is common feature-deep aching pain in weakened muscles and the back. Are manifestation of sensory nerve
fiber involvement is self-limited and should be treated with standard analgesics.
Autonomic
-Bladder dysfunction may occur in severe cases but is usually transient
-Very severe requiring critical care -loss of vasomotor control with wide fluctuation in BP, postural hypotension,
and cardiac dysrhythmias.
NB. Fever and constitutional symptoms are absent at the onset
Mordidity-course
-Most patients require hospitalization, and almost 30% require ventilatory assistance at some time during the
illness.-Once clinical worsening stops and the patient reaches a plateau, the crisis is usually past.
- Improvement may begin within days of the plateau.
-However, in severe cases of GBS requiring critical care management, autonomic involvement is common.
- Usual features are loss of vasomotor control with wide fluctuation in blood pressure, postural hypotension, and
cardiac dysrhythmias.
-These features require close monitoring and management and can be fatal.

86
Subtypes of GBS
a) AIDP-Acute Inflammatory Demyelinating Polyradiculoneuropathy
–Main feature is demyelination and affects adults more than children.
- Recovery is rapid
b) AMAN-Acute Motor Axonal Neuropathy
c) AMSAN-Acute Motor -Sensory Axonal Neuropathy.
d) M. Fisher Syndrome-Also demyelinating.
-Has Ataxia, Areflexia and Ophthalmoplegia elaborate anti.GQIb antibodies.

DIAGNOSIS
Diagnostic Criteria Required
1. Progressive weakness of >2 limbs due to neuropathy
2. Areflexia
3. Disease course <4 weeks of weakness
4. Exclusion of other causes:
-Vasculitides-SLE, Polyarteritis nodosa, Chaug-straus syndrome
-Toxins-Lead, organophosphates, botulinism, diphtheria
-Porphyrias
-Localized spinal cord or caudal equine syndrome
Supportive
1. Relatively symmetrical weakness
2. Less sensory involvement
3. Facial nerve and other CN involvement
4. Absence of fever
5. CSF findings (acellular and raised proteins)
6. Electrophysiologic suggestive of demyelination
If the diagnosis is strongly suspected, treatment should be initiated without waiting for evolution of the
characteristic electrodiagnostic and CSF findings to occur.
-GBS patients with risk factors for HIV or with CSF pleocytosis should have a serologic test for HIV.

Investigations
Clinical diagnosis
Lab
Lumbar puncture
-CSF findings are distinctive, consisting of an elevated CSF protein level (100 to 1000 mg/dL) with normal cells. -
The CSF is often normal when symptoms have been present for <48 h; by the end of the first week the level of
protein is usually elevated.
Electromyography
-Electro diagnostic features are mild or absent in the early stages and lag behind the clinical evolution.
- In cases with demyelination prolonged distal latencies, conduction velocity slowing, evidence of conduction
block, and temporal dispersion of compound action potential are the usual features.
-In cases with primary axonal pathology, the principal electrodiagnostic finding is reduced amplitude of
compound action potentials without conduction slowing or prolongation of distal latencies.

TREATMENT
Supportive measures
1. Admission as is medical emergency. Do Lung vital capacity-Normal 4l. With decreased vital capacity
monitor every 2 hours and if fall below 2l transfer to ICU.
2. Prophylaxis to prevent DVT
3. Springs to support foot drop or hand drop to prevent contracture formation during recovery.
4. Active and passive exercises of the limbs.
5. Chest physiotherapy
6. Skin care-turning and kept dry.
7. Antibiotics cover to avoid infections especially while on ICU ventilators.
8. Care of the bladder-Catheterization. Condom catheters in men.
9. Analgesia for pain-Paracetamol.

87
HIV ASSOCIATED NEPHROPATHY (HIVAN)
Introduction
-Renal disease is a relatively common complication in patients with HIV disease.
-Renal disease in HIV infection can result from
1. Direct kidney infection with HIV/HIV associated nephropathy (HIVAN)
2. Due to an opportunistic infection or neoplasm
3. Drugs used to treat HIV and opportunistic infections and their resulting adverse effects
Specific
-Treatment should be initiated as soon after diagnosis as possible. Each day counts; ~2 weeks after the first motor
symptoms, immunotherapy is no longer effective.
-Either high-dose intravenous immune globulin (IVIg) or plasmapheresis can be initiated, as they are equally
effective
-IVIg is usually administered as five daily infusions for a total dose of 2 g/kg body weight.
-A course of plasmapheresis, consisting of ~40 to 50 mL/kg plasma exchange (PE) daily for 4 to 5 days, is usually
employed.
In patients who are treated early in the course of GBS and improve, relapse may occur in the second or third week..

PROGNOSIS AND RECOVERY

-Approx. 85% of patients with GBS achieve a full functional recovery within several months to a year, although
minor findings on examination (such as areflexia) may persist.
-The mortality rate is <5% in optimal settings; death usually results from secondary pulmonary complications. -
Other factors that worsen the outlook for recovery are
 Advanced age
 Fulminant or severe attack
 Delay in the onset of treatment.

DDX
1.Chronic inflammatory demyelinating polyneuropathy
2. Tick paralysis
3.Transverse myelitis
4. Poliomyelitis
5. Toxins-Lead, organophosphates, botulinism, diphtheria
Porphyrias
6.Folate or vit. B12deficiency
7.Hereditary neuropathies
8.Neoplasia-Spinal cord compression
Spinal cord syndromes, particularly postinfection
9. Vasculitidis-SLE, Polyarteritis nodosa, Chaug-straus syndrome
10.Myasthenia Gravis
11.Polymyositis

Complications
1. Persistent paralysis
2. Respiratory failure, mechanical ventilation
3. Hypotension or hypertension
4. Thromboembolism, pneumonia, skin breakdown
5. Cardiac arrhythmia
6. Ileus
7. Aspiration
8. Urinary retention
9. Psychiatric problems such as depression and anxiety

-Among the drugs commonly associated with renal damage in patients with HIV disease is
1) Pentamidine
2) Amphotericin B
3) Anti-virals-Adefovir, Cidofovir,Foscarnet

88
 4) TMP/SMZ may compete for tubular secretion with creatinine and cause an increase in the serum creatinine
level.
5) Sulfadiazine may crystallize in the kidney and result in an easily reversible form of renal shutdown.
6) Indinavir-associated renal calculi. One of the most common drug-induced renal complications Occur ~10%
of patients receiving this HIV protease inhibitor. It may present with a variety of manifestations, ranging
from asymptomatic hematuria to renal colic. Adequate hydration is the mainstay of treatment and
prevention for this condition.
4. Prerenal azotemia due to volume depletion resulting from salt wasting, poor nutrition, nausea, vomiting and
diarrhea

Definition
-HIV-associated nephropathy (HIVAN) is due to direct infection by the HIV virus-consists of a pentad of findings,
including
(1) Proteinuria
(2) Azotemia
(3) Normal blood pressure
(4) Normal-to-large kidneys on ultrasonography images (5) Focal segmental glomerulosclerosis on renal biopsy
findings.
-Once diagnosed, rapid progression to renal failure and end-stage renal disease (ESRD) leading to death or the need
for dialysis was the norm in the pre–antiretroviral therapy era. HAART therapy has been shown to retard the
progression of renal disease in persons with HIVAN.
-Antiretroviral therapy has changed the natural course of this disease.
-HIVAN has both tubulointerstitial and glomerular components.
-HIVAN must be considered in patients who are seropositive for HIV and have proteinuria.
Race
-HIVAN is observed predominantly among African Americans and is the third leading cause of ESRD among black
persons aged 20-64 years.
Sex
-HIVAN is observed more often in men than in women, with a male-to-female ratio of 10:1. The mean age of
persons with HIVAN is 33 years.

Pathogenesis
-The cellular target for developing HIVAN is likely the renal glomerular and tubular epithelium.
-Renal glomerular and tubular epithelial cells are productively infected by HIV-1 in patients with HIVAN, localized
replication of HIV-1 in the kidney and the existence of a renal viral reservoir is thought to occur.
-Exact mechanisms of virus-induced renal injury remain undetermined.
-The net and long-standing glomerular and tubular epithelial cell damage leads to proteinuria, glomerulosclerosis,
and tubulointerstitial scarring.
Genetics
-Since not all infected with HIV develop HIVAN, there may be a genetic predisposition. The type of host response
to the HIV infection itself may be what determines who develops nephropathy.
Histology
-On ultrasound images or when examined at autopsy, HIVAN patients have enlarged and echogenic kidneys. This
may result from prominent interstitial expansion by cellular infiltrate and markedly dilated tubules containing
voluminous casts.
-Light microscopy
 Focal-segmental glomerulosclerosis.
 The glomerular capillary tuft is collapsed may be segmentally or globally sclerosed.
 Visceral epithelial cells are hypertrophied and form a characteristic pseudocrescent in the Bowman space.
 Tubulointerstitial scarring, atrophy, and marked dilatation of the tubules (microcystic dilatations)
-Immunofluorescent microscopy -Positive staining for albumin, IgG, IgM, C3, and, IgA, in mesangial or sclerotic
areas.
-Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation, and focal foot
process effacement.

Clinical presentation

89
-HIVAN patients typically present with a nephrotic like syndrome consisting of
1) Nephrotic-range proteinuria (>3.5 g/d)
2) Azotemia
3) Hypoalbuminemia
-Occasionally with edema and Hyperlipidemia.
-Normal renal function upon presentation is uncommon. The CD4 count in these patients is usually depressed below
200 cells/mL, but HIVAN has been reported in patients with higher CD4 counts.
-The prognosis for renal survival is worse in patients with clinical AIDS, especially if their CD4 count is less than
50 cells/mL.
-Patients with HIVAN are not typically hypertensive, even in the face of renal insufficiency.
-Kidneys are usually normal-to-large and highly echogenic on ultrasonography images.
-Routine urinalysis may occasionally reveal findings of nonnephrotic proteinuria in patients being evaluated for
other medical conditions.
T-he urinalysis reveals microhematuria, leukocytes, hyaline casts, and oval fat bodies, but no cellular casts.
-Serum complement levels are normal

Indications for biopsy

-To distinguish HIVAN from other forms of renal disease as, immune complex glomerulonephritis, IgA
nephropathy.
-The typical practice is to obtain a renal biopsy specimen if the patient's daily protein excretion is greater than 1
gram.

MANAGEMENT
-Most patients present with HIVAN with the CD 4 count below 200 and start of anti-retroviral drugs retard the
progression to chronic renal failure.
1st line
-Stavudine (D4T) +Lamivudine (3TC) +Nevirapine(NVP)
OR
-Stavudine (D4T) +Lamivudine (3TC) +Efavirenz(EFV)

Doses
-Stavudine-30mg BD
-Lamivudine-150mg BD
-Nevirapine-200mg BD (OD for first 2 weeks)
-Efavirenz-600mg OD (at night)
-NB. OD NVP is recommended for the first 2 weeks of treatment to reduce the incidence of hepatotoxicity and
severe rash.
2nd line
-Zidovudine (AZT) + Didanosine (ddI) + LPN/r (kaletra)
OR
-Zidovudine (AZT) + Didanosine (ddI) + NVP
Doses
-Zidovudine -300mg BD
-Didanosine-250 mg OD in those <60 kg and 400mg OD in those >60 kg
-Kaletra(LPN/r)-400mg/100mg BD
-Fixed dose combination are available for the following drug combinations-improve compliance by reducing the pill
burden.
-AZT/3TC-Combivir
-D4T/3TC
-D4T/3TC/NVP
Corticosteroids
-Corticosteroids offer some short-term benefit.
-Prednisone at 60 mg/d for 2-11 weeks, followed by a slow taper.
ACE inhibitors
-In patients with advanced renal insufficiency, captopril was noted to improve renal survival.

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-May be related to a hemodynamic effect, a reduction in the transglomerular passage of serum proteins, and an
antiproliferative effect mediated, in part, by inhibiting transforming growth factor-beta.
-Use angiotensin-converting enzyme inhibitors if patients do not have hyperkalemia or if their serum creatinine level
is greater than 2 mg/dL.
Cyclosporine
-In pediatric populations cyclosporine can be effective in reducing the proteinuria observed in persons with HIVAN.
HYPERTENSION
7TH JOINT NATIONAL COMMITTEE ON HYPERTNSION
Dialysis
-Hemodialysis is the accepted modality of ESRD therapy in this population.
-Because of increased susceptibility to infections, peritoneal dialysis has not been
Classification of Hypertension widely advocated.

BP SBP* DBP*
Classification mmHg mmHg

Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 140-159 or 90-99

Hypertension

Stage 2 >160 >100

Hypertension

Need for JNC 7

(1) Publication of many new hypertension observational studies and clinical trials
(2) Need for a new, clear, and concise guideline that would be useful for clinicians
(3) Need to simplify the classification of blood pressure
(4) Clear recognition that the JNC reports were not being used to their maximum benefit
-Classification of BP for adults ages 18 and older.
-The classification is based on the average of two or more properly measured seated BP readings on each of two or
more office visits.

Cardiovascular disease risk

-As the population ages, the prevalence of hypertension increases unless broad and effective preventive measures
are implemented.
-Individuals who are normotensive at age 55 have a 90 percent lifetime risk for developing hypertension.
-The relationship between BP and risk of CVD events is continuous, consistent, and independent of other risk
factors.
The higher the BP, the greater is the chance
 Heart attack
 Heart failure
 Stroke
 Kidney disease.
-For individuals 40–70 years of age, across the entire BP range from 115/75 to 185/115 mmHg each increment of 20
mmHg SBP or 10 mmHg in DBP doubles the risk of CVD.
-The classification “Prehypertension,”, recognizes this relationship and signals the need for increased education of
health care professionals and the public to reduce BP levels and prevent the development of hypertension in the
general population.

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Hypertension prevention strategies are available to achieve this e.g. Lifestyle Modifications
Benefits of lowering the Blood pressure
-Antihypertensive therapy has been associated with reductions
 stroke incidence by 35–40%
 myocardial infarction 20–25%
 heart failure >50 %

control Blood pressure rates

-Goal blood pressure treatment in hypertension is BP below 140/90 mmHg or below 130/80 mmHg for patients with
diabetes or chronic kidney disease.
-In the majority of patients, controlling systolic hypertension has been considerably more difficult than controlling
diastolic hypertension.
-Systolic hypertension is a more important CVD risk factor than DBP except in patients younger than age 50 years.
It also occurs much more commonly in older persons.
-Effective BP control can be achieved in most patients who are hypertensive, but the majority will require two or
more antihypertensive drugs.
-Challenges in BP control
 Patient compliance to drug intake
 clinicians fail to prescribe lifestyle modifications
 Inappropriate antihypertensive drug doses
 Inappropriate antihypertensive drug combinations

Accurate blood pressure measurement in the office

-The auscultatory method of BP measurement with a properly calibrated and validated instrument should be used.
-Persons should be seated quietly for at least 5 minutes in a chair (rather than on an exam table), with feet on the
floor, and arm supported at heart level.
-Measurement of BP in the standing position is indicated periodically, especially in those at risk for postural
hypotension.
-An appropriate-sized cuff (cuff bladder encircling at least 80 percent of the arm) should be used to ensure accuracy.
-At least two measurements should be made. SBP is the point at which the first of two or more sounds is heard phase
1), and DBP is the point before the disappearance of sounds (phase 5).
-Clinicians should provide to patients, verbally and in writing, their specific BP numbers and BP goals.

PATIENT EVALUATION
History
1. To assess lifestyle and identify cardiovascular risk factors
Major risk factors
Modifiable
 Hypertension
 Cigarette smoking
 Hyperlipidaemia
 Diabetes mellitus
Non-modifiable factors
 Age (older than 55 for men, 65 for women)
 Family history of premature cardiovascular disease(men under age 55 or women under age 65)
 Male gender
Minor risk factors
 Obesity* (body mass index ≥30 kg/m2)
 Physical inactivity
 Microalbuminuria or estimated GFR <60 mL/min
 Stress type A personality
 Low HDL
 Post menopausal estrogen deficiency

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  Excessive Alcohol intake
 Homocysteine
 Lipoprotein a
 Chronic inflammation
 High fat diet

(2) To reveal identifiable causes of high BP

 Chronic kidney disease
 Endocrine causes
-Primary aldosteronism
- Pheochromocytoma
-Thyroid or parathyroid disease
-Cushings syndrome
-Acromegaly
 Renovascular disease
 Coarctation of the aorta
 Drug-induced or related causes
-Chronic steroid therapy
 Sleep apnea

(3) To assess the presence or absence of target organ damage and CVD

 Heart
-Left ventricular hypertrophy
-Angina or prior myocardial infarction
-Prior coronary revascularization
-Heart failure
 Brain
-Stroke or transient ischemic attack
 Chronic kidney disease
 Peripheral arterial disease
 Retinopathy

Physical examination-Conventional CVS examination plus:

-Appropriate measurement of BP, with verification in the contralateral arm
-Examination of the optic fundi
-Calculation of body mass index (BMI) (measurement of waist circumference also may be useful)
-Auscultation for carotid, abdominal, and femoral bruits
-Palpation of the thyroid gland
-Thorough examination of the heart and lungs;
-Examination of the abdomen for enlarged kidneys, masses, and abnormal aortic pulsation
-Palpation of the lower extremities for edema and pulses; and neurological assessment.

Laboratory Tests and Other Diagnostic Procedures

Routine laboratory tests recommended before initiating therapy include:
Lab
1. FHG
HB level
2. U/E/C
Urea, electrolyte (Na+, K+, Ca+) and creatinine. Estimation of creatinine clearance
(140-Age)* Body Weight
Serum creatinine
3. Urinalysis-Microalbinaemia
4. Random blood sugar/Fasting Blood sugar

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5. Fasting Lipid profile after 9- to 12-hour fast, which includes high density lipoprotein cholesterol and low-density
lipoprotein cholesterol, and triglycerides
Imaging
6. CXR
7. ECG
7. Echocardiograph
-Optional tests include measurement of urinary albumin excretion or albumin/creatinine ratio.
Other tests may be done to diagnose the etiology of secondary hypertension

MANAGEMENT OF HYPERTENSION
Goals of Therapy
The ultimate public health goal of antihypertensive therapy is the reduction of cardiovascular and renal morbidity
and mortality.
Since most persons with hypertension, especially those age >50 years, will reach the DBP goal once SBP is at goal,
the primary focus should be on achieving the SBP goal.
Treating SBP and DBP to targets that are <140/90 mmHg is associated with a decrease in CVD complications.
In patients with hypertension and diabetes or renal disease the BP goal is <130/80 mmHg

NON -PHARMACOLOGICAL
Lifestyle Modifications
-Adoption of healthy lifestyles by all persons is critical for the prevention of high BP and is an indispensable part of
the management of those with hypertension.
Major lifestyle modifications shown to lower BP include
1. Weight reduction
-In those individuals who are overweight or obese.
-Maintain normal body weight body mass index 18.5–24.9 kg/m2
-Reduction by 5–20 mmHg/10 kg weight loss
2. Physical activity
- Engage in regular aerobic physical activity such as brisk walking (at least 30 min per day, most days of the week
3. Adopt DASH
(Dietary Approaches to Stop HTN)
-Consume a diet rich in fruits, vegetables
-Low fat dairy products with a reduced content of saturated and total fat.
-Monounsaturated fats and omega 3 and 6 oils should have less CVS risks.
3. Dietary sodium reduction
-Reduce dietary sodium intake to no more than 100mmol per day (2.4 g sodium or 6 g sodium chloride).
4.).
5. Moderation of alcohol Limit consumption
- To no more than consumption 2 drinks (30 mL ethanol) per day in most men and to no more than 1 drink per day
in women and lighter weight persons.
-Benefits of Lifestyle modifications
 Reduce BP
 Enhance antihypertensive drug efficacy
 Decrease cardiovascular risk.
Combinations of two (or more) lifestyle modifications and drug therapy achieve even better results.

Pharmacologic Treatment
-Most patients require combination of anti hypertensive drugs to achieve goal BP control.
-Commonly used groups of drugs include:
1) Angiotensin converting enzyme inhibitors (ACEI)
2) Angiotensin receptor blockers (ARBs)
3) Beta-blockers (BBs)
4) Calcium channel blockers (CCBs)
5) Diuretics

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-Diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension.
-Diuretics enhance the antihypertensive efficacy of multidrug regimens, can be useful in achieving BP control, and
are more affordable than other antihypertensive agents.
Despite these findings, diuretics remain underutilized.
-Thiazide-type diuretics should be used as initial therapy for most patients with hypertension, either alone or in
combination with one of the other classes (ACEIs, ARBs, BBs, CCBs)
Thiazide diuretics
 Chlorothiazide
 hydrochlorothiazide
 chlorthalidone
 polythiazide
 indapamide
 metolazone
Loop diuretics
 bumetanide (Bumex†
 furosemide (Lasix†)
 torsemide (Demadex†)
Potassium-sparing diuretics
 amiloride (Midamor†)
 triamterene (Dyrenium)
Aldosterone receptor blockers
 eplerenone (Inspra)
 spironolactone (Aldactone†)
Beta-Blockers
 atenolol (Tenormin†)
 betaxolol (Kerlone†)
 bisoprolol (Zebeta†)
 metoprolol (Lopressor†)
 metoprolol extended release (Toprol XL)
 nadolol (Corgard†)
 propranolol (Inderal†)
 propranolol long-acting (Inderal LA†)
 timolol (Blocadren†)
BBs with intrinsic sympathomimetic activity
 acebutolol (Sectral†)
 penbutolol (Levatol)
 pindolol (generic)
Combined alpha- and BBs
 carvedilol (Coreg)
 labetalol (Normodyne, Trandate†)
Angiotensin converting enzyme inhibitors (ACEIs)
 benazepril (Lotensin†)
 captopril (Capoten†)
 enalapril (Vasotec†)
 fosinopril (Monopril)
 lisinopril (Prinivil, Zestril†)
 moexipril (Univasc)
 perindopril (Aceon)
 quinapril (Accupril)
 ramipril (Altace)
 trandolapril (Mavik)
Angiotensin II Receptor antagonists
 candesartan (Atacand)
 eprosartan (Teveten)
 irbesartan (Avapro)
 losartan (Cozaar)

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  olmesartan (Benicar)
 telmisartan (Micardis)
 valsartan (Diovan)
Calcium channel Blockers
Non-Dihydropyridines
 diltiazem extended release (Cardizem LA)
 verapamil immediate release (Calan, Isoptin†)
 verapamil long acting (Calan SR, Isoptin SR†)
 verapamil—Coer, Covera HS, Verelan PM)
Calcium channel blocker
Dihydropyridines
 amlodipine (Norvasc)
 felodipine (Plendil)
 isradipine (Dynacirc CR)
 nicardipine sustained release (Cardene SR)
 nifedipine long-acting (Adalat)
 nisoldipine (Sular)
Alpha-1 blockers
 doxazosin (Cardura)
 prazosin (Minipress†)
 terazosin (Hytrin)
Central alpha-2 agonists
 clonidine (Catapres†)
 methyldopa (Aldomet†)
 reserpine (generic)
 guanfacine (Tenex†)
Direct vasodilators
 Hydralazine (Apresoline†)
 Minoxidil (Loniten†)

SPECIAL CONSIDERATIONS
Ischemic Heart Disease
-Ischemic heart disease (IHD) is the most common form of target organ damage associated with hypertension.
-In patients with hypertension and stable angina pectoris, the first drug of choice is usually a BB; alternatively, long-
acting CCBs can be used.
-In patients with acute coronary syndromes (unstable angina or myocardial infarction), hypertension should be
treated initially with BBs and ACEIs, with addition of other drugs as needed for BP control.
-In patients with postmyocardial infarction, ACEIs, BBs, and aldosterone antagonists have proven to be most
beneficial.
-Intensive lipid management and aspirin therapy are also indicated.
Heart Failure
-Heart failure (HF), in the form of systolic or diastolic ventricular dysfunction, results primarily from systolic
hypertension and IHD.
-Fastidious BP and cholesterol control are the primary preventive measures for those at high risk for HF.
In asymptomatic individuals with demonstrable ventricular dysfunction, ACEIs and BBs are recommended.
-For those with symptomatic ventricular dysfunction or end-stage heart disease, ACEIs, BBs, ARBs and aldosterone
blockers are recommended along with loop diuretics.
Diabetic Hypertension
-Combinations of two or more drugs are usually needed to achieve the target goal of <130/80 mmHg.
-Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs are beneficial in reducing CVD and stroke incidence in patients
with diabetes.
ACEI- or ARB-based treatments favorably affect the progression of diabetic nephropathy and reduce albuminuria
and ARBs have been shown to reduce progression to macroalbuminuria.
Chronic Kidney Disease
-In people with chronic kidney disease (CKD), as defined by either

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(1) Reduced excretory function with an estimated GFR below 60 ml/min per 1.73 m2 (corresponding approximately
to a creatinine of >1.5 mg/dL in men or
>1.3 mg/dL in women)
(2) The presence of albuminuria (>300 mg/day or 200 mg albumin/g creatinine), therapeutic goals are to slow
deterioration of renal function and prevent CVD. Hypertension appears in the majority of these patients, and they
should receive aggressive BP management, often with three or more drugs to reach target BP values of<130/80
mmHg.
-ACEIs and ARBs have demonstrated favorable effects on the progression of diabetic and non diabetic renal
disease. A limited rise in serum creatinine of as much as 35 percent above baseline with ACEIs or ARBs is
acceptable and is not a reason to withhold treatment unless hyperkalemia develops.
-With advanced renal disease (estimated GFR <30 ml/min 1.73 m2, corresponding to a serum creatinine of 2.5–3
mg/dL), increasing doses of loop diuretics are usually needed in combination with other drug classes.
Cerebrovascular Disease
The risks and benefits of acute lowering of BP during an acute stroke are still unclear; control of BP at intermediate
levels (approximately 160/100 mmHg) is appropriate until the condition has stabilized or improved.
-Recurrent stroke rates are lowered by the combination of an ACEI and thiazide-type diuretic
Hypertension in women
Oral contraceptives may increase BP, and the risk of hypertension increases with duration of use.
Women taking oral contraceptives should have their BP checked regularly. Development of hypertension is a reason
to consider other forms of contraception. In contrast, menopausal hormone therapy does not raise BP.
Women with hypertension who become pregnant should be followed carefully because of increased risks to mother
and fetus.
-Methyldopa, BBs, and vasodilators are preferred medications for the safety of the fetus.
-ACEI and ARBs should not be used during pregnancy because of the potential for fetal defects and should be
avoided in women who are likely to become pregnant.
-Preeclampsia, which occurs after the 20th week of pregnancy, is characterized by new-onset or worsening
hypertension, albuminuria, and hyperuricemia, sometimes with coagulation abnormalities.
-In some patients, preeclampsia may develop into a hypertensive urgency or emergency and may require
hospitalization, intensive monitoring, early fetal delivery, and parenteral antihypertensive and anticonvulsant
therapy
Potential favorable effects of anti-hypertensives
-Thiazide-type diuretics are useful in slowing demineralization in osteoporosis.
-BBs can be useful in the treatment of atrial tachyarrhythmias/ fibrillation, migraine, thyrotoxicosis (short term),
essential tremor, or perioperative hypertension.
-CCBs may be useful in Raynaud’s syndrome and certain arrhythmias,
- Alpha-blockers may be useful in prostatism.
Potential unfavorable effects
-Thiazide diuretics should be used cautiously in patients who have gout or who have a history of significant
hyponatremia.
-BBs should generally be avoided in individuals who have asthma, reactive airways disease, or second or third
degree heart
block.
- ACEIs and ARBs should not be given to women likely to become pregnant and are contraindicated in those
who are.
-ACEIs should not be used in individuals with a history of angioedema.
-Aldosterone antagonists and potassium-sparing diuretics can cause hyperkalemia and should generally be avoided
in patients who have serum potassium values more than 5.0 mEq/L while not taking medications.

Obesity and the metabolic syndrome

-Obesity (BMI >30 kg/m2) is an increasingly prevalent risk factor for the development of hypertension and CVD.
Metabolic syndrome as the presence of three or more of the following conditions:
1) Abdominal obesity (waist circumference >40 inches in men or >35 inches in women)
2) Glucose intolerance (fasting glucose >110 mg/dL)
3) BP >130/85 mmHg
4) High triglycerides (>150 mg/dL) or low HDL (<40 mg/dL in men or <50 mg/dL in women).

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-Intensive lifestyle modification should be pursued in all individuals with the metabolic syndrome, and appropriate
drug therapy should be instituted for each of its components as indicated.

Left ventricular hypertrophy

-Left ventricular hypertrophy (LVH) is an independent risk factor that increases the risk of subsequent CVD.
Regression of LVH occurs with aggressive BP management, including weight loss, sodium restriction, and treatment
with all classes of antihypertensive agents except the direct vasodilators hydralazine, and minoxidil.

Peripheral arterial disease

-Peripheral arterial disease (PAD) is equivalent in risk to IHD. Any class of antihypertensive drugs can be used
in most
PAD
patients.
Other risk factors should be managed aggressively, and aspirin should be used.
Postural hypotension
-A decrease in standing SBP >10 mmHg, when associated with dizziness or fainting, is more frequent in older
patients with systolic hypertension, diabetes, and those taking diuretics, venodilators (e.g., nitrates, alpha-blockers,
and sildenafil like drugs), and some psychotropic drugs.
-BP in these individuals should also be monitored in the upright position. Caution should be used to avoid volume
depletion and excessively rapid dose titration of antihypertensive drugs.

Resistant Hypertension
-Resistant hypertension is the failure to reach goal BP in patients who are adhering to full doses of an appropriate
three-drug regimen that includes a diuretic.
Causes
1. Improper BP Measurement
2. Identifiable Causes of Hypertension.
3. Volume Overload and Pseudo tolerance
• Excess sodium intake
• Volume retention from kidney disease
• Inadequate diuretic therapy
4. Drug-Induced or Other Causes
• Non adherence
• Inadequate doses
• Inappropriate combinations
• Nonsteroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors
• Cocaine, amphetamines, other illicit drugs
• Sympathomimetics (decongestants, anorectics)
• Oral contraceptives
• Adrenal steroids
• Cyclosporine and tacrolimus
• Erythropoietin
• Licorice (including some chewing tobacco)
• Selected over-the-counter dietary supplements and medicines
(e.g., ephedra, ma haung, bitter orange)
5. Associated Conditions
• Obesity
• Excess alcohol intake

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HYPERTENSIVE EMERGENCIES
Introduction
-Joint National Committee (JNC-7) has introduced a new classification system for HTN.
Pre-hypertension
 Systolic blood pressure(SBP) 120-139
 Diastolic blood pressure(DBP) 80-89
Stage I HTN
 SBP 140-159
 DBP 90-99
Stage II HTN
 SBP >160
 DBP >100
-Hypertensive crises encompass a spectrum of clinical presentations where uncontrolled BPs lead to progressive or
impending target organ dysfunction (TOD).
-The clinical distinction between hypertensive emergencies and hypertensive urgencies depends on the presence of
acute TOD and not on the absolute level of the BP.
Hypertensive emergency
-Hypertensive emergencies represent severe HTN with acute impairment of an organ system (eg central nervous
system [CNS], cardiovascular, renal).
- In these conditions, the BP should be lowered aggressively over minutes to hours.
Hypertensive urgency
-Hypertensive urgency is defined as a severe elevation of BP, without evidence of progressive TOD.
-These patients require BP control over hours to days.

Pathophysiology:
-The pathophysiology of hypertensive emergencies is not well understood. However, an abrupt rise in vascular
resistance seems to be a necessary initial step. The 3 major organ systems affected by high BP are the CNS,
cardiovascular system, and renal system.
Central nervous system
-Cerebral autoregulation is the inherent ability of the cerebral vasculature to maintain a constant cerebral blood flow
(CBF) despite changes in blood pressure.
-As mean arterial pressure (MAP) increases, the cerebral endothelium is disrupted and the blood-brain barrier can
become interrupted.
-This leads to cerebral edema and microhemorrhages. Patients with chronic HTN can tolerate higher MAPs before
they have disruption of their autoregulation system. However, such patients also have increased cerebrovascular
resistance and are more prone to cerebral ischemia when flow decreases.
-Hypertensive encephalopathy is one of the clinical manifestations of cerebral edema and microhemorrhages seen
with dysfunction of cerebral autoregulation.
Cardiovascular system
-HTN affects the structure and function of the coronary vasculature and left ventricle.
-HTN also activates the renin-angiotensin-aldosterone system, causing systemic vasculature constriction. This
results in increasing myocardial oxygen demand by increasing the left ventricular wall tension and leads to left
ventricular hypertrophy and coronary compression.
-During hypertensive emergencies, the left ventricle cannot overcome systemic vascular resistance. This leads to left
ventricular failure and pulmonary edema or myocardial ischemia.
Renal system
-Chronic HTN causes pathologic changes to the small arteries of the kidney. The arteries develop endothelial
dysfunction and impaired vasodilation, which alter renal autoregulation.
-When the renal autoregulatory system is disrupted, the intraglomerular pressure starts to vary directly with the
systemic arterial pressure, thus offering no protection to the kidney during BP fluctuations.
-During a hypertensive crisis, this can lead to acute renal ischemia.

Mortality/Morbidity:
-Death from both ischemic heart disease and stroke increase progressively as the BP increases. For every 20 mm Hg
systolic or 10 mm diastolic increase in BP, the mortality rate from both ischemic heart disease and stroke doubles.

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-The morbidity and mortality of hypertensive emergencies depend on the extent of TOD on presentation and the
degree to which BP is controlled subsequently.
- With BP control and medication compliance, the 10-year survival rate of patients with hypertensive crises
approaches 70%.
Sex:
-Overall, the prevalence and incidence of HTN is slightly higher in men than in women.
-Hypertensive crises are two times more frequent in males than in females.

Age:
- Hypertensive crises are more common among elderly persons.

Etiology
-The most common hypertensive emergency is a rapid unexplained rise in BP in a patient with chronic essential
HTN.
-Other causes
A) Renal parenchymal disease
 Chronic pyelonephritis.
 Primary glomerulonephritis.
 Tubulointerstitial nephritis (accounts for 80% of all secondary causes)
B) Renovascular disease
 Atherosclerotic disease
 fibromuscular dysplasia
 polyarteritis nodosa
c) Systemic disorders with renal involvement
 Systemic lupus erythematosus
 Systemic sclerosis
 Vasculitides
D) Endocrine
 Pheochromocytoma
 Cushing syndrome
 Primary hyperaldosteronism
E) Drugs
 Cocaine
 Amphetamines
 Cyclosporine
 Clonidine withdrawal
 Phencyclidine
 diet pills, oral contraceptive pills
F) Drug interactions
 Monoamine oxidase inhibitors with tricyclic antidepressants, antihistamines, or tyramine-containing food
G) CNS
 CNS trauma
 spinal cord disorders, such as Guillain-Barré syndrome
Others
-Coarctation of the aorta
-Preeclampsia/eclampsia
-Postoperative hypertension

Clinical presentation.

History:
-The history should focus on
 The presence of TOD
 Circumstances surrounding the HTN
 Any identifiable etiology.

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-Assess whether specific symptoms suggesting TOD are present.
 Chest pain - Myocardial ischemia or infarction
 Sharp retrosternal pain radiating to the back.- Aortic dissection
 Dyspnea - Pulmonary edema, congestive heart failure
 Neurologic symptoms - Seizures, visual disturbances, altered level of consciousness (hypertensive
encephalopathy
-Presence of previous TOD, particularly renal and cerebrovascular disease
-Duration and severity of preexisting HTN
-Degree of BP control
-Medications
 Details of antihypertensive drug therapy and compliance
 Intake of over-the-counter preparations such as sympathomimetic agents
 Use of illicit drugs such as cocaine.
-Date of last menstrual period
-Other medical problems (eg, prior HTN, thyroid disease, Cushing disease, systemic lupus, renal disease)

Physical:
-The physical examination should assess whether TOD is present.
-Vitals
 BP should be measured in both the supine position and the standing position (assess volume depletion)
 BP should also be measured in both arms (a significant difference suggests an aortic dissection)
-Fundoscopy
The presence of new retinal hemorrhages, exudates, or papilledema suggests a hypertensive emergency.
-Cardiovascular - Evaluate for the presence of heart failure.
 Jugular venous distension
 Crackles
 Peripheral edema
-Abdomen - Abdominal masses or bruits
-CNS
 Level of consciousness
 Visual fields
 Focal neurologic signs

Differential Diagnosis
 Acute Coronary Syndrome
 Aneurysm, Abdominal
 Congestive Heart Failure and Pulmonary
 Edema
 Cushing Syndrome
 Delirium Tremens
 Dissection, Aortic
 Encephalitis
 Glomerulonephritis, Acute
 Headache, Cluster Migraine Tension
 Hyperthyroidism, Thyroid Storm, and Graves Disease
 Myocardial Infarction
 Pregnancy, Eclampsia Preeclampsia
 Stroke, Hemorrhagic Ischemia
 Intracranial bleeds
Investigations
1. Electrolytes, BUN, and creatinine levels to evaluate for renal impairment
2. CBC and smear to exclude microangiopathic anemia
3. Urinalysis (UA)
Dipstick UA to detect hematuria or proteinuria (renal impairment)

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Microscopic UA to detect RBCs or RBC casts (renal impairment
4. Optional studies
 Toxicology screen
 Pregnancy test
 Endocrine testing
Imaging Studies:
1. Chest radiography is indicated in patients with chest pain or shortness of breath.
 Cardiac enlargement
 Pulmonary edema
 Widened mediastinum
2. Head CT scans are indicated in patients with abnormal neurologic examinations.
 Intracranial bleeding
 Cerebral edema
 Cerebral infarction
3. Electrocardiogram (ECG) to assess for evidence of myocardial ischemia or left ventricular hypertrophy
4. Chest CT scan, Tran esophageal echocardiography, or aortic angiogram is indicated in cases where aortic
dissection is suspected.

Treatment
-Patients with TOD usually require admission and rapid lowering of BP using intravenous (IV) medications.
-Suggested medication depends on the affected organ system.
-Even in cases of hypertensive emergencies, the BP should not be lowered to normal levels.
-Rapid reduction in BP below the cerebral, renal, and/or coronary autoregulatory range will result in marked
reduction in organ blood flow, possibly leading to ischemia and infarction.
-In general, the MAP should be lowered by no more than 20-25% in the first hour of treatment. If the patient
remains stable, the BP should then be lowered to 160/100-110 in the next 2-6 hours. Please note the exceptions to
this general rule listed below.
-These BP goals are best achieved by a continuous infusion of a short-acting, titratable, parenteral antihypertensive
agent along with constant, intensive patient monitoring.
-Rapid BP reduction is indicated in the following circumstances:
1. Acute myocardial ischemia
 Nitroglycerin IV
 Beta-blockers IV
2. CHF with pulmonary edema
 Nitroglycerin IV
 Lasix IV
 Nitroprusside IV
3. Acute aortic dissection:
In cases of acute aortic dissection, the SBP should be decreased as rapidly as possible to a goal of 100-110 mm Hg
or lower.
Labetalol IV
Alternative - Nitroprusside IV with beta-blocker IV (eg, esmolol)
4. CVA:
-Evidence exists those patients who have acute strokes have better outcomes with higher BPs. Antihypertensive
therapy is not routinely recommended for patients with acute stroke and HTN.
-Recent ischemic stroke and a SBP >220 mm Hg or a DBP > 120-140 mm Hg can undergo cautious reduction of BP
by about 10-15% (with IV nitroprusside or IV labetalol), if the patient is carefully monitored for neurologic
deterioration related to the lower pressure.
-Intracranial hemorrhage (ICH): A precipitous fall in SBP may compromise cerebral perfusion and increase
mortality.
-The controlled lowering of BP with IV nitroprusside or IV labetalol (in the absence of bradycardia) is currently
recommended only when the SBP is >200 mm Hg or the DBP is >110.

-Monoamine oxidase (MAO)-tyramine interactions with acute hypertension

 Phentolamine IV
-Pheochromocytoma

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  Phentolamine IV
 Labetalol IV
-Hypertensive encephalopathy
 Nitroprusside IV
 Labetalol IV
 Fenoldopam IV
-Acute renal failure
 Fenoldopam IV
 Nicardipine IV
 Beta-blockers IV
-Eclampsia
 Hydralazine IV
 Labetalol IV
 Magnesium IV
Outpatient Management
-The Joint National Committee on High Blood Pressure has published a series of recommendations for appropriate
follow-up, assuming no TOD.
 Prehypertension (SBP 120-139, DBP 80-89: BP should be rechecked within 1 year.
 Stage I HTN (SBP 140-159, DBP 90-99): BP should be rechecked within 2 months.
 Stage II HTN: (SBP > 160 or DBP >100): Refer to source of care within 1 month.
-If BP is >180/110, patient should be evaluated and treated within 1 week
Complications
 Congestive heart failure
 Myocardial infarction
 Renal failure
 Retinopathy
 Cerebrovascular accident
 Hypertensive encephalopathy
 Abrupt lowering of BP may result in inadequate cerebral or cardiac blood flow, leading to stroke or
myocardial ischemia.

HYPERTENSIVE ENCEPHALOPATHY
Definition
-Brain dysfunction or damage resulting from malignant hypertension, clinically manifesting as headache, nausea,
emesis, seizures, altered mental status (in some cases progressing to coma), papilledema, and retinal hemorrhage.
-Focal neurologic signs may develop. Pathologically, this condition may be associated with the formation of
ischemic lesions in the brain (brain ischemia).
-The clinical symptoms usually are reversible with prompt initiation of therapy.
-In the evaluation of an encephalopathic patient, exclude systemic disorders and various cerebrovascular events that
may present with a similar constellation of clinical findings
Introduction
-Hypertensive crisis is classified as hypertensive emergency or hypertensive urgency.
-Acute or ongoing vital target organ damage, such as damage to the brain, kidney, or heart, in the setting of severe
hypertension is considered a hypertensive emergency. It requires a prompt reduction in blood pressure within
minutes or hours.
-The absence of target organ damage in the presence of severe elevation of blood pressure with diastolic blood
pressure frequently greater than 120 mm Hg is considered hypertensive urgency, and it requires reduction in blood
pressure within 24-48 hours.
- A continuum exists between the clinical syndrome of hypertensive urgency and emergency; hence, their distinction
may be imprecise.
-Hypertensive encephalopathy occurs with the accelerated malignant phase of hypertension. The terms accelerated
and malignant were used to describe the retinal findings associated with hypertension.
-Accelerated hypertension is associated with group 3 Keith-Wagener-Barker retinopathy, which is characterized by
retinal hemorrhages and exudates on funduscopic examination

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-Malignant hypertension is associated with group 4 Keith-Wagener-Barker retinopathy, which is characterized by
the presence of papilledema, heralding the neurologic impairment from an elevated intracranial pressure.
Pathophysiology
-The clinical manifestations of hypertensive encephalopathy are due to increased cerebral perfusion from the loss of
blood-brain barrier integrity, resulting in exudation of fluid into the brain.
-In normotensive individuals, an increase in systemic blood pressure over a certain range (ie, 60-125 mm Hg)
induces cerebral arteriolar vasoconstriction, thereby preserving a constant cerebral blood flow and an intact blood-
brain barrier.
-In chronically hypertensive individuals, the cerebral autoregulatory range gradually is shifted to higher pressures as
an adaptation to chronic elevation of systemic blood pressure.
-This cerebral autoregulatory response is overwhelmed during a hypertensive emergency in which the acute rise in
systemic blood pressure exceeds the individual's cerebral autoregulatory range, resulting in hydrostatic leakage
across the capillaries within the central nervous system.
-With persistent elevation of the systemic blood pressure, arteriolar damage and necrosis occur. The progression of
vascular pathology leads to:
Generalized vasodilatation
 Cerebral edema
 Papilledema
 Neurologic deficits and altered mentation
Frequency:
-With adequate control, less than 1% of patients experience a hypertensive crisis.
Mortality/Morbidity
-The morbidity and mortality associated with hypertensive encephalopathy are related to the degree of brain
damage.
Without treatment, the 6-month mortality rate for hypertensive emergencies is 50%, and the 1-year mortality rate
approaches 90%.
Race:
-More prevalent in black people.
Sex
-Hypertension is more prevalent in men than in women.
Age
-Hypertensive encephalopathy mostly occurs in middle-aged individuals who have a long-standing history of
hypertension.
Clinical presentation
History:
-Most patients have a history of hypertension.
-Of those without a prior history of hypertension, place emphasis on past medical history, medication list, and
medication compliance. Actively seek drug-induced causes.
-Patients usually have vague neurologic signs and symptoms of raised ICP
Symptoms
1) -Severe bursting headache Headaches are usually anterior and constant in nature.
2) -Projectile vomiting
3) -Blurring of vision
4) -Convulsions/seizures
5) –Drowsiness/altered mentation
Signs
1) -Vital signs-increased BP and decreased pulse rate (cushings reflex)
2) -Anisocoria-unequal pupils
3) -Papiloedema on fundoscopy
4) -Nerve palsy eg 3rd and 6th cranial nerves
5) -Irregular breathing/slowed then fast
-Patients also may present with symptoms resulting from other end organ damage. ie
CVS
Aortic dissection
 Congestive heart failure
 Angina or MI

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 Palpitations, irregular heart beat, and dyspnea
RENAL
Hematuria
Acute renal failure

Physical
-A thorough and complete neurologic and funduscopic examination is essential in evaluation of patients.
-Funduscopic examination:
-Grade IV retinal changes are associated with hypertensive encephalopathy
Papilledema
 Hemorrhage, exudates, and cotton-wool spots
-Neurologic examination
Altered mental status ranging from confusion to coma.
 CN palsy-esp. CN VI and III
-Include a vascular examination to evaluate for vasculopathy because radiologic examinations might not acutely
identify ischemic stroke
-Other target organ damage that may be found includes the following:
 Cardiovascular-S3, elevated neck veins, peripheral edema, murmurs, abdominal pulsations, diminished
pulses.
 Renal - Acute renal failure, pulmonary edema, and peripheral edema.
 Pulmonary - Pulmonary edema, rales, and wheezes

Etiology
-The most common cause is abrupt blood pressure elevation in the chronically hypertensive patient.
-Conditions predisposing a patient to elevated blood pressure can cause the same clinical situation.
A) Drugs
1) Withdrawal from hypertensive agents (eg, clonidine)
2) Sympathomimetic agents (eg, cocaine, amphetamines, phencyclidine [PCP], lysergic acid diethylamide
[LSD
3) Ingestion of tyramine-containing foods in combination with monoamine oxidase inhibitors .or TCA
B) Renal and adrenal causes
1) Chronic renal parenchymal disease
2) Acute glomerulonephritis
3) Renovascular hypertension
4) Pheochromocytoma
c) CNS and autonomic
1) Encephalitis, meningitis
2) Head trauma
3) Autonomic hyperactivity
d) Pregnancy complications-Eclampsia and pre-eclampsia
E) Collagen vascular disease-Vasculitis

DDx
Eclampsia
 Encephalopathy-Dialysis Hepatic, Uraemic, Metabolic acidosis-Alcohol, DKA
 Head Trauma
 Pheochromocytoma
 Intracranial bleed-Subarachnoid Hemorrhage
Subdural Hematoma
 Acute thrombotic stroke
 Cerebral embolus
 CNS mass lesions
 Encephalitis-Infectious
Investigations
Lab Studies

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-Hypertensive encephalopathy is a diagnosis of exclusion; evaluate other etiologies as indicated clinically in the
workup.
-Evaluation includes determining the extent of hypertensive damage and excluding intracranial processes.
1. CBC count:
-Obtain a CBC count to determine whether MAHA is present.
-WBC count rule out infectious process
2. Urinalysis, BUN, and creatinine:
-With hypertensive nephropathy, an elevated creatinine with hematuria, proteinuria and casts may be present.
3. Cardiac enzymes and ECG
-Exclude myocardial ischemia with cardiac enzymes and ECG
4. Urine toxicology screen:
-This study is important in excluding drug-induced hypertensive encephalopathy.
5. Random blood sugars-R/o DKA
6. ABG s if in respiratory distress-Acid base imbalances.
Imaging Studies
1. Head CT scan to evaluate the presence of stroke, hemorrhage, or intracranial masses
2. CXR-to evaluate for possible complications of hypertensive encephalopathy, including aspiration due to altered
mentation.
Chest radiographs can also be used to evaluate for other conditions, eg, acute pulmonary edema and aortic
dissection.
3. Renal U/S and Doppler to exclude renovascular causes and chronic kidney diseases.
4. Echocardiograpy to assess heart function and exclude complications

TREATMENT
Medical Care:
-In patients without hypertension, cerebral autoregulation preserves a relatively constant cerebral blood flow at a
range of mean arterial blood pressures of 60-90 mm Hg. In chronically hypertensive patients, autoregulation is
altered and shifted upward to maintain a relatively constant cerebral blood flow at a higher mean arterial blood
pressure range.
-When initiating therapy, the baseline blood pressure must be considered to avoid excessive blood pressure lowering
and prevent cerebral ischemia. Lowering the mean arterial pressure by 25% and the diastolic blood pressure to 100-
110 mm Hg usually is a safe maneuver because of the pressure autoregulatory cerebral blood flow range.
-Acute arterial blood pressure monitoring is required for adequate titration of pharmacologic agents and monitoring
of end organ function.

DRUGS
1. Nitroprusside
-First-line medication for hypertensive encephalopathy.
-Decreases systemic vascular resistance via direct dilatation of arterioles and veins.
-May cause intracerebral shunting of blood, increasing ICP.
-Frequently used as initial therapy because of its rapid onset and short duration of action.
-Nitroglycerin has been used to provide a rapid reduction in blood pressure complicating myocardial ischemia.
- The reduction in blood pressure may be severe and can cause further complications due to venodilatory effects in
volume-contracted individuals. Nitroprusside and nitroglycerin pose a theoretical risk of intracranial shunting of
blood. Thus, an increasing number of authorities are considering labetalol the preferred agent.
-Dose: 0.5-1 mcg/kg/min IV infusion, titrate to desired BP
Adverse
-Potential for cyanide toxicity occurs with prolonged infusion (>72 h) and high infusion rate (>3 mcg/kg/min);
Manifest: Hyperreflexia, worsening mental status, and toxicity in the presence of metabolic acidosis; Treatment for
cyanide toxicity includes amyl nitrate, thiosulfate, and hydroxocobalamin;
-Hypoxia by inhibition of hypoxia-induced vasoconstriction in the pulmonary vasculature causing perfusion to
nonventilated areas of the lung
Labetalol

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-Competitive and selective alpha1-blocker and nonselective beta-blocker with predominantly beta effects at low
doses. Onset of action is 5 min, with half-life of 5.5 h. Provides a steady, consistent drop in BP without
compromising cerebral blood flow.
-Because of nonselective beta-blocking properties, it should be avoided in severe reactive airways disease and
cardiogenic shock.
20 mg IV bolus, then 20-80 mg IV bolus q10min; not to exceed 300 mg; 2 mg/min IV infusion alternatively, titrate
to desired BP; not to exceed 300 mg
-Trimethaphan camsylate is used to reduce the shearing force in the presence of aortic dissection.
Hydralazine
-Has a limited role owing to reflex tachycardia, and it should not be used with suspected coronary artery disease.
-Has also unpredictable BP control.
Nicardipine (Cardene)
-Calcium channel blocker.
-Potent rapid onset of action, ease of titration, and lack of toxic metabolites.
-Effective but limited reported experience in hypertensive encephalopathy
Diaxozide
-Although the clinical impact has not been determined, diazoxide is avoided because of the impact of decreased
cerebral blood flow.
- If neurological deterioration worsens with therapy, reconsider the extent of blood pressure lowering or consider
alternate diagnoses
Outpatient Care
-Regularly reassess hypertension because it is a chronic problem.
- Adequate control of hypertension is essential in preventing the progression of target organ disease.
-Discharge patients on antihypertensives that were effective in maintaining an adequate blood pressure range during
hospitalization.
Prevention
-Lifestyle modifications, including
weight reduction to decrease body mass index (BMI) to less than 27
 Moderation of alcohol and sodium intake
 Increasing physical activity
 Avoidance of tobacco products
 Patients should adhere to antihypertensive therapy and schedule reassessment at regular intervals to modify
failing regimens.
Complications of hypertensive encephalopathy
 Coma and Death
 Stroke
 Nephropathy
 Myocardial
ischemia/infarction
Retinopathy
Peripheral vascular disease.

HYPOKALAEMIA

Background

Hypokalemia is defined as a plasma potassium level of less than 3.5 mEq/L in children. It is frequently
present in pediatric patients who are critically ill. Potassium is the most abundant intracellular cation and
is necessary for maintaining a normal charge difference between intracellular and extracellular
environments. Potassium homeostasis is integral to normal cellular function and is tightly regulated by
specific ion-exchange pumps, primarily by cellular, membrane-bound, sodium-potassium adenosine
triphosphatase (ATPase) pumps. Derangements of potassium regulation often lead to neuromuscular,
gastrointestinal, and cardiac conduction abnormalities.

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Pathophysiology

Hypokalemia may be due to a total body deficit of potassium, which may result from long-term inadequate
intake, long-term diuretic or laxative use, and chronic diarrhea, hypomagnesemia, or hyperhidrosis. Acute
causes of potassium depletion include diabetic ketoacidosis, severe gastrointestinal losses from vomiting
and diarrhea, dialysis, and diuretic therapy. Hypokalemia may also be the manifestation of large
potassium shifts from the extracellular to intracellular space, as seen with alkalosis, insulin,
catecholamines, sympathomimetics, and hypothermia.

Other recognizable causes include renal tubular disorders, such as distal renal tubular acidosis, Bartter
and Gitelman syndromes, periodic hypokalemic paralysis, hyperthyroidism, administration of beta2-
adrenergic agents, and hyperaldosteronism. Other mineralocorticoid excess states that may cause
hypokalemia include cystic fibrosis (with hyperaldosteronism from severe chloride and volume depletion),
Cushing syndrome, and exogenous steroid administration.

Mortality/Morbidity

 Mortality is rare, except when hypokalemia is severe or occurs following cardiac surgery, when
accompanied by arrhythmia, or in a patient who has underlying heart disease and requires
digoxin therapy.
 Short-term morbidity is common and may include gastrointestinal hypomotility or ileus; cardiac
dysrhythmia; QT prolongation; appearance of U waves that may mimic atrial flutter, T-wave
flattening, or ST-segment depression; and muscle weakness or cramping.

Race

 Racial differences may be present in predisposing conditions such as Bartter syndrome, Gitelman
syndrome, Conn syndrome (i.e., hyperaldosteronism), Cushing syndrome, and familial
hypokalemic paralysis. In addition, significant hypokalemia and hypokalemic paralysis develop in
2-8% of Asians with hyperthyroidism.

Sex

 No known sex predilection has been noted.

Age

 Viral gastrointestinal infections tend to be more common in infants and younger children. Younger
children with emesis or diarrhea are at an increased risk of hypokalemia because the depletion of
fluid volume and electrolytes from gastrointestinal loss is relatively higher than that in older
children and adults.
 Insulin-dependent diabetes mellitus that results in diabetic ketoacidosis (with its inherent fluid and
potassium loss) is more common in children. Excessive corticosteroid and mineralocorticoid
secretion, as in Cushing and Conn syndromes, is a less common cause of hypokalemia in the
pediatric patient. Periodic hypokalemic paralysis may appear in childhood or young adulthood,
precipitated by rest after strenuous exercise, physical or metabolic stress (e.g., exposure to cold,
alcohol ingestion), a high-carbohydrate meal, or exposure to exogenous insulin or epinephrine.
Hypokalemia due to hyperthyroidism is generally observed in adults.

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History

 Hypokalemia due to excessive loss is usually accompanied by a history of gastrointestinal loss

(emesis or diarrhea), urinary output, or sweating. This may be exacerbated by inadequate oral
intake.
 Query about current or recent treatment with medications, including insulin, albuterol or other
beta2-sympathomimetics, corticosteroids, diuretics, laxatives, enemas, or bowel-prep solutions.
 The patient may have had similar episodes in the past. Familial historical data may include
surgery for pituitary or adrenal tumors or acute intermittent episodes of paralysis, with or without
association with hyperthyroidism.

Physical

 Physical examination findings may frequently be within the reference range. Occasionally, muscle
weakness is evident.
 Cardiac arrhythmias and acute respiratory failure from muscle paralysis are life-threatening
complications that require immediate diagnosis.
 Cardiovascular examination findings may also be within normal limits. Occasionally, tachycardia
with irregular beats may be heard. Severe hypokalemia may manifest as bradycardia with
cardiovascular collapse.
 Hypoactive bowel sounds may suggest hypokalemic gastric hypomotility or ileus.

Causes

 Hypokalemia may be due to a total body deficit of potassium, which may occur chronically with
the following:
o Prolonged diuretic use
o Inadequate potassium intake
o Laxative use
o Diarrhea
o Hyperhidrosis
o Hypomagnesemia
 Acute causes of potassium depletion include the following:
o Diabetic ketoacidosis
o Severe gastrointestinal losses from vomiting and diarrhea
o Dialysis and diuretic therapy
 Hypokalemia may also be due to excessive potassium shifts from the extracellular to the
intracellular space, as seen with the following:
o Alkalosis
o Insulin use
o Catecholamine use
o Sympathomimetic use
o Hypothermia
 Other recognizable causes of hypokalemia include the following:
o Renal tubular disorders, such as Bartter and Gitelman syndromes
o Type I or classic distal tubular acidosis
o Periodic hypokalemic paralysis
o Hyperaldosteronism
 Other states of mineralocorticoid excess that may cause hypokalemia include the following:
o Cystic fibrosis with hyperaldosteronism from severe chloride and volume depletion
o Cushing syndrome
o Exogenous steroid administration
 Other conditions that may cause hypokalemia include acute myelogenous, monomyeloblastic, or
lymphoblastic leukemia.

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  Drugs that may cause hypokalemia include the following:
o Theophylline
o Verapamil (with overdose)
o High-dose penicillin
o Ampicillin
o Carbenicillin
o Drugs associated with magnesium depletion, such as aminoglycosides, amphotericin B,
and cisplatin

Hyperthyroidism

WORKUP

Lab Studies

 Serum electrolyte tests: Screen for concurrent electrolyte abnormalities, which may affect
treatment.
 Blood gas analysis

o Assess acid-base status.

o Alkalosis may induce hypokalemia, and treatment of acidosis may worsen existing
hypokalemia.
 Drug screen (serum or urine)
o Amphetamines and other sympathomimetic stimulants can cause hypokalemia.
o Other drugs that can cause hypokalemia include verapamil (with overdose), theophylline,
amphotericin B, aminoglycosides, and cisplatin.
 Serum adrenocorticotropic hormone (ACTH), cortisol, renin activity, and aldosterone tests:
Evaluate for suspected Cushing, Conn, or adrenal hyperplasia syndromes, including 11-beta-
hydroxylase deficiency.
 Simultaneous serum insulin and C-peptide tests: Because hyperinsulinism can cause transient
hypokalemia, elevated serum insulin without appropriately elevated C-peptide suggests
exogenous insulin administration, which may represent Münchhausen-by-proxy syndrome.

Imaging Studies

 MRI: Obtain a brain MRI if a brain or pituitary tumor is suspected as a cause of hypercortisolism.
 Ultrasonography and CT: Perform abdominal ultrasonography or CT scanning if an adrenal tumor
or hyperplasia is suspected.

Other Tests

 Electrocardiography: Although ECG changes may be helpful if present, their absence should not
be taken as reassurance of normal cardiac conduction. The ECG in hypokalemia may appear
normal or may have only subtle findings immediately before clinically significant dysrhythmias.
o Ventricular dysrhythmia
o Prolongation of QT interval
o ST-segment depression
o T-wave flattening
o Appearance of U waves

110
 o During therapy, monitor for changes associated with overcorrection and hyperkalemia,
including a prolonged QRS, peaked T waves, bradyarrhythmia, sinus node dysfunction,
and asystole.

TREATMENT

Medical Care

 Treatment depends on severity and etiology.

 Unlike hyponatremia, in which the total body sodium deficit can be readily estimated, serum
potassium may not accurately reflect total body stores. Indeed, during diabetic ketoacidosis,
serum potassium levels are usually initially elevated, even in the face of severe depletion of total
body potassium. Correction of acidosis in diabetic ketoacidosis may cause a precipitous drop in
serum potassium levels.
 Transient, asymptomatic, or mild hypokalemia may spontaneously resolve or may be treated with
enteral potassium supplements.
 Symptomatic or severe hypokalemia should be corrected with a solution of intravenous
potassium.

Surgical Care

 Except for excision of tumors leading to hypokalemia, management is nonsurgical.

Consultations

 After resolution, consultation with an endocrinologist, geneticist, or specialist in metabolic disease

may be necessary to diagnose and manage predisposing conditions.
 Consultation with a dietitian may be helpful in cases of hypokalemia due to inadequate dietary
intake.

Diet

 Dietary modification may be necessary for patients with excessive potassium losses (e.g., diuretic
or laxative use) or patients with hypokalemia who are at increased risk, such as those receiving
digoxin.
 Avoidance of specific foods (e.g., licorice, which may have aldosteronelike activity) may also be
necessary for high-risk individuals.

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MEDICATION

Medical therapy is aimed at potassium supplementation by the enteral (i.e., oral or through feeding tubes)
or parenteral route. Transient, asymptomatic, or mild hypokalemia may resolve spontaneously, or it may
be treated using enteral potassium supplements. Symptomatic or severe hypokalemia should be
corrected with intravenous potassium preparations.

Drug Category: Potassium supplements

These agents are used to restore body potassium storage. Electrolytes are used to correct disturbances
in fluid and electrolyte homoeostasis or acid-base balance and to reestablish osmotic equilibrium of
specific ions.

Potassium chloride (also citrate, acetate, bicarbonate,

Drug Name
gluconate)
First choice for IV therapy. Essential for transmission
of nerve impulses; contraction of cardiac muscle; and
maintenance of intracellular tonicity, skeletal and
smooth muscles, and normal renal function. Gradual
potassium depletion occurs via renal excretion,
Description
through GI loss, or because of low intake. Depletion
may result from diuretic therapy, primary or
secondary hyperaldosteronism, diabetic ketoacidosis,
severe diarrhea, vomiting, or inadequate replacement
during prolonged parenteral nutrition.
IV replacement: 10-40 mEq IV infused over 2-3 h; not
Adult Dose to exceed 40 mEq/h; may repeat q3-4h prn; modify
infusion rate for specific requirements

112
 PO supplementation: 50-100 mEq/d PO divided
bid/tid or qd as SR formulation; larger doses may be
needed in severe depletion to replenish potassium
body storage
Usual dose for potassium replacement: 0.5-1 mEq/kg
IV; not to exceed 30-40 mEq/dose
Not to exceed 0.3-0.5 mEq/kg/h for noncritical
hypokalemia; however, this rate may be inadequate in
life-threatening hypokalemia
Infusion rates: >0.5 mEq/kg/h can be delivered but
Pediatric Dose
requires ECG monitoring to detect potentially fatal
arrhythmia, especially ventricular dysrhythmia,
because it can rapidly lead to cardiac arrest
Oral supplementation is based on body weight,
ranging from 2-4 mEq/kg/d PO in divided doses to
avoid gastric distress
Undiluted IV administration; hyperkalemia, renal
failure, conditions in which potassium retention is
present, oliguria or azotemia, crush syndrome, severe
hemolytic reactions, anuria, and adrenocortical
Contraindications
insufficiency
Acidosis (alkaline forms of potassium such as
potassium bicarbonate, citrate, acetate, or gluconate
can be used in the face of metabolic acidosis)
Co administration with drugs that elevate potassium
(e.g., potassium-sparing diuretics, ACE inhibitors)
may cause severe hyperkalemia; hypokalemia may
Interactions
result in digoxin toxicity in patients taking digoxin;
caution if discontinuing potassium administration in
patients taking digoxin
Pregnancy A - Safe in pregnancy
Do not infuse rapidly; high plasma concentrations of
potassium may cause death due to cardiac
depression, arrhythmias, or arrest; plasma levels do
not necessarily reflect tissue levels; monitor
potassium replacement therapy whenever possible by
means of continuous or serial ECG; IV potassium
must be diluted before administration, when a
concentration >40 mEq/L is infused, local pain and
phlebitis also may follow
Precautions Solid potassium supplements can produce or
aggravate gastric ulcers and can produce strictures or
stenotic lesions; patients with a predisposition to
these lesions should use liquid formulations
GI complaints, including nausea, stomach pain,
vomiting, and flatulence, are some of the more
common adverse drug reactions with the oral
preparations
Closely monitor potassium levels to avoid
hyperkalemia

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FOLLOW-UP

Further Inpatient Care

 After the initial phase of therapy is completed, focus further inpatient care on matching potassium
intake to losses, periodic testing of serum potassium levels, and electrocardiographic monitoring
for hypokalemia or hyperkalemia due to therapy.
 Alleviation of aggravating conditions, simplification of medication administration, and patient
education form the basis of ongoing patient health and safety.

Further Outpatient Care

 If the condition is expected to persist beyond inpatient care, patients should receive follow-up
medical care for home treatment.
 Additional medical follow-up must be obtained for associated medical conditions.

In/Out Patient Meds

 Other than potassium supplementation as described above, no additional medications are

required.

Transfer

 Patients with severe or symptomatic hypokalemia require transfer to an ICU for intravenous
potassium supplementation and continuous electrocardiographic monitoring.

Complications

 Hyperkalemia from excessive potassium replacement

 Cardiac dysrhythmia
 Gastric erosions
 Strictures

Prognosis

 With adequate control of potassium levels and resolution of any predisposing condition, prognosis
is excellent.

Patient Education

 Patients should be educated in terms of predisposing conditions. The importance and risks
involved with potassium supplementation and the warning signs of hypokalemia or overtreatment
must be emphasized upon discharge from the hospital.
 Knowledge of cardiopulmonary resuscitation and education on timely access to emergency
medical services may prevent morbidity or mortality.
 Ongoing communication is essential for reducing the risks and in therapy, especially in patients
with chronic conditions associated with hypokalemia.

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 HYPOTHYROIDISM
 For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see
eMedicine's patient education article Low Potassium.

MISCELLANEOUS

Medical/Legal Pitfalls

 Failure to adequately communicate the risks of treatment

 Failure to appropriately monitor patients receiving potassium supplementation for complications,
especially patients with renal failure or patients receiving potassium-sparing diuretics or
angiotensin-converting enzyme inhibitors
 Failure to follow serum potassium and other electrolyte concentrations during or after therapy
 Treating a patient on the basis of a low serum potassium value that is false because of a
sampling or laboratory error (or failing to treat a patient with symptoms of actual hypokalemia
because of an elevated serum potassium value that is false because of a sampling or laboratory
error)

-Iodine deficiency remains the most common cause of hypothyroidism worldwide.

-In areas of iodine sufficiency, autoimmune disease (Hashimoto's thyroiditis) and iatrogenic causes (treatment of
hyperthyroidism) are most common
Causes of Hypothyroidism
A. Primary Hypothyroidism
1) Autoimmune hypothyroidism: Hashimoto's thyroiditis, atrophic thyroiditis
2) Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or
cancer
3) Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid
drugs, p-aminosalicyclic acid, interferon-α and other cytokines, aminoglutethimide
4) Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation
5) Iodine deficiency
6) Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel's
thyroiditis
7) Overexpression of type 3 deoiodinase in infantile hemangioma
8) Transient
9) Silent thyroiditis, including postpartum thyroiditis
10) Subacute thyroiditis
11) Withdrawal of thyroxine treatment in individuals with an intact thyroid
B.Secondary Hypothyroidism
1) Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan's syndrome,
trauma, genetic forms of combined pituitary hormone deficiencies
2) Isolated TSH deficiency or inactivity
3) Bexarotene treatment
4) Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

Clinical Presentation
-Signs and Symptoms of Hypothyroidism (Descending Order of Frequency)
Symptoms
1) Tiredness, weakness
2) Cold, dry skin, which may be rough and scaly: Skin may appear yellow but does not involve the sclera,
unlike in jaundice
3) Hair loss
4) Difficulty concentrating and poor memory
5) Constipation
6) Weight gain with poor appetite
7) Dyspnea

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 8) Hoarse voice (pressure symptoms in the neck from thyroid enlargement).
9) Menorrhagia (later oligomenorrhea or amenorrhea),loss of libido,infertiltity,galactorea due to increased
prolactin
10) Paresthesia
11) Impaired hearing-mild nerve deafness
12) Sleep apnea and daytime somnolence-obstructive sleep symptoms due to/ caused by hypofunction of upper
airway muscles and weakness of the diaphragm.
13) Joint pains and muscle cramps
14) Depression, dementia, and other psychiatric disturbances
Signs
1) Dry coarse skin
2) cool peripheral extremities
3) Puffy face, hands, and feet (myxedema)
4) Hair loss involving scalp, the lateral third of the eyebrows, and, also, skin, genital, and facial hair
5) Bradycardia
6) Increased peripheral resistance may be accompanied by hypertension, particularly diastolic
7) Peripheral edema
8) Macroglosia
9) Peripheral neuropathy
10) Delayed tendon reflex relaxation
11) Carpal tunnel syndrome
12) Serous cavity effusions
13) Impaired memory
14) Ataxia due to cerebellar dysfuction
NB. Thyroid-associated ophthalmopathy, which usually occurs in Graves ‘disease, occurs in about 5% of patients
with autoimmune hypothyroidism

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CONGENITAL HYPOTHYROIDISM
Prevalence
-Hypothyroidism occurs in about 1 in 4000 newborns.
- It may be transient, especially if the mother has TSH-R blocking antibodies or has received antithyroid drugs, but
permanent hypothyroidism occurs in the majority.
Etiology
- Neonatal hypothyroidism is due to
 Thyroid gland dysgenesis in 80 to 85%
 Inborn errors of thyroid hormone synthesis in 10 to 15%
 TSH-R antibody-mediated in 5%
Sex
- Twice as common in girls.
Clinical Manifestations
-The majority of infants appear normal at birth
-Less than 10% are diagnosed based on clinical features which include
 Prolonged jaundice
 Feeding problems
 Hypotonia
 Enlarged tongue
 Delayed bone maturation
 Umbilical hernia
-Importantly, permanent neurologic damage results if treatment is delayed.
-Typical features of adult hypothyroidism may also be present
-Other congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism.
Diagnosis and Treatment
-Because of the severe neurologic consequences of untreated congenital hypothyroidism, neonatal screening
programs have been established in developed countries.
-These are generally based on measurement of TSH or T4 levels in heel-prick blood specimens.
-When the diagnosis is confirmed, T4 is instituted at a dose of 10 to 15 µg/kg per day and the dosage is adjusted by
close monitoring of TSH levels.
-T4 requirements are relatively great during the first year of life, and a high circulating T 4 level is usually needed to
normalize TSH.
-Early treatment with T4 results in normal IQ levels, but subtle neurodevelopmental abnormalities may occur in
those with the most severe hypothyroidism at diagnosis or when treatment is suboptimal.

AUTOIMMUNE HYPOTHYROIDISM
HASHIMOTOS THYROIDITIS
-Autoimmune hypothyroidism may be associated with a goiter (Hashimoto's, or goitrous thyroiditis) or, at the later
stages of the disease, minimal residual thyroid tissue (atrophic thyroiditis).
-Autoimmune process gradually reduces thyroid function; there is a phase of compensation when normal thyroid
hormone levels are maintained by a rise in TSH.
-. Later, free T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage
(usually TSH > 10 mU/L), which is referred to as clinical hypothyroidism or overt hypothyroidism.
Prevalence
-Autoimmune hypothyroidism is up to 4 per 1000 women and 1 per 1000 men.
--It is more common in Japanese
Age
-The most commonly affected age range is 30-50 years, with the peak incidence in men occurring 10-15 years later.
-Overall the incidence of hypothyroidism increases with age in both men and women.
Pathogenesis
In Hashimoto's thyroiditis, there is a marked lymphocytic infiltration of the thyroid with
 germinal center formation
 Atrophy of the thyroid follicles
 oxyphil metaplasia
 Absence of colloid
 Mild to moderate fibrosis.
-In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte infiltration is less pronounced, and thyroid
follicles are almost completely absent.
-Atrophic thyroiditis likely represents the end stage of Hashimoto's thyroiditis rather than a distinct disorder.
-Susceptibility to autoimmune hypothyroidism is determined by a combination of genetic and environmental factors,
and the risk of either autoimmune hypothyroidism or Graves' disease is increased among siblings.
- HLA-DR3, -DR4, and -DR5 increased susceptibility
117 which may explain the relationship with other
-Genetic associations are shared by other autoimmune diseases,
autoimmune diseases eg type 1 DM, Addison disease, pernicious anemia, and vitiligo
-Environmental-A high iodine intake may increase the risk of autoimmune hypothyroidism by immunologic effects
or direct thyroid toxicity
-congenital rubella syndrome, in which there is a high frequency of autoimmune hypothyroidism.
-Antibodies binding to and blocking the thyroid-stimulating hormone (TSH) receptor have also been described and
may contribute to further impairment in thyroid function.
-The result is inadequate thyroid hormone production and secretion, although, initially, both preformed thyroxine
(T4) and triiodothyronine (T3) may "leak" into the circulation from damaged cells.
-Patients with Hashimoto thyroiditis have antibodies to various thyroid antigens, the most frequently detected of
which include antithyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg), and, to a lesser extent, TSH receptor-
blocking antibodies. Nevertheless, a small percentage of patients with Hashimoto thyroiditis (approximately 10-
15%) may be antibody negative.
-Other antithyroid antibodies found in AITD (including Hashimoto thyroiditis) include thyroid-stimulating antibody
and cytotoxic antibody.
-Other variants of AITD include the following conditions:
1) Atrophic thyroiditis
2) Juvenile thyroiditis
3) Postpartum thyroiditis
4) Silent thyroiditis
Clinical presentation
History
-Hypothyroidism is usually insidious in onset, with signs and symptoms slowly progressing over months to years
- The history may be suggestive of other autoimmune associations.
-Patients most commonly present with nonspecific symptoms suggestive of overt hypothyroidism.
-Patients with long-standing, severe hypothyroidism could present in myxedema coma precipitated by some major
stress or infection.
-Patients may present because of goiter rather than symptoms of hypothyroidism. The goiter may not be large but is
usually irregular and firm in consistency
-Rarely, uncomplicated Hashimoto's thyroiditis is associated with pain
Aspects of the hypothyroidism-Above

Investigations
1. A normal TSH level excludes primary (but not secondary) hypothyroidism.
2. If the TSH is elevated, an unbound T 4 level is needed to confirm the presence of clinical hypothyroidism, but T 4 is
inferior to TSH when used as a screening test, as it will not detect subclinical or mild hypothyroidism.
-Circulating unbound T3 levels are normal in about 25% of patients, reflecting adaptive responses to
hypothyroidism.
- T3 measurements are therefore not indicated.
3. The presence of thyroid autoantibodies, typically anti-TPO and also anti-Tg antibodies, delineates the cause of
hypothyroidism as Hashimoto thyroiditis or its variant. However, 10-15% of patients with Hashimoto thyroiditis
may be antibody negative

Imaging
Ultrasound
-Assess thyroid size, echotexture, and, in assessing for the presence of thyroid nodules
-Defining a nodule as solid or cystic
-Defining features suggestive of malignancy such as irregular margins, a poorly defined halo, microcalcification,
and increased vascularity on Doppler interrogation.
-Facilitating fine-needle aspiration of nodules in general and in particular small or poorly defined nodules when
indicated and in patients with distorted neck anatomy.
Other Tests
Evaluate complications of hypothyroidism in some patients
1. FBC: anemia, usually from decreased erythropoiesis.
-In 15% of patients, the anemia is of the IDA with microcytosis and hypochromia.
-Although this can be a normocytic normochromic anemia, the most common morphologic abnormality is a
macrocytic anemia that may be partially due to deficient vitamin B-12 and folate intake.
2. Lipid profile: Total cholesterol, (LDL), and triglyceride levels may be elevated
3. Creatine kinase: Creatine kinase levels, predominantly the MM isoenzyme from skeletal muscle and the aldolase
enzyme, are frequently elevated in severe hypothyroidism.

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4. Prolactin: Prolactin may be elevated in primary hypothyroidism. This is thought to be caused by overlap
secretion due to stimulation of the lactotroph by the elevated TRH level. The decreased clearance of prolactin in
hypothyroidism may also play a contributory role
Imaging
-CXR-may show small pleural effusions.
-ECG -may show low-voltage QRS tracing, nonspecific ST-wave changes, and premature ventricular contractions.
-Prolongation of the QT interval with torsade de pointes and ventricular tachycardia may be noted.
-Echocardiogram may show some pericardial effusion in severe cases of hypothyroidism.

Procedures
-Perform fine-needle aspiration of any dominant or suspicious thyroid nodules in order to exclude malignancy or
presence of a thyroid lymphoma in fast-growing thyroid goiters
Histologic Findings
-diffuse lymphocytic and plasma cell infiltration with formation of lymphoid follicles from follicular hyperplasia
and damage to the follicular basement membrane.
-Atrophy of the thyroid parenchyma is usually evident. Correlation with the presence of thyroid autoantibodies,
namely anti-TPO and also anti-Tg, is helpful for confirming the definite diagnosis.

TREATMENT
-No residual thyroid function, the daily replacement dose of levothyroxine (T4) is usually 1.6 µg/kg body weight
(typically 100 to 150 µg).
-In many patients, however, lower doses suffice until residual thyroid tissue is destroyed.
-In patients who develop hypothyroidism after the treatment of Graves' disease, there is often underlying
autonomous function, necessitating lower replacement doses (typically 75 to 125 µg/d).
-Adult patients under 60 without evidence of heart disease may be started on 50 to 100 µg levothyroxine (T 4) daily.
The dose is adjusted on the basis of TSH levels, with the goal of treatment being a normal TSH, ideally in the lower
half of the reference range.
-TSH responses are gradual and should be measured about 2 months after instituting treatment or after any
subsequent change in levothyroxine dosage.
-The clinical effects of levothyroxine replacement are often slow to appear. Patients may not experience full relief
from symptoms until 3 to 6 months after normal TSH levels are restored. Some change in symptoms can be noticed
as soon as 24 hrs
-Adjustment of levothyroxine dosage is made in 12.5- or 25-µg increments if the TSH is high; decrements of the
same magnitude should be made if the TSH is suppressed.
-Patients with a suppressed TSH of any cause, including T 4 overtreatment, have an increased risk of atrial
fibrillation and reduced bone density.
-Dessicated animal thyroid preparations (thyroid extract USP), they are not recommended as potency and
composition vary between batches.
-There is no place for liothyronine alone as long-term replacement, because the short half-life necessitates three or
four daily doses and is associated with fluctuating T 3 levels.
-Once full replacement is achieved and TSH levels are stable, follow-up measurement of TSH is recommended at
annual intervals and may be extended to every 2 to 3 years; if a normal TSH is maintained over several years.
-It is important to ensure ongoing compliance; however, as patients do not feel any difference after missing a few
doses of levothyroxine, this sometimes leads to self-discontinuation.
-In patients of normal body weight who are taking ≥200 µg of levothyroxine per day, an elevated TSH level is often
a sign of poor compliance.
- This is also the likely explanation for fluctuating TSH levels, despite a constant levothyroxine dosage.
-Because T4 has a long half-life (7 days), patients who miss doses can be advised to take up to three doses of the
skipped tablets at once.
-Other causes of increased levothyroxine requirements must be excluded, particularly malabsorption (e.g., celiac
disease, small-bowel surgery), estrogen therapy, and drugs that interfere with T 4 absorption or clearance such as
cholestyramine, ferrous sulfate, calcium supplements, lovastatin, aluminum hydroxide, rifampicin, amiodarone,
carbamazepine, and phenytoin.
Special Treatment Considerations

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-Rarely, levothyroxine replacement is associated with pseudotumor cerebri in children. Idiosyncratic and occurs
months after treatment has begun.
-Women with a history or high risk of hypothyroidism should ensure that they are euthyroid prior to conception and
during early pregnancy as maternal hypothyroidism may adversely affect fetal neural development.
-Thyroid function should be evaluated once pregnancy is confirmed and at the beginning of the second and third
trimesters. The dose of levothyroxine may need to be increased by ≥50% during pregnancy and returned to previous
levels after delivery.
-Elderly patients may require up to 20% less thyroxine than younger patients. In the elderly, especially patients with
known coronary artery disease, the starting dose of levothyroxine is 12.5 to 25 µg/d with similar increments every 2
to 3 months until TSH is normalized.
-In some patients it may be impossible to achieve full replacement, despite optimal antianginal treatment.

MYXEDEMA COMA
-State of extreme hypothyroidism with a very high mortality rate (approaching 60%).
-Patients with this condition usually present with an acute precipitating condition and usually in the following
settings:
1) Long-standing undiagnosed hypothyroidism
2) Discontinuation of T4 replacement therapy
3) Failure to institute T4 replacement after radioactive iodine ablation of the thyroid in Graves disease or after
total thyroidectomy

Clinical manifestations
1) Obtundation or coma
2) Hypothermia
3) Hypoventilation
4) Bradycardia
5) Hyponatremia
6) Hypoglycemia
7) Hypotension
8) Other features of hypothyroidism
- Besides having an elevated TSH level, these patients may have undetectable free T4 levels.
-.Myxedema coma almost always occurs in the elderly and is usually precipitated by factors that impair respiration,
 Drugs (especially sedatives, anesthetics, antidepressants)
 Pneumonia
 congestive heart failure
 myocardial infarction
 gastrointestinal bleeding
 cerebrovascular accident
 Sepsis should also be suspected
 Exposure to cold may also be a risk factor
Pathogenesis
-Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in pathogenesis
-Hypoglycemia and dilutional hyponatremia also contribute to the development of myxedema coma.
Management
-Therapy should be conducted in an acute care unit, where the patients may require the following: Supportive
measure
1) Ventilatory support for hypoventilation and carbon dioxide retention and gas analysis
2) ECG monitoring and a Swan-Ganz catheter for hemodynamic monitoring
3) Judicious rewarming to avoid excessive vasodilatation, which would increase oxygen consumption and could lead
to worsening of hypotension and vascular collapse
4) Any precipitating factors should be treated, including the early use of broad-spectrum antibiotics, pending the
exclusion of infection
5) Fluid restriction with or without hypertonic saline and Lasix to promote water diuresis
-Hypertonic saline or intravenous glucose may be needed if there is hyponatremia or hypoglycemia

Drugs

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-Levothyroxine
- Initially IV bolus of 500 µg, which serves as a loading dose.
-Then continued at 50 to 100 µg/d.
-If suitable intravenous preparation is not available, the same initial dose of levothyroxine can be given by
nasogastric tube (though absorption may be impaired in myxedema).
-An alternative is to give liothyronine (T 3) intravenously or via nasogastric tube, in doses ranging from 10 to 25 µg
every 8- 12 h.
-This treatment has been advocated because T 4 → T3 conversion is impaired in myxedema coma.
-However, excess liothyroxine has the potential to provoke arrhythmias.
-Another option is to combine levothyroxine (200 µg) and liothyronine (25 µg) as a single, initial intravenous bolus
followed by daily treatment with levothyroxine (50 to 100 µg/d) and liothyronine (10 µg every 8 h).
Hydrocortisone
-Parenteral hydrocortisone (50 mg every 6 h) should be administered, as there is impaired adrenal reserve in
profound hypothyroidism

NB.The metabolism of most medications is impaired, and sedatives should be avoided if possible or used in reduced
doses. Medication blood levels should be monitored, when available, to guide dosage.

INFECTIVE ENDOCARDITIS
Definition
- Infective endocarditis is defined as a microbial colonization of the inner lining of the heart. Can involve valves, the
mural endocardium, or a septal defect. The prototypic lesion at the site of infection, the vegetation), is a mass of
platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. Endocarditis can be broken down
into the following categories:
i. Native valve (acute and subacute) endocarditis
ii. Prosthetic valve (early and late) endocarditis
iii. Endocarditis related to intravenous drug use
1. Native valve endocarditis (acute and subacute)
-Native valve acute endocarditis usually has an aggressive course. Virulent organisms, such as Staphylococcus
aureus and group B streptococci, are typically the causative agents of this type of endocarditis. Underlying structural
valve disease may not be present.
-Subacute endocarditis usually has a more indolent course than the acute form. Alpha-hemolytic streptococci or
enterococci, usually in the setting of underlying structural valve disease, typically are the causative agents of this
type of endocarditis.
2. Prosthetic valve endocarditis (early and late)
-Early prosthetic valve endocarditis occurs within 60 days of valve implantation. Staphylococci aureus and
epidermidis, gram-negative bacilli, and Candida species are the common infecting organisms.
-Late prosthetic valve endocarditis occurs 60 days or more after valve implantation. Alpha-hemolytic streptococci,
enterococci, and staphylococci are the common causative organisms.
3. Endocarditis related to intravenous drug use Endocarditis in intravenous drug abusers commonly involves the
tricuspid valve. -S aureus is the most common causative organism. Fungal colonization’s also common eg Candida
albicans.
-Acute endocarditis is a hectically febrile illness, rapidly damages cardiac structures, hematogenously seeds
extracardiac sites, and, if untreated, progresses to death within weeks. Subacute endocarditis follows an indolent
course; causes structural cardiac damage only slowly, if at all; rarely causes metastatic infection; and is gradually
progressive unless complicated by a major embolic event or ruptured mycotic aneurysm.

Pathophysiology:
-All cases of IE develop from a commonly shared process:
1.Formation of thrombi on endocardium
2.Bacteremia (nosocomial or spontaneous) that delivers the organisms to the valve's surface
3.Adherence of the organisms
4.Eventual invasion of the valvular leaflets

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-Infective endocarditis generally occurs as a consequence of nonbacterial thrombotic endocarditis, which results
from turbulence or trauma to the endothelial surface of the heart. Transient bacteremia then leads to seeding of
lesions with adherent bacteria, and infective endocarditis develops.
-Pathologic effects due to infection can include local tissue destruction and embolic phenomena. In addition,
secondary autoimmune effects, such as immune complex glomerulonephritis and vasculitis, can occur
-In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from
intravenous catheters or pacing wires (ie, NIE). S aureus can invade the endothelial cells (endotheliosis) and
increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial
thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or
neoplasia.
-IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic
valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve.
-Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection. The microorganisms that most
commonly produce endocarditis (ie, S aureus; S viridans; group A, C, and G streptococci; enterococci) resist the
bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus.

Clinical presentation

History
-Present illness history is highly variable. Symptoms commonly are vague, emphasizing constitutional complaints,
or complaints may focus on primary cardiac effects or secondary embolic phenomena.
-Primary cardiac disease may present with signs of congestive heart failure due to valvular insufficiency. Secondary
phenomena could include focal neurologic complaints due to an embolic stroke or back pain associated with
vertebral osteomyelitis.
-Fever and chills are the most common symptoms.
-Anorexia, weight loss, malaise, headache, myalgias, night sweats, shortness of breath, cough, or joint pains are
common complaints.
-As many as 20% of cases present with focal neurologic complaints and stroke syndromes.
-Dyspnea, cough, and chest pain are common complaints of intravenous drug users. This is likely related to the
predominance of tricuspid valve endocarditis in this group and secondary embolic showering of the pulmonary
vasculature.

Physical:
-Mild-moderate Pallor
-Fever, possibly low-grade and intermittent, is present in 90% of patients.
-Heart murmurs –esp. Change in the characteristics of a previously noted murmur occurs
-Gallop rhythm.

Causes
a)Native valve endocarditis
Rheumatic valvular disease (30%)
 Congenital heart disease (15% of NVE)
 Mitral valve prolapse with an associated murmur (20% of NVE)
 Degenerative heart disease - Including calcific aortic stenosis due to a bicuspid valve, Marfan syndrome, or
syphilitic disease
-Up to 70% of cases are caused by Streptococcus species including Streptococcus viridans, Streptococcus bovis, and
enterococci. Staphylococcus species cause 25% of cases and generally demonstrate a more aggressive acute course.
b)Endocarditis in intravenous drug use
-This condition most commonly involves the tricuspid valve, followed by the aortic valve.
-Pulmonary manifestations may be prominent in patients with tricuspid infection: pleuritic chest pain, e chest
radiographic abnormalities.
-S aureus is the most common (<50% of cases) etiologic organism. Other\ organisms include streptococci, fungi,
and gram-negative rods (eg, pseudomonads, Serratia species).
c)Prosthetic valve endocarditis

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-Early disease, which presents shortly after surgery, has a different bacteriology and prognosis than late disease,
which presents in a subacute fashion similar to native valve endocarditis.
-Infection associated with aortic valve prostheses may lead to: local abscess ,fistula formation and valvular
dehiscence.
-This may lead to shock, heart failure, heart block, shunting of blood to the right atrium, pericardial tamponade, and
peripheral emboli to the central nervous system and elsewhere.
-Endocarditis can occur in association with intravascular devices.
-Infection that occurs early after surgery may be caused by a variety of pathogens, including S aureus and S
epidermidis.
-Late disease is most commonly caused by streptococci.
-Fungal endocarditis- found in intravenous drug users and intensive care unit patients who receive broad-spectrum
antibiotics.Blood cultures are often negative, and diagnosis frequently is made after microscopic examination of
large emboli.
-One or more classic signs of infective endocarditis are found in as many as 50% of patients. They include the
following:
Petechiae - Common but nonspecific finding
 Splinter hemorrhages - Dark red linear lesions in the nailbeds
 Finger clubbing
 Osler nodes - Tender subcutaneous nodules usually found on the distal pads of the digits
 Janeway lesions - Nontender maculae on the palms and soles
 Roth spots - Retinal hemorrhages
 Conjunctival hemorrhage
-Neurologic disease due to embolic stroke with focal neurologic deficits is the .Other etiologies include intracerebral
hemorrhage and multiple microabscesses.
-Signs of systemic septic emboli are due to left heart disease and are more commonly associated with mitral valve
vegetations. Multiple embolic pulmonary infections or infarctions are due to right heart disease.
-Signs of congestive heart failure, such as distended neck veins, frequently are due to acute left-sided valvular
insufficiency ,Pericardial rub ,Pleural friction rub
-Tender Splenomegaly
-Other signs

Organism clinical features

 Streptococcus viridans
-50-60% of cases of subacute disease. Most clinical signs and symptoms are mediated immunologically.
Streptococcus intermedius group
-This infection can be acute and subacute. It accounts for 15% of streptococcal IE cases. It is unique among the
streptococci; it can actively invade tissue and lead to abscess formation
Group D streptococci

-Most cases are subacute.The source is GIT or genitor-urinary tract. It is the third most common cause of IE. Group
B streptococci
o Acute disease is observed in pregnant patients and older patients with underlying diseases (eg,
cancer, diabetes, alcoholism).
o The mortality rate is 40%.
o Complications include metastatic infection, arterial thrombi, and congestive heart failure.
o It often requires valve replacement for cure.
 Group A, C, and G streptococci
o Acute disease resembles that of S aureus (30-70% mortality rate), with suppurative complications.

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 o Group A organisms respond to penicillin alone.
o Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).
 S aureus
o Overall, this is the most common cause of IE, including PVE, acute IE, and IVDA IE.
o Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.
o More than half the cases are not associated with underlying valvular disease.
o The mortality rate is 40-50%.
o S aureus is the second most common cause of nosocomial BSIs, second only to coagulase-
negative staphylococci (CONS).
o A dramatic rise has occurred in cases of methicillin-resistant S aureus infections (50% of isolates),
of both the hospital- and community-acquired varieties. Sixty percent of individuals are
intermittent carriers of methicillin-resistant S aureus or methicillin-sensitive S aureus.
o The primary risk factor for contracting an S aureus BSI is the presence of intravascular lines.
Other risk factors include cancer, diabetes, corticosteroids, IVDA, alcoholism, and renal failure.
o The realization that approximately 50% of staphylococcal bacteremias acquired in the hospital or
in the community arise from infected vascular catheters has led to the reclassification of
staphylococcal BSIs. The concept of health care–associated BSIs indicates that BSIs have been
acquired not only in the hospital but also in any type of health care facility (eg, nursing home,
dialysis center) compared with those that are acquired at home.
o Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with
intravascular catheters.
 Coagulase-negative S aureus
o This is a subacute disease.
o It behaves similarly to S viridans infection.
o It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.
 Pseudomonas aeruginosa
o This is usually acute, except when it involves the right side of the heart in IVDA IE.
o Surgery is commonly required for cure.
 HACEK organisms (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)
o These organisms usually cause subacute disease.
o They account for approximately 5% of IE cases.
o They are the most common gram-negative organisms isolated from patients with IE.
o Complications may include massive arterial emboli and congestive heart failure.
o Cure requires ampicillin, gentamicin, and surgery.
Fungi
o These most frequently cause subacute disease.
o The most common organism of both fungal NVE and fungal PVE is Candida albicans.
o Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.
o Aspergillus species are observed in fungal PVE and NIE. Bartonella species
o The most commonly involved species is Bartonella quintana.

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 o IE typically develops in males who are homeless with extremely substandard hygiene. Bartonella
must be considered in cases of culture-negative endocarditis among individuals who are homeless.
 Polymicrobial IE
o Pseudomonas and enterococci are the most common combination of organisms.
o It is observed in cases of IVDA IE.
o The cardiac surgery mortality rate is twice that associated with single-agent IE.

ISCHAEMIC CEREBROVASCULAR ACCIDENT (STROKE)

Definition
-Stroke is characterized by the sudden loss of circulation to an area of the brain, resulting in a corresponding loss of
neurologic function
-Nonspecific term encompassing a heterogeneous group of pathophysiologic causes including
Thrombosis
 Embolism
 Hemorrhage.
-Strokes currently are classified as either hemorrhagic or ischemic.
-Acute ischemic stroke refers to strokes caused by thrombosis or embolism and accounts for 80% of all strokes.
Pathophysiology:
-On the macroscopic level, ischemic strokes most often are caused by extracranial embolism or intracranial
thrombosis.
-On the cellular level, any process that disrupts blood flow to a portion of the brain causes an ischemic cascade,
leading to the death of neurons and cerebral infarction.

Embolism
-Emboli may arise from
a) The heart
-The sources of cardiogenic emboli include
1) Valvular thrombi (eg, in mitral stenosis, endocarditis, prosthetic valves)
2) Mural thrombi (eg, in myocardial infarction [MI] .MI is associated with a 2-3% incidence of embolic
stroke, of which 85% occur in the first month after MI
3) Atrial fibrillation
4) Dilated cardiomyopathy
5) Atrial myxomas.
b) Extracranial arteries
c) Rarely, the right-sided circulation (paradoxical emboli).

Lacunar infarcts
-Lacunar infarcts account for 13-20% of all cerebral infarctions and usually involve the small terminal vasculature
of the subcortical cerebrum and brainstem.
-Commonly occur in patients with small vessel disease, such as diabetes and hypertension.
-Small emboli or an in situ process called lipohyalinosis is thought to cause lacunar infarcts. The most common
lacunar syndromes include pure motor, pure sensory and ataxic hemiparetic strokes.
-Due to small size and well-defined subcortical location, lacunar infarcts do not lead to impairments in cognition,
memory, speech, or level of consciousness.

Thrombosis
-The most common sites of thrombotic occlusion are cerebral artery branch points, especially in the distribution of
the internal carotid artery.
-Risks to arterial thrombosis:
1-Atherosclerosis (i.e. ulcerated plaques) and platelet adherence.
-All other risk factors for atherosclerosis catalyze this process.
2-Arterial stenosis (i.e. turbulent blood flow) causes injury with thrombus formation.
Less commonly

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3-Polycythemia
4-Sickle cell anemia
5-Protein C and S deficiency
6-Fibromuscular dysplasia of the cerebral arteries
7-Prolonged vasoconstriction from migraine headache disorders.
8-Any process that causes dissection of the cerebral arteries also can cause thrombotic stroke (eg, trauma, thoracic
aortic dissection, and arteritis).
-Thrombus formed may either embolize or occlude the artery
Ischemic cascade
-Within seconds to minutes of the loss of perfusion to a portion of the brain, an ischemic cascade sets in.
-If unchecked causes a central area of irreversible infarction (umbra) surrounded by an area of potentially reversible
ischemic penumbra.
-On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and membrane ion-transport
systems fail. The resulting influx of calcium leads to the release of a number of neurotransmitters, including large
quantities of glutamate, which in turn activates N-methyl-D-aspartate (NMDA) and other excitatory receptors on
other neurons.
-These neurons then become depolarized, causing further calcium influx, further glutamate release, and local
amplification of the initial ischemic insult.
-This massive calcium influx also activates various degradative enzymes, leading to the destruction of the cell
membrane and other essential neuronal structures.
-Free radicals, arachidonic acid, and nitric oxide are generated by this process, leading to further neuronal damage.
-Within hours to days after a stroke, specific genes are activated, leading to the formation of cytokines and other
factors that in turn cause further inflammation and microcirculatory compromise. Ultimately, the ischemic penumbra
is consumed by these progressive insults, coalescing with the infarcted core, often within hours of the onset of the
stroke.
-The central goal of therapy in acute ischemic stroke is to preserve the ischemic penumbra. This can be
accomplished by limiting the severity of ischemic injury (ie, neuronal protection) or reducing the duration of
ischemia (ie, restoring blood flow to the compromised area).
-Studies suggest that reperfusion must occur within 3 hours.

Clinical presentation
History
-Stroke should be considered in any patient presenting with an acute neurologic deficit (focal or global) or altered
level of consciousness.
-No historical feature distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting, headache, and
change in level of consciousness are more common in hemorrhagic strokes.
-Common symptoms of stroke include
Abrupt onset of hemiparesis, monoparesis, or quadriparesis
 Sudden decrease or loss consciousness
 Monocular or binocular visual loss, visual field deficits, diplopia
 Dysarthria
 Others-Ataxia, vertigo; aphasia
-Although such symptoms can occur alone, they are more likely to occur in combination.
-Time of onset of these symptoms important for thrombolytic therapy.
-Risk factors for ischemic stroke include
1) Advanced age (the risk doubles every decade)
2) Hypertension
3) Smoking
4) Heart disease (coronary artery disease, left ventricular hypertrophy, chronic atrial fibrillation)
5) Hypercholesterolemia.
6) Diabetics mellitus
7) Diseases associated with increased blood viscosity –sickle cell, AML
8) Oral contraceptives
9) Previous stroke episode
10) Transient ischemic attacks (TIAs) precede nearly 30% of ischemic strokes. If left untreated, one third of
TIAs lead to ischemic stroke: 20% within the first month, and 50% within the first year.

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DDx
1) Seizures
2) Systemic infections –Meningitis, herpes encephalitis
3) Brain tumors
4) Toxic-metabolic causes, such as hyponatremia
5) Trauma
6) Subdural hematoma/ subarachnoid haemorrhage
7) Hypertensive encephalopathy
8) Conversion disorders
9) Positional vertigo
-Others-syncope, transient global amnesia, dementia, demyelinating disease, myasthenia gravis, parkinsonism
Physical
-The physical examination always includes a careful head and neck examination for signs of trauma, infection, and
meningeal irritation.
-A careful search for the cardiovascular causes of stroke requires examination of the
Ocular fundi (retinopathy, emboli, hemorrhage)
 Heart (Pulse irregularities, murmurs, gallops)
 Peripheral vasculature (palpation of carotid, radial, and femoral pulses, auscultation for carotid bruits)
-Patients with a decreased level of consciousness should be assessed to ensure that they are able to protect their
airway.-Neurologic examination.
1) Mental status and the level of consciousness
2) Exam for Meningeal irritation
3) Cranial nerves
4) Peripheral motor function-Tone, bulk, gait, reflexes, co-ordiantion. and sensory function
5) Cerebellar function
-NB. Central facial weakness from a stroke should be differentiated from the peripheral weakness of Bell palsy.
With peripheral lesions (Bell palsy), the patient is unable to lift the eyebrows or wrinkle the forehead.
Clinical correlation.
-Anterior cerebral artery occlusions primarily affect
Frontal lobe function
 Altered mental status
 Impaired judgment
 Contralateral lower extremity weakness
 Hyperesthesia, and gait apraxia.
-Middle cerebral artery (MCA) occlusions
Contralateral hemi paresis and hyperesthesia
 Ipsilateral hemianopsia (blindness in one half of the visual field)
 Gaze preference toward the side of the lesion.
 Agnosia is common
 Receptive or expressive aphasia may result if the lesion occurs in the dominant hemisphere
-NB. Since the MCA supplies the upper extremity motor strip, weakness of the arm and face is usually worse than
that of the lower limb.
-Posterior cerebral artery occlusions affect
Vision and thought, producing homonymous hemianopsia, cortical blindness, visual agnosia
 Altered mental status
 Impaired memory.
-Vertebrobasilar artery occlusions are notoriously difficult to detect because they cause a wide variety of cranial
nerve, cerebella, and brainstem deficits. These include
Vertigo and Nystagmus
 Diplopia
 Visual field deficits
 Dysphagia
 Dysarthria
 Facial hyperesthesia
 Syncope,
 Ataxia.

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  Loss of pain and temperature sensation occurs on the ipsilateral face and contralateral body. In
contrast, anterior strokes produce findings on one side of the body only.

Lab Studies:
1. CBC
-May reveal a cause for the stroke (eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide
evidence of concurrent illness (eg, anemia).
2. RBS-DM or hypoglycemia.
3. Fasting glucose and lipid profiles-DM and hyperlipidaemias.
4. Blood slide for malaria-acute presentation
5. Electrolytes-electrolte imbalances may mimic stroke.
6. BUN and creatinine-in HTN to check the state of kidneys.
7. Cardiac enzymes-MI may cause mural thrombus.
8-ECG –up to 60% of all cardiogenic emboli are associated with atrial fibrillation or acute MI.
9. Coagulation studies may reveal a coagulopathy and are useful when thrombolytics or anticoagulants are to be
used.
10. Toxicology screens may be useful in selected patients.
11. As indicated one can do the following
-VDRL-Mycotic aneurysms.
-ANA and ANCA-connective tissue disorders and vasculitides.
-Anti-phospholipids antibodies.
Imaging Studies:
1. Head CT scan-Emergent noncontrast head CT scanning is mandatory for rapidly distinguishing ischemic from
hemorrhagic infarction and for defining the anatomic distribution of stroke.
acute ischemic stroke may be triaged to receive thrombolytic therapy, while patients with hemorrhagic stroke are
taken down a completely different diagnostic and therapeutic pathway.
-R/O hematomas, neoplasms, and abscesses.
-Most patients who have had onset of ischemic stroke symptoms within 6 hours initially will have normal findings
on CT scan. After 6-12 hours, sufficient edema is recruited into the stroke area to produce a regional hypodensity on
CT scan

2. Noninvasive arterial studies

-Carotid duplex scanning is reserved for patients with acute ischemic stroke in whom carotid artery stenosis or
occlusion is suspected.
-Transcranial Doppler ultrasound is useful for evaluating more proximal vascular anatomy, including the MCA,
intracranial carotid artery, and vertebrobasilar artery
-Results of these studies may guide the decision to initiate anticoagulation or to perform carotid endarterectomy.
3. Echocardiography
-Echocardiography is reserved for patients with acute ischemic stroke in whom cardiogenic embolism is suspected.
4, MRI
-MRI is useful for patients with acute ischemic stroke involving cerebellar or lacunar pathology

Procedures:
Angiography
-In patients who characterization of the cerebrovascular anatomy might lead to change in medical or surgical
management, such as patients with subtle occlusive diseases (eg, fibromuscular dysplasia, vasculitis) or arterial
dissection.
-Angiography continues to play an important role in the preoperative evaluation of carotid artery disease.

MANAGEMENT
a) Supportive care
b) Treatment of neurologic complications
c) Antithrombotic therapy
d) Thrombolytic therapy

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Supportive Therapy
a) Airway and breathing:
-NB GCS less than or equal to 8, require intubation.
-The goal of mechanical ventilation is hyperventilation, which decreases intracranial pressure by decreasing cerebral
blood flow.
-The recommended endpoint of hyperventilation is an arterial pCO 2 of 30-35 mm Hg.
-Supplemental oxygen requirements should be guided by pulse oximetry.
b) Circulation:
-Patients require IV access and cardiac monitoring in the ICU.
-Since overhydration can cause cerebral edema and dehydration can lead to underperfusion of the ischemic
penumbra, care must be taken to appropriately individualize the administration of intravenous fluids.
-Normoglycemic patients should not be given excessive glucose-containing intravenous fluids, as glucose may
exacerbate ischemic cerebral injury.
c) BP control:
-Since lowering the systemic blood pressure also may cause underperfusion of the ischemic penumbra, only severe
hypertension (systolic BP >220 mm Hg, diastolic BP >120 mm Hg, or mean arterial BP >140 mm Hg) or
hypertension associated with hemorrhagic stroke transformation, cardiac ischemia, aortic dissection, or renal
damage should be treated.
-Agents-include intravenous nitroprusside or labetalol.
-NB. Use of sublingual nifedipine may cause extreme hypotension
d) Fever control:
-Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates ischemic neuronal injury.
e) Cerebral edema control:
-Cerebral edema occurs in up to 15% of patients with ischemic stroke, reaching maximum severity 72-96 hours after
the onset of stroke.
-Hyperventilation and mannitol are used routinely to decrease intracranial pressure quickly and temporarily.
-No evidence exists supporting the use of corticosteroids to decrease cerebral edema in acute ischemic stroke.
f) Seizure control:
-Although seizure prophylaxis is not indicated, prevention of subsequent seizures with standard antiepileptic therapy
is recommended.
Other medications
-Calcium channel blockers (eg, nimodipine) may prevent calcium influx is one of the earliest events in the ischemic
cascade.
Anti-coagulation
-Heparin prevents recurrent cardioembolic strokes and may help inhibit ongoing cerebrovascular thrombosis
-May have definite benefit in cases of MI and associated stroke.
Risks-Overall, intracranial hemorrhage occurs in 1-4% of patients who receive an anticoagulant for TIA or acute
stroke.
-Contra-indications for coagulation therapy.
uncontrolled hypertension
 Hemorrhagic stroke
 uncontrolled bleeding at another site
 avoided in patients at risk for hemorrhagic transformation, eg, patients who have had large hemispheric
strokes, with signs such as combined hemiparesis and hemisensory deficits, or strokes showing early
hypodense areas on cranial CT scan.
-Patients with cardioembolic strokes also may be at risk for hemorrhagic transformation and it is thought that should
not be given anticoagulants until at least 48 hours after symptom onset because of the risk of hemorrhagic
transformation (5-7 d for large cardioembolic strokes).
- Immobilized stroke patients may benefit from low-dose subcutaneous unfractionated or low-molecular-weight
heparin, which reduces the risk of deep vein thrombosis.
Anti-thrombotics
-Anti-platelets are used in primary prophylaxis against stroke.
-Some have also been shown to reduce early recurrence of stroke.
-Aspirin (Bayer, Anacin, Bufferin) - Blocks prostaglandin synthetase action, which in turn inhibits prostaglandin
synthesis and prevents formation of platelet-aggregating thromboxane A2. Also acts on hypothalamic heat-regulating
center to reduce fever.

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-1.3 g/d PO divided bid/qid
-Ticlopidine (Ticlid) - Second-line antiplatelet therapy for patients who cannot tolerate aspirin or in whom aspirin
not effective
Thrombolytics
-Recombinant tissue-plasminogen activators -- Thrombolytics restore cerebral blood flow in acute ischemic stroke,
leading to improvement or resolution of neurologic deficits. Unfortunately, thrombolytics also cause intracranial
hemorrhage.
-While both streptokinase and rt-PA have been shown to benefit patients with acute MI, only alteplase has been
shown to benefit selected patients with acute ischemic stroke.

HAEMORRHAGIC STROKE/INTRACEREBRAL HAEMORRHAGE

Introduction
-Hemorrhagic stroke accounts for 10-15% of all strokes and is associated with higher mortality rates than cerebral
infarctions.
-Patients with hemorrhagic stroke present with similar focal neurologic deficits but tend to be more ill than patients
with ischemic stroke.
-They are more likely to have headache, altered mental status, seizures, nausea and vomiting, and/or marked
hypertension; however, none of these findings distinguish reliably between hemorrhagic and ischemic strokes.
Pathophysiology
-Bleeding occurs directly into the brain parenchyma. The usual mechanism is thought to be leakage from small
intracerebral arteries damaged by chronic hypertension. Other mechanisms include
Bleeding diatheses
 Iatrogenic anticoagulation
 Cerebral amyloidosis.
 Cocaine abuse.
-Has as a predilection for certain sites in the brain, including the thalamus, putamen, cerebellum, and brain stem. In
addition to the area of the brain injured by the hemorrhage, the surrounding brain can be damaged by pressure
produced by the mass effect of the hematoma.
-A general increase in intracranial pressure may occur.

Clinical presentation

History:
-Patients' symptoms vary depending on the area of the brain affected and the extent of the bleeding.
-Hemorrhagic strokes are more likely to exhibit symptoms of increased intracranial pressure than other types of
stroke. Headache, often severe and sudden onset, Nausea and/or vomiting
-Seizures

Physical:
-Hypertension commonly is a prominent finding.
-An altered level of consciousness or coma is more common with hemorrhagic strokes than with ischemic strokes.
Often, this is due to an increase in intracranial pressure.
-Meningismus may result from blood in the ventricles.
-Focal neurologic deficits-The type of deficit depends upon the area of brain involved.
-If the dominant hemisphere (usually left) is involved, a syndrome consisting of right hemiparesis, right hemisensory
loss, left gaze preference, and right visual field cut, and aphasia may result.
-If the nondominant (usually right) hemisphere is involved, a syndrome of left hemiparesis, left hemisensory loss,
right gaze preference, and left visual field cut may result. Nondominant hemisphere syndrome also may result in
neglect when the patient has a left-sided hemi-inattention and ignores the left side.
-If the cerebellum is involved, the patient is at high risk of herniation and brainstem compression. Herniation may
cause a rapid decrease in the level of consciousness, apnea, and death.
-Other signs of cerebellar or brainstem involvement includes the following:
Gait or limb ataxia
 Vertigo or tinnitus
 Nausea and vomiting

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  Hemiparesis or quadriparesis
 Hemisensory loss or sensory loss of all 4 limbs
 Eye movement abnormalities resulting in diplopia or nystagmus
 Oropharyngeal weakness or dysphagia
 Crossed signs (ipsilateral face and contralateral body)
Causes
1. Hypertension (up to 60% of cases)
2. Advanced age (risk factor)
3. Cerebral amyloidosis (affects people who are elderly and may cause up to 10% of ICHs)
4. Coagulopathies (eg, due to underlying systemic disorders)
5. Anticoagulant therapy
6. Thrombolytic therapy for acute myocardial infarction (MI) and acute ischemic stroke (can cause iatrogenic
hemorrhagic stroke)
7. Abuse of cocaine and other sympathomimetic drugs
8. Arteriovenous malformation
9. Intracranial aneurysm
10. Vasculitis
11. Intracranial neoplasm-Bleeding due to a brain tumor
12. History of prior stroke (risk factor

KAPOSI SARCOMA
Background
Kaposi sarcoma (KS) was described initially in 1872 by a Hungarian dermatologist, Moritz Kaposi.
Definition
-Multifocal angiosarcoma
-Spindle-cell tumor derived from endothelial cell lineage.
-This condition carries a variable clinical course ranging from minimal mucocutaneous disease to extensive organ
involvement.
Epidemiology
-Was mainly found among the Africans, Jews and the Europeans.
-In Africa-Zaire, Uganda ,Kenya, Malawi,TZ, Zimbabwe
Americas-mainly amongst the homosexuals.
-Region with the highest incidence is Kitu in Zaire where it forms up to 12 % of all the tumors.

Epidemiological classification
KS can occur in several different clinical settings.
a) Epidemic AIDS-related KS
This entity occurs in patients with advanced HIV infection, and is the most common presentation of KS. It’s an
AIDS-defining illness
In Africa and developing regions, epidemic AIDS-related KS is common in heterosexual adults and occurs less often
in children. Visceral involvement is common. AIDS-related KS is the most clinically aggressive form of KS.

b) Immunocompromised KS
-Following solid-organ transplantation or in patients receiving immunosuppressive therapy.
-However, individuals with congenital immunodeficient states are not at increased risk for developing KS.
-The average time to development of KS following transplantation is 30 months.
-Visceral involvement is common.

c) Classic KS
-Occur in elderly men of Mediterranean and Eastern European background.
-Usually carries a protracted and indolent course.
-Common complications include venous stasis and lymphedema.
-As many as 30% of patients with classic KS subsequently may develop a second malignancy.
-Visceral involvement is uncommon.

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d) Endemic African KS
This entity occurs in men who are HIV seronegative in Africa and may carry an indolent or aggressive course.

Race:
-In Africa and developing regions, epidemic AIDS-related KS is common in heterosexual adults and occurs less
often in children.
-Classic KS typically occurs in elderly men of Mediterranean and Eastern European background.
-Endemic African KS occurs in HIV seronegative men in Africa

Sex:
-AIDS-related KS: In the United States, this condition occurs primarily in homosexual males, bisexual men, and in
the female sexual partners of bisexual men.
-African KS occurs in heterosexual men and women with equal frequency.
-Classic KS occurs primarily in males, with a male-to-female ratio of 10:1.

Age:
-AIDS-related KS generally occurs in adults.
-Classic KS typically occurs in patients aged 50-70 years.
-African KS occurs in people of a younger age 35-40 yrs.

Pathophysiology:
-KS is caused by an excessive proliferation of spindle cells thought to have an endothelial cell origin from a single
cell clone.
-Human herpes virus 8 (HHV-8) –Kaposi sarcoma herpes virus infection in background of immune suppression
(HIV or other causes) play central role in the pathophysiology.
-Factors that are thought to contribute to the development of KS in individuals infected with HHV-8 and HIV
include an abnormal cytokine milieu associated with HIV infection (interleukin [IL]-6, IL-1, granulocyte-
macrophage colony-stimulating factor [GM-CSF], basic fibroblast growth factor [bFGF], and oncostatin M, tumor
necrosis factor [TNF]) and the HIV-tat protein, which acts as a mitogen for KS cells.

Mortality/Morbidity:
-AIDS-related KS, unlike other forms of KS, tends to have an aggressive clinical course.
-Morbidity may occur from extensive cutaneous, mucosal, or visceral involvement.
-In patients receiving highly active antiretroviral therapy (HAART), the disease often has a more indolent clinical
course or may regress spontaneously.
-The most common causes of morbidity include
 Cosmetically disfiguring cutaneous lesions
Lymphedema
Gastrointestinal involvement
 Pulmonary involvement -Pulmonary involvement is the most common cause of mortality.

Clinical presentation
History
-AIDS-related KS carries a variable clinical course ranging from minimal mucocutaneous disease to widespread
organ involvement.
-Most patients present with cutaneous disease. Visceral disease occasionally may precede cutaneous manifestations.
- Lesions have involving virtually every organ.
Cutaneous lesions - Occur in virtually all patients
Multiple skin lesions
Tumor-associated lymphedema - Typically manifested by lower extremity or facial involvement, thought to
occur secondary to obstruction of lymphatic channels
Lymphadenopathic KS -lymphadenopathy
 Pain associated with ambulation - Due to lesions involving the soles of the feet
At times, a Köbner phenomenon appears evident, with nodules at sites of trauma
Gastrointestinal - Lesions can occur anywhere within gastrointestinal tract

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 Often asymptomatic and clinically indolent
Odynophagia, dysphagia
Nausea, vomiting, abdominal pain
Hematemesis, hematochezia, melena
Bowel obstruction
Pulmonary - May be difficult to distinguish from opportunistic infections
Cough
Dyspnea
Hemoptysis
Chest pain
May have asymptomatic radiographic finding

DDx
Bacillary angiomatosis
This entity often is difficult to distinguish clinically from KS. It is caused by Rochalimaea species, a slow-growing,
fastidious gram-negative bacillus that is readily treated with antibiotics. Bacillary angiomatosis lesions typically
possess capillary proliferation and neutrophilic inflammation. In contrast, KS lesions display slit like vascular spaces
containing lymphoplasmacytic infiltrates. A skin biopsy is required to establish diagnosis.
 Hematoma
 Hemangioma
 Lymphangioma
 Neurofibroma.
 Dermatofibroma
 Nodal myofibroma
 Arteriovenous malformation
 Pyogenic granuloma
Purpura
Blue Rubber Bleb Nevus Syndrome
Melanocytic naevi
Melanoma
Nodular leprosy
Onchocerchiasis

Physical Examination
KS is described in 3 forms including:
Localized nodular
Locally aggressive
Generalized KS
-Cutaneous KS may be exophytic or infiltrative. KS also occurs as a large infiltrating mass or as multiple cone-
shaped friable tumors. These 2 variants, termed locally aggressive KS, may adhere firmly to underlying anatomic
structures including bone
Cutaneous KS occur in 6 stages including
 Macular- discrete red or purple patches
Papular
Plaque
 Nodular -may be spongy to the touch
Ulcerative
Lymphadenopathic
-Cutaneous lesions may occur at any location but typically are concentrated on the lower extremities and the head
and neck region. Lesions usually non-pruritic. And vary in size
-Lesions may assume a brown, pink, red, or violaceous color and may be difficult to distinguish in dark-skinned
individuals.
-Lesions may be discrete or confluent and typically appear in a linear, symmetric distribution, following Langer
lines.
-Mucous membrane involvement is common (palate, gingiva, and conjunctiva). Ulcerated or bulky tumor
involvement may interfere with speech or mastication.

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A few unusual varieties of KS also exist.
-Telangiectatic KS is an eruption of pink translucent nodules with prominent telangiectasia.
-Ecchymotic KS appears as periorbital ecchymoses.
-Keloidal KS is evident as somewhat brown-to-violaceous keloidal nodules.
-Cavernous KS is a rare type of locally aggressive KS characterized by cutaneous tumors that histologically
resemble cavernous hemangiomas; however, the endothelial cells and their nuclei are large and prominent, bulging
into the cavity.
-Lymphangioma like KS is a rare variant in which dilated vascular spaces produce a bullous-appearing eruption,
typically on the lower legs. The lesions are easily compressible and appear clinically to be fluid-filled. The vascular
channels are lined by banal-appearing endothelial cells permeating the dermis in the absence of spindle cell
proliferation

Causes:
-Coinfection with HIV and HHV-8 (Kaposi sarcoma-associated herpes virus [KSHV])
-Iatrogenic immunosuppression (including corticosteroids)
-Elevated degree of expression of numerous cytokines and angiogenic growth factors, including TNF-alpha, IL-6,
bFGF, and oncostatin

Lab Studies:
1. CD4 lymphocyte counts and plasma HIV viral-load studies should be performed for patients with HIV
infection.
2. FHG and ESR- Anemia if haematemesis, chronic illness or HIV itself
3. Organ Kaposi-U/E and C and LFT .Also before chemotherapy
Imaging Studies:
1. Chest radiographs: Radiographic findings are variable and nonspecific. They may include
Diffuse reticulonodular infiltrates
 Interstitial infiltrates
 Pleural effusions
 Hilar or mediastinal lymphadenopathy
 Isolated pulmonary nodule.
2. CT-Scan of Chest or Abdomen
3. Abdominal U/S
4. Severe limb involvement-X-ray show any bone infiltration
Thallium or gallium scans: These studies may help to differentiate pulmonary KS from infection. Pulmonary KS
lesions typically demonstrate intense thallium uptake and no gallium uptake, whereas infection often is gallium avid
and thallium negative.
Definitive Diagnosis
A punch biopsy of the skin or transbronchial biopsy (lung) is necessary to establish a definitive diagnosis.
Bronchoscopy:
-Pulmonary involvement typically is characterized by a slightly raised (submucosal) cherry-red lesion. Biopsy
generally is avoided due to the risk of bleeding.
-Esophagogastroduodenoscopy (EGD) or colonoscopy:
-Gastrointestinal lesions frequently are observed.
-The yield of endoscopic biopsy may be low secondary to the submucosal location of many lesions.

Histologic Findings:
Typical histologic findings include
 Proliferation of spindle cells
Prominent slit- like vascular spaces
Extravasated red blood cells.
Histopathologic classification is based on relative contribution of spindle cells, fibrosis, and nuclear pleomorphism,
sometimes divided into 3 histopathologic forms, which include
(1) A mixed form with an equal amount of spindle cells, vascular clefts, and capillaries. Respond well to
chemotherapy good prognosis. Like benign disease.
(2) a monomorphic type with 1 cell type predominating,
(3) An anaplastic form with cellular pleomorphism and numerous mitotic figures.

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Type 2 and 3 poor response to chemotherapy and bad prognosis.

Staging of Kaposi sarcoma

Stage I
-Localized nodular KS, with more than 15 cutaneous lesions or involvement restricted to 1 bilateral anatomic site,
and few, if any, gut nodules.
Stage II
-Includes both exophytic destructive lesions and locally infiltrative cutaneous lesions as locally aggressive KS.

Stage III (generalized lymphadenopathic KS)

-Has widespread lymph node involvement, with or without skin lesions, but with no visceral involvement.

Stage IV (disseminated visceral KS)

Involvement of multiple visceral organs.

With each stage

A: Associated opportunistic infection(s) is evident.
B: Patient is HIV-I seropositive.
C: Cutaneous anergy or other evidence of severe immunodeficiency is present

The AIDS Clinical Trials Group (ACTG) staging:

Good risk
Tumor (T) - Confined to skin and/or lymph nodes and/or minimal oral disease
Immune system (I) - CD4 greater than 200/mm3
Systemic illness (S) - No history of opportunistic infection, more than 10% involuntary weight loss, or diarrhea
persisting more than 2 weeks
Karnofsky performance status greater than 70
Poor risk
Tumor (T) - Tumor-associated edema or ulceration, extensive oral KS, gastrointestinal KS, KS in other non-nodal
viscera
Immune system (I) - CD4 less than 200/mm3
Systemic illness (S) - History of opportunistic infection, unexplained fever, night sweats, more than 10%
involuntary weight loss, or other HIV-related illness (ie, lymphoma, neurologic disease)
Karnofsky performance status less than 770

MANAGEMENT
Medical Care:
A)Antiretroviral therapy
-Optimal control of HIV infection using HAART is an integral part of successful KS therapy.
-The choice of therapy beyond HAART must be individualized and depends on the extent of disease, the presence
and nature of the symptoms, the rate of disease progression, and the overall therapeutic goals.
B)Local therapy:
-For local disease and locally aggressive disease.
-May also be for palliation of locally advanced symptomatic disease
-This therapy also is well suited for individuals with significant comorbidities and refractory or resistant disease.
-Local therapy fails to halt the development of new KS lesions.
i) Radiation therapy:
This is the most widely used and effective local therapy. Responses occur in 80-90% of patients. A higher
cumulative dose (40 Gy) results in better local control
ii) Intralesional vinblastine
Commonly is used and generally is well tolerated. Adverse effects include skin discoloration and superficial
erythema. The lesion is injected with 0.1 mL/cm2 (at a concentration of 0.2 mg/mL).
iii) Cryotherapy
Entails liquid nitrogen applied topically and may be useful for small facial lesions. Cryotherapy may cause skin
hypopigmentation.

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iv) Topical retinoids:
IL-6 is a cytokine implicated in the pathogenesis of KS. Retinoic acid down-regulates IL-6 receptor expression. A
0.1% (alitretinoin [Panretin]) gel is available commercially and may be applied topically 2-4 times daily. This agent
generally is well tolerated but may cause local erythema and irritation.

c) Systemic therapy
Indicated for extensive or symptomatic visceral disease, rapidly progressive mucocutaneous disease, and
symptomatic lymphedema.

i)Interferon-alfa:
-Have antiangiogenic, antiviral, and immunomodulatory properties.
-Time to clinical response is long (i.e. 4 month).
- Interferon-alfa is most effective when the CD4 count is greater than 150-200/mL or when administered in
conjunction with antiretroviral therapy.
-This therapy entails subcutaneous administration daily or 3 times weekly.
-Response may occur with low (1 million U/m2), intermediate (30 million U/m2), or high doses (50 million U/m2).
-Toxicity is more common and severe with higher doses; symptoms may include fatigue, flu-like symptoms,
myalgia, arthralgia, fever, myelosuppression, and hepatotoxicity.

b)Chemotherapy
Is not used with curative intent. It is capable of achieving rapid tumor regression and palliation of tumor-related
symptoms.
-Chemotherapy is indicated for symptomatic visceral or rapidly progressive mucocutaneous disease.
Combination therapy preferred to single agents.
Eg
ABVD-Adriamycin, Bleomycin, Vincristine and Dacarbazine
VAP-Vincristine, Adramycin, Paclitaxel.

Surgical Care:
Solitary KS lesions may be excised surgically
Acute presentations causing abdominal obstruction, perforation of intestines, Haemorrhage,

LEISHMANIASIS
Background:
-Leishmaniasis is a zoonotic infection caused by the protozoa belonging to the genus Leishmania. –
-Leishmaniasis is transmitted by sandflies (Phlebotomus species)
-Leishmania is intracellular parasites that infect the mononuclear phagocytes.
-The spectrum of human disease ranges from self-healing localized ulcers to widely disseminated progressive
lesions of the skin, mucus membranes, and the entire reticuloendothelial system

Epidemiology
-The Leishmania species infecting humans mainly are the
 Visceral leishmaniasis (kala azar) caused by Leishmania donovani
Cutaneous leishmaniasis caused by Leishmania tropica and Leishmania brasiliensis.
-Visceral leishmaniasis distributed all over the world but predominantly is encountered in India, South America,
Central Asia, Middle East, and Africa.
-Cutaneous leishmaniasis caused by L tropica is seen mainly along the shores of the Mediterranean, through the
Middle East, central Africa, and parts of India.
-Cutaneous leishmaniasis caused by L brasiliensis is confined mainly to Central America and South America.
-Geographical distribution of leishmaniasis is limited by
Distribution of the sandfly
 Its susceptibility to cold climates
 Its tendency to take blood from humans or animals only
 Its capacity to support the internal development of specific species of Leishmania.

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Pathophysiology:
- Zoonotic diseases because the infection is being maintained in endemic areas in dogs, wild rodents, and other
animals.
-Leishmania is obligatory intracellular parasites
-Transmitted by the sandfly belonging to the genera Phlebotomus and Lutzomyia.
-Of 500 known phlebotomine species, only about 30 of them have been positively identified as vectors of the
disease.
-The reservoir of infection in Indian kala azar is humans, whereas it is the rodents in African kala azar, foxes in
Brazil and Central Asia, and canines in the Mediterranean and Chinese kala azar.
Life cycle
-The parasite exists in 2 forms, the amastigote form and the promastigote form.
-The amastigote form occurs in humans, whereas the promastigote form occurs in the sandfly and in artificial culture
-Only the female sandfly transmits the protozoan, infecting itself with the Leishmania parasites contained in the
blood it sucks from its human or mammalian host.
-During a period of 4-25 days, the parasite continues its development inside the sandfly, where it undergoes major
transformation into the promastigote form.
-A large number of flagellate forms (promastigotes) are produced by binary fission.
-Multiplication occur the mid gut of the sandfly, and the flagellates tend to migrate to the pharynx and buccal cavity
of the sandfly.
-A heavy pharyngeal infection is observed between the sixth and ninth day of an infected blood meal.
-Following the bite, flagellates entering the circulation into cells of reticuloendothelial system where they change
into the amastigote form.
-The amastigote forms also multiply by binary fission, with the multiplication continuing until the host cell is
packed with the parasites and ruptures, liberating the amastigotes into circulation.
-The free amastigotes then invade fresh cells, thus repeating the cycle and, in the process, infecting the entire
reticuloendothelial system.
-The spleen is enlarged with a thickening of the capsule, it is soft and fragile, its vascular spaces are dilated and
engorged with blood, and the reticular cells of Billroth are increased markedly and packed with the amastigote forms
of the parasite.
- In the liver, the Kupffer cells are increased in size and number and infected with amastigote forms
-Bone marrow turns hyperplastic, and parasitized macrophages replace the normal hemopoietic tissue
-Some of the free amastigotes are drawn by the sandfly during its blood meal, thus completing the cycle.
-Cutaneous leishmaniasis is caused by L tropica. Morphologically, it is indistinguishable from L donovani. The life
cycle is exactly the same as that of L donovani except that the amastigote form resides in the large mononuclear
cells of the skin.
Methods of transmission
-The predominant mode of transmission is the bite of sandfly
-.Different species of sandfly act as vectors in different parts of the world
-Uncommon modes of transmission are through congenital transmission, through blood transfusion, and, rarely,
through inoculation of cultures.

Pathogenesis
-After inoculation by sandflies, the flagellates (promastigote form) bind to macrophages in skin
-The outcome of Leishmania infection appears to depend on the complex interaction between the parasite's virulence
and the immune response of the host.
-Promastigotes activate complement through the alternate pathway and are opsonized.
-The most important immunological feature is a marked suppression of the cell-mediated immunity to leishmanial
antigens.
- In persons with asymptomatic self-resolving infection, T-helper cells predominate, although immune suppression
years later can result in disease.
-An overproduction of both specific immunoglobulins and nonspecific immunoglobulins also occurs.
The increase in gamma globulin leads to a reversal of the albumin-globulin ratio commonly seen in this disease.
Clinical presentation
History: Visceral leishmaniasis

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-The spectrum of illness ranges from asymptomatic infection to severe life-threatening infection also known
variously as:
 Kala azar
Dumdum fever
Assam fever
 Infantile splenomegaly
-It occurs in the following 4 main regions
A) E. AFRICA
-Agent-L. donovani (EA)
-L.dovoni (Sudan)
-Vector: Phlebotomus martini
-Age group-Old children and young adults
-Reservoir-No known .Although some rodents are found infected they are not many to qualify as reservoirs
-Kenya-areas involved include the following Machakos, Kitui, Tharaka, Samburu, West Pokot, Turkana, and
Baringo

B) INDIAN subcontinent
-Pakistan, Bangladesh
-Species-L. donovani donovani
-Vector-Phlebotomus argentine
-Receivoir-Not known
-Peak-Young adults

C. Mediteranean-
- (S.Italy, Spain, Portugal, and Morocco)
-Agent-L. donovani infantum
-Age-Young children
-Recervoir-Domestic dogs, foxes

d.)South and central America

-Young children most affected.
-Recevir-Deomestic dogs and foxes
-Vector-Sandfly (Lutzomya fly).

Symptoms
-Is the most severe form of leishmaniasis and usually is fatal within 2 years if left untreated.
-The incubation period usually is 3-6 months but can be months or years.
-Young malnourished children are the most susceptible to developing progressive infection
1-Site of the bite the skin sloughs off forming an ulcer-leishmanoma.
2-Fever and night sweats-continuous or remittent
3- Late presentation
 Edema caused by hypoalbuminemia,
Hemorrhage caused by thrombocytopenia
Growth failure caused by features of chronic infection.
4-General malaise, easy fatiguabiltity, anorexia-Anaemia
Recurrent infections-leucopenia
5-Abdominal swelling or discomfort.
6-Fulminant forms of visceral leishmaniasis may present with pancytopenia and hepatic failure.
Other presentation
7-GIT-dysentery-infiltration by amastigotes
8-Resp-dry coughs sometimes productive
9-Skin hyper-pigmentation –kala azar
Physical:
1. Parlour
- Anemia almost always is present and usually is severe.

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-It is normochromic and normocytic and caused by various factors, including replacement of marrow by the
parasites, splenic sequestration, hemorrhage, hemodilution, and hemolysis.
- Leukopenia also is observed and may contribute to secondary infections.
-Thrombocytopenia contributes to the hemorrhagic tendency observed in some cases. Petechiae and ecchymosis
may be seen in the extremities
2. Jaundice with mildly elevated enzyme levels is rarely seen and is considered a bad prognostic sign.
3. Marked splenomegaly
4. Hepatomegaly
5. Lymphadenopathy
6. The skin is dry, thin, and scaly, and hair is lost.
As the disease progresses, the skin on the hands, feet, abdomen and face may become darkened, giving the name
kala azar or black fever.
7. Pedal edema is observed more commonly in children.
-If untreated, death occurs within 2 years and often is caused by bacterial pneumonia, septicemia, dysentery,
tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequela

Post–kala azar dermal leishmaniasis

-Follows the treatment of visceral leishmaniasis in approximately 10% of cases in India and 2% of cases in Africa.
-Lesions in India develop 1-2 years after treatment of the original disease and may persist for as long as 20 years.
-In Africa, they usually appear during or shortly after treatment and persist only for a few months.
-Dermal lesions are categorized into 3 types, as follows:
a) Depigmented macules are the earliest lesions and are seen in the trunk and extremities.
b) Erythematous patches -in the nose, cheeks, and chin with a butterfly distribution. They are photosensitive,
becoming prominent toward the middle of the day.
c) Yellowish pink nodules –on face and replace the earlier lesions. The absence of ulceration distinguishes
these nodules from those of cutaneous leishmaniasis (oriental sore).
Cutaneous leishmaniasis
-Occurs mainly in 2 forms
 Oriental sore caused by L tropica
American cutaneous leishmaniasis caused by L brasiliensis.
-No difference in the pathology of the lesions caused by L tropica and L brasiliensis exists.
-Cutaneous leishmaniasis produces skin lesions mainly on the face, arms, and legs.
-Although this form is often self-healing, it can create serious disability and permanent scars.
-After recovery or successful treatment, cutaneous leishmaniasis induces immunity to reinfection by the species of
Leishmania that caused the disease.
-Diffuse cutaneous leishmaniasis is associated with a deficient cell-mediated immunity that enables the parasite to
disseminate in the subcutaneous tissues.
- It starts as a single lesion and spreads slowly over the face, ears, extremities, and buttocks until the whole body is
affected.
-The lesions are neither destructive nor erosive but are disfiguring.
-The lesions are misdiagnosed as leprosy and are resistant to treatment.

Mucocutaneous leishmaniasis,
-Also called espundia in South America, causes disfiguring lesions to the face
-it destroys the mucous membranes of the nose, mouth, and throat.
-The lesions commonly arise at the mucocutaneous junction around the nose and may spread inward, destroying
tissues and leading to deformity.
- The lesions heal by scarring, causing the typical tapir or camel nose.
-It carries a significant mortality rate. Children rarely are affected.

Investigations
Lab Studies:
1. FBC
-A normochromic normocytic anemia
-leucopenia, neutropenia,
-Thrombocytopenia

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2. Elevated gamma globulins, and a reversal of the albumin-globulin ratio
3. Direct evidence of infection

Smear.
-The parasite can be demonstrated through direct evidence from peripheral blood, bone marrow, or splenic aspirates
BM Aspirate taken from the iliac crest(preferred ) or Sternum)
-The smears are stained in Leishman, Giemsa, or Wright stains.
-The chances of finding L donovani are greatly enhanced by adopting the following methods:
(1) Thick film
(2) By centrifuging

Culture:
-Novy-McNeal-Nicolle medium. NNN media takes 12-24 hrs
-RPMI media takes 6-12 hours
-Schneider media-upto 90 days
Animal inoculation:
-This is a sensitive method but can take several weeks
-The sample is inoculated intraperitoneally or intradermally into the skin of the nose and feet.
-The parasites can be demonstrated from the ulcers and nodules that develop from the sites of inoculation.
Indirect evidence of infection
1. Detection of hypergammaglobinemia
- The aldehyde and the antimony tests were the initial tests used to diagnose kala azar.
-The aldehyde test is a demonstration of the increase in gamma globulin levels observed in kala azar.
-Take approximately 1 mL of blood in a small glass tube and add 1-2 drops of 40% formalin.
-Formation of milky-white–like opacity and jellification indicates a positive result.
-The antimony test also depends on the rise in serum gamma globulin.
-A positive test is indicated by a white flocculent precipitate seen when a urea stibamine solution comes in contact
with serum.
2. Immunological tests:
-The direct agglutination test
-Immunofluorescent antibody test
-complement fixation
-PCR
- Cross-reactions can occur with leprosy, Chagas disease, malaria, and schistosomiasis.
3-Leishmanin skin test (Montenegro test)
- is a delayed hypersensitivity reaction. Injecting intradermally 0.1 mL of killed promastigote antigen.
-The test is read after 72 hours.
- The leishmanin skin is negative during active visceral leishmaniasis and usually becomes positive only after
successful therapy.
-It also is positive in dermal leishmaniasis.

Medical Care:
-Supportive treatment includes
 high-calorie diet
Blood transfusions
Treatment of secondary infections
- Sodium stibogluconate, a pentavalent antimonial compound (Sbv), is the drug of choice in treatment of visceral
leishmaniasis
-Amphotericin B deoxycholate is the drug of choice in India, while the lipid formulation liposomal amphotericin is
used in Europe.
-Miltefosine
-Efficacy and convenient oral administration will have an important role to play in the future, preferably as a
combination for first-line treatment of visceral leishmaniasis.
-Earliest signs of improvement are an improvement in the symptoms.
-Regression of splenomegaly takes a few months.

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Pentavalent antimony compounds
Sodium stibogluconate and meglumine antimonate
-For visceral leishmaniasis, these compounds are the drugs of choice
- Sodium stibogluconate Acts by interfering with the metabolism of the parasite.
-Patients with long-standing disease may require long-term therapy.
-Can be given at recommended dose for 30 days without toxicity.
-Pharmacokinetic parameters are similar with IV/IM administration.
-Primary unresponsiveness ranges from 2-8%.
-Relapse rate usually is <10% but has been reported to be as high as 30% in Kenya.
-Dose 20mg/kg/day for 20 days
Adverse-
-May precipitate arrhythmia with concurrent use of drugs that prolong the QT interval (eg, antiarrhythmics, TCAs,
cisapride, moxifloxacin, thioridazine)

Aminosidine (paromomysin)
-Amebicidal and antibacterial aminoglycoside obtained from a strain of Streptomyces rimosus, active in intestinal
amebas
-Dose-16-20 mg/kg/d IV/IM divided tid for 21 d
Xanthine oxidase inhibitor - Allopurinol (Zyloprim)
-Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine.
-Reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.
- Not effective as monotherapy for leishmaniasis.
Antibiotic agents
-Two available preparations are pentamidine isethionate (Pentam) and pentamidine dimethanesulfonate (Lomidine).
-Pentamidine dimethane sulphonate given in the same dose schedule is more effective than pentamidine isethionate.
Immunomodulatory agents
-Interferons are naturally occurring cytokines that possess various biological functions, which include
immunosuppressive action.
-They are produced by cells in response to virus, double-stranded ribonucleic acid (RNA), antigen, or mitogen, and
are classified in relation to biochemical properties and cell of origin.
-They are commercially produced with recombinant DNA technology.

Cutaneous Leishmaniasis
-Most self limited by L. ethiopica may not be self limited.
1-Heat therapy
2-Cryotherapy
3-Ulcer excision and skin graft
4-Local gels-aminocidine

-For ethiopica and diffuse cutaneous leishmaniasis treated as visceral leishmaniasis.

LEUKEMIAS
Definition
-Neoplastic clonal proliferation of the haemopoetic cell lines in the bone marrow with release into circulation of
abnormal cells.
Classification
Based on clinical presentation
-Acute-Rapid onset and progression and without treatment death in few months (2-3 months).
-Acute leukemia’s have arrested maturation of the haemopoetic cells with predominance of blast cells in circulation.
-Chronic-Insidious onset and slow progressing and without treatment death in months to years.
-Mature cells and some blasts in circulation-maturation spectrum of cells.
Based on cell types
-Lymphoid
-Myeloid types.

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ACUTE LYMPOBLASTIC LEUKEMIA
Definition
-ALL- is a malignant (clonal) proliferation of early lymphoid precursors in the bone marrow with replacement of the
normal hematopoietic cells of the marrow.
Pathophysiology:
-The malignant cells of ALL are lymphoid precursor cells (i.e., lymphoblast) that are arrested in an early stage of
development.
-This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations.
-The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal
blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees.
-The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.
Frequency:
-ALL is the most common type of leukemia in children.
- In adults, it is less common than acute myelogenous leukemia (AML)
Mortality/Morbidity:
-Only 20-40% of adults with ALL are cured with current regimens.
-ALL in pediatrics is more responsive.
Sex:
-ALL is slightly more common in men than in women.
Age:
-ALL is more common in children than in adults

Etiology
-Most leukemias occurring after exposure to radiation are AML rather than ALL
-Rarely patients have an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS) that
evolves to ALL. -However, most patients with MDS that evolves to acute leukemia develop AML rather than ALL
-However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML
rather than ALL.
-Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults. These abnormalities included
balanced translocations as occur in cases of AML. However, abnormalities of chromosome number (hypodiploidy,
hyperdiploidy) are much more common in ALL than in AML.

Clinical picture
History:
Patients with ALL present with either
(1) Symptoms relating to direct infiltration of the marrow or other organs by leukemia cells or
(2) Symptoms relating to the decreased production of normal marrow elements.
-Infiltration of the marrow by massive numbers of leukemia cells frequently manifests as bone pain.
-This pain can be severe and is often atypical in distribution.
-Uncommonly (10-20%), patients may present with left upper quadrant fullness and early satiety due to
splenomegaly.
-Other patients, particularly those with T-cell ALL, present with symptoms related to a large mediastinal mass, such
as shortness of breath.
-Symptoms of leukostasis (e.g., respiratory distress, altered mental status) because of the presence of large numbers
of lymphoblasts in the peripheral circulation, leukostasis is much less common in persons with ALL compared to
AML and occurs only in patients with the highest WBC counts, i.e., several hundred thousand per microliter.
-Symptoms of anemia are common and include fatigue, dizziness, palpitations, and dyspnea upon even mild
exertion.
-Patients with ALL often have decreased neutrophil count; despite an increased total WBC count have increased risk
of infection.
-Patients with ALL often have fever without any other evidence of infection.
-However, in these patients, one must assume that all fevers are from infections until proven otherwise because a
failure to treat infections promptly and aggressively can be fatal. Infections are still the most common cause of death
in patients undergoing treatment for ALL

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-Bleeding symptoms due to thrombocytopenia .The thrombocytopenia, however, tends to be less severe than that
observed in patients with AML
-Some may have (DIC) at the time of diagnosis, usually as a result of sepsis.
-Consequently, some patients may present with hemorrhagic or thrombotic complications.
-Signs relating to leukostasis include respiratory distress and altered mental status
Physical:
-Patients commonly have physical signs of anemia, including pallor and a cardiac flow murmur.
-Fever and other signs of infection, including lung findings of pneumonia, can occur.
-Thrombocytopenia usually demonstrates petechiae, particularly on the lower extremities.
-A large number of ecchymoses is usually an indicator of a coexistent coagulation disorder such as DIC.
-Signs relating to organ infiltration with leukemia cells include hepatosplenomegaly and, to a lesser degree,
lymphadenopathy.
-Occasionally, patients have rashes resulting from infiltration of the skin with leukemic cells.
Investigations
Lab Studies:
1. A CBC count with differential
 Anemia
 Thrombocytopenia to varying degrees.
 High, normal, or low WBC count, but usually exhibit neutropenia.
-Appropriate cultures, in particular blood cultures, fever or with other signs of infection without fever.
2. Coagulation Screen
 Prothrombin time
 APTT/fibrinogen
 fibrin degradation products
-May suggest concomitant DIC, which results in an elevated prothrombin time, decreased fibrinogen levels, and the
presence of fibrin split products.
NB. Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with
DIC.
3. PBF
 Circulating blasts are usually seen.
 Schistocytes are sometimes seen if DIC is present.
4. Elevated LDH and uric acid level.
5. LFT and BUN/creatinine prior to the initiation of therapy.
Imaging Studies:
1. CXR-may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of T-cell ALL.
2. ECG -chemotherapeutic agents used in the treatment of acute leukemia are cardiotoxic.

Procedure
-Bone marrow aspiration and biopsy are the definitive diagnostic tests to confirm the diagnosis of leukemia.
Tests
Cytochemical Staining
-Positive TdT- terminal deoxynucleotidyl transferase and PAS (Periodic Acid Schiff) is the hallmark of ALL.
-ALL is negative to myeloperoxiadase and Sudan black
-TdT also helps distinguish ALL from malignancies of more mature lymphocytes (i.e., NHL).
Immunophenotying /Flow cytometry-Cell markers
-Positive confirmation of lymphoid (and not myeloid) lineage by flow cytometric demonstration of lymphoid antigens
e.g. CD3 (T-lineage ALL), CD19 (B-lineage ALL)
-Myeloid series-CD 13, CD 14, CD 33 and CD 34
Cytogenetics and Chromosomal studies.
-Approximately 15% of patients with ALL have a t(9;22)bcr-abl translocation (ie,Philadelphia), but other
chromosomal abnormalities also may occur, such as t(4;11), t(2;8), and t(8;14)
-The diagnosis of ALL is made when at least 30% lymphoblasts (FAB classification) or 20% lymphoblasts (WHO
classification) are present in the bone marrow and/or peripheral blood

Histologic Findings:
-French-American-British Classification

143
L1 –
 Small cells with homogeneous chromatin
 regular nuclear shape, small or absent nucleolus
 scanty cytoplasm
 subtype represents 25-30% of adult cases
L2 –
 Large and heterogeneous cells
 Heterogeneous chromatin, irregular nuclear shape, and nucleolus often large
 subtype represents 70% of cases (most common)
L3
 Large and homogeneous cells
 multiple nucleoli
 moderate deep blue cytoplasm, and cytoplasmic vacuolization that often obscure the nucleus (most
prominent feature)
 subtype represents 1-2% of adult cases
-The WHO classifies the L1 and L2 subtypes of ALL as precursor B lymphoblastic leukemia/ lymphoblastic
lymphoma or precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending on the cell of origin.
-The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt
lymphoma/leukemia.

MANAGEMENT
Supportive
1. Hydration
2. Nutritional build up
3. Blood transfusion to HB at least 10 g/dl before chemotherapeutics.
4. Antibiotics prophylaxis in neutropenia and antifungal if infection.
5. Platelet concentrates in thrombocytopenia
Drugs
-Currently, only 20-30% of adults with ALL are cured with standard chemotherapy regimens.
-Traditionally, the 4 components of ALL treatment are
a) Induction
b) Consolidation
c) Maintenance
d) CNS prophylaxis
a). Induction
-Standard induction therapy typically involves either:
-4-drug regimen given over the course of 4-6 weeks
1) Vincristine
2) Prednisone
3) Anthracycline-Adriamycin/doxorubicin
4) cyclophosphamide or L-asparaginase
-5-drug regimen includes both L-asparaginase and cyclophosphamide.
-Using this approach, complete remissions are obtained in 65-85% of patients.
-The rapidity with which a patient's disease enters complete remission is correlated with treatment outcome
b). Consolidation.
-Ara-C-cytosine arabinoside in combination with:
-An anthracycline (daunorubicin/adriamycin) or epipodophyllotoxin (etoposide)

c). Maintenance therapy

-Up to 2 years on treatment on combinations from the following drugs:-
1) Vincristine
2) Prednisone
3) Methotrexate
4) 6-mercaptopurine.
d). CNS Prophylaxis
-Intrathecal methotraxate

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Complications:
-Death may occur as a result of uncontrolled infection or hemorrhage. This may occur even after the use of
appropriate blood product and antibiotic support.
-The most common complication is failure of the leukemia to respond to chemotherapy. These patients do poorly
because they usually do not respond to other chemotherapy regimens.
Prognosis:
-Patients with ALL are divided into 3 prognostic groups:-
 Good risk includes
(1) No adverse cytogenetics
(2) Age younger than 30 years
(3) WBC count of less than 30,000/mL
(4) Complete remission within 4 weeks.
 Intermediate risk does not meet the criteria for either good risk or poor risk.
 Poor risk includes
(1) Adverse cytogenetics [(t9; 22), (4; 11)]
(2) Age older than 60 years
(3) Precursor B-cell WBCs with WBC count greater than 100,000/mL
(4) Failure to achieve complete remission within 4 weeks.

ACUTE MYELOBLASTIC LEUKEMIA

Etiology
a) Antecedent hematologic disorders
 Myelodysplastic syndrome
 Aplastic anemia
 Myelofibrosis
 Paroxysmal nocturnal hemoglobinuria
 Polycythemia Vera.
-Myelodysplastic syndrome -Disease of the bone marrow of unknown etiology that occurs most often in older
patients and manifests as progressive cytopenias Patients with low-risk MDS (e.g., refractory anemia with normal
cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (e.g., refractory anemia
with excess blasts-type 2) frequently do develop AML.
b) Congenital disorders
 Bloom syndrome
 Down syndrome
 congenital neutropenia
 Fanconi anemia
 neurofibromatosis.
-Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.
c) Familial syndromes
d) Environmental exposures
 Radiation –therapeutic or accidental
 Cigarette smoking
 Chemicals- benzene is associated with aplastic anemia and pancytopenia. These patients often develop
AML.
 Cytotoxics-Alkylating agents and toposomerase II inhibitors as etoposide.

The newer WHO classification

a) AML with recurrent genetic abnormalities
 AML with t(8;21)(q22;q22), (AML1/ETO)
 AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22), (CBFB/MYH11)
 APL with t(15;17)(q22;q12), (PML/RARa) and variants
 AML with 11q23 (MLL) abnormalities
b) AML with multilineage dysplasia
 Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD)
 Without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages
c) AML and MDS, therapy related

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  Alkylating agent or radiation-related type
 Topoisomerase II inhibitor type
 Others
d) AML, not otherwise classified

Histologic Findings:
-The older, more traditional, FAB classification is as follows:
M0 - Undifferentiated leukemia
M1 - Myeloblastic without differentiation
M2 - Myeloblastic with differentiation
M3 - Promyelocytic
M4 - Myelomonocytic
M4eo - Myelomonocytic with eosinophilia
M5 - Monoblastic leukemia
M5a - Monoblastic without differentiation
M5b - Monocytic with differentiation
M6 - Erythroleukemia
M7 - Megakaryoblastic leukemia
-The newer WHO classification is as follows:
 AML, minimally differentiated
 AML, without maturation
 AML, with maturation
 Acute myelomonocytic leukemia
 Acute monoblastic or monocytic leukemia
 Acute erythroid leukemia
 Acute megakaryoblastic leukemia
 Acute basophilic leukemia
 Acute panmyelosis and myelofibrosis
 Myeloid sarcoma

Investigations
As ALL
-CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees.
-Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.

MANAGEMENT
a). Supportive management- As ALL Above
b). Chemotherapy
-Treatment of acute myelogenous leukemia (excluding acute promyelocytic leukemia)
Induction therapy:
-The most common approach is called”3 and 7,”
-3 days of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone) Plus 7-days of cytosine
arabinoside (araC)
-These regimens require adequate cardiac, hepatic, and renal function.
-Using these regimens, approximately 50% of patients achieve remission with one course.
-Another 10-15% enters remission following a second course of therapy.
Consolidation therapy in younger patients
-In patients aged 60 years or younger, treatment options for consolidation therapy include:
 high-dose araC
 Autologous stem cell transplantation
 Allogeneic stem cell transplantation.
Consolidation therapy in older patients:
-No standard consolidation therapy exists for patients older than 60 years.
- Options include a clinical trial, high-dose araC in selected patients, or repeat courses of standard-dose
anthracycline and araC (2 and 5; i.e., 2 d of anthracycline and 5 d of araC).

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-Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic
transplantation

LIVER BIOPSY
-Modes of biopsy
1) Blind percutaneous approach after percussion of the chest wall
2) Ultrasound or CT guided biopsy
3) Intravascular tissue sampling via the hepatic vein
4) Intra-abdominal biopsy at laparoscopy or laparotomy.
-The choice of one technique over another is based on availability, personal preference, and the clinical situation.
-Adequate liver biopsy for accurate evaluation. In general, a sample of 1.5 mm in length that is 1.2-2 mm in
diameter and contains at least 6-8 portal triads is considered adequate.
-Liver biopsy is generally safe and is currently considered the criterion standard for the evaluation of hepatic
inflammation and fibrosis.
Indications for Liver Biopsy
-In most cases, noninvasive imaging studies such as CT scan or ultrasound are now obtained first.
1. Confirmation of diagnosis and prognostication ie
-Liver cirrhosis-(alcohol, alpha1-antitrypsin deficiency, primary biliary cirrhosis, Wilson's disease,
hemochromatosis, etc); assess and stage level of activity; assess complications
-Chronic hepatitis, with or without cirrhosis, to identify cases of chronic activity hepatitis (liver biopsy mandatory
for diagnosis) and differentiate this entity from chronic persistent hepatitis and lobular hepatitis
-Multisystem disease with liver involvement, where traditional diagnostic techniques have not been fruitful (eg,
sarcoidosis, amyloidosis, tuberculosis, glycogen storage disease)
-Staging of lymphoma
-Unexplained hepatomegaly
-Cholestasis of unknown etiology, where prior studies for biliary obstruction are negative
-Selected cases of hepatitis of unknown etiology, in order to differentiate viral from drug-induced etiologies (not
always possible) or to assess complications, such as cholestasis
-Diagnosis of hepatoma or metastatic neoplasms
2. Following a case of liver transplantation to evaluate and manage rejection.
3. Evaluation of response to treatment
Contraindications to liver Biopsy
1. Impaired coagulation
 INR >1.5
 PTI <75%
 Thrombocytopenia, platelet count less than 60,000/ul.
2. Anaemia <10g/dl.
3. Local infection near needle entry site, such as right sided pleural effusion or empyema, right lower lobe
pneumonia, local cellulitis, infected ascites or peritonitis.
4. Tense ascites (low yield technically, risk of leakage, the ascitis washes off the clot formed on the biopsy site).
5. High-grade extrahepatic biliary obstruction with jaundice (increased risk of bile peritonitis).
6. Possible hemangioma-vascular tumours.
7. Possible echinococcal (hydatid) cyst.
8. Relative-lack of compatible blood for transfusion and uncooperative patient.

Patient Preparation
-Procedures and risks of the procedure are explained and consent is obtained.
-All aspirin products and nonsteroidal agents must be discontinued at least 5 days beforehand.
-If taking oral anticoagulants (Coumadin®), hospitalization is required to convert to heparin therapy before biopsy.
-Patient is NPO after midnight the evening prior
-Screening laboratory studies include
Laboratory
1) CBC
2) Type and crossmatch for possible transfusion
3) Coagulation screen-INR and PTI, bleeding time

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 4) Liver function tests are optional
5) RFT’s
Imaging
6) Abdominal U/S –liver architecture, bile dusts, any masses, R/O hemangioma, echinococcus
7) CXR-If pneumonia or pleural effusion suspected on examination, PA and lateral chest x-ray is obtained.
-Premedication with meperidine and/or diazepam may be administered

Biopsy Technique
-Variety of needle types is available for obtaining a liver biopsy specimen
-Needles may be divided into 3 broad categories:-
Suction needles (Jamshidi, Klatskin, and Menghini)
cutting needles (Tru-cut and Vim-Silverman),
Spring-loaded cutting needles.
-Each needle type has proposed advantages and disadvantages.
-Suction needles are thought to yield desirable sample size but may fragment cirrhotic livers.
-Conversely, cutting needles do not fragment liver tissue but may deliver inadequate tissue samples.
- Spring-loaded needles are thought to decrease the amount of time that the needle is in the liver but may increase
patient discomfort due to the clicking noise of the triggering mechanism.
-Needle selection is largely a result of physician preference and experience.

Aftercare
1) Bed rest
2) Positioning
3) Monitor vitals
4) Analgesia
5) Check Haematocrit before discharge
1. Bed rest
-Strict bed rest is enforced for 24 hours
2. Positioning
-For the first 2 hours patient is positioned on his right side.
-After 5 hours, patient may be allowed to sit up.

3 .Monitor vitals
-Patient is monitored in a recovery area with frequent vital signs post biopsy
 Every 15 minutes for first 2 hours.
 Every 30 minutes for the next 2 hours
 Hourly for next 8 hours.
-Following this, vitals every 4 hours are permissible.
-Diet is restricted to clear liquids for several hours, then full liquids as tolerated.
4. Analgesics
-Acetaminophen is usually sufficient for pain control.
5. Haematocrit before discharge
-Recheck hematocrit 24 hours after procedure before approving hospital discharge.

Special Instructions
-In the appropriate high-risk patient, antibiotic prophylaxis for infective endocarditis may be considered.

Complications
1. Pain
-The most common adverse event
-Usually it is confined to the right shoulder, probably referred pain from diaphragmatic pleura. Analgesia is required
in approximately 20% of patients with acetaminophen sufficient in most cases.
-Symptoms resolve in 1-2 days.
2. Hemorrhage
- Minor episodes are common but usually Self-limited
-Significant hemorrhage is less frequent but is the most common cause of death from liver biopsy

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-Bleeding usually results from a tear of a distended portal or hepatic vein. Specific sites include:-
The abdominal cavity (hemoperitoneum)
Liver capsule (subcapsular hematoma)
Liver parenchyma (intrahepatic hematoma)
 Biliary tree (hemobilia)
-Postulated risk factors are coagulopathy, amyloid liver, hepatocellular injury, hemangioma, and vascularized tumor.
3. Bile leakage with peritonitis
-Associated with severe obstruction of the larger bile ducts.
-This is felt to result from laceration of a small, distended duct or from puncture of the gallbladder.
-With the widespread use of noninvasive imaging, the size of the bile ducts is known prebiopsy and the complication
rate has declined.
4. Laceration of internal organs and viscera.
- Right kidney, gallbladder, colon, pancreas, and diaphragm.
5. Bacteremia, Sepsis and abscess formation.
6. Pneumothorax and/or pleural effusion, Hemothorax.
7. Arteriovenous fistula.
8. Subcutaneous emphysema.

LIVER CIRRHOSIS AND COMPLICATIONS

Definition
-Cirrhosis represents the final common histologic pathway for a wide variety of chronic liver diseases.
-Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of
normal liver architecture into structurally abnormal nodules.
-The progression of liver injury to cirrhosis may occur over weeks to years.
-Some patients with cirrhosis are completely asymptomatic and have a reasonably normal life expectancy. Some
have most severe symptoms of end-stage liver disease and have a limited chance for survival.
- Common signs and symptoms may stem from
 Decreased hepatic synthetic function (eg, coagulopathy)
Decreased detoxification capabilities of the liver (eg, hepatic encephalopathy)
Portal hypertension (eg, variceal bleeding).
Etiology
1. Most common cause is Hepatitis B.
-Chronic Hepatitis C also causes cirrhosis.
2. Alcoholic liver disease
3. Autoimmune hepatitis
4. Biliary cirrhosis –Primary or secondary
-Secondary biliary cirrhosis associated with chronic extrahepatic bile duct obstruction
5. Primary sclerosing cholangitis
6. Hemochromatosis
7. Wilson disease
8. Alpha-1 antitrypsin deficiency
9. Granulomatous disease (eg, sarcoidosis)
10. Type IV glycogen storage disease
11. Drug-induced liver disease
Methotrexate
 Alpha methyldopa
 Amiodarone
12. Venous outflow obstruction (eg, Budd-Chiari syndrome, veno-occlusive disease)
13. Chronic right-sided heart failure –Cardiac cirrhosis

Pathophysiology of Hepatic Fibrosis

-Alteration in the normally balanced processes of extra cellular matrix production and degradation.
-Extra cellular matrix, is composed of collagens (especially types I, III, and V), glycoproteins, and proteoglycans.
-Stellate cells (ito cells), located in the perisinusoidal space, are essential for the production of extracellular matrix.
They may become activated into collagen-forming cells by a variety of paracrine factors.

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-Factors released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. Factors include
transforming growth factor beta1 (TGF-beta1)
-Increased collagen deposition in the space of Disse (the space between hepatocytes and sinusoids) and the
diminution of the size of endothelial fenestrae lead to the capillarization of sinusoids.
-Activated stellate cells also have contractile properties.
-Both capillarization and constriction of sinusoids by stellate cells contribute to the development of portal
hypertension.
Pathophysiology of Portal Hypertension
-The normal liver has the ability to accommodate large changes in portal blood flow without appreciable alterations
in portal pressure.
-Portal hypertension results from a combination of increased portal venous inflow and increased resistance to portal
blood flow.
-Intrahepatic vascular resistance is explained by fixed changes in the hepatic architecture. Such changes include the
formation of regenerating nodules and the production of collagen by activated stellate cells. Collagen, in turn, is
deposited within the space of Disse.
-Stellate cells serve as contractile cells for adjacent hepatic endothelial cells. The nitric oxide produced by the
endothelial cells, in turn, controls the relative degree of vasodilation or vasoconstriction produced by the stellate
cells. In cirrhosis, decreased local production of nitric oxide leads to increased resistance.
-The portal hypertension of cirrhosis is caused by the disruption of hepatic sinusoids. However, portal hypertension
may be observed in a variety of noncirrhotic conditions classified as Pre hepatic and intra-hepatic causes.
 Pre hepatic causes
Splenic vein thrombosis
Portal vein thrombosis.
-These conditions commonly are associated with hypercoagulable states and with malignancy (eg, pancreatic
cancer).
 Intrahepatic
 Divided into presinusoidal, sinusoidal, and postsinusoidal conditions.
-The classic form of presinusoidal disease is caused by the deposition of Schistosoma oocytes in presinusoidal portal
venules, with the subsequent development of granulomata and portal fibrosis.
-The classic sinusoidal cause of portal hypertension is cirrhosis
-Schistosomiasis is the most common noncirrhotic cause of variceal bleeding worldwide.
-The classic postsinusoidal condition is an entity known as veno-occlusive disease. Obliteration of the terminal
hepatic venules e.g. pyrrolizidine alkaloids and high-dose chemotherapy that precedes bone marrow transplantation.
Post hepatic portal HTN
Chronic right-sided heart failure
 Tricuspid regurgitation
 Obstructing lesions of the hepatic veins and inferior vena cava.
-The latter and the symptoms they produce are termed Budd-Chiari syndrome.
-Predisposing conditions include hypercoagulable states, tumor invasion into the hepatic vein or inferior vena cava,
and membranous obstruction of the inferior vena cava. Inferior vena cava webs are observed most commonly in
South and East Asia and are postulated to be due to nutritional factors.
-Symptoms of Budd-Chiari syndrome are attributed to decreased outflow of blood from the liver, with resulting
hepatic congestion and portal hypertension.
-These symptoms include hepatomegaly, abdominal pain, and ascites. Cirrhosis only ensues later in the course of
disease.
-Differentiating Budd-Chiari syndrome from cirrhosis by history or physical examination may be difficult. Thus,
Budd-Chiari syndrome must be included in the differential diagnosis of conditions that produce ascites and varices.
-Hepatic vein patency is checked most readily by performing an abdominal ultrasound with Doppler examination of
the hepatic vessels.
-Abdominal CT scan with intravenous contrast, abdominal MRI, and visceral angiography also may provide
information regarding the patency of hepatic vessels.
Consequences of portal hypertension.
-Normal as 3-6 mm Hg. Portal hypertension is defined as a sustained elevation of portal pressure above normal.
-Portal pressure above 8 mm Hg is believed to be the threshold above which ascites potentially can develop.
-Portal pressure above 12 mm Hg is the threshold for the potential formation of varices. High portal pressures may
predispose patients to an increased risk of variceal hemorrhage.

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ASCITES
-Ascites is defined as an accumulation of excessive fluid within the peritoneal cavity and may be a complication of
both hepatic and nonhepatic diseases.
-The 4 most common causes of ascites:-
Cirrhosis
 Neoplasm
 Congestive heart failure
 Tuberculous peritonitis
-Ascitis can be broadly classified as:
a) Non-peritoneal Ascites
b) Peritoneal Ascites
Non Peritoneal Ascites
-In transudative ascites, fluid cross into the liver capsule because of an imbalance in Starling forces. Ascites protein
is less than 2.5 g/dL. Classic causes of transudative ascites are portal hypertension secondary to cirrhosis and
congestive heart failure.
a) Intrahepatic portal hypertension
 Cirrhosis
Fulminant hepatic failure
Veno-occlusive disease
b) Extrahepatic portal hypertension
 Hepatic vein obstruction (ie, Budd-Chiari syndrome)
Congestive heart failure
c) Hypoalbuminemia
 Nephrotic syndrome
Protein-losing enteropathy
Malnutrition
d) Miscellaneous disorders
 Myxedema
Ovarian tumors
Pancreatic ascites
 Biliary ascites
e) Chylous
 Secondary to malignancy
Secondary to trauma/surgery
Secondary to portal hypertension (Cirrhosis).

-In exudative ascites, fluid was said to weep from an inflamed or tumor-laden peritoneum. In general, ascites protein
was greater than 2.5 g/dL. Examples included peritoneal carcinomatosis and tuberculous peritonitis
Peritoneal Causes of Ascites
a) Malignant ascites
 Primary peritoneal mesothelioma
Secondary peritoneal carcinomatosis
b) Granulomatous peritonitis
 Tuberculous peritonitis
Fungal and parasitic infections (eg, Candida,
Histoplasma, Cryptococcus, Schistosoma mansoni, Strongyloides, Entamoeba histolytica)
Sarcoidosis
 Foreign bodies (ie, talc, cotton and wood fibers, starch, barium)
b) Vasculitis
 Systemic lupus erythematosus
Henoch-Schönlein purpura
c) Miscellaneous disorders
 Eosinophilic gastroenteritis
Whipple disease
Endometriosis
-Attributing ascites to diseases of nonperitoneal or peritoneal origin is more useful.

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-Serum-ascites albumin gradient (SAAG) used for differentiating these conditions. Nonperitoneal diseases produce
ascites with a SAAG greater than 1.1 g/dL
-Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, most often is due to malignancy (eg,
lymphoma) but occasionally is observed postoperatively and following radiation injury. Chylous ascites also may be
observed in the setting of cirrhosis. The ascites triglyceride concentration is greater than 110 mg/dL. In addition,
ascites triglyceride concentrations are greater than those observed in plasma. Patients should be placed on a low-fat
diet, which is supplemented by medium-chain triglycerides. Treatment with diuretics and large-volume paracentesis
may be required.

Clinical features of ascites:-

-Abdominal distention
- Bulging flanks
-Shifting dullness
-Elicitation of a "puddle sign" in patients in the knee-elbow position.
-A fluid wave may be elicited in patients with massive tense ascites.
-However, physical examination findings are much less sensitive than performing abdominal ultrasonography,
which can detect as little as 30 mL of fluid. Furthermore, ultrasound with Doppler can help assess the patency of
hepatic vessels
-Factors associated with worsening of ascites include excess fluid or salt intake, malignancy, venous occlusion (eg,
Budd-Chiari syndrome), progressive liver disease, and spontaneous bacterial peritonitis (SBP).

Paracentesis in the diagnosis of ascites

-Determining whether ascites is exudates or transudate.
-Paracentesis also should be performed when SBP is suggested by the presence of abdominal pain, fever,
leukocytosis, or worsening hepatic encephalopathy.
-Ascites Tests:-
-Mirocoscopy, culture and Sensitivity
 Cell count and differentials
Gram stain
Stain for AFB
 Cultures-special medial for mycobacterium
-Biochemistry
 Albumin with simultaneous Serum Albumin for Serum Ascitic Albumin Gradient (SAAG)
LDH
Bilirubin
 Amylase
Glucose
-Ascitic fluid with more than 250 PMNs/mm3 defines neutrocytic ascites and SBP.
-Many cases of ascites fluid with more than 1000 PMNs/mm 3 (and certainly >5000 PMNs/mm3) are associated with
appendicitis or a perforated viscus with resulting bacterial peritonitis. Appropriate radiologic studies must be
performed in such patients to rule out surgical causes of peritonitis.
-Lymphocyte-predominant ascites possibility of underlying malignancy or tuberculosis.
-Grossly bloody ascites may be observed in malignancy and tuberculosis.
-The yield of ascites culture increased by directly inoculating 10 mL of ascites into aerobic and anaerobic culture
bottles at the patient's bedside.
Medical treatment of ascites
1. Sodium restriction
-Salt restriction is the first line of therapy.
- Less than 2000 mg sodium per day.
-Refractory ascites less than 500 mg sodium per day.
2. Diuretics
-Considered the second line of therapy.
-Spironolactone (Aldactone) blocks the aldosterone receptor at the distal tubule.
-It is dosed at 50-300 mg once per day. Although the drug has a relatively short half-life, its blockade of the
aldosterone receptor lasts for at least 24 hours.
-Adverse effects

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 Hyperkalemia
 Gynecomastia, and lactation.
-Other potassium-sparing diuretics, including amiloride and triamterene, may be used as alternative agents,
especially in patients complaining of gynecomastia.
-Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone.
-The drug blocks sodium reuptake in the loop of Henle.
- It is dosed at 40-240 mg per day in 1-2 divided doses.
-Aggressive diuretic therapy in patients with massive ascites can safely induce a 0.5- to 1-kg weight loss per day
-Diuretic therapy should be held in the event of electrolyte disturbances, azotemia, or induction of hepatic
encephalopathy.
-Albumin infusion may protect against the development of renal insufficiency in patients with SBP. Patients
receiving cefotaxime and albumin at 1 g/kg/day experienced a lower risk of renal failure
3. Large-volume paracentesis
-Aggressive diuretic therapy is ineffective in controlling ascites in approximately 5-10% of patients.
-Such patients with massive ascites may need to undergo large-volume paracentesis in order to receive relief from
symptoms of abdominal discomfort, anorexia, or dyspnea. The procedure also may help reduce the risk of umbilical
hernia rupture.
-Large-volume paracentesis is thought to be safe in patients with peripheral edema and in patients not currently
treated with diuretics.
4. Peritoneovenous shunts
-LeVeen shunts and Denver shunts -Plastic tubing inserted subcutaneously under local anesthesia connects the
peritoneal cavity to the internal jugular vein or subclavian vein via a pumping chamber.
-These devices are successful at relieving ascites and reversing protein loss in some patients.
-Complications include
 Peritoneal infection, sepsis
Disseminated intravascular coagulation
Congestive heart failure
 Shunts may clot and block
-Its a reasonable form of therapy for patients with refractory ascites who are not candidates for TIPS or liver
transplantation.
5. Porto systemic shunts and transjugular intrahepatic portosystemic shunts (TIPS)
-Main Indication for portocaval shunt surgery is the management of refractory variceal bleeding.
- But by decompressing the hepatic sinusoid, may improve ascites.
-Complications include
 Hepatic encephalopathy
Stent stenosis requiring revision.
Mortality from the surgery
-TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS placement produces a
decrease in sinusoidal pressure and a decrease in plasma renin and aldosterone levels, with subsequent improved
urinary sodium excretion.
-TIPS use should be reserved for patients with Child class B cirrhosis or patients with Child class C cirrhosis
without severe coagulopathy or encephalopathy.
6. Liver transplantation
- Liver transplantation should be considered as a potential means of salvaging the patient prior to the onset of
intractable liver failure or hepatorenal syndrome.
Hepatorenal syndrome
-Renal dysfunction observed in patients with cirrhosis and is caused by the vasoconstriction of large and small renal
arteries and the impaired renal perfusion that result.
-The syndrome may represent an imbalance between renal vasoconstrictors and vasodilators. Plasma levels of a
number of vasoconstricting substances are elevated in patients with cirrhosis and include angiotensin, antidiuretic
hormone, and norepinephrine. Renal perfusion appears to be protected by vasodilators, including prostaglandins E2
and I2 and atrial natriuretic factor.
-Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. They may potentiate renal
vasoconstriction, with a resulting drop in glomerular filtration. Thus, the use of NSAIDs is contraindicated in
patients with decompensated cirrhosis.

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-Most patients with hepatorenal syndrome are noted to have minimal histological changes in the kidneys. Kidney
function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation. In
fact, a kidney donated by a patient dying from hepatorenal syndrome functions normally when transplanted into a
renal transplant recipient.
-Hepatorenal syndrome progression may be slow (type II) or rapid (type I).
-Type I disease frequently is accompanied by rapidly progressive liver failure. Hemodialysis offers temporary
support for such patients.
-In type II hepatorenal syndrome, patients may have stable or slowly progressive renal insufficiency. Many such
patients develop ascites that is resistant to management with diuretics.
- In hepatorenal syndrome, renal dysfunction cannot be explained by preexisting kidney disease, prerenal azotemia,
the use of diuretics, or exposure to nephrotoxins.
-Nephrotoxic medications, including aminoglycoside antibiotics, should be avoided in patients with cirrhosis.
-Patients with early hepatorenal syndrome may be salvaged by aggressive expansion of intravascular volume with
albumin and fresh frozen plasma and by avoidance of diuretics.
Spontaneous bacterial peritonitis
-SBP is observed in 15-26% of patients hospitalized with ascites. The syndrome arises most commonly in patients
whose low-protein ascites (<1 g/dL) contains low levels of complement, resulting in decreased opsonic activity.
- SBP appears to be caused by the translocation of GI tract bacteria across the gut wall and also by the
hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, Streptococcus
pneumoniae, Klebsiella species, and other gram-negative enteric organisms.
-Classic SBP is diagnosed by the presence of neutrocytosis, which is defined as greater than 250 polymorphonuclear
(PMN) cells per mm3 of ascites, in the setting of a positive ascites culture. Culture-negative neutrocytic ascites is
observed more commonly.
-Both conditions represent serious infections that carry a 20-30% mortality rate.
Treatment
-5-day course of cefotaxime at 1-2 g intravenously every 8 hours.
-Alternatives include oral ofloxacin and other intravenous antibiotics with activity against gram-negative enteric
organisms. Many authorities advise repeat paracentesis in 48-72 hours in order to document a decrease in the ascites
PMN count to less than 250 cells/mm3 and to assure the efficacy of therapy.
-Other complications of massive ascites
Abdominal discomfort
 Anorexia
 Decreased oral intake
 Diaphragmatic elevation may lead to symptoms of dyspnea.
 Pleural effusions may result from the passage of ascitic fluid across channels in the diaphragm.
 Umbilical and inguinal hernias are common in patients with moderate and massive ascites. Timely large-
volume paracentesis also may help to prevent this disastrous complication.

HEPATIC ENCEPAHALOPATHY
Definition
-Hepatic encephalopathy is a syndrome observed in some patients with decompensated cirrhosis that is marked by
 Personality changes
Intellectual impairment
Depressed level of consciousness.
-The diversion of portal blood into the systemic circulation appears to be a prerequisite for the syndrome.
-Thus may also develop in patients who do not have cirrhosis who undergo portocaval shunt surgery.
Pathogenesis
1. The ammonia hypothesis
-Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids, purines, and urea.
-Normally, ammonia is detoxified in the liver by conversion to urea and glutamine.
- In liver disease or portosystemic shunting, portal blood ammonia is not converted efficiently to urea. Increased
levels of ammonia may enter the systemic circulation because of portosystemic shunting.
-Ammonia has multiple neurotoxic effects, including
 Altering the transit of amino acids, water, and electrolytes across the neuronal membrane.
Inhibit the generation of both excitatory and inhibitory postsynaptic potentials.

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-Therapeutic strategies to reduce serum ammonia levels tend to improve hepatic encephalopathy. However,
approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore,
many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy.

2. The gamma-aminobutyric acid (GABA) hypothesis

-GABA is a neuroinhibitory substance produced in the GI tract.
-When GABA crosses the extra permeable blood-brain barrier of a patient with cirrhosis, it interacts with
supersensitive postsynaptic GABA receptors.
-The GABA receptor, in conjunction with receptors for benzodiazepines and barbiturates, regulates a chloride
ionophore. Binding of GABA to its receptor permits an influx of chloride ions into the postsynaptic neuron, leading
to the generation of an inhibitory postsynaptic potential.
-Administration of benzodiazepines and barbiturates to patients with cirrhosis increases GABA-ergic tone and
predisposes patients to depressed consciousness.
-The GABA hypothesis is supported by fact that flumazenil (a benzodiazepine antagonist) transiently can reverse
hepatic encephalopathy in patients with cirrhosis.
Clinical features of hepatic encephalopathy
-The symptoms of hepatic encephalopathy may range from mild to severe .Symptoms are graded on the following
scale:
Grade 1
Mild confusion
 Euphoria or depression
 decreased attention
 slowing of ability to perform mental tasks
 Irritability
 Disorder of sleep pattern (ie, inverted sleep cycle)
Grade 2
Drowsiness
 Lethargy
 Gross deficits in ability to perform mental tasks
 Obvious personality changes,
 Inappropriate behavior
Intermittent disorientation (usually for time)
Grade 3
Somnolent but arousable.
 Unable to perform mental tasks
 Disorientation to time and place
 Marked confusion, amnesia
 Occasional fits of rage
 Speech is present but incomprehensible
Grade 4
Coma, with or without response to painful stimuli
-. Findings upon physical examination include asterixis and fetor hepaticus.
Investigations
Laboratory
1) An elevated arterial or free venous serum ammonia level is the classic abnormality
2) (EEG) changes of high-amplitude low-frequency waves and triphasic waves. In some patients
- EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status when ruling out
seizure activity may be necessary.
3)-CT scan and MRI studies of the brain may be important in ruling out intracranial lesions when the diagnosis of
hepatic encephalopathy is in question. Common precipitants of hepatic encephalopathy.
- Common precipitants of hyperammonemia in cirrhotic patients and worsening mental status are:-
 Diuretic therapy
 Renal failure
 GI bleeding
 Infection

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  Constipation
 Dietary protein overload
 Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic agents.
-Differential diagnosis for hepatic encephalopathy:-
1-Intracranial lesions (eg, subdural hematoma, intracranial bleeding, cerebrovascular accident, tumor, abscess)
2-Infections (eg, meningitis, encephalitis, abscess)
3-Metabolic encephalopathy (eg, hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, uremia)
4-Hyperammonemia from other causes (eg, secondary to ureterosigmoidostomy, inherited urea cycle disorders)
5-Toxic encephalopathy due to alcohol (eg, acute intoxication, alcohol withdrawal, Wernicke encephalopathy)
6-Toxic encephalopathy due to drugs (eg, sedative-hypnotics, antidepressants, antipsychotic agents, salicylates)
7-Organic brain syndrome
8-Postseizure encephalopathy
Management of hepatic encephalopathy
NB
-Nonhepatic causes of altered mental function must be excluded in patients with cirrhosis who have worsening
mental function.
-A check of the blood ammonia level may be helpful in such patients.
-Medications that depress CNS function, especially benzodiazepines, should be avoided.
-Precipitants of hepatic encephalopathy should be corrected (eg, metabolic disturbances, GI bleeding, infection,
constipation).
Medications
1. Lactulose
-In acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms.
-This nonabsorbable disaccharide stimulates the passage of ammonia from tissues into the gut lumen and inhibits
intestinal ammonia production.
- Initial lactulose dosing is 30 mL orally once or twice daily. Dosing is increased until the patient has 2-4 loose
stools per day. Dosing should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating.
Higher doses of lactulose may be administered via either a nasogastric tube or rectal tube to hospitalized patients
with severe encephalopathy.
-Other cathartics, including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, Go-Lytely), also
may be effective in patients with severe encephalopathy.
2. Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, paromomycin, and oral quinolones) serve as
second-line agents. They work by decreasing the colonic concentration of ammoniagenic bacteria. Neomycin dosing
is 250-1000 mg orally 2-4 times daily.
3. Low-protein diets- High levels of aromatic amino acids contained in animal proteins lead to increased blood
levels of the false neurotransmitters tyramine and octopamine, with resulting worsening of encephalopathy
symptoms.

OTHER MANIFESTATIONS OF CIRRHOSIS

-Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle wasting.
-Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin telangiectasias, palmar erythema,
white nails, disappearance of lunulae, and finger clubbing, especially in the setting of hepatopulmonary syndrome.
-Patients with cirrhosis may experience increased conversion of androgenic steroids into estrogens in skin, adipose
tissue, muscle, and bone. Males may develop gynecomastia and impotence. Loss of axillary and pubic hair is noted
in both men and women. Hyperestrogenemia also may explain spider angiomata and palmar erythema.

Hematologic manifestations
-Anemia may result from folate deficiency, hemolysis, or hypersplenism, varices
-Thrombocytopenia usually is secondary to hypersplenism and decreased levels of thrombopoietin.
-Coagulopathy results from decreased hepatic production of coagulation factors. If cholestasis is present, decreased
micelle entry into the small intestine leads to decreased vitamin K absorption, with reduction in hepatic production
of factors II, VII, IX, and X. -Patients with cirrhosis also may experience fibrinolysis and disseminated intravascular
coagulation.

Pulmonary and cardiac manifestations

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-Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the diaphragmatic elevation
caused by massive ascites may alter ventilation-perfusion relations. Interstitial edema or dilated precapillary
pulmonary vessels may reduce pulmonary diffusing capacity.
-Patients also may have hepatopulmonary syndrome (HPS). In this condition, pulmonary arteriovenous anastomoses
result in arteriovenous shunting.
-Classic HPS is marked by the symptom of platypnea and the finding of orthodeoxia, but the syndrome must be
considered in any patient with cirrhosis who has evidence of oxygen desaturation. HPS most readily is detected by
echocardiographic visualization of late-appearing bubbles in the left atrium following the injection of agitated saline.
-Some cases of HPS may be corrected by liver transplantation. Pulmonary hypertension is observed in
approximately 1% of patients with cirrhosis. Its etiology is unknown.

Hepatocellular carcinoma &cholangiocarcinoma

-Hepatocellular carcinoma (HCC) occurs in 10-25% of patients with cirrhosis
-HCC is observed less commonly in primary biliary cirrhosis and is a rare complication of Wilson disease.
-Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis.

Other diseases associated with cirrhosis

-Other conditions that appear with increased incidence in patients with cirrhosis include peptic ulcer disease,
diabetes, and gallstones.

Assessment of the severity of cirrhosis

-The most common tool for gauging prognosis in cirrhosis is the Child-Turcotte-Pugh (CTP) system. CTP score
may predict life expectancy in patients with advanced cirrhosis. A CTP score of 10 or greater is associated with a
50% chance of death within 1 year.

1 points 2 points 3 points

Encephalopathy None Stage 1-2 Stage 3-4

Ascites Absent Slight Moderate

Bilirubin (mg/dL) <2 2-3 >3

Bilirubin in PBC or
<4 4-10 10
PSC (mg/dL)

Albumin (g/dL) >3.5 2.8-3.5 <2.8

Prothrombin time
<4 s or 4-6 s or >6 s or
(seconds prolonged
INR <1.7 INR 1.7-2.3 INR >2.3
or INR)

-Child-Turcotte-Pugh Scoring System for Cirrhosis:-

Child class A=5-6 points
Child class B=7-9 points
Child class C=10-15 points
-Class A, have normal bilirubin and albumin values, with no evidence of ascites, encephalopathy, or malnutrition.
-Class B patients have more severe disease, characterized by mild hyperbilirubinemia and hypoalbuminema, and
mild degrees of ascites and encephalopathy with good nutritional status.
-Patients with the most advanced cirrhosis, Class C have at least moderate elevations of bilirubin and
hypoalbuminemia, with marked ascites, severe encephalopathy, and obvious malnutrition.

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MANAGEMENT OF LIVER CIRRHOSIS
-Specific medical therapies may be applied to many liver diseases in an effort to diminish symptoms and prevent or
forestall the development of cirrhosis.
-Examples include
 Prednisone and azathioprine for autoimmune hepatitis
Interferon and other antiviral agents for hepatitis B and C
Phlebotomy for hemochromatosis
 Ursodeoxycholic acid for primary biliary cirrhosis
Zinc and penicillamine for Wilson disease.
-These therapies become progressively less effective if chronic liver disease evolves into cirrhosis. Once cirrhosis
develops, treatment is aimed at the management of complications as they arise.
- Certainly variceal bleeding, ascites, and hepatic encephalopathy are among the most serious complications
experienced by patients with cirrhosis. However, attention also must be paid to patients' chronic constitutional
complaints.
Nutrition
-Many patients complain of anorexia, which may be compounded by the direct compression of ascites on the GI
tract. Care should be taken to assure that patients receive adequate calories and protein in their diets. Patients
frequently benefit from the addition of commonly available liquid and powdered nutritional supplements to the diet.
Only rarely can patients not tolerate proteins in the form of chicken, fish, vegetables, and nutritional supplements.
Institution of a low-protein diet in the fear that hepatic encephalopathy might develop places the patient at risk for
the development of profound muscle wasting.
Adjunctive therapies
a) Zinc deficiency
-Commonly is observed in patients with cirrhosis. Treatment with zinc sulfate at 220 mg orally twice daily may
improve dysgeusia and can stimulate appetite. Furthermore, zinc is effective in the treatment of muscle cramps and
is adjunctive therapy for hepatic encephalopathy.
b) Pruritus
-Is a common complaint in both cholestatic liver diseases (eg, primary biliary cirrhosis) and in noncholestatic
chronic liver diseases (eg, hepatitis C). Although increased serum bile acid levels once were thought to be the cause
of pruritus, endogenous opioids are more likely to be the culprit pruritogens.
-Mild itching complaints may respond to treatment with antihistamines.
-Cholestyramine is the mainstay of therapy for the pruritus of liver disease. Other medications that may provide
relief against pruritus include:-
Ursodeoxycholic acid
 Ammonium lactate 12% skin cream
 Naltrexone (an opioid antagonist)
 Rifampin
 Gabapenin
 Ondansetron.
c) Osteoporosis
-Supplementation with calcium and vitamin D is important in patients at high risk for osteoporosis, especially
patients with chronic cholestasis, patients with primary biliary cirrhosis, and patients receiving corticosteroids for
autoimmune hepatitis. Bisphosphonates (eg, alendronate sodium).
-The discovery of decreased bone mineralization upon bone densitometry studies
d). Muscle wasting
-Regular exercise, including walking and even swimming, should be encouraged in patients with cirrhosis, lest the
patient slip into a vicious cycle of inactivity and muscle wasting
e). Vaccinations
-Patients with chronic liver disease should receive vaccination to protect them against hepatitis A.
- Other protective measures include vaccination against hepatitis B, pneumococci, and influenza.
Drug hepatotoxicity in the patient with cirrhosis
-Medications frequently associated with drug-induced liver disease include NSAIDs, isoniazid, valproic acid,
erythromycin, amoxicillin/clavulanate, ketoconazole, and chlorpromazine.
-NSAID use may predispose patients with cirrhosis to develop GI bleeding.
-Patients with decompensated cirrhosis are at risk for NSAID-induced renal insufficiency, presumably because of
prostaglandin inhibition and worsening of renal blood flow.

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- Other nephrotoxic agents such as aminoglycoside antibiotics also should be avoided.
Surgery in the patient with cirrhosis.
-A study of nonshunt abdominal surgeries demonstrated a 10% mortality rate for patients with Child class A
cirrhosis as opposed to a 30% mortality rate for patients with Child class B cirrhosis and a 75% mortality rate for
patients with Child class C cirrhosis. -Thus, unless absolutely necessary, surgery should be avoided in the patient
with cirrhosis.
Monitoring the patient with cirrhosis
-Patients with cirrhosis should undergo routine follow-up monitoring of their
 Complete blood count
Renal
Liver chemistries
 Prothrombin time.
-Monitor stable patients 3-4 times per year
-Follow-up endoscopy is performed in 2 years if varices are not present.
-If varices are present, treatment is initiated with a nonselective beta-blocker (eg, propranolol, nadolol), aiming for a
25% reduction in heart rate.
-Such therapy offers effective primary prophylaxis against the new onset of variceal bleeding.

LUNG CANCER
-Extrathoracic nonmetastatic symptoms are caused by the secretion of endocrine or endocrine-like substances by the
tumor. These paraneoplastic syndromes are classified as:-
(1) Metabolic
 Cushing's syndrome
 excessive antidiuretic hormone
 hypercalcemia
 ectopic gonadotropin
(2) Neuromuscular
 carcinomatous myopathy
 peripheral neuropathy,
 subacute cerebellar degeneration
 Eaton-Lambert
 myasthenia syndrome
 polymyositis
 encephalomyelopathy
(3) Skeletal
 Clubbing
 Hypertrophic pulmonary osteoarthropathy
(4) Dermatologic
 acanthosis nigricans
 scleroderma
 dermatomyositis
(5) Vascular
 migratory thrombophlebitis
 nonbacterial verrucal endocarditis
 arterial thrombosis
(6 hematologic
 Anemia
 fibrinolytic purpura
 nonspecific leukocytosis
 polycythemia
-Hypercalcemia due to a parathyroid hormone-like substance is most often associated with squamous cell
carcinoma.

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-Other paraneoplastic syndromes are most often associated with adenocarcinoma or small-cell carcinoma.

LYMPHOMAS
HODGKINS LYMPHOMA
Introduction
Hodgkin disease (HD) is a potentially curable malignant lymphoma with distinct histology, biologic behavior, and
clinical characteristics.
Histologically, the picture is unique, with 1-2% of neoplastic cells (Reed-Sternberg [RS] cells) in a background of a
variety of reactive mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and
histiocytes.
Pathophysiology:
The RS cells represent a clonal proliferation of B-lymphocytes that derive from the germinal centers of lymph nodes
They consistently express CD15 and CD30 antigens. CD30 is expressed in the majority of nodular sclerosis (NS)
and mixed-cellularity subtypes of HD.
CD15 is a marker of late granulocytes, monocytes, and activated T cells. It can be induced by viral infections along
with the interleukin 2 (IL-2) receptor (CD25).
CD19 and CD20, which are B-lymphocyte antigens, are uncommon in NS HD and mixed-cellularity Hodgkin
disease (MCHD).
Up regulation of bcl2 has been shown to be of prognostic significance, which correlates with EBV expression.
Sex:
HD is more common in males than in females
This male predominance is particularly evident in children, where 85% of the cases are in males.
Age:
Age-specific incidence rates have a bimodal distribution in both sexes, peaking in young adults (aged 15-34 y) and
older individuals (>55 y).

Clinical presentation
History:
-Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of patients).
-Constitutional symptoms
 Unexplained weight loss
 Fever
 night sweats
-Large mediastinal mass or lung involvement
 Chest pain
 Cough
 shortness of breath or difficulty in breathing
 Rarely, hemoptysis is observed.
-Patients may present with pruritus
-Alcohol-induced pain at sites of nodal disease is specific for HD
-Intermittent fever-. Infrequently, the classic Pel-Ebstein fever (high fever for 1-2 wk followed by an afebrile period
of 1-2 wk is observed.
-Back or bone pain occurs rarely.

Physical:
-Palpable painless lymphadenopathy. It is described as rubbery adenopathy. Occurs in
 The cervical area (60-80%)
 Axilla (6-20%)
 Inguinal area (6-20%)
-Involvement of the Waldeyer ring or occipital or epitrochlear areas is observed infrequently.
-Splenomegaly may be present.
-Patients may have hepatomegaly.
-Superior vena cava syndrome resulting from massive mediastinal lymphadenopathy is observed rarely.
-Central nervous system (CNS) symptoms or signs may be due to paraneoplastic syndromes, including cerebellar
degeneration, neuropathy, Guillain-Barré syndrome, or multifocal leukoencephalopathy.

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Causes:
Exact etiology unknown.
- (EBV), may be involved in the pathogenesis of HD.
-In as many as 50% of HD cases, the tumor cells are EBV-positive; EBV positivity is higher with MCHD (60-70%)
versus NS HD (15-30%). Almost 100% of HIV-associated HD cases are EBV-positive.
-Patients with HIV infection have a higher incidence of HD compared to the population without HIV infection.
However, HD is not considered an AIDS-defining neoplasm.
-Genetic predisposition may play a role in the pathogenesis of HD. Approximately 1% of patients with HD have a
family history of the disease.

Investigations
Lab Studies:
1. FBC- (for anemia, lymphopenia, neutrophilia, or eosinophilia) should be performed.
The anemia -chronic disease. However, it may be due to bone marrow involvement or the presence of an
autoantibody (positive findings on a warm Coombs test). Cytopenias are common in advanced disease. Platelet
counts can be increased or decreased.
2. (ESR) -An elevated ESR has been associated with worse prognosis.
3. Lactate dehydrogenase (LDH) may be increased. LDH may correlate with the bulk of disease.
4. U/E/C and LFT’s
Alkaline phosphatase (which indicates bony metastasis),
5. Urinalysis may demonstrate proteinuria. Nephrotic syndrome may be associated with HL.

Imaging
-CXR-for mediastinal involvement.
-CT scans of the chest, abdomen, and pelvis
-Possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or splenomegaly with or without
focal parenchymal abnormalities, lung nodules or infiltrates, and pleural effusions.
A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding.
-Abdominal U/S

Procedures:
A histological diagnosis always is required.
Biopsy
- An excisional lymph node biopsy is recommended-for mode architecture as well.
-With neck lymphadenopathy that may be due to a head and neck cancer, a fine-needle aspiration usually is advised
as the initial diagnostic step, followed by excisional biopsy if squamous cell histology is excluded.
Staging laparotomy
Includes splenectomy, needle and wedge biopsy of the liver, and biopsies of the paraaortic, mesenteric, portal, and
splenic hilar lymph nodes. Currently, this procedure is very rarely indicated.
Bilateral bone marrow biopsies
Bone marrow involvement is more common in elderly individuals, in patients with advanced-stage disease, in the
presence of systemic symptoms, and in patients with a histology indicating a poor prognosis
Histologic Findings
(WHO) classification, the first 4 subtypes are referred to as classic HD.
1. Nodular sclerosis Hodgkin disease - 60-80%
-Show a nodular pattern. The broad bands of fibrosis divide the node into "nodules." The capsule is thickened. --The
characteristic cell is the lacunar-type RS cell
-Adolescents and young adults
-Usually involves the mediastinum and other supra-diaphragmatic sites.
2. Mixed-cellularity Hodgkin disease - 15-30%
RS cells are of the classic type (large, with bilobate, double or multiple nuclei, and a large eosinophilic inclusion
like nucleolus).
-It commonly affects the abdominal lymph nodes and spleen.
-Patients with this histology typically have advanced-stage disease with systemic symptoms and immunodeficiency.
3. Lymphocyte-depleted Hodgkin disease - Less than 1%

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-diffuse and often appears hypocellular.
- Large numbers of RS cells and bizarre sarcomatous variants are present. It is associated with older age and HIV
positivity. Patients usually present with advanced-stage disease. EBV proteins are expressed in many of these
tumors. Many cases of LDHD diagnosed in the past actually were non-Hodgkin lymphomas, often of the anaplastic
large-cell type.
4. Lymphocyte-rich classic Hodgkin disease - 5%
In this type of HD, RS cells of the classic or lacunar type are observed, with a background infiltrate of lymphocytes.
It requires immunohistochemical diagnosis. Some cases may have a nodular pattern. Clinically, the presentation and
survival patterns are similar to those for MCHD.
5. Nodular lymphocyte-predominant Hodgkin disease - 5%
-In contrast subtypes, the typical RS cells are rare.
- Instead, a variant of RS cells, the lymphocytic and histiocytic cells (L&H), or popcorn cells (their nuclei resemble
an exploded kernel of corn), are seen within a background of inflammatory cells, predominantly benign
lymphocytes.
-The L&H cells are positive for B-cell antigens, such as CD19 and CD20
-Has distinct natural history characterized by a generally indolent clinical course, late relapses, and the subsequent
development of aggressive non-Hodgkin lymphomas
. -Patients are usually young males who present with localized disease to the peripheral lymph nodes.
-With localized disease may be treated with involved-field radiotherapy alone.
-The above features, reminiscent of low-grade non-Hodgkin lymphoma, have led to the separate classification of this
entity
Staging:
-The Ann Arbor classification (1971) is used most commonly.
- Clinical staging involves assessment of disease extent by clinical examination and imaging techniques.
-When staging laparotomies are used as part of staging, disease extent is designated pathologic staging.
Stage I- denotes a single lymph node area or single extranodal site.
Stage II- denotes 2 or more lymph node areas on the same side of the diaphragm.
Stage III- denotes lymph node areas on both sides of the diaphragm.
Stage IV- denotes disseminated or multiple involvements of extranodal organs.
-Involvement of the liver or the bone marrow is considered stage IV disease.
- For staging classifications, the spleen is considered a lymph node area.
-A or B designations denote the presence or absence of B symptoms.
-B designation includes the presence of 1 or more of the following:
(1) Fever (temperature >38°C)
(2) Drenching night sweats
(3) Unexplained loss of more than 10% of body weight within the preceding 6 months.
A designation is the absence of the above
Treatment.
-Stages 1-2A-Radiotherapy.
-Stages 2B-3B-Chemotherapy and Radiotherapy
-Above stage 3B-Chemotherapy.
-However, in our setting, all the stages are given chemotherapy and radiotherapy to the involved sites above stage
3B.
-Stages below 3B are given upper and lower mantel radiotherapy.
-Chemotherapy-Cyclophosphamide, Hydroxydaunorubicin, Oncovin (Vincristine), Prednisone and Procarbazine.
(CHOPP).
-Adriamycin, Bleomycin, Vinblastine, and Dacarbazine. (ABVD).
-Peripheral stem-cell transplantation-helps restore marrow fxn after myeloblative therapy-as do agents that
stimulate progenitor cells e.g. Filgrastim.
Prognosis
1) Stage of the tumour
2) bulk of nodal disease
3) the extent of subdiaphragmatic involvement
-Depending on the stage, the cure rates are;
Stage 1 - 84%
Stage 2 - 64%

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 Stage 3 - >50%
Stage 4 - <22%.
Spread in HD takes place via the lymphatics, hematogenous routes, and direct extension.
Complications of treatment.
1. Secondary malignancies-Usually a carcinoma, the probability of which increases by 1% per year after the
3rd year of completing the treatment. Also AML and non-Hodgkin`s lymphoma
2. Myelofibrosis.
3. Lung fibrosis.
4. Recurrents (8-12 years after rx)
5. Hypothyroidism.
6. Chemotherapy-Nausea, alopecia, infertility in men and infections.

MALARIA

SEVERE MALARIA
Epidemiology
-Malaria continues to be a major global health problem, with over 40% of the world’s population – more than 2.4
Billion people – exposed to varying degrees of malaria risk in some 100 countries.
- In addition, with modern rapid means of travel, large numbers of people from nonmalarious areas are being
exposed to infection which may only seriously affect them after they have returned home.
-Plasmodium falciparum causes the most serious form of the disease, and is common in the tropics. The situation is
complicated by the increasing occurrence of P. falciparum parasites that are resistant to chloroquine and other
antimalarial drugs.
-Prompt action is especially important for high-risk groups such as young children and pregnant women.
Introduction
-Severe malaria is caused by Plasmodium falciparum infection and usually occurs as a result of delay in treating an
uncomplicated attack of falciparum malaria.
-Sometimes, however, especially in children, severe malaria may develop very rapidly.
-Recognizing and promptly treating uncomplicated P. falciparum malaria is therefore of vital importance.
Uncomplicated malaria

Clinical presentation.
History
-The presentation of uncomplicated P. falciparum malaria is very variable and mimics that of many other diseases.
-Although fever is common, it is absent in some cases. The fever is initially persistent rather than tertian (spikes of
fever on alternate days.)
- The fever may or may not be accompanied by rigors. True rigors are relatively unusual in acute falciparum
malaria.
-The patient commonly complains of fever, headache, and aches and pains elsewhere in the body, and occasionally
of abdominal pain and diarrhoea.
-In a young child there may be irritability, refusal to eat and vomiting.
-History of travel to malaria endemic area or treatment for malaria.
Physical examination
-Fever may be the only sign.
-Dehydration may be evident from vomiting and high fever.
-Some patients the liver and spleen are palpable.
-Unless the condition is diagnosed and treated promptly the clinical picture may deteriorate at an alarming rate and
often with catastrophic consequences.

Investigations
1. Blood slide for MPS- Asexual malaria parasites are usually demonstrable
2. Lumbar puncture-The opening pressure at lumbar puncture is usually normal in adults, but may be elevated;
cerebrospinal fluid (CSF) is clear, with fewer than 10 white cells per μl; the protein is often slightly raised, as is the
CSF lactic acid concentration.
-Rule out other encephalopathies, e.g. bacterial, fungal or viral meningoencephalitides..

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-.NB.A variety of nonspecific electroencephalographic abnormalities has been described.
3. CT-scans brain is usually normal.

Management
Definitive management
1. Quinine
-Loading dose-20 mg/Kg dihydrochloride salt diluted in
10 ml /kg 5% dextrose by IV infusion over 4 hours; then 8 hours after the start of the loading dose, give:
-Maintenance dose of quinine, 10 mg salt/kg in 10ml/kg 5 % dextrose over 4 hours. Maintenance dose be repeated
every 8 hours, calculated from the beginning of the previous infusion, until the patient can swallow. Then
-Oral treatment- quinine tablets, 10 mg salt/kg, 8-hourly to complete a 7-day course of treatment. OR
-Single dose of 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine (maximum 1500 mg sulfadoxine–75 mg
pyrimethamine)
2. Artesunate
-2.4 mg/kg (loading dose) IV, followed by 1.2 mg/kg at 12 and 24 hours, then 1.2 mg/kg daily for 6 days.
-If the patient is able to swallow, the daily dose can be given orally.
3. Artemether
-3.2 mg/kg (loading dose) IM, followed by 1.6 mg/kg daily for 6 days.
-If the patient is able to swallow, the daily dose can be given orally.
-N.B. If parenteral administration is not possible, artemisinin or artesunate suppositories may be given.
Artemisinin suppositories
-40 mg/kg (loading dose) intrarectally, then 20 mg/kg 24, 48 and 72 hours later, followed by an oral antimalarial
drug.
Artesunate suppositories
-200 mg intrarectally at 0, 12, 24, 36, 48 and 60 hours may prove to be highly effective and is in trial. A loading
dose of 4 mg/kg intrarectally, followed by 2 mg/ kg at 4, 12, 48 and 72 hours has been used in Viet Nam. This
treatment should be followed by an oral antimalarial drug.3

Severe falciparum malaria

-A patient with severe falciparum malaria may present with confusion or drowsiness with extreme weakness
(prostration).
-Forms of severe malaria include:
1. Cerebral malaria, defined as unrousable coma not attributable to any other cause in a patient with falciparum
malaria.
2. Generalized convulsions.
3. Anemia
4. Jaundice.
5. Haemoglobinuria.
6. Acute renal failure
7. Fluid and electrolyte disturbances
8. Metabolic acidosis with respiratory distress.
9. Hypoglycemia.
10. Abnormal bleeding.
11. Acute pulmonary edema and acute respiratory distress Syndrome (ARDS).
12. Circulatory collapse, shock, septicaemia (“algid malaria”).
13. Hyperpyrexia
14. Hyperparasitaemia.

-NB These severe manifestations can occur singly or, more commonly, in combination in the same patient.
-Predisposing factors for complications of P. falciparum malaria:
(1.) Extremes of age.
(2.) Pregnancy, especially in primigravidae and in 2 nd half of pregnancy.
(3.) Immunosuppressed - patients on steroids, anti-cancer drugs, immunosuppressant drugs.
(4.) Immunocompromised - patients with advanced tuberculosis and cancers.
(5.) Splenectomy.
(6.) Lack of previous exposure to malaria (non-immune) or lapsed immunity

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(7.) Pre-existing organ failure.

CEREBRAL MALARIA
Clinical features
-The adult patient with cerebral malaria is comatose, the depth of consciousness being variable
-Convulsions and retinal haemorrhages are common; papilloedema is rare.
-A variety of transient abnormalities of eye movement, especially disconjugate gaze.
-Fixed jaw closure and tooth grinding (bruxism) are common.
-Pouting may occur or a pout reflex may be elicited (by stroking the sides of the mouth.
-Mild neck stiffness occurs but neck rigidity and photophobia are absent.
-The commonest neurological picture in adults is one of a symmetrical upper motor neuron lesion. Motor
abnormalities such as decerebrate rigidity and decorticate rigidity (arms flexed and legs stretched),occur.
-Hepatosplenomegaly is common.
-The abdominal reflexes are invariably absent; this is a useful sign for distinguishing hysterical adult patients with
fevers of other causes in whom these reflexes are usually brisk.
Supportive Care
-The comatose patient should be given meticulous nursing
Care
1. Insert a urethral catheter using a sterile technique, unless the patient is anuric.
2. Insert a nasogastric tube and aspirate stomach contents.
3. Keep an accurate record of fluid intake and output.
4. Monitor and record the level of consciousness (using the Glasgow coma scale)
-Also monitor vital signs temperature, respiratory rate and depth, blood pressure, pulse rate.
5. Treat convulsions if and when they arise with diazepam or paraldehyde.
 A slow intravenous injection Diazepam (0.15 mg/kg of body weight, max. 10 mg for adults) OR
Intramuscular injection of paraldehyde (0.1 ml/kg of body weight), will usually control convulsions.
-NB Diazepam can also be given intrarectally (0.5–1.0 mg/kg of body weight) if injection is not possible.
-Paraldehyde should if possible be given from a sterile glass syringe. A disposable plastic syringe may be used
provided that the injection is given immediately the paraldehyde is drawn up, and that the syringe is never reused

ANAEMIA
-Anaemia is common in severe malaria.
-Anaemia is a particularly important complication of malaria in young children and in pregnant women
-In developing countries of the tropics, pre-existing anemia, most commonly due to malnutrition and helminthiasis,
compounds the problem
-In falciparum malaria, anemia can develop rapidly due to profound hemolysis. The degree of anemia correlates
with parasitemia and schizontemia. It is also associated with high serum bilirubin and creatinine levels.
-Pregnancy, secondary bacterial infections and bleeding disorders like disseminated intravascular coagulation can
aggravate the anemia.
-Anemia in malaria is multifactorial.
a) Haemolysis of RBC infected by the protozoa
b) Accelerated destruction of non-parasitized red cells (major contributor in anemia of severe malaria)
c) Bone marrow dysfunction that can persist for weeks
d) Shortened red cell survival
e) Increased splenic clearance
f) Massive gastrointestinal haemorrhage can also contribute to the anemia of malaria.
g) Drug caused haemolysis.

Management
• If the packed cell volume (haematocrit) falls below 20% or the hemoglobin concentration falls below 7 g/dl, give a
transfusion of pathogen-free compatible fresh blood or packed cells. (Stored bank blood may be used if fresh blood
is not available.)
• Provided that the patient’s renal function is adequate, give small intravenous doses of furosemide (frusemide), 20
mg, as necessary during the blood transfusion to avoid circulatory overload.
• Remember to include the volume of transfused cells or blood in calculations of fluid balance.

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RENAL FAILURE
-Renal failure as a complication of malaria is virtually confined to adults.
-There is a rise in serum creatinine and blood urea, oliguria and eventually anuria due to acute tubular necrosis.
-Although usually oliguric, renal failure may occasionally be polyuric.
-The mechanism of acute tubular necrosis in malaria is not fully understood. Acute renal failure is usually reversible.
Management
• Exclude dehydration (hypovolaemia) by clinical examination
• Carefully infuse isotonic saline, monitoring the jugular venous pressure clinically with the patient propped up to
45º
• Peritoneal dialysis or haemodialysis is indicated if the patient remains oliguric after adequate rehydration and the
blood urea and creatinine rise progressively.
• Peritoneal dialysis should not be undertaken lightly. If possible, refer the patient to a dialysis unit or centre.

HYPOGYCEMIA
-Hypoglycemia is an important manifestation of falciparum malaria. It occurs in three different groups of patients
which may overlap:
• Patients with severe disease, especially young children
• Patients treated with quinine or quinidine, as a result of quinine-induced hyperinsulinaemia;
• Pregnant women, either on admission or following quinine treatment
-In conscious patients, hypoglycaemia may present with classical symptoms of anxiety, sweating, dilatation of the
pupils, breathlessness, and oliguria, a feeling of coldness, tachycardia and light-headedness.
-This clinical picture may develop into deteriorating consciousness, generalized convulsions, extensor posturing,
shock and coma.
-The diagnosis is easily overlooked because all these clinical features also occur in severe malaria itself.
-A deterioration in the level of consciousness may be the only sign.
-If possible, confirm by biochemical testing, especially in the high-risk groups mentioned above.

Management
• If hypoglycaemia is detected by blood testing or suspected on clinical grounds, give 50% dextrose, 50 ml
-This should be diluted in an approximately equal volume of any infusion fluid and infused over a period of about 5
minutes.
• Follow with a continuous intravenous infusion of 5% or 10% dextrose.
• Continue to monitor blood glucose levels (using a “stix” method if available, or clinically and biochemically if not)
in order to regulate the dextrose infusion.
-Hypoglycaemia may recur even after treatment with intravenous dextrose

FLUID AND ELECTROLYTE IMBALANCES

-Patients with severe falciparum malaria often show the following on admission: clinical evidence of hypovolaemia
– Low jugular venous pressure, postural hypotension, and oliguria with high urine specific gravity; and clinical signs
of dehydration – dry mucous membranes and decreased skin turgor.
-Acidotic breathing – hyperventilation, deep breathing
– May develop in severely ill patients who are shocked, hypoglycaemic, hyperparasitaemic or in renal failure. This
is usually due to lactic acidosis, and lactic acid concentrations in both blood and CSF are raised.
-Perfusion is improved by correcting hypovolaemia.
Management
• Look for evidence of dehydration and hypovolaemia:
– Dry mucous membranes,
– reduced skin turgor,
– Relatively cool extremities,
– Postural drop in blood pressure (as the patient is propped up from lying flat to 45º),
– Reduced peripheral venous filling, or slow capillary refill time
– Low jugular venous pressure,

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– reduced urine output,
– High urine specific gravity,
– Urine sodium concentration less than 20 mmol/l.
• If there is evidence of dehydration, give only isotonic fluid (0.9% saline) by intravenous infusion, but avoid
circulatory overload as it may rapidly precipitate fatal pulmonary edema.
• Monitor blood pressure, urine volume (every hour) and jugular venous pressure.
• Improve oxygenation by
– clearing airway,
– increasing concentration of inspired oxygen,
– supporting ventilation artificially, if necessary.

CIRCULATORY COLLAPSE-ALGID MALARIA.

-Some patients are admitted in a state of collapse, with a
 Systolic blood pressure less than 80 mmHg (10.7 kPa) in the supine position (less than 50 mmHg
(6.67 kPa) in children);
Cold, clammy, cyanotic skin
Constricted peripheral veins
 Rapid feeble pulse
-This clinical picture is often associated with a complicating Gram-negative septicaemia.
-Circulatory collapse is also seen in patients with pulmonary oedema or metabolic acidosis, and following massive
gastrointestinal haemorrhage or ruptured spleen.
-Dehydration with hypovolaemia may also contribute to hypotension.
-Possible sites of associated infection should be sought, e.g. lung, urinary tract (especially if indwelling catheter),
meninges (meningitis), intravenous injection sites, intravenous lines.
Management
• Correct hypovolaemia with an appropriate plasma expander (fresh blood, plasma, dextran 70 or polyglycans). If
these are not available give isotonic saline.
• Take a blood culture and start the patient on broad spectrum antibiotics immediately, e.g. a penicillin or
cephalosporin combined with a single dose of gentamicin.
• Once the results of blood culture and sensitivity testing are available, give the appropriate antibiotic.
• Monitor central venous pressure

ABNORMAL BLEEDING AND DIC

Bleeding gums
 Epistaxis
 Petechiae
 Subconjunctival haemorrhages
-DIC, complicated by clinically significant bleeding, e.g. haematemesis or melaena, occurs in fewer than 10% of
patients.
-It is more common in non-immune patients with imported malaria in the temperate zone.
-Thrombocytopenia is very common in falciparum malaria, usually without other coagulation abnormalities.
-In most cases it is unaccompanied by bleeding.
- The platelet count usually returns to normal after successful treatment of the malaria.

Management
• Transfuse fresh blood, clotting factors or platelets as required.
• Give vitamin K, 10 mg, by slow intravenous injection.

HYPERPARASITAEMIA.
-In general, and especially in non-immune subjects, high parasite densities (above 5%) and peripheral schizontaemia
are associated with severe disease however, in highly endemic malarious areas, partially immune children can
tolerate surprisingly high densities (20–30%) often without clinical symptoms.
Management

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• Antimalarial therapy should be initiated immediately, preferably by a parenteral route.
• If parasitaemia exceeds 10% in severely ill patients, especially those deteriorating after chemotherapy, exchange
transfusion with screened blood should be considered where facilities are available.

HAEMAGLOBINURIA
-Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop intravascular haemolysis and
haemoglobinuria precipitated by primaquine and other oxidant drugs, even in the absence of malaria.
-Haemoglobinuria associated with malaria (“blackwater fever”) is uncommon and malarial haemoglobinuria usually
presents in adults as severe disease with anaemia and renal failure.
Management
• Continue appropriate antimalarial treatment
• Transfuse screened fresh blood if needed.
• Monitor central venous pressure to avoid fluid overload and hypovolaemia.
• If oliguria develops and blood urea and serum creatinine levels rise (i.e. if acute renal failure develops), peritoneal
dialysis or haemodialysis may be required. If possible, refer the patient to a dialysis unit or centre.

PULMONARY EDEMA
Clinical features
-Pulmonary edema is a grave complication of severe malaria, with a high mortality (over 80%).
-It may appear several days after chemotherapy has been started and at a time when the patient’s general condition is
improving and the peripheral parasitaemia is diminishing.
-In most cases there are features of adult respiratory distress syndrome (ARDS), implying increased pulmonary
capillary permeability. Pulmonary oedema may also arise iatrogenically from fluid overload.
-The two conditions are difficult to distinguish clinically and may coexist in the same patient.
-Pulmonary oedema is often associated with other complications of malaria and may also occur in vivax malaria.
The first indication of impending pulmonary oedema is an increase in the respiratory rate, which precedes the
development of other chest signs .The arterial pO2, is reduced.
-Hypoxia may cause convulsions and deterioration in the level of consciousness and the patient may die within a
few hours.
Management
• Keep the patient upright; raise the head of the bed or lower the foot of the bed.
• Give a high concentration of oxygen by any convenient method available, including mechanical ventilation.
• Give the patient a diuretic, such as furosemide (frusemide), 40 mg, by intravenous injection. If there is no
response, increase the dose progressively to a maximum of 200 mg.
• In well-equipped intensive care units, mechanical ventilation with positive end-expiratory pressure (PEEP), a wide
range of vasoactive drugs and haemodynamic monitoring will be available.
If there is pulmonary oedema due to overhydration in addition to the above:
• Stop all intravenous fluids.
• Can administer diuretic with good urine output.

HIGH FEVERS
-High fever (39–40 ºC) is especially common in children and may contribute to convulsions and altered
consciousness.
-There is evidence that high body temperature in pregnant women contributes to fetal distress .
-Sustained very high body temperatures (42 ºC and above), which may cause permanent severe neurological
sequelae in patients with heat-stroke, are rarely seen in malaria.
Management
• Monitor rectal temperature frequently.
• If rectal temperature is above 39 ºC, remove the patient’s clothes, apply tepid sponging and fanning, and give
paracetamol, 15 mg/kg of body weight, by mouth, suppository or nasogastric tube.

METABOLIC ACIDOSIS

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-Metabolic acidosis (predominantly lactic acidosis) has been now recognized as a principal pathophysiological
feature of severe manifestations of P. falciparum malaria like cerebral malaria and severe anemia.
-It is the single most important determinant of survival and can lead to respiratory distress syndrome. Lactic
acidosis has been identified as an important cause of death in severe malaria.
-Lactic acidosis in severe malaria has been attributed to several causes:
1) Increased production of lactic acid by parasites (through direct stimulation by cytokines)
3) Decreased clearance by the liver
4) Most importantly the combined effects of several factors that reduce oxygen delivery to tissues
-Marked reductions in the deformability of uninfected RBCs may compromise blood flow through tissues
-Dehydrated and hypovolemia can exacerbates microvascular obstruction by reducing perfusion pressure
-Destruction of RBCs and anemia further compromises oxygen delivery.
-Mean venous blood lactate concentrations have been found to be almost twice as high in fatal cases as in survivors
and to correlate with levels of tumour necrosis factor and interleukin 1-alpha.
-Sustained hyperlactataemia has been found to be the best overall prognostic indicator of outcome.
Management:
-Maintenance of airway patency and oxygen delivery; intubate if the patient is unconscious, in severe shock, or
otherwise unstable
-Establish an intravenous (IV) line; replace adequate intravascular fluid volume if the patient has tachycardia,
hypotension, or other signs of poor tissue perfusion like poor capillary refill.
-Monitor for cardiac dysrhythmias.
-The use of sodium bicarbonate is controversial and generally should be avoided

MALIGNANT MELANOMA
Introduction
-Melanoma is a tumor that develops as a result of the malignant transformation of melanocytes.
-Melanocytes cells are derived from the neural crest.
-Melanomas usually occur on the skin but can arise in other locations where neural crest cells migrate, such as in the
gastrointestinal tract, eye or brain.
-Melanoma predominantly is an adult disease with a peak incidence in the 4th decade and no sex prevalence.
-A patient's risk of developing a second primary melanoma after diagnosis of the first one is 3-5%.
Incidence
-The incidence is estimated to be rising rapidly by almost 6% per year.
Morbidity and Mortality
-Early diagnosis and treatment before metastasis most important in management.
While only 5% of skin cancers are melanomas, about two-thirds of all deaths from skin cancer are due to melanomas
Etiology/risk factors
1. Family history
-Positive family history in 5-10% of patients
-With at least one affected relative, 2.2-fold higher risk
2. Personal characteristics
-Blue eyes, fair and/or red hair, pale complexion
-Skin reaction to sunlight - Easily sunburned
-Freckling
3. Benign and/or dysplastic melanocytic nevi - Number rather than size has better correlation
4. Immunosuppressive states - Transplant patients, hematologic malignancies
5. Sun exposure during adolescence
High UV-B radiation
 Low latitude
 Number of blistering sunburns
6. Atypical mole syndrome (formerly termed B-K mole syndrome, dysplastic nevus syndrome, familial atypical
multiple mole melanoma)
Pathophysiology
-Benign melanocytic nevi are markers of melanoma risk rather than direct precursors; however, dysplastic nevi are
believed to degenerate over time into melanoma.

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-Lentigo maligna is believed to be a pre-invasive precursor of lentigo maligna melanoma, and at least 5% progress
to malignancy
Clinical presentation
-Patients usually present with skin lesions that have changed in size, color, contour, or configuration. The acronym
"ABCDE" is the hallmark of international public awareness campaigns and may be used to remember the physical
characteristics suggestive of malignancy. ABCDE stands for
A-Asymmetry of shape
B-Border irregular
C-Color variations (especially red, white, and blue tones in a brown or black lesion) or deepening of pigmentation
D-Diameter greater than 6 mm (size), or recent increase in size
E-Elevated surface, erosions or ulcerations, bleeding, crusting
-Other symptoms of the lesions
Itching, pain, ulcerate, Bleed, Develop satellites
Biopsy
-Perform biopsy on all lesions suggestive of melanoma in the thickest part.
-If the resection will not result in a disfiguring defect, excisional biopsy with a 2-cm skin margin and extending to
the subcutaneous tissue is suggested for lesions less than 1.5 cm in diameter.
-If the lesion is large or located in an anatomic area where skin removal would cause disfigurement, an incisional
biopsy may be performed.
-A full-thickness core punch biopsy in the most raised or irregular area is suggested with the understanding that this
area may not be the thickest area.
Skin anatomy
-The skin is composed of multiple layers.
-The epidermis is the most superficial layer, and it contains keratinocytes in various stages of development.
-Melanocytes are located in the deepest layer of the epidermis.
- A basement membrane separates the epidermis from the underlying dermis, which is divided into 2 zones,
papillary dermis and reticular dermis. Subcutaneous tissue is deep to the reticular dermis.

Histological classification
-Four major types of melanomas exist based on growth pattern.
1. Superficial spreading melanoma
2. Nodular melanoma
3. Lentigo maligna melanoma
4. Acral lentiginous melanoma
-Other more unusual types include mucosal lentiginous melanoma, desmoplastic melanoma, and verrucous
melanoma.
1. Superficial spreading melanoma
-Commonest up to 70% of melanomas in white population. Histologically
Appear singly or in nests along the dermal-epidermal junction
May migrate into the stratum granulosum or stratum corneum
These cells can invade the papillary dermis with an inflammatory lymphocytic infiltrate.
-Clinically
Usually arise in a preexisting dysplastic nevus.
 Typically, this lesion changes slowly over several months to years.
 They are usually flat but may become irregular and elevated in later stages.
 The lesions average 2 cm in diameter with variegated colors and peripheral notches and/or indentations.
2,Nodular melanoma
-They comprise approximately 15-30% of melanoma Histology
Characterized by extensive vertical growth into the dermis with a minimal radial component.
-Clinical
 These tumors typically are blue-black but may lack pigment in some circumstances.
 They are known to arise without a preexisting lesion. May develop at the site of a preexisting nevus and
rapidly becomes a palpable, elevated, firm nodule

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 Location in areas of constant trauma or irritation, lower limb or the back.
Pigmented Lesions
-The appearance of a new pigmented nevus should arouse suspicion of melanoma.
-About one-third of all melanomas arise from pigmented nevi.
-Since the average white adult has 15-20 nevi, a clear idea of the indications for biopsy or excision should be
developed. Recognition and early excision of atypical pigmented lesions are potentially lifesaving, since surgery is
the only effective treatment.
Benign /common naevi
Junctional nevi
-Are usually small, circumscribed, light brown or black, flat or only slightly elevated, and rarely contain hair. They
are found on all areas f the body, and moles of the mucous membranes, genitalia, soles, and palms are usually of this
type.
-The nevus cells are located in the epidermis and at the dermal-epidermal junction.
Intradermal nevi
-Range from small spots to extensive areas covering much of the body.
-Have variable shape and surface configuration, are usually brown or black, and often are slightly elevated.
-Nevus cells are confined to the dermis, and the lesions are basically benign.
Compound nevi have both junctional and intradermal elements.
Blue nevi
-Are circumscribed, flat or dome-shaped, bluish-black lesions, usually on the hands, face, or arms.
-Although benign, they may closely resemble nodular melanoma and require diagnostic excisional biopsy.
Premalignant lesions
Dysplastic nevi
-Are larger (5-12 mm) than common nevi.
-They have macular and papular components, are variegated in color (tan-brown) on a pink base, and have
indistinct, irregular edges.
-Unlike common nevi, dysplastic nevi are most prevalent on covered body areas, though they can appear anywhere.
Any suspicious lesions should be excised. An accurate family history should be obtained in such cases, and first-
degree relatives should be examined.
Congenital nevi
-Occur in about 1% of newborns, and most lesions are small.
-Along with dysplastic nevi, these lesions are now classified as precursors of melanoma.
-Lifetime risk of melanoma developing in large congenital nevi (> 20 cm) is 5-20%, with some increased risk in
smaller lesions as well.
-Prophylactic excision is cosmetically prohibitive in many cases, and these lesions must be carefully monitored for
suspicious change.
-Other pigmented lesions, including basal cell carcinomas, seborrheic keratoses, and actinic keratoses, occasionally
resemble melanoma and require biopsy for diagnosis.

3.Lentigo maligna melanoma

-4-10% of melanomas. Show dermal and epidermal changes from sun exposure.
-Clinical.
Larger than 3 cm
 Flat, tan, and begin as small, freckle-like lesions.
 They occur in sun-exposed areas (eg, face and neck of older individuals).
 Marked notching of the borders is present.
-Lentigo maligna melanoma usually arises within a Hutchinson freckle (lentigo maligna).
The histologic appearance
Irregularly shaped hyperchromatic cells that form spindle-shaped nests.
 The epidermis is atrophic
 The dermis contains solar elastosis with chronic inflammatory infiltrates.
5.Acral lentiginous melanoma
-This tumor comprises 2-8% of melanomas in whites and 35-60% of melanomas in dark-skinned people.
-Histology
Occur in dermal-epidermal junction with microinvasion into the papillary dermis.
 The cells have increased melanin granule production, which fills their dendritic extensions.

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-Clinical
Occur on the palms of the hands, beneath the nailbeds, and on the soles of the feet.
 They may appear as flat, tan, or brown stains with irregular borders on the palms and soles
 Subungual lesions can be brown or black, with ulcerations in later stages.
-No correlation with a worse prognosis is demonstrated for these lesions when tumor thickness is considered.
6.Desmoplastic melanoma
-These lesions account for approximately 1% of melanoma cases; they are fairly rare.
- They demonstrate a tendency for perineural invasion, especially in the head and neck.
-They have a propensity for higher local recurrence rates but lower regional metastasis rates.

Classification and staging

-Two classification schemes have been developed, based on either:
1. The vertical thickness of the lesion in millimeters (Breslow classification)
2. The anatomic level of invasion of the layers of skin
(Clarks staging)
-Breslow classification scheme is used almost exclusively now since it more accurately predicts future tumor
behavior.
-The TNM (tumor, node, and metastasis) system is used for clinical staging

Breslow classification -Thickness of lesion

o Stage 1Thickness of 0.75 mm or less
o Stage 2 Thickness of 0.76-1.50 mm
o Stage 3 Thickness of 1.51-4.00 mm
o Stage 4 Thickness greater than 4.00 mm

Clark classification
o Level I - Involves only epidermis (in situ melanoma); no invasion
o Level II - Invades papillary dermis
o Level III – Papillary-reticular dermis interface
o Level IV - Invades reticular dermis
o Level V - Invades into subcutaneous tissue

TNM classification
Primary tumor (pT)
pTx - Primary tumor cannot be assessed
pT0 - No evidence of primary tumor
pTis - Melanoma in situ (Clark level [CL] I)
pT1 - Tumor 0.75 mm or less in thickness; invades papillary dermis (CL II)
pT2 - Tumor 0.76-1.50 mm in thickness and/or invades to papillary-reticular dermal interface (CL III)
pT3 - Tumor 1.51-4.00 mm in thickness and/or invades reticular dermis (CL IV)
 pT3a - Tumor 1.51-3.00 mm in thickness
 pT3b - Tumor 3.01-4.00 mm in thickness
pT4 - Tumor greater than 4.00 mm in thickness and/or invades subcutaneous tissue (CL V) and/or
satellite(s) within 2 cm of the primary tumor
pT4a - Tumor greater than 4.00 mm in thickness and/or invades subcutaneous tissue
pT4b - Satellite(s) within 2 cm of primary tumor
Regional lymph nodes (N)
NX - Regional lymph nodes cannot be assessed
N0 - No regional lymph node metastasis
N1 - Metastasis 3 cm or less in greatest dimension in any regional lymph node
N2 - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s) and/or in-transit
metastasis N2a - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s)
N2b - In-transit metastasis
N2c - Both N2a and N2b
Distant metastasis (M)
MX - Distant metastasis cannot be assessed

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 M0 - No distant metastasis
M1 - Distant metastasis
M1a - Metastasis in skin or subcutaneous tissue or lymph node(s) beyond the regional lymph nodes
M1b - Visceral metastasis.

Management
-Surgical therapy-wide margin excision. If the lesion has not spread beyond the primary site, it is potentially curable.
Stage I
-For a T1 lesion, 1-cm excision margins are adequate, but lesions greater than 1 mm require 2-cm margins. Studies
demonstrate no improvement in recurrence or survival rates with larger margins of resection. Attempt primary
closure and perform skin grafting or flap closure if necessary. For lesions with a depth greater than 1 mm, many
recommend sentinel lymph node biopsy at the time of wide local excision (see "Stage II," below).
Stage II
-Perform a 2-cm surgical resection on stage II lesions. No recurrence or survival advantage exists when 2-cm
margins are compared to wider margins (4-6 cm).
Smaller resection decreases the need for skin grafting and inpatient hospital stay.
-Perform a complete therapeutic lymphadenectomy on patients with suspected lymph node metastases based on
physical examination. This consists of excision of all lymph nodes in the affected regional lymph node basin.
-Consider sentinel lymph node biopsy if no clinically positive nodes are present. Using blue dye and/or radioisotope
injected at the site of the primary melanoma, the first-echelon node can be identified within the regional lymph node
basin. Send this sentinel node to the pathologist for analysis using routine stains, immunohistochemistry, and even
polymerase chain reaction in some centers.
-If the sentinel node is positive, then predictive importance exists of regional lymph node metastases; perform a
complete lymph node dissection.
-The correlation is based on the thickness of the primary tumor. If the sentinel lymph node is negative, a 99%
chance exists that all others are negative. This procedure is becoming the standard of care for tumors greater than 1
mm in depth.
-Hyperthermic arterial limb perfusion with melphalan for extremity melanomas has been studied as an adjuvant
therapy. One study found it to be beneficial in that it produced higher response rates and overall survival rates than
those for surgery alone. Other studies do not demonstrate benefit.
-Adjuvant chemotherapy and/or biological therapy also are under clinical evaluation. One study demonstrated that
high-dose interferon alfa-2b resulted in prolonged relapse-free survival and overall survival compared to no
adjuvant therapy. A follow-up study by the same group demonstrated in preliminary results that high-dose interferon
offered patients a relapse-free survival benefit over patients who did not receive adjuvant treatment but not over
those who received low-dose interferon.
-Neither high-dose nor low-dose interferon had a significant overall survival advantage compared to observation
alone. High-dose interferon can be associated with significant toxic side effects (ie, liver toxicity), and some patients
require dose reduction since it may not be well tolerated.
Stage III
-Wide local excision of the primary tumor with 2-cm margins remains the first-line therapy.
-. Skin grafting or other tissue-transfer technique may be necessary to close the defect.
-Perform regional lymph node dissection, since a stage III melanoma represents nodal disease.
- If the nodal status is unknown, consider a sentinel lymph node biopsy to determine if the disease is stage I, II, or
III.
-As in stage II disease, a higher rate of treatment failure exists with wide local excision alone in this group compared
to stages 0 and I. Many clinical trials currently are exploring similar options as adjuvant therapy.
Stage IV
-Advanced metastatic melanoma usually is refractory to standard therapy; thus, consider these patients for clinical
trials.
-Some treatments have reported various objective responses, although they usually are short lived.
-Dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine (CCNU), produced a 20% objective
response rate.
-Response rates for interferon alfa and interleukin-2 range from 8-22% and 10-20%, respectively.
-Currently, other studies in progress are comparing other cytotoxic and biologic drug regimens.

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Prognosis
1) Size of the tumor and the depth of invasion. Small tumors with minimal invasion (< 0.7 mm) are usually
curable by wide local excision.
2) The prognosis is usually favorable in lentigo maligna melanoma and in superficial spreading melanomas
without deep invasion. Most nodular melanomas, particularly if ulcerated and associated with deep
invasion, have a poor prognosis.
3) Lesions of the extremities have a more favorable prognosis than those of the trunk, and
4) Women with malignant melanoma have better survival statistics at 5 and 10 years than men.
METABOLIC SYNDROME
-Starting in the 1960s and 1970s, researchers began to document a clustering of the elements of cardiovascular risk
in certain patients.
-It wasn’t until 1988 that a unifying cause—insulin resistance—was proposed and the term syndrome X applied.
-After several name changes over the past two decades, the name became metabolic syndrome.
-Key components of metabolic syndrome
1) Central adiposity
2) Dyslipidemia (Hypertriglyceridemia and low levels of high-density lipoprotein cholesterol)
3) Hypertension
4) Insulin resistance- Glucose intolerance
-Metabolic syndrome is associated with proinflammatory/ prothrombotic state that may include
 Elevated levels of C-reactive protein
Endothelial dysfunction
Hyperfibrinogenemia
 increased platelet aggregation
increased levels of plasminogen activator inhibitor
elevated uric acid levels
 Microalbuminuria
 Shift toward small, dense particles of low-density lipoprotein (LDL) cholesterol.
 Insulin resistance has also been implicated in polycystic ovary syndrome and nonalcoholic steatohepatitis
(NASH).
-The coexistence of these conditions in the same patient is related to an increased incidence of cardiovascular
disease and its consequences.
-Risk factors include
Poor diet
 Sedentary lifestyle
 Genetic predisposition.
Etiology
-The etiology of the metabolic syndrome has not been established definitively.
-One hypothesis presumes that the primary cause is insulin resistance.
-Insulin resistance correlates with visceral fat measured by waist circumference or waist to hip ratio.
-The link between insulin resistance and cardiovascular disease probably is mediated by oxidative stress, which
produces endothelial cell dysfunction, promoting vascular damage and atheroma formation.

Diagnostic criteria for metabolic syndrome

Adult Treatment Program III diagnostic criteria (any 3 of the following)
1. Abdominal girth /Waist circumference
Men >102 cm (40 in)
Women >88 cm (35 in)
2. Fasting plasma HDL-C
Men <40 mg/dL (1.03 mmol/L)
Women <50 mg/dL (1.29 mmol/L)
3. Fasting plasma triglycerides
≥150 mg/dL (1.7 mmol/L)
4. Fasting blood glucose ≥110 mg/dL (6.1 mmol/L)
5. Blood pressure ≥130/85 mm Hg

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WHO diagnostic criteria (insulin resistance plus any 2 of the following)
1. Abdominal/central obesity
Waist to hip ratio: > 0.90 (men)
Waist to hip ratio: > 0.85 (women)
OR BMI >30kg/m2
2. Fasting plasma HDL-C
Men <35 mg/dL (0.9 mmol/L)
Women <39mg/dL (1.0 mmol/L)
3. Fasting plasma triglycerides
≥150 mg/dL (1.7 mmol/L)
4. Fasting blood sugar
-Impaired glucose tolerance, Insulin resistance, DM type2
-Impaired glucose tolerance is defined as two-hour glucose levels of (7.8 to 11.0 mmol) on the 75-g oral glucose
tolerance test, and (5.6 to 6.9 mmol per L) on Fasting blood sugar.
5. Blood pressure ≥140/90 mm Hg
6. Microalbuminuria Urinary albumin to creatinine ratio: 30 mg per g or albumin excretion rate: 20 mcg per minute
Abdominal fat distribution is a more sensitive indicator of metabolic syndrome than body mass index (BMI). Also,
BMI is less useful for assessing body weight in heavily muscled persons, athletes, and certain racial groups.
Treatment
-The National Cholesterol Education Program–Adult Treatment Panel III has identified metabolic syndrome as an
indication for vigorous lifestyle intervention.
-Effective interventions include
Diet
 Exercise
 Judicious use of pharmacologic agents to address specific risk factors.
 Weight loss significantly improves all aspects of metabolic syndrome.
-Increasing physical activity and decreasing caloric intake by reducing portion sizes will improve metabolic
syndrome abnormalities, even in the absence of weight loss.
-Specific dietary changes that are appropriate for addressing different aspects of the syndrome include
Reducing saturated fat intake to lower insulin resistance
 Reducing sodium intake to lower blood pressure
 Reducing high-glycemic–index carbohydrate intake to lower triglyceride levels
 A diet that includes more fruits, vegetables, whole grains, monounsaturated fats, and low-fat dairy products
will benefit most patients with metabolic syndrome.
-Each patient specific risk factors should be assessed, clearly communicating these risk factors to patients,
identifying appropriate interventions to address specific risks, and assisting patients in identifying barriers to
behavior change.
Weight loss:
-Although some persons with metabolic syndrome are of normal weight, many are overweight or obese, and weight
loss through long-term behavior modification and a reduced-calorie diet is the goal.
-Even just moderate weight loss can moderately lower blood pressure, decrease total cholesterol, and reduce the
percentage of body weight due to fat. Obesity experts recommend as an initial goal a weight loss of 10% of baseline
over a 6-month period
Physical activity:
-The physical activity needed for improved health seems on the surface to be manageable for almost anyone: 30
minutes of moderate exercise 5 days a week. The activity can be broken up during the day as fits the person’s
schedule.
-Exercise generally improves circulation, increases high-density lipoprotein cholesterol (HDL-C) levels, and burns
calories.
-Muscles are the primary disposal and storage site of glucose and as exercise leads to more muscle and less fat,
blood glucose tends to stabilize at a normal level.
Hypertension:
-Weight loss, exercise, and a diet low in sodium offer a sound first approach for antihypertensive therapy.
-However, if these steps do not reduce blood pressure to an acceptable level, medication may be necessary.
-HTN is important contributor to many complications of metabolic syndrome. Thus its control in metabolic
syndrome is crucial.

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-Goal BP should match that recommended for patients with diabetes less than130/80 mm Hg.
-Recommendations of JNC apply-As an initial approach; a thiazide diuretic should be used in most cases of
uncomplicated hypertension.
-Diuretic therapy can be used alone or in combination with a drug in the other classes of antihypertensives (eg, ACE
inhibitor, ARB, calcium channel blocker).
Triglycerides, HDL-C: Strategies to decrease triglycerides and increase HDL-C incorporate
(1) Increased physical activity,
(2) Limited fat and alcohol intake,
(3) Limited dietary sugar and carbohydrates
(4) Smoking cessation.
-These lifestyle changes may need to be complemented by medications that can better control risk factors.
-Agents include 3-hydroxy- 3-methylglutaryl coenzyme A reductase inhibitors (“statins”), fibric acid derivatives,
and niacin.
-In patients whose Framingham score for heart attack risk is less than 20, the goal for low-density lipoprotein
cholesterol (LDL-C) is a concentration less than 130 mg/dL (3.4 mmol/L), and statin use can help achieve that level.
-For patients whose Framingham score is greater than 20, the LDL-C goal is less than 100 mg/dL (2.6 mmol/L).
Adjunctive use of a fibric acid derivative, such as gemfibrozil or fenofibrate, can help reduce triglyceride levels and
improve HDL-C levels.
-If niacin is used in a patient whose fasting plasma glucose level is 110 to 126 mg/dL (6.1 to 7.0 mmol/L), it may
increase production of endogenous glucose and incite diabetes. Niacin use requires careful monitoring.
Glucose intolerance:
-Persons with impaired glucose tolerance (IGT) (fasting blood glucose, 110 to 126 mg/dL) are at risk for diabetes,
cardiovascular disease, and metabolic syndrome.
- Annually, IGT carries a 1% to 10% rate of progression to diabetes. Medication to treat insulin resistance before
diabetes occurs is controversial, but it is an area of high interest and active investigation.
-It has been shown that metformin hydrochloride reduced diabetes risk by 31% in patients with IGT. Beyond
metformin, thiazolidinediones can modify insulin levels as well as other parameters, most specifically triglyceride
levels,

MITRAL REGURGITATION
-Mitral regurgitation (MR) is characterized by an abnormal reversal of blood flow from the left ventricle to the left
atrium.
Pathophysiology:
-The mitral or bicuspid atrioventricular is composed of the mitral annulus, papillary muscles, chordae tendineae the
leaflets.
-Abnormalities in any of these structures can cause MR. The leaflets are continuous with each other at their lines of
attachment, called commissures, and are tethered to the left ventricle by the chordae tendineae.
-Chordae tendineae attach to papillary muscles and prevent prolapse of the mitral valve leaflet to prevent reflux of
blood into the left atrium.
-MR can be caused by organic disease or a functional lesion (i.e., a normal valve may regurgitate [leak] because of
global annular dilatation, focal myocardial dysfunction, or both).
- Congenital MR is rare but is commonly associated with myxomatous mitral valve disease and can be associated
with cleft of the mitral valve in persons with Down syndrome.
-In acute mitral valve regurgitation, the incompetent mitral valve allows the ventricular ejection fraction to reflux
into the left atrium.
-This volume overload is intensified by the inability of the atrium and ventricle to immediately dilatate, resulting in
elevated left atrial and pulmonary venous pressures and acute pulmonary edema.
- The net reduction in forward stroke volume reduces systemic perfusion, can result in hemodynamic deterioration,
and can lead to cardiogenic shock.
-In chronic mitral valve regurgitation, the distensibility of the left atrium and ventricle are increased over time.
- This dilatation of the left atrium decreases left atrial pressures, thus increasing preload. The left ventricle dilatates
and, via the process of eccentric hypertrophy, generates a larger stroke volume without a significant rise
-The LV dilatation may further prohibit the coaptation of the mitral valve leaflets during systolic ejection, leading to
progression of LV dilatation and overload.

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-Patients with compensated MR may remain asymptomatic for years despite the presence of severe volume
overload.
-Ultimately, most people with MR decompensate over the long term.
Morbidity
- Natural history studies of patients with rheumatic MR have shown 5- and 10-year survival rates of 80% and 60%,
respectively.
Sex: MR is independently associated with female sex.
Age: MR is independently associated advanced age
Clinical presentation
History:
-Mitral regurgitation can be tolerated for many years.
-The initial symptoms of dyspnea and fatigue can rapidly progress to orthopnea and paroxysmal nocturnal dyspnea
-Patients with anginal-type pain may have underlying ischemia.
-In those with Mitral Valve Prolapse, palpitations and atypical chest pain are the most frequent complaints. Two
thirds are female, often with an underlying panic disorder.
-With underlying coronary artery disease (CAD), regurgitation usually is associated with symptoms of angina
pectoris.
-Regurgitation also can develop acutely with myocardial infarction, secondary to papillary muscle rupture..
-When mitral regurgitation is due to left ventricular dilatation and altered valve function, patients often have chronic
left-sided heart failure.
-In acute mitral regurgitation from sudden disruption of the mitral valve, the symptoms are due to acute pulmonary
edema.
Physical:
-With chronic MR, the characteristic holosystolic apical murmur, which radiates to the left axilla and sternal border,
may be accompanied by a ventricular gallop (signifying LV dysfunction) followed by an early diastolic rumble
caused by the large inflow of blood from a dilatated left atrium.
-If the MR is caused by LV dilatation and depressed ventricular contractile function, this murmur may be mid, late,
or holosystolic and may be accompanied by the aforementioned LV (S 3) gallop. In this setting, the murmur is
usually grade II/VI or less.
-With acute mitral valve regurgitation, a harsh murmur, usually grade III or IV/VI, is heard and is accompanied by a
palpable thrill at the apex of the heart.
Causes

Acute MR
1. Ruptured chordae or papillary muscle due to acute myocardial infarction or trauma
2. Perforation of the mitral valve leaflet
3. Acute failure of a prosthetic valve

Chronic MR
1. Rheumatic heart disease
2. Mitral valve prolapse
3. Coronary artery disease
4. Annular calcification
5. Connective-tissue disorder -Ehlers-Danlos syndrome
-Marfan syndrome, Osteogenesis imperfecta, Systemic lupus erythematosus (SLE)
6. LV dilatation
7. Prosthetic valves

Imaging Studies:
1. Chest radiography
-Evidence of LV enlargement due to volume overload may be observed, although pulmonary congestion,
represented by increased pulmonary markings, may not be observed until heart failure has developed.
-Left atrial enlargement also may be observed as a prominence along the right sternal border.
2. Echocardiograph
3. Electrocardiography
-Acute MR is often accompanied by MI

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-LV dilatation and hypertrophy
-Left atrial enlargement in chronic mitral valve regurgitation produces a negative P wave in lead V 1, but atrial
fibrillation may be observed in the late stages.
4. Cardiac catheterization
-Left ventriculography confirms mitral valve regurgitation by demonstrating a flow of contrast into the left atrium.
- LV end-diastolic and end-systolic dimensions can be measured and used to calculate the ejection fraction
--Catheterization can also help detect lesions within the aortic valve, coexistent coronary artery disease through
selective coronary artery injection, and other cardiac anomalies such as septal defects
MANAGEMENT
Medical therapy
1. Afterload-reducing agents, such as nitrates and antihypertensive drugs, are helpful for maintaining the forward-
flow state in persons with mitral valve regurgitation.
2. If atrial fibrillation is encountered, digitalis therapy is considered.
3. Similar to other valvular diseases, prophylactic antibiotics are administered prior to any interventional treatment.
However, the current American Heart Association guidelines for endocarditis prophylaxis in patients with mitral
prolapse indicate that patients with no murmur and normal leaflets are at low risk; therefore, antibiotic prophylaxis
is not necessary.
4. In late-stage mitral valve regurgitation, heart failure develops; diuretics and inotropic agents are administered, and
consultation with a specialist in cardiothoracic surgery is arranged.
5. The use of balloon counterpulsation should be considered as a preoperative measure
Surgical Care:
-Indications for surgical intervention
1. Acute mitral regurgitation (MR) with congestive heart failure or cardiogenic shock
2. Class III/IV symptoms (ie, patient symptomatic while at rest or with minimal activity)
3. Class I/II (few or no) symptoms with evidence of deteriorating LV function as evidenced by
 An ejection fraction less than 0.55,
fractional shortening less than 30%
Either the end-diastolic diameter approaching 75 mm or the end-systolic diameter approaching 50 mm
4. Systemic emboli
5. End-systolic volume index greater than 60 mL/m2 - Most commonly used parameter

Surgical options
-Mitral valve reconstruction with mitral annuloplasty, quadratic segmental resection, shortening of the elongated
chordae, or posterior leaflet resection
-Mitral valve replacement with either a mechanical valve (requiring lifelong anticoagulation) or a bioprosthetic
porcine valve

MITRAL STENOSIS

Introduction
-Mitral stenosis (MS) is a narrowing of the inlet valve into the left ventricle that prevents proper opening during
diastolic filling.
-Mitral valve leaflets that are typically thickened, commissures that are fused, and/or chordae tendineae that are
thickened and shortened.
-The most common cause of mitral stenosis is rheumatic fever (RF).
-After the initial episode of RF, a latency period of 20-40 years occurs until the onset of symptoms. The natural
history of mitral stenosis is typically progressive, with a slow and stable course early on, followed by progressive
acceleration in the later years.

Pathophysiology
-The serum of patients with RF contains antibodies to the type 5 streptococcal M protein, which cross-reacts with
myocardial tissue. Pathologic examination of the mitral valve at this time reveals proliferation of fibroblasts and
macrophages.
-Subsequent disease may occur as a consequence:
1) Healing of the rheumatic process
2) Sub clinical repetitive rheumatic insults

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 3) Chronic rheumatic activity
4) Progressive hemodynamic stresses on the traumatized valve
-Some patients experience a chronic stable disease, while others have an accelerated course necessitating early
surgical intervention.
-The normal area of the mitral valve orifice is 4-6 cm2, Narrowing of the valve area to less than 2.5 cm2 impedes the
free flow of blood and causes a build up of left atrial pressure (LAP) to promote normal transmitral flow volume.
-Critical mitral stenosis occurs when the opening is reduced to 1 cm2. At this stage, a LAP of 25 mm Hg is required
to maintain a normal cardiac output.
-With progressive stenosis, critical flow restriction reduces left ventricular output.
-The increase in LAP also enlarges the left atrium and raises pulmonary venous and capillary pressures.
- As the disease evolves, chronic elevation of LAP eventually leads to pulmonary hypertension, tricuspid and
pulmonary valve incompetence, and secondary right heart failure.
Prevalence
Both RF and mitral stenosis remain common in developing nations, and progression of mitral stenosis tends to be
more rapid .
Mortality/Morbidity:
Overall, the 10-year survival of untreated patients with mitral stenosis is 50-60%, depending on symptoms at
presentation.
-In untreated patients, the causes of death are as follows:
Progressive heart failure in 60-70%
 Systemic embolism in 20-30%
 Pulmonary embolism in 10%
 Infection in 1-5%
Sex:
- Although the attack rate for RF is roughly equal among genders, mitral stenosis is 2-3 times more common in
women than in men.
Age:
-Occasionally, patients can become symptomatic before age 20 years.
-Progression more rapid in the developing countries.

CLINICAL PRESENTATION
History
-Inquire about the history suggestive of acute RF
 Sore throat
Abnormal movement
Skin rash or skin swellings
 Multiple and shifting joint pains
-Also history of repeated streptococcal pharyngitis or scarlet fever in childhood.
-Many patients are asymptomatic.
-Some patients may develop symptoms during physiologic stress such as infection, exercise, fever, or pregnancy.
-In late disease- symptoms of left heart failure) are most common
 Exertional dyspnea
Orthopnea
Paroxysmal nocturnal dyspnea
 Cough and wheezing. Attacks of frank pulmonary edema may occur.
Hemoptysis from pulmonary venous hypertension which results in rupture of anastomosis between
bronchial vein
-Chest pain due to right ventricular ischemia. And later with right sided failure then oedema, distended neck veins
and tender hepatomegaly. If unrecognized may lead to cirrhosis of the liver and ascites.
-Ortner syndrome may occur if an enlarged left atrium impinges on the left recurrent laryngeal nerve, causing
hoarseness.
-Patients may present with complications of mitral stenosis.
-i) New-onset atrial fibrillation-present as palpitations. Atrial fibrillation is common –about 40% of those with
significant stenosis, and it increases in frequency with age and with the increasing size of the left atrium

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ii) Systemic embolism- from left atrial thrombi Up to 70% of clinically evident embolic events involve the central
nervous system, resulting in stroke, transient ischemia, or death. An age greater than 35 and the presence of atrial
fibrillation are the most significant associated risk factors for embolism in mitral stenosis patients;
iii) Infective endocarditis
Precipitant of the heart failure if already on treatment
FAILURE-
F-Forgotten medication,
A-Arrhythmia/Anaemia,
I-Ischaemia/Infarct/Infection
L-Lifestyle (Na and fluid uptake)
U-Upregulation (increased CO in pregnancy, hyperthyroidism)
R-Renal failure,
E-Embolus

Physical examination
-Signs of left heart failure-Respiratory distress, evidence of pulmonary edema (eg, rales),Digital clubbing
-Low volume pulse
-Pulse may be irregular due to artrial fibrillation.
-Cardiac examination of stenotic mitral valve (best at the apex with the patient in the left lateral recumbent position)
 Observe for active precordium
Feel the tapping apex-prominent 1st heart sound
Palpable diastolic thrill
 Prominent 1st heart sound-(An accentuated S1) followed by S2
Opening snap (OS)
Characteristic mid-diastolic low-pitched, rumbling murmur best heard at the apex with the patient in left
lateral position with the breath held in expiration and with the bell of the stethoscope.

-The duration, and not intensity, of the murmur is a guide to the severity of mitral valve narrowing. However,
murmur may diminish in intensity as the stenosis increases.
-The OS and diastolic murmur are often reduced during inspiration and augmented during expiration. Amyl nitrite
inhalation, coughing, isometric or isotonic exercise, and sudden squatting all are useful in accentuating a faint or
equivocal murmur of mitral stenosis.
Signs of right heart strain/failure eg
-Right ventricular lift may be felt.
-A loud pulmonic closure (P2) may be noted in the left parasternal region in patients with pulmonary hypertension.
-Jugular venous distention, ascites, hepatomegaly, and peripheral edema may be noted.
-Auscultation may reveal a systolic murmur of TR, a Graham Steele murmur of Pulmonary Regurgitation (a high-
pitched, decrescendo, early diastolic murmur of pulmonary insufficiency), and an S 4.
-Large a waves in the jugular pulse indicate the presence of pulmonary hypertension or tricuspid stenosis; with atrial
fibrillation, the A wave is absent.
Signs of complications from mitral stenosis
-Endocarditis - Fever, changing murmur, and classically splinter hemorrhage, finger clubbing, petechiae, Roth spots,
Osler nodes, or Janeway lesions
-Atrial fibrillation
-Systemic embolization
Other findings
-A holosystolic murmur of mitral regurgitation may accompany the valvular deformity of mitral stenosis.
-“Mitral facies” characterized by pinkish purple patches on the cheeks may be present.
-NB. Differentiating an Austin Flint murmur from a mitral stenosis rumble, since the quality of the murmurs is
similar. The Austin Flint murmur is due to the convergence of the mitral orifice flow and the jet of aortic
regurgitation, which results in audible turbulence. The administration of amyl nitrite causes a marked transient fall
in systemic vascular resistance, with an. increase in heart rate and stroke volume. A diastolic rumble caused by
mitral stenosis will increase in intensity, whereas the Austin Flint murmur will decrease as the degree of aortic
regurgitation is reduced by a fall in systemic blood pressure.
-It should not be given to patients with significant aortic stenosis, unstable angina pectoris, or other conditions in
which even brief hypotension could exacerbate the condition.

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Etiology
1. Rheumatic fever (most common, all others are rare)
2. Congenital mitral stenosis
3. Degenerative conditions in the elderly. (Calcification of the mitral valves)
4. Systemic lupus erythematosus (SLE) and Rheumatoid arthritis (RA)
5. Malignant carcinoid
6. Mucopolysaccharidoses (of the Hunter-Hurler phenotype)
7. Others-Fabry disease, Whipple disease, Methysergide

Imaging Studies:

CXR
-Cardiomegaly with
1) Straightening of the aortic knuckle due to LA enlargement
2) Splaying of the carina-LA enlargement
3) Double shadow by the LA and RA on the right border of the heart.
4) Indentation of the esophagus on Barium swallows
5) Rarely, calcification of the mitral valve may be seen.
6) Redistribution of blood flow to the upper lung fields Kerley B-lines (short peripheral lines, perpendicular to the
pleura) are found in most patients with pulmonary venous hypertension.
Kerley A-lines (long, dense lines radiating from the hilum) are seen in patients with severe, chronic mitral stenosis
7) Long-standing mitral obstruction may lead pulmonary hemosiderosis

Echocardiography
4-modes include M-mode (motion-mode), 2-dimensional, Doppler, and transesophageal echocardiography
-Morphology of the mitral valve
-Measuring orifice size and chamber sizes
-Detailing leaflet mobility
-Thickness
-Calcification, fusion, and appearance of the commissures
-Ventricular wall motion and ejection fraction
-It provides anatomic and functional information on cardiac chambers and facilitates recognition of other structural
abnormalities.
-Transvalvular pressure gradient and pulmonary arterial pressure and determines whether mitral regurgitation, aortic
regurgitation, and other valvular abnormalities coexist

ECG
1-Left atrial enlargement: P mitrale, a wide (<0.12 s) and notched or bifid P wave in limb lead II.and/or a biphasic P
wave in lead V1 with a wide negative deflection greater than 0.04 seconds.
NB.P pulmonale is a tall, peaked P wave (height at least 2.5 mm) in limb lead II, associated with right atrial
enlargement from either severe pulmonary hypertension or concomitant tricuspid stenosis or regurgitation.
2-Atrial fibrillation usually develops in the presence of preexisting left atrial enlargement.
3-With severe pulmonary hypertension, right-axis deviation and right ventricular hypertrophy can be seen. The
ECG of right ventricular hypertrophy typically shows tall R waves in the right chest leads, and the R wave may be
taller than the S wave in lead V1.
4-In addition, right-axis deviation and right precordial T-wave inversions are often present.

Cardiac catheterization
-measures absolute left- and right-sided pressure when pulmonary artery pressure elevation is out of proportion to
mean gradient and valve area.
-Coronary angiography may be performed in selected patients.

MANAGEMENT

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MULTIPLE MYELOMA
Definition
-Is malignancy of plasma cells resulting from the monoclonal proliferation of B cells, with a resultant increase of a
single immunoglobulin (monogammopathy).
-It is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to
plasma cell leukemia
Incidence
-Multiple myeloma is the most common primary neoplasm of the skeletal system.
Pathophysiology:
-Plasma cells are a subset of B cells, which produce antibodies. Antibody molecules are composed of two
polypeptide chains: a light chain and a heavy chain.
-Cleavage of each chain results in the production of Fab and Fc fragments; the Fab fragment is termed the Bence-
Jones protein and is found in the urine of patients with myeloma.
-An individual plasma cell can produce antibody molecules of only a single immunoglobulin to combine with a
single antigen. As such, a plasma cell is termed monoclonal.
-If malignant transformation occurs in a single plasma cell eg in multiple myeloma its clones produce only a single
type of immunoglobulin, and electrophoresis demonstrates a monoclonal peak corresponding to this particular
immunoglobulin.
-Other causes of monoclonal gammopathy include:
-Control symptoms
 Treat elevated pulmonary venous pressure
LV systolic dysfunction
Heart failure.

General
1-avoid strenuous physical activity.
2-Sodium intake should be restricted
3- Maintenance doses of oral diuretics should be continued.
4-beta-blockade may be useful for patients ONCE oedema cleared ACE inhibitors for those in CCF
5-Prevent recurrent acute rheumatic disease. Monthly Benzathine Penicillin
6-Manage atrial fibrillation Patients with atrial fibrillation are especially likely to show symptomatic improvement
when heart rates are controlled with medication. Digoxin has been popular for rate control in atrial fibrillation
7-Rate control should be maintained with digitalis, a beta-blocker, or a calcium channel blocker. Digitalis works
well but has a slow onset of action. A calcium channel blocker may become the preferred agent for its lower
tendency to convert the rhythm and risk embolization.
8-Anticoagulation is necessary in patients who are unable to maintain normal sinus rhythm.
-Anticoagulation is also beneficial for cases with normal sinus rhythm with a prior embolic event or a left atrial
dimension greater than 55 mm noted by echocardiography
- Patients with atrial fibrillation are especially likely to show symptomatic improvement when heart rates are
controlled with medication.
- Digoxin has been popular for rate control in atrial fibrillation

Surgical management
-Definitive management is valve replacement.
Other options
1. Percutaneous Mitral Balloon Valvuloplasty
2. Closed or open mitral commissurotomy

 Waldenström macroglobulinemia
 Leukemia
 Lymphoma
-Diffuse hypergammaglobulinemia is seen in infections, as well as collagen vascular disorders, rheumatoid arthritis,
and ulcerative colitis.
-Infections produce a polyclonal response, since multiple antigens are present on a single bacillus or virus and
activate multiple plasma cells.
-If a monoclonal protein elevation is discovered in a patient and additional tests often do not reveal an underlying
etiology, the condition is termed monoclonal gammopathy of undetermined significance (MGUS).
-Most of these patients do not progress to multiple myeloma but must be followed up regularly to evaluate for an
increase in monoclonal protein levels or the development of lytic bone lesions.

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Etiology
-The cause of multiple myeloma is unknown. Current theories involve chronic antigenic stimulation of a plasma
cell, which results in transformation and the development of myeloma.
Factors include:
1. Genetic predisposition
-Investigating whether HLA-Cw5 or HLA-Cw2 may play a role in the genesis of myeloma.
2. Environmental or occupational causes
-Exposure to industrial chemicals as heavy metals, dyes, petroleum products, asbestos
3. MGUS:
-Approximately 19% of patients with MGUS develop multiple myeloma within 2-19 years.
4. Radiation.

Pathology.
Myeloma can be an insidious disease and can cause systemic ailments, including
1) Pancytopenia-Increased Infections,bleeding,anameia
2) Renal failure
3) Pathologic fractures
4) Spinal cord compression
5) Electrolytes abnormalities as hypercalcemia and hperuricaemia. Also kidney impairment causes other
electrolyte disturbances.
6) Hyper- viscosity
7) Amyloidosis
Pancytopenia
Expansion of a single line of plasma cells that replace normal bone marrow and produce monoclonal
immunoglobulins .Production of all the other cell lines reduced
Pathological fractures
Bony involvement typically is lytic in nature leading to secondary osteoprorosis.
Since bone loss occurs mostly in the axial skeleton, patients with myeloma are at risk for compression fractures of
the spine and pathologic fractures of the major weight-bearing bones of the body As a result, in more than 80% of
patients, the disease manifests with bone destruction and pain
Kidney pathology
Multiple myeloma affects the kidneys in several ways. The most common means of renal injury
1. Direct tubular injury by the light chain filtered-light chain nephropathy.
2. Amyloidosis of the kidney- of the light chain type.
3. Hypercalcemia may lead to metastatic calcification
4. Urate nephropathy
5. Dehydration-pre renal azotemia
6. Hperviscosity with the blockade of renal vasculature.
7. Recurrent infection of kidney-pyeonephritis.
8. Chronic use of NSAIDS may lead to nephropathy.
Hypercalcemia.
The mechanisms include bony involvement and, possibly, humoral mechanisms.
Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia.
Amyloidosis
Can involve any organ in the body and is of the light chain type.
Hyperviscosity
Due to the monoclonal hypergammaglobulinaemia may cause thrombotic events in the peripheral vessels or the
cerebral vaculature

Clinical presentation.
History:
1.Bone pain
This is the most common presenting symptom. Up to 70% of patients have bone pain at presentation.
The lumbar vertebrae are one of the most common sites of pain.
2.Pathologic fractures and bone lesions

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Pathologic fractures are very common; 93% of patients have more than one site of bony involvement.
A common presentation is a severe bony event.
3.Spinal cord compression
Back pain, weakness, numbness, or dysesthesias in the extremities.
NB.The most common cause of generalized weakness in patients with myeloma is anemia, which may be quite
severe.
4. Symptoms of pancytopenia.
Bleeding-resulting from thrombocytopenia.
In some patients, monoclonal protein may absorb clotting factors and lead to bleeding, but this development is rare.
Infection-Abnormal humoral immunity and leukopenia may lead to infection. Pneumococcal organisms are
commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common among
patients with myeloma
Anaemia-weakness, dizziness, easy fatiguability.
5.Hypercalcemia
Present with confusion, somnolence, bone pain, constipation, nausea, and thirst.
6.Hyperviscosity
Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases,
resulting in complications such as stroke, myocardial ischemia, or infarction.
Patients may report headaches and somnolence, and they may bruise easily and may have hazy vision. Patients
typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum.
7.Neurologic symptoms
Carpal tunnel syndrome is a common complication of myeloma.
Meningitis (especially resulting from pneumococcal or meningococcal infection) is more common in patients with
myeloma.
Some peripheral neuropathies have been attributed to myeloma.
8. Renal impairement.
Decreased urine production or oliguria.
Flank pains.

Physical:
1-Patients may have pallor resulting from anemia.
2-Ecchymoses or purpura resulting-thrombocytopenia.
3-Bony tenderness is common, resulting from focal lytic destructive bone lesions or pathologic fracture.
4-Neurologic findings may include a sensory level change), weakness, or carpal tunnel syndrome.
5-Extramedullary plasmacytomas, which consist of soft tissue masses of plasma cells, are not uncommon.
Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most
common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal
lesions.
6-Amyloidosis
-The shoulder pad sign is defined by bilateral swelling of the shoulder joint
-Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules.
-Macroglossia is a common finding in patients with amyloidosis.
-Skin lesions described as wax-colored papules and nodules may occur in patients with amyloidosis and are
observed most commonly on the face, lips, ears, and torso.
-Patients may develop raccoonlike dark circles around their eyes following any procedure that parallels a prolonged
Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this observation
-Hepato spenomegaly
7-Palapable kidneys-maybe tender.

Investigations
Lab Studies:
1.CBC count to determine if the patient has anemia, thrombocytopenia, or leukopenia
Also ESR.
2.Serum U/E/C
-.Serum Uric acid
3.LFT

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Serum total protein, albumin and globulin
ALP-Bone iso-enzyme normal or slight elevation.
3.Serum protein electrophoresis
Serum protein electrophoresis is used to determine the type of each protein present and may indicate a characteristic
curve (ie, where the spike is observed
4. Urine protein electrophoresis immunofixation.
Urine protein electrophoresis is used to identify the presence of the Bence Jones protein in urine
Immunofixation is used to identify the subtype of protein (ie, IgA lambda)
5.Urinalysis
-Quantification of proteinuria is useful for diagnosis (>1 g of protein in 24 h is a major criterion) and for monitoring
the patient's response to therapy.
-Creatinine clearance can be useful for defining the severity of the patient's renal impairment.
-Quantitative immunoglobulin (ie, IgG, IgA, IgM) level

6.Beta-2 microglobulin
Beta-2 microglobulin is a very strong predictor of outcome; some studies suggest it is more powerful than stage.
Surrogate marker for the overall body tumor burden.
It is increased in patients with renal insufficiency without myeloma, which is one reason that it is a useful
prognosticator in myeloma. The prognosis of patients with myeloma and impaired renal function is reduced.
7.C-reactive protein
C-reactive protein is useful for prognostication.
C-reactive protein is a surrogate marker of interleukin 6 activity. Interleukin 6 is often referred to as the plasma cell
growth factor.
8. Check serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels.
Imaging Studies:
Plain Skeletal radiograph series.
Complete skeletal series at diagnosis, including the skull the long bones and the spine.
Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent. MRI scan
-Findings from MRI scans of the vertebrae are often positive when plain radiographs are not.
-Clear view of the spinal column and to assess the integrity of the spinal cord
BMA/Biopsy
Bone marrow aspirate and biopsy samples to calculate the percent of plasma cells in the aspirate (reference range,
<3%) and to look for sheets or clusters of plasma cells in the biopsy specimen.
Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are smooth (round or
oval) in contour with clumped chromatin and have a perinuclear halo or pale zone. The cytoplasm is basophilic.
Myeloma cells have cytoplasmic inclusions, which include Mott cells, Russell bodies, grape cells, and morula cells.
Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps. This infiltration is different
from the lympho-plasmacytic infiltration observed in patients with Waldenström macroglobulinemia.
Diagnostic criteria
A minimum of 10-15% of a bone marrow aspirate demonstrating plasma cells. Plus
1. Radiographic survey demonstrating lytic lesions.
OR
2.Monoclonal immunoglobulin in the urine or blood

Durie and Salmon Classification of Multiple Myeloma

Stage I--Multiple myeloma cell mass <0.6 cells 3 1012 per m2

All of the following features are present:

1. Hemoglobin value >10 g per dL (100 g per L)

2. Serum calcium value normal (<12 mg per dL [2.99 mmol per L])
3. Normal bone structure on radiographs (grade 0) or solitary plasmacytoma only

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 4. Low M-component production rates (IgG value <50 mg per dL [0.5 g per L], IgA value <30 mg per dL
[0.3 g per L], urine light chain M component on protein electrophoresis <4 g per 24 hours)

Stage II--Multiple myeloma cell mass 0.6 to 1.2 cells 3 10 12 per m2

Features fitting neither stage I or stage III

Stage III--Multiple myeloma cell mass >1.2 cells 3 1012 per m2

One or more of the following features are present:

1. Hemoglobin value <8.5 g per dL (85 g per L)

2. Serum calcium value >12 mg per dL (2.99 mmol per L)
3. Advanced lytic bone lesions (grade 3)
4. High M-component production rates (IgG value >70 mg per dL [0.7 g per L], IgA value >50 mg per dL
[0.5 g per L], urine light chain M component on protein electrophoresis >12 g per 24 hours)

Subclassification:

A. Relatively normal renal function (serum creatinine <2 mg per dL [176 µmol per L])
B. Abnormal renal function (serum creatinine >2 mg per dL [176 µmol per L])

MANAGEMENT
Multiple myeloma is treated with several categories of medications.
Chemotherapeutic agents are used to reduce the disease burden
The regimen used most often is melphalan and prednisone (M and P).
Both drugs are typically administered by mouth for 4-7 days; the cycle is repeated every 4-6 weeks, depending on
count recovery.
Alternatively, VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin
(Adriamycin), with 4 daily oral doses of dexamethasone (Decadron)
Other drugs-IFN
-Thalidomide

Bisphosphonates
Are used to promote bone healing and to provide secondary prophylaxis against skeletal-related events (eg,
hypercalcemia, bone fracture, spinal cord compression, need for radiation, and need for surgery).
Zoledronate (Zometa) may be significantly more potent than pamidronate
Erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

MULTIPLE SCLEROSIS

Definition
-Is an inflammatory, demyelinating disease of the central nervous system (CNS)
- Patients commonly present with an individual mix of neuropsychological dysfunction, which tends to progress
over years to decades.
-The diagnosis of MS is based on a classic presentation ie
 Optic neuritis
Transverse myelitis
Internuclear ophthalmoplegia
 Paresthesias
-Plus other neurologic abnormalities

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-Typical findings on an MRI also help establish a diagnosis of MS.
-Patients with atypical presentations and/or a normal or atypical MRI may require evoked potential studies, to
uncover sub clinical neurologic abnormalities, or cerebral spinal fluid (CSF) analysis, which also serves to exclude
treatable disorders and document MS-like immune activity in the CNS.
-About 70% of patients present with the more favorable Relapsing-remitting (RR) type, which is characterized by
acute exacerbations with full or partial remissions.
-For these patients long term use of the following in management:-.
beta-interferon
 Glatiramer acetate,-a synthetic form of myelin basic protein (MBP) that has fewer side effects than
interferon.
-Both drugs cause reductions in both clinical disease activity and progression of MS lesions on MRI.
-The remaining patients present with chronic progressive MS, which is subdivided further into:-
(a) Primary-progressive (PP)
(b) Relapsing-progressive (RP) which is a pattern combining features of RR and RP and is intermediate in clinical
severity
(c) Secondary-progressive (SP)-many patients with RR progress to over time.
-Treatment for those with chronic progressive MS is less satisfying than for those with RR.
-Patients with SP type may respond to beta-interferons and sometimes low dose of methotrexate.

Pathophysiology:
-MS is regarded as an autoimmune disease
-The autoantigen in MS most likely is one of several myelin proteins eg,-Proteolipid protein [PLP]
-Myelin oligodendrocyte glycoprotein [MOG]
-MBP
-Microglial cells and macrophages perform jointly as antigen-presenting cells, resulting in activation of cytokines,
complement, and other modulators of the inflammatory process, targeting specific oligodendroglia cells and their
membrane myelin.
-The pathologic hallmark of MS is multicentric, multiphasic CNS inflammation and demyelination.
- MS lesion was thought to evolve through episodes of demyelination and remyelination into a chronic burned-out
plaque with relative preservation of axons and gliosis.
-However, axonal transections do occur during acute exacerbations and axonal injury contribute to clinical disability
-Lesions characteristically involve the following:-
 Optic nerve
Cerebellum- periventricular white matter
Brain stem
 Basal ganglia
Spinal cord
-The peripheral nervous system rarely is involved
Mortality/Morbidity:
-MS affects quality of life rather than duration of life.
-Worsening disability from any cause is strongly associated with increased mortality rate.
-Deaths attributable to MS are the result of fulminant MS, which is rare; complications from chronic disability (eg,
pneumonia, pulmonary embolism, infected decubiti); and suicide.
Race:
-MS is 5 times more prevalent in temperate climates than in the tropics,
Sex:
-Throughout adulthood the female-to-male ratio is 2:1
Age:
- MS rarely occurs in those younger than 20 years or those older than 50 years.

Clinical presentation
History:
-Exacerbations of MS are characterized by new symptoms that reflect CNS involvement.
-These symptoms typically are separated in time (eg, by months or years) and in anatomical location
-Patients who improve after acute attacks have relapsing remitting MS (RRMS).

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-However, during the natural course of RRMS, approximately 75-85% of patients enter a stage referred to as
secondary progressive MS (SPMS).
-Patients with primary progressive MS (PPMS) tend to accumulate disability without interruption (ie, without
remissions) from the time of disease onset.
-Patients with PPMS typically respond poorly to the current therapeutic options for MS, accumulate disability faster
than other patients, and tend to have more weakness of the legs as well as incontinence (a reflection of greater spinal
cord involvement).
-Patients who have RRMS but accumulate disability between and during attacks can be defined as having relapsing
progressive disease (RPMS)
Classic MS symptoms
1. Sensory loss (ie, paresthesias) usually is an early complaint
2, Motor –weakness or paralysis
3. Autonomic (eg, bladder, bowel, sexual dysfunction) spinal cord symptoms may be present.
4. Cerebellar symptoms (eg, Charcot triad of dysarthria, ataxia, and tremor) may occur.
5. Constitutional symptoms, especially fatigue (which occurs in 70% of cases) and dizziness, may be present.
6. Subjective difficulties with attention span, concentration, memory, and judgment may be noted any time during
the disease course.
7. Depression is common, but euphoria is less common.
-Over the course of the disease, 5-10% of patients develop an overt psychiatric disorder (eg, manic depression,
paranoia, major depression) or dementia.
8. Eye symptoms, including diplopia on lateral gaze, occur in 33% of patients
9. Trigeminal neuralgia may occur.
Optic neuritis (ON)
-Inflammation or demyelination of optic nerve is the initial presentation of 15% of patients with MS.
- Acute onset (ie, occurring over minutes or hours, rarely days) of single eye visual blurring, decreased acuity (ie,
usually scotoma), decreased color perception, and/or discomfort of the moving eye(s) are symptoms that are
indicative of ON.
-The 3 phenomena associated with ON or compressive/ ischemic neuritis are as follows:
a) Phosphenes, or flashes of light, usually are precipitated by eye movements.
b) Uhthoff phenomenon or deterioration of vision is induced by exercise, a hot meal, or a hot bath.
c) The Pulfrich effect occurs when latencies between the eyes are unequal, resulting in a sense of disorientation in
moving traffic.
Physical examination
-Classic MS findings on neurologic examination include the following:
Eye-Optic neuritis
-Acutely, retrobulbar involvement; hence, funduscopy results are normal. "The patient sees nothing and the doctor
sees nothing."
-When inflammation involving the retina is extensive, look for presence of a macular star
-After several weeks, optic atrophy may be seen
-An afferent pupillary defect may be seen in the affected eye.
-Visual acuity usually is impaired (ie, subtle to total blindness)
-The classic finding is bilateral internuclear ophthalmoplegia (INO), a lesion in the median longitudinal fasciculus
(MLF) resulting in a weakness in adduction of the ipsilateral eye with nystagmus on abduction of the contralateral
eye, an incomplete or slow abduction of the ipsilateral eye upon lateral gaze, with complete preservation of
convergence
-Other eye findings include abnormal pupillary responses, acquired pendular nystagmus or sinusoidal involuntary
oscillations of one or both eyes, and/or loss of smooth eye pursuit
-Regardless of the stage or classification, most authorities question the diagnosis of MS in a patient without at least
one of these findings.
Spinal cord involvement
-Sphincter paralysis and unchanging level
-Distinguish from Guillain-Barré syndrome
-Paralysis, spasticity, and hyperreflexia are indicative of upper motor neuron dysfunction (ie, lateral corticospinal
tracts).
-Decreased joint position and vibration sense (ie, dorsal columns) are common findings

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-Decreased pain and temperature (ie, lateral spinothalamic tracts) are less common. The sparing of these symptoms
may be diagnostically helpful
-The degree of corticospinal tract findings tends to correlate with bladder, bowel, and sexual dysautonomias.
Cerebellar findings:
- Disequilibrium, truncal or limb ataxia, scanning (ie, monotonous) speech, intention tremor, and saccadic dysmetria
are common cerebellar findings.
-Lhermitte sign: - Neck flexion results in an electric shocklike feeling in the torso or extremities
Acute transverse myelitis
-Strongly consider mechanical compression in the differential diagnosis
-Acute partial loss of motor, sensory, autonomic, reflex, and sphincter function below the level of the lesion
indicates acute transverse myelitis.
-Devic syndrome is acute transverse myelitis accompanied by bilateral ON.
Acute disseminated encephalitis
-Most commonly, altered mental status and/or personality changes
-Focal findings (eg, cranial nerve defects, hemiparesis, focal seizures, autonomic dysfunction)
-Cranial nerve defects
-Ataxia
-Dysphasia
-Meningismus, usually less common and pronounced than in meningitis
-Unusual findings in MS include the absence of eye findings and isolated motor, sensory, cerebellar, and cranial
nerve lesions.
Causes:
-Believed to result from an autoimmune process.
-This has both genetic and environmental cause of the immune dysregualtion.
-Environmental-human herpesvirus-6 (HHV-6) variant B group 2, while others implicate Chlamydia pneumonia.
-Polygene inheritance accounts for a familial rate of 10-20%;

DDX
1. Amyotrophic Lateral Sclerosis
2. Guillain-Barré Syndrome
3. HIV Infection and AIDS
4. Lumbar (Intervertebral) Disk Disorders
5. Sarcoidosis
6. Spinal Cord Infections espTB
7. Spinal Cord Injuries
8. Spinal cord tumour
9. Stroke, Hemorrhagic
10. Stroke, Ischemic
11. Subdural Hematoma
12. Syphilis
13. Systemic Lupus Erythematosus
14. Tick-Borne Diseases, Lyme
15. Transient Ischemic Attack
16. Trigeminal Neuralgia

Investigations
Lab Studies:
-Baselines and R/o Infections, tumours
1. Tests for B-12 and folate levels or evidence of subacute combined degeneration of the spinal cord
2. Antinuclear antibody (ANA) titers.
3. Antiphospholipid antibody syndrome-DVT as well. This syndrome is typically assessed with blood tests for the
following: anticardiolipin, anti-beta2 glycoprotein I, and antiprothrombin antibodies.
4. An elevated erythrocyte sedimentation rate (ESR) and positive titers of rheumatoid factor (RF) should help
identify the presence of a vasculitic disorder that may be mimicking MS.
5. If patients come from an endemic region for Lyme disease or have been exposed to tick bites, the physician
should check Lyme titers.

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Management
1. Supportive
-Skin care
-Sphincter care
-Nutrition
-Chest physiotherapy
-DVT prophylaxis
2. Seek and treat the acute precipitating factor
-Infections
-Metabolic abnormality
3. Acute exacerbations
-The most widely used treatment is intravenous (IV) methylprednisolone, 1g IV qid for 3-5 days. This medication
may help expedite the timing of recovery but will not affect the actual degree of recovery.
4. RR type-long term management with beta-interferons and Glatiramer acetate

MYOCARDIAL INFARCTION
Definition
-Myocardial infarction (MI) is the necrosis of heart muscle secondary to prolonged ischemia.
-This usually results from an imbalance of oxygen supply and demand.
Background
-MI is considered, part of a spectrum referred to as acute coronary syndromes (ACSs), which also include unstable
angina, ST elevation MI (STEMI) and non–ST-elevation MI (NSTEMI).
-Patients with ischemic discomfort may or may not have ST-segment elevation. Most of those with ST-segment
elevation will develop Q waves. Those without ST elevations will ultimately be diagnosed with unstable angina or
NSTEMI based on the presence of cardiac enzymes.
-MI may lead to impairment of systolic function or diastolic function and to increased predisposition to arrhythmias
and other long-term complications.
Pathophysiology
-Acute MI occurs due to ischemia of the myocardial due to the perfusion /oxygen demand mismatch.
-In majority of case this is due to coronary artery disease>90% of cases.
-AMI due coronary artery disease generally occurs when coronary blood flow decreases abruptly after a thrombotic
occlusion of a coronary artery previously narrowed by atherosclerosis.
-Slowly developing, high-grade coronary artery stenoses usually do not precipitate AMI because of development of
a rich collateral network over time.
-AMI occurs when a coronary artery thrombus develops over atherosclerotic plaque when it fissures, ruptures, or
ulcerates leading to platelet activation and aggregation, coagulation pathway activation, and endothelial
vasoconstriction occur and lead to coronary thrombosis and occlusion.
-This injury is produced or facilitated by factors such as
cigarette smoking
 Hypertension
 Lipid accumulation.
-Atherosclerotic plaques prone to rupture are those with a rich lipid core and a thin fibrous cap
-After an initial platelet monolayer forms at the site of the ruptured plaque, various agonists (collagen, ADP,
epinephrine, serotonin) promote platelet activation. Platelets also release of thromboxane A 2 cause further
vasoconstrictor, further platelet activation vicious cycle propagate occlusion.
-. Total occlusion of the vessel for more than 4-6 hours results in irreversible myocardial necrosis, but reperfusion
within this period can salvage the myocardium and reduce morbidity and mortality

- Non-atherosclerotic causes of MI include

Coronary vasospasm as seen in variant (Prinzmetal) angina
 Patients using cocaine and amphetamines
 Coronary emboli from sources such as an infected heart valve
 Occlusion of the coronaries due to vasculitis

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  Other causes leading to mismatch of oxygen supply and demand, such as acute anemia from GI bleeding
 MI induced by chest trauma has also been reported, usually following severe chest trauma such as motor
vehicle accidents and sports injuries.
-The amount of myocardial damage caused by coronary occlusion depends on
(1) Territory supplied by the affected vessel
(2) Degree of occlusion of vessel
(3) Duration of coronary occlusion
(4) Presence of collateral blood supply.
(5) Demand for oxygen of the myocardium whose blood supply has been suddenly limited
(6) Native factors that can produce early spontaneous lysis of the occlusive thrombus
(7Adequacy of myocardial perfusion in the infarct zone when flow is restored in the occluded epicardial coronary
artery.
Frequency
-MI is a leading cause of morbidity and mortality in the United States
-There has been a progressive increase in the proportion of patients who are diagnosed with NSTEMI compared
with STEMI.
-MI continues to be a significant problem in industrialized countries and is becoming an increasingly significant
problem in developing countries
Mortality
-One third of patients who experience STEMI will die within 24 hours of the onset of ischemia and many of the
survivors will suffer significant morbidity.
-For many patients, the first manifestation of coronary artery disease is sudden death likely from malignant
ventricular dysrhythmia.
-More than one half of deaths occur in the prehospital setting.
-In-hospital fatalities account for 10% of all deaths. An additional 10% of deaths occur in the first year
postinfarction.

Sex:
-Male predilection before onset of menopause.
-After menopause the risk is almost equal but woman have worse prognosis because of atypical presentation.
Age:
-MI occurs most frequently in persons older than 45 years. Certain subpopulations younger than 45 years are at risk,
Cocaine and amphetamine abusers.
 Insulin-dependent diabetics
 Patients with hypercholesterolemia
 Positive family history for early coronary disease
Risk factors for MI
-Same as risk factors for atherosclerosis
-Major non-modifiable factors
Sex
 Age
 Family history
-Major Modifiable factors
DM
 Cigarette smoking
 HTN
 Hyperlipidaemia
-Minor factors-Diet, obesity, relative inactivity, homocyteine, low HDL, Post menopausal women, impaired
fibrinolysis, Chlamydia infection, Stress

-Other immediate risk factors are those with

Unstable angina
 Prinzmetal's variant angina
-Less common underlying medical conditions predisposing patients to AMI include:
 Hypercoagulability
Collagen vascular disease

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 Cocaine abuse
 Intracardiac thrombi or masses that can produce coronary emboli.
Clinical presentation
-In up to one-half of cases, a precipitating factor appears to be present before AMI
Vigorous physical exercise
 Emotional stress
 Medical or surgical illness
-Although AMI may commence at any time of the day or night, circadian variations have been reported such that
clusters are seen in the morning within a few hours of awakening. The increased frequency early in the day may be
due to a combination of an increase in sympathetic tone and an increased tendency to thrombosis between 6:00
A.M. and 12 noons.
Symptoms
1. Chest pain
-Most common presenting complaint. May be described as the worst pain the patient has ever felt. Prolonged chest
discomfort lasting longer than 30 minutes is most compatible with infarction
-The pain is deep and described it are heavy, squeezing, and crushing, sometimes may be stabbing or burning
-It is similar in character to the discomfort of angina pectoris but usually is more severe and lasts longer.
-Typically the pain is retro sternal and/or the epigastrium may radiate to left arm. Less common sites of radiation
include the abdomen, back, lower jaw, and neck
-The pain of AMI may radiate as high as the occipital area but not below the umbilicus.
- The pain may commence when the patient is at rest.
-When the pain begins during a period of exertion, it does not usually subside with cessation of activity, in contrast
to angina pectoris.
2. Dyspnea
- may accompany chest pain or occur as an isolated complaint, indicates poor ventricular compliance in the setting
of acute ischemia.
-Dyspnea may be the patient's anginal equivalent, and in an elderly person or the diabetic patient, it may be the only
complaint.
3. Nausea
-Nausea with or without vomiting, abdominal pain often are present in infarcts involving the inferior or posterior
wall.
4. Anxiety
5. Lightheadedness with or without syncope
6. Cough
7. Diaphoresis
8. Wheezing
-Elderly patients and those with diabetes may have particularly subtle presentations and may complain of
Sudden-onset breathlessness, which may progress to pulmonary edema
 Sudden loss of consciousness
 Confusional state
 Sensation of profound weakness
 Sudden death
-As many as half of MIs are clinically silent in that they do not cause the classic symptoms described above and
consequently go unrecognized by the patient.
Physical examination
-The physical examination can often be unremarkable.
-Patients with ongoing symptoms usually will lie quietly in bed and appear pale and diaphoretic.
-Hypertension may precipitate MI or it may reflect elevated catecholamines due to anxiety, pain, or exogenous
sympathomimetics.
-Hypotension may indicate ventricular dysfunction due to ischemia. Hypotension in the setting of MI usually
indicates a large infarct secondary to either decreased global cardiac contractility or a right ventricular infarct.
-Acute valvular dysfunction may be present. Valvular dysfunction usually results from infarction that involves the
papillary muscle. Mitral regurgitation due to papillary muscle ischemia or necrosis may be present.
-Rales may represent congestive heart failure.
-Neck vein distention may represent pump failure. With right ventricular failure, cannon jugular venous a waves
may be noted.

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-Third heart sound may be present (S3)
-Fourth heart sound (S4) sound is a common finding in patients with poor ventricular compliance that is due to a
preexisting heart disease or hypertension.
-Dysrhythmias may present as an irregular heart beat or pulse.
-Low-grade fever is not uncommon.

Etiology
-The most frequent cause of MI is rupture of an atherosclerotic plaque within a coronary artery with subsequent
arterial spasm and thrombus formation.
Other causes include the following:
1-Coronary artery vasospasm
2-Ventricular hypertrophy (eg, left ventricular hypertrophy 3-[LVH], idiopathic hypertrophic subaortic stenosis
[IHSS], underlying valve disease)
4-Hypoxia due to carbon monoxide poisoning or acute pulmonary disorders (Infarcts due to pulmonary disease
usually occur when demand on the myocardium dramatically increases relative to the available blood supply.)
5-Coronary artery emboli, secondary to cholesterol, air, vegetations from damaged valves
6-Drugs-Cocaine, amphetamines, and ephedrine
7-Arteritis
8-Coronary anomalies, including aneurysms of the coronary arteries
9-Increased afterload or inotropic effects, which increase the demand on the myocardium
10-Aortic dissection, with retrograde involvement of the coronary arteries
11-Although rare, pediatric coronary artery disease may be seen with Marfan syndrome, Kawasaki disease,
Takayasu arteritis, progeria, and cystic medial necrosis
DDx
1. Respiratory
 Pneumothorax, Pneumomediastinum
Pulmonary Embolism
Pneumonia
 Pulmonary oedema
Chronic Obstructive Pulmonary Diseases
2. Other heart problems.
 Acute Coronary Syndrome –Unstable angina
Congestive Heart Failure
Dissection, Aortic
 Pericarditis
Myocarditis
Cardiac tamponade
 Aortic Stenosis
 Mitral Regurgitation
 Shock, Cardiogenic
3. GastroEsophageal
 Esophageal spasm
Esophagitis
GERD
 Gastroenteritis
4. Pancreatobiliary systems
 Pancreatitis
Cholecystitis and Biliary Colic
Cholelithiasis
5. Chestwall
 Costochondritis
Investigations
Lab Studies:
1) Cardiac enzymes
a) Troponin I and T
begin to rise 4-8 hours after an MI

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  peak 12 - 24 hours
 remain elevated for up to 14days
-The preferred biomarker for diagnosis.Troponins has the greatest sensitivity and specificity in detecting MI.
-The test result is both diagnostic as well as prognostic of outcome.
- Troponin is a complex of three proteins on the thin filaments of skeletal and cardiac muscle fibers. During muscle
contraction the troponin complex regulates the interaction between the thick and thin filaments.
-This complex consists of troponin T (TnT), troponin I (TnI) and troponin C (TnC). Troponin C is identical in
skeletal and cardiac muscle, but the amino acid sequences of troponin T and troponin I found in cardiac muscle is
different from that of the troponins in skeletal muscle.
-These isoforms of cardiac troponins, cTnT and cTnI, are very specific to cardiac muscle and their presence in blood
indicates cardiac tissue necrosis. Because of this specificity, cardiac troponin T or I is now the preferred cardiac
marker
-For early detection of myocardial necrosis, sensitivity of this laboratory test is superior to that of the CK-MB.
b) CK and Creatine kinase–MB (CK-MB)
begin to rise within 6-10 hours after injury
 Peak at 18-24 hours
 subside over 72 hours
-A level within the reference range does not exclude myocardial necrosis.
NB.CK-has two subunits, B (brain) and M (muscle) combine to form 3 isoenzymes of CK: CK-MM (CK-1), CK-
MB (CK-2), CK-BB (CK-3). Elevations in total CK activity occur in conditions affecting brain, skeletal muscle, and
heart muscle. CK-MB (CK-2) is found almost entirely in myocardial tissue and elevations of this isoenzyme more
specific for MI.
-Occasionally, very small infarcts can be missed by CK-MB; therefore, a troponin level should be measured for
patients suspected of having had MI who have negative serial CK-MBs.
c) Myoglobin
-Blood levels of myoglobin become
Elevated within 2 hours of an MI
 Peak within 4-10 hours
 Return to normal within 24 hours
-Levels rise early in the course of MI. Has emerged as an ideal early marker.
-Myoglobin, a low-molecular-weight heme protein found in cardiac and skeletal muscle, is released more rapidly
from infarcted myocardium than troponin and CK-MB and may be detected as early as 2 hours after MI.
-The marker has high sensitivity but poor specificity.
- Thus, its presence is not diagnostic of MI, but it still has utility in the early triage of chest pain patients.
-When performed in conjunction with other studies, it may be useful for the early detection of MI. and detection of
any recurrences of MI.
d) Serum lactate dehydrogenase (LDH) level rises above the reference range within 24 hours of MI, reaches a
peak within 3-6 days, and returns to the baseline within 8-12 days.
Other Lab Test
1. Complete blood count
-Anemia is suspected as a precipitant. Transfusion with packed red blood cells may be indicated.
-Leukocytosis may be observed within several hours after an AMI. It peaks in 2-4 days and returns to levels within
the reference range within 1 week.
2. Urea/Electrolytes /Creatinine
-Potassium and magnesium levels should be monitored and corrected. Potassium imbalances especially hypokalemia
predispose to arrhythmia
-Creatinine levels must be considered before using an angiotensin-converting enzyme (ACE) inhibitor.
3. C-reactive protein (CRP) and ESR
-C-reactive protein marker of acute inflammation. Patients without biochemical evidence of myocardial necrosis but
with elevated CRP are at increased risk of a subsequent ischemic event.
-ESR rises above reference range values within 3 days and may remain elevated for weeks.
Imaging Studies:
a) CXR
-Chest radiography may provide clues to an alternative or complicating diagnosis eg, aortic dissection,
pneumothorax.
-Complications of MI such as pulmonary edema secondary to heart failure.

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b) Echocardiography
-Wall motion abnormalities and overall ventricular function.
-Echocardiography also can identify complications of MI (eg, valvular insufficiency, ventricular dysfunction,
pericardial effusion).
c) Technetium-99m sestamibi scan
-Technetium-99m is a radioisotope that is taken up by the myocardium in proportion to the blood flow and is only
minimally redistributed after initial uptake. This allows for time delay between injection of the isotope and imaging.
-It has potential use in identifying infarct in patients with atypical presentations or in patients with ECGs that are not
interpretable.
d) ECG
-Results indicating high probability of MI:
ST-segment elevation greater than 1 mm in 2 anatomically contiguous leads
 Presence of new Q waves.
-Results indicating intermediate probability of MI
ST-segment depression
 T-wave inversion
 Other nonspecific ST-T wave abnormalities.
-Results indicating low probability of MI are normal findings on ECG; however, normal or nonspecific findings on
ECG do not exclude the possibility of MI.
-Localization of MI based on distribution of ECG abnormalities is as follows:
 Inferior wall - II, III, aVF
Lateral wall - I, aVL, V4-V6
Anteroseptal - V1-V3
 Anterolateral - V1-V6
Right ventricular - RV4, RV5
Posterior wall - R/S ratio >1 in V1 and V2; T-wave changes (ie, upright) in V1, V8, and V9
Procedures:
-Percutaneous coronary interventions (PCIs) are a group of catheter-based technologies used to establish coronary
reperfusion.
-Angiography provides essential knowledge of the extent of coronary disease, and is performed prior to PCI.
- PCI may then be performed as a primary intervention or due to failure of thrombolysis.
-Evidence suggests that primary PCI is more effective than thrombolysis. They have fewer bleeding complications
and less recurrent ischemia when compared with thrombolysis. PCI restores coronary artery patency in more than
90% of patients
-Percutaneous transluminal coronary angioplasty (PTCA) (balloon angioplasty) is the primary therapeutic modality
used at centers where it can provide reperfusion as quickly as fibrinolytic therapy.
-Coronary artery bypass graft may be indicated based on angiographic findings.

MANAGEMENT
-Initial therapy for acute MI is directed toward restoration of perfusion in order to salvage as much of the
jeopardized myocardium as possible. This may be accomplished through medical or mechanical means, such as
angioplasty or coronary artery bypass grafting.
-Further treatment is aimed at:
(1) Restoration of the balance between the oxygen supply and demand to prevent further ischemia
(2) Pain relief
(3) Prevention and treatment of complications
1. Oxygen
-Supplemental oxygen should be administered to all patients especially with arterial oxygen desaturation (SaO2 less
than 90%).
2. Analgesia-Morphine
-Morphine sulfate (2 to 4 mg IV with increments of 2 to 8 mg IV repeated at 5- to 15-minute intervals) is the
analgesic of choice for management of pain associated with STEMI. It also relieves anxiety
3. Aspirin and anti-platelets
-Aspirin should be chewed by patients who have not taken aspirin before presentation with STEMI. The initial dose
should be 162 mg to 325 mg.
-In a dose of 162 mg or more, aspirin produces a rapid clinical antithrombotic effect caused by immediate and near-

195
total inhibition of thromboxane A2 production. Aspirin now forms part of the early management of all patients with
suspected STEMI and should be given promptly, and certainly within the first 24 hours, at a dose between 162 and
325 mg and continued indefinitely at a daily dose of 75 to 162 mg
-Use clopidogrel (Plavix) in case of aspirin allergy.

Other anti-platelets
-Administer a platelet glycoprotein (GP) IIb/IIIa-receptor antagonist
Eptifibatide
 Tirofiban
 Abciximab
-In addition to aspirin and unfractionated heparin, above drugs given to patients with continuing ischemia or with
other high-risk features and to patients in whom PCI is planned.
-The addition of IV platelet glycoprotein (GP) IIb/IIIa-receptor antagonists to aspirin and heparin improves both
early and late outcomes, including mortality, Q-wave MI, need for revascularization procedures, and length of
hospital stay
4. Nitrates-Nitroglycerin
-Patients with ongoing ischemic discomfort should receive sublingual nitroglycerin (0.4 mg) every 5 minutes for a
total of 3 doses, after which an assessment should be made about the need for intravenous nitroglycerin.
-Intravenous nitroglycerin is indicated for relief of ongoing ischemic discomfort, control of hypertension, or
management of pulmonary congestion.
NB. Contra. SBP less than 90 mm Hg, severe bradycardia (less than 50 bpm), tachycardia (more than 100 bpm), or
suspected RV infarction.
-Contra. Patients who have received a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours
(48 hours for tadalafil).
5. Beta-Blockers
-It is reasonable to administer IV beta-blockers promptly to STEMI patients without contraindications, especially if
a tachyarrhythmia or hypertension is present.
-Beta-blockers reduce the rates of reinfarction and recurrent ischemia and possibly reduce the mortality rate if
administered within 12 hours after MI. Administer routinely to all patients with MI unless a contraindication is
present
-Immediate beta-blocker therapy appears to reduce the magnitude of infarction and incidence of associated
complications in subjects not receiving concomitant fibrinolytic therapy, the rate of reinfarction in patients receiving
fibrinolytic therapy, and the frequency of life-threatening ventricular tachyarrhythmias
Eg-Metoprolol
-Esmolol
-Atenolol
6) ACE inhibitors-Enalapril,Captopril
-Reduce mortality rates after MI.
-They reduce post infarction heart remodeling. Administer ACE inhibitors as soon as possible as long as the patient
has no contraindications and remains in stable condition.
-ACE inhibitors have the greatest benefit in patients with ventricular dysfunction.
-Continue ACE inhibitors indefinitely after MI.
-Angiotensin-receptor blockers may be used as an alternative in patients who develop adverse effects, such as a
persistent cough
7.) Thrombolytic therapy
-Has been shown to improve survival rates in patients with acute MI if administered in a timely fashion in the
appropriate group of patients.
-If PCI capability is not available or will cause a delay greater than 90 minutes, then the optimal approach is to
administer thrombolytics within 12 hours of onset of symptoms in patients with ST-segment elevation greater than
0.1 mV in 2 or more contiguous ECG leads, new left bundle-branch block (LBBB), or anterior ST depression
consistent with posterior infarction.
-Tissue plasminogen activator (t-PA) is superior to streptokinase in achieving a higher rate of coronary artery
patency; however, the key to efficacy lies in the speed of the delivery of therapy.
-High patency rate is achieved if platelet glycoprotein IIb/IIIa receptor antagonist is combined with a half dose of
thrombolytic agent as the initial reperfusion strategy.
Streptokinase

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-Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots, as well as fibrinogen and
other plasma proteins. Non-specific acts on both the free and fibrin bound plasminogen.
-Increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h occurs with IV infusion of streptokinase
Adjunctive therapy with heparin not needed.
-Dose-1.5 million IU over1I hour IV infusion.
-Local delivery by catheter admin 10,000-25000 IU loading dose then 4000IU/min up to 75 minutes during
angiography.
NB.For peripheral arterial occlusion admin loading dose IV infusion of 250,000 IU then 100,000 IU per hour for 1-3
days
Anistreplase
(Anisoylated Plasminogen- Streptokinase activator Complex)
-Non–fibrin-specific agent that activates conversion of plasminogen to plasmin and has half-life of 90 min.
However, does not have any benefit over streptokinase, although has higher rate of allergic and bleeding
complications. Easier to administer than t-PA, has lower cost and does not require heparinization.
-Dose- 30 IU over 2-5 min
-Other non-specific thrombolytic is Urokinase-human enzyme from the kidney.

Alteplase, t-PA
-Fibrin-specific agent with brief half-life of 5 min. Adjunctive therapy with IV heparin necessary to maintain
patency of arteries recanalized by t-PA, especially during first 24-48 h.
-Dose-15 mg IV initial bolus, followed by 50 mg IV over next 30 min, and then 35 mg IV over next h; total dose not
to exceed 100 mg
Reteplase
-Recombinant plasminogen activator that forms plasmin after facilitating cleavage of endogenous plasminogen.
Heparin and aspirin usually administered concomitantly and after reteplase
-Dose-10 IU IV over 2 min, followed by second 10-IU IV dose after 30 min.
8) Anticoagulation
-Only required with admin of specific fibrinolytic-Alteplase, Reteplase, Tenectaplase.
-Unfractionated Heparin –10,000 IU TID
-Fractionated -LMW- Enoxaparin (Lovenox) -- Enhances inhibition of factor Xa and thrombin by increasing
antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Dose- 1 mg/kg SC bid

Discharge medications and lifestyle modification

1. The long-term use of aspirin in patients who have had an MI results in significant reduction in subsequent
mortality rate.
2. Beta-blocker therapy has confirmed therapeutic benefit in survivors of acute MI. This therapy is most beneficial
in patients with the highest risk.
3. ACE inhibitor use in patients with known CAD has been shown to reduce mortality rate.
4. Lipid-lowering therapy in the secondary and primary prevention of CAD -Atorvastatin.
5. Smoking cessation
-Risk of recurrent coronary events decreases 50% at 1 year after smoking cessation
-Bupropion has been shown to increase the chances of patients' success in achieving smoking cessation.
6. Alcohol consumption-Reduce excess use
7. Antioxidant therapy, including vitamin E, has not shown clear benefit in the prevention of coronary events.
NB. Long-term anticoagulant (ie, warfarin) therapy is not routinely used in post-MI patients but as an alternative
in patients who cannot take antiplatelet agents.
-Patients with known LV thrombus, atrial fibrillation, or severe wall motion abnormalities have shown benefit from
long-term anticoagulation, maintaining the international normalized ratio (INR) between 2 and 3.

Complications:
1. Arrhythmia
-Close monitoring and immediate treatment of arrhythmias may be the most important part of the treatment of a
post-MI patient within the first 48 hours.
-Exacerbating factors, such as electrolyte disturbances (especially potassium and magnesium), hypoxemia, drugs, or
acidosis, and correct them accordingly.

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NEPHROTIC SYNDROME
Definition
-The syndrome is characterized by
1) Proteinuria
2) Hypoalbuminemia
3) Edema
4) hyperlipidaemia
5) Lipiduria
6) Hypercoagulability
-Key component of the syndrome is Proteinuria
Defined as: > 3.5g/1.73m2/24 hrs
But in Practice: > 3.0 – 3.5g/24 hrs
-Other components of the syndrome and metabolic complications are all secondary to proteinuria :-
-The kidney function is often normal
-Hypoalbuminaemia (albumin <25g/L)
-Oedema
-EMU Protein: creatinine ratio (>200mg/mmol) * more accurate (EMU early morning urine)
Pathogenesis
-Ventricular fibrillation and/or ventricular tachycardia occurring within the first 48 hours may be due to ischemia; -
Immediate cardio version is the treatment of choice
2. CCF can be due to systolic dysfunction or diastolic dysfunction in the setting of MI.
3. Valve dysfunction due to damage of chordae tendinae.
4. Ventricular rapture
5. Ventricluar septal defects with communication.
6. Thrombus formation over the infarction or due to arrhythmia. (Mural thrombi).
7. Pericarditis
8. Ventricular aneurysm.
9. Recurrent MI

Proteinuria
-Due to increase in glomerular permeability and not to a decrease in tubular reabsorption of filtered
plasma proteins. Albumin is the main constituent of urinary protein
-By definition, the urinary protein excretion exceeds 3 g/1.73 m 2/day
-This influenced by glomerular filtration rate, the plasma concentration of albumin, and dietary protein
intake.
-Thus a high protein intake in nephrotic patients leads to an increase in proteinuria and albumin
synthesis. Recently, it has been shown that nonsteroidal anti-inflammatory agents as well as angiotensin-
converting enzyme inhibitors may decrease the proteinuria.
-Other plasma proteins lost in urine include-
 Peptide hormones
 Clotting inhibitors eg anti-thrombin factor III ,Protein C and S
 Transferrin
 Hormone-carrying proteins.-transporter protein.
-Highly selective proteinuria has been defined as clearance of molecules similar to albumin (66,000
daltons), transferrin (88,000 daltons), and small amounts of gamma globulins (150,000 daltons), and
exclusion from urine of higher molecular weight plasma proteins.
-In patients with lesser degrees of selectivity, there is clearances of larger globulins eg alpha 2-
macroglobulin.
Edema
-The hypoalbuminemia leads to a decrease in plasma oncotic pressure, which results in an imbalance of
Starling forces at the level of the peripheral capillaries.
-At the arteriolar end, the hydrostatic pressure within the capillary exceeds the oncotic pressure, leading
to an egress of fluid into the interstitial space.
-Intravascular volume falls, thereby stimulating activation of the renin-angiotensin-aldosterone axis and
the sympathetic nervous system and release of vasopressin (antidiuretic hormone), and suppressing
atrial natriuretic peptide release. These neural and hormonal responses promote renal salt and water
retention, thereby restoring intravascular volume and triggering further leakage of fluid to the interstitium
-However, primary renal salt and water retention may also contribute to edema formation in some cases.
-Ascitis may also occur due to the generalized fluid retention:
-It may be associated with:
-Venous Dilation – of abdominal wall

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 -Umbilical hernia
-Rectal prolapse
-↑ Respiratory difficulty
-Scrotal/labial pain
-Anasarca
Hyperlipidemia
-Due increased hepatic lipoprotein synthesis that is triggered by reduced oncotic pressure
-LDL and cholesterol are increased in the majority of patients, whereas VLDL and triglycerides tend to rise in
patients with severe disease.
–Abnormal lipid metabolism due to the loss of lipoprotein C may be contributor.
-Hyperlipidemia may accelerate atherosclerosis and progression of renal disease.
Hypercoagulability
-multifactorial in origin:-
1-Increased urinary loss of antithrombin III, proteins C and S (natural anti-coagulants)
2-Increased clotting factors synthesis by the liver- Fibrinogen and Factors V, VII, VIII, X
3-Impaired fibrinolysis
4-Increased platelet aggregability and thrombocytosis
5-Accelerated thromboplastin generation
6-Hypovolaemia
-As a consequence of these perturbations, patients can develop spontaneous peripheral arterial or venous
thrombosis, renal vein thrombosis, and pulmonary embolism.
-Clinical features that suggest acute renal vein thrombosis include:-
 Sudden onset of flank or abdominal pain
 Gross hematuria
 Left-sided varicocele (the left testicular vein drains into the renal vein)
 Increased proteinuria
 Acute decline in GFR.
-Chronic renal vein thrombosis is usually asymptomatic. Renal vein thrombosis is particularly common (up to 40%)
in patients with nephrotic syndrome due to membranous glomerulopathy, membranoproliferative
glomerulonephritis, and amyloidosis.
Other complications include:-
1) Protein calorie malnutrition with Growth and developmental delays in children.
2) Iron-resistant microcytic hypochromic anemia due to transferrin loss and also due to decreased erythropoietin
from kidneys.
3) Hypocalcaemia and secondary hyperparathyroidism can occur as a consequence of vitamin D deficiency due
to enhanced urinary excretion of cholecalciferol-binding protein
4) Loss of thyroxine-binding globulin can result in depressed thyroxine levels.
5) An increased susceptibility to infection may reflect low levels of IgG that result from urinary loss and
increased catabolism.
6) Unpredictable changes in the pharmacokinetics of therapeutic agents that are normally bound to plasma
proteins.
7) Renal failure- due do progression of the renal involvement or due to volume depletion and the inappropriate
increase in angiotensin II
8) Hypovolemia-fluid loss into the interstitium
9) Hypertension-Renin angiotensin aldosterone system stimulated to hypovolemia
Primary Nephrotic Syndrome(Idiopathic)
1. Minimal change GN The most common cause (80%) of nephrotic syndrome in children
2. Membranous GN-The most common primary renal cause of nephrotic syndrome in adults in developing countries.
3. Focal segmental Glomerulosclerosis
4. Rapidly progressive GN
5. MembranoProliferative GN
6. IgA glomerulopathy
Secondary Nephrotic Syndrome
a). Metabolic diseases:
-Diabetes mellitus is the most common cause of secondary nephrotic syndrome in adults in developing countries;
amyloidosis

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b). Autoimmune diseases:
-SLE, Henoch-Schonlein purpura, vasculitides, Sarcoidosis
C). Malignancies
1. Solid tumors (kidney malignancy, colorectal)
2. Lymphomas and leukemia
3. Multiple myeloma
d). Infections
1. Bacterial-Post streptococcal GN, Endocarditis, syphyllis, TB
2. Protozoal-malaria, toxoplasmosis
3. Viral-CMV, hepatitis B and C, HIV, EBV
4. Fungal-Candida
5. Helminthic-Schistosomiasis, Trypanisomiasis , leishmaniasis
e). Drugs
-Penicillamine, mephenytoin, Trimethadione, Probenicid
-Heavy metals- gold, mercury
f). Hereditary causes
-Alports syndrome
-Congenital nephritic syndrome
-Nail-patella syndrome
.-Sickle cell disease
CLINICAL PRESENTATION
History
-Swelling of the face; periorbital edema is a common presentation. Then other dependent areas as the
feet and ankle.
-This is followed by swelling of the entire body-anasarca can be the presenting symptom.
-In certain instances, patients notice frothy urine, which leads to investigations that reveal evidence of
nephrotic syndrome.
-A hypercoagulable state leading to thrombotic complications, such as deep vein thrombosis of the calf
veins or the renal vein, may be the first clue indicating nephrotic syndrome.
History suggestive of predisposing factors
- History of acute or chronic infections, drugs, allergies, systemic symptoms (vasculitis, malignancy)
-HTN, DM
-Malaria treatment, risk for schistosomiasis
-Connective tissue disease-rash, joint pains and any pains in muscles
-Recurrent sore throat, or skin ulcers or swellings
-Wt loss, night sweat and general fatigue-malignancy
-Sickle cell disease
-Blood transfusions
-Any sexually transmitted infections.
Familial history
-DDX-R/ o hx suggestive Cardiac dz, liver dz.
Physical:
-Patients present with increasing edema over a few days or weeks, lethargy, poor appetite, weakness, and occasional
abdominal pain.
-The initial episode and the subsequent relapses may follow an apparent viral upper respiratory tract infection.
-Edema is the predominant feature and initially develops around the eyes and lower extremities. With time, the
edema becomes generalized and may be associated with an increase in weight, the development of an ascitic or
pleural effusion, and a decline in urine output.
-Hematuria and hypertension are unusual but manifest in a minority of patients.
- Xanthelasma and Xanthomata - Widespread yellow nodules or plaques, especially of the skin, composed of lipid-
laden histiocytes, especially on the elbows and knees.
Investigations
a). Lab Studies:
1. Urinalysis
 The ratio of urinary protein to urinary creatinine
 24-hour protein excretion

200
  Hematuria
 UTI-Nitrites
 Determination of light-chain protein excretion.
-Proteinuria-Adults excrete up to 150 mg/d.
-Spot proteinuria >1g/L
-Urinary protein to urinary creatinine ratio >200mg/mmol or ratio of urinary protein to urinary creatinine of greater
than 2 when using creatinine in mg/dl.
-A quantitative estimation of 24-hour urine protein excretion is the standard method, but EMU testing and
determining the ratio of urinary protein to urinary creatinine is the method of choice for proteinuria quantification.
2. Blood
-FBC and ESR
-U/E/C
-LFT-serum albumin
-Fasting Serum lipids and differential and
-Random Blood sugar.
3. Screen
-Hepatitis B and hepatitis C testing
-HIV screening
-VDRL
-Serum complements values,
-Varicella serology.
-Malaria slide
- Antinuclear antibodies
-Antistreptolysin O titers
Others
-Performing serum protein electrophoresis or urine protein electrophoresis can be useful for detecting the etiology of
nephrotic syndrome.
-Serum protein electrophoresis or immunofixation for light-chain proteins
b). Imaging Studies:
-Renal ultrasonography is an essential tool to help establish the presence of 2 kidneys that are of normal size and
architecture.
-The presence of hydronephrosis or cysts in the kidney that will undergo biopsy mandates caution.
- Similarly, small kidneys may not yield enough information and may be associated with an increased incidence of
RF
c). Renal biopsy
- Before attempting a renal biopsy, ensure that a renal ultrasound scan is ordered to confirm:-
 that the patient has 2 functioning kidneys
 that the kidneys are of normal size
 The kidney architecture is normal (ie, devoid of cysts and vascular malformations).
- A renal biopsy is indicated in the following circumstances:
1)-Steroid resistance
2)-Frequent relapses or steroid dependency
3)-Significant chronic nephritic manifestations
4)-Adult nephrotic syndrome:
-Probably even paediatrics locally
-30 – 45% minimal change disease (MCD)
5)-Confirm the etiology of nephrotic syndrome
6)-Guiding therapy and assessing prognosis
NB-Renal biopsy is not indicated in adults when the nephrotic syndrome is due to an obvious cause such as diabetes
mellitus, ie, when the patient has other diabetes-related overt complications
MANAGEMENT
Aims
 Induce prompt remission
 Minimize complications and subsequent mortality
 Treat underlying disease
General supportive measure

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1. Monitor vital signs-4 hourly
2. Restrict salt intake
3. Restrict fluids in severe edema –give fluids as previous day output + 400ml
4. Mantain a Daily fluid input/out chart
5. Daily weight measurement and abdominal girth measurement incase of ascitis
6. Bed rest in acute phase and ambulation as soon as possible as its hypercoagulable state
7.? Normal protein diet. Severe protein loss consider protein rich diet Vs risk of more glomerular injury
-If patient obese due to steroid restrict the calorie intake
Symptomatic treatment
Edema
-Diuretics and intravenous albumin may be needed.
-Furosemide (1 mg/kg/d)
-spironolactone (2 mg/kg/d) Achieving a satisfactory Diuresis is difficult when the patient's serum albumin level is
less than 1.5 g/dL.
-An effective regimen is to give salt-poor albumin at 1 g/kg, followed by intravenous furosemide.
-Close monitoring is obligatory to prevent pulmonary edema. Some evidence suggests that albumin may delay the
response to steroids and may even induce more frequent relapses, probably by causing severe glomerular epithelial
damage.
-The time required for remission is prolonged with a longer duration of administration and larger volumes of infused
albumin.
-Fluid removal and weight loss remain transient unless proteinuria remits.

2. Infection
-Care taken with puncture sites and procedures should observe aseptic techniques
-Prophylactic Antibiotics
-? Immunizations- influenza, pneumococcal, HBV, varicella
-Immunoglobulin
3. Hyperlipidaemia
-“Statins” – lipid lowering agents
-HMGCoA reductase inhibitors
4. Hypercoagulable State
-Anticoagulants
 Heparin may be ineffective as loss of anti thrombin III
 Warfarin
5. Bone Disease
-Vit D, Ca++ supplements
-Bisphosphonates (osteoporosis).
6. Proteinuria
-Angiotensin Converting Enzyme (ACE) inhibitors
-Angiotensin2 Receptor blocker (ARB)
-[*NSAIDs *nephrectomy]

Treatment of underlying cause

1. Treatment of infections
2. Control of metabolic syndrome and autoimmune conditions eg DM, SLE
3. Management of malignancies-reduce the tumor mass
4. Withdraw any drug culprits

NEUROLOGICAL EXAMINATION
a) Higher functions
b) Meninges
c) Cranial nerves (CNs)
d) Sensory system
e) Motor system
f) Cerebellum
g) System survey

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HIGHER FUNCTIONS
 Mental status
 Gait
 Speech.
Mini Mental status
-Mini mental status examination
1. Orientation
-What is the (year) (season) (date) (day) (month)? 5
-Where are we: (country) (city) (part of city) (number of flat/house) (name of street)? 5
2. Registration
-Name three objects: one second to say each.
-Then ask the patient to name all three after you have said them.
-Give one point for each correct answer.
-Then repeat them until he learns all three.
-Count trials and record. 3
3. Attention and calculation
-Serial 7s: one point for each correct.
-Stop after five answers.
-Alternatively spell 'world' backwards. 5
4. Recall
-Ask for the three objects repeated above.
-Give one point for each correct. 3
5. Language
-Naming: Show the patient a wrist-watch and ask him or her what it is. Repeat for pencil. Score 0-2.
Repetition: Ask the patient to repeat the sentence after you. Allow only one trial. Score 0 or 1.
Three-stage command: Give the patient a piece of plain blank paper and repeat the command. Score 1 point for each
part correctly executed.
-Reading: On a blank piece of paper, print the sentence 'Close your eyes' in letters large enough for the patient to see
clearly. Ask him or her to read it and do what it says. Score 1 point only if he or she actually closes his eyes.
Writing: Give the patient a blank piece of paper and ask him or her to write a sentence for you. Do not dictate a
sentence; it is to be written spontaneously. It must contain a subject and verb and be sensible. Correct grammar and
punctuation are not necessary.
Copying: On a clean piece of paper, draw intersecting pentagons (as below),

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6. Memory

-Memory is the ability to register and recall prior sensory input.

-Recent and remote memory functions are differently affected depending on the disease process.

-Remote memory is relatively preserved in chronic dementing processes, with major disturbances in
the attention span and recent memory. On the contrary, all aspects of memory are impaired in acute
encephalopathies.

7. Intelligence

-Intelligence is the ability to quickly and successfully apply previous knowledge to a new situation
and to use reason in solving problems. Vocabulary, fund of knowledge, calculations (eg, serial-7
calculations), abstraction (eg, use of proverbs), and judgment (eg, what to do with a found wallet) are
good indicators of intelligence.

8. Psychological disturbances

-A brief survey of the other aspects of psychological function may be helpful in revealing
abnormalities of thought process (eg, circumstantiality and tangentiality); of perception (eg, illusions
and hallucination); or of thought content (eg, delusions of grandeur). Patients with these findings
should be referred for appropriate evaluation.
GAIT
-Gait is the attitude of a person in the upright position. Abnormal types are described below.
a). Hemiparetic gait
-In hemiparesis, facial paresis may not be obvious. In mild cases, subtle features of facial paralysis (eg, flattening of
the nasolabial fold on 1 side compared to the other, mild asymmetry of the palpebral fissures or of the face as the
patient smiles) may be sought
-The patient therefore has to circumduct the affected leg to ambulate.
-In hemiplegic patients in whom all the paralysis is on the same side of the body, the lesion is of the contralateral
upper motor neuron. In most cases, the lesion lies in the cortical, subcortical, or capsular region (therefore above the
brainstem).
-In the alternating or crossed hemiplegias, CN paralysis is ipsilateral to the lesion, and body paralysis is
contralateral. In such cases, CN paralysis is of the lower motor neuron type, and the location of the affected CN
helps determine the level of the lesion in the brainstem.
-Therefore, paralysis of CN III on the right side and body paralysis on the left (Weber syndrome) indicates a
midbrain lesion, whereas a lesion of CN VII with crossed hemiplegia (Millard-Gubler syndrome) indicates a pontine
lesion, and CN XII paralysis with crossed hemiplegia (Jackson syndrome) indicates a lower medullary lesion.
b). Ataxic gait
-In ataxia, the patient spreads his or her legs apart to widen the base of support to compensate for the imbalance
while standing or walking. In severe cases, patients stagger as they walk. The heel-to-toe or tandem walking
maneuvers and standing on 1 leg uncover subtle forms of ataxia.
-Ataxia results from midline lesions of the cerebellum and may be isolated or associated with other cerebellar
findings
-When the lesion is unilateral, the patient may veer to the side of the lesion. With bilateral cerebellar involvement,
the patient may fall to either side.
c). Shuffling gait
-The individual takes short steps to the point of practically not moving forward or making little progress. In other
words, the patient appears to shuffle his or her legs rather than put them forward. In some patients, the steps (albeit
short) and pace may vary with a tendency for the patient to accelerate (festinating gait) as he or she walks.
-Both types are seen in Parkinson disease and may be associated with other extra pyramidal signs.
d). Steppage gait
-In steppage (high-stepping, slapping), the individual takes high steps as if climbing a flight of stairs while walking
on a level surface. This peculiar gait pattern results from the patient trying to avoid injury to the feet (from dragging

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them) by stepping high. However, as the patient puts the feet down 1 by 1, they slap the ground, hence the
description of a foot-slapping gait.
-This is 1 condition that can be diagnosed even before the patient enters the room because the sound is so
characteristic.
-Steppage gait is seen in chronic peripheral neuropathies and can be the result of the functional elongation of the
legs due to bilateral drop foot.
e). Spastic or scissor gait
-In this condition, the legs are held in adduction at the hip and the thighs rub against each other as the patient walks.
Spasm of the inner thigh muscles also occurs. If the spasm is severe, with each advancing step the knees tend to
slide over each other like the blades of a pair of scissors.
- This is typically seen in cerebral diplegia, a form of cerebral palsy.
f). Antalgic gait
-Patient favors the affected painful (usually lower) extremity and walks, putting weight on the normal leg.
- The hand held over hip on the affected side is typical in patients with radicular pain.
SPEECH
-Speech enables communication between individuals. Abnormalities include dysphonia, dysarthria, and dysphasia or
aphasia.
1. Dysphonia or aphonia
-Dysphonia is the impairment or inability to phonate. As a result, the voice becomes hoarse. In extreme cases, it is
absent, and the patient is mute.
-The most frequent cause of this problem is the common cold, which results in dysphonia due to inflammation of the
larynx.
-Dysphonia may also occur in patients with hypothyroidism, as a result of thickening of the vocal cords from
amyloid deposits.
-Neurologic causes include unilateral recurrent laryngeal nerve paralysis and lesions of the vagus nerve. Intermittent
hoarseness may affect patients with vagus nerve stimulator implants, which are used for the treatment of certain
medically intractable forms of epilepsy (MIE) and pharmacoresistent depression (PRD).
2. Dysarthria or anarthria
-Dysarthria is the inability to articulate spoken words. The quality of oration is impaired, but the content remains
intact (eg, slurred speech).The patient's ability to understand and synthesize speech remains intact. It results from
paralysis of pharyngeal, palatal, lingual, or facial musculature.
-It also is observed with cerebellar lesions and/or disease (eg, scanning or staccato speech)
3. Dysphasia or aphasia
-In dysphasia, the ability to process language is impaired, resulting in an inability to understand (ie, receptive or
sensory or Wernicke aphasia), transfer signals from the Wernicke to the Broca area (ie, conduction aphasia), or
properly execute speech (ie, expressive, motor, or Broca aphasia).
-The combination of Broca and Wernicke aphasias is referred to as global aphasia.
4. Transcortical aphasias
-Another function that is impaired in all 4 of the aphasias mentioned above is repetition. This finding is important in
the diagnosis of transcortical aphasias.
- When repetition is preserved in a patient with Broca aphasia, it signifies transcortical motor aphasia, and the lesion
is anterior to the Broca area.
-When repetition is preserved in Wernicke aphasia, it is called transcortical sensory aphasia, and the lesion is
posterior to the Wernicke area.
-Transcortical mixed aphasia and global aphasia are similar except for the preservation of repetition, and results
from combined lesions anterior to the Broca and Wernicke areas, respectively.
MENINGEAL SIGNS
1. Nuchal rigidity or neck stiffness is tested by placing the examiner's hand under the patient's head and gently trying
to flex the neck. Undue resistance implies diffuse irritation of the cervical nerve roots from meningeal inflammation.
2. The Brudzinski sign is flexion of both knees during the maneuver to test nuchal rigidity. This indicates diffuse
meningeal irritation in the spinal nerve roots.
3. The Kernig sign is elicited by flexing the hip and knee on 1 side while the patient is supine, then extending the
knee with the hip still flexed.
-Hamstring spasm results in pain in the posterior thigh muscle and difficulty with knee extension.
-With severe meningeal inflammation, the opposite knee may flex during the test

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4. The Lasègue or straight-leg raising (SLRT) sign is elicited by passively flexing the hip with the knee straight
while the patient is in the supine position. Limitation of flexion due to hamstring spasm and/or pain indicates local
irritation of the lower lumbar nerve roots.
5. Reverse SLR is elicited by passively hyperextending the hip with the knee straight while the patient is in the
prone position. -Limitation of extension due to spasm and/or pain in the anterior thigh muscles indicates local
irritation of the upper lumbar-nerve roots.
CRANIAL NERVE EXAMINATION
Olfactory nerve - CN I
-The olfactory nerves consist of small unmyelinated axons that originate in the olfactory epithelium in the roof of
the nasal cavity; they pierce the cribriform plate of the ethmoid and terminate in the olfactory bulb. Lesions of the
nerve result in parosmia (altered sense of smell) or anosmia (loss of smell).
-The common cold is the most frequent cause of dysfunction. Dysfunction can be associated with fractures of the
cribriform plate of the ethmoid bone. Frontal lobe tumors may compress the olfactory bulb and/or tracts and cause
anosmia, but this is rare occurrence.
-Olfactory function is tested easily by having the patient smell common objects such as coffee or perfume.
Commercially available scented scratch papers may also be used.
Optic nerve - CN II
-Relay information from the rods and cones of the retina.
-The temporal derivations reach the ipsilateral and the nasal derivations the contralateral superior colliculi and the
lateral geniculate bodies.
- From there, axons extend to the calcarine cortex by means of the optic radiation, traversing the temporal (Myer
loop) and parietal lobes.
- Fibers responsible for the pupillary light reflex bypass the geniculate body and reach the pretectal area, from where
they innervate the parasympathetic (midline) portion of the third-nerve nucleus, enabling the consensual pupillary
reflex. The following testing is appropriate:
1-Acuity, by using the Snellen chart (near and distant vision)
2-Visual fields, by means of confrontation or perimetry if indicated
3-Color, with use of an Isihara chart or by using common objects, such as a multicolored tie or color accent markers
4-Funduscopy
-Lesions of the visual pathways result in blindness and pupillary abnormalities, such as the Marcus-Gunn pupil
(retinal or optic nerve disease), scotomata, quadrant or hemianopsias (optic tract and radiation), and hemianopsias
with macular sparing (calcarine cortex).
Oculomotor nerve - CN III
-The oculomotor nucleus of the nerve is located in the midbrain and innervates
-the pupillary constrictors;
- Levator palpebrae superioris
-The superior, inferior, and medial recti; and the inferior oblique muscles.
-Lesions of CN III result
Ptosis
 The eye is frequently turned out (exotropia).
 Mydriasis
Trochlear nerve - CN IV
-The nucleus of the nerve is located in the midbrain. It innervates the superior oblique muscle, which incycloducts
and infraducts the eye.
-Trochlear nerve typically allows a person to view the tip of his or her nose.
-An isolated right superior oblique paralysis results in exotropia to the right (R), double vision that increases on
looking to the (L), and head tilt to the right (R). The mnemonic is R, L, R (ie, the marching rule). The rule is L, R, L
for left superior oblique paralysis.
-This rule and the lack of ptosis and/or pupillary involvement allow easy distinction of the exotropia of CN IV
paralysis from that seen in CN III paralysis.

Trigeminal nerve - CN V
-The nucleus of the nerve stretches from the midbrain (ie, mesencephalic nerve) through the pons (ie, main sensory
nucleus and motor nucleus) to the cervical region (ie, spinal tract of the trigeminal nerve).

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-It provides sensory innervation for the face and supplies the muscles of mastication.
-Paralysis of the first division (ophthalmic; V1) is usually seen in the superior orbital fissure syndrome and results in
sensory loss over the forehead along with paralysis of CN III and CN IV.
-Paralysis of the second division (maxillary; V2) results in loss of sensation over the cheek and is due to lesions of
the cavernous sinus; it also results in additional paralysis of V1, CN III and CN IV. Isolated V2 lesions result from
fractures of the maxilla. -Complete paralysis of CN V results in sensory loss over the ipsilateral face and weakness
of the muscles of mastication.
-Test muscle of mastication by tensing the masseter and feeling for the bulk. Attempted opening of the mouth also
results in deviation of the jaw to the paralyzed side.
Abducens nerve - CN VI
-The nucleus of the nerve is located in the paramedian pontine region in the floor of the fourth ventricle.
-It innervates the lateral rectus, which abducts the eye.
-Isolated paralysis results in esotropia and inability to abduct the eye to the side of the lesion.
- Patients complain of double vision on horizontal gaze only. This finding is referred to as horizontal homonymous
diplopia, which is the sine qua non of isolated CN VI paralysis.
- Paralysis of CN VI may result from increased intra cranial pressure without any lesion in the neuraxis, and it may
result in false localization if one is not aware of it.
Facial nerve - CN VII
-The nucleus of the nerve lies in pons ventral, lateral, and caudal to the CN VI nucleus; its fibers elevate the floor of
the fourth ventricle (facial colliculus) as they wind around the CN VI nucleus.
-The nerve leaves the cranial cavity through the stylomastoid foramen and innervates the muscles of facial
expression and the stapedius.
-Its sensori- motor nerve, it also innervates a small strip of skin of the posteromedial aspect of the pinna and around
the external auditory canal.
-The nervus intermedius of Weisberg conducts taste sensation from the anterior two thirds of the tongue and
supplies autonomic fibers to the submaxillary and sphenopalatine ganglia, which innervate the salivary and lacrimal
glands.
-A lower-motor-neuron lesion of the nerve, also known as peripheral facial paralysis, results in complete ipsilateral
facial paralysis
1) Patient can’t wrinkle skin of forehead
2) Eye closure is impaired-exposure keratitis risk
3) The ipsilateral palpebral fissure is wider.
4) Face draws to the opposite side as the patient smiles
5) Patient can’t close the mouth and whistle
6) Close the mouth and blow air try to apply pressure bilaterally.
7) Atrophy of nasolabial fold
-In an upper motor neuron lesion, also known as central facial paralysis, only the lower half of the face is paralyzed.
Eye closure is usually preserved. And patients can wringle the forehead.
Vestibulocochlear nerve - CN VIII
-The vestibulocochlear or statoacoustic nerve enters the brainstem at the pontomedullary junction and contains the
incoming fibers from the cochlea and the vestibular apparatus, forming the eighth CN.
-It serves hearing and vestibular functions, each of which is described separately.
-Hearing loss may be conductive or sensorineural. Three tests help in evaluating the auditory component of the
nerve.
-The Weber test involves holding a vibrating tuning fork against the forehead in the midline. The vibrations are
normally perceived equally in both ears because bone conduction is equal.
In conductive hearing loss, the sound is louder in the abnormal ear than in the normal ear.
In sensorineural hearing loss, lateralization occurs to the normal ear.
-The sensitivity of the test can be increased (up to 5 dB) by having the patient block his or her external ear canals by
simultaneously pressing the index fingers at the introit.
-Rinne test, the vibrating tuning fork is placed over the mastoid region until the sound is no longer heard. It is then
held at the opening of the ear canal on the same side. A patient with normal hearing should continue to hear the
sound. In conductive hearing loss, the patient does not continue to hear the sound, since bone conduction in that case
is better than air conduction. In sensorineural hearing loss, both air conduction and bone conduction are decreased to
a similar extent.

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-In the Schwabach test, the patient's hearing by bone conduction is compared with the examiner's hearing by placing
the vibrating tuning fork against the patient's mastoid process and then to the examiner's. If the examiner can hear
the sound after the patient has stopped hearing it, then hearing loss is suspected.
-The vestibular portion transmits information about linear and angular accelerations of the head from the utricle,
saccule, and semicircular canals of the membranous labyrinth to the vestibular nucleus.
- Linear acceleration is monitored by the macules in the utricles and saccules
-Angular acceleration is monitored by the cristae contained in the ampullae in the semicircular canals.
-These signals reach the superior (Bechterew), lateral (Deiters), medial (Schwalbe), and inferior (Roller) nuclei and
project to the pontine gaze center through the medial longitudinal fasciculus
- To the cervical and upper thoracic levels of the spinal cord through the medial vestibulospinal tract
-To the cervical, thoracic, and lumbosacral regions of the ipsilateral spinal cord through the lateral vestibulospinal
tract
-To the ipsilateral flocculonodular lobe, uvula, and fastigial nucleus of the cerebellum through the
vestibulocerebellar tract.
-The Romberg test is performed to evaluate vestibular control of balance and movement. When standing with feet
placed together and eyes closed, the patient tends to fall toward the side of vestibular hypo function.
-When asked to take steps forward and backward, the patient progressively deviates to the side of the lesion. -
Romberg test may also be positive in patients with polyneuropathies, and diseases of the dorsal columns, but these
individuals do not fall consistently to 1 side as do patients with vestibular dysfunction.
- Caloric stimulation Test is produced by irrigating the ears with warm and cool water, which causes convection
currents in the endolymph. The currents cause movement of the cupula in the ampulla of the horizontal semicircular
canal; the movement is in one direction during cooling and in the opposite direction during warming.
-Irrigating the ear with cool water produces nystagmus to the opposite side; warm water produces nystagmus to the
same side. A mnemonic device is COWS (Cold to the Opposite and Warm to the Same).
Glossopharyngeal nerve - CN IX
-The nucleus of the nerve lies in the medulla and is anatomically indistinguishable from the CN X and CN XI nuclei
(nucleus ambiguous).
- Its main function is sensory innervation of the posterior third of the tongue and the pharynx. It also innervates the
pharyngeal musculature, particularly the stylopharyngeus, in concert with the vagus nerve.
-Vascular stretch afferents from the aortic arch and carotid sinus, as well as chemoreceptor signals from the latter,
travel in the nerve of Herring to join the glossopharyngeal nerve; they reach the nucleus solitarius, which in turn is
connected to the dorsal motor nucleus of the vagus and plays a part in the neural control of blood pressure.
-Lesions affecting the glossopharyngeal nerve result in loss of taste in the posterior third of the tongue and loss of
pain and touch sensations in the same area, soft palate, and pharyngeal walls.
-CN IX and CN X travel together, and their clinical testing is not entirely separable. Therefore, examination of CN
IX is discussed with that of the vagus nerve.
Vagus nerve - CN X
-Starting in the nucleus ambiguous, the vagus nerve has a long and tortuous course providing motor supply to the
pharyngeal muscles (except the stylopharyngeus and the tensor veli palati), palatoglossus, and larynx.
- It innervates the smooth muscles of the tracheobronchial tree, esophagus, and GI tract up to the junction between
the middle and distal third of the transverse colon.
-The vagus provides secretomotor fibers to the glands in the same region and inhibits the sphincters of the upper GI
tract.
-Along with visceral sensation from the same region, the nerve participates in vasomotor regulation of blood
pressure by carrying the fibers of the stretch receptors and chemoreceptors (ie, aortic bodies) of the aorta and
providing parasympathetic innervation to the heart.
-The pharyngeal gag reflex (ie, tongue retraction and elevation and constriction of the pharyngeal musculature in
response to touching the posterior wall of the pharynx, tonsillar area, or base of the tongue) and the palatal reflex (ie,
elevation of the soft palate and ipsilateral deviation of the uvula on stimulation of the soft palate) are decreased in
paralysis of CN IX and CN X.
-In unilateral CN IX and CN X paralysis, touching these areas results in deviation of the uvula to the normal side.
-Unilateral paralysis of the recurrent laryngeal branch of CN X results in hoarseness of voice.
-Bilateral paralysis results in stridor and requires immediate attention to prevent aspiration and its attendant
complications.
Spinal accessory nerve - CN XI

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-From the nucleus ambiguous, the spinal accessory nerve joins the vagus nerve in forming the recurrent laryngeal
nerve to innervate the intrinsic muscles of the larynx. The spinal portion of the nerve arises from the motor nuclei in
the upper 5 or 6 cervical segments, enters the cranial cavity through the foramen magnum, and exits through the
jugular foramen, and provides motor innervation to the sternocleidomastoid (SCM) and the mid and upper thirds of
the trapezius.
-In testing, functional symmetry of the SCM and the trapezius muscles should be evaluated.
-Have the patient push the face against resistance to the right and to the left. When the right SCM is weak, pushing
to the opposite (ie, left) side is impaired, and vice versa.
-Shrugging of the shoulder is impaired ipsilaterally when the trapezius is weak.
Hypoglossal nerve - CN XII
-The nucleus of this nerve lies in the lower medulla, and the nerve itself leaves the cranial cavity through the
hypoglossal canal (anterior condylar foramen). It provides motor innervation for all the extrinsic and intrinsic
muscles of the tongue except the palatoglossus.
-To test the hypoglossal nerve, have the patient protrude the tongue; when paralyzed on 1 side, the tongue deviates
to the side of paralysis on protrusion.
-Check for atrophy and fasciculation and of the tongue.

MOTOR EXAMINATION
1. Bulk -Trophic state
-Assess the 3 Ss: size, shape, and symmetry of a muscle.
-Atrophy, hypertrophy, or abnormal bulging or depression in a muscle is an important diagnostic finding in the
presence of different muscle diseases or abnormalities.
2. Muscle tone
-Muscle tone is the permanent state of partial contraction of a muscle and is assessed by passive movement.
-Hypotonia may be seen in lower motor neuron lesions, spinal shock, and some cerebellar lesions.
-Hypertonia may manifest as spasticity or rigidity.
-Pyramidal lesions result in spasticity that may manifest as a clasp-knife phenomenon (ie, resistance to passive
movement with sudden giving way, usually toward the completion of joint flexion or extension).
-Bilateral frontal lobe lesions may result in paratonia or gegenhalten (German for against-stop), in which resistance
increases throughout flexion and extension.
- Extra pyramidal lesions –It may result in a cogwheel (stepwise) or lead-pipe (uniform) resistance to passive
movement.
3. Muscle strength
0-No movement
1-Feeble movement which can’t move a joint
2-Movement with gravity eliminated
3-Movemnt against gravity
4-Movemnt against partial resistance
5-Full strength
4. Abnormal Movements
-Include fibrillations, fasciculations, asterixis, tics, myoclonus, dystonias, chorea, athetosis, hemiballismus, and
seizures.
-Fibrillations are not visible to the naked eye except possibly those in the tongue.
-Fasciculations may be seen under the skin as quivering of the muscle. Although fasciculations are typically benign
(particularly when they occur in the calf), if widespread, they can be associated with neuromuscular disease,
including amyotrophic lateral sclerosis (ALS).
-Asterixis can be elicited by having the patient extend both arms with the wrists dorsiflexed and palms facing
forward and eyes closed. Brief jerky downward movements of the wrist are considered a positive sign. Asterixis is
commonly seen with metabolic encephalopathies.
-Tics are involuntary contractions of single muscles or groups of muscles that result in stereotyped movements.
Gilles de la Tourette syndrome can manifest with multiple tics and elaborate complex movements and vocalizations.
-Myoclonus, as the word implies, is a muscle jerk; it is a brief (<0.25 s), generalized body-jerk, which is sometimes
asymmetric. These occur alone or in association with various primarily generalized epilepsies.

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-Dystonias are muscle contractions that are more prolonged than myoclonus and result in spasms. Examples include
blepharospasm, spasmodic torticollis, oromandibular dystonia, spasmodic dysphonia,
-In athetosis, the spasms have a slow writhing character and occur along the long axis of the limbs or the body itself;
the patient may assume different and often peculiar postures.
-The term chorea means dance. Quasi-purposeful movements affect multiple joints with a distal preponderance.
-Hemiballismus is a violent flinging movement of half of the body. It is associated with lesions of the subthalamic
nucleus (ie, body of Louis).
-Seizures may result in orofacial or appendicular automatisms, repeated eye blinks, or tonic or clonic motor activity.
5. Reflexes
-3 categories on the basis of their clinical significance.
a). Primitive reflexes
-These include the glabellar tap, rooting, snout, sucking, and palmomental reflexes. As a rule, these signs are
generally absent in adults.
-When present in the adult, these signs signify diffuse cerebral damage, particularly of the frontal lobes (hence the
term frontal-lobe release signs).
b). Superficial reflexes
-These are segmental reflex responses that indicate the integrity of cutaneous innervation and the corresponding
motor outflow.
-These include the corneal, conjunctival, abdominal, cremasteric, anal wink, and plantar (Babinski) reflexes.
-The corneal and conjunctival reflexes may be elicited by gently touching the appropriate structure with a sterile
wisp of cotton. The normal response is bilateral winking. Absence of such a response implies CN V paralysis.
Blinking of only 1 eye suggests weakness of CN VII on the side that does not wink.
-The abdominal reflex can be elicited by drawing a line away from the umbilicus along the diagonals of the 4
abdominal quadrants. A normal reflex draws the umbilicus toward the direction of the line that is drawn.
-The cremasteric reflex is elicited by drawing a line along the medial thigh and watching the movement of the
scrotum in the male. A normal reflex results in elevation of the ipsilateral testis.
-The anal wink reflex is elicited by gently stroking the perianal skin with a safety pin. It results in puckering of the
rectal orifice owing to contraction of the corrugator-cutis-ani muscle.
-The plantar reflex.-The normal response is plantar flexion of the great toe, which is considered an absent (negative)
Babinski sign. Dorsiflexion of the great toe (Babinski sign present) suggests an upper motor neuron lesion and also
is referred to as a positive Babinski sign. Dorsiflexion of the big toe also may be associated with fanning out of the
other toes,
c). Deep tendon reflexes
- The musculocutaneous nerve supplies the biceps muscle. The radial nerve supplies the brachioradialis and triceps.
-The femoral nerve supplies the quadriceps femoris, which enables the knee jerk, and the tibial nerve supplies the
gastrocnemius and the soleus.
Roots Rested
-Biceps-C5
-Triceps-C7
-Brachioradialis-C6
-Knee jerk-L3, L4
-Ankle jerk-S4
Grading of Reflexes
-Grade0 –Absent reflexes
-Grade 1-hyporesponsive only with reinforcement
-Grdae2-Normal response
-Grade3-Brisk but without spread to neighboring muscles
-Grade4-Associated with a few beats of unsustained clonus
-Grade5-Sustained Clonus

SENSORY EXAMINATION

a). Noncortical sensory system

-Light touch, pain, heat, cold, and vibration sensations can be included in this group. Also Proprioception
-Light touch is tested by touching the skin with a wisp of cotton or tissue.
- Pain is tested by using a sharp object such as an open safety pin.

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-Temperature can be tested by touching the patient's skin with 2 test tubes, 1 with warm water and the other with
cold water.
-Vibration is tested with a tuning fork, preferably with a frequency of 128 Hz. Compare findings on the 2 sides, and
also compare findings with those in the same body part of the examiner.

b). Cortical sensation

-Higher-order aspects of sensation, or cortical sensation,
 Graphesthesia- asks the patient to close their eyes and identify letters or numbers that are being traced
onto their palm or the tip of their finger.
 Stereognosis, ask the patient to close their eyes and identify various objects by touch using one hand at a
time.
 Test also tactile extinction on double simultaneous tactile stimulation. Form of hemineglect that occur
with right parietal lobe lesion
-Note that Graphesthesia, stereognosis, and extinction cannot reliably be tested for unless primary sensation is intact
bilaterally

CEREBELLAR EXAMINATION
-The cerebellum provides an important feedback loop for coordination of muscle activity by integrating the
functions of the cortex, basal ganglia, vestibular apparatus, and spinal cord.
-Midline cerebellar dysfunction results in ataxia of gait, difficulty in maintenance of upright posture, and truncal
ataxia.
-Acute neocerebellar hemispheric lesions result in additional signs. The following are various cerebellar signs:
1) Ataxia- Gait is tested by having the patient walk normally and in tandem. In the latter, the patient is asked
to walk with 1 foot immediately in front of the other (ie, heel to toe). A tendency to sway or fall to 1 side
indicates ataxia, suggesting ipsilateral cerebellar dysfunction. Wide based gait may occur.
2) Hypotonia, and asthenia
3) Intention tremor -Intention tremor refers to an oscillating tremor that accelerates in pace on approaching the
target
4) Dyssynergia - (incoordination) Dyssynergia or incoordination results in loss of smoothness of execution of
a motor activity.
5) Dysmetria - Dysmetria results in overshooting or undershooting of a target while attempting to reach an
object. Having the patient attempt to touch alternately his or her nose and the examiner's finger.
6) Dysrhythmia and Dysdiadochokinesis
7) Dysarthria (staccato or scanning speech)
8) The patient with cerebellar disease cannot brake the movement of the limb, and the forearm flies backward
in a wide arc. This abnormal response is known as the rebound phenomenon
9) Nystagmus-Rapid oscillating movements of the eyes

NEUROCUTANEOUS SYSTEM
Several neurologic conditions have telltale cutaneous stigmata
-Loss of skin pigmentation as in vitiligo
-white hair-lock in Vogt-Harada-Koyanagi disease
-cutaneous tumors or ash-leaf spots in tuberous sclerosis
-cutaneous eruptions over a dermatome which may signify herpes zoster
-Coffee-brown pigmented (ie, café au lait) spots of varying sizes, usually greater than 1.5 cm in diameter, and
axillary freckling are seen in neurofibromatosis. These are observed in addition to or in the absence of the
characteristic blubbery subcutaneous tumors that give the condition its name.
-Tufts of hair (satyr's tail), dimples, and large moles along the spine may indicate spina bifida occulta or
diastematomyelia of the spinal column.
Other neurological signs
1. Anisocoria
-This refers to pupillary asymmetry, which may result from sympathetic or parasympathetic dysfunction.
- Sympathetic dysfunction results in Horner syndrome, in which the pupil is small but reacts to light.

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-Argyll-Robertson pupil, seen in neurosyphilis, is irregular and small; it does not react to light, but does
accommodate.
-In parasympathetic paralysis, the affected pupil is larger and reacts poorly or not at all to light.
-A benign form of tonic pupil is seen in Adie syndrome, Holmes-Adie syndrome (ie, tonic pupil with absent patellar
and Achilles reflexes), and Ross syndrome (ie, tonic pupil with hyporeflexia and progressive segmental
hypohidrosis).
2. Chvostek sign
-This is seen in hypocalcemia. Tapping the cheek at the angle of the jaw precipitates tetanic facial contractions.
3. Cogan sign
-This is seen in myasthenia gravis. It refers to transient baring of the sclerae above the cornea as the patient resumes
the primary eye position after looking down.
4. Dalrymple sign
-This refers to the upper-lid retraction seen in thyroid ophthalmopathy.
5. Doll's-eye maneuver
-This refers to turning the head passively with the patient awake and fixated or when the patient is in a coma. In the
former, the eyes remain fixated at the original focus when all gaze pathways are normal; in the latter, the eyes
deviate in the opposite direction when the brainstem is intact.
6. Gower sign
-This sign, seen in severe myopathies, occurs when the patient attempts to stand up from the floor. Patients first sit
up, then assume a quadrupedic position, and then climb up their own legs by using their arms to push themselves up.
7. Jaw jerk
-This is elicited by placing the examiner's index finger on the patient's lower jaw and then striking it with the reflex
hammer. An exaggerated reflex indicates the presence of a pontine lesion. When the rest of the examination findings
are normal, it may indicate physiologic hyperreflexia.
8. Kayser-Fleischer ring
-This is a brownish ring around the limbus of the cornea. It is best demonstrated during an ophthalmologic slit lamp
examination.
9. Lhermitte sign
-This refers to the sensation of electricity associated with cervical spinal cord lesions during passive or active flexion
and extension of the neck. Once considered pathognomonic of multiple sclerosis, it simply is the result of electricity
generation by the hypersensitive, demyelinated, or injured spinal cord; this sign can be associated with any lesion in
or around the cord.
10. Marcus-Gunn pupil
-This sign requires a swinging-flashlight test to assess. As the flashlight swings from 1 eye to the other, the
abnormal pupil dilates as the light swings back from the normal side. No anisocoria is seen. The phenomenon is also
called a paradoxical pupillary reflex and indicates an afferent (optic nerve) pupillary defect.

NUTRITIONAL SUPPORT

-Nutritional Support may supplement normal feeding, or completely replace normal feeding into the
gastrointestinal tract.
Benefits of Nutritional Support

1. Preservation of nutritional status

2. Prevention of complications of protein malnutrition

3. Reduce Post-operative complications

Who requires nutritional support?

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1-Patients already with malnutrition - surgery/trauma/sepsis

2-Patients at risk of malnutrition Thus

a) Depleted reserves

b) Cannot eat for > 5 days

c) Impaired bowel function

d) Critical Illness

e) Need for prolonged bowel rest

How do we detect malnutrition?
Nutritional Assessment

1. History

-Dietary history, significant weight loss within last 6 months

15% loss of body weight
o Compare with ideal weight
o Beware the patient with ascites/ oedema

2. Physical examination

3. Anthropometric measurements

4. Laboratory investigations
Types of Nutritional Support
Enteral Nutrition
Parenteral Nutrition

Enteral Feeding is best

1. More physiologic

2. Less complications

3. Gut mucosa preserved

4. No bacterial translocation

5. Cheaper
Enteral Feeding is indicated

1. When nutritional suport is needed

2. Functioning gut present

3. No contra-indications no ileus, no recent anastomosis, no fistula

Types of feeding tubes

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-Naso-gastric tubes

-Oro-gastric tubes

-Naso-duodenal tubes

-Naso-jejunal tubes

-Gastrostomy tubes
Percutaneous Endoscopic Gastrostomy (PEG)
Open Gastrostomy

-Jejunostomy tubes
Complications of enteral feeding
12% overall complication rate
1. Gastrointestinal complications -Distension, Nausea and vomiting, Diarrhea, Constipation, Intestinal ischaemia

2. Mechanical complications Malposition of feeding tube

Sinusitis, Ulcerations / erosions, Blockage of tubes

3. Metabolic complications

5. Infectious complications Aspiration Pneumonia, Bacterial

Contamination

Parenteral Nutrition

-Allows greater caloric intake BUT:

-Is more expensive

-Has more complications

-Needs more technical expertise

Indications for parenteral nutrition

1. Abnormal Gut function-cannot absorb

2. Cannot consume adequate amounts of nutrients by enteral feeding

3.Can not retain orally

4. Are anticipated to not be able to eat orally by 5 days

5. Prognosis warrants aggressive nutritional support

Two main forms of parenteral nutrition

Peripheral Parenteral Nutrition
Central (Total) Parenteral Nutrition

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Peripheral Parenteral Nutrition: Given through peripheral vein

-short term use

-mildly stressed patients

-low caloric requirements

-needs large amounts of fluid

-contraindications to central TPN

TPN
What to do before starting TPN
a)-Nutritional Assessment

b)-Venous access evaluation -Need venous access to a “large” central line with fast flow to avoid
thrombophlebitis

c)-Baseline weight

d)-Baseline lab investigations

1. Full blood count

2. Coagulation screen

3. Screening Panel # 1

4. Ca++, Mg++, PO42-

5. Lipid Panel # 1

6. Other tests when indicated

How much Fluids to give?
 Cater for maintenance & on going losses
 Normal maintenance requirements
 By body weight 30 to 50 ml/kg/day
 Add on going losses based on I/O chart
 Consider insensible fluid losses also
Eg add 10% for every o C rise in temperature

Caloric requirements:
-Based on Total Energy Expenditure

-Can be estimated using predictive equations

-TEE = REE + Stress Factor + Activity Factor

-Can be measured using metabolic chart

-Schofield Equation 35 to 40 kcal/kg/day (2000-3000kcal/day at rest)

How much CHO & Fats?

215
-Not more than 4 mg / kg / min Dextrose(less than 6 g / kg / day)

-Not more than 0.7 mg / kg / min Lipid(less than 1 g / kg / day)

How much Fat?

-Fats usually form 25 to 30% of calories required

-1g of fat = 9 kcal
 Not more than 40 to 50%
 Increase usually in severe stress
 Aim for serum TG levels < 350 mg/dl (3.95 mmol /L)
How much CHO?

-CHO usually form 70-75 % of calories

-1g of CHO= 4kcal

How much protein to give?

-Based on calorie : nitrogen ratio

-Based on degree of stress & body weight

-Based on Nitrogen Balance

-Calorie: Nitrogen Ratio
-Normal ratio is 150 cal: 1g Nitrogen

-Critically ill patients 85 to 100 cal: 1 g Nitrogen in

Based on Stress & BW Protein requirement

 Non-stress patients 0.8 g / kg / day
 Mild stress 1.0 to 1.2 g / kg / day
 Moderate stress 1.3 to 1.75 g / kg / day
 Severe stress 2 to 2.5 g / kg / day
-Based on Nitrogen Balance Aim for positive balance of

1.5 to 2 g / kg / day
Electrolyte Requirements

-Cater for maintenance + replacement needs

 Na+ 1 to 2 mmol/kg/d (or 60-120 meq/d)
 K+ 0.5 to 1 mmol/kg/d (or 30 - 60 meq/d)
 Mg++ 0.35 to 0.45 meq/kg/d(or 10 to 20 meq /d)
 Ca++ 0.2 to 0.3 meq/kg/d (or 10 to 15 meq/d)
 PO42- 20 to 30 mmol/d
Trace Elements

-Total requirements not well established

-Commercial preparations exist to provide RDA

 Zn 2-4 mg/day
 Cr 10-15 ug/day
 Cu 0.3 to 0.5 mg/day
 Mn 0.4 to 0.8 mg/day
Other Additives
Vitamins
 Give 2-3x that recommended for oral intake

216
  us give 1 ampoule MultiVit per bag of TPN
 MultiVit does not include Vit K-can give 1 mg/day or 5-10 mg/wk
Medications
Insulin
 can give initial SI based on sliding scale according to hypocount q6h (keep <11 mmol/l)
 once stable, give 2/3 total requirements in TPN & review daily
 alternate regime

– 0.1 u per g dextrose in TPN

– 10 u per litre TPN initial dose

Other medications
 TPN Monitoring Clinical Review
 Lab investigations
 Adjust TPN order accordingly

Clinical Review
 Clinical examination
 Vital signs
 Fluid balance
 Catheter care
 Sepsis review
 Blood sugar profile
 Body weight
Lab investigations
 Full Blood Count
 Renal Panel # 1
 Ca++, Mg++, PO42-
 Liver Function Test
 Iron Panel
 Lipid Panel
 Nitrogen Balance

Complications related to TPN

Mechanical Complications
Metabolic Complications
Infectious Complications

Mechanical Complications
 Pneumothorax
 Air embolism
 Arterial injury
 Bleeding
 Brachial plexus injury
 Catheter malplacement
 Catheter embolism
 Thoracic duct injury

Metabolic Complications

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OPPORTUNISTIC INFECTIONS IN HIV/AIDS INFECTION
Abnormalities related to excessive or inadequate administration

-Hyper / hypoglycaemia

-Electrolyte abnormalities

-Acid-base disorders

-Hyperlipidaemia

-Hepatic complications

-Biochemical abnormalities

-Cholestatic jaundice too much calories (carbohydrate intake too much fat

-Acalculous cholecystitis
Infectious Complications
Insertion site contamination
Catheter contamination
 Improper insertion technique
 Use of catheter for non-feeding purposes
 Contaminated TPN solution
 Contaminated tubing
Secondary contamination
 septicaemia

Stopping TPN
 Stop TPN when enteral feeding can restart
 Wean slowly to avoid hypoglycaemia
 Monitor hypocounts during wean
 Give IV Dextrose 10% solution at previous infusion rate for at least 4 to 6h
 Alternatively, wean TPN while introducing enteral feeding and stop when enteral intake
meets TEE

Effect of Antiretroviral Therapy on the Incidence and Management of OIs

-Antiretroviral therapy (ART) reduces the incidence of OIs and improves survival, independent of the use of
antimicrobial prophylaxis, and reduces overall mortality among persons with HIV-1 infection.
-Potent ART does not replace the need for antimicrobial prophylaxis among patients with severe immune
suppression.
-However, ART is the cornerstone of the overall strategy to reduce morbidity attributed to HIV-1–related infections
and other HIV-1–related processes.
-The clinical benefit of ART in reducing the risk for OIs over the short term demonstrated for those with a CD4+ T
lymphocyte count <200 cells/μL.
-There is also benefit in patients with CD4+ T lymphocyte counts >200 cells/μL, although the overall benefit of
starting ART in this population is uncertain.
Initiation of ART in the Setting of an Acute OI (Treatment-Naïve Patients)
-The benefits of ART in the setting of an acute OI include the improvement in immune function that would
potentially contribute to faster resolution of the OI.

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OSTEOARTHRITIS
-The beneficial effect of initiating ART during an acute OI has been best demonstrated for OIs for which there are
limited or no effective therapies as cryptosporidiosis, microsporidiosis, Kaposi sarcoma and Progressive multifocal
leukoencephalopathy (PML)
-Another benefit of immediate initiation of potent ART during an acute OI is the reduction in risk for a second OI.
-Arguments against the immediate initiation of ART concurrent with the diagnosis of an OI include
 Additive drug toxicities
 Distinguishing toxicities caused by antiretroviral (ARVs) from toxicities related to drugs used to manage
OIs
 Drug interactions between OI therapies and ART
 Inflammatory immune reconstitution syndromes to complicate the OI management
-Drug interactions pose the biggest problem for the treatment of patients with tuberculosis (TB), but ART regimens
compatible with TB treatment are available.
-Immune reconstitution syndromes are characterized by fever and worsening of the clinical manifestations of the OI
or new manifestations weeks after the initiation of ART.
-Determining the absence of recrudescence of the underlying OI and new drug toxicity or a new OI is important.
-Incase of immune reactivation syndrome, adding NSAIDS or corticosteroids to alleviate the inflammatory reaction.
The inflammation might take weeks or months to subside.
-Immune reconstitution syndrome is most commonly seen TB patients. Patients can experience high fevers,
worsening lymphadenopathy or transient-to-severe worsening of pulmonary infiltrates, and expanding central
nervous system lesions
Management of Acute OIs in the Setting of ART
-OIs that develop after patients have been started on potent ART can be categorized into three groups.
a) Within 12 weeks of starting ART- These cases are thought to be subclinical infections that have been unmasked
by early immune reconstitution and are not considered to be early failure of ART
b)>12 weeks after ART started- Among patients with suppressed HIV-1 RNA levels and sustained CD4+ T
lymphocyte counts >200 cells/μL .Determining whether these represent a form of immune reconstitution syndrome
as opposed to incomplete immunity with the occurrence of a new OI is difficult. Specific therapy is indicated.
c) The third group includes OIs that develop among patients who are experiencing virologic and immunologic
failure while on potent ART. These represent clinical failure of ART.
When to Initiate ART in the Setting of an OI
-No consensus has been reached about the optimal time to start ART in the presence of a recently diagnosed OI.
-The decision to start potent ART should consider
1) Availability of effective therapy for the OI
2) The risk for drug interactions
3) Overlapping drug toxicities
4) Risk and consequences of an inflammatory immune reconstitution syndrome
5) Willingness and ability of patients to take and adhere to their regimens.
-In cases of cryptosporidiosis, microsporidiosis, PML, and Kaposi sarcoma, the early benefits of potent ART
outweigh any increased risk, and potent ART should be started as soon as possible.
-In the setting of TB disease, MAC, PCP and cryptococcal meningitis, awaiting a response to OI therapy is usually
warranted before initiating ART.
-When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started, and ART should be
continued.
-When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated,
potent ART should be continued, and if the CD4+ T cell response to ART has been suboptimal, modification of the
ART regimen may be considered.
-When an OI occurs in the setting of virologic failure, OI therapy should be started, and the ART regimen should be
modified to achieve better virologic control.

-By far the most common form of arthritis in the elderly.

-Also known as osteoarthrosis and degenerative joint disease,
-characterized by a slowly progressive deterioration of a joint in which
1) Localized loss of cartilage
2) subchondral sclerosis

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 3) cyst formation
4) osteophytosis
5) Capsular and synovial thickening.
-Osteoarthritis is a dynamic condition, characterized by both reparative and degradative processes.
- Osteoarthritis has been divided into two main types:

A) Primary or idiopathic form

-Divided into subsets depending on clinical features

B) Secondary osteoarthritis
-In which some underlying condition is present. eg
a) childhood anatomic abnormalities (e.g., DDH, slipped femoral epiphyses)
b) Inheritable metabolic disorders ( alkaptonuria, Wilson's disease, hemochromatosis)
c) Neuropathic arthropathy (Charcot's joints)
d) Hemophilic arthropathy
e) Acromegalic arthropathy
f) Paget's disease
g) Hyperparathyroidism
h) Noninfectious inflammatory arthritis (e.g., rheumatoid arthritis, spondyloarthropathies)
i) Gout, calcium pyrophosphate deposition disease (pseudogout)
j) Septic or tuberculous arthritis
k) Post-traumatic
-Diabetic patients have a higher incidence of osteoarthritis than nondiabetics.
Incidence/Prevalence in USA:
· Estimates of radiographic evidence of OA - range from 33% to almost 90% in those people over the age of 65
Predominant age:
· Over age 40 (for symptomatic disease)
· Leading cause of disability in those over age 65
Predominant sex:
-Until middle age, osteoarthritis occurs with the same frequency in men and women, but after the age of 50
symptomatic osteoarthritis is more common in women, and this difference in prevalence widens with increasing
age.
-Women are also more likely to have multiple joint involvements.

Etiology
Genetic
-Genetic factors play a role in the development of Heberden's nodes. The genetic mechanism appears to involve a
single autosomal gene, sex influenced, dominant in women and recessive in men
-Characterized by the onset of primary generalized osteoarthritis at a young age
-Aging alone does not cause osteoarthritis, but matrix alterations that occur with aging may facilitate the process.
-Trauma, especially in the form of excessive repetitive impulse loading over many years, is likely to be an
important risk factor. Certain occupations are associated with a high incidence of osteoarthritis in specific joints that
are otherwise rarely involved in osteoarthritis. A single severe insult to a joint may lead to osteoarthritis many years
later.
-Chronic malalignment and ligamentous instability (either congenital or secondary to joint injury) resulting in
abnormal biomechanical forces are important factors in the development of osteoarthritis. Eventually, chondrocytes
react to trauma by enhancing the enzymatic breakdown of cartilage matrix while mounting an insufficient repair
response.

Pathophysiology
Biomechanical and metabolic changes
-In cartilage, such as decreased total proteoglycans content, shortening of the glycosaminoglycan branches, and a
decrease in the length of the subunit core protein. As the disease advances, the hyaluronate bind ring region becomes
defective, resulting in lack of aggregation. The total content of collagen in cartilage does not change in
osteoarthritis. However, the collagen fibers are less uniform in size and the weave is looser. Eventually the
supporting collagen network is disrupted, following the proteoglycans molecules to expand and imbibe water. This

220
exposure of water-binding proteoglycans explains the increased water content in osteoarthritic cartilage and its
swelling when immersed in water.
Inflammatory
-Synthesis and release of degradative enzymes, including acid cathepsins, neutral proteases, sugar-splitting
enzymes, and sulfatases
-Collagenase enzyme activity, which is difficult to demonstrate in normal cartilage, was positively correlated with
the severity of human osteoarthritic lesions based on histologic criteria.
-Concurrently with this accelerated breakdown of cartilage matrix, the chondrocyte increases its synthesis of
proteoglycans, type II collagen, and hyaluronic acid, in an attempt to reverse the depletion of matrix constituents
-The products of regenerating cartilage appear to differ slightly in structure and function from their normal
counterparts.
-Eventually, the disease progresses to a stage where tissue changes are so severe that the chondrocyte "fails," and
synthesis of matrix constituents diminishes.
-Immunological factors are all implicated in pathogenesis of osteoarthritis interleukin-1 and tumor necrosis factor,
enhance the enzymatic degradation of cartilage matrix and that a number of growth factors stimulate matrix
formation
Focal, chronic synovitis, characterized by lymphocyte and mononuclear cell infiltration, is frequently seen in
osteoarthritis.
-This is probably due to secretion of inflammatory mediators initiated by the release of hydroxyapatite or calcium
pyrophosphate crystals or by cartilage breakdown components, and/or the presence of immune complexes in the
surface of the cartilage.

Risk factors
· Age over 50
. Obesity (weight bearing joints)
· Prolonged occupational or sports stress

Differential diagnosis
· Distinguish from other types of arthritis by absent systemic findings, minimal articular inflammation, and
distribution of involved joints (e.g., distal and proximal interphalangeal joints, not wrist and metacarpophalangeal
joints)
· In spine, distinguish from osteoporosis, metastatic disease, multiple myeloma, other bone disease
. Neurologic complications of osteoarthritis of the cervical spine may be confused with amyotrophic lateral
sclerosis, spinal cord tumors, and basilar artery disease

Laboratory
- Not helpful (sedimentation rate not increased)

Imaging
-X-rays usually normal early; later often show
 Narrowed joint space
 osteophyte formation
 subchondral bony sclerosis
 cyst formation
 Erosions may occur on surface of distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints
when OA is associated with inflammation (erosive osteoarthritis).
-In advanced cases, there is gross deformity and subluxation. Osteoporosis is not a feature of osteoarthritis
Disorders that may alter lab results:
- In secondary OA, the underlying disorder may have abnormal lab results, e.g., hemochromatosis - abnormal iron
studies

Pathological findings
-Synovial fluid may have a slightly increased white blood cell count, predominantly mononuclear
-Calcium pyrophosphate dihydrate and/or apatite crystals may occasionally be seen in effusions and require
polarized light microscopy or special techniques to see
·-Subchondral bone trabecular microfractures

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-Degradation response produced by release of proteolytic enzymes, collagenolytic enzymes, prostaglandins, and
immune responses
Diagnostic procedures
 Joint aspiration
-May be helpful to distinguish between OA and chronic inflammatory arthritides
-OA - cell count usually < 500 cells/mm3, predominantly mononuclear
-Inflammatory - cell count usually > 2000 cells/mm3, predominantly neutrophils

Clinical presentation
The joints commonly affected in osteoarthritis are the
 distal and proximal interphalangeal joints of the hands
 First carpometacarpal join
 the first metatarsophalangeal joint
 the hip and the knee,
 spine
-For reasons that are unclear, the wrist, elbow, shoulder, and ankle are spared, except with previous trauma or
congenital anomaly.
1) Pain on motion and later also at rest;
2) Limitation of motion due to incongruity of joint surfaces, muscle or capsular contracture
2) Stiffness (especially morning and after sitting so-called gelling) of less than 30 minutes duration
3) Joint enlargement (e.g., Heberden's nodes of distal interphalangeal joints)
-Heberden's nodes are characterized by bony enlargement of the dorsolateral and dorsomedial aspects of the distal
interphalangeal joints of the fingers.

-Flexor and lateral deviation of the distal phalanx are common.

Similar nodes at the proximal interphalangeal joints are known as Bouchard's nodes.
-Heberden's nodes are prevalent in the elderly. They may be single, but they usually are multiple. In most patients
they develop slowly over months or years, giving rise to little or no pain. In a few patients, they evolve rapidly with
involvement of the first carpometacarpal joint is common and is frequently symptomatic.
- Marked osteophytosis at this site leads to a characteristic squaring appearance of the hands.
5) Tenderness usually absent; may be associated with synovitis, with tenderness along joint margin
6) Crepitation as late sign
· Local pain and stiffness with osteoarthritis of spine, with radicular pain (if there is compression of nerve

Management
-Enhancement and preservation of functional ability, such as walking, dressing, and living independently.
-The principal aims on
 Protecting joints from excessive loading
 Maintaining joint motion and stability
 Reducing symptoms of pain and stiffness.
NB
-Erosive inflammatory osteoarthritis is a variant of osteoarthritis of the hands.
-This entity, which most often affects postmenopausal women, involves the distal and proximal interphalangeal
joints and less often the metacarpophalangeal joints. Painful inflammatory episodes eventually lead to joint
deformities and sometimes to ankylosis.
-After years of intermittent acute flares, the joints become quiescent. The clinical picture may be confused with
rheumatoid arthritis

General measures
1) Reassurance of absence of generalized systemic disease, with recognition of potential disability from
osteoarthritis
2) Weight reduction if obese
3) General fitness program
4) Heat (local, tub baths, etc.)
5) Physical therapy to maintain or regain joint motion and muscle strength. Quadriceps strengthening exercises can
relive pain and disability of the knee.

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6) Protect joints from overuse (e.g., cane, crutches, walker, neck collar, elastic knee support

Biomechanical Approaches to Therapy

-Correction of excessive and harmful loading becomes a high priority.
1. Patients with obesity lose weight
2 Reducing the load in affected joints include the use of
 walking aids
 wedged insoles that change the angle of the legs,
 Heel lift if one leg is shorter than the other
3. Occupational therapy to modify activities of daily living can reduce unnecessary overloading of the joints of the
upper and lower extremities.

Exercise Program
-A structured exercise program does not appear to accelerate joint destruction, and is believed to be important in the
maintenance of normal cartilage. Aerobic, low-impact exercises in patients with symptomatic osteoarthritis of the
eight-bearing joints improved their aerobic capacity, endurance, ability to walk, and sense of well-being, without
increasing their joint symptoms.
-Several short periods of walking, interspersed with rest periods, are preferable to sustained walking for the patient
with osteoarthritis of the hip or the knee.
-A body-toning exercise program such as regular swimming or riding stationary bicycle is well tolerated. Strenuous
exercises and stair climbing should be avoided whenever possible.
-Specific exercises to improve the strength of muscle groups include isometric, isokinetic, and isotonic exercises.

Pharmacological management
-Use of NSAIDS

Surgery
Arthroscopic Joint Debridement
-Flaps of undermined cartilage and frayed cartilage can cause pain and muscle spasm if they become caught in the
joint

Realignment Osteotomies
-In the early stages of osteoarthritis of the hip and knee, the weight-bearing areas of the joint are primarily affected.
-Osteotomies are used to redirect the weight to areas of cartilage that have remained relatively intact

Joint Fusion
-Joint fusion involves removing the joint and holding the bones on either side of the joint together so that they heal
to form one longer bone.
- Joint fusion has always been the most effective way to permanently eliminate the pain

Total Joint Arthroplasty

-Total joint arthroplasties are procedures that replace the articular surfaces of joints with one or more artificial
substances including: metal, ultra-high-density polyethylene, ceramic, and Silastic

-Arthroplasties of the hip and knee should not be considered unless the joint is irreversibly damaged, with areas of
full-thickness loss of cartilage,

PEPTIC ULCER DISEASE

Definition
-Peptic ulcer disease (PUD) refers to a discrete mucosal defect in the portions of the gastrointestinal tract (gastric or
duodenal) exposed to acid and pepsin secretion.
-The mucosal break, 3 mm or greater in size with depth,
Pathophysiology:
-Results from imbalances between the mucosa protective factors and those that tend to cause injury to mucosa.

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-Injurious factors include the following:
1) H pylori- leading cause of PUD and is associated with virtually all ulcers not induced by NSAIDs
2) NSAIDs
3) Acid and pepsin.
4) Cigarette Smoking
5) Ethanol
6) Bile acids
7) Steroids
8) Psychological stress.
Important protective or defensive factors are
-Mucus
-Bicarbonate
-Mucosal blood flow
-Prostaglandins
-Alkaline tide
-Hydrophobic layer
-Restitution
-Epithelial renewal.

Causes:
1. H pylori infection
-Most common cause of PUD
-Associated with up to 70-80% of duodenal ulcers: however, rate is decreasing, suggesting an increasing number of
H pylori–negative ulcers
-Prevalence in complicated ulcers (ie, bleeding, perforation) significantly lower than that found in uncomplicated
ulcer disease
Found in:
-90% patients with duodenal ulceration
-70% patients with gastric ulceration
-60% patients with gastric cancer

2. NSAIDS
-Second most common cause of PUD
-Addition of steroids potentiates risk
-Accounts for many H pylori–negative ulcers
3. Severe physiologic stress
 -Burns
 -CNS trauma
 -Surgery
 -Severe medical illness
4. Hypersecretory states (uncommon)
 -Gastrinoma (Zollinger-Ellison syndrome) or multiple endocrine Neoplasia (MEN-I)
 -Antral G cell hyperplasia
 -Systemic mastocytosis
 -Basophilic leukemias
5. Systemic diseases with an increased risk of PUD
 Cirrhosis
 Chronic pulmonary disease
 Renal failure and renal transplantation.
6. Additional rare, miscellaneous causes include
 Radiation-induced or chemotherapy-induced ulcers
 vascular insufficiency (crack cocaine),
 Duodenal obstruction.

DDX

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-Biliary Colic
-Cholecystitis
-Cholelithiasis
-Gastritis, Acute
-Gastritis, Chronic
-Gastroesophageal Reflux Disease
-Mesenteric Artery Ischemia
-Myocardial Ischemia
-Pancreatic Cancer or Pancreatitis, Acute
Chronic

Clinical presentation
History:
1-Epigastric pain (the most common symptom)
 Gnawing or burning
 Occurs 1-3 hours after meals
 Relieved by food or antacids
 Might occur at night
 Might radiate to back (consider penetration)
2-Nausea
3-Vomiting, which might be related to partial or complete gastric outlet obstruction
4-Dyspepsia, including belching, bloating, distention, fatty food intolerance
5-Heartburn
6-Chest discomfort
7-Anorexia, weight loss
8-Hematemesis or melena resulting from gastrointestinal bleeding
-Dyspeptic symptoms that might suggest PUD are not specific because only 20-25% of patients with symptoms
suggestive of peptic ulceration are found on investigation to have a peptic ulcer.
Physical:
In uncomplicated PUD, clinical findings are few and nonspecific.
-Epigastric tenderness
-Parlor-mild-moderate
-Succussion splash resulting from partial or complete gastric outlet obstruction

Lab Studies:
-In most patients with uncomplicated PUD, routine laboratory tests are usually unhelpful.
-Documentation of PUD depends on radiographic and endoscopic confirmation.
-If the diagnosis of PUD is unclear or complicated and PUD is suspected, obtaining CBC, liver function tests
(LFTs), amylase, and lipase might be useful.
Imaging Studies:
Upper gastrointestinal series
a)Double-contrast radiography
However, it has been replaced largely by diagnostic endoscopy, when available.
-It is not as sensitive as endoscopy for the diagnosis of small ulcers (<0.5 cm).
-It does not allow for obtaining a biopsy to rule out malignancy in the setting of a gastric ulcer or to assess for H
pylori infection in the setting of a gastroduodenal ulcer.
b)Upper GI endoscopy
-Preferred diagnostic test in the evaluation of patients with suspected PUD
-Highly sensitive for the diagnosis of gastric and duodenal ulcers
-Allows for biopsies and cytologic brushings in the setting of a gastric ulcer in order to differentiate a benign ulcer
from a malignant lesion
-Allows for detection of H pylori infection with antral biopsies for a rapid urease test and/or histopathology in
patients with PUD
 Rapid urease tests are considered the endoscopic diagnostic test of choice. One or more gastric biopsy
specimens are placed in the rapid urease test kit. If H pylori are present, bacterial urease converts urea to
ammonia, which changes pH and produces a color change.

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  Histopathology, the criterion standard for the diagnosis of H pylori
 Culture primarily is used in research studies
Non endoscopic or noninvasive tests
Special studies
-Obtaining a serum gastrin is useful in patients with recurrent, refractory, or complicated PUD and is useful in
patients with a family history of PUD to screen for Zollinger-Ellison syndrome
-A secretin stimulation test can be performed to distinguish Zollinger-Ellison syndrome from other conditions with a
high serum gastrin, such as achlorhydria and antisecretory therapy with a proton pump inhibitor.
Medical treatment
Tripple therapy
-Initial treatment typically requires a triple therapy with 2 antibacterial agents and an acid inhibitor, typically a
proton-pump inhibitor (PPI).
-Drug regimens most often include 2 weeks of antibacterial therapy concomitant with 4 weeks of acid suppression

-In adults, standard Maastricht triple therapy is a combination of a PPI, amoxicillin, and clarithromycin.
- In the event eradication fails, a quadruple therapy with PPI, bismuth, metronidazole, and tetracycline has been
suggested.

Less favorable options

H2 Antagonists
-65% healing at one month
-85% healing at two months
-If stop treatment - 90% recurrence at 2 years
-If maintenance therapy - 20% recurrence at 5 years

Surgical Care:
-With the success of medical therapy, surgery has a very limited role in the management of PUD.
-Potential indications for surgery include refractory disease, and complications of PUD include the following:
 Perforation usually is managed emergently with surgical repair.
 Obstruction -may persist or recur despite endoscopic balloon dilation.
 Massive hemorrhage and hemodynamic instability, recurrent bleeding on medical therapy, and failure of
therapeutic endoscopy to control bleeding.
-The appropriate surgical procedure depends on the location and nature of the ulcer.
 Carbon breath tests detect active H pylori infection by testing for the enzymatic activity of bacterial
urease. In the presence of urease produced by H pylori, labeled carbon dioxide (heavy isotope, carbon-13,
or radioactive isotope, carbon-14) is produced in the stomach, absorbed into the bloodstream, diffused into
the lungs, and exhaled.
 Fecal antigen testing identifies active H pylori infection by detecting the presence of H pylori antigens in
stools. This test is more accurate than antibody testing and less expensive than urea breath tests.
 Serology-Antibodies (immunoglobulin G [IgG]) to H pylori can be measured in serum by ELISA

 Additional surgical options for refractory or complicated PUD include vagotomy and pyloroplasty,
vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I) or gastrojejunal reconstruction
(Billroth II), or a highly selective vagotomy.
SURGICAL ASPECTS OF PUD
BLEEDING
When should operation be performed?
What operation should be done?
Clinical predictors of continued/recurrent bleeding
1) Shock (SBP < 100 mmHg)
2) Anemia (hemoglobin <7, <10)
3) High transfusion requirement (2000 cc/24, 5 units total)
4) Age > 60 (comorbidities)
5) Bleeding rate of > 600cc/hour as measured hematemesis

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-Clinical and endoscopic features can predict rebleeding and mortality
-Early operation an appropriate consideration, ideally after stabilization, if rebleeding risk is high
-Availability of endoscopic hemostatic techniques can greatly diminish need for urgent surgery in many, but not all
cases
Value of endoscopic treatment and re-treatment
-80-100% initial hemostasis rates
-75% success with endoscopic retreatment
-Slight increased risk of perforation with thermal re-rx
Choice of operation--gastric ulcers
-Generally higher rebleeding rate with gastric lesions compared to duodenal
-Location and setting influence choice of operation
Gastric ulcer typology (Modified Johnson Classification)
Type I: incisura, lesser curve
Type II: associated duodenal ulcer disease
Type III: antral/prepyloric
Type IV: high lesser curve/gastroesophageal junction
Type V: associated with NSAID use

Choice of operation--type I, II, III

-Distal gastrectomy incorporating ulcer and Billroth I reconstruction
-No vagotomy necessary in pure type I setting
-Add vagotomy if type II, ongoing ulcerogenic stimulus (alcohol, steroids, NSAID’s), type III within 3 cm of
pylorus
-Consider vagotomy and pyloroplasty with oversew or wedge excision if unacceptable risk for gastrectomy, accept
15% higher risk of rebleeding
Billroth I (gastroduodenostomy)
Billroth II (gastrojejunostomy)
Choice of operation--type IV
-Pauchet procedure (distal gastrectomy with lesser curve tongue-extension to incorporate higher ulcer and Billroth
I reconstruction)
-Csendes operation (gastrectomy incorporating portion of GE junction on lesser curve side and
esophagogastrojejunostomy)
-Kelling-Madlener procedure (antrectomy with oversew/bx of ulcer left in situ)
Operation for bleeding duodenal ulcer
-Truncal vagotomy and pyloroplasty with oversew most attested and efficient operation in less stable patient
-Antrectomy a useful alternative in stable patient with large ulcers (>2 cm)
-Increased bleeding and rebleeding with giant ulcers
-Nissen closure technique can be a helpful adjunct with large posterior ulcers into pancreas or adjacent structures
What about H. pylori?
• Clear data available showing lower rebleeding rates with H. pylori eradication
PEPTIC PERFORATION
Nonoperative treatment
Operative treatment
–risk status
–definitive surgery vs. simple closure
–? laparoscopy
Nonoperative treatment-Indications
1. Water soluble contrast study documenting sealed perforation
2. Age<70
3. NG tube, antibiotics, acid suppression, IVF
4. Improving exam and clinical signs within 12 hours
-70% success rate in avoiding surgery, 35% longer hospital stay
Operative treatment--risk assessment
-Age>70

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-perforation>24 hours
-SBP<100
-poorly controlled comorbid conditions define high risk patient
Graham patch
Benefits of definitive operation
-High risk of recurrent ulcer disease (48-60%) if simple closure done, though this can be lowered by long term acid
suppression
-PCV lowers above to 3-7%, can be combined with patch closure
GASTRIC OUTLET OBSTRUCTION
-Acute vs. chronic, natural history
-Nonsurgical options
-Surgical options
Natural history--peptic gastric outlet obstruction
-68% of acute obstructions and 98% chronic obstructions ultimately require surgery
-Nonoperative strategies for peptic GOO
Balloon dilation
-76% immediate improvement, but only 38% objective improvement at 3 mos.
Issues
-Parietal cell vs. truncal vagotomy
-Dilation vs. drainage
-Type of drainage procedure
 Pyloroplasty/duodenoplasty (Heineke-Mikulicz, Finney)
 Gastroduodenostomy (Jaboulay)
 Gastrojejunostomy
 Antrectomy/anastomosis

PERICARDIAL EFFUSION
Definition
-Pericardial effusion defines the presence of an abnormal amount and/or character of fluid in the pericardial space.
-Cardiac tamponade is a clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in
reduced ventricular filling and subsequent hemodynamic compromise.
Introduction
-It can be caused by a variety of local and systemic disorders, or it may be idiopathic.
-Pericardial effusions can be acute or chronic, and the time course of development has a great impact on the patient's
symptoms.
-Treatment varies, and is directed at both removal of the pericardial fluid and alleviation of the underlying cause,
which usually is determined by a combination of fluid analysis and correlation with co morbid illnesses.
-Cardiac tamponade is a medical emergency. The overall risk of death depends on the speed of diagnosis, the
treatment provided, and the underlying cause of the tamponade
Pathophysiology:
-The pericardial space normally contains 15-50 cc of fluid, which serves as lubrication for the visceral and parietal
layers of the pericardium.
-This fluid is thought to originate from the visceral pericardium and is essentially an ultrafiltrate of plasma. Total
protein levels are generally low; however, the concentration of albumin is increased in pericardial fluids owing to its
low molecular weight.
-The cause of abnormal fluid production depends on the underlying etiology, but usually it is secondary to injury or
insult to the pericardium (i.e., pericarditis).
-Transudative fluids result from obstruction of fluid drainage, which occurs through lymphatic channels.
-Exudative fluids occurs secondary to inflammatory, infectious, malignant, or autoimmune processes within the
pericardium.
-Clinical manifestations of pericardial effusion are highly dependent upon the rate of accumulation of fluid in the
pericardial sac. -Rapid accumulation of pericardial fluid may cause elevated intrapericardial pressures with as little
as 80 cc of fluid, while slowly progressing effusions can grow to 2 liters without symptoms.
-The underlying pathophysiologic process for the development of tamponade is markedly diminished diastolic
filling because transmural distending pressures are insufficient to overcome the increased intrapericardial pressures.

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-Systemic venous return is also altered during tamponade. Because the heart is compressed throughout the cardiac
cycle due to the increased intrapericardial pressure, systemic venous return is impaired and right atrial collapse
occurs. During inspiration, intrapericardial and right atrial pressures decrease because of negative intrathoracic
pressure. This results in augmented systemic venous return to right-sided chambers and a marked increase in the
right ventricular volume. Because the pulmonary vascular bed is a vast and compliant circuit, blood preferentially
accumulates in the venous circulation, at the expense of LV filling.
-This results in a reduced cardiac output.
-The amount of pericardial fluid needed to impair the diastolic filling of the heart depends on the rate of fluid
accumulation and the compliance of the pericardium. Rapid accumulation of as little as 150 mL of fluid can result in
a marked increase in pericardial pressure and can severely impede cardiac output, whereas 1000 mL of fluid may
accumulate over a longer period without any significant effect on diastolic filling of the heart. This is due to
adaptive stretching of the pericardium over time. A more compliant pericardium can allow considerable fluid
accumulation over a longer period without hemodynamic insult.
Age:
-Observed in all age groups
-Mean occurrence in fourth or fifth decades; earlier in patients with HIV

Causes:
1. Idiopathic
2. Hydropericardium - Congestive heart failure, valvular disease
3. Neoplastic - Malignant, nonmalignant.
-Not all cancer-associated effusions are malignant.
- Mediastinal lymphoma, Hodgkin disease, and metastatic breast cancer have been found to cause transient
effusions, likely due to impaired lymphatic drainage, which do not cause long-term sequelae.
-Also Lung cancer.
4. Infectious - Bacterial, viral, fungal, parasitic, tuberculosis, HIV related
5. Autoimmune or connective tissue disorders – SLE, RA, systemic sclerosis, vasculitides
6. Trauma
7. Uremic pericarditis
8. Drugs
9. Postpericardiotomy syndrome
10. Chylopericardium.
11. Myxedema
12. Radiation.

DDX.
Cardiac Tamponade

Cardiomyopathy, Dilated

Myocardial Infarction

Myocardial Ischemia

Pericarditis, Acute

Pericarditis, Constrictive
 Pericarditis, Constrictive-Effusive

Pericarditis, Uremic
 Pulmonary Edema, Cardiogenic
Pulmonary Embolism

Clinical presentation
History:
a) Cardiovascular
Chest pain, pressure, discomfort
 Light-headedness, syncope
 Palpitations

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b) Respiratory - Cough, dyspnea, hoarseness
c) Gastrointestinal – Hiccough
d) Neurologic - Anxiety, confusion
Pericarditis
-The most common symptom of acute pericarditis is precordial or retrosternal chest pain, usually described as sharp
or stabbing.
-Pain may be of sudden or gradual onset and may radiate to the back (left trapezial ridge), neck, left shoulder, or
arm.
-Movement or inspiration may aggravate the pain.
-Pain may be most severe when the patient is supine and can be relieved when the patient leans forward while
sitting.
-Common associated signs and symptoms include low-grade intermittent fever, dyspnea, cough, and dysphagia.
- In tuberculous pericarditis, fever, night sweats, and weight loss were commonly noted (80%).
-Patients can present with acute abdominal pain.
Physical:
Pericarditis
-Pericardial friction rub, which is best heard at the lower left sternal border or apex when the patient is positioned
sitting forward or on hands and knees. A friction rub may be distinguished from a cardiac murmur by its changing
character from heartbeat to heartbeat and patient position changes.
-Fever: Fevers usually are low grade, but they occasionally reach 104°F.
-Cardiac arrhythmias: Premature atrial and ventricular contractions occasionally are present.
Cardiac tamponade
-Cardiovascular
Classic Beck triad of pericardial tamponade - Hypotension, muffled heart sounds, jugular venous
distension
 Pulsus paradoxus-, defined as a decrease in systolic blood pressure of more than 10 mm Hg with
inspiration, signaling falling cardiac output during inspiration
 Pericardial friction rub - Best heard in seated and bent forward position with the holding of breath, at end
exhalation, with diaphragm of stethoscope
 Widened pulse pressure
 Tachycardia
 Hepatojugular reflux - Can be observed by applying pressure to the periumbilical region. A rise in the
jugular venous pressure (JVP) of greater than 3 cm H 2O for greater than 30 seconds suggests elevated
central venous pressure .Transient elevation in JVP may be normal.
-Respiratory
Tachypnea
Cyanosis-may occur
 Decreased breath sounds (secondary to pleural effusions)
 Ewart sign - Dullness to percussion and bronchial breathing beneath the angle of left scapula from
compression of the left lung by pericardial fluid
-Gastrointestinal – Hepatosplenomegaly
-Extremities-Weakened peripheral pulse, Edema
-Kussmaul's sign-rise in JVP on inspiration. Seen in conditions in which right ventricular filling is limited by:
 Pericardial fluid,
 Non-compliant pericardium or
 Myocardium

-The classical differential diagnosis is:

Constrictive pericarditis
 Restrictive cardiomyopathy
 Cardiac tamponade

Investigations
Lab Studies:
1. U/E/C-Metabolic abnormalities (e.g., renal failure)

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2. CBC count with differential
Leukocytosis for evidence of infection, as well as cytopenias, as signs of underlying chronic disease (e.g.,
cancer, HIV)
3. Cardiac enzymes - To rule out myocardial ischemia
4. Thyroid-stimulating hormone
- Thyroid-stimulating hormone screen for hypothyroidism
5. Rickettsial antibodies - If high index of suspicion of tick-borne disease
6. Rheumatoid factor, ANA, ANCA, and complement levels-connective tissue diseases.
7. Pericardiocentesis
-The Light criteria (for exudative pleural effusion) found to be as reliable in distinguishing between exudative and
transudative effusions
Total protein fluid-to-serum ratio >0.5
 Total protein >3.0 mg/dl
 LDH fluid-to-serum ratio >0.6
 LDH fluid level exceeds two thirds of upper-limit of normal serum level
 LDH >300 U/dl
 Specific gravity >1.015
 Glucose fluid-to-serum ratio <1
-Cell count - Elevated leukocytes (i.e., >10,000) with neutrophil predominance suggests bacterial or rheumatic
cause, although unreliable
-Gram stain and AFB.
-Cultures - Signals and identifies infectious etiology
-Fluid hematocrit for bloody aspirates - Hemorrhagic fluid hematocrits usually significantly less than simultaneous
peripheral blood hematoma
8. Balloon pericardotomy
-A catheter is placed in the pericardial space under fluoroscopy, which, after inflation of the balloon, creates a
channel for passage of fluid into the pleural space, where reabsorption occurs more readily.
-This may be useful for recurrent effusions.
9. Pericardial sclerosis
-Several pericardial sclerosing agents have been used with varying success rates (e.g., tetracycline, doxycycline,
cisplatin, 5-fluorouracil).
10. Pericardioscopy
-This procedure is not universally available.
-It may increase diagnostic sensitivity in cases of unexplained pericardial effusions. It allows for visualization of
pericardium and for pericardial biopsies
Imaging Studies:
CXR
Cardiomegaly
 A third of patients have a coexisting pleural effusion
Echocardiogram
This is the criterion standard for noninvasive diagnosis
 Pericardial effusion appears as an "echo-free" space between the visceral and parietal pericardium
 False-positive echocardiograms can occur in pleural effusions, pericardial thickening, increased pericardial
fat (especially the anterior epicardial fat pad), atelectasis, and mediastinal lesions.
 Transesophageal echocardiography: -useful in characterizing loculated effusions
CT scan
May detect as little as 50 cc of fluid\
 Fewer false-positives than with echocardiography
MRI
Can detect as little as 30 cc of pericardial fluid
 May be able to distinguish hemorrhagic and nonhemorrhagic effusions

Other Tests:
ECG: Classic findings include

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 low voltage, sinus tachycardia
 Electrical alternans
 PR-segment depression
 Diffuse ST elevation if pericarditis is present
Procedures:
Pericardiocentesis
-This procedure is used for diagnostic as well as therapeutic purposes.
-Support for the use of echocardiographic guidance is increasing, unless emergent treatment is required.
-Indications include impending hemodynamic compromise (i.e., pericardial tamponade), suspected infectious
etiology, and uncertain etiology.
-Attaching an ECG electrode to the pericardiocentesis needle is also useful for avoiding myocardial puncture.
-Electrical activity will be seen on the monitor when the needle comes into contact with atrial or ventricular
myocardium.
-Complications of pericardiocentesis include ventricular rupture, dysrhythmias, pneumothorax, myocardial and/or
coronary artery laceration, and infection.
-Recurrence rates within 90 days may be as high as 90% in patients with cancer

Medical Care:
-Initially, medical care is focused on determination of the underlying etiology.
-Intravenous fluid resuscitation may be helpful in cases of hemodynamic compromise.
-Antineoplastic therapy (e.g., systemic chemotherapy, radiation) in conjunction with pericardiocentesis has been
shown to be effective in reducing recurrences of malignant effusions.
-Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are helpful in patients with autoimmune
conditions.
Surgical Care:
Subxiphoid pericardial window with pericardiostomy
-This procedure is associated with low morbidity, mortality, and recurrence rates.
-It can be performed under local anesthesia.
-It may be less effective when effusion is loculated.
-It may replace pericardiocentesis as initial treatment for stable pericardial effusions.
-May be safer and more effective at reducing recurrence rates than pericardiocentesis.
Thoracotomy
-This should be reserved for patients in whom conservative approaches have failed.
-Thoracotomy allows for creation of a pleuropericardial window, which provides greater visualization of
pericardium.
Video-assisted thoracic surgery
-Video-assisted thoracic surgery (VATS) enables resection of a wider area of pericardium than the subxiphoid
approach without the morbidity of thoracotomy.
-One disadvantage of VATS is that it requires general anesthesia with single lung ventilation, which may be difficult
in otherwise seriously ill patients.
Median sternotomy
-This procedure is reserved for patients with constrictive pericarditis.
-Operative mortality rate is high (5-15%).

PHEOCROMOCYTOMAS
The tumor may be associated with such neurocutaneous syndromes as
 Neurofibromatosis
 von Hippel-Lindau disease
 tuberous sclerosis
 Sturge-Weber syndrome
 Component of multiple endocrine neoplasia 2.
SIGNS AND SYMPTOMS:
Paroxysmal spells (the "5 P's")
 Pressure - sudden increase in blood pressure
 Pain - headache, chest and abdominal pain

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  Perspiration
 Palpitation
 Pallor
Additional symptom
 Constipation
 Tremor
 Weight loss
 Anxiety
Signs
à Hypertension - paroxysmal in half of the patients
à Orthostatic hypotension
à Grade II to IV retinopathy
à Fever
à Hyperglycemia
à Hypercalcemia
à Erythrocytosis

Catecholamine-producing tumor - "Rule of 10:"

 10% are extra-adrenal
 10% are multiple or bilateral
 10% are malignant
 10% recur after surgical removal
 10% occur in children
 10% are familial
 10% present as adrenal incidentalom
 10% of patients are asymptomatic

RISK FACTORS:
· Familial pheochromocytoma
· Multiple endocrine neoplasia types II A and B-
MEN II A Syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, and
hyperparathyroidism.
MEN IIB A syndrome characterized by, medullary carcinoma of the thyroid, and pheochromocytoma, often
associated with a marfanoid habitus, multiple mucosal neuromas
NB
MEN 1
A syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, and pituitary gland.
· Neurofibromatosis
· Von Hippel-Lindau syndrome

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ACUTE RHEUMATIC FEVER
Major Jones criteria
1.Migratory polyarthriris
2.Subcuateous nodules
3.Eryhthema marginatum
4.Pancarditis
5.Sydenham’s Chorea
Minor Criteria
Clinical
1.Fever
2.arthralgia
3.Previous evidence of acute rheumatic fever or RHD
Laboratory
1.Raised ESR or C-reactive proteins
2.Prolonged PR interval
3.Leucocytosis
PLUS
Evidence of strep infection
Antibody levels against one or more streptococcal extracellular products, such as streptolysin O, are regularly
increased.
Antistreptolysin O (ASO) is elevated in approximately 80% of cases; ASO levels of at least 250 Todd’s units in
adults 333 units in children
Other available antibody tests are
-Antideoxyribonuclease B (anti-DNase B)
-antihyaluronidase (AH
-Antistreptokinase (ASK), and antinicotinamide-adenine dinucleotidase (anti-NADase).
Diagnosis-2 major criteria
1 major and 2 minor criteria

The clinical Keith-Wagener-Barker classification (1939) describes the combined effects of hypertension and
arteriosclerosis on the retinal vessels
. It
divides such changes into four grades.
Grade 1. Arterial tortuousity, localized arterial spasm or narrowing, silver wiring.
Grade 2. Extensive or generalized arteriolar narrowing resulting in changes in arteriovenous crossing (arterial
nicking).
Grade 3. Haemorrhages or exudates.
Grade 4. Papilloedema.

Folate deficiency may also result from increased loss of folate secondary to renal dialysis or the administration of
some drugs such as phenytoin, primidone, barbiturates, methotrexate, nitrofurantoin, or sulfasalazine

Onycholysis (destruction of the nails) is seen with hyperthyroidism, fungal nail infection, and psoriasis.

Causes of thyrotoxicosis
A.Primary hyperthyroidism
1) Graves' disease
2) Toxic multinodular goiter
3) Toxic adenoma
4) Functioning thyroid carcinoma metastases
5) Activating mutation of the TSH receptor
6) Activating mutation of Gsα (McCune-Albright syndrome)
7) Struma ovarii
8) Drugs: iodine excess (Jod-Basedow phenomenon)
B. Secondary hyperthyroidism
1) TSH-secreting pituitary adenoma
2) Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis
3) HCG-secreting tumors

234
Causes of Hypothyroidism

4) Gestational thyrotoxicosis
C. Thyrotoxicosis without hyperthyroidism
1) Sub acute thyroiditis
2) Silent thyroiditis
3) Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma
4) Ingestion of excess thyroid hormone (thyrotoxicosis factitia)

Nb. Circulating TSH levels are low in these forms of secondary hyperthyroidism.

A.Primary Hypothyroidism
12) Autoimmune hypothyroidism:
 Hashimoto's thyroiditis
 Atrophic thyroiditis
13) Drugs:
 iodine excess (including iodine-containing contrast media)
 Amiodarone
 Lithium
 Anti-thyroid drugs
 p-aminosalicyclic acid
 interferon-α
 other cytokines, aminoglutethimide

14) Iatrogenic:
 131I treatment
 Subtotal or total thyroidectomy
 External irradiation of neck for lymphoma or cancer
15) Congenital hypothyroidism
 Absent or Ectopic thyroid gland
 Dyshormonogenesis
 TSH-R mutation
16) Infiltrative disorders
 Amyloidosis
 Sarcoidosis
 Hemochromatosis
 Scleroderma
 Cystinosis
 Riedel's thyroiditis
17) Iodine deficiency
18) Overexpression of type 3 deoiodinase in infantile hemangioma
19) Transient
20) Silent thyroiditis, including postpartum thyroiditis
21) Subacute thyroiditis
22) Withdrawal of thyroxine treatment in individuals with an intact thyroid
B.Secondary Hypothyroidism
5) Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan's syndrome,
trauma, genetic forms of combined pituitary hormone deficiencies
6) Isolated TSH deficiency or inactivity
7) Bexarotene treatment
8) Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

NEUROFIBROMATOSIS
Description
The most common of the neurocutaneous syndromes (phakomatosis), consisting of Neurofibromatosis Type 1 (1 in
4,000) and Neurofibromatosis Type 2 (1 in 50,000).

235
Although named similarly, and both autosomal dominant disorders,they are two distinctly different conditions with
genes now identified on two separate chromosomes.
Type 1 (NF 1) is also known as von Recklinghausen disease
Type 2 (NF 2) as bilateral acoustic neurofibromatosis
System(s) affected:
Nervous, Skin/Exocrine, Musculoskeletal
Genetics:
·NF1: autosomal dominant inheritance.
Nearly 50% of cases are attributed to new mutations. The NF 1 gene mapped to chromosome 17. Prenatal diagnosis
possible.
·NF2: Autosomal dominant inheritance. The NF 2 gene mapped on chromosome 22.
Predominant sex: Male = Female

SIGNS AND SYMPTOMS:

· NF1: Two or more of the following:
Skin
1) Six or more cafe au lait spots measuring 5 mm or more in prepubertal individuals or 15 mm or more in
adults (97%)
2) Two or more neurofibromata
3) Axillary or inguinal freckling (91%)
Eye
4) Two or more Lisch nodules (30%)- iris harmatoma
5) Optic glioma (4%)
Bone
6) Characteristic osseous lesions such as sphenoid dysplasia, long bone cortical thinning, ribbon ribs,
angular scoliosis (6%)
Family
7) First degree relative with NF 1, according to above criteria
Symptoms and Signs:
The most common presenting symptoms are cognitive or psychomotor problems such as school difficulties; 40% of
patients have learning disabilities, and mental retardation is seen in 8%.
-The history should focus on lumps or masses causing disfigurement, functional problems, or pain.
Visual problems; strabismus or amblyopia dictates a search for optic glioma
-Any progressive neurologic deficit might call for studies to rule out tumor of the spinal cord or central
neurofibroma
blood pressure and examine the spine for scoliosis and the limbs for pseudarthroses.
Head measurement often shows macrocephaly. Hearing and vision need to be assessed.
The eye examination should include a check for proptosis and iris Lisch nodules; he optic disk should be examined
for atrophy or papilledema.
Short stature and precocious puberty are occasional findings. An examination for neurologic manifestations of
tumors (eg, asymmetric reflexes, spasticity) is important.
NF2: When one or more present, diagnosis is likely:
1) Bilateral vestibular schwannomas
2) Family history of NF 2, plus unilateral 8th nerve mass or
3) family history and any two of the following: neurofibroma, meningioma , glioma, schwannoma, and
juvenile posterior subcapsular lenticular opacity.
CAUSES:
· Congenital

RISK FACTORS:
· Family history

DIFFERENTIAL DIAGNOSIS:
· NF1:
à Familial cafe au lait spots (autosomal dominant) ¾ no other NF1 features

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Patients with Albright's syndrome often have larger cafe au lait spots with precocious puberty. Many normal
individuals have one or two cafe au lait spot
· NF2:
à Solitary acoustic neuroma (develops later in life and is not hereditary)
Management
NF1:
-General outpatient follow-up of symptomatic patients for early identification of complications
-Periodic exams with particular attention to CNS findings and close attention to any masses or focally arising
"new" pain
-Referral for psychosocial issues of family and affected individuals
-Educational intervention for children with learning disabilities or ADHD (40%)
· NF2:
-Annual neurologic examination
-Annual ophthalmologic exam
-Annual hearing examination or more frequently as necessitated
-Hearing augmentation as needed
-Speech therapy as needed
-Counseling and education regarding insidious problems associated with hearing loss, balance, or sense of direction

SURGICAL MEASURES:
· NF1: Surgical treatment if indicated for scoliosis, plexiform neurofibromata or malignancy
NF2: excision of tumor as indicated

POSSIBLE COMPLICATIONS:
NF1:
Disfigurement: skin neurofibromata develop
1) primarily on exposed areas
2) -Scoliosis: common: most cases mild
3) CNS: A large head is common but rarely associated with hydrocephalus.
4) Optic glioma or other CNS tumors arise usually during childhood (5-10%).
5) Learning disability: common; often diagnosed upon entering school. May be associated with attention
deficit hyperactivity disorder (ADHD)
6) Rare Complications:
-Mental retardation
- Epilepsy
- Hypertension
- Variable onset of puberty
- Slightly higher risk for malignancy (e.g. Wilms, leukemia, rhabdosarcoma)
EXPECTED COURSE/PROGNOSIS:
· NF1: Variable; most patients have a mild expression and lead normal lives
· NF2: Variable

Von Hippel Lindau syndrome

-One of the neurocutaneous syndromes (phakomatoses).
-A familial cancer syndrome with predisposition to ocular and -CNS hemangioblastomas, renal cell carcinoma, and
pheochromocytomas.
Prognosis is variable.
Autosomal dominant with gene locus at chromosome region 3p25-3p26

Drugs that are well recognised causes of gynaecomastia include:

- Digoxin
- Cimetidine

237
- Spironolactone
- Anti-androgens
- Alcohol
- Marijuana
- Various others, but these associations are not so common or well described.

Other causes:
- Obesity
- Hyperprolactinaemia
- Hypogonadism
- Underlying hormone secreting tumour
- Underlying breast cancer

HYDROMYELIA AND SYRINGOMYELIA

-Hydromyelia is a symmetric dilatation of the central canal of the spinal cord.
-Usually, the dilated cavity communicates with the fourth ventricle and is lined by ependyma. The fluid within the
cystlike lesion is similar to CSF.
-The enlargement may extend over many segments and terminate at the level of the conus medullaris.
-Hydromyelia is often associated with other malformations of the central nervous system, including communicating
hydrocephalus, Arnold-Chiari malformation and aqueductal stenosis.
- The diagnosis can be made by MRI. Patients often have symptoms and findings related to the associated
malformations, and what part, if any, the dilated central canal contributes to the problem is unclear.
-Therapy is often directed at the associated lesions; treatment is rarely directed at the central canal itself.
Syringomyelia
Destruction or degeneration of gray and white matter adjacent to the central canal of the cervical spinal cord leads to
cavitation and accumulation of fluid within the spinal cord. The precise pathogenesis is unclear, but many cases are
associated with Arnold-Chiari malformation, in which there is displacement of the cerebellar tonsils, medulla, and
fourth ventricle into the spinal canal, sometimes with accompanying meningomyelocele.
-The syrinx may be localized or may involve many segments, and often the cervical area is involved.
-If the lesion extends into the brain stem, the disorder is referred to as syringobulbia.
- The fluid within the cyst often has a yellowish tint and a higher protein content than CSF.
-May be associated with intramedullary tumors, spinal cord trauma, arterial insufficiency, and developmental
anomalies at the cervicomedullary junction.
-The clinical features of the disease depend on the associated lesions and the size and location of the cyst.
-Segmental signs, such as wasting of the small muscles of the hand, sensory deficits involving the arms, and absence
of tendon reflexes, are often present
-Pressure on descending tracts may cause spasticity in the legs.
-The cavity often destroys the commissural fibers, resulting in a dissociated sensory disturbance with loss of pain
and temperature sensations but preservation of touch sensation in a segmental distribution.
-Changes in respiration may occur secondary to involvement in the cervicomedullary region.
-Thoracic kyphoscoliosis is usually present
- In patients with Arnold-Chiari malformation, there are commonly skeletal abnormalities on plain x-rays of the
skull and cervical spine. CT scans show caudal displacement of the fourth ventricle. MRI or positive contrast
myelography may demonstrate the malformation itself. Focal cord enlargement is found at myelography or by MRI
in patients with cavitation related to past injury or intramedullary neoplasms
Management
Treat underlying conditions ie
Treatment of Arnold-Chiari malformation with associated syringomyelia is by suboccipital craniectomy and upper
cervical laminectomy, with the aim of decompressing the malformation at the foramen magnum.
-The cord cavity should be drained, and if necessary an outlet for the fourth ventricle can be made.
-In cavitation associated with intramedullary tumor, treatment is surgical, but radiation therapy may be necessary if
complete removal is not possible
-Posttraumatic syringomyelia is also treated surgically if it leads to increasing neurologic deficits or to intolerable
pain.

Felty’s Syndrome

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Chronic rheumatoid arthritis with leukopenia, splenomegaly, pigmented skin spots on the extremities, anemia, and
thrombocytopenia.
Usual course - chronic.
Caplan's syndrome (development of large nodules in the lung parenchyma of patients with rheumatoid arthritis
who also have pneumoconiosis)

MULTIPLE ENDOCRINE NEOPLASIA

MEN 1 (Wermer's Syndrome)

-The most common multiglandular syndrome
-Biochemical testing identifies affected individuals by age 14-18 years, but the syndrome usually becomes clinically
manifest in the fourth decade
-Hyperparathyroidism occurs in over 80% of patients; it presents with hypercalcemia and usually involves
hyperplasia or adenomas of several parathyroid glands.
Pancreatic islet cell tumors occur in about 75% of patients gastrinomas are the most common tumor and can result
in gastric hyperacidity (Zollinger-Ellison syndrome) with peptic ulcer disease or diarrhea. Islet cell tumors may also
secrete insulin, somatostatin, or glucagon.
Pituitary adenomas occur in about 60% and may secrete prolactin, growth hormone, or ACTH but are usually
nonfunctional; such tumors may produce local pressure effects and hypopituitarism.
Surgical treatment of hyperparathyroidism in MEN 1 can induce prolonged remissions, but relapse is typical.
Aggressive parathyroid resection can cause permanent hypoparathyroidism. Medical treatment of
hyperparathyroidism with bisphosphonates (eg, alendronate) is thus an important option.

MEN 2a (Sipple's Syndrome)

It too is inherited as an autosomal dominant trait. In MEN 2a, patients may have
Medullary thyroid carcinoma (> 90%); Hyperparathyroidism (20-50%), due to hyperplasia or multiple
adenomas in over 70% of cases; Pheochromocytomas (20-35%), which are often bilateral; or Hirschsprung's
disease.
The medullary thyroid carcinoma is of mild to moderate aggressiveness and generally occurs in the third or fourth
decade in the familial syndrome and in the sixth decade in sporadic cases.

MEN 2b
Patients with MEN 2b have a syndrome characterized by mucosal neuromas (> 90% with bumpy lips, enlarged
tongue, Marfan-like habitus),
Pheochromocytomas (60%),
Medullary thyroid carcinoma (80%), which can be quite aggressive.
Patients also have intestinal abnormalities (75%), skeletal abnormalities (87%), and delayed puberty (43%).
The medullary thyroid carcinoma is aggressive and tends to present in the third to fourth decades.

ACHALASIA (Cardiospasm; Esophageal Aperistalsis; Megaesophagus)

A neurogenic esophageal disorder of unknown origin characterized by impaired esophageal peristalsis and a lack of
lower esophageal sphincter relaxation.
-Achalasia may be caused by a malfunction of the myenteric plexus of the esophagus that results in denervation of
esophageal muscle.
Symptoms and Signs
Achalasia occurs at any age but usually begins between ages 20 and 40.
Dysphagia for both solids and liquids is the major symptom; other symptoms include regurgitation, chest pain, and
nocturnal cough. Increased pressure at the lower esophageal sphincter produces obstruction with secondary dilation
of the esophagus.
Diagnosis
Barium x-ray of the esophagus demonstrates the absence of progressive peristaltic contractions during swallowing.
The esophagus is dilated, frequently enormously, but is narrowed and beaklike at the lower esophageal sphincter.
Esophageal manometry shows aperistalsis, increased lower esophageal sphincter pressure, and incomplete
sphincteric relaxation with swallowing. Esophagoscopy reveals dilation but no obstructing lesion.

239
The esophagoscope usually passes readily into the stomach; difficulty doing so should raise the possibility of
malignancy or stricture.
Prognosis
Pulmonary aspiration and secondary cancer are the determining prognostic factors. Nocturnal regurgitation with
coughing suggests aspiration. Pulmonary complications secondary to aspiration are difficult to manage
Treatment
The aim of treatment is to reduce the pressure and thus the obstruction at the lower esophageal sphincter.
-Forceful or pneumatic dilation of the sphincter with a dilating instrument is indicated initially; results are
satisfactory in about 85% of patients, but repeated dilations may be needed. Esophageal rupture and secondary
mediastinitis requiring surgery occur in < 1% of patients.
-Nitrates (eg, nitroglycerin 0.4 mg sublingually before meals)
-Calcium channel blockers (eg, nifedipine 10 mg po qid) may reduce lower esophageal sphincter pressure and
prolong the time between dilations Achalasia
-chemical denervation of cholinergic nerves in the distal esophagus by direct injection of botulinum toxin into the
lower esophageal sphincter muscle. Clinical improvement occurs in 70 to 80% of patients, but results may ast for
only 6 mo to 1 yr.
- A Heller myotomy, in which the muscular fibers in the lower esophageal sphincter are cut, is usually reserved for
patients who fail to respond to dilation; its success rate is about 85%.
Surgery can now be performed by video-assisted laparoscopic techniques. Symptomatic GERD follows surgery in
about 15% of patients.

IBD
A barium enema
Crohns disease
- “rose thorn” ulcers is typical of Crohn’s disease
- a “cobblestone” mucosa
-strictures in the bowel wall.
Ulcerative colitis
A barium enema in ulcerative colitis typically shows fuzzy mucosal margins, pseudopolyps and, in chronic disease,
a “lead pipe” colon (shortening of the colon and loss of haustra).
Formation of crypt abscesses
Ulcerative colitis has a strong association with HLA-B27.
Coeliac Disease has a strong association with HLA-DR3.

Irritable Bowel Syndrome

Is the name given to a group af abdominal symptoms, for which no organic cause can be found.
Clinical features may include, central/lower abdominal pain, bloating, altered bowel habit (alternating diarrhoea and
constipation), tenesmus and abdominal tenderness.

Warfarin in DVT and other Indications

-The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5
(desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions.
-The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds
5.0.
-Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6
months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness.
-Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor,
proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors.
-Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF).
Maximum efficacy requires an INR > 2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75
years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced
to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients.
Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (eg, in young
people with isolated AF where the annual baseline risk of stroke is < 1%). In patients with AF, aspirin is less
effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia).

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-In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves,
but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day)
further decreases the risk of embolism but increases the risk of gastrointestinal bleeding.

ANTI-TB ADVERSE EFFECTS

Hepatotoxicity is the most common cause of iatrogenic disease in anti-TB treatment.

-Anti-TB drugs can induce various degrees of hepatotoxicity,from a transitory asymptomatic rise in transaminases
(which in extreme cases may lead to interruption of TB treatment) to acute liver failure (ALF) (when hepatic
encephalopathy occurs and prothrombin time is <50%, usually leading to the need for liver transplantation or even
to death). The frequency of
hepatotoxicity in different countries varies from 1% to 10%.
-Hepatotoxicity due to isoniazid is most common, as isoniazid has been used for TB treatment (both latent and
active TB) since 1952.
-However, pyrazinamide is the most hepatotoxic among essential anti-TB drugs, in particular at doses >30 mg per
kg per day.
Rifampicin has a low hepatotoxicity. However, due to its enzyme inducer effect it may increase the toxicity of
isoniazid when the two drugs are combined.
-Mild hepatotoxicity (a rise in transaminases of three to five times the normal level) does not require any
modification in treatment, only more frequent visits and laboratory tests.
- In cases of moderate hepatotoxicity (a rise in transaminases of between three and five and 10 times the normal
level)
chemotherapy should be stopped as soon as possible, controlling for the risk of ALF should be started and patients
should be hospitalised if necessary. However, the risk of ALF is low.
-Severe hepatotoxicity (a rise in transaminases >10 times the normal level) occurs in one out of every 1,000 cases
treated, and is associated with a high fatality rate of ~2.5%. Hepatitis is the usual clinical manifestation at this
degree of toxicity and the risk of
ALF is high. Spontaneous survival after ALF is <10%. The only treatment that increases survival is liver
transplantation (survival rates >80%).

ANTI-TB CNS PENETRATION

The anti-TB drugs that are most useful for the treatment of CNS TB are:
-INH (CSF penetration 100%)
-RMP (10–20%)
-EMB (25–50% inflamed meninges only)
-PZA (100%)
-STM (20% inflamed meninges only)
-LZD (20%)
-Cycloserine (80–100%)
-Ethionamide (100%)
-PAS (10–50%) (inflamed meninges only)
The use of steroids is routine in TB meningitis (see section below).
Multidrug-resistant tuberculosis
-Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to INH and RMP.
-Isolates that are multiply-resistant to any other combination of anti-TB drugs but not to INH and RMP are not
classed as MDR-TB.
-MDR-TB that is also resistant to three or more of the six classes of second-line drugs is called "extensively drug-
resistant tuberculosis" (XDR-TB) and is associated with a significantly poorer mortality rate, however, the
principles of treatment are the same.
-Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients
without this information. If treating a patient with suspected MDR-TB, the patient should be started on SHREZ
pending the result of laboratory sensitivity testing.
A gene probe for rpoB is available in some countries and this serves as a useful marker for multidrug resistant TB
-When sensitivities are known and the isolate is confirmed as resistant to both INH and RMP, five drugs should be
chosen in the following order (based on known sensitivities)
- Aminoglycoside (e.g., amikacin, kanamycin) or polypeptide (e.g., capreomycin)

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  PZA
 EMB
 fluoroquinolones: moxifloxacin is preferred to ciprofloxacin or ofloxacin;
 rifabutin
 cycloserine
 a thioamide: prothionamide or ethionamide
 PAS
 a macrolide: e.g., clarithromycin
 linezolid
 high-dose INH (if low-level resistance

Drugs are placed nearer the top of the list because they are more effective and less toxic; drugs are placed nearer the
bottom of the list because they are less effective, or more toxic, or more difficult to obtain

Mondor's disease
-Is-Thrombophlebitis of superficial veins of breast and anterior thoracic wall
-First described in detail by Henri Mondor in 1939, this condition is a rare entity characterized by a sclerosing
thrombophlebitis of the subcutaneous veins of the anterior chest wall. The sudden appearance of a subcutaneous
cord, which is initially red and tender and subsequently becomes a painless, tough, fibrous band that is accompanied
by tension and skin retraction, is characteristic. The condition, though benign and self-limited, has been associated
with breast cancer. It requires only symptomatic therapy. However, the physician must be aware of its existence to
properly diagnose it and to rule out the presence of systemic disorders, especially breast cancer.
-Subcutaneous penile vein thrombosis (penile Mondor disease) has also been described (Al-Mwalad, 2006). Its
pathogenesis is unknown. It appears suddenly as almost painless indurations on the penile dorsal surface.
Pathophysiology:
The pathophysiology has been explained as pressure on the vein with stagnation of blood or as direct trauma to the
vein itself. In cases that do not show such evidence, the most reasonable explanation is on the basis of repeated
movement of the breast along with the contracting and relaxing pectoral muscles, which causes stretching and
relaxing of the veins
CVS
Pulmonary systolic Blood pressure-Varies between 15 and 30 mmHg in health
3rd heard sound-Due to rapid ventricular filling.
4th Heart sound-Due to artrial contraction.

Causes of Rectal bleeding

 Colorectal carcinoma
 Polyps
 Diverticula disease
 Haemorrhoids
 Angiodysplasia.
 Anal fissure
 Trauma
 Radiation proctitis

Complications of colonic diverticulosis

95% of complications of colonic diverticulosis occur in the sigmoid colon as this is the site where diverticula
predominantly occur. Complications include
 Acute diverticulitis
 Perforation
 Fistula or abscess formation
 Bowel obstruction
 Haemorrhage

DVT

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Aortic Dissection
 70% of tears occur in the ascending aorta above the aortic valve
 20% occur in the descending thoracic aorta
 8% in the aortic arch
 2% in the abdominal aorta.
-FDPs are only able to detect massive fibrin deposition, such as in DIC. Thus not sensitive
-D-Dimers are a subclass of FDP that is more sensitive and is routinely used as part of the screen for DVT and PE
however D-Dimers are not 100% sensitive so further investigations must be based upon the clinical picture as well
as the D-Dimer result.
-Ultrasound is not a realiable technique to exclude thrombosis below the knee. However, it has a good sensitivity
and specificity for above knee thrombosis

Poor prognostic factors in acute pancreatitis

 Indicators can be remembered by the following mnemonic: PANCREAS
PaO2 < 8 kPa
Age over 55
Neutrophilia
Calcium (low)
Raised Urea
Enzyme elevation: LDH, AST
Albumin <32g/L
Sugar (glucose >10 mmol/L)
Colonic cancer-Occurence
 The majority are found in the Rectum: 45%.
 Sigmoid: 25%.
 Caecum and ascending colon: 15%.
 Transverse colon: 10%.
 Descending colon: 5%.

Parinaud's syndrome
Parinaud's Syndrome, also known as Dorsal Midbrain Syndrome or Pretectal Syndrome is named for Henri
Parinaud (1844-1905), considered to be the father of French ophthalmology.
-It is a cluster of abnormalities of eye movements and pupil dysfunction, characterized b
1.Paralysis of upgaze
2.Pseudo-Argyll Robertson pupils (light-near dissociation)
3.Convergence-Retraction nystagmus
4.Eyelid retraction (Collier's sign)
-It has less commonly been associated with spasm of accommodation, pseudoabducens palsy (also known as
thalamic esotropia), see-saw nystagmus and associated ocular motility deficits including skew deviation, oculomotor
nerve palsy, trochlear nerve palsy and internuclear ophthalmoplegia.
Parinaud's Syndrome results from injury, either direct or compressive, to the dorsal midbrain. Classically, it has been
associated with 3 major groups:
a)Young men with brain tumors in the Pineal Gland or midbrain
b)Women in their 20s-30s with Multiple Sclerosis
c)Older men following stroke of the upper brainstem
-However, it has also been associated with obstructive hydrocephalus, midbrain hemorrhage, cerebral arteriovenous
malformation, trauma and brainstem toxoplasmosis
-The eye findings of Parinaud's Syndrome generally resolve slowly over months, especially with resolution of the
causative factor.
-However, rapid resolution after normalization of intracranial pressure following placement of a ventriculoperitoneal
shunt has been reported.

PNEUMOCYSTIS JEROVECI PNEUMONIA

Definition
Etiology
-Pneumocystis jiroveci pneumonia (PCP) is caused by Pneumocystis jiroveci, a ubiquitous organism classified as a
fungus but that shares biologic characteristics with protozoa.

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-The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the pneumocystis that
infects rodents, and Pneumocystis jiroveci refers to the distinct species that infects humans.
-PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jiroveci usually occurs in early
childhood; two thirds of healthy children have antibody to P. jiroveci by age 2–4 years
-PCP is a result either of reactivation of latent infection or new exposure to the organism spread among persons can
occur by the airborne route.
-Approximately 90% of cases occurred among patients with CD4+ T lymphocyte counts of <200/μLin HIV
infection.
-Other factors associated with a higher risk of PCP include
 CD4+ T lymphocyte percentage <15%
 Previous episodes of PCP
 Oral thrush
 Recurrent bacterial pneumonia
 Unintentional weight loss
 Higher plasma HIV-1 RNA
Other causes of immunosuppression
 Hematologic malignancies
 Long-term steroids or immunosuppressant therapy
 Organ-transplant recipients
 Congenital -Thymic dysplasia ,Severe combined immunodeficiency, Hypogammaglobulinemia
 Patients with severe malnutrition

Clinical Manifestations
History
-The most common manifestations of PCP among HIV-1–infected persons are
1) subacute onset of progressive exertional dyspnea
2) Fever
3) Nonproductive cough
4) Chest discomfort that worsens over a period of days to weeks.
NB. The fulminant pneumonia observed among non-HIV-1–infected patients is less common
Physical examination
-In mild cases, pulmonary examination is usually normal at rest.
-With exertion, tachypnea, tachycardia, and diffuse dry (“cellophane”) rales might be observed
-Fever is apparent in the major cases and might be the predominant symptom among some patients.
-Stigmata of HIV/AIDS-Oral thrush, Oral hairy leukoplakia, Onychomycoses, Kaposi sarcoma
-Extrapulmonary disease is rare but can present in any organ Unexplained lymphadenopathy, Hepato-splenomegaly,
Choroid lesions in absence of intraocular inflammation

Investigation
Laboratory
1. Hypoxemia-the most characteristic laboratory abnormality
-Mild-to-moderate (room air arterial oxygen [pO2] of >70 mm/Hg or alveolar-arterial O2 difference, [A-a] DO2 <35
mm/Hg)
-Moderate-to-severe levels (pO2 <70 mm/Hg or [A-a] DO2 >35 mm/Hg).
-Oxygen desaturation with exercise is indicative of an abnormal A-a gradient but is nonspecific
2. Elevation of LDH levels to >500 mg/dL is common but nonspecific.
Imaging
1. CXR
Typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hilar in a butterfly
pattern

244
Bilateral interstitial infiltrates in an HIV-infected patient with Pneumocystis carinii pneumonia (PCP).

Many other diseases may have a similar presentation, including

 Mycobacterial TB
 Fungal, viral or bacterial pneumonias
 Heart failure
 Kaposi's sarcoma
 Pulmonary emboli.-multiple
-However, patients with early disease might have a normal chest radiograph
-In addition, atypical presentations with nodules, asymmetric disease, blebs and cysts, upper lobe localization, and
pneumothorax occur.
-Spontaneous Pneumothorax in a patient with HIV-1 infection should raise the suspicion of PCP
-Cavitation or pleural effusion is uncommon in the absence of other pulmonary pathogens or malignancy, and the
presence of a pleural effusion might indicate an alternative diagnosis.
-Approximately 13%–18% of patients with documented PCP have another concurrent cause of pulmonary
dysfunction (e.g., TB, Kaposi sarcoma, or bacterial pneumonia)
2. CT-Scan
-Demonstrates patchy ground-glass attenuation
3. Gallium scans showing increased pulmonary uptake

Definitive diagnosis
-Sputum induction and bronchoalveolar lavage are now the diagnostic methods of choice for PCP.
-Spontaneously expectorated sputum has low sensitivity.
-Organism is identified by stains demonstrating the cyst wall or the trophozoite.
-Stains for the cell wall preferred include:
1) Gomori- Methenamine Silver
2) Gram-Weigert
3) Toluidine blue

Methenamine silver stain of a bronchoalveolar lavage specimen showing a cluster of P. carinii cysts.

245
-Cresyl violet, Giemsa, Diff-Quik, and Wright stains detect both the cyst and trophozoite forms but do not stain the
cyst wall.
-Direct immunofluorescent staining may be done.
-Because transbronchial biopsy carries a 10 percent risk of pneumothorax, it is usually reserved for use in situations
in which bronchoalveolar lavage fails to reveal PCP in a patient with a compatible presentation, or when another
process, such as tuberculosis, fungal infection or neoplasm, is suspected
NB.Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens
for days or weeks after effective therapy is initiated.

Treatment Recommendations
-Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice given intravenously (severe disease) or
orally (mild-moderate disease)
Dosage: The daily dosage, administered orally or intravenously in three divided doses is:
-TMP 15 to 20 mg /kg
-SMZ 75 to 100 mg /kg.
In oral admin. For mild –moderate disease can administer 2-double strength tablets TID.
NB. Single strength tablet TMP 80 mg SMX 400mg
Double strength tablet TMP 160mg SMX 800mg.
-Therapy is continued for 21 days in persons infected with HIV and 14 days in non-HIV-infected patients
-Since HIV-infected patients respond more slowly than non-HIV-infected patients, it is prudent to wait at least 7
days after the initiation of treatment before concluding that therapy has failed.
-Patients with moderate-to-severe disease, as defined by room air pO2 <70 mm/Hg or arterial-alveolar O2 gradient
>35 mm/Hg, should receive corticosteroids as early as possible, and certainly within 72 hours after starting specific
PCP therapy
-The preferred corticosteroid dose and regimen is:
 prednisone 40 mg by mouth BD for days 1–5
 40 mg daily for days 6–10
 20 mg daily for days 11–21
-Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary.
M.O.A. TMP-SMX
-Trimethoprim-sulfamethoxazole sequentially inhibits two enzymes in folate metabolism essential for DNA
synthesis: dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS)
Adverse effects
-Include nausea and vomiting

Maculopapular rash,Fever,Pruritus

Bone marrow suppression-Pancytopenia

Hepatitis

Pancreatitis

Aseptic meningitis

Interstitial Nephritis, renal stones-Advice on high water consumption

-Management of adverse effects by means of antiemetic, antihistamines or antipyretics may enable completion of a
course of therapy.
-The dose must be adjusted for abnormal renal function. Oral outpatient therapy of TMP-SMX is highly effective
among patients with mild-to-moderate disease

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-Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMP-
SMX
Alternative therapeutic regimens include
Mild-Moderate Disease
1. TMP plus Dapsone
-TMP (15 mg/kg per day orally) plus dapsone (100 mg/d orally)
2. Clindamycin plus Primaquine
-Clindamycin (600 mg QID IV or 300 - 450 mg QID orally) plus primaquine (15 to 30 mg of base per day orally)
3. Atovaquone alone
-Atovaquone alone (750 mg twice daily orally).
NB. Dapsone and primaquine should be used with caution in patients with glucose-6-phosphate dehydrogenase
deficiency.
Moderate to severe Disease
1. Pentamidine
-Single daily dose of 4 mg/kg by slow intravenous infusion.
-Pentamidine is highly toxic; its major side effects are hypotension, cardiac arrhythmias, dysglycemias, azotemia,
electrolyte changes, and neutropenia.
2. Trimetrexate is administered intravenously as a single daily dose of 45 mg/m2 plus folinic acid is given orally
or intravenously at a dose of 20 mg/m2 QID to prevent bone marrow suppression.

PCP PROPHYLAXIS
Indications
Primary prophylaxis is indicated for HIV-infected patients at high risk of developing pneumocystosis and secondary
prophylaxis is done after recovery from the first episode of PCP.Generally indications include:
1) CD4+ cell counts of <200/uL
2) History of oropharyngeal candidiasis (grade 3 disease)
3) >50,000-100,000/ml viral load
4) CD4 200-400 but CD 4 count falling rapidly (CD4 loss of >1/3 every 3 months)
5) Wasting syndrome of HIV
6) Prior episode of PCP even if it occurred at CD4 count >200/uL
Options
1. TMP-SMZ
-One double-strength tablet of TMP-SMZ (160 mg TMP, 800 mg SMZ) per day is the prophylactic regimen of
choice.
-The major limitation of TMP-SMZ treatment is the high frequency of adverse reactions among HIV-infected
patients.
-Recommended alternative regimens include TMP-SMZ at a reduced dose-one single strength tablet per day (80 mg
TMP, 400 mg SMZ) or Reduced frequency one double strength tablet 3 times/week.
2. Dapsone alone
-Dapsone alone at a daily oral dose of 100 mg
3. Dapsone plus Pyrithemine plus Folinic acid
-Dapsone at a dose of 50 mg/d combined with weekly oral doses of pyrimethamine (50 mg) and folinic acid (25 mg)
4. Pentamidine
-Pentamidine at a monthly dose of 300 mg administered by Respigard nebulizer. This can cause bronchospasm and
thus combined with salbutamol in asthmatics
5. Atovaquone at an oral dose of 1500 mg/d.
-PCP prophylaxis can be stopped when the CD4 >200/ul for a period >3 months but not when the initial infection
occurred at CD4 count >200/ul.

Prognosis
1) The arterial oxygen pressure
2) The alveolar-arterial oxygen gradient.

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PRIMARY HYPERPARATHYROIDISM
-The vast majority of patients with primary hyperparathyroidism, 80% to 85%, have a single adenoma that varies
in size
-Approximately 20% of patients with primary hyperparathyroidism have a pathologic process involving all four
glands with hyperplasia. Four-gland hyperplasia may occur sporadically but is seen also in conjunction with
multiple endocrine neoplasia (MEN) type I or I
-The rarest presentation of primary hyperparathyroidism is parathyroid carcinoma, occurring in well under 1% of
patients.
3) Neutrophil counts and IL-8 levels in BAL fluid
4) Chest radiographic abnormalities
5) Serum LDH and albumin levels,
6) Management of HIV infection with ARV
7) Concurrent pulmonary infections complicate management, but the presence of cytomegalovirus usually
does not affect the outcome of pneumocystosis.

COMPLICATIONS OF PCP
1. Hypoxemia and respiratory failure
-A pathophysiologic process similar to ARDS occurs in patients with severe PCP
-These patients may need intubation and have a significantly worse prognosis.
2. Pneumothorax
-Due to inflammation and tissue necrosis, cysts may form and subsequently rupture, leading to spontaneous
pneumothorax.
-If large enough, chest tube intervention may be necessary.
3. Extrapulmonary disease
-In 1% of patients, hematogenous dissemination of the organism occurs.
-Reported sites of involvement include bone marrow, spleen, liver, lymph nodes, small intestine, and the eyes.
- Less common sites include adrenal glands, kidney, pituitary, skin, thyroid, ear, and the gastrointestinal tract.

Predominant age: Age greater than 50

Predominant sex: Females > Males (4:1)
Clinical presentation
-"Painful bones, renal stones, abdominal groans and psychic moans." You must think of it to diagnose it.

Bone disease
-Skeletal:
 Bone pain and tenderness
 Cystic bone lesions
 Skeletal demineralization
 Spontaneous fracture
 Vertebral collapse
 Osteoporosis
-The classic bone disease of primary hyperparathyroidism is osteitis fibrosa cystica.
-Clinically, patients develop bone pain and occasional pathologic fractures.
- Resorption of bone caused by excessive secretion of parathyroid hormone is associated with several typical
radiologic signs. Subperiosteal resorption of the distal phalanges is the most specific sign of primary
hyperparathyroidism.
-Similar radiologic changes may be present in the skull, where a moth-eaten or salt-and-pepper pattern is evident.
The distal third of the clavicles may demonstrate tapering of bone density.
-Locally destructive lesions appearing as bone cysts or "brown tumors" in the long bones and pelvis constitute
another skeletal manifestation of primary hyperparathyroidism Brown tumors are collections of osteoclasts
intermixed with poorly mineralized woven
-There is greater bone; cortical bone (long bones) as compared with cancellous bone (spine).

Kidney disease
 Nephrolithiasis
 Nephrocalcinosis-deposition of calcium-phosphate crystals throughout the renal parenchyma.
 Reduced glomerular filtration rate
 Thirst
 Polydipsia
 Polyuria

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-The most common association between primary hyperparathyroidism and the kidney is hypercalciuria.
-Urinary calcium excretion over 250 mg daily.

Gastrointestinal
 Abdominal distress
 Gastroduodenal ulcer
 Pancreatitis, Pancreatic calcification
 Constipation
 Vomiting, Anorexia
 Weight loss

Mental
-Fatigue, Apathy, Anxiety, Depression, Psychosis

· Neurologic
-Somnolence, Coma, Diffuse EEG abnormalities

· Neuromuscular
-Muscle fatigue, Weakness, Hypotonia

Cardiovascular:
-Hypertension, Short QT interval

· Articular/periarticular:
- Arthralgia, Gout, Pseudogout, Periarticular calcification

· Ocular:
- Band keratopathy, Conjunctivitis, Conjunctival calcium deposits

PULMONARY HYPERTENSION AND COR PUMONALE.

Definitions
-Primary pulmonary HTN (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no
apparent cause.
PPH is also termed precapillary pulmonary hypertension or idiopathic pulmonary arterial hypertension (IPAH).
- The diagnosis is usually made after excluding other known causes of pulmonary hypertension.
-Normal Systolic pulmonary pressure-range 20-30 mmHg and dependent on RV stroke volume; elastance of main
pulmonary artery and branches; reflectance wave from arterioles, which is influenced by tone and diastolic pressure
factors.
-Diastolic pressure 8-12 mm Hg, Mean pressure 12-17 mm Hg, Pulmonary wedge pressure 5-12 mm Hg.
-Secondary pulmonary artery HTN (SPAH) is defined as a pulmonary artery systolic pressure higher than 30 mm
Hg or a pulmonary artery mean pressure higher than 20 mm Hg secondary to either a pulmonary or a cardiac
disorder
-Cor pulmonale is defined as an alteration in the structure and function of the right ventricle caused by a primary
disorder of the respiratory system commonly leading to pulmonary HTN.

Pathophysiology
Primary Pulm. HTN
-Pathophysiology not clear but an insult (eg, hormonal, mechanical, other) to the endothelium resulting in a cascade
of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle)
proliferation.
-At least 15-20% of patients with IPAH have a familial form related to sporadic genetic defects(BMPR-II gene)
-Early in the disease, thrombotic pulmonary arteriopathy occurs characterized by in situ thrombosis of small
muscular arteries of the pulmonary vasculature.
-In later stages, as the pulmonary pressure continues to rise, remodeling of the pulmonary vasculature occurs with
intimal fibrosis and replacement of normal endothelial structure.

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Associated conditions
1. Portal hypertension (thus porto-pulmonary HTN) shunting of splanchnic blood lead to exposure of the pulmonary
circulation to substances in the splanchnic circulation that normally are detoxified via the liver. This may lead to
endothelial injury and thus Pulmonary HTN.
2. Connective tissue diseases
 CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and
telangiectasia) variant of scleroderma
 SLE
-However, connective tissue diseases are sometimes thought of as causing secondary pulmonary HTN.

Secondary Pulmonary HTN.

-Three predominant pathophysiologic mechanisms may be involved in the pathogenesis of SPAH
(1) Hypoxic vasoconstriction
(2) decreased area of the pulmonary vascular bed
(3) volume/pressure overload.
Hypoxic vasoconstriction
-Chronic hypoxemia causes pulmonary vasoconstriction by a variety of actions on pulmonary artery endothelium
and smooth muscle cells ie
-Down-regulation of endothelial nitric oxide synthetase and reduced production of the voltage-gated potassium
channels
-Chronic hypoxemia leading to pulmonary HTN may occur
1) Chronic obstructive pulmonary disease (COPD),
2) Hypoventilation disorders (eg, obstructive sleep apnea, adenoid hypertrophy).
3) Neuromuscular disorder causing hypoventilation eg poliomyelitis, myasthenia gravis
4) High-altitude disorders
5) Disorders of the chest wall kyphoscoliosis
6) Interstitial lung diseases
Obliteration of pulmonary vasculature
1) Collagen vascular diseases.
 Scleroderma –CREST syndrome-Calcinosis, Raynauds phenomena, Esophageal motility disorder,
Sclerodactyly, Telangiectasia
 SLE,Chaug-straus syndrome,Good pastures disease,wenengers syndrome
2) Acute pulmonary embolism
3) Chronic proximal pulmonary emboli
4) HIV infection
5) Portal hypertension
6) Drugs
 Fenfluramine
 crack cocaine
 amphetamines
 aminorex
 chemotherapeutic drugs-Bleomycin(lung fibrosis)
 Tryptophan
7) Infections-Schistosomiasis, TB, Fungal pneumonitis
8) Increased blood viscosity due to blood disorders, eg, polycythemia Vera, sickle cell disease, macroglobulinemia
9) Pulmonary capillary hemangiomatosis
Volume and pressure overload
-Pulmonary blood volume overload is caused by left-to-right shunts ie atrial or ventricular septal defects.
-Left atrial hypertension causes a passive rise in pulmonary arterial systolic pressure in order to maintain a driving
force across the vasculature. Over time, persistent pulmonary hypertension accompanied by vasculopathy occurs.
This may occur secondary to left ventricular dysfunction eg
 Mitral valvular disease
 Constrictive pericarditis
 Aortic stenosis
 Cardiomyopathy.

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-Pulmonary venous obstruction is a rare cause of pulmonary hypertension. This may occur secondary to mediastinal
fibrosis, anomalous pulmonary venous drainage, or pulmonary venoocclusive disease.
-Right ventricular hypertrophy
 Left parasternal or subxiphoid heave
 A prominent A wave in the jugular venous pulse
 Right-sided fourth heart sound also can be present and reflects the increase in the filling pressure of the
right ventricle.
-Right ventricular failure
 Distended neck veins with a prominent V wave
 Right ventricular third heart sound
 Holosystolic tricuspid insufficiency murmur accentuated during inspiration
 Tender hepatomegaly, may be pulsatile
 Peripheral edema.
 Pleural effusions and ascites are uncommon, even in severe cor pulmonale.

Cor pulmonale
-In chronic cor pulmonale, right ventricular hypertrophy (RVH) generally predominates. In acute cor pulmonale,
right ventricular dilatation mainly occurs.

Clinical presentation
-The clinical manifestations are frequently masked by the underlying etiology.
History
 Dyspnea upon exertion or at rest
 Fatigue and Lethargy
 Syncope with exertion
 Chest pain
 Cough
 Hemoptysis
 Hoarseness (due to compression of the recurrent laryngeal nerve by the distended pulmonary artery)
 In advanced stages, passive hepatic congestion lead to anorexia, right upper quadrant abdominal
discomfort, and jaundice
 Swelling of the legs
-Obtaining a careful history may help exclude some of the numerous causes of secondary pulmonary hypertension.
Important clues to a specific secondary cause include
 Known history of heart disease.
 TB treatment or chronic cough
 Occupational or residential exposure to industrial emissions.
 History deep venous thrombosis or pulmonary embolism
 Raynaud phenomenon, arthritis or arthralgias, rash
 Heavy alcohol consumption and cigarette use.
 Yellowness of eyes -hepatitis
 Tx or predisposed to schistosoma infection
 Heavy snoring
 Daytime hypersomnolence
 Morning headaches, morbid obesity, and a family history of hypertension.
Physical examination
-Signs of the underlying lung disease
 with an increase in chest diameter
 labored respiratory efforts with retractions of the chest wall
 hyperresonance to percussion
 diminished breath sounds, wheezing
 distant heart sounds
 Sometimes cyanosis.
Signs of pulmonary hypertension
 Splitting of the second heart sound with accentuation of the pulmonic component

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  A systolic ejection murmur with sharp ejection click over the region of the pulmonary artery may be heard
in advanced disease, along with a diastolic pulmonary regurgitation murmur.

INVESTIGATIONS
Lab.
1. ABG’s -assess for hypoxemia.
2. FHG
-Anemia-chronic illnesses
-Polycythemia-COPD, polycythemeia rubra Vera
-Sickle cell disease,
-Eosinophilia-Chaug-Straus, Parasitic infections-schistosomiasis.
-Lymphocytosis-TB.
3. A collagen vascular disease screen
 Erythrocyte sedimentation rate-ESR
 Rheumatoid factor levels-Rh
 Antinuclear antibody levels.-ANA
 Anti-neutrophil cytoplasmic antibody- ANCA
4. LFT’s- may indicate liver disease associated with portal hypertension.
5. HIV testing, HBV and HCV.
6. U/E/C-Kidney involvement in connective tissue disease.
7. D-dimers-throboembolic phenomena.
8. Hypercoagulability states can be evaluated by serum levels of proteins S and C, antithrombin III, factor V
Leyden, anticardiolipin antibodies, and homocysteine.

Imaging Studies:
1. CXR
-Pulmonary HTN-enlargement of central pulmonary arteries, attenuation of peripheral vessels, and oligemic lung
fields.
-Right ventricular hypertrophy and right atrial dilatation
2. Echocardiography
-Signs of chronic right ventricular pressure overload are present, which include increased thickness of the right
ventricle with paradoxical bulging of the septum into the left ventricle during systole.
-In later stages, right ventricular dilatation occurs, leading to right ventricular hypokinesis.
-Right atrial dilatation and tricuspid regurgitation are also present.
- Doppler echocardiography
-Most reliable noninvasive method to estimate pulmonary arterial pressure.
-Tricuspid regurgitation -Tricuspid regurgitation is generally detected in more than 90% of patients with severe
SPAH.
Other Tests.
3. ECG.
i) RVH- R-V1 +S-V6> 35mm, Right axis deviation
Strain-T-wave and ST-segment inversion
ii) Right atrial enlargement-P-pulmonale-Peaked P-wave (increased P-wave amplitude)
iii) In acute cor pulmonale secondary to acute pulmonary embolism, the S1Q3T3 pattern may be observed, along with
incomplete or complete right bundle branch block.
iv) Patients with severe underlying obstructive lung disease may have low-voltage QRS on their ECG, reflecting the
interposition of hyperexpanded lung between the heart and chest
4. Ventilation perfusion lung scan
-Ventilation perfusion scan should be performed to exclude chronic thromboembolic pulmonary hypertension.
-Diffuse mottled perfusion can be observed in patients with primary pulmonary hypertension, as opposed to
segmental or subsegmental mismatched defects observed in patients with SPAH.
5. Pulmonary function tests
-These tests may show an obstructive pattern suggestive of COPD or a restrictive pattern suggestive of an interstitial
lung disease.
-In selected cases pulmonary angiography, and chest CT scanning may be indicated to determine underlying
etiology

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Procedures.
Cardiac catheterization:
-Right-heart catheterization is considered the most precise method for diagnosis and quantification of pulmonary
hypertension.
-It is indicated when echocardiography cannot assess the severity a tricuspid regurgitant jet, thus excluding an
assessment of pulmonary hypertension

Medical Care:
Acute cor pulmonale
-Cardiopulmonary support for patients experiencing acute cor pulmonale with resultant acute right ventricular
failure includes fluid
-Massive pulmonary embolism administration of thrombolytic agents or surgical embolectomy,
Chronic cor pulmonale
-Oxygen therapy, diuretics, vasodilators, digitalis, theophylline, and anticoagulation therapy are all different
modalities used in the long-term management of chronic cor pulmonale.
1. Oxygen therapy
-Esp. underlying COPD. With cor pulmonale, the partial pressure of oxygen (PO 2) is likely to be below 55 mm Hg
and decreases further with exercise and during sleep. Oxygen therapy relieves hypoxemic pulmonary
vasoconstriction, which then improves cardiac output, lessens sympathetic vasoconstriction, alleviates tissue
hypoxemia, and improves renal perfusion.
2. Diuretics
-Management of chronic cor pulmonale, particularly when the right ventricular filling volume is markedly elevated.
Diuretics may result in improvement of the function of both the right and left ventricles
-Excessive volume depletion can lead to decline in cardiac output. Another potential complication of diuresis is the
production of a hypokalemic metabolic alkalosis, which diminishes the effectiveness of carbon dioxide stimulation
on the respiratory centers and lessens ventilatory drive.
3. Vasodilator drugs
-Management of chronic cor pulmonale with modest results.
-Calcium channel blockers, particularly oral sustained-release nifedipine and diltiazem, can lower pulmonary
pressures, although they appear more effective in primary rather than secondary pulmonary hypertension.
4. Digoxin
-Shown to be beneficial in patients with associated atrial fibrillation due to atrial enlargement.
5. Theophylline
-Reduce pulmonary vascular resistance and pulmonary arterial pressures acutely in patients with chronic cor
pulmonale secondary to COPD.
-Theophylline has a weak inotropic effect and thus may improve right and left ventricular ejection. As a result,
considering the use of theophylline as adjunctive therapy in the management of chronic or decompensated cor
pulmonale is reasonable in patients with underlying COPD.
6. Anticoagulation e.g. Warfarin
-Anticoagulation therapy may be used in patients with cor pulmonale secondary to thromboembolic phenomena and
with underlying primary pulmonary arterial hypertension

REITERS SYNDROME
-A triad of features including arthritis, conjunctivitis, and urethritis or cervicitis.
-It occurs most commonly in young men, is associated with HLA-B27 in 80% of white patients and 50-60% of
blacks,
Epidemiologically
-Similar to other reactive arthritis syndromes characterized by sterile inflammation of joints from infections
originating at non-articular sites.
-A fourth feature may be buccal ulceration or balanitis. (It is possible for only two features to be present.)
Two forms:

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-Sexually transmitted; symptoms usually begin 7-14 days after exposure -Chlamydia trachomatis or perhaps
Ureaplasma urealyticum).
-Post-dysentery-infection (with shigella, salmonella, yersinia, campylobacter)
System(s) affected:
-Musculoskeletal, Skin/Exocrine, Renal/Urologic
Genetics:
- HLA-B27 tissue antigen present in 60-80% of patients
Incidence/Prevalence in USA:
-0.24-1.5% incidence after epidemics of bacterial dysentery; complicates 1-2% cases of non-gonococcal urethritis
Predominant age: 20-40 years
Sex: Male > Female

CAUSES:
· Chlamydia trachomatis the usual causative organism of post venereal variety. Male: female ratio 9:1
· Dysenteric form following enteric bacterial infection due to Shigella, Salmonella, Yersinia, and Campylobacter
organisms.
-This form more likely in women, children and the elderly.

RISK FACTORS:
· Sexual intercourse 7-14 days prior to illness
· Food poisoning or bacterial dysenteric outbreak

DIFFERENTIAL DIAGNOSIS:
· For specific diagnosis, arthritis associated with urethritis for longer than one month
· Rheumatoid arthritis
· Ankylosing spondylitis
· Arthritis associated with inflammatory bowel disease
. Psoriatic arthritis
· Juvenile rheumatoid arthritis
· Bacterial arthritis including gonococcal

Clinical presentation

a) Musculoskeletal:
-Asymmetric arthritis (especially knees, ankles, MTP joints).
-Enthesopathy (inflammation at tendinous insertion into bone) such as plantar fasciitis, digital periostitis, Achilles
tendinitis
-Spondyloarthropathy (spine and sacroiliac joint involvement)

b) Urogenital tract:
-Urethritis
-Prostatitis
-Occasionally cystitis
-Balanitis
-Cervicitis - usually asymptomatic

c) Eye:
- Conjunctivitis of one or both eyes
-Occasionally scleritis, keratitis, corneal ulceration.
-Rarely uveitis and iritis.

d) Skin:
-Mucocutaneous lesions (small, painless, superficial ulcers on oral mucosa, tongue, glans penis)
-Keratoderma blennorrhagica (hyperkeratotic skin lesions of palms and soles and around nails)

e) Constitutional: Fever, malaise, anorexia, weight loss

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-Can appear seriously ill (fever, rigors, tachycardia, and exquisitely tender joints)

f) Others may be involved

 Cardiovascular:-Occasionally pericarditis, murmur, conduction defects, aortic incompetence
 Nervous system:-Rarely peripheral neuropathy, cranial neuropathy, meningoencephalitis, neuropsychiatric
changes

LABORATORY:
· Blood
o WBC 10,000-20,000
o Neutrophilic leukocytosis
o Elevated erythrocyte sedimentation rate
o Moderate normochromic anemia
o Hypergammaglobulinemia
· Synovial fluid
o WBC 1000-8000 cells/mm3
o Bacterial culture negative
· Collaborative tests
o Cultures or serology positive for Chlamydia trachomatis, or stools positive for Salmonella, Shigella,
Yersinia or Campylobacter support the diagnosis

PATHOLOGICAL FINDINGS:
· A seronegative spondyloarthropathy (similar to ankylosing spondylitis, enteric arthritis and psoriatic arthritis)
· Villous formation in joints
· Joint hyperemia
· Joint inflammation
· Prostatitis
· Seminal vesiculitis
. Skin biopsy similar to psoriasis
· Non-specific conjunctivitis

SPECIAL TESTS: Histocompatibility antigen HLA-B27 positive in 60-80% of cases in non-HIV related Reiter's

IMAGING:
· X-ray
-Periosteal proliferation, thickening
 Spurs
 Erosions at articular margins
 Residual joint destruction
 Syndesmophytes (spine)
 Sacroiliitis

Management
-Treatment is symptomatic
-No treatment necessary for conjunctivitis. Iritis may require treatment.
- Treatment unnecessary for mucocutaneous lesions
-Physical therapy during recovery phase
-Arthritis may be prominent and disabling during the acute phase

MEDICATIONS
· Symptomatic management
-NSAIDs have been the mainstay of therapy.
-Antibiotics may also have some role. Antibiotics given at the time of a nongonococcal sexually transmitted
infection reduce the chance that the individual will develop Reiter's syndrome
-NSAID's including indomethacin, naproxen; intraarticular or systemic corticosteroids for refractory arthritis and
enthesitis

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-Specific treatment of pathogenic microorganism should be attempted:
-C. trachomatis - doxycycline 100 mg po bid for 7-14 days
-Salmonella, Shigella, Yersinia Campylobacter infections ciprofloxacin 500 mg po bid for 5 days (course may be
extended to 14-28 days to eradicate chronic carrier state)
-For gastrointestinal upset - antacids
· For iritis - intraocular steroids
· For keratitis - topical steroids

POSSIBLE COMPLICATIONS:
· Chronic or recurrent disease in 5-50%
· Ankylosing spondylitis develops in 30-50% of HLA-B27 positive patients
· Urethral strictures
· Cataracts and blindness
· Aortic root necrosis

EXPECTED COURSE/PROGNOSIS:
· Urethritis within 1-15 days after sexual exposure
· Onset of Reiter's syndrome within 10-30 days of infection
· Mean duration 19 weeks but the arthritis may last months to years.
· Poor prognosis associated with local disease involving heel, eye or heart

RENAL OSTEODYSTROPHY
-Renal osteodystrophy is a multifactorial skeletal disorder of bone remodeling seen in end-stage renal disease.
-The actions of some of the factors involved are well defined, and successful strategies have been designed to
prevent them.
-Renal osteodystrophy is classified as osteitis fibrosa, osteomalacia, or mixed, mild, or adynamic disease, according
to the histologic features

Osteitis Fibrosa
-The classic histologic form of renal osteodystrophy is osteitis fibrosa, which is caused by secondary hyper-
-Parathyroidism with contributions from locally derived cytokines and a deficiency of 1, 25 dihydroxy-
cholecalciferol.
-Renal retention of phosphate results in hyper -phosphatemia, which reduces serum ionized calcium levels, therefore
inducing hyperparathyroidism.
-The hyperparathyroidism increases bone resorption, which may normalize serum calcium levels by releasing the
osseous storage of calcium.
-A hallmark of osteitis fibrosa is marrow fibrosis, caused by the activation of marrow mesenchymal cells, which
differentiate into fibroblast-like cells secreting the fibrous tissue occupying peritrabecular spaces.
-Another feature of this disorder is the increased frequency of bone remodeling, leading to increased resorption of
bone.
-The increased resorption is caused by an increase in both the number and the activity of osteoclasts.
-Bone formation is also increased, as reflected by increased amounts of osteoid and nonlamellar bone, which are
hallmarks of a high rate of bone turnover.
-In osteitis fibrosa the focus of abnormal remodeling activity is often in the cortical osteons of long bones, leading to
increased cortical porosity as a result of resorption and remodeling.
-Osteitis fibrosa may be associated with osteopenia and fractures, but measurements of bone density do not correlate
well with bone strength because of confounding variables, such as dystrophic mineralization and the accumulation
of woven bone (mineralized, nonlamellar, immature bone), which is much weaker than its lamellar counterpart.
-Another important factor in the pathophysiology of renal osteodystrophy is the deficiency of 1,25-dihydroxy-
cholecalciferol. In end-stage renal disease, this deficiency results in decreased intestinal absorption of calcium and
increased secretion of parathyroid hormone.

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-The clearest clinical role of Vit.D3 in renal osteodystrophy is its ability to prevent secondary hyperparathyroidism
by correcting hypocalcemia and inhibiting parathyroid hormone gene transcription.
-Besides hypocalcemia and a deficiency of Vit.D3, chromosomal deletions and decreased concentrations of vitamin
D receptors in parathyroid tissue also cause secondary hyperparathyroidism in patients with end-stage renal disease

Osteomalacia
-Osteomalacia is a common component of bone disease in patients with end-stage renal disease, although its
prevalence is decreasing.
-The disorder is characterized by
Low rates of bone turnover
 Mineralization defect
 Accumulation of unmineralized osteoid (bone matrix).
-The cause of osteomalacia in renal osteodystrophy is multifactorial.
-The low serum calcium level directly induced by hyperphosphatemia is a major factor.
-Hyperphosphatemia also decreases the efficacy of 1-hydroxylase, which decreases the levels of Vit D3 thus the
ability of the gut to absorb calcium.
-Aluminum-induced bone disease is an additional cause of osteomalacia. Aluminum negatively effects bone
formation through inhibition of osteoblastic activity as well as hydroxyapatite crystal formation.
-Aluminum may be introduced from
Dialysate solutions
 Antacids
 Aluminum-containing phosphate-binding agents used to combat the hyperphosphatemia of renal failure.
-Such intoxication causes defective mineralization and increased matrix synthesis by existing osteoblasts but long-
term inhibition of osteoblast differentiation. Intoxication also affects osteoclasts and inhibits their function.
-The incidence of osteomalacia has decreased with the elimination of aluminum exposure in patients with end-stage
renal disease.
-Exposure to iron, either alone or in combination with aluminum, may also cause osteomalacia.
-The accumulation of unmineralized osteoid and the decrease in bone turnover despite resorptive activity result in a
considerably weakened skeleton.
-Patients with osteomalacia often have skeletal deformities bone pain, fractures, and marked musculoskeletal
disability.
-This form of osteodystrophy is refractory to treatment with vitamin D sterols.

Adynamic Bone Disease

-Patients with end-stage renal disease who do not have secondary hyperparathyroidism ie
Post parathyroidectomy
 Overtreated with calcium and vitamin D
 Diabetes mellitus
 Aluminum intoxication.
-The association between continuous ambulatory peritoneal dialysis and adynamic renal bone disease may be related
to the greater transfer of calcium from the dialysate to the patient and suppression of parathyroid hormone secretion
that occurs with this form of dialysis as compared with hemodialysis.
-Hypersecretion of parathyroid hormone may thus be required to maintain normal rates of bone formation in patients
with end-stage renal disease, and the need to maintain bone remodeling at a normal level may be an inherent
stimulus for hyperparathyroidism in such patients.
-The presence of adynamic bone disease in patients with end-stage renal diseases that have normal parathyroid
function suggests that the production of one or more suppressors of bone formation is increased eg interleukin-11,
Interleukin-1 and TNFalpha
-In addition to the direct suppression of bone remodeling in end-stage renal disease, a deficiency of a factor involved
in bone formation or growth may contribute to adynamic bone disease.
-Osteogenic protein-1 (also called bone morphogenic protein-7), a potent osteoblast growth factor, is produced by
normal renal tubular cells.A deficiency of this factor may lead to the need for more parathyroid hormone.
-Another important factor contributing to osteopenia in patients with end-stage renal disease is hypogonadism
-In both women and men ESRD, serum concentrations of gonadal steroids tend to be low, as a result of a complex
set of endocrine and nonendocrine factors.

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-These factors include variable decreases in the secretion of FSH and LH and increased secretion of prolactin. As a
result, anovulation, amenorrhea or oligomenorrhea, infertility, impotence, loss of libido, oligospermia, and
gynecomastia can occur.
-Microfractures would be expected to cause bone pain in patients with osteopenia due to adynamic bone disease.
-Metastatic deposition causes soft tissue calcifications. Elevated phosphate levels may result in a high calcium-
phosphate product causing deposits in the soft tissues. This also can be affected by the degree of alkalosis, as well as
local tissue injury. Areas that are particularly affected by soft tissue calcification include medium-sized blood
vessels, periarticular soft tissues (tumoral calcinosis), and viscera such as the heart, lung and kidney.

Types of renal osteodystrophy

Osteitis fibrosa -50%
-Peritrabecular fibrosis, increased remodeling — resorption and formation
-Pathogenesis-Secondary hyperparathyroidism, secondary role of cytokines and growth factors
Osteomalacia -7%
- Increased osteoid, defective mineralization
-Pathogenesis-Hypocalcemia, hyperphosphatemia Aluminum deposition
Mixed disease-13
-Features of both osteitis fibrosa and osteomalacia
-Secondary hyperparathyroidism and aluminum deposition, plus unknown factors
Mild disease -3%
-Slightly increased remodeling
-Early or treated secondary hyperparathyroidism
Adynamic renal bone disease-27%
-Hypocellular bone surfaces, no remodeling
-Aluminum deposition, parathyroid hormone suppression, and other factors (deficiency of bone growth factors or
increased suppressors of bone remodeling)

Mortality/Morbidity:
- Clinically, osteomalacia is subtler than rickets, particularly in mild or moderate disease. Mildly affected patients
may present with nonspecific bone pain and tenderness and possibly hypotonia.
- Severely affected patients may have difficulty ambulating and may walk with a waddling gait.
-Milkman syndrome is a condition in which the patient experiences multiple insufficiency fractures that are often
bilateral and symmetric. Typical sites include the concave surface of the femoral neck, axillary margin of the
scapula, pubic rami, and ribs. Skeletal deformity can occur in the vertebral bodies and skull (basilar invagination),
and fractures can occur in the vertebrae and long bones.
-The immature skeleton may reveal the following characteristic findings:
 In neonates, posterior flattening and squaring of the skull (eg, craniotabes) may be observed.
In early childhood, bowing deformities of arms and legs are common
In older children, scoliosis, vertebral endplate deformities, basilar invagination of the skull, triradiate
deformity of the pelvis, and slipped capital femoral epiphysis may be observed.
-Renal osteodystrophy also may present with nonspecific signs and symptoms, including
Weakness
 Bone pain
 Skeletal deformity.
-Presentation varies markedly with age. Adults may present with findings of osteomalacia, while children typically
show growth retardation. As a result, complications differ depending on the patient's age.
- The most common complication of renal osteodystrophy is fracture, which may be insufficiency fractures through
osteomalacic bone or pathologic fractures through brown tumors or amyloid deposits
-Dialysis patients may experience carpal tunnel syndrome, osteomyelitis, septic arthritis, and osteonecrosis. Renal
transplant patients may experience osteonecrosis, tendinitis, tendon rupture, and fracture.
Sex
-Men comprise 54% of ESRD patients, and women, 46%.
Age
- Rickets and osteomalacia are different manifestations of the same underlying pathologic process, depending on
whether the patient is a child or an adult, respectively.

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-The demarcation is made at the time of closure of the growth plates. Renal osteodystrophy causes rachitic and some
osteomalacic changes in the child and osteomalacia and secondary hyperparathyroidism in adults.

DIAGNOSIS
Lab.
1.U/E/C
-Renal function
-Electrolytes especially-ca2+, mg, phosphates
2. Hormonal assay-Parathyroid hormone, Vit.D3
3. Alkaline phosphatase
-Patients with adynamic bone disease tend to have normal or reduced bone density, only slightly elevated serum
alkaline phosphatase concentrations, relatively normal serum parathyroid hormone concentrations, an absence of
bone aluminum, and hypercalcemia.
-Parathyroid hormone measurements an be used to differentiate osteitis fibrosa or mixed disease from adynamic
bone disease but are not sufficient to establish the type of osteodystrophy in an individual patient,. However, a bone
biopsy remains the best way to ascertain the type of renal osteodystrophy.
Imaging
Plain x-ray
-Radiographic examination in patients with osteomalacia may reveal only osteopenia. Characteristically, however,
coarsened trabecula is present. Complications such as Looser zones and complete fractures can be diagnosed
radiographically. Findings of renal osteodystrophy diagnosed with conventional radiography include osseous
resorption, soft tissue calcification, osteopenia, amyloid deposition, and fracture.

CURRENT MANAGEMENT RECOMMENDATIONS

-The mainstays of the prevention and treatment of renal osteodystrophy continue to be phosphate bindersmand
supplemental calcium.
1. Control of Serum Phosphate
A low-phosphate diet
 A phosphate binder, either calcium carbonate or calcium acetate,
-NB.aluminum-containing phosphate binders should be avoided.
Reducing dialysate magnesium concentrations and adding magnesium-containing binders to decrease the calcium
salts may allow both the control of serum phosphate concentrations and higher doses of calcitriol. Magnesium
inhibits mineralization, however, and its use requires careful monitoring of serum magnesium concentrations.
2. Control of Serum Calcium
-Calcium malabsorption is very common in end-stage renal disease because of deficient Vit.D3
-Serum calcium concentrations need to be maintained at the high end of the normal range in order to prevent or
suppress over secretion of parathyroid hormone
-A dialysate calcium concentration of 7 mg per deciliter (1.75 mmol per liter) provides an influx of approximately
800 mg per treatment.
-The positive calcium balance is greater in patients treated with continuous ambulatory peritoneal dialysis than in
those treated with hemodialysis, providing more effective suppression of parathyroid hormone secretion.
- This effect, along with greater phosphate removal,19 is probably the basis for the higher prevalence of adynamic
renal bone disease that is associated with continuous ambulatory peritoneal dialysis. When calcium salts are required
to control hyperphosphatemia, the increased dialysate calcium concentration may cause hypercalcemia
-The dialysate calcium concentration should be reduced to 5 mg per deciliter (1.25 mmol per liter), a level that will
not affect the calcium balance and will allow for sufficient oral intake of calcium salts to maintain normal serum
phosphate concentrations.
- The timing of oral calcium intake is important; calcium taken between meals is more a calcium supplement than a
phosphate binder.
3. Use of Vitamin D Analogues
-Calcitriol and other vitamin D preparations (vitamin D, alfacalcidol, dihydrotachysterol, and calcifediol) have been
widely used to treat secondary hyperparathyroidism, as well as to correct deficient endogenous production vit D3.
-These agents lessen bone pain, improve bone histologic characteristics, and suppress parathyroid hormone secretion
by both raising serum calcium concentrations and inhibiting parathyroid hormone gene transcription.47 Calcitriol is
the most potent agent in suppressing parathyroid hormone secretion, but it and all other vitamin D preparations can
cause hypercalcemia.

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-None of these agents should be used in the presence of hyperphosphatemia, to avoid high concentrations of serum
calcium–phosphorus products and extra skeletal calcification.
- Intermittent intravenous or oral administration of calcitriol is perhaps the most effective means of suppressing
parathyroid hormone secretion.
- Since vitamin D preparations suppress parathyroid hormone secretion and decrease the proliferation of osteoblasts,
these agents should not be given to patients with adynamic bone disease.
-The use of vitamin preparations associated with a lower incidence of hypercalcemia before the initiation of therapy
for end-stage renal disease will contribute substantially to the prevention of osteodystrophy.
4. Reduction of exposure to excess iron or aluminum
-Treatment with aluminum chelating agents to reduce aluminum toxicity.

SICKLE CELL DISEASE

Background:
Pathophysiology:
-Sickle cell anemia is an autosomal recessive genetic disease that results from the substitution of valine for glutamic
acid at position 6 of the beta-globin gene, leading to production of a defective form of hemoglobin, hemoglobin S
(HbS).
-Deoxygenation of the heme moiety of HbS leads to hydrophobic interactions between adjacent HbS molecules,
which then aggregate into larger polymers, distorting the red blood cell (RBC) into the classic sickle shape.
-The major consequence of this sickle shape is that RBCs become much less deformable; therefore, they obstruct the
microcirculation. Tissue hypoxia, which promotes further sickling, results.
-Sickle-shaped RBCs are rapidly hemolyzed and have a life span of only 10-20 days (vs. the normal 120 d).
-Patients who are homozygous for the HbS gene have full-blown sickle cell anemia. Patients who are heterozygous
for the HbS gene are carriers of the condition.
-Under stressful conditions, carriers may display some clinical manifestations (e.g., severe hypoxia). If both
members of a couple are carriers, they have a 25% risk of producing a child who is homozygous for the HbS gene.
-The clinical manifestations of sickle cell anemia are diverse, and any organ system may be affected.
-Some of the acute presentation of sickle cell disease.
1) Vasoocclusive (Painful crisis)
2) Aplastic crisis
3) Hemolytic crisis
4) Sequestration crisis (splenic, hepatic, chest)
1. Vasoocclusive crisis (Painful Crisis)
-Occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied.
-Pain is the most frequent complaint during these episodes, and it is ischemic in origin. Recurrent episodes may
cause irreversible organ damage.
-Bones pain (e.g., femur, tibia, humerus, lower vertebrae) frequently are involved. Involvement with the femoral
head results in avascular necrosis.
-Joints and soft tissue involvement present as dactylitis or as hand and foot syndrome (painful and swollen hands
and/or feet in children).
-When it involves abdominal organs, vasoocclusive crisis can mimic an acute abdomen. With repeated episodes, the
spleen auto infarcts, rendering it fibrotic and functionless in most adults with sickle cell anemia.
-The liver also may infarct and progress to failure with time.
-Papillary necrosis is a common renal manifestation of vasoocclusion, leading to isosthenuria (i.e. inability to
concentrate urine).
-Vasoocclusive crises can involve the lungs and cause an acute chest syndrome.
-CNS manifestations of vasoocclusive crises include
Cerebral infarction (children)
Cerebral hemorrhage (adults)
Seizures
 Transient ischemic attacks
Cranial nerve palsies
Meningitis
 Sensory deficits

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  Acute coma.
-Cerebrovascular accidents are not uncommon in children, and they tend to be recurrent. These patients are often
maintained on hypertransfusion programs to suppress HbS.
-Vaccination
 Pneumococcal vaccination
Influenza vaccination
Hepatitis B vaccination
-Precipitating event, preceding trauma, or family history of similar episodes
-Skin ulceration, especially over bony prominences (malleoli),
-Retinal hemorrhages.
-Corpus cavernosum, preventing blood return from the penis and leading to priapism.
2. Aplastic Crisis
Bone marrow stops producing new RBCs .This is most commonly seen in patients with Parvovirus B19 infection or
folic acid deficiency.
3. Sequestration crisis
Hematologic crises are manifested by a sudden exacerbation of anemia, with a corresponding drop in the
hemoglobin level. This can be due to acute splenic sequestration in which sickled cells block splenic outflow,
leading to the pooling of peripheral blood in the engorged spleen (seen in young patients with functioning spleens).
Less commonly, it is due to hepatic sequestration.
4. Hemolytic crisis
Acute exacerbation of the anemia, and presentation with jaundice.
5. Infectious crisis
-Infectious crises are due to underlying functional asplenia in most adults with sickle cell anemia, leading to
defective immunity against encapsulated organisms (e.g., Haemophilus influenzae, Streptococcus pneumoniae).
-Individuals with infectious crisis also have lower serum immunoglobulin M (IgM) levels, impaired opsonization,
and sluggish alternative complement pathway activation.
-Sicklers also exhibit increased susceptibility to other common infectious agents, including Mycoplasma
pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli

Clinical presentation
History:
-Pain is the most common presentation of vasoocclusive crisis.
 Location - Extremities, abdomen, back, flank, chest, and joints; whether monoarticular or
oligoarticular
Duration and mode of onset (acuity of onset)
Character - Migrating, diffuse in the abdomen; pleuritic in acute chest syndrome
 Previous similar episodes (painful crises tend to recur in the same pattern)
-Infection
 Fever
Cough (whether productive, color of sputum)
Urinary symptoms (polyuria, hematuria, dysuria)
 Shortness of breath or dyspnea (suggestive of acute chest syndrome)
-Neurological symptoms
 Aphasia
Unilateral weakness
Paresthesias
-Vomiting and diarrhea predispose to dehydration
-Visual blurring (retinal hemorrhage)
-Neck stiffness and severe headache (concerning for meningitis)
-Noticeable increase in weakness or pallor
-Syncope (most common presentation in acute sequestration crisis)
-Previous intake of analgesics (type and dose, if possible) and folic acid
-Surgical history (helps rule out other causes of abdominal pain)
-Previous hemoglobin levels and previous transfusion

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Physical:
Vital signs
-Hypotension and tachycardia may be signs of septic shock or sequestration crisis. With the severe anemia that
accompanies aplastic crisis, patients may exhibit signs of high-output congestive heart failure (CHF).
-Orthostasis suggests hypovolemia.
-Tachypnea suggests pneumonia, CHF, or acute chest syndrome. Hypoxia was commonly seen in patients with acute
chest syndrome.
-Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever.
-Examine head and neck to look for meningeal signs or possible source of infection (e.g., otitis, sinusitis).
-Auscultate the heart to search for signs of congestive heart failure.
-Auscultate the lungs to search for signs of pneumonia, CHF, or acute chest syndrome (similar to pulmonary
embolism).
-Palpate for tenderness (abdomen, extremities, back, chest, and femoral head) and hepatosplenomegaly.
-Observe for pallor, icterus, and erythema or edema of the extremities or joints.
-Perform neurological examination to search for focal neurological deficits.
Causes:
Vasoocclusive crises often are precipitated by the following:
 Cold weather (due to vasospasm)
Hypoxia (flying in unpressurized aircraft)
Infection
 Dehydration (especially from exertion or during warm weather)
Acidosis
Alcohol intoxication
 Emotional stress
 Pregnancy
 Exertional stress, particularly when compounded with heat and hypovolemia.
Aplastic crises often are preceded by the following:
 Infection with Parvovirus B19
Folic acid deficiency
Ingestion of bone marrow toxins (e.g., phenylbutazone)
Acute chest syndrome has been linked to fat embolism and infections

Lab Studies:
1. FHG
-Anemia –drop of more than 2 g/dL from baseline is indication for transfusion.
Low reticulocyte count-Aplastic crisis
High-hemolytic crisis
-Leukocytosis is expected in all patients with sickle cell anemia. Major elevation in the WBC count (ie, >20,000 per
mm3) with a left shift raises suspicion for infection.
-The platelet count is often elevated.
2. PBF-sickle-shaped RBCs are found along with target cells. Presence of Howell-Jolly bodies indicates that the
patient is asplenic.
3. ABG- in respiratory distress
4. LFT’s in patients with abdominal pain. An elevated baseline indirect bilirubin level may be normal because of
chronic hemolysis.
5. ECG for patients with symptoms of chest pain and/or pulse irregularities.
6. Type and cross-match in case transfusion is necessary.
7. Urinalysis -fever or signs of urinary tract infection (UTI). Patients with sickle cell anemia often have hematuria
and isosthenuria. If signs of urinary tract infection are present, obtain a urine Gram stain and culture.
8. Sickling test –done at initial diagnosis of sickle cell disease.
9. Hemoglobin electrophoresis
Differentiates individuals who are homozygous from those who are heterozygous and other haemoglobinopathies.
A homozygous patient will have hemoglobin SS (HbSS, 80-90%), hemoglobin F (HbF, 2-20%), and hemoglobin A2
(HbA2, 2-4%).
Imaging Studies:

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1. CXR
Radiographic findings may initially be normal in patients with acute chest syndrome.
2. Bone radiography
-Perform in patients with localized bone tenderness.
-Do not differentiate between osteomyelitis and bone infarction in the early stages. Radiographic signs of
osteomyelitis may not appear for 8-10 days.
A view of the vertebral column shows typical fish-mouth appearance of vertebrae in patients with sickle cell anemia.
This is due to expansion of the bone marrow.
3. Ultrasonography
Use in patients with abdominal pain to rule out cholecystitis or an ectopic pregnancy.
Assess liver and spleen size.
4. Head CT or MRI is used in cases of neurologic crisis.
Bone scans can aid in early differentiation of bone infarction and osteomyelitis

COMPREHENSIVE CARE OF SICKLE CELL ANAEMIA PATIENTS

Includes:
1-Health maintenance with appropriate prophylactic measures
2-Early diagnosis and treatment of acute symptoms
3-Periodic medical assessment with monitoring for the development of chronic organ damage
4-Family and patient education and psychosocial support
5-Genetic counseling

HEALTH MAINTENANCE
a) Immunization and Prophylactic drugs.
Immunization –in addition to the KEPI immunization as the following additional immunization is necessary.
1. The pneumococcal vaccine should be administered at age 2 years with subsequent boosters
2. Meningococcal vaccine is administered as a single quadrivalent vaccine when the child is older than 2 years.
3. The influenza virus vaccine is administered annually
4. Hepatitis A vaccine. (hepatitis B if never received in childhood)
KEPI vaccination schedule

Age Vaccination
At birth
BCG and Birth OPV

6 weeks
DPT/HepB/Hib 1 and OPV 1

10 weeks
DPT/HepB/Hib2 and OPV2

14 weeks
DPT/HepB/Hib 3 and OPV 3

9 months
Measles

9 months
Yellow Fever (in the four endemic districts of Baringo, Koibatek, Keiyo and
Marakwet).

Drugs prophylaxis
1. Penicillin V
Prophylaxis for encapsulated organisms is instituted as soon as the diagnosis of sickle cell disease is established,
preferably by age 2 month

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-An initial dose of 125 mg of penicillin V or G bid is recommended.
-The dose is increased to 250 mg bid by age 3 years.
-Allergy to penicillin, erythromycin may be substituted.
2. Folic acid therapy.
-For patients younger than 6 months, the usual dose is 0.1 mg/d.
-For infants aged 6 months to 1 year, the usual dose is 0.25 mg/d.
-For children aged 1-2 years, the usual dose is 0.5 mg/d.
-For patients older than 2 years, the dose is 1 mg/d. and even adult
3. Hydroxyurea
Which increases fetal hemoglobin production, reduces the incidence of pain episodes and acute chest syndromes in
some patients who are severely affected.
4. Malarial prophylaxis
-Mefloquine as a single weekly oral dose according to the following schedule:
5 to 12 years, 1/2 tablet;
>12 years, 1 tablet.
-Proguanil as a daily oral dose according to the following schedule:
5 to 12 years, 1 tablet;
>12 years, 2 tablets
-Use of insecticide treated mosquito nets.
Other aspects
b) Good nutrition
Balanced diet and water consumption should always be increased to avoid dehydration
c) General hygiene
Avoid diarrheal illness may precipitate a crisis.

B. ACUTE ILLNESS AND CRISES PROMPT DIAGNOSIS AND TREATMENT

Definition of illness requiring immediate medical care, including emergencies
1) T >38.5oC
2) Pain inadequately relieved by home measures
3) Significant respiratory symptoms (e.g. severe cough, shortness of breath, chest pain)
4) Abdominal pain, distension and/or acute enlargement of the spleen
5) Any neurologic symptom or sign - even if transient
6) Significant increase in pallor, fatigue and/or lethargy
7) Priapism episode persisting >3-4 hr with no resolution
8) Significant vomiting or diarrhea
-Acute illness characterized by any of the signs or symptoms listed above can prove rapidly life-threatening.
And prompt medical evaluation important.

TRANSFUSION THERAPY FOR ACUTE COMPLICATIONS

-Red blood cell transfusions play an important role in the treatment of some acute illnesses in patients with sickle cell
disease.
-For severe complications, timely transfusions may be life saving
Indications:
a) Acute exacerbation of baseline anemia
Aplastic crisis
 Sequestration crisis- Splenic sequestration, Hepatic sequestration
 Hemolytic crisis
b) Severe vaso-occlusive events
Acute chest syndrome
 Stroke
c) Severe infection
Acute multiorgan failure syndrome
c) Preparation for procedures
General anesthesia and surgery
 Radiographs with ionic contrast

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Selection of transfusion products
Leukocyte-depleted, packed red blood cells are recommended.
Transfusion method
A simple transfusion of packed RBC is appropriate for most situations characterized by acute exacerbation of
anemia.
Partial exchange transfusion, generally by erythrocytapheresis, may be needed for severe life-threatening illness or
in situations where relatively high baseline hemoglobin precludes a simple transfusion that would risk
hyperviscosity by increasing the hemoglobin level to > 10-11gm/dl.
Volume considerations
Simple transfusion with 10cc/kg of packed RBC typically raises the hemoglobin about 2gm/dl.
Patients with severe anemia that develops over several days (i.e. aplastic crisis) may be at risk for volume overload
and congestive heart failure from rapid infusion of RBC.
Thus, slow correction of the anemia (e.g. 4-5 cc/kg packed RBC over 4 hr, often with furosemide) or isovolemic
partial exchange transfusion may be needed to prevent precipitation of heart failure.
Hyperviscosity
Because sickle red cells are poorly deformable, simple red cell transfusions that increase the hemoglobin levels to
>10-11gm/dl may cause hyperviscosity in patients not receiving chronic transfusions and should be avoided

INPATIENT MANAGEMENT OF FEVER IN CHILD WITH SICKLE CELL DISEASE

DIAGNOSTICS
1. CBC, diff, platelet, and reticulocyte count initially and daily until improving (compare with patient's baseline
data).
2. CXR if tachypnea, cough, chest or abdominal pain, or any respiratory symptoms are present or subsequently
develop.
3. Septic Screen
Blood culture
 Urinalysis, and urine M/C/S
 CSF-if indicated
 Stool ova and cyst, M/c/S if indicated.
4. U/E/C-Electrolytes, BUN, creatinine
5. Liver function tests –Direct and indirect bilirubin, ALT
6. DIC screen for very severe pain or any evidence of encephalopathy (R/O acute multi-organ failure syndrome).
7. RUQ, epigastric or severe abdominal pain -abdominal ultrasound, liver function tests, amylase and lipase for (R/O
cholelithiasis, cholecystitis, pancreatitis).
8. Type and crossmatch if Hb is 1-2 gm/dl or more below baseline or if evidence of acute chest syndrome present
9. Consider orthopedic consult with aspiration for culture of bone or joint if osteomyelitis or septic arthritis suspected.
FLUIDS, GENERAL CARE:
IV + PO 1½ x maintenance.
Increased fluids may be needed if patient is dehydrated or if insensible losses are increased (e.g. persistent fever).
Avoid excessive fluids, which may precipitate or exacerbate acute chest syndrome.
MEDICATION/TREATMENT:
1. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h.
-Substitute clindamycin 10 mg/kg IV q 6 hr for patients with known or suspected cephalosporin allergy.
-Prophylactic penicillin should be discontinued while patient is receiving broad-spectrum antibiotics.
2. Acetaminophen 15 mg/kg po q 4 hr. (maximum daily dose 75 mg/kg).
-May add ibuprofen 10 mg/kg po q 6-8 h if no contraindication (i.e. gastritis, ulcer, coagulopathy, or renal impairment).
Limit more frequent dosing to 72 hr maximum duration.
3.02 by nasal cannula or face mask if needed to keep pulse ox 92% or  patient's baseline value, if >92%. The
etiology of a new or increasing supplemental 02 requirement should be investigated. Avoid excessive or unnecessary
02, which may suppress the reticulocyte count and exacerbate anemia.
4. Consider transfusion with RBC if Hb is 1-2 gm/dl or more below baseline and patient shows any signs of
cardiovascular compromise.

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MONITORING:
1. Vital signs q 2 hr until stable, then q 4 hr (suspect septic shock)
2. Consider CR monitor and ICU for any signs cardiovascular instability.
3. Record I & O, daily weight.
4. Pulse ox for severe illness or if respiratory signs or symptoms present

DISCHARGE CRITERIA:
1. Adequate pain relief on oral analgesics.
2. Taking adequate oral fluids and be able to take po medications (e.g. prophylactic penicillin) if applicable.
3. Afebrile >24 hr. with negative cultures for >24-48 hr. if applicable.
4. Resolution of any pulmonary symptoms or documentation of adequate oxygenation on room air.
5. Stable hemoglobin/hematocrit
Follow-up arranged.

INPATIENT MANAGEMENT OF VASO-OCCLUSIVE PAIN IN CHILD WITH SICKLE CELL DISEASE

MONITORING:
1. Vital signs q 4 hr
2. Record I+0, daily weight
3. Strongly consider continuous pulse ox if any respiratory symptoms present or if on parenteral narcotics
4. Consider CR monitor
DIAGNOSTICS (If not previously obtained):
1. CBC, diff, platelet count, and reticulocyte count initially and daily until improving. (Compare with patient's
baseline data.)
2. CXR if cough, chest pain, hypoxemia or any respiratory symptoms present or develop after admission.
Patients with severe vaso-occlusive pain are at increased risk for acute chest syndrome (see p. 20).
3. If febrile, blood culture and other cultures (e.g. urine, CSF) and urinalysis as indicated.
4. Consider renal (BUN, Creat) and liver (fractionated bili, ALT) function tests for very severe pain or any
evidence of encephalopathy (R/O acute multi-organ failure syndrome).
5. Consider abdominal ultrasound, liver function tests, and/or amylase and lipase for RUQ, epigastric or severe
abdominal pain (R/O cholelithiasis, cholecystitis, and pancreatitis)
6. Type and crossmatch if Hb is 1.5-2.0 gm/dl or more below baseline and/or if evidence of acute chest syndrome
(see acute chest syndrome care path) or cardiovascular compromise present. Consider requesting, if available,
minor-antigen-matched, sickle-negative, and leukocyte-depleted RBC.
FLUIDS, GENERAL CARE:
1. IV + P.O. 1-1½ x maintenance. Increased fluids may be needed if patient is dehydrated and/or insensible
losses are increased (e.g. persistent fever). Avoid excessive fluids, which may precipitate or exacerbate acute
chest syndrome.
2. Incentive spirometry - 10 breaths q 2 hr when awake
3. Encourage ambulation and activity
MEDICATION/TREATMENT:
1. Morphine sulfate 0.05 - 0.15 mg/kg/dose IV q 2 hr or 0.05 - 0.1 mg/kg/hr continuous infusion or via PCA. (For
PCA give 1/3-1/2 of total maximum dose by continuous infusion, with 1/2-2/3 via PCA boluses.)
-Alternative analgesics including hydromorphone 0.01-0.02 mg/kg IV q 3-4 hr may be appropriate in selected cases.
-Consider use of ketoralac 0.5 mg/kg (30 mg maximum dose) IV q 6-8 hr in addition to opioid analgesia if no
contraindication present (i.e. gastritis, ulcer, coagulopathy, dehydration, or renal impairment). Do not use ibuprofen
with ketorolac
-Repeated doses of meperidine (Demerol) should be avoided because of the risk of seizures.
2 Ibuprofen 10 mg/kg po q 6-8 hr or other anti-inflammatory agent if no contraindication present (i.e.ketoralac,
gastritis, ulcer, coagulopathy, or renal impairment). Limit more frequent dosing to 72hrs maximum duration.
3. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if febrile. Substitute clindamycin 10 mg/kg IV q 6 hr for known
or suspected cephalosporin allergy. Strongly consider adding vancomycin 10-15 mg/kg IV q 8 h for severe
febrile illness or for proven or suspected CNS infection.
4. If applicable, continue prophylactic penicillin. Prophylactic penicillin should be discontinued while patient is
receiving broad-spectrum antibiotics.

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5. Consider pain team consultation.
6. 02 by nasal cannula or face mask as needed to keep pulse ox >92% or > patient's baseline value, if >92%. The
etiology of a new or increasing supplemental 0 2 requirement should be investigated. Avoid excessive or
unnecessary 02, which may suppress the reticulocyte count and exacerbate anemia.
7. Offer heating pads or other comfort measures previously used by patient. Avoid ice or cold packs.
8. Consider colace or laxative for narcotic-induced constipation.
9. Reassess pain control on a regular basis (at least twice daily) by discussing efficacy and side effects with
patient/family. Analgesics may be weaned as tolerated by decreasing dose, not by prolonging interval between
doses. Discuss analgesic changes with patient/family.

ACUTE CHEST SYNDROME IN CHILD WITH SICKLE CELL DISEASE

DEFINITION:
An acute illness associated with lower respiratory symptoms, hypoxemia, or new infiltrate on CXR.

MONITORING:
1. Hospitalize
2. Vital Signs q 2-4 hr
3. Continuous pulse ox
4. Record I+O, daily weight

DIAGNOSTICS:
1. CBC, diff, platelet count, and reticulocyte count initially and daily until improving. (Compare with patient's
baseline values.)
2. CXR initially, repeats for clinical deterioration
3. Consider:
a) Type and crossmatch for severe illness or if Hb >1 gm/dl below baseline. .
b) Blood cultures if febrile
c) Blood gas for severe illness
d) Renal (BUN, Creat) and liver (fractionated bili, ALT) function tests for severe illness or if diffuse
encephalopathy present (R/O acute multiorgan failure syndrome)
FLUIDS, NUTRITION, GENERAL CARE:
1. Maintain "euvolemia". IV + P.O. 1-1½ x maintenance. More fluid is appropriate only if patient is dehydrated or
if insensible losses are increased (e.g. persistent fever).
2. Incentive spirometry - 10 breaths q 2 h when awake
3. Encourage ambulation, activity
MEDICATIONS/TREATMENTS:
1. Oxygen to pulse ox  92% or baseline value, if >92%.
2. Acetaminophen 15 mg/kg po q 4 hr or prn T >38.0 oC (maximum daily dose 75 mg/kg/day).
3. Ibuprofen 10 mg/kg po q 6-8 hr if no contraindication present (i.e. ketorolac, gastritis, ulcer, coagulopathy, renal
impairment). Limit more frequent dosing to 72 hr maximum duration.
4. Morphine 0.05 - 0.15 mg/kg IV q 2 hr
Alternative analgesics including hydromorphone (0.015-0.02 mg/kg IV q 3-4 hr may be appropriate in selected
cases. Consider use of ketorolac 0.5 mg/kg (30 mg maximum dose) IV q 6-8 h (72 h maximum duration) to
reduce or avoid opioids if no contraindication present (ie. gastritis, ulcer, coagulopathy, dehydration, or renal
impairment). Do not use ibuprofen with ketorolac.
5. Cefotaxime or cefuroxime 50 mg/kg q 8 h IV. Substitute clindamycin 10 mg/kg IV q 6 h for patient with
known suspected cephalosporin allergy. Prophylactic penicillin should be discontinued while patient is
receiving broad-spectrum antibiotics.
6. Azithromycin 10 mg/kg po first dose, then 5mg/kg qd, erythromycin 10 mg/kg q 6 h po, or other macrolide
antibiotic
7. Strongly consider adding vancomycin 10-15 mg/kg IV q 8 hr for severe illness, or nafcillin or vancomycin if
large infiltrate with pleural effusion present.
8. Consider one dose of furosemide 0.5-1.0 mg/kg IV if signs of fluid overload present.

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9. Consider trial of bronchodilators, especially if patient has history of reactive airway disease or wheezing on
exam.
10. Consider positive pressure ventilation (nasal CPAP or mask BiPAP) for patients with poor respiratory effort or
reduced ventilation.
11. Consider red cell transfusion:
a) Simple transfusion for moderately severe illness, especially if Hb >1 gm/dl below baseline (do not
transfuse acutely to Hb >10 gm/dl, Hct >30%).
b) Partial exchange transfusion to Hb 10 gm/dl and Hb S or Hb S+C (patient's RBC) 30% for severe or
rapidly progressive disease (may require transfer to ICU and transfusion medicine consult for
erythrocytapheresis). Remove femoral or central venous catheters as soon as possible after exchange
transfusion to reduce risk of thrombosis.
12. See other Clinical Care Paths for acute splenic sequestration, aplastic crisis, stroke, priapism, if present.

DISCHARGE CRITERIA:
1. Improved pulmonary symptoms and documentation of adequate oxygenation on room air.
2. Afebrile 24 hr. and negative cultures for  24-48 hr if applicable.
3. Stable hemoglobin/hematocrit.
4. Taking adequate oral fluids and able to take po medications if applicable.
5. Adequate pain relief, if needed, with oral analgesics.
5. Follow-up plans coordinated with hematology service. On a case by case basis, consider follow-up pulmonary
function testing and the possibility of chronic transfusions (p. 27) or hydroxyurea (p. 28).

APLASTIC CRISIS
IN CHILD WITH SICKLE CELL DISEASE

DEFINITION:
An acute illness associated with Hb below patient's baseline value with a substantially decreased reticulocyte count
(often <1%). Most cases are caused by acute infection with human parvovirus. If acute enlargement of spleen is
present, consider coexistent splenic sequestration Parvovirus also has been associated with other acute complications
of sickle cell disease which may occur during aplastic crisis, including pain, bone marrow necrosis, acute chest
syndrome, and stroke.

MONITORING:
1. Hospitalize for evidence of cardiovascular compromise, for inability to provide appropriate transfusion support as
outpatient, and/or for concerns about reliability of follow-up.
2. Vital signs q 2 hr until stable, then q 4 hr. if hospitalized.
3. Consider CR monitor and continuous pulse ox
4. Record I+O, daily weight

DIAGNOSTICS:
1. CBC, diff, platelet count, and reticulocyte count initially, then q 12-24 hr.
2. Type and crossmatch.
3. Blood culture, urinalysis, and urine culture if febrile. Consider CSF and other cultures.
4. Consider CXR if febrile or if any signs or symptoms of respiratory illness present.
5. Consider diagnostic tests for parvovirus.

FLUIDS, GENERAL CARE:

1. IV + PO @ 1 X maintenance. More fluids may be needed if insensible losses are increased (e.g. persistent fever).
Avoid excessive fluids which may precipitate congestive heart failure.
2. Contact isolation for presumed parvovirus infection (no pregnant care providers).

MEDICATION/TREATMENT:

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1. RBC transfusions for symptomatic anemia and/or Hb <5 gm/dl with no evidence of erythroid recovery; usually 5-
6 cc/kg over 4 hrs with close observation for fluid overload. Transfusion may need to be repeated.
2. Cefotaxime or cefuroxime 50 mg/kg IV q 8 hr if febrile. Substitute clindamycin 10 mg/kg IV q 6 hr for patients
with known or suspected cephalosporin allergy. Strongly consider adding vancomycin 10-15 mg/kg IV q 8 hr for
severe febrile illness and/or for proven or suspected CNS infection.
3. If applicable, continue prophylactic penicillin. Prophylactic penicillin should be discontinued while patient is
receiving broad-spectrum antibiotics.
4. 02 by nasal cannula or face mask if needed to keep pulse ox 92% or  patient's baseline value, if >92%. The
etiology of a new or increasing supplemental 02 requirement should be investigated. 02, 2 liters by nasal cannula
or 35% by face mask, can be given empirically for the severely anemic child who is to receive RBC transfusions.
5.Acetaminophen 15 mg/kg po q 4 hr (maximum daily dose 75 mg/kg) and/or ibuprofen 10 mg/kg po q 8 hr for any
fever and/or mild pain. (Hyperthermia may exacerbate cardiovascular compromise with severe anemia.).

INPATIENT MANAGEMENT OF PROLONGED PRIAPISM

IN CHILD WITH SICKLE CELL DISEASE
DEFINITION: Priapism is a prolonged painful erection of the penis that commonly occurs in children and adolescents
with sickle cell disease, often starting during the early morning hours.
It occurs in two forms:
a)stuttering episodes which last less than 2-4 hours but are often recurrent and may precede a severe episode, and
(b) Severe events that last more than 2-4 hours and may eventually result in impotence. Simple maneuvers such as
increasing oral fluids, taking analgesics, urination, moderate exercise, and/or taking a bath or shower may help end an
episode of priapism, and no further specific intervention may be required.
Patients who have frequent episodes >2 within one month or >4 within one year, priapism prophylaxis with
pseudoephedrine 30 mg/po hs (<10 years) or 60 mg/po hs (>10 years) should be considered.
-Any episode that lasts longer than 3-4 hours should be considered an emergency that requires prompt medical
intervention
MONITORING:
1. Vital signs q 2-4 h.
2. Record I+O, daily weight.
3. Strongly consider continuous pulse ox if receiving parenteral narcotics.

DIAGNOSTICS (if not previously obtained):

1. CBC, diff, platelet count, and reticulocyte count initially and daily until improving. (Compare with patient's
baseline data.)
2. Consider type and crossmatch.
3. Urinalysis and urine culture.
4. Blood culture if febrile. Consider other cultures (e.g. CSF).

FLUIDS, GENERAL CARE:

1. IV fluids - 10 cc/kg over 1 hr, then IV + PO = 1½ x maintenance
2. Encourage ambulation
3. Incentive spirometry - 10 breaths q 2 hr when awake if on parenteral narcotics

MEDICATION/TREATMENT:
1. Aspiration and irrigation. The lateral side of the penis is prepped with betadine and approximately 0.5 ml of 1%
lidocaine is infiltrated subcutaneously into the lateral surface of the penis and then more deeply into the tunica
albuginea.
A 23 gauge needle is inserted into the corpora cavernosa and as much blood as possible is aspirated into a dry 10 ml
syringe through a three-way stopcock.
Another 10 ml syringe containing 1:1,000,000 solution of epinephrine (ie 1ml of 1:1,000 epinephrine
diluted in 1 liter of normal saline) is attached to the three-way stopcock.
The corpora cavernosa are irrigated with 10 ml of the 1:1,000,000 epinephrine solutions, with additional blood
aspirated via dry syringes until detumescence has occurred. Some urologists prefer using a dilute solution of
phenylephrine as an alternative to epinephrine.

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The needle is withdrawn and five minutes of firm pressure (timed by the clock) is applied by the physician doing the
procedure to prevent hematoma formation.
2. Never use ice or cold packs.
3. Morphine sulfate 0.05-0.15 mg/kg/dose.
4. Mild to moderately severe pain - acetaminophen with codeine (1 mg/kg) po q 4 hr.
5. Ibuprofen 10 mg/kg po q 6-8 h if no contraindication present (i.e. ketorolac, gastritis, ulcer, coagulopathy, or renal
impairment). Limit more frequent dosing to 72 hr maximum duration.
6. Reassess pain control at least twice daily. Analgesics may be weaned as tolerated by decreasing dose, not by
prolonging interval between doses.
7. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if febrile.
8. 02 by nasal cannula or face mask if needed to keep pulse ox 92% or
9. Consider transfusion if no evidence of detumescence within 12 hrs:
a) Partial exchange or erythrocytapheresis to Hb> 10gm/dl and Hb S (patient's RBC) <30%.
b) May consider simple transfusion as alternative to partial exchange transfusion if Hb <6-7 gm/dl (do not
transfuse acutely to Hb >10 gm/dl,
10. Observe for severe headache or neurologic signs or symptoms. (Ischemic stroke may occur 1-10 days after onset
of priapism, especially following transfusion.)

ACUTE STROKE OR NEUROLOGIC EVENT

IN CHILD WITH SICKLE CELL DISEASE
DEFINITION: Stroke, defined as an acute, clinically apparent neurological event, occurs in 8-11% of children with
Hb SS. Common presenting symptoms and signs include hemiparesis, monoparesis, aphasia or dysphasia, seizures,
severe headache, cranial nerve palsy, stupor, and coma. Stroke may occur without warning as an isolated event or
may complicate other complications of sickle cell disease such as acute chest syndrome or aplastic crisis. Acute
neurologic symptoms or signs require urgent evaluation and treatment.

DIAGNOSTICS:
1. Document duration of acute symptoms, any prior neurologic symptoms or trauma, and results of any previous
CNS imaging studies (ie. CT, MRI, MRA, or TCD).
2. Document details of the neurologic exam.
3. Type and crossmatch for transfusion
4. CBC, diff, platelet count, and reticulocyte count initially and as clinically indicated (compare with patient's
baseline data).
6. Consider screening coagulation profile.
7. Blood and urine cultures if febrile.
8. Electrolytes initially and daily until stable.
9. CT-Scan or MRI.
10. Consider CSF culture if febrile and no contraindication present.

TRANSCRANIAL DOPPLER U/S

-Stroke, defined as an acute, clinically apparent neurological event, occurs in 8-11% of children with Hb SS.
-Most strokes are ischemic events caused by stenosis or occlusion of large cerebral arteries such as the intracranial
internal carotids and middle cerebrals.
-Stroke causes significant long-term neurologic sequelae in at least 50% of cases. Chronic transfusion after a first
stroke reduces markedly the high risk of recurrent stroke, but this is a suboptimal approach because it does not prevent
the initial neurologic injury.
-Transcranial Doppler (TCD) U/S provides a non-invasive method for identifying children with Hb SS who are at high
risk for developing a first stroke.
-High risk patients are those with increased blood velocity in large cerebral vessels, indicative of vascular narrowing.
Patients with mean blood-flow velocity in the internal carotid or middle cerebral artery of >200cm/second are at highest
risk. A prospective randomized study demonstrated that chronic transfusions reduce the risk of first stroke in such high

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risk patients. These data have led some to recommend routine TCD screening of children with sickle cell anemia, and
the initiation of a chronic transfusion program for those with abnormal screening tests

FLUIDS, GENERAL:
1. IV + PO@ 1 x maintenance

MEDICATION/TREATMENT:
1. Partial exchange transfusion or erythrocytapheresis to Hb 10 gm/dl and Hb S (patient's RBC) <30%
2. Simple transfusion with RBC to Hb approximately 10 gm/dl may be considered as an alternative to partial
exchange transfusion for stable patients with Hb <6-7 gm/dl (do not transfuse acutely to Hb >10 gm/dl, Hct
>30%).
3. Rx seizures if present.
4. Rx increased intracranial pressure if present.
5. 02 by nasal cannula or face mask
7. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if febrile.
CHRONIC TRANSFUSION PROTOCOL
Overview:
-Some severe manifestations of sickle cell disease warrant maintenance therapy with chronic blood transfusions.
-The goal is to suppress erythropoiesis sufficiently and to provide enough normal red blood cells to maintain the
percentage of the patient's cells (i.e. hemoglobin S) at less than 30%.
-Experience has shown that this approach significantly reduces the risk of recurrent stroke. Such transfusions also
reduce markedly the incidence of many other sickle-related complications such as vaso-occlusive pain and acute chest
syndrome.
-In addition to preventing acute complications, chronic transfusions may prevent the progression of chronic organ
damage and even reverse some pre-existing organ dysfunction. This has been shown most clearly in patients with Hb
SS and functional asplenia, some of whom show improved splenic reticuloendothelial function after receiving chronic
transfusions.
-Many children with sickle cell disease treated with chronic transfusions also experience an increased sense of well
being, with improved energy levels, exercise tolerance, growth velocity and sexual development.
-Thus, transfusions to chronically replace sickle cells with normal erythrocytes can be considered a specific therapy
that markedly ameliorates the disease

Indications:
Stroke
Indications in Selected Patients
 Transient ischemic attack
 Abnormal TCD
 Severe or recurrent acute chest syndrome
Severe debilitating pain
 Following splenic sequestration (as alternative to observation or early surgical splenectomy)
 Recurrent priapism
 Chronic organ failure
 Intractable leg ulcers
Severe chronic anemia with high output cardiac failure
Selected pregnancies

Outpatient Transfusions:
-PRBC 10-15 ml/kg given over 3-4 hr with standard monitoring.
-Frequency of transfusions (usually q 3-4 weeks) is adjusted to maintain Hb S<30% (typically with nadir Hb >9-10
gm/dl).
-For patients receiving chronic transfusions for stroke who have had no recurrent neurologic events for 3 years,
consider decreasing frequency of transfusions to maintain Hb S <50%.
-Serial erythrocytapheresis is an alternative approach to chronic simple transfusions that is associated with
substantially less iron loading and should be seriously considered for patients with adequate venous access.
-Patients should be immunized to hepatitis A and B.
-Continue prophylactic penicillin if applicable.

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Iron Chelation:
-Initiation of chelation with desferroxamine should be considered after 1 year of chronic transfusions
and/or when serum ferritin is increased to 1500-2000 g/L. Hepatic iron content >4 mg/gm dry wt
liver tissue (as determined by liver biopsy) also has been used as an indication for beginning iron chelation.
Initial dose is 40-50 mg/kg/d s.c. in at least 8-10 cc sterile water infused over 10-12 hr, 5-6 nights per
week. Measurement of 24 hr urinary iron excretion in response to a single dose of desferroxamine can
help document drug efficacy

MONITORING FOR CHRONIC ORGAN DAMAGE AND COMPLICATIONS

1. Prior to each transfusion:
-CBC, reticulocyte count, type and cross, antibody screen.
-Consider serum ferritin and Hb S quantitation
2. Every 3-6 months
Height, weight, physical exam
 Hb electrophoresis
 Serum ferritin
 ALT
Assess acceptance and compliance of patient and family with desferroxamine therapy

3. Annually
LFTs –Bilirubins, enzymes, Proteins.
 Renal function-BUN and creatinine.
 Serology for Hepatitis B and C, HIV, and HTLV I-II serology
 Electrolytes-Sodium, potassium, calcium, phosphorus
 Thyroid function tests
 Fasting glucose, and other endocrine studies as indicated.
 Consider 24 hr urinary iron excretion with 12 hr dose of subcutaneous desferroxamine (usually
40-50 mg/kg
 Audiology evaluation
 Ophthalmology examination
Consider CXR, EKG, echocardiogram
Consider CNS evaluation including MRI, MRA, and/or neurocognitive testing for patients with stroke
Consider metaphyseal and spinal radiographs.
Consider liver biopsy for histology and quantitative iron –if indicated.
NB. Immediate - Audiology evaluation if any symptoms present (e.g. tinnitus, difficulty hearing)
-Ophthalmology consultation for any new visual symptoms

FAMILY AND PATIENT EDUCATION

1. Patient’s families should have counseling and education regarding clinical manifestations associated with the
disorder and its complications.
-Reinforcement should occur incrementally during the course of ongoing care.
2. Families should be educated on the importance of hydration, diet, outpatient medications, and immunization
protocol.
3. Family should be instructed on proper splenic palpation and observation of pallor, jaundice, and fever.
4. Genetic counseling of patient before marriage.

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SYPHYLIS
Definition
-Chronic systemic infection caused by Treponema pallidum.
-Usually sexually transmitted and is characterized by episodes of active disease interrupted by periods of latency.
After an incubation period averaging 2 to 6 weeks, a primary lesion appears, often associated with regional
lymphadenopathy.
-A secondary bacteremic stage, associated with generalized mucocutaneous lesions and generalized
lymphadenopathy, is followed by a latent period of subclinical infection lasting many years.
-In about one-third of untreated cases, the tertiary stage is characterized by progressive destructive mucocutaneous,
musculoskeletal, or parenchymal lesions; aortitis; or symptomatic central nervous system (CNS) disease.
ETIOLOGY
-The Spirochaetes include three
a) Leptospira, which causes human leptospirosis;
b) Borrelia, which causes relapsing fever and Lyme disease
c) The genus Treponema includes
 T. pallidum pallidum, which causes venereal syphilis
 T. pallidum pertenue, which causes yaws
 T. pallidum endemicum, which causes endemic syphilis or bejel
 T. carateum, which causes pinta

MANIFESTATIONS

Primary Syphilis
Painless chancre
-The typical primary chancre usually begins as a single painless papule that rapidly becomes eroded and usually
becomes indurated, with a characteristic cartilaginous consistency on palpation of the edge and base of the ulcer
.Usually located on the penis, whereas in homosexual men it is often found in the anal canal or rectum, in the mouth
- In women, common primary sites are the cervix and labia.
-The genital lesions must be differentiated from those of include
Traumatic superinfected lesions.
 Lesions of herpes simplex virus infection
 Lesions of chancroid.
-Primary genital herpes may produce inguinal adenopathy, but the nodes are tender of multiple painful vesicles
Chancroid produces painful, superficial, exudative, non-indurated ulcers, more often multiple than in syphilis
adenopathy is common, can be either unilateral or bilateral, is tender, and may be suppurative.
Regional lymphadenopathy
-Regional lymphadenopathy usually accompanies the primary syphilitic lesion, appearing within 1 week of the
onset of the lesion. The nodes are firm, nonsuppurative, and painless.
-The chancre generally heals within 4 to 6 weeks (range, 2 to 12 weeks), but lymphadenopathy may persist for
months.

Secondary Syphilis
a) Localized or diffuse symmetric mucocutaneous lesions
-The skin rash consists of macular, papular, papulo-squamous, and occasionally pustular syphilides; often more than
one form is present simultaneously.
-Initial lesions are bilaterally symmetric, pale red or pink, nonpruritic, discrete, round macules that measure 5 to 10
mm in diameter and are distributed on the trunk and proximal extremities.
-These lesions, which may progress to necrotic lesions (resembling pustules) in association with increasing
endarteritis and perivascular mononuclear infiltration, are distributed widely, frequently involve the palms and soles
and may occur on the face and scalp.
-Tiny papular follicular syphilides involving hair follicles may result in patchy alopecia (alopecia areata), with loss
of scalp hair, eyebrows, or beard.
-In warm, moist, intertriginous body areas, including the perianal area, vulva, scrotum, inner thighs, axillae, and
skin under pendulous breasts, papules can enlarge and become eroded to produce broad, moist, pink or gray-white,
highly infectious lesions called condylomata lata

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-Superficial mucosal erosions, called mucous patches, the lips, oral mucosa, tongue, palate, pharynx, vulva and
vagina, glans penis, or inner prepuce.
b) Generalized nontender lymphadenopathy
c) Constitutional symptoms
-May accompany or precede secondary syphilis include
Sore throat
 Fever
 Weight loss
 Malaise and anorexia
Headache and meningismus
-Acute meningitis occurs in only 1 to 2% of cases. However, T. pallidum has been recovered from CSF during
primary and secondary syphilis in 30% of cases; this finding is often but not always associated with other CSF
abnormalities.
-Less common complications of secondary syphilis include
Hepatitis
 Nephropathy-AGN, Nephrotic syndrome
 GIT-hypertrophic gastritis, patchy proctitis, ulcerative colitis, or a rectosigmoid mass.
 Arthritis
 Periostitis.
 Ocular findings -unexplained pupillary abnormalities, optic neuritis, and a retinitis pigmentosa syndrome,
classic iritis (especially granulomatous iritis) or uveitis.
-The diagnosis of secondary syphilis is in eye often considered only after the patient fails to respond to steroid
therapy. T. pallidum has been demonstrated in the aqueous humor from these patients.

Latent Syphilis
-Positive serologic tests for syphilis, together with a normal CSF examination and the absence of clinical
manifestations of syphilis, indicate a diagnosis of latent syphilis.
-The diagnosis is often suspected on the basis of
History of primary or secondary lesions
 History of exposure to syphilis
 Delivery of an infant with congenital syphilis
-Pregnant women with latent syphilis may infect the fetus in utero. Moreover, syphilis has been transmitted through
the transfusion of blood from patients with latent syphilis of many years' duration.
-It was previously thought that untreated late latent syphilis had three possible outcomes:
(1) It could persist throughout the lifetime of the infected individual
(2) It could end in the development of late syphilis,
-The more sensitive treponemal antibody tests rarely, if ever, become negative without treatment. About 30% of
untreated patients with latent syphilis develop clinically evident late syphilis

TERTIARY SYPHYLIS

NEUROSYPHYLIS
-Although mixed features are common, the major clinical categories of symptomatic neurosyphilis include:
 Meningeal-<1 year after infection
Meningovascular-5 to 10 years
Parenchymatous syphilis-25 to 30 years includes general paresis and tabes dorsalis
-However, particularly in the antibiotic era, often presents not as a classic picture but rather as mixed and subtle or
incomplete syndromes.
Meningeal syphilis
-May involve either the brain or the spinal cord, and patients may present with
Headache
Nausea and vomiting
Neck stiffness
Cranial nerve palsies
Seizures
Changes in mental status.

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Meningovascular syphilis
-Reflects diffuse inflammation of the pia and arachnoid together with evidence of focal or widespread arterial
involvement of small, medium, or large vessels.
-The most common presentation is a stroke syndrome involving the middle cerebral artery of a relatively young
adult; however, unlike the usual thrombotic or embolic stroke syndrome of sudden onset, meningovascular syphilis
often becomes manifest after a subacute encephalitic prodrome (with headaches, vertigo, insomnia, and
psychological abnormalities), which is followed by a gradually progressive vascular syndrome.
General paresis
-Reflect widespread parenchymal damage and include abnormalities corresponding to the mnemonic paresis:
P-personality
 A-affect
 R-reflexes (hyperactive)
 E- Eye (e.g., Argyll Robertson pupils)
 S-sensorium impaired (illusions, delusions, hallucinations)
 I- intellect (a decrease in recent memory and in the capacity for orientation, calculations, judgment, and
insight)
 S-speech abnormalities
Tabes dorsalis
-Presents as symptoms and signs of demyelination of the posterior columns, dorsal roots, and dorsal root ganglia.
-Symptoms include
Ataxic wide-based gait
 Footslap
 Paresthesia with loss of position, deep pain, and temperature sensations
 Bladder disturbances, impotence
 Areflexia
 Trophic joint degeneration (Charcot's joints) and perforating ulceration of the feet can result from loss of
pain sensation
-The small, irregular Argyll Robertson pupil, a feature of both tabes dorsalis and paresis, reacts to accommodation
but not to light. Optic atrophy also occurs frequently in association with tabes.

Late Lesions of the Eyes

-Iritis associated with pain, photophobia, and dimness of vision or chorioretinitis occurs not only during secondary
syphilis but also as a relatively common manifestation of late syphilis.
-Adhesions of the iris to the anterior lens may produce a fixed pupil, not to be confused with Argyll Robertson
pupil.

Late Benign Syphilis (Gumma)

-Gummas may be multiple or diffuse but are usually solitary lesions that range from microscopic size to several
centimeters in diameter.
-They consist of a granulomatous inflammation with a central necrosis surrounded by mononuclear, epithelioid, and
fibroblastic cells; occasional giant cells; and perivasculitis. T. pallidum may be demonstrated in them.
-Commonly involved sites include the skin and skeletal system, the mouth and upper respiratory tract, the larynx,
the liver, and the stomach; however, any organ may be involved.
-Gummas of the skin produce painless and indurated nodular, papulo-squamous, or ulcerative lesions that form
characteristic circles or arcs, with peripheral hyperpigmentation.
-Gummas are usually indolent and may heal spontaneously with scarring, but they may also be explosive in onset
and are often destructive. The lesions other chronic granulomatous conditions ie
Tuberculosis
 Sarcoidosis
 Leprosy
 Deep fungal infections
-Skeletal gummas most frequently involve the long bones of the legs, although any bone may be affected. Trauma
may predispose a specific site to involvement. Presenting symptoms usually include focal pain and tenderness.
Radiographic abnormalities with advanced gummas of bone include periostitis or destructive or sclerosing osteitis.
Upper respiratory gummas can lead to perforation of the nasal septum or palate. Gummatous hepatitis may produce
epigastric pain and tenderness as well as low-grade fever and may be associated with splenomegaly and anemia.

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-Treatment with penicillin results in rapid healing of active gummatous lesions.

CARDIOVASCULAR SYPHYLIS
-Cardiovascular manifestations are attributable to endarteritis obliterans of the vasa vasorum, which provide the
blood supply to large vessels.
-This condition produces medial necrosis with destruction of elastic tissue, particularly in the ascending and
transverse segments of the aortic arch, resulting in
Uncomplicated aortitis
 Aortic regurgitation
 Saccular aneurysm
 Coronary ostial stenosis
-Symptoms appear from 10 to 40 years after infection. Occur more at an earlier age among men than among
women.
-Linear calcification of the ascending aorta on chest x-ray films suggests asymptomatic syphilitic aortitis, as
arteriosclerosis seldom produces this sign.
-Syphilitic aneurysms-usually saccular, occasionally fusiform-do not lead to dissection.
-It may also involve abdominal aorta, but these aneurysms tend to occur above the renal arteries, whereas
arteriosclerotic abdominal aneurysms are usually found below the renal arteries.
-With increasing age, the nervous system is also affected in up to 40% of patients with cardiovascular syphilis.

Congenital Syphilis
-Transmission of T. pallidum may occur at any stage of pregnancy, but the lesions of congenital syphilis generally
develop after the fourth month of gestation, when fetal immunologic competence begins to develop.
-This timing suggests that the pathogenesis of congenital syphilis depends on the immune response of the host
rather than on a direct toxic effect of T. pallidum.
-The risk of infection of the fetus during untreated early maternal syphilis is estimated to be 75 to 95%, decreasing
to about 35% for maternal syphilis of >2 years' duration.
-Adequate treatment of the mother before the 16th week of pregnancy should prevent fetal damage. Untreated
maternal infection may result in a rate of fetal loss of up to 40% (with stillbirth more common than abortion because
of the late onset of fetal pathology), prematurity, neonatal death, or nonfatal congenital syphilis.
-Among infants born alive, only fulminant congenital syphilis is clinically apparent at birth, and these babies have a
very poor prognosis. The most common clinical problem is the healthy-appearing baby born to a mother with a
positive serologic test.
-The manifestations of congenital syphilis can be divided into three types according to their timing:
(1) Early manifestations, which appear within the first 2 years of life (often between 2 and 10 weeks of age), are
infectious and resemble the manifestations of severe secondary syphilis in the adult;
Rhinitis, or "snuffles" The earliest sign of congenital syphilis
 Mucocutaneous lesions -bullae (syphilitic pemphigus), vesicles, superficial desquamation, petechiae, and
(later) papulo-squamous lesions, mucous patches, and condylomata lata.
 Bone changes - osteochondritis, osteitis, and periostitis.
 Hepatosplenomegaly
 Lymphadenopathy
 Anemia, thrombocytopenia, and leukocytosis
 Jaundice
-Neonatal congenital syphilis must be differentiated from other generalized congenital infections, including rubella,
cytomegalovirus or herpes simplex virus infection, and toxoplasmosis, as well as from erythroblastosis fetalis.
-Neonatal death is usually due to pulmonary hemorrhage, secondary bacterial infection, or severe hepatitis.
(2) Late manifestations, which appear after 2 years and are noninfectious
(3) Residual stigmata.
-Late congenital syphilis is that which remains untreated after 2 years of age.
-Cardiovascular syphilis rarely develops in late congenital syphilis, whereas interstitial keratitis is much more
common and occurs between the ages of 5 and 25.
-Other manifestations are
Eighth-nerve deafness
 Recurrent arthropathy
 Bilateral knee effusions are known as Clutton's joints.

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-Asymptomatic neurosyphilis is present in about one-third of untreated patients, and clinical neurosyphilis occurs in
one-quarter of untreated individuals over 6 years of age. Gummatous periostitis occurs between the ages of 5 and 20
and, as in nonvenereal endemic syphilis, tends to cause destructive lesions of the palate and nasal septum.
-Characteristic stigmata include Hutchinson's teeth-centrally notched, widely spaced, peg-shaped upper central
incisors and "mulberry" molars sixth-year molars with multiple, poorly developed cusps.
-The abnormal facies of patients with congenital syphilis include frontal bossing, saddle nose, and poorly developed
maxillae. Saber shins, characterized by anterior tibial bowing, are rare. Rhagades are linear scars at the angles of the
mouth and nose that are caused by secondary bacterial infection of the early facial eruption.
-Other stigmata include unexplained nerve deafness, old chorioretinitis, optic atrophy, and corneal opacities due to
past interstitial keratitis

SYSTEMIC LUPUS ERYTHROMATOSUS

Definition
-An autoimmune disease involving multiple organ systems that is defined clinically and associated with antibodies
directed against cell nuclei.
-Its multisystem manifestations and attendant complications from use of immunosuppressive agents make the
diagnosis and management of this entity challenging.
Pathophysiology:
-Auto antibodies, circulating immune complexes and T lymphocytes all contribute to the expression of disease.
-Organ systems affected include dermatologic, renal, central nervous system (CNS), hematologic, musculoskeletal,
cardiovascular, pulmonary, the vascular endothelium, and gastrointestinal.
The American College of Rheumatology (ACR) criteria for SLE - “SOAP BRAIN MD” acronym:
Must include 4 of the following at any time during a patient's history (specificity 95% and sensitivity 75%):
Serositis - Pleurisy, pericarditis
Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific
Arthritis - Nonerosive Jaccoud type
Photosensitivity - Unusual skin reaction to light exposure
Blood disorders - Leukopenia, lymphopenia, thrombocytopenia, Coombs test–positive anemia
Renal involvement - Proteinuria (>0.5 g/d or positive on dipstick testing; cellular casts)
Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160)
Immunologic phenomena - Lupus erythematosus (LE) cells; anti–double-stranded DNA (dsDNA); anti-Smith (Sm)
antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or
lupus anticoagulant); biologic false-positive serologic test results for syphilis
Neurologic disorder - Seizures or psychosis
Malar rash - Fixed erythema over the cheeks and nasal bridge
Discoid rash - Raised rimmed lesions with keratotic scaling and follicular plugging

Incidence
Internationally:
Incidence varies worldwide. In Northern Europe, it has been reported to be 40 cases per 100,000.
Mortality/Morbidity:
-Early deaths usually are caused by active disease.
-Atherosclerosis is a leading cause in late deaths.
- Infection and nephritis are major causes of mortality in all stages of SLE.
-After dialysis or transplantation, a reduction in disease activity and flares has been reported.
-Thrombosis, often secondary to antiphospholipid syndrome, carditis, pneumonitis, pulmonary hypertension, stroke,
myocardial infarction, and cerebritis cause severe morbidity and mortality.
Race:
SLE is more common in blacks (1:250) than in whites (1:1000). However, all ethnic groups are susceptible.
Sex:
-Ninety percent of cases are in women.

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-Also, women who are exposed to estrogen-containing oral contraceptives or hormone replacement have an
increased risk of developing SLE.
-The sex distribution is more equal in those who develop SLE during childhood or when older than 50 years.
Age:
Most (80%) cases have been reported to occur in women in their childbearing years.

Clinical presentation
History:
-The mean length of time between onset of symptoms and diagnosis is 5 years.
-The disease is characterized by exacerbations and remissions.
-Many women relate flares of their lupus to the postovulatory phase of the menstrual cycle, with resolution of
symptoms at the time of menses.
a)-Systemic symptoms include a low-grade fever, fatigue, malaise, anorexia, nausea, and weight loss.
Initial presentation may involve one or more organ systems.
b) Arthralgias (53-95%)
- are the initial complaint in many patients. Often, the pain is out of proportion to physical findings.
c) Malar, butterfly rash over the cheeks and bridge of the nose (55-90%)
- with photosensitivity to ultraviolet (UV) light has been reported (mostly in whites). It also often involves the chin
and ears.
d) Painful or painless ulcers in the nose and mouth are frequent complaints.
e) CNS symptoms
-may range from mild cognitive dysfunction to a history of seizures (12-59%).
- Any region of the brain, meninges, spinal cord, and cranial and peripheral nerves can be involved.
-CNS events often occur when SLE is active in other organ systems.
- Intractable headaches and difficulties with memory and reasoning are the most common features of neurologic
disease in patients with lupus.
-Psychiatric symptoms (high-dose steroids also can cause psychosis [5-37%]) - If the psychosis gets worse after
stopping the steroid, it is most likely related to the disease process.
f) Serositis
-Pleuritic pain (31-57%), dyspnea, cough, fever, and chest pain are important cardiopulmonary complaints.
g) GIT
Patients may present with abdominal pain, diarrhea, and vomiting.
- Intestinal perforation and vasculitis are important diagnoses to exclude.
A number of other symptoms can be elicited by history which can help identify other pathology, including the
following:
Stroke, Pulmonary embolus, Deep venous thrombosis (DVT), Acute ischemia, Retinal vasculitis

Physical:
a)-Fever is a challenging problem in SLE.
-It can be a manifestation of active lupus or a representation of infection, malignancy, or a drug reaction.
b)-Malar rash is a fixed erythema sparing the nasolabial folds. It is a butterfly rash that can be flat or raised over the
cheeks and bridge of the nose. It also often involves the chin and ears.
c) Discoid rash occurs in 20% of patients with SLE and can be disfiguring secondary to scarring.
-It presents as erythematous patches with keratotic scaling over sun-exposed areas of the skin and may occur in the
absence of any systemic manifestations.
d) All patients experience painless or painful oral or vaginal ulcers at some time in their illness, which are helpful
in making the diagnosis.
e) GIT- vague abdominal discomfort, nausea, and diarrhea. Acute crampy abdominal pain, vomiting, and diarrhea
may signify vasculitis of the intestine.
f) Joint findings
-Tenderness, edema, and effusions accompany polyarthritis that is symmetric, nonerosive, and usually
nondeforming.
-It frequently involves the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands, as
well as the wrists and knees.
-Consider avascular necrosis, which is common in patients receiving glucocorticoids.
-Also consider septic arthritis when one joint is inflamed out of proportion to all other joints.

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g) CNS
-All types of seizures have been reported, with grand mal being the most common.
-Sensory or sensorimotor neuropathies are also common.
-Incidence of stroke is high in the first 5 years of disease. Patients with antiphospholipid antibodies are at higher risk
for such events.
h) Eye-Funduscopic examination is important in patients with visual complaints.
-Retinal vasculitis can lead to blindness and are demonstrated by sheathed narrow retinal arterioles with white
exudates adjacent to the vessels.
i) Renal system
Specific signs and symptoms of renal disease may not be apparent until advanced nephrotic syndrome or renal
failure is present; therefore, obtaining a urine analysis and serum BUN and creatinine levels on a regular basis is
important.
j) CVS
-Atherosclerosis occurs prematurely in patients with SLE and is an independent risk factor for cardiovascular
disease]
-Pulmonary HTN, vasculitis with digital infarcts, and splinter hemorrhages may be observed.
-Systolic murmurs are reported in up to 70% of cases. They may be secondary to fever, hypoxia, anemia, or Libman-
Sacks endocarditis (associated with antiphospholipid antibodies).
-Pericarditis has an incidence of 20-30% and is the most common presentation of heart involvement. It is usually
associated with small effusions, but it may involve larger effusions when uremia is concomitant. Myocarditis can
cause heart failure, arrhythmias, and sudden death
k) Pulmonary findings
-Tachypnea, cough, and fever are common manifestations of lupus pneumonitis.
-Hemoptysis may signify pulmonary hemorrhage. However, infection is the most common cause of infiltrates seen
on radiographs

Lab Studies:
1. Complete blood count (CBC)
-Leukopenia, which generally is a good index for disease activity
-Lymphopenia
-Anemia of chronic disease (60-80%)
-Evidence of a hemolytic anemia (10%
-Thrombocytopenia (30-50% of cases), which may be profound secondary to antiplatelet antibodies or to
antiphospholipid antibodies
(ESR) or C-reactive protein (CRP)-Inflammatory response
2-The partial thromboplastin time (PTT) may be elevated secondary to lupus anticoagulant (antiphospholipid
antibody), which is associated with thrombosis.
3-Urinalysis-Pyuria, Hematuria, Granular cast, Proteinuria
4-Blood urea nitrogen (BUN) and creatinine
Usually not elevated at the onset of disease
Can be useful for the determination of any progression of renal disease
5. LFTs: These may be mildly elevated in acute SLE or in response to therapies such as azathioprine or nonsteroidal
anti-inflammatory drugs (NSAIDS).
6. Creatinine kinase: Creatinine kinase levels may be elevated in myositis or overlap syndrome

5-Immunological
ANA - Screening test; sensitivity 95%; not diagnostic without clinical features
Anti-dsDNA - High specificity; sensitivity only 70%; level variable based on disease activity
Anti-Sm - Most specific antibody for SLE; only 30-40% sensitivity
Anti-SSA (Ro) or Anti-SSB (La) - Present in 15% of patients with SLE and other connective tissue diseases such as
Sjögren syndrome; associated with neonatal lupus

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Anti-ribosomal P - Uncommon antibodies that may correlate with lupus cerebritis
Anti-RNP - Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective tissue disease
with overlap SLE, scleroderma, and myositis Anticardiolipin - IgG/IgM variants measured with enzyme-linked
immunoassay (ELISA) among the antiphospholipid antibodies used to screen for antiphospholipid antibody
syndrome
Lupus anticoagulant - Multiple tests (eg, Direct Russell Viper Venom test) to screen for inhibitors in the clotting
cascade in antiphospholipid antibody syndrome
Coombs test - Coombs test–positive anemia to denote antibodies on RBCs
Anti-histone - Drug-induced lupus (DIL) ANA antibodies often this type (eg, with procainamide or hydralazine;
perinuclear antineutrophil cytoplasmic antibody [p-ANCA]–positive in minocycline-induced DIL)

Imaging Studies:
CXR-Effusion, Infiltrates, Cardiomegaly
Echocardiogram -may be indicated to evaluate any effusion causing pericardial pain or any valvular pathology and
to confirm any signs of pulmonary hypertension.
(MRI) is most useful for assessing brain pathology.
(CT) is useful to rule out bleeding or mass lesions.
Other Tests:
Cerebrospinal fluid (CSF) analysis is recommended when the diagnosis of CSF lupus is in question or infection is a
possible cause of symptoms.
-High protein levels in 50% of patients and pleocytosis may be found.
May indicate cerebritis but is not specific for it.

Causes:
-Many of the clinical manifestations of SLE are caused by the effects of circulating immune complexes on various
tissues or to the direct effects of antibodies to cell surface components.
-A genetic predisposition to the development of SLE exists. The concordance rate in monozygotic twins is 25-70%.
Each patient manifests his or her disease differently
-If a mother has SLE, her daughter's risk of developing the disease is 1:40, and her son's risk is 1:250
-Photosensitivity is clearly a precipitant of skin disease.
- The presence of antiphospholipid antibodies in patients dictates a constellation of signs caused by thrombosis.

DDX:
1. Metastatic malignancy
2. Fever of unknown origin (FUO)
3. Mixed connective tissue disease
4. Psychogenic rheumatism
5. Scleroderma
6. Discoid lupus
7. Hemoptysis

Drug-induced lupus
Before making a diagnosis of SLE, ruling out drugs as the cause of the condition is important.
 Procainamide
Hydralazine
Isoniazid
 Methyl dopa
Chlorpromazine
Quinine
Many patients receiving these medications have positive antinuclear antibody test results and other serologic
findings. Only a few have the clinical manifestations.
Drug-induced lupus differs from SLE by the following features:
-Sex ratios are nearly equal.
-Nephritis and central nervous system features are not commonly present.
-No antibodies to native DNA or hypocomplementemia are present.

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-When the drug is discontinued, the patient has resolution of clinical manifestations and reverting of abnormal
laboratory values to normal

Management
-Conservative management with nonsteroidal anti-inflammatory drugs including salicylates is recommended for
arthritis, arthralgias, and myalgias not requiring immunosuppression.
-Only initiate high-dose glucocorticoids and cytotoxic agents by, or in consultation with, a rheumatologist.
-Patients with thrombosis require anticoagulation with warfarin for a (INR) of 2-3.
Antibiotics may be appropriate in the treatment of ordinary and opportunistic infections.
Management of individual emergencies that may be complications of SLE in the individual patient
-These can include strokes, acute myocardial infarctions, hemoptysis, respiratory distress, and pulmonary emboli
-In patients presenting with fever, treating for an infection empirically may be necessary until culture results have
been received.

Complications:
1) Vasculitis and its various complications (eg, intestinal perforations)
2) Pericarditis
3) Myocarditis
4) Lupus pneumonitis
5) Pulmonary hemorrhage, pulmonary hypertension
6) Proliferative glomerulonephritis
7) Hemolytic anemia, thrombocytopenia
8) Intravascular thrombosis (eg, stroke and myocardial infarctions)
9) Complications of high dose glucocorticoid therapy viz; osteoporosis, poor wound healing, truncal obesity,
moon facies, buffalo hump.
10) Complications of cytotoxic agents

Prognosis:
-Prognosis has improved over the last few years.
-Mortality typically is due to renal failure or infection.

Patient Education:
-Protection from the sun
-Compliance with medications and follow-up appointments

TUBERCULOSIS
Definition
-Chronic infectious disease caused by - Mycobacterium tuberculosis - an acid- fast bacillus bacterium.
Classification
Can be classified based on organ involved:
1) Pulmonary tuberculosis (PTB)
Smear +ve PTB
Smear -ve PTB
2) Extra-pulmonary TB-Tuberculosis meningitis, Spinal TB, Genitourinary, GIT, Musculoskeletal.
3) Disseminated TB.
Classification initial or re-infections
1) Primary TB
2) Secondary/Reactivated TB.
Epidemiology
-The commonest affected age group is from 15-45 years with males>females.
Predisposing factors to pulmonary TB;
1) HIV/AIDS infection
2) Other immunosuppressive states-leukaemia, steroids, Diabetes mellitus, Radiation, end-stage renal disease
3) Silicosis
4) Poor socio-economic status -overcrowded slums and poor housing

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 5) Malnutrition.
6) Silicosis-pneumoconiosis.
7) Post gastrectomy, jejunoileal bypass
8) Limited access to health services
Primary TB
Pulmonary
-Initial infection with the bacilli is usually pulmonary (by droplet spread).
-In areas of high prevalence this form of disease observed in children and is frequently localized to the middle and
lower lung zones.
-A peripheral lesion forms (Ghon focus), & its draining nodes are infected (Ghon complex). There is early distant
spread of the bacilli, then an immune response suspends further multiplication at all sites
Presentation
-Primary tuberculosis is usually asymptomatic in immune-competent healthy persons.
-In children and in persons with impaired immunity, such as those with malnutrition or HIV infection, primary
pulmonary tuberculosis may progress rapidly to clinical illness with:
1) Chronic Cough >3 weeks
2) Mucopurulent Sputum ± AAFBs. May be blood tinged or overt haemoptysis may occur
3) Fever and night Sweats
4) Weight loss and anorexia
5) Pleuritic chest pain -subpleural parenchymal lesions
6) Extensive disease may produce dyspnea and (occasionally) adult respiratory distress syndrome (ARDS).
Erythema nodosum - An inflammatory disease of the deep dermis and subcutaneous fat (panniculitis) characterized
by tender red nodules, predominantly in the pretibial region but occasionally involving the arms or other areas.
Physical findings
-Are of limited use in pulmonary tuberculosis. Many patients have no abnormalities detectable by chest
examination.
-Some have rales in the involved areas during inspiration, especially after coughing.
-Occasionally, rhonchi due to partial bronchial obstruction.
-Pleural effusion-stony dullness and decreased breath sounds
-Pericardial effusion may cause muffled heart sounds and raised JVP.
-Severe disease with pulmonary HTN-left parasternal heave and any features of right sided heart failure-Raised
JVP, Tender hepatomegaly, peripheral edema
-Systemic features include fever (often low-grade and intermittent) and wasting. In some cases, pallor and finger
clubbing develop.
-The most common hematologic findings are mild anemia and leukocytosis. Hyponatremia due to the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH) has also been reported.

EXTRA-PULMONARY TB
-In order of frequency, the extrapulmonary sites most commonly involved in tuberculosis are
1) Lymph nodes
2) Pleura
3) Genitourinary tract
4) Bones and joint
5) Meninges
6) Peritoneum
-However, virtually all organ systems may be affected.
Lymph-Node Tuberculosis (Tuberculous Lymphadenitis)
-The commonest presentation of extrapulmonary tuberculosis >25 % of cases. Particularly frequent among HIV-
infected patients.
-Lymph-node tuberculosis presents as painless swelling of the lymph nodes, most commonly at cervical and
supraclavicular sites.
-Lymph nodes are usually discrete in early disease but may be inflamed and have a fistulous tract draining caseous
material may then become matted.
-Systemic symptoms are usually limited to HIV-infected patients, and concomitant lung disease may or may not be
present.

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-Tuberculosis resulting from extension into the skin from underlying atypical mycobacterial infection, most
commonly of cervical lymph nodes leads to the formation of scrofuloderma.
-The diagnosis is established by fine-needle aspiration or surgical biopsy. Examination for granulomas –caseating
and AFB. DDX-Lymphomas or metastatic carcinomas
Pleural Tuberculosis
-Results from penetration by a few tubercle bacilli into the pleural space.
-Depending on the extent of reactivity, the effusion may be small, remain unnoticed, and resolve spontaneously or
may be sufficiently large to cause symptoms such as fever, pleuritic chest pain, and dyspnea
O/E. dullness to percussion and absence of breath sounds
-CXR reveals the effusion and, in no more than one-third of cases, also shows a parenchymal lesion.
-Thoracentesis is required to ascertain the nature of the effusion. The fluid is straw colored and at times
hemorrhagic; it is an exudate with:
Protein concentration >50% of that in serum
Normal to low glucose concentration
PH that is generally <7.2
WBC (usually 500 to 2500/mL)
 AFB very rarely seen on direct smear, but cultures may be positive for M. tuberculosis in up to 1/3 of
cases.
Needle biopsy of the pleura is often required for diagnosis and reveals granulomas and/or yields a positive culture in
up to 70% of cases. This form of pleural TB responds well to chemotherapy.
Tuberculous empyema is a less common complication of pulmonary tuberculosis. It is usually the result of the
rupture of a cavity, with delivery of a large number of organisms into the pleural space, or of a bronchopleural
fistula from a pulmonary lesion.
-A chest radiograph may show pyopneumothorax with an air-fluid level.
-The effusion is purulent and thick and contains large numbers of lymphocytes.
-An acid-fast smear of pleural fluid is often found to be positive when examined by microscopy, as is culture of the
pleural fluid.
-Surgical drainage is usually required as an adjunct to chemotherapy. Tuberculous empyema may result in severe
pleural fibrosis and restrictive lung disease.

Tuberculosis of the Upper Airways

-Nearly always a complication of advanced cavitary pulmonary tuberculosis, may involve the larynx, pharynx, and
epiglottis.
-Symptoms include hoarseness of voice and dysphagia in addition to chronic productive cough.
-Findings depend on the site of involvement, and ulcerations may be seen on laryngoscopy.
-Acid-fast smear of the sputum is often positive, but biopsy may be necessary in some cases to establish the
diagnosis. --Cancer may have similar features but is usually painless.

Genitourinary Tuberculosis
-Usually due to hematogenous seeding following primary infection.
-Renal tuberculosis originates in the cortex of the kidney. Tuberculosis of the kidney progresses slowly.
-Usually no renal pain and little or no clinical disturbance until involvement of the calyces or the pelvis.
-Pus and organisms may then be discharged into the urine.
- The infection then proceeds to the pelvic mucosa and the ureter, particularly its upper and vesical ends. This may
lead to stricture and back pressure (hydronephrosis).
-Parenchymal destruction may occur, causing spread into the medulla and associated papillary necrosis or cavitation.
-Urinary frequency, dysuria, hematuria, and flank pain are common presentations.

Investigations
1. Urinalysis reveals sterile pyuria and hematuria.
-M/Culture-AFB and Culture of three morning urine specimens -diagnosis 90% cases.
2. Abdominal ultrasound-Kidneys, ureters, bladder and prostate (men) or uterus –females.
-Severe ureteral strictures may lead to hydronephrosis and renal damage.
3. IVU -Calcifications and ureteral strictures are suggestive findings.
-Genital tuberculosis is diagnosed more commonly in females than in males.

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-In females, affects the fallopian tubes and the endometrium and may cause infertility, pelvic pain, and menstrual
abnormalities.
-Diagnosis requires biopsy or culture of specimens obtained by dilatation and curettage.
-In males, tuberculosis preferentially affects the epididymis, producing a slightly tender mass that may drain
externally through a fistulous tract; orchitis and prostatitis may also develop.
-Genitourinary tuberculosis responds well to chemotherapy.

GI –Typically affects the ileocaecal junction & associated lymph nodes following consumption of raw milk/meat
containing M. bovis.
TB of the Adrenals
-The adrenals may become infected with tuberculosis organisms via the bloodstream, causing adrenal masses. TB
may also cause calcification and adrenal insufficiency (Addison's disease).

Skeletal Tuberculosis
-In bone and joint disease, pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent
paravertebral lymph nodes.
-Weight-bearing joints (spine, hips, and knees-in that order) are affected most commonly.
-Spinal tuberculosis (Pott's disease or tuberculous spondylitis) often involves two or more adjacent vertebral bodies.
-Children- upper thoracic spine most common site while adults the lower thoracic and upper lumbar vertebrae.
-From the anterior superior or inferior angle of the vertebral body, the lesion reaches the adjacent body, also
destroying the intervertebral disk. With advanced disease, collapse of vertebral bodies results in kyphosis (gibbus).
-A paravertebral "cold" abscess may also form. In the upper spine, this abscess may track to the chest wall as a
mass; in the lower spine, it may reach the inguinal ligaments or present as a psoas abscess in anterior aspect of
thigh.
-DDx-LN, Saphenous varix, femoral or inguinal hernia, Aneurysm.
-Rigidity of the spine is due to muscular spasm, which results from an effort to minimize pain by immobilization.
The early symptoms of night cries and restlessness are explained by pain felt when the protective spasm is relaxed
during sleep.
Investigations
1. MRI- reveals the characteristic lesion and suggests its etiology, DDx-includes other infections and tumors.
2. CT-Scan
3. Aspiration of the abscess or bone biopsy confirms the tuberculous etiology, as cultures are usually positive and
histologic findings highly typical.

Spinal TB
-My be inform of spinal meningitis or tuberculous spondylitis
a) Tuberculous spinal meningitis
- May present in acute, subacute, or chronic form.
-It is characterized by myelopathy, with progressive ascending paralysis, eventually resulting in basal meningitis
-In acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory
deficits and urinary retention. DDx- transverse myelitis or Guillain-Barré syndrome.
-Subacute form dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia.
-Chronic form might mimic a very slowly progressive spinal cord compression or a nonspecific arachnoiditis.
B) Tuberculous spondylitis (Pott`s disease or spinal caries)
-Present as compressive myelopathy resulting in paraplegia. Spinal TB also accounts for about 50% of all bone and
joint TB.
-Complication of Pott's disease is paraplegia, which is usually due to an abscess or a lesion compressing the spinal
cord.
-Paraparesis due to a large abscess is a medical emergency and requires abscess drainage.
-Tuberculosis of the hip joints causes pain and limping; tuberculosis of the knee produces pain and swelling and
sometimes follows trauma.
Management
-Skeletal tuberculosis responds to chemotherapy, but severe cases may require surgery.
-In the lumbar region, may result in psoas abscess that often calcifies. Causes back pain and fever and variable
neurological deficits. Including local and radicular pain, limb motor and sensory loss, and sphincter disturbances
-Eventually, lead to paraplegia. Responds to chemotherapy.

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Indications for surgery
-Cord compression-ascending paralysis
-kyphosis or gibbus deformity impairing stability or respiration.

Gastrointestinal Tuberculosis
-Any portion of the GIT may be involved.
-Various pathogenetic mechanisms are involved:
 Swallowing of sputum with direct seeding,
 Hematogenous spread
 Rarely ingestion of milk from cows affected by bovine tuberculosis.
-The terminal ileum and the cecum are the sites most commonly involved.
-Clinical presentation
1) Abdominal pain (at times similar to that associated with appendicitis)
2) Diarrhea or constipation
3) Intestinal Obstruction
4) Hematochezia
5) Palpable mass in the abdomen.
6) Fever, weight loss, and night sweats are also frequent.
-As surgery is required in most cases, the diagnosis can be established by histologic examination and culture of
specimens obtained intraoperatively.
-Tuberculous peritonitis follows either the direct spread of tubercle bacilli from ruptured lymph nodes and
intraabdominal organs or hematogenous seeding.
-Nonspecific abdominal pain, fever, and ascites.
-Paracentesis reveals an exudative fluid with a high protein content and leukocytosis that is usually lymphocytic
(although neutrophils occasionally predominate).
-The yield of direct smear and culture is relatively low; peritoneal biopsy is often needed to establish the diagnosis.

Tuberculous Pericarditis
-The onset may be subacute, although an acute presentation, with fever, dull retrosternal pain, and a friction rub, is
possible.
-An effusion eventually develops in many cases; CVS symptoms and signs of cardiac tamponade may occur
-Diagnosis can be facilitated by pericardiocentesis under echocardiographic guidance. Analysis of fluid done.
-Even with treatment, complications may develop, including chronic constrictive Pericarditis with thickening of the
pericardium, fibrosis, and sometimes calcification, which may be visible on a chest radiograph.
-Isoniazid prophylaxis - 5mg/Kg (max 300mg) for 6months plus pyridoxine 12.5mg daily.
Indications; Not done in Kenya except in paediatrics
Infants HIV +ve with sputum +ve TB contact
Infants born to mother with TB
PPD +ve HIV children
2° prophylaxis
Symptomatic HIV + adults
Investigations
Microbiology
-Clinical samples (sputum, pleural fluid, urine, pus, ascites, or CSF) for AFB stain and culture
-If sputum -ve, bronchoscopy with bronchoalveolar lavage (nebulise with NS then do chest physiotherapy) +/-
biopsy
-Gastric lavage
-Biopsy any suspicious lesions in liver, lymph nodes, or bone marrow
-AAFBs are bacilli that resist acid-alcohol decolourization under auramine or Ziehl-Neelsen (ZN) staining
a) Procedure for ZN Staining/AFB stain
1. Make a smear and fix the smear by flaming.
2. Flood smear with carbol fuchsin
3. Heat gently making sure the smear remains covered with carbol fuchsin stain for about 5 minutes.
4. Wash off the carbol fuchsin with water.
5. Decolourize with acid alcohol (3% H2SO4/HCL + 95% Ethanol) until no more pink colour comes off
6. Wash off excess acid with water.

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7. Counterstain with Methylene Blue or Malachite Green (apply for 3-4mins)
8. Wash off counterstain, place in draining rack to dry.
9. Examine under oil emulsion
Results
-Bright red/pink organisms on a Blue background (methylene blue counter stain) or Green background (malachite
green)
-Other methods-auramine-rhodamine staining and fluorescence microscopy
b) Cultures
-Cultures undergo prolonged incubation 6weeks in solid media- Lowenstein-Jensen medium
-Using liquid media in BACTEC technique this is reduced to 2-3 weeks.
-TB PCR –Investigational. Has not been shown to add any more value than just ZN stain
c) Histology
-Caseating granulomas
Imaging
-HIV infection no CXR pattern is typical for HIV
-CXR is helpful in the diagnosis of TB in smear -ve PTB, Extra-pulmonary TB & TB in children;
-Inactive disease;
 Normal radiograph, Scarring & sequaelae
 Calcification in lungs, LN & Pleura

TREATMENT
Aims for treatment of TB
1) Cure the tuberculosis
2) Prevent relapse of the disease
3) To prevent death from the active disease and late effects
4) Prevent the development of acquired drug resistance
5) To prevent transmission of the disease to others
-WHO adopted DOTS as the interventional strategy to achieve the above aims
5-Components of DOTS(Direct Observed Treatment Short-course)
1 Sustained political commitment.
2 Access to quality-assured sputum microscopy.
3 Standardized short-course chemotherapy for all cases of TB under proper case management conditions, including
direct observation of treatment.
4 Uninterrupted supplies of quality-assured drugs.
5 Recording and reporting system enabling outcome assessment of all patients and assessment of overall programme
performance.
Essential anti-TB treatment
-3-properties of anti-tuberculosis treatment include
 Bactericidal activity
 Sterilizing activity
 Prevention of development of resistance
-The essential anti-TB drugs posses this properties to variable degree.
-Isoniazid and Rifampicin are the most powerful bactericidal agents. Rifampicin is the most powerful sterilizing
agent
-Pyrazinamide and streptomycin are also bactericidal against certain population of the bacilli.
-Pyrazinamide is only active in an acidic environment while streptomycin is active against rapidly multiplying
bacilli.
-Ethambutol and thiocetazone prevent the emergence of resistance.
-In 2 phases, Intensive with DOT & Continuation phase
-Consists of initial phase (intensive phase) of 2 months followed by continuation phase of 4-6moths.
-During the intensive phase the tubercle bacilli is killed rapidly. The infectious patients quickly become non-
infective within 2 weeks of intensive phase.
-The most smear positive patients turn smear negative in 2 months.
-In continuation phase the sterilizing effect of the drugs eliminate the remaining bacilli and prevent relapse.
Regimens
Diagnosis Treatment

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a) Adult smear +ve + Extra-pulmonary TB 2ERHZ / 6EH
Or Short Course treatment 2ERHZ/4RH
b) Adult smear –ve + Extra-pulmonary TB 2RHZ / 6EH
c) Re-treatment (below) 2SERHZ /1ERHZ / 5ERH
i. Relapse – Smear +ve TB treated & cure
ii. Treatment failure – Smear +ve despite 5(8) months on anti-TB treatment
iii. Resumed – Treatment interrupted now resuming
d) < 15yrs smear –ve + Extra-pulmonary TB 2RHZ / 4RH
* Rifater® - RHZ Ethizide® - EH
* Rifinah® - RH
* Rifafor® -RHZE
.Classification of treatment outcomes.
Cure
-Patient who is sputum negative at the 5th month, 7th and 8th month of 8-month regimen
-Patient sputum negative at 2nd month, 5th and 6th month in 6-month regimen.
Treatment completed
-Patient who has completed treatment but who does not meet the criteria to be classified as a cure or a failure.
Treatment failure
-Patient who is sputum smear-positive at 5 months or later during treatment.
Default
-Patient whose treatment was interrupted for two consecutive months or more.
Case definitions
New.
-A patient who has never had treatment for TB or who has taken antituberculosis drugs for less than 1 month.
Relapse.
-A patient previously treated for TB who has been declared cured or treatment completed, and is diagnosed with
bacteriologically positive (smear or culture) tuberculosis.
Transfer in.
-A patient who has been transferred from another TB register to continue treatment.
Other. All cases that do not fit the above definitions. This group includes
-Chronic case, a patient who is sputum-positive at the end of a re-treatment regimen.

Anti-TB Drugs Adverse effects

Minor Adverse Continue anti-TB drugs, check drug doses
-Anorexia, nausea, abdominal pain Pyrazinamide, Rifampicin Give drugs with small meals
or last thing at night
-Joint pains Pyrazinamide. Admin Aspirin
-Burning sensation in the feet Isoniazid. Admin Pyridoxine 100 mg daily
-Orange/red urine Rifampicin Reassurance. Patients should be told when starting treatment that this commonly
happens and is normal
Major Stop responsible drug(s)
-Itching, skin rash -Thioacetazone Stop anti-TB drugs,
(S, H, R, Z)
-Deafness (no wax on auroscopy) Streptomycin Stop streptomycin, use Ethambutol
-Dizziness (vertigo and nystagmus) Streptomycin Stop streptomycin, use Ethambutol
-Jaundice (other causes excluded) Isoniazid, Stop anti-TB drugs,-hepatitis Pyrazinamide, Rifampicin
-Confusion (suspect drug-induced most anti-TB drugs Stop anti-TB drugs. Acute liver failure if jaundice present)
Urgent liver function tests and prothrombin time
-Visual impairment Ethambutol Stop Ethambutol
(Other causes excluded)
-Shock, purpura, acute renal failure Rifampicin Stop Rifampicin Symptoms.

Post-primary TB
-In immune-compromised states;
a) Most commonly HIV infection
b) Malignancy-leukemia, lymphoma

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 c) Drugs-cytotoxics and BM suppressants, Steroids -prolonged use
d) Diabetes mellitus, end-stage renal failure
e) Debilitation -old age
f) Other conditions-Silicosis, Post-gastrectomy
-Mechanisms relevant for the development of TB include;
1) Reactivation of existence dormant bacilli
2) Progression from recent infection to disease
3) Re-infection
-Reactivation disease results from endogenous reactivation of latent infection and is usually localized to the apical
and posterior segments of the upper lobes, where the high oxygen concentration favors mycobacterial growth
- The initial lesion increases in size and can evolve in different ways
-The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease.
-Some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs
-Massive hemoptysis may develop with the erosion of a fully patent vessel located in the wall of a cavity.
Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen's aneurysm) or from
aspergilloma formation in an old cavity.
-Pleural effusion, a frequent finding, results from the penetration of bacilli into the pleural space from an adjacent
subpleural focus
-Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces tuberculous
pneumonia.
-Enlarged lymph nodes may compress bronchi, causing obstruction and subsequent segmental or lobar collapse
-Partial obstruction may cause obstructive emphysema, and bronchiectasis may also develop.
-Individuals with such chronic disease continue to discharge tubercle bacilli into the environment.
-Thus patients present with:
1) Cough ≥ 3wks ± blood stained sputum
2) Intermittent fever, anorexia & Night sweats
3) Weight loss
4) History of contact with a case of TB
5) Generalised fatigue and malaise.
6) Sub pleural disease causes chest pain and pleurisy
7) Severe disease may cause shortness of breath
8) Haemoptysis (may be massive)
9) Pleural effusion
10) Superimposed pulmonary infection
11) An aspergilloma / mycetoma may form in cavities

TUBERCULOUS MENINGITIS $ TUBERCULOMA

Epidemiology
-Before HIV the most important determinant for the development of TBM was age. In populations with high TB
prevalence TBM differs from pulmonary and other extra-pulmonary tuberculosis, in that the peak age is from 0–4
years.
-In populations with lower TB prevalence, most cases of TBM are in adults. Risk factors identified for these people
are alcoholism, diabetes mellitus, malignancy, and recent corticosteroid use.
-HIV increases the lifetime risk of developing clinical
TB postinfection to 1 in 3.HIV also predisposes to the development of extrapulmonary TB, and in particular TBM,
risk increases as the CD4 count declines.
-Constitutes either reactivation of latent infection, or new infection
-BCG vaccination is thought to be protective against
TBM and other extra-pulmonary forms of TB
-Close correlation exists between the observed incidence of TBM in children aged 0–4 years, and the population’s
annual average risk of infection with M tuberculosis. The incidence of TBM has been calculated to represent 1% of
the annual risk of infection. The main reason for the spread of tuberculosis is poverty, with resulting homelessness,
malnutrition, and breakdown of public health infrastructure
Pathophysiology
-Tuberculous meningitis results from the hematogenous spread of primary or post primary pulmonary disease.

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-Bacilli seed to the Meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci
of metastatic caseous lesions. These are termed Rich foci.
-The second step in the development of TBM is increase in size of a Rich focus until it ruptures into the
subarachnoid space.
-The location of the expanding tubercle (i.e., Rich focus) determines the type of CNS involvement. Tubercles
rupturing into the subarachnoid space cause meningitis.
-Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses.
-A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction
which can lead to infarction.
-Basal meningitis accounts for the frequent dysfunction of cranial nerves III, VI, and VII, eventually leading to
obstructive hydrocephalus due to obstruction of basilar cisterns.
- Neurological pathology is produced adhesion formation, obliterative vasculitis, and encephalitis or myelitis.
-An obliterative vasculitis of both large and small
vessels can result in infarction and stroke syndromes. These commonly occur in the territories of the internal carotid,
Proximal middle cerebral and the perforating vessels to the basal ganglia.
-Infarction through vasculitis is the mechanism by which
Many of the diverse clinical neurological abnormalities in TBM occur, and accounts for an appreciable part of the
irreversible neurological sequelae.
-The intensity of the basal inflammatory can result in encephalitis. Oedema occurring as a consequence can to rising
intracranial pressure and the global neurological deficit.
-A rare complication of TBM is tuberculous Encephalopathy .Usually occurring in a young child with progressive
primary TB, the presentation is of reducing conscious level with few focal signs and minimal meningism. Diffuse
oedema and white matter pallor with demyelination are found pathologically. The pathogenesis
is uncertain, but is presumed to be immune mediated. Reports suggest a good response to corticosteroids.
Clinical presentation
Stages of TBM
Stage I
Early nonspecific symptoms and signs, including
Apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting
No alterations in consciousness.
Stage II
Altered consciousness without coma or delirium
Focal neurological signs-including monoplegia, hemiplegia, aphasia, and tetraparesis
Symptoms and signs of meningism and meningitis –neck stiffness and kerning positive.
Cranial nerve palsies-abrupt onset blindness or ophthalmoplegia may occur.
 Abnormal involuntary movements-choreoathetosis and hemiballismus, myoclonus and cerebellar
dysfunction
Stage III
 Advanced disease with stupor or coma
 Severe neurological deficits
 Seizures/convulsions
 Posturing-decerebrate or decorticate rigidity
 Abnormal movements
 SIADH

Fundoscopy in TBM
-Papiloedema
-May reveal the presence of a retinal tuberculoma/ tubercles or a small grayish-white choroidal nodule.
-These lesions are more common in military TB
-In children, pallor of the disc may be observed.
DDx of TBM
A. Infections
1) Fungal - Cryptococcus, histoplasmosis, actinomycetic, nocardiasis, candidiasis, coccidiosis
2) Bacterial - Partially treated bacterial meningitis (strep, staph, neiseria meningitides), brain abscess.
Spirochetes - Lyme disease syphilis, leptospirosis
3) Parasitic - Cysticercosis, acanthamebiasis, angiostrongylosis, toxoplasmosis, trypanosomiasis

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 4) Viral – Herpes meningoencephalitis, CMV, PML-progressive multifocal leucoenecepalopathy, HIV
encepatholapathy.
B.Neoplastic - Metastatic, lymphomas
C.Vascular- Multiple emboli, Sinus thrombosis, Subdural haemorrhage, subarachnoid haemorrhage.
D.Connective tissue diseases as Sarcoidosis, SLE
Investigations
1. In >1/2 cases, evidence of old pulmonary lesions or a military pattern is found on CXR.
2. Lumbar puncture is the cornerstone of diagnosis.
CSF findings
Measure the CSF pressure.-Up to 18cm of water normal.
Straw colored fluid that clots on standing –high proteins
Lab. Leukocytosis- lymphocytosis 100 and 100 cells/mm3 is more usual, although in the first 10 days
PMN leucocytes ma predominate
High protein content of 1 to 8g/L(Normal proteins up to 0.45 g/L)
Low glucose concentration(less than 2/3 serum glucose or absolute value less than 2.2 mmol/L)
 AFB- on direct smear of CSF sediment in only 20% of case. To increase the yield good volume should be
collected 10ml which then centrifuged before stain.
 Also do India ink stain
Culture of CSF is diagnostic in up to 80% of cases.
3. Imaging studies (CT and MRI) may show hydrocephalus basilar meningeal thickening, infarcts, oedema, and
tuberculomas. Tuberculoma show as contrast-enhanced ring lesions
The radiological DDx- includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, toxoplasmosis,
meningeal metastases, and lymphoma.
4. Monteux Test-tuberculin testing may be more useful in
children, with 86% having greater than 15 mm of induration with 5 units purified protein
derivative (PPD).
A course of steroid treatment is useful in the management of acute disease, reducing effusion, facilitating
hemodynamic recovery, and thus decreasing mortality
Admin Predinsolone for 6 weeks with anti-Tb treatment.
Military or Disseminated Tuberculosis
Due to hematogenous spread of tubercle bacilli.
Lesions are usually yellowish granulomas 1 to 2 mm in diameter that resemble millet seeds.
Milliary like tuberculosis the tubercles are >2mm
HIV & TB
Infection by HIV destroys the immune defence mechanism of the body by targeting the T- lymphocytes.
In normal circumstances, the lifetime risk of development of tuberculosis from latent disease is 10% while this risk
increases to 10 times in HIV infected people.
Early HIV infection (CD4 >200cells/mm3) - Smear +ve reactivated upper-lobe open cavitatory PTB. Seen in 20%
HIV patients
Late HIV stages -Smear -ve PTB - Miliary & atypical pulmonary TB.Extrapulmonary TB - Pericardial, abdominal,
meningeal
Interactions of HIV & TB;
Summary
-Mantoux tests become negative
-Increased reactivation of latent TB
-Presentation may be atypical
-Previous BCG vaccination does not prevent development of TB
-Smears may be -ve for AAFBs; +ve smears tend to contain few AAFBs - follow-up sputum examinations at 2, 5 &
8 months
-Atypical CXR - lobar or bibasal pneumonia, hilar lymphadenopathy
-Extrapulmonary & disseminated disease
-HAART & anti-TB therapy drug interaction toxicities.
-ARVs should be deferred until after intensive (rifampicin containing) phase of treatment.
- If a decision is made to start ARVs in the intensive phase of treatment, e.g. in cases where immune suppression is
thought to be extreme, & the patient's survival without ARVs is unlikely, then Efavirenz rather than Nevirapine
should be used as Rifampicin ↓ blood levels of NVP

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-Alternatively rifampicin should be substituted for Rifabutin or Rifapentin that have less hepatic microsomal
enzyme induction.
-Immune reconstitution inflammatory response (IRIS) - ARV reconstitutes CD4 count & immune function, which
may lead to a paradoxical worsening of TB symptoms after the start of ARV.
Drug prophylaxis in HIV
-Septrin prophylaxis - 960mg/d OD PO (I double strength tablet daily) .this should be taken by all HIV positive
patients. Active in prevention of the following illnesses
PCP
Toxoplasmosis
Malaria
Common bacterial infections including pneumonia and sepsis
 Diarrhoea including that caused by isospora belli.

Active TB
Apical opacification
Peri-hilar LN is best demonstrated with a Lateral CXR
Pleuro-Pericardial effusion
Milliary infiltrates <2mm or military like infiltrates are > than 2mm
 Cavitation
Mantoux Tuberculin Test
-The Mantoux tuberculin skin test is the intradermal injection on the volar (palmar) surface of the forearm of 0.1 mL
(5 tuberculin units (TU)) of purified protein derivative (PPD) stabilized with Tween 80. The amount of induration is
a cell mediated response to the test is measured 48–72 hr after administration. A positive test indicates immunity,
previous exposure or BCG. A strong positive test (skin reaction ≥10 mm) in a BCG-vaccinated HIV -ve child or
adult or >5mm in a HIV+ve child probably means active infection.
-Occasional patients will have the onset of induration more than 72 hr after placement of the test; this is a positive
result.
Factors that depress the skin test reaction:
Host-related factors
- Overwhelming tuberculosis
- Immunosuppression by disease (Sarcoidosis, AIDS, Lymphoma) or drugs
- Corticosteroid therapy may decrease the reaction to tuberculin, but the effect is variable.
Tuberculin skin testing done at the time of initiating corticosteroid therapy is usually reliable.
False-negative reactions to tuberculin
Poor technique
Misleading the results
Anergy
False-positive reactions
Cross-sensitization to antigens of nontuberculous mycobacteria (NTM); produce < 10–12 mm of
induration.
Previous vaccination with Bacille Calmette-Guérin (BCG) 3-6mo before

Dosages of essential Anti-TB drugs

Isoniazid
5mg/kg
Rifampicin
10mg/kg
Streptomycin
15mg/kg
Ethambutol
15mg/kg
Pyrazinamide
25mg/kg

Fixed dose combinations Tablet

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Isoniazid/Rifampicin (Rifinah®) 75mg/150mg or
150mg/300mg

Isoniazid/Rifampicin 75mg/150mg/400mg
/Pyrazinamide (Rifater®)

Isoniazid/Rifampicin 75mg/150mg/400mg/275mg
/Pyrazinamide/Ethambutol
(Rifafor®)
Steroid therapy
-Dexamethasone 8-10mg/d BD is indicated in;
1) TB meningitis - 2-4wks
2) Miliary TB - 2-4wks
3) Moderate pleural effusion - 2-4wks
4) Pericardial effusion - 6wks
5) Endobronchial TB
-A trial of therapy in patients with pneumonia not responding to antibiotic therapy is indicated for 2wks
Multi Drug resistant TB
Multi-drug resistance TB (MDR-TB)
-TB resistant to at least Isoniazid & Rifampicin indicated by lack of a favorable clinical response after 2-3 weeks
of therapy and 3 AFB smears are positive
-2nd line anti tuberculous disease.
1) Amikacin (Am)
2) Capreomycin (Cm)
3) Ciprofloxacin (Cx)
4) Cycloserine (Cs)
5) Ethionamide (Et)
6) Kanamycin (Km)
7) Ofloxacin (O) b
8) p-Aminosalicylic bacteriostatic acid (PAS)
9) Protionamide (Pt)
10) Thiocetazone
-A standardized re-treatment regimen should include at least 4 drugs never used by the patient, including an
injectable (capreomycin, amikacin or kanamycin) and a fluoroquinolone.
-Treatment should be given daily and directly observed. Bacteriological results (smear and, if possible, culture)
should be monitored
-An initial phase of at least 6 months with 4 drugs should be followed by a continuation phase of 12-18 months with
at least 3 of the most active and best-tolerated drugs.
-If the results of susceptibility tests for essential and reserve drugs are available and the full range of reserve drugs is
available, the treatment regimen may be tailored according to the susceptibility pattern.
-Treatment regimens with reserve antituberculosis drugs remain much more expensive than regimens with essential
antituberculosis drugs

Specific drugs
Isoniazid
-Has a 20-60% CNS penetration
1. Peripheral neuropathy - treat with pyridoxine 40mg/d or Vit B complex. Isoniazid promotes the excretion of
pyridoxine
2. Hepatitis – jaundice
3. systemic lupus erythematosus-like syndrome
4. Agranulocytosis
5. GIT disturbance - take drug with light meal or before going to bed
6. Pellagra - Isoniazid therapy has also been associated with niacin deficiency, presumably because of induced
pyridoxine deficiency, which decreases the conversion of tryptophan to niacin.
-Others-optic atrophy, seizures, and psychiatric
Rifampicin

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1. Hepatitis - jaundice (Withdraw if LFTs >X3)
2. Red urine & tears
3. Hemolytic anaemia and thrombocytopenia
4. Flu-like syndrome (fever, chills, malaise & headache)
5. Pruritus ± flushing ± rash involving the face & scalp often with redness & watering of the eyes
NB.SOB ± shock & collapse, abdominal pain & nausea
Pyrazinamide
1. Hepatitis - Jaundice
2. Arthralgia
3. Hyperuricaemia. Gout is a contraindication; treat as gout till end of therapy
Ethambutol
1. Blurred vision & red-green colour blindness; optic neuritis
Streptomycin
1. Numbness around the mouth & tingling
2. Tinitus - risk ↑ with dosage & age; may lead to CN-VIII damage → Deafness ± ataxia - reduce dose by 1/4gm

Complications of TB
1. Breakthrough TB - Recurrence of clinical symptoms of TB after completion of the intensive phase of treatment
2. Haemoptysis - Bed rest + sedation (Largactil 25mg BD)
3. Spontaneous pneumothorax (collapse of the lung) - expansion of the lung with underwater seal drainage tube
4. Pleural effusion;
-Mild - improves after therapy
-Moderate - in the 1st 2-4wks of therapy - Prednisolone 20mg BD to reduce adhesions, pleural thickening & speed
clearance of the fluid
-Severe - aspiration
5. Cardio-pulmonary insufficiency (heart lung disease resulting in cor pulmonale)
6. Bronchiectasis
7. Fibrosis of the lungs may lead to pulmonary HTN
8. Lung abscess
7. Pericardial effusion - Prednisolone 20mg BD for 6 wks - Prevents pericardial fibrosis & constrictive pericarditis

UPPER GIT BLEEDING

-UGIB is defined as bleeding derived from a source proximal to the ligament of Treitz.
-Acute gastrointestinal (GI) bleeding is a potentially life-threatening abdominal emergency
Incidence
-The incidence of upper gastrointestinal bleeding (UGIB) is approximately 0.1 % of the general population.
-Bleeding from the upper GI tract is approximately 4 times as common as bleeding from the lower GI tract and is a
major cause of morbidity and mortality.
-The use of various endoscopic techniques, medical therapies, and visceral angiography has progressively
diminished the role of surgery in the emergent management of UGIB
-Nevertheless, operative intervention still represents the most definitive intervention and remains the final
therapeutic option for many bleeding lesions of the upper GI tract.
-Of patients who develop UGIB, 3-15% requires a surgical procedure.
Clinical presentation
-Haematemesis and melaena are the most common presentations of acute UGIB, and patients may present with both
symptoms. Occasionally, a brisk UGIB manifests as hematochezia.
In order of frequency:
1. Hematemesis in 40-50% patients.
2. Melena in 70-80% of patients.
3.Hematochezia
4. Syncope
5. Presyncope
Symptoms 30 days prior to admission

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1. Dyspepsia, Epigastric pain, Heartburn
2. Diffuse abdominal pain
3. Dysphagia
4. Weight loss
5Jaundice
-The history findings can be extremely helpful in determining the location of the GI hemorrhage.
-Alcohol abuse or a history of cirrhosis should elicit consideration of portal gastropathy or esophageal varices -A
history of recent nonsteroidal anti-inflammatory drug (NSAID) abuse -a gastric ulcer or chronic back –pain –need
for NSAIDs
-History of treatment for Peptic ulcers-bleeding could be PUD or gastric ulcers.

Diagnoses for UGIB

1) Gastric ulcer and duodenal ulcer
2) Esophageal varices /Gastric varices
3) Mallory-Weiss tear, Boerhave tear
4) Esophagitis, Hemorrhagic gastritis
5) Neoplasm-Esophageal ca, stomach ca, Kaposi sarcoma.
6) Dieulafoy lesion
7) Arterio-venous malformations.
8) Angiodysplasia
9) Hemophilia
10) Pancreatic pseudo cyst and pancreatic pseudo aneurysm
11) Foreign body 14.Merkels diverticulum
12) Coagulopathy 13.Aortoenteric fistula

MANAGEMENT
-Resuscitation of a hemodynamically unstable patient begins with assessing and addressing the ABCs (i.e., airway,
breathing, circulation) of initial management.
-Earliest opportunity is taken to intubate the patient and avoid risk of aspiration.
-Using two large bore venous access in the antecubital fossa. Replace blood loss with crystalloid in the ration of 1
ml of blood loss replaced by 3ml of crystalloid.
-Urethral catheter for monitoring the urine production.
-Continuously monitor the resuscitation measures especially the circulatory aspect:
Urine output should be 30-50ml/hr
 BP monitoring systolic BP not <90mmHg
 Decrease in BP and urine output suggest need for colloids but a decrease in urine output but normal BP
suggest need for crystalloids
 Pulse. Pulse should be less than 120/minute
 Pulse oximetry
 CVP monitoring the best to avoid over-infusion
 State of patient should be calm
-Once the maneuvers to resuscitate are underway, insert a nasogastric tube (NGT) and perform an aspirate and
lavage procedure.
-This should be the first procedure performed to determine whether the GI bleeding is emanating from above or
below the ligament of Treitz.
- If the stomach contains bile but no blood, UGIB is less likely. If the aspirate reveals clear gastric fluid, a duodenal
site of bleeding may still be possible
Surgical therapy:
Endoscopy
-Both diagnostic and therapeutic Upper GIT bleeding.
-Endoscopy should be performed immediately after endotracheal intubation (if indicated) and hemodynamic
stabilization.
-Endoscopy is now the method of choice for controlling active ulcer hemorrhage and variceal bleeds.
Methods for hemostasis.
1) Injection of vasoactive agents
2) Injection of sclerosing agents

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 3) Coagulation-types
Bipolar electrocoagulation
Thermal probe coagulation
Laser photocoagulation
Argon plasma coagulator
4) Band ligation
5) Pressure tamponade –with Constant probe
6) Application of hemostatic materials, including biologic glue
-The 3 most popular methods of hemostasis are injection therapy, coaptive coagulation, and laser phototherapy
1. Vasoactive agent injection
a) Epinephrine -diluted (1:10,000) and injected as 0.5- to 1-mL aliquots.
-Works by inducing vasoconstriction and decreasing blood flow to the area.
-This allows for increased platelet function and clot formation to attain hemostasis.
-However, the tamponade effect produced by injecting the volume of drug into the tissue surrounding the bleeding
lesion may also facilitate hemostasis.
b) Injecting a volume of sterile isotonic sodium chloride solution and providing a tamponade effect also leads to
hemostasis, although not as effectively as epinephrine
2. Sclerosant injection
-The sclerosant solutions used today include
Absolute ethanol
 Polido-canol
 Sodium tetradecyl sulfate.
-These achieve hemostasis by inducing thrombosis, tissue necrosis, and inflammation at the site of injection.
-When large volumes are injected, the area of tissue necrosis can produce an increased risk of local complications
such as perforation.

3. Coaptive coagulation
-Uses direct pressure and thermal therapy to achieve hemostasis.
-Thermal therapy includes monopolar and bipolar electrocoagulation and heater-probe application.
-The bleeding vessel is isolated, compressed, and tamponaded prior to coagulation therapy. By using both
maneuvers, the depth of tissue injury is minimized.
-Coaptive coagulation is as effective as injection therapy in achieving hemostasis
-Combining injection therapy with heater-probe coagulation can be used in an attempt to reduce the rebleeding rate
in high-risk patients who have spurting arterial bleeding observed during endoscopy

Other aspects of treatment

Duodenal Ulcers
-Proton pump inhibitors decrease rebleeding rates in patients with bleeding ulcers associated with an overlying clot
or visible nonbleeding vessel in the base of the ulcer.
-It is administered at the same time as endoscopy.
-The indications for surgery in patients with bleeding peptic ulcers are as follows:
1) Severe life-threatening hemorrhage not responsive to resuscitative efforts
2) Failure of medical therapy and endoscopic hemostasis with persistent recurrent bleeding
3) A coexisting reason for surgery such as perforation, obstruction, or malignancy
4) Prolonged bleeding with loss of 50% or more of the patient’s blood volume
5) A second hospitalization for peptic ulcer hemorrhage

-The 3 most common operations performed for a bleeding duodenal ulcer are as follows
a) Truncal vagotomy and pyloroplasty with suture ligation of the bleeding ulcer
b) Truncal vagotomy and antrectomy with resection or suture ligation of the bleeding ulcer
c) Proximal (highly selective) gastric vagotomy with duodenostomy and suture ligation of the bleeding ulcer
-The purpose of the vagotomy is to divide the nerves to the acid-producing body and fundus of the stomach.
-This inhibits the acid production that occurs during the cephalic phase of gastric secretion.
-Although acid secretion is controlled, gastric motility and gastric emptying is affected

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-Eradication of H pylori can reduce the risk of rebleeding
-Lansoprazole 30 mg plus amoxicillin at 1 g plus clarithromycin at 500 mg q12h for 2 weeks.
To diagnose H.pylori
a) The endoscopic tests include culture, histology, and a rapid urease test (RUT). RUTs are based on the urease-
producing activity of H pylori. If urease is present, then urea is hydrolyzed, thus releasing ammonia that raises the
pH.
b) Available nonendoscopic tests are the urea breath test and serologic testing.

GASTRIC ULCERS
-The 3 most common complications of a gastric ulcer that surgical intervention is hemorrhage, perforation, and
obstruction.
-The goals of surgery are to correct the underlying emergent problem, prevent recurrent bleeding or ulceration, and
exclude malignancy.
-A bleeding gastric ulcer is most commonly managed by a distal gastrectomy that includes the ulcer with a
gastroduodenostomy or a gastrojejunostomy reconstruction.
The common operations for the management of a bleeding gastric ulcer include
(1) Truncal vagotomy and pyloroplasty with a wedge resection of the ulcer
(2) Antrectomy with wedge excision of the proximal ulcer, (3) Distal gastrectomy to include the ulcer with or
without truncal vagotomy
(4) Wedge resection of the ulcer only.
-The choice of operation type of ulcer and hemodynamic stability of the patient to withstand an operation.
-Five types of gastric ulcers occur, based on their location and acid-secretory status.
Type 1 gastric ulcers are located on the lesser curvature of Are not associated with a hypersecretory acid
state.
Type 2 ulcers represent a combination of 2 ulcers that are associated with a hypersecretory acid state. The
1st ulcer in body of the stomach, 2nd ulcer in the duodenum.
Type 3 ulcers are prepyloric ulcers. They are associated with high acid output and are usually within 3 cm
of the pylorus.
Type 4 ulcers are located high on the lesser curvature of the stomach and (as with type 1 ulcers) are not
associated with high acid output.
Type 5 ulcers are related to the ingestion of NSAIDs or aspirin. These ulcers can occur anywhere in the
stomach.
-A vagotomy is added to manage type 2 or type 3 gastric ulcers.

3. VARICEAL BLEEDS
Pharmacologic therapy
-The patient with acute variceal bleeding may initially be treated with
 Intravenous vasopressin and nitroglycerine
Somatostatin, or one of its analogs (e.g., octreotide).
-Vasopressin is a potent splanchnic and systemic vasoconstrictor, including coronary vasoconstriction.
-Nitroglycerin should be concomitantly administered to titrate and maintain the SBP in the range of 90-100 mm Hg.
-Nitroglycerin should be initiated at 40 mcg/min to protect the coronary arteries from the profound adverse
cardiovascular effects of the vasopressin.
- The intravenous infusion of vasopressin is started at 0.2-0.4 U/min.
Endoscopy
-The 2 main endoscopic techniques available to control variceal bleeding are endoscopic sclerotherapy and
endoscopic variceal band ligation.
- Endoscopic sclerotherapy involves injecting a sclerosing agent, such as ethanolamine or polidocanol, into the varix
lumen (intravariceal) or immediately adjacent to the vessel (paravariceal) to create fibrosis in the mucosa overlying
the varix, which leads to hemostasis.
-Endoscopic variceal banding ligation consists of the placement of a rubber band around the varix. This technique is
performed by first sucking the varix into a sheath attached to the distal end of the endoscope. Once the varix is
suctioned into the sheath, a trigger device allows the deployment of a rubber band around the varix, a procedure that
strangulates the varix.
-Variceal banding associated with significantly lower mortality rates, lower variceal rebleeding, less esophageal
perforation, and stricture formation compared to sclerosants

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Balloon tamponade
-Can be a life-saving maneuver when medical and endoscopic efforts fail to control the bleeding. Achieve temporary
control of the bleeding but recurrent bleeding with release of the tamponade occurs in most patients
-They are also cause complications as
Airway obstruction
 Aspiration
 Esophageal necrosis with rupture
- Because of the severe life-threatening complications and limited use, the tubes are used only as a temporary
measure while the patient is resuscitated.
-The tubes act as a bridge to help stabilize the patient until a time when the patient is prepared for either a repeat
endoscopy procedure or a portal pressure decompression through a radiological or surgical method
-The 2 most commonly used tubes are the Sengstaken-Blakemore tube and the Minnesota tube. These tubes have an
esophageal balloon and a gastric balloon that are inflated to produce a tamponade effect after confirming appropriate
anatomical placement.
-Before use endotracheal intubation to secure and protect the patient’s airway
-Major complications of balloon tamponade
1) Esophageal rupture
2) Tracheal rupture
3) Duodenal rupture
4) Respiratory tract obstruction
5) Aspiration
6) Hemoptysis
7) Tracheoesophageal fistula
8) Jejunal ruptures
9) Thoracic lymph duct obstruction
10) Esophageal necrosis
11) Esophageal ulcer
-Minor complications
1) Nasopharyngeal bleeding
2) Chest pain
3) Balloon impaction and/or migration (nausea and vomiting)
4) Alar necrosis
-The tube is first introduced into the stomach, and a small amount of air is injected into the gastric balloon.
-A radiograph is then obtained to confirm placement in the stomach. Once proper placement is confirmed, the
gastric balloon is inflated with 300-350 mL of air and is pulled up into the gastric fundus, compressing the
gastroesophageal junction.
-The tube is secured to the facemask of a football helmet placed on the patient’s head.
-The esophageal balloon is then inflated to a pressure of 40 mm Hg. Another radiograph is obtained to confirm
proper placement of both tubes. Deflate the esophageal balloon every 4 hours for 15 minutes to avoid esophageal
pressure necrosis.
- Do not leave the entire tube in place for more than 24-48 hours.
Transjugular intrahepatic portosystemic shunt
-Transjugular intrahepatic portosystemic shunt (TIPS) decompression of the portal system can be achieved through
either radiologic or surgical methods.
-The goal is to reduce intravariceal pressure to less than 12 mm Hg. The TIPS procedure for bleeding
esophagogastric varices that is unresponsive to endoscopic and pharmacologic first-line treatment
-By surgery -Portacaval shunt (end-to-side) or (side-to-side).

VITAMIN B12 ASSOCAIETED NEUROLOGICAL DISEASE

Pathophysiology
Vitamin B-12 structure (cobalamin)

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-Is a complex molecule in which a cobalt atom is contained in a corrin ring.
-Vitamin B-12 is available in animal protein; strict vegetarians may obtain it from legumes (poor source)
Body stores
-Total body stores are 2-5 mg, of which half is stored in the liver.
-The recommended daily intake is 2 mcg/d in adults; pregnant and lactating women require 2.6 mcg/d. Children
require 0.7 mcg/d and, in adolescence, 2 mcg/d. Because vitamin B-12 is highly conserved through the enterohepatic
circulation, cobalamin deficiency from malabsorption develops after 2-5 years and deficiency from dietary
inadequacy in vegetarians develops after 10-20 years.
-Deficiency causes are mainly nutritional and malabsorptive, Pernicious anemia being most common
Physiology of absorption
-After ingestion, the low stomach pH cleaves cobalamin from other dietary protein. The free cobalamin binds to
gastric R binder, a glycoprotein in saliva, and the complex travels to the duodenum and jejunum, where pancreatic
peptidases digest the complex and release cobalamin.
-Free cobalamin can then bind with gastric intrinsic factor (IF), a 50-kd glycoprotein produced by the gastric parietal
cells, the secretion of which parallels that of hydrochloric acid.
-Hence, in states of achlorhydria, IF secretion is reduced, leading to cobalamin deficiency.
-Importantly, up to 99% of ingested cobalamin requires IF for absorption. only 1% of free cobalamin is absorbed
passively in the terminal ileum. Thus Oral replacement with large vitamin B-12 doses is appropriate for PA.
-Once bound with IF, vitamin B-12 is resistant to further digestion. The complex travels to the distal ileum and binds
to a specific mucosal brush border receptor, cublin, which facilitates the internalization of cobalamin-IF complex in
an energy-dependent process.
-Once internalized, IF is removed and cobalamin is transferred to other transport proteins, transcobalamin I, II, and
III (TCI, TCII, TCIII).
-Eighty percent of cobalamin is bound to TCI/III, whose role in cobalamin metabolism is unknown. The other 20%
binds with TCII, the physiologic transport protein produced by endothelial cells. Its half-life is 6-9 min, thus
delivery to target tissues is rapid.
-The cobalamin-TCII complex is secreted into the portal blood where it is taken up mainly in the liver and bone
marrow as well as other tissues.
-Once in the cytoplasm, cobalamin is liberated from the complex by lysosomal degradation.
An enzyme-mediated reduction of the cobalt occurs by cytoplasm methylation to form methylcobalamin or by
mitochondrial adenosylation to form adenosylcobalamin, the 2 metabolically active forms of cobalamin.

NO pathomechanisms in vitamin B-12 deficiency

-NO can oxidize the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive,
inhibiting Homocysteine conversion to methionine and depleting the supply of SAM.
- Patients with sufficient vitamin B-12 body stores can maintain cellular functions after NO exposure, but in patients
with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations.
Causes of B12 deficiency
Check

Vitamin B-12 role in bone marrow function

-In the cytoplasm, methylcobalamin serves as cofactor for methionine synthesis by allowing transfer of a methyl
group from 5-methyl-tetrahydrofolate (5-methyl-THF) to homocysteine (HC), forming methionine and demethylated
tetrahydrofolate (THF).
-This results in reduction in serum homocysteine, which appears to be toxic to endothelial cells. Methionine is
further metabolized to S-adenosylmethionine (SAM).
-THF is used for DNA synthesis. After conversion to its polyglutamate form, THF participates in purine synthesis
and the conversion of deoxyuridylate (dUTP) to deoxythymidine monophosphate (dTMP), which is then
phosphorylated to deoxythymidine triphosphate (dTTP). dTTP is required for DNA synthesis
- In vitamin B-12 deficiency, formation of dTTP is impaired and accumulation of 5-methyl-THF is occurs, trapping
folate in its unusable form and leading to retarded DNA synthesis.
-RNA contains dUTP (deoxyuracil triphosphate) instead of dTTP, allowing for protein synthesis to proceed
uninterrupted and resulting in macrocytosis and cytonuclear dissociation.
-Both deficiencies lead to megaloblastic anemia and disordered maturation in granulocytic lineages; therefore, folate
supplementation can reverse the hematologic abnormalities of vitamin B-12 deficiency but has no impact on the
neurologic abnormalities of vitamin B-12 deficiency, indicating both results from different mechanisms.

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Vitamin B-12 role in the peripheral and central nervous systems
-CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear.
Reduced SAM or elevated methylmalonic acid (MMA) may be involved.
-SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions
are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids
such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which
may account for the encephalopathy and myelopathy.
-In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to
structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be
relevant to mental status changes may occur.
-Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin,
adenosylcobalamin, a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin
B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and
hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent
abnormal myelination, possibly leading to defective nerve transmission.

Clinical presentation-
History:
-The neurologic features are attributable to pathology in
Peripheral nerves
 Optic nerves
 Posterior and lateral columns of the spinal cord (subacute combined degeneration)
 Brain-Dementia
-Although the clinical features of vitamin B-12 deficiency may consist of a classic triad of weakness, sore tongue,
and paresthesias, these are not usually the chief symptoms.
-Onset is subacute or gradual, although more acute courses have been described, in particular after NO exposure.
-Onset is often with a sensation of cold, numbness, or tightness in the tips of the toes and then in the fingertips,
Simultaneous involvement of arms and legs is uncommon, and onset in the arms is even rarer. Paresthesias are
ascending and occasionally involve the trunk, leading to a sensation of constriction in the abdomen and chest.
-Untreated patients may develop limb weakness and ataxia.
-Psychiatric or cognitive symptoms
-Visual symptoms -subacute progressive decrease in visual acuity, usually caused by bilateral optic neuropathy and
rarely pseudo tumor cerebri or optic neuritis. Other symptoms include lightheadedness and impaired taste and smell.
-Rare autonomic features include orthostasis, sexual dysfunction, and bowel and bladder incontinence.
Non-neurological symptoms:
-Constitutional symptoms- anorexia, weight loss low grade fever, fatigue and malaise.
-CVS-syncope, dyspnea, orthopnea, palpitations, and angina.
-GIT-heartburn, flatulence, constipation, diarrhea, sore tongue, and early satiety.

Physical Examination
-Most patients exhibit signs of peripheral nervous system (PNS)-neuropathy or spinal cord involvement
(myelopathy).
-Or combination of both.
-Objective sensory abnormalities usually result from posterior column involvement and less often from PNS disease.
-Early in the course, poor joint position and vibration sense predominate. Typically, the legs are affected before the
arms. A Romberg sign is commonly found. The gait may be wide based.
-Absent ankle reflexes with relative hyperreflexia at the knees. Plantars are initially flexor and later extensor. A
Hoffman sign may be found (mixture of upper motor and lower motor neuron lesions).
- As the disease progresses, ascending loss of pinprick, light touch, and temperature sensation occurs.
Later, depending on the predominance of posterior column versus cortical spinal tract involvement, ataxia or spastic
paraplegia predominates. Then, PNS involvement causes distal limb atrophy.
-Cognitive testing may reveal mild impairment or frank dementia.
-Non neurologic manifestations include the following:

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-General
Lemon-yellow waxy pallor
Premature whitening of hair
 Flabby bulky frame
 Mild icterus
 Blotchy skin pigmentation in dark-skinned patients
-Cardiovascular - Tachycardia, congestive heart failure
-GIT- Beefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges

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