Audio file 1: Cellular Injury 1

CHAPTER 1: CELULAR REACTION TO INJURY

Key issues hypoxia, cyanide poisoning, free radicals, apoptosis, growth alternations (i.e. hypertrophy, atrophy, hyperplasia, etc)
I. Hypoxia = inadequate oxygenation of tissue (same definition of as shock). Need O2 for oxidation phosphorylation pathway
where you get ATP from inner Mito membrane (electron transport system, called oxidative phosphorylation). The last rxn is O 2 to
receive the electrons. Protons are being kicked off, go back into the membrane, and form ATP, and ATP in formed in the mitochondria
A. Terms:
1. Oxygen content = Hb x O2 satn + partial pressure of arterial oxygen (these are the 3 main things that carry O 2 in our blood)
In Hb, the O2 attaches to heme group (O2 saturation). Partial pressure of arterial O 2 is O2 dissolved in plasma. In RBC, four heme
groups (Fe must be +2; if Fe+ is +3, it cannot carry O2)Therefore, when all four heme groups have an O2 on it, the O2 satn is 100%.
2. O2 sat is the O2 IN the RBC is attached TO the heme group = (measured by a pulse oximeter)
3. Partial pressure of O2 is O2 dissolved in PLASMA
O2 flow: from alveoli through the interphase, then dissolves in plasma, and increases the partial pressure of O 2, diffuses through the
RBC membrane and attaches to the heme groups on the RBC on the Hb, which is the O 2 sat. Therefore if partial pressure of O 2 is
decreased, O2 satn HAS to be decreased (B/c O2 came from amount that was
dissolved in plasma)
Causes of tissue hypoxia:
1. Ischemia (decrease in ARTERIAL blood flow NOT venous)
MCC Ischemia is thrombus in muscular artery (b/c this is the mcc death in USA = MI, therefore MI is good example of
ischemia b/c thrombus is blocking arterial blood flow, producing tissue hypoxia)
Other causes of tissue ischemia: decrease in Cardiac Output (leads to hypovolemia and cardiogenic shock) b/c there is a
decrease in arterial blood flow.
2. 2 nd MCC of tissue hypoxia = hypoxemia
Hypoxia = big term
Hypoxemia = cause of hypoxia (they are not the same); deals with the partial pressure of arterial O 2 (O2 dissolved in
arterial plasma, therefore, when the particle pressure of O2 is decreased, this is called hypoxemia).
Here are 4 causes of hypoxemia:
a. Resp acidosis (in terms of hypoxemia) in terms of Daltons law, the sum of the partial pressure of gas must =760 at atmospheric
pressure (have O2, CO2, and nitrogen; nitrogen remains constant therefore, when you retain CO 2, this is resp acidosis; when CO2 goes
up, pO2 HAS to go down b/c must have to equal 760. Therefore, every time you have resp acidosis, from ANY cause, you have
hypoxemia b/c low arterial pO2; increase CO2= decrease pO2, and vice versa in resp alkalosis).
b. Ventilation defects best example is resp distress syndrome (aka hyaline membrane dz in children). In adults, this is called Adult
RDS, and has a ventilation defect. Lost ventilation to the alveoli, but still have perfusion; therefore have created an intrapulmonary
shunt. Exam question: pt with hypoxemia, given 100% of O2 for 20 minutes, and pO2 did not increase, therefore indicates a SHUNT,
massive ventilation defect.
c. Perfusion defects knock off blood flow
MCC perfusion defect = pulmonary embolus, especially in prolonged flights, with sitting down and not getting up. Stasis in veins of
the deep veins, leads to propagation of a clot and 3-5 days later an embolus develops and embolizes. In this case, you have ventilation,
but no perfusion; therefore there is an increase in dead space. If you give 100% O 2 for a perfusion defect, pO2 will go UP (way to
distinguish vent from perfusion defect), b/c not every single vessel in the lung is not perfused. Therefore, perfusion defects because an
increase in dead space, while ventilation defects cause intrapulmonary shunts.
To tell the difference, give 100% O2 and see whether the pO2 stays the same, ie does not go up (shunt) or increases
(increase in dead space).
d. Diffusion defect something in the interphase that O2 cannot get throughie fibrosis. Best exampleSarcoidosis (a restrictive lung
disease); O2 already have trouble getting through the membrane; with fibrosis it is worse. Another examplePulmonary edema; O 2
cannot cross; therefore there is a diffusion defect. Another example is plain old fluid from heart failure leads to dyspnea, b/c activated
the J reflex is initiated (innervated by CN10); activation of CN10, leads to dyspnea (cant take a full breath) b/c fluid in interstium of
the lung, and the J receptor is irritated.
These are the four things that cause hypoxemia (resp acidosis, ventilation defects, perfusion defects, and diffusion defects).
3. Hemoglobin related hypoxia
In the case of anemia, the classic misconception is a hypoxemia (decrease in pO 2). There is NO hypoxemia in anemia, there is normal
gas exchange (normal respiration), therefore normal pO2 and O2 saturation, but there is a decrease in Hb.
That is what anemia is: decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O 2 that gets to tissue, therefore get tissue

hypoxia and the patient has exertional dyspnea with anemia, exercise intolerance.
a. Carbon monoxide (CO): classic heater in winter; in a closed space with a heater (heater have many combustable materials;
automobile exhaust and house fire. In the house fire scenario, two things cause tissue hypoxia:
1) CO poisoning and 2) Cyanide poisoning b/c upholstery is made of polyurethrane products. When theres heat, cyanide gas is
given off; therefore pts from house fires commonly have CO and cyanide poisoning.
CO is very diffusible and has a high affinity for Hb, therefore the O2 saturation, will be decreased b/c its sitting on the heme
group, instead of O2 (remember that CO has a 200X affinity for Hb).
(Hb is normal its NOT anemia, pO2 (O2 dissolved in plasma) is normal, too); when O2 diffuses into the RBC, CO already sitting there,
and CO has a higher affinity for heme. To treat, give 100% O2. Decrease of O2 satn = clinical evidence is cyanosis
Not seen in CO poisoning b/c cherry red pigment MASKS it, therefore makes the diagnosis hard to make. MC symptom of CO
poisoning = headache
b. Methemoglobin:
Methemoglobin is Fe3+ on heme group, therefore O2 CANNOT bind. Therefore, in methemoglobin poisoning, the only thing screwed
up is O2 saturation (b/c the iron is +3, instead of +2). Example: pt that has drawn blood, which is chocolate colored b/c there is no O 2
on heme groups (normal pO2, Hb concentration is normal, but the O 2 saturation is not normal); seat is empty, but cannot sit in it, b/c
its +3. RBCs have a methemoglobin reductase system in glycolytic cycle (reduction can reduce +3 to +2).
Example: Pt from rocky mountains was cyanotic; they gave him 100% O 2, and he was still cyanotic (was drinking water in mountains
water has nitrites and nitrates, which are oxidizing agents that oxidize Hb so the iron become +3 instead of +2). Clue was that O 2 did
not correct the cyanosis. Rx: IV methylene blue (DOC); ancillary Rx = vitamin C (a reducing agent).
Most recent drug, Dapsone (used to Rx leprosy) is a sulfa and nitryl drug. Therefore does two things:
1) produce methemoglobin and 2) have potential in producing hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies.
Therefore, hemolysis in G6PD def is referring to oxidizing agents, causing an increase in peroxide, which destroys the RBC; the same
drugs that produce hemolysis in G6PD def are sulfa and nitryl drugs. These drugs also produce methemoglobin. Therefore, exposure
to dapsone, primaquine, and TMP-SMX, or nitryl drugs (nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia,
G6PD def, and methemoglobinemia b/c they are oxidizing agents. Common to see methemoglobinemia in HIV b/c pt is on TMP-SMX
for Rx of PCP. Therefore, potential complication of that therapy is methemoglobinemia.
c. Curves: left and right shifts
Want a right shifted curve want Hb with a decreased affinity for O 2, so it can release O2 to tissues. Causes: 2,3 bisphosphoglycerate
(BPG), fever, low pH (acidosis), high altitude (have a resp alkalosis, therefore have to hyperventilate b/c you will decrease the CO 2,
leading to an increase in pO2, leading to a right shift b/c there is an increase in synthesis of 2,3 BPG).
Left shift CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis Therefore, with CO, there is a decrease in O 2 satn
(hypoxia) and left shift.
4. Problems related to problems related to oxidative pathway
a. Most imp: cytochrome oxidase (last enzyme before it transfers the electrons to O 2. Remember the 3 Cs cytochrome oxidase,
cyanide, CO all inhibit cytochrome oxidase.
Therefore 3 things for CO (1) decrease in O 2 sat (hypoxia), (2) left shifts (so, what little you carry, you cant release), and (3) if you
were able to release it, it blocks cytochrome oxidase, so the entire system shuts down
b. Uncoupling ability for inner mito membrane to synthesize ATP. Inner mito membrane is permeable to protons. You only want
protons to go through a certain pore, where ATP synthase is the base, leading to production of ATP; you dont want random influx of
protons and that is what uncoupling agents do.
Examples: dinitrylphenol (chemical for preserving wood), alcohol, salicylates. Uncoupling agents causes protons to go right through
the membrane; therefore you are draining all the protons, and very little ATP being made. B/c our body is in total equilibrium with
each other, rxns that produce protons increase (rxns that make NADH and FADH, these were the protons that were delivered to the
electron transport system). Therefore any rxn that makes NADH and FADH that leads to proton production will rev up rxns making
NADH and FADH to make more protons. With increased rate of rxns, leads to an increase in temperature; therefore, will also see
HYPERTHERMIA. Complication of salicylate toxic = hyperthermia (b/c it is an uncoupling agent).
Another example: alcoholic on hot day will lead to heat stroke b/c already have uncoupling of oxidative phosphorylation
(b/c mito are already messed up). These are all the causes of tissue hypoxia (ischemia, Hb related, cyto oxidase block, uncoupling
agents). Absolute key things!
5. What happens when there is:
a. resp acidosis Hb stays same, O2 satn decreased, partial pressure of O2 decreased (O2 sat decreased b/c pO2 is decreased)
b. anemia only Hb is affected (normal O2 satn and pO2)
c. CO/methemoglobin Hb normal, O2 satn decreased, pO2 normal
Rx CO 100% O2; methemo IV methyline blue (DOC) or vit C (ascorbic acid)

C. Decreased of ATP (as a result of tissue hypoxia)

1. Most imp: have to go into anaerobic glycolysis; end product is lactic acid (pyruvate is converted to lactate b/c of increased NADH);
need to make NAD, so that the NAD can feedback into the glycolytic cycle to make 2 more ATP.
Why do we have to use anaerobic glycolysis with tissue hypoxia? Mitochondria are the one that makes ATP; however, with anaerobic
glycolysis, you make 2 ATP without going into the mitochondria. Every cell (including RBCs) in the body is capable of performing
anaerobic glycolysis, therefore surviving on 2 ATP per glucose if you have tissue hypoxia.
Mitochondrial system is totally shut down (no O2 at the end of the electron transport system can only get 2 ATP with anaerobic
glycolysis). Good news get 2 ATP. Bad news build up of lactic acid in the cell and outside the cell (increased anion-gap metabolic
acidosis with tissue hypoxia) due to lactic acidosis from anaerobic glycolysis.
However, causes havoc inside the cell b/c increase of acid within a cell will denature proteins (with structural proteins messed up, the
configuration will be altered); enzymes will be denatured, too. As a result, cells cannot autodigest anymore [b/c enzymes are destroyed
b/c buildup of acid. Tissue hypoxia will therefore lead to COAGULATION necrosis (aka infarction). Therefore, buildup of lactic acid
within the cell will lead to Coagulation necrosis.
2. 2nd problem of lacking ATP: all ATP pumps are screwed up b/c they run on ATP. ATP is the power, used by muscles, the pump,
anything that needs energy needs ATP. Na/K pump blocked by digitalis to allow Na to go into cardiac muscle, so Ca channels open
to increase force of contraction (therefore, sometimes you want the pump blocked), and sometimes you want to enhance it.
With no ATP, Na into the cell and it brings water, which leads to cellular swelling (which is reversible). Therefore, with tissue hypoxia
there will be swelling of the cell due to decreased ATP (therefore will get O2 back, and will pump it out therefore it
is REVERSiBLE). In true RBC, anaerobic glycolysis is the main energy source b/c they do not have mitochondria; not normal in other
tissues (want to utilize FAs, TCA, etc).
3. Cell without O2 leads to irreversible changes.
Ca changes with irreversible damage Ca/ATPase pump. With decrease in ATP, Ca has easy access into the cell. Within the cell, it
activates many enzymes (ie phospholipases in the cell membranes, enzymes in the nucleus, leading to nuclear pyknosis (so the
chromatin disappears), into goes into the mito and destroys it). Ca activates enzymes; hypercalcemia leads to acute pancreatitis b/c
enzymes in the pancreas have been activated.
Therefore, with irreversible changes, Ca has a major role. Of the two that get damaged (mito and cell membrane), cell membrane is
damaged a lot worse, resulting in bad things from the outside to get into the cell. However, to add insult to injury, knock off
mitochondria (energy producing factory), it is a very bad situation (cell dies)CK-MB for MI, transaminases for hepatitis (SGOT and
AST/ALT), amylase in pancreatitis.
II. Free Radicals
Liver with brownish pigment lipofuscin (seen on gross pic; can also be hemosiderin, bilirubin, etc; therefore need to have a case
with the gross pic); end products of free radical damage are lipofuscin b/c certain things are not digestible (include lipids).
A. Definition of free radical compound with unpaired electron that is out of orbit, therefore its very unstable and it will damage
things.
B. Types of Free Radicals:
1. Oxygen: We are breathing O2, and O2 can give free radicals. If give a person 50% O2 for a period of time, will get superoxide free
radicals, which lead to reperfusion injury, specially after giving tPA when trying to rid a damaged thrombus. Oxygentated blood goes
back into the damaged cardiac muscle= reperfusion injury. Kids with resp distress syndrome can get free radical injury and go blind
b/c they destroy the retina called retinopathy prematurity; also leads to bronchopulmonary dysplasia, which leads to damage in the
lungs and a crippling lung disease.
2. Water in tissues converted to hydroxyl free radicals, leading to mutations in tissues. Complication of radiation therapy is CANCER
(MC cancer from radiation is leukemia, due to hydroxyl free radicals). Fe2+ produces hydroxyl free radicals b/c of the fenton rxn.
This is what makes Fe overload diseases so dangerous, b/c wherever Fe is overloaded, leads to hydroxyl free radicals which will
damage that tissue (therefore, in liver leads to cirrhosis, in heart leads to restrictive cardiomyopathy, in pancreas leads to failure, and
malabsorption, along with diabetes).
Audio file 2: Cell Injury 2
3. Tylenol (aka acetaminophen): MCC drug induced fulminant hepatitis b/c free radicals (esp targets the liver, but also targets the
kidneys). Cytochrome P450 in liver metabolizes drugs, and can change drugs into free radicals. Drugs are often changed in the liver to
the active metabolite ie phenytoin.
Where in the liver does acetaminophen toxicity manifest itself? right around central vein.
Treatment: N-acetylcysteine; how? Well, the free radicals can be neutralized. Superoxide free radicals can be neutralized with
supraoxide dismutase (SOD). Glutathione is the end product of the hexose/pentose phosphate shunt and this shunt also generates
NADPH.
Main function is to neutralize free radicals (esp drug free radicals, and free radicals derived from peroxide). Glutathione gets used up
in neutralizing the acetaminophen free radicals. Therefore, when give n-acetylcysteine (aka mucamist); you are replenishing
glutathione, therefore giving substrate to make more glutathione, so you can keep up with neutralizing acetaminophen free radicals.
(like methotrexate, and leukovorin rescue using up too much folate, leukovorin supplies the substrate to make DNA, folate
reductase).
4. Carbon tetrachloride: CCl4 can be converted to a free radical in the liver (CCl3) in the liver, and a free radical can be formed out of
that (seen in dry cleaning industry).

5. Aspirin + Tylenol = very bad for kidney (takes a long time for damage to be seen). Free radicals from acetaminophen
are destroying the renal medulla *only receives 10% of the blood supply-relatively hypoxic) and renal tubules. Aspirin is
knocking off the vasodilator PGE2, which is made in the afferent arteriole. Therefore AG II (a vasoconstrictor) is left in
charge of renal blood flow at the efferent arteriole. Either sloughing of medulla or destroyed ability to concentrate/dilute
your urine, which is called analgesic nephropathy (due mainly to acetaminophen).
III. Apoptosis
Programmed cell death. Apoptotic genes programmed to die (theory). Normal functions:
(1) embryo small bowel got lumens from apoptosis.
(2) King of the body Y chromosome (for men); MIF very imp b/c all mullarian structures (uterus, cervix, upper 1/3 of vagina) are
gone, therefore, no mullarian structures. MIF is a signal working with apoptosis, via caspasases. They destroy everything, then wrap
everything in apoptotic bodies to be destroyed, and lipofuscin is left over.
(3)For woman Xchromosome; only have one functioning one b/c the other is a barr body. Absence of y chromosome caused
germinal ridge to go the ovarian route, therefore apoptosis knocked off the wolfian structures (epidydymis, seminal vesicles, and vas
deferens).
(4)Thymus in anterior mediastinum large in kids; if absent, it is DiGeorge syndrome (absent thymic shadow), and would also
have tetany; cause of thymus to involute is apoptosis.
(5) Apoptosis is the major cancer killing mechanism.
(6) Process of atrophy and reduced cell or tissue mass is due to apoptosis. Ex. Hepatitis councilman body (looks like eosinophilic
cell without apoptosis) of apoptosis (individual cell death with inflammation around it). Just needs a signal (hormone or chemical)
which activate the caspases, and no inflammation is around it. Apoptosis of neurons loss brain mass and brain atrophy, and leads to
ischemia. Red cytoplasm, and pynotic nucleus. Atherosclerotic plaque. Therefore, apoptosis is involved in embryo, pathology,
and knocking off cancer cells.
IV. Types of necrosis manifestations of tissue damage.
A. Coagulation Necrosis: Results often from a sudden cutoff of blood supply to an organ i.e. Ischemia (definition of ischemia
= decrease in arterial blood flow). In ischemia, there is no oxygen therefore lactic acid builds up, and leads to coagulation necrosis.
Gross manifestation of coagulation necrosis is infarction. Under microscope, looks like cardiac muscle but there are no striations, no
nuclei, bright red, no inflammatory infiltrate, all due to lactic acid that has denatured and destroyed all the enzymes (cannot be broken
down neutrophils need to come in from the outside to breakdown). Therefore, vague outlines = coagulation necrosis (see color
change in heart).
1. Pale vs hemorrhagic infarctions: look at consistency of tissue.
(a) Good consistency = grossly look pale: infarct: heart, kidney, spleen, liver (rarest of the organ to infarct b/c dual blood
supply); ie coagulation necrosis. Example of a pale infarction of the spleen, most likely due to emboli from left side of
heart; causes of emboli: vegetations (rarely embolize in acute rheumatic fever); infective endocarditis; mitral
stenosis (heart is repeatedly attacked by group A beta hemolytic streptococcus); and clots/thrombi. The worst arrhythmia
associated with embolization in the systemic circulation is atrial fib b/c there is stasis in the atria, clot formation, then it
vibrates (little pieces of clot embolize).
Gangrenous Necrosis: dry and wet gangrene: Picture of a dry gangrene not wet gangrene b/c theres no pus. Occurs
in diabetics with atherosclerosis of popliteal artery and possible thrombosis; (dry gangrene related to coagulation necrosis
related with ischemia (definition of ischemia = decrease in arterial blood flow), which is due to atherosclerosis of the popliteal artery.
Pathogenesis of MI: coronary thrombosis overlying the atheromatous plaque, leading to ischemia, and lumen is blocked due to
thrombosis. MCC nontraumatic amputation = diabetes b/c enhanced atherosclerosis (popliteal artery = dangerous artery).
Coronary is also dangerous b/c small lumen. In wet gangrene, its complicated by infective heterolysis and consequent liquefactive
necrosis (b) Loose consistency of tissue= hemorrhagic infarct: bowel, testes (torsion of the testes), especially the lungs b/c is has a
loose consistency and when the blood vessels rupture, the RBCs will trickle out, leading to a hemorrhagic appearance.
Example: hemorrhagic infarction of small bowel due to indirect hernia. 2nd MCC of bowel infarction is getting a piece of small bowel
trapped in indirect hernial sac. MCC of bowel infarction is adhesions from previous surgery.
Example: In the Lung hemorrhagic infarction, wedge shaped, went to pleural surface, therefore have effusion and exudates;
neutrophils in it; have pleuritic chest pain (knife-like pain on inspiration). Pulmonary embolus leads to hemorrhagic infarction.
B. Liquefactive Necrosis:
Exception to rule of Coagulation necrosis seen with infarctions: brain.
MC site of infarction from carotid artery why we listen for a bruit (hearing for a noise that is going thru a vessel that has a
narrow lumen place with thrombus develops over atherosclerotic plaque and leads to stroke); leads to transient ischemic
attacks is little atherosclerotic plaques going to little vessels of the brain, producing motor and sensory abnormalities, that
go away in 24 hrs. Brain with meshwork in brain, astrocytes is analogous to the fibroblasts b/c of protoplasmic processes.
Therefore, acting like fibroblast (cant make collagen), but its protoplasmic processes gives some structure to the brain. Therefore,
infarction of the brain basically liquefies it (has no struct), and you see a cyst space liquefactive necrosis. Therefore, exception to the
rule of infarctions not being coagulative necrosis is the brain and it undergoes liquefactive necrosis (no struc, therefore leaves a hole).
Cerebral abscess and old atherosclerotic stroke -both are liquefactive necrosis. Liquefactive liquefies; think neutrophil, b/c their job
is to phagocytosis with their enzymes (to liquefy); liquefactive necrosis relates to an infection with neutrophils involved (usually
acute infection producing an abscess or an inflammatory condition, which liquefies tissue). Therefore, liquefactive necrosis usually
applies to acute inflammation, related to neutrophils damaging the tissue. Exception to the rule: liquefactive necrosis related to infarct
(not an inflammatory condition, it just liquefies) (slide shows liquefactive necrosis due to infection in the brain). So, if you infarct the

brain, or have an infection, or have an abscess it is the same process liquefactive necrosis.
Example: Abscess gram + cocci in clusters. Why are they in clusters? Coagulase, which leads to abscesses with staph aur.
Coagulase converts fibrinogen into fibrin, so it localizes the infection, fibrin strands get out, resulting in an abscess.
Strep: releases hyaluronidase, which breaks down GAGs in tissue, and infection spreads through the tissue (cellulitis).
From point of view of necrosis, neutrophils are involved, therefore it is liquefactive necrosis.
Example: ABSCESS: Lung yellowish areas, high fever and productive cough; gram stain showed gram + diplococcus,
which is strep pneumoniae. (MCC of bronchopneumonia.). Not hemorrhagic b/c its pale, and wedged shaped necrosis at the
periphery, which leads to pleuritic chest pain.
Example: pt with fever, night sweats, wt loss M tb, which has granulomatous (caseous) necrosis. Pathogenesis of granuloma
(involves IL-12 and subset of helper T cells and + PPD).
C. Caseous (cheesy consistency) Necrosis: either have mycobacterial infection (any infections, including atypicals, or systemic
fungal infection); these are the ONLY things that will produce caseation in a granuloma. It is the lipid in the cell wall of the organisms
leads to cheesy appearance. Sarcoidosis get granulomas, but they are not caseous b/c they are not mybacterium or systemic fungi
(hence noncaseating granulomas). Crohns dz get granulomas, but not caseous b/c not related to mycobacterium or systemic fungi.
D. Fat Necrosis:
1. Enzymatic Fat Necrosis: unique to pancreas
Example: pt with epigastric distress with pain radiating to the back pancreatitis (cannot be Peptic Ulcer Dz b/c pancreas is
retroperitoneal), therefore just have epigastric pain radiating to the back. A type of enzymatic FAT necrosis (therefore necrosis related
to enzymes). Enzymatic fat necrosis is unique to the pancreas b/c enzymes are breaking down fats into FAs, which combine with Ca
salts, forming chalky white areas of enzymatic fat necrosis (chalky white areas due to calcium bound to FAs saponification
(soap/like salt formation)); these can be seen on x-rays b/c have calcium in them.
Example: A pt with pain constently penetrating into the back, show x-ray of RUQ. Dx is pancreatitis and esp seen in alcoholics. Histo
slide on enzymatic fat necrosis bluish discoloration, which is calcification (a type of dystrophic calcification-calcification of
damaged tissue). What enzyme would be elevated? Amylase and lipase (lipase is more specific b/c amylase is also in the parotid
gland, small bowel, and fallopian tubes). What type of necrosis? Another example: Enzymatic fat necrosis.
Underlying cause? Alcohol produces a thick secretion that will lead to activation of enzymes; which leads to pancreatitis.
Therefore, whenever you see blue discoloration and atherosclerotic plaque in a pancreas, it will be calcium.
2. Traumatic Fat Necrosis: Example: woman with damage to breasts is TRAUMATIC FAT necrosis (not enzymatic); it can
calcify, can look like cancer on mammogram. Diff btwn that and calcification in breast cancer is that it is painFUL. (cancer =
painless). Traumatic fat tissue usually occurs in breast tissue or other adipose tissue
E. Fibrinoid necrosis: (the -oid means: looks like, but isnt)
Therefore, looks like fibrin, but is not fibrin.it is the necrosis of immunologic dz:
Examples of immunologic dz:
Palpable purpura = small vessel vasculitis (immune complex type III)
Fibrinoid necrosis has immune complex deposition of small vessel.
Pathogenesis of immune complex: damage of type III HPY (an immune complex is an Ag-Ab circulating in the circulation; it
deposits wherever circulation takes it ie glomerulus, small vessel, wherever). It activates the complement system (the alt
system), which produces C5a, which is chemotactic to neutrophils. Therefore, damage done as a result of type III HPY is
done by neutrophils. And they are there b/c the immune complex activated the alternative complement system. The
complex has little to do with the damage, its the neutrophils do eventual damage)
Henoch-Scholein purpura feel persons legs, and see palpable purpura (due to type III HPY).
Rhematic fever (vegetations off the mitral valve) have fibrin like (fibrinoid necrosis) materials (necrosis of immunologic dz).
Morning stiffness = rheumatoid arthritis, see fibrnoid necrosis b/c immunologic damage. Therefore, fibrinoid necrosis is necrosis of
immunologic damage (in vessel its a vasculitis, in kidney its a glomerulonephritis, and in lupus glomerulonephritis involving
immune complexes).
F. Liver: Triad area: portal vein, hepatic artery, bile duct. Liver is unique b/c it has dual blood supply and so hepatic artery and
and portal vein will dump blood into sinusoids. Other examples of sinusoid organs are BM and spleen. Characteristic of
sinusoids: gaps between endothelial cells, with nothing there so things can fit through (things like RBCs and inflammatory cells).
GBM is fenestrated, have little tiny pores within the cells, for filtration. Sinusoids have gaps so large cells can get through them
(not true with GBM b/c it is intact, and lil pores allow filtration). Portal vein blood and hepatic artery blood go through sinusoids,
and eventually taken up by central vein, which becomes the hepatic vein. The hepatic vein dumps into the inf vena cava, which
goes to the right side of the heart. Therefore, there is a communication between right heart and liver. Right HF (blood fills
behind failed heart), therefore the liver becomes congested with blood, leading to nutmeg liver (aka congestive hepatomegaly).
If you block the portal vein, nothing happens to the liver, b/c it is BEFORE the liver. Blockage of hepatic vein leads to budd chiari
and liver becomes congested. Which part of liver is most susceptible to injury normally? Around central vein, b/c it gets first
dibbies on O2 coming out of the sinusoids (zone 1). Zone 2 is where yellow fever will hit (midzone necrosis) due to ides egypti.
Zone 3, around portal vein, which will have least O2 (analogous to renal medulla, which only receives 10% of the blood supply,
and the cortex receives 90%). Fatty change is around zone 3 (part around central vein). Therefore, when asking about
acetaminophen toxicity, which part is most susceptible? Around the central vein b/c it gets the least amount O2, and therefore
cannot combat free radical injury.

1. Alcohol related liver damage :

(a) MCC fatty change: alcohol.

(b) Metabolism of alcohol: NADH and acetyl CoA (acetate is a FA, and acetyl CoA can be converted to FAs in the cytosol). NADH is
part of the metabolism of alcohol, therefore, for biochemical rxns: What causes pyruvate to form lactate in anaerobic glycolysis?
NADH drove it in that direction, therefore always see lactic acidosis (a form of metabolic acidosis) in alcoholics b/c increased NADH
drives it in that direction. Also, in fasting state, alcoholic will have trouble making glucose by gluconeogenesis b/c need pyruvate to
start it off. However, you have lactate (and not pyruvate) therefore alcoholics will have fasting hypoglycemia.
Acetyl CoA can also make ketone bodies (acetoacetyl CoA, HMG CoA, and beta hydroxybutyric acid). See beta hydroxybutyric
ketone bodies in alcoholics b/c its a NADH driven reaction. Therefore, two types of metabolic acidosis seen in alcoholics are lactic
acidosis (b/c driving pyruvate into lactate) and increased synthesis of ketone bodies b/c excess acetyl CoA; main ketoacid = beta
hydroxybutyric acid.
Why does it produce fatty change? In glycolysis, around rxn 4, get intermediates dihydroxyacetone phoshphate (NADH
rxn) and is forced to become glycerol 3-phosphate. Big time board question! With glycerol 3 phosphate shuttle, get
ATP. Also imp to carbohydrate backbone for making tryglycerides (add 3 FAs to glycerol 3 phosphate, and you get
TGs). In liver, the lipid fraction if VLDL (endogenous TG is synthesized in the liver from glycerol 3 phosphate derived from
glycolysis). Restricting fat will NOT decrease the synthesis of VLDL. Restricting carbs WILL decrease the VLDL synthesis b/c it is
glucose intermediate it is made from. Glycerol 3 phosphate is a product of glycolysis which is why fatty liver is most commonly due
to alcoholism (this rxn)!
Audio file 3: Inflammation 1
2. Kwashiorkor kid with fatty change. The mechanism: when you make VLDL, and to be able to get it out of the liver, the VLDL
must be surrounded by apoproteins. In kwashiorkor, there is decreased protein intake; they have adequate number of calories, but its
all carbs. Therefore, they cannot get VLDL that they made in the liver out b/c there are no apolipoproteins to cover it and put it out in
the bloodstream and solubilize it in water. Lipid and water do not mix; therefore it is necessary to put proteins around the lipid to
dissolve it in water. Therefore, the protuberant abdomen in these pts is there for two reasons: 1) decreased protein intake which
decreases oncotic pressure, leading to ascites. 2) The biggest reason is that they have huge livers related to fatty change. The
mechanism for fatty change is different from alcohol b/c in alcohol; the mech is due to increased synthesis of VLDL. In this case,
there is a lack of protein to put around the VLDL and export it out of the liver.
3. Hemosiderin and Ferrtin: brief discussion: Ferritin = soluble form of circulating Fe, and is a good marker for Fe in BM. It is the test
of choice in diagnosing any Fe related problem Fe def anemia, or Anemia of Chronic Dz or Fe overload dzs such as
hemochromatosis and hemosiderosis (would be elevated). Ferritin is a soluble form of Fe, while hemosiderin is an insoluble form of
Fe storage, and is stored in macrophages and BM. Stain it with Prussian blue.
V. Types of calcification: dystrophic and metastatic
A. Dystrophic calcification: means abnormal calcification. The damaged tissue gets calcified.
1. Example: Seen in enzymatic fat necrosis (chalky white areas on x-ray are a result of dystrophic calcification).
2. Example: football player with hematoma in foot, that becomes calcified dsystrophically (Ca binds and co-produces dystrophic Ca
deposits). Serum Ca is normal, but damaged tissue becomes calcified. Occurs in atheromatous plaques (causes serious tissue damage),
therefore they are difficult to dissolve (need to be on the ornish diet a vegan diet).
3. MCC aortic stenosis (MCC: congenital bicuspid aortic valve) = dystrophic calcification (also leads to a hemolytic anemia).
Slide: the aorta has only 2 valves doing the job of three, and gets damaged, leading to dystrophic calcification which
narrows orifice of valve, leading to aortic stenosis.
B. Metastatic calcification: In cases of Hypercalcemia or hyperphosphatemia, Calcium is actually made to deposit in normal
tissues, non-damaged tissues.
MCC hypercalcemia (outside of hospital) = primary hyperparathyroidism
MCC hypercalcemia (inside the hospital) = malignancy induced hypercalcemia.
With hypercalcemia, can put Ca in NORMAL tissues; this is called metastatic calcification. In dystrophic calcification there is
Damaged tissue with normal serum Ca levels. Metastatic calcification is when there is high Ca or phosphorus serum levels (actually
when Ca is deposited into bone, it is the phosphorus part of solubility product that drives Ca into bone). High phosphate levels (very
dangerous) will take Ca and drive it into normal tissue. This is why have to put a pt with renal failure on dialysis (have high
phosphorus serum levels) therefore need to dialyze the phosphate b/c the phosphate will drive Ca into normal tissue ie heart,
conduction system, renal tubules, basement membrane (nephrocalcinosis) all lead to damage.
VI. Cell Membrane Defects
A. RBC membrane defect: Spherocytosis is a defect in spectrin within RBC cell membrane; if you cant see a central area of
pallor (if you dont see a donut) then its a spherocyte. Absence of spectrin with in the RBC does not allow the RBC to form a
biconcave disk; it is defective, and therefore forms a sphere.
B. Ubiquitin stress protein. High ubiquitin levels are associated with high levels of stress. Some of the intermediate filaments
(keratin, desmin, vimentin) are part of the superstructure of our cells (frame of the cell, upon which things are built).
When these intermediate filaments get damaged, the ubiquitin marks then for destruction. The intermediate filaments have been
tagged (ubiquinated) and marked for destruction. Some of these products have names, for example: there are open spaces within the
liver tisse, these spaces are fat and they are probably due to alcohol. The ubiquinited products of the liver are called Mallory bodies.
These are the result of ubiquinated filaments called keratin and these are seen in alcoholic hepatitis.
Another example: Silver stain of neurofibilary tangles Jacob crutzfelt and alzheimers dz. Tau protein is associated with
neurofib tangles; this is an example of a ubiquinated neurofilament. Example: Substantia nigra in Parkinsons Dz include
inclusions called Lewy bodies, neurotransmitter deficiency is dopamine. Lewy bodies are ubiquinated neurofilaments. Therefore,
Mallory bodies, Lewy bodies, and neurofib tangles are all examples of ubiquintation.

VII. Cell Cycle- very very important: big big big time
A. Different types of cells:
1. Labile cells cell where the division is via a stem cell. Three tissues that has stem cells: bone marrow, basement membrane of skin,
and the base of crypts in the intestine. These cells have the tendency of being in the cell cycle a lot. In pharm: there are cell cycle
specific and cell cycle nonspecific drugs. The cells that are most affected by these drugs are the labile cells b/c they are in the cell
cycle. Complications of these drugs are BM suppression, diarrhea, mucocidis, and rashes on the skin (there are stem cells in all these
tissues!).
2. Stable cells in resting phase, Go phase. Most of perenchymal organs (liver, spleen, and kidney) and smooth muscle are
stable cells. Stable cells can ungo division, but most of the time they are resting, and something must stimulate them to get into the
cell cycle and divide ie a hormone or a growth factor. For example: estrogen in woman will help in the proliferative phase of the
menstrual cycle. The endometrial cells are initially in the Go phase and then the estrogen stimulated the cells to go into the the cell
cycle. Therefore, they can divide, but they have to be invited by a hormone or a growth factor.
3. Permanent cells can no longer get into the cell cycle, and have been permanently differentiated. The other types of muscle cells:
striated, cardiac and neuronal cells. Only muscle that is NOT a permanent tissue = smooth muscle; hyperplasia = increase in #, while
hypertrophy = increase in size. Would a permanent cell be able to under hyperplasia? NO, b/c that means more copies of it. Can it go
under hypertrophy? Yes. A smooth muscle cell can undergo hyperplasia AND hypertrophy.
B. Different phases of cell cycle:
1. G1 phase: The most variable phase of cell cycle is the G1 phase. Compare with menstrual cycle: The most variable phase
is the proliferative phase (not the secretory phase). The prolifertive phase varies with stress; however, once ovulation has
occurred, it is 14 days. Therefore, proliferative phase is analogous to G1 phase of the cell cycle b/c it can be shorter or lengthened;
none of the other phases (S, G2, and M phase) changes, they stay the same. Therefore, in cancer cells, ones with a longer cell cycle
will have a longer G1 phase, and cancer cells with a shorter cell cycle will have a shorter G1 phase.
G1 phase is the mastermind of everything. Cyclin dependent kinase (kinase = phosphorylation = activation).
Phosphorylation usually involves sending a message to activate something. Glucagon is a phosphorylator, while insulin is a
dephosphorylator. Glucagon will phosphorylate protein kinase and activate it, while Insulin would dephosphorylate protein
kinase and inactivate it.
G1 to S phase: Inactive Cyclin d dependent kinase: Cyclin d activates it, and G1 phase makes cyclin D. Once cyclin D is
made in the G1 phase, it then activates the enzyme: cyclin dep. kinase (therefore it is now active). Key area to control in cell cycle:
transition from G1 to S phase. Because if you have a mutation and it goes into S phase, it then becomes
duplicated, then you have the potential for cancer. Two suppressor genes that control the transition: (1) Rb suppressor
gene: located on chromosome 13, which makes the Rb protein, which prevents the cell from going from the G1 to the S
phase. In general, to go from G1 to S, the active cyclin dep kinase phosphorylates the Rb protein; when it is
phosphorylated=activation, it can go from the G1 phase to the S phase. A problem occurs if there is a mutation. Therefore
the enzyme is checked by (2) p53 suppressor gene: located on chromosome 17, which makes a protein product that inhibits
the cyclin d dep kinase. Therefore, it cannot go into the S phase; p53 is the number 1, most imp gene that regulates
human cancer.
Example: HPV inactivates Rb suppressor gene and p53 suppressor gene. HPV makes two genes products E6 (which
knocks off the p53) and E7 (which knocks of the Rb suppressor gene).
If you have a point mutation the Rb suppressor gene, the Rb suppressor gene is knocked off, there will be no Rb protein, and the cell
will progress to the S phase b/c it is uncontrolled. This mutation in the Rb suppressor gene predisposing to many cancers, such as
retinoblastoma, osteogenic sarcoma (ie kid with pain around knees, Codmans triangle sunburst appearance on x-rays), and breast
cancer (Rb suppressor can be involved). Depending on the age bracket, it hits in different areas. If you knock of p53 suppressor gene:
the kinase will be always active, it will always phosphorylate the Rb protein, and that means that it will always go into the S phase,
and this is bad. If you knock off any of those genes, the cell will go into the S phase. The p53 suppressor gene is the guardian of the
genome, b/c it gives the cell time to detect if there are any defects/abnormalities in the DNA (splicing defects, codon thing, whatever,
etc). DNA repair enzymes can splice out the abnormality, correct it, and the cell is ready to go to the S phase. If the cell has too much
damaged DNA, then it is removed by apoptosis. Therefore this gene is imp b/c it gives the cell an opportunity to clean its DNA before
going into the S phase.
2. S phase = synthesis phase, where everything is doubled, includes DNA and chromosomes (from 2N to 4N). For example:
if its in muscle, it will have double the number of contractile elements.
3. G2 phase = where tubulin is made (imp to microtubule of the mitotic spindle); it is blocked by etoposide and bleomycin.
4. M phase = mitosis; where the cell divides into two 2N cells. The cell can either go into the Go resting phase, or can
continue dividing in the cycle, or can be permanently differentiated. p53 gene makes a protein to inhibit the kinase,
therefore prevents the Rb protein from being phosphorylated, therefore stays in the G1 phase. Therefore, when you knock it
off, no one is inactivating the kinase, and the cell is constantly phosphorylated and that keeps the cell dividing, and then has
the potential to lead to cancer.
C. Drugs that act on the cell cycle:
1. Drugs acting on S phase:
a) Ergot alkaloids work on the mitotic spindle in S phase
b) Methotrexate works in S phase: Example: pt with rheumatoid arthiritis has macrocytic anemia. Drug responsible for
this is in what phase of the cell cycle? S phase b/c it is methotrexate blocking dihydrofolate reductase

2. Drugs acting on G2 phase:

a) Etoposide
b) Bleomycin
3. Drugs acting on M phase:
a) Grisiofulvin in M phase
b) Paclitaxel specifically works in the M phase: Clinical scenario: this drug is a chemotherapy agent made from a yew
tree? Paclitaxel (m phase)
c) Vincristine and Vinblastine
d) This drug used to be used for the treatment of acute gouty arthritis but b/c of all the side effects is no longer used.
What drug and where does it act? Colchicine (m phase)
4. Clinical scenario that does not work on the cell cycle: HIV + person with dyspnea and white out of the lung, on a
drug; ends up with cyanosis; which drug? Dapsone
VII. Adaptations to environmental stress: Growth alterations
A. Atrophy: Diagnosis: the decrease in tissue mass and the cell decreases in size. The cell has just enough organelles to survive, ie
less mitochondria then normal cells, therefore, just trying to eek it out until whatever it needs to stimulate can come back.
1. Example: hydronephrosis, the compression atrophy is causing thinning of cortex and medulla, MCC hydronephrosis is stone in the
ureter (the pelvis is dilated). Question can be asked what kind of growth alteration can occur here. Answer is atrophy b/c of the
increased pressure on the cortex and the medulla and produces to ischemia, blood flow decreases and can produce atrophy of renal
tubules.
2. Example: Atrophied brain due to atherosclerosis (MC) or degeneration of neurons (alzheimers, related to beta amyloid protein,
which is toxic to neurons) 3. Example: In muscle, many causes of atrophy ie Lou Gehrigs Dz (amylateral sclerosis) knock off
neurons to the muscle, so it is not stimulated, leading to atrophy.
4. Example: Endocrine related:
a) Hypopituitarism will lead to atrophy of adrenal cortex: the zona fasiculata and retiucularis layers of the adrenal cortex; NOT the
glomerulosa b/c ACTH has nothing to with stimulating aldosterone release. The fasiculata is where glucocorticoids (cortisol) are
made, while reticularis is where sex hormones are made (17 ketosteroids and testosterone). ACTH is responsible for stimulating these,
therefore zona fasiculata and zona reticularis are atrophied.
b) Taking thyroid hormone will lead to atrophy of thyroid gland. This is due to a decrease of TSH and therefore nothing
is stimulating the thyroid gland which leads to atrophy.
5. Example: Slide showing a biopsy of a pancreas in a patient with cystic fibrosis. What is growth alteration? Atrophy, b/c the CFTR
regulator on csome 7 is defective and has problems with secretions. The secretions become thicker and as a result, it blocks the ducts
and so that means that the glands that were making the fluids (the exocrine part of the gland) cannot make fluids b/c of the back
pressure blocking the lumen of the duct, which leads to atrophy of the glands, which then leads to malabsorption in all children with
cystic fibrosis.
6. Example: Slide of an aorta, with atherosclerotic plaque, which leads to atrophy of the kidney and secondary HTN (renovasuclar HP,
leading to high renin level coming out of the kidney). In the other kidney, it is overworked, therefore there is hypertrophy (renin level
coming out of this vein is decreased and suppressed).
B. Hypertrophy increase of the SIZE of cell, not number
Scenario: A cell biology question: what is the N of this?
Hypertrophy of a cardiac muscle (permanent muscle), suppose there is a block just before the G2 phase. What is the
number of chromosomes? Answer: # of csomes is 4N, b/c it already underwent synthesis: already doubled.
1 N = sperm (23 csomes)
2 N = normal (diploid cell)
3 N = trisomy
4 N = double the number
C. Hyperplasia increase in the # of cells
In normal proliferative gland, there are thousands of mitoses, therefore see more glands with hyperplasia.
1. Example leading to cancer: With unopposed estrogen, you may end up with cancer, b/c if you didnt have progesterone (undoes
what estrogen did-counteracts the estrogen), you will get cancer. The cells will go from hyperplasia, to atypical hyperplasia to
endometrial cancer. Therefore hyperplasia left unchecked there is an increased risk of cancer. One exception: benign prostatic
hyperplasia; hyperplasia of the prostate does NOT lead to cancer; just urinary incontinence.
2. Example: gravid uterus (womans uterus after delivery). This is an example of 50:50: 50% hypertrophy of the smooth
muscle cells in the wall of the uterus, and 50% related to hyperplasia.
3. Example: Bone marrow: normally should have 3X as many WBCs as RBCs. Slide shows few WBCs, and increased
RBCs. Therefore, have RBC hyperplasia. This is not expected to be seen in Iron def anemia nor in thalassemias b/c in those, there a
defect in Hb production. It is expected to be seen in chronic obstructive pulmonary dz (COPD) b/c the hypoxemia causes the release
of hormone EPO (erythropoietin); which is made in the endothelial cells of the peritubular capillaries. So in the slide this is an
example of EPO stimulated marrow.
4. Example: psoriasis on elbow an example of hyperplasia (unregulated proliferation of squamous cells in the skin), leading to red

skin, and raised red plaque, b/c excessive stratum corneum. This is why methotrexate works here, b/c its a cell cycle specific for the S
phase, and prevents the basal cells from proliferating.
5. Example: prostate gland and bladder hyperplasia of prostate glands, it a hormone related hyperplasia; all hormone
stimulated glands undergo hyperplasia, not hypertrophy. The wall of the bladder is too thick; b/c urine has to go out thru a
narrow opening in the urethra, therefore the muscle has to work harder which leads to hypertrophy of smooth muscle cells
of the bladder wall (more urine must go out against a greater force b/c of an increase in after load).
D. Metaplasia replacement of one adult cell type by another
1. Example: Slide of an esophagus, part of if is all ulcerated away. On a section surrounding the ulcer (right at the edge of
the muscosa) there are mucous secreting cells and goblet cells (these are grandular cells). These cells are not supposed to
be present in lower esophagus; squamous cells should be there (not glandular cells). Metastatic grandular: Barrets
esophagus is a precursor for adenocarcinoma. Adenocarcinoma has surpassed squamous cell carcinoma of mid-esophagus
as the MC cancer of the esophagus. Therefore, GERD is the number one precursor to esophageal cancer (adenocarcinoma).
Audio file 4: Inflammation 2
2. Example: Lining of mainstem bronchus ciliated columnar, pseudostatified columnar. In smokers, this would be an
example of metaplasia would be squamous
3. Example: There are increased goblet cells within mainstem bronchus of an old smoker, also see goblet cells in the terminal
bronchial. Normally there are goblet cells in the mainstem bronchus but there are no goblet cells in the terminal bronchus, therefore
this is an example of hyperplasia.
4. Example: Goblet cells in the stomach are abnormal (should be in the intestines, only). This is a glandular metaplasia, which is a
precursor for adenocarcinoma of the stomach. H. pylori are a precursor for adenocarcinoma in the stomach. B/c H. pylori causes
damage to pylorus and antral mucosa b/c it is a chronic gastritis which intestinal glandular metaplasia, which is a precursor for
adenocarcinoma. MCC adenocarcinoma of the stomach = H. pylori.
5. Example: Cases where metaplasia causes an increased risk to caner:
a) Remember that if hyperplasia is left unchecked, could potentially lead to cancer. For example: in endometrial hyperplasia the MC
precursor lesion to endometrial carcinoma due to unopposed estrogen. The exception is prostatic hyperplasia, which doesnt become
cancer.
b) Metaplasia can also go through a process leading to cancer:
(1) In lung, ciliated columnar epithelium BECOMES squamous, therefore, this is called SQUAMOUS metaplasia; this will lead to
squamous dysplasia, which then proceeds to cancer (squamous carcinoma);
(2) In distal esophagus, went from squamous to glandular epithelium b/c squamous epithelium cannot handle the acid, therefore it
needs mucous secreting epithelium as a defense against cellular injury. However, the glandular metaplasia can go on to an atypical
metaplasia, predisposing to adenocarcinoma of the distal esophagus.
(3) Parasites: 2 parasites produce cancer: chlonorchis sinesis leads to cholangiocarcinoma (Chinese liver fluke); and schistosoma
hematoabium. The schistosoma hematobium causes bladder cancer by causing the transitional epithelium to undergo squamous
metaplasia. This leads to squamous dysplasia, and then on to squamous cancer.
Transitional epithelium leads to squamous epithelium (called metaplasia), then dysplasia, then on to cancer.
E. Dysplasia is really an atypical hyperplasia.
1. Example: Slide of a squamous epithelium is disorganized, with nuclei that are larger near the surface and the basal cell layer is
responsible for the dividing; cells at top are bigger than the ones that are dividing, it has lack orientation.
If it was found during a cervical biopsy in pt with HPV infection, or if it was found in the mainstem bronchus biopsy, you should be
able to tell that it is dysplastic. Therefore dysplasia, whether glandular or squamous, is a precursor for cancer.
2. Example: There was a farmer with lesion on the back of his neck (can grow on any part of the body, due to sun exposure), which
could be scraped off and grew back actinic keratosis (aka solar keratosis) is a precursor for sq. cell carcinoma of the skin. UV-B
light damages the skin. Actinic keratosis does not predispose to basal cell carcinoma, even though basal cell carcinoma is the most
common skin cancer.
(6:38) Acute Inflammation
A. Cardinal signs of inflammation
In the scenario with a bee sting: you will see redness (rubor). The king of vasodilators is histamine and it vasodilates the
arterioles. Therefore, histamine is responsible for the redness of acute inflammation (ie bee sting), and is working on
arterioles. Now if we felt the area, it will be warm (Calor = heat), this is due to vasodilating the arterioles, which is caused
by histamine. For example in endotoxic and septic shock, the skin is warm b/c you are vasodilated. Tumor is a raised
structure caused by histamine. Histamine can lead to increased vessel permeability in the venules; is arterial thicker than
venules? Yes. The venules are very thin; they basically have an endothelial cell with a basement membrane, all you have to
is drill a hole through the BM and you are out. Therefore, increased vessel permeability occurs at the venule level, not the
arterial level. Histamine contracts the endothelial cells, and leaves the BM bare, leading to increased vessel permeability,
producing an exudate, and swelling of tissue, hence tumor of acute inflammation.
The area may hurt (Dolor = pain) but histamine does not have anything to do with this. Bradykinin is part of the kininogen system
between factor 11 and Hageman factor 12. So when you activate the intrinsic pathway, you automatically activate the kininogen

system. When you activate factor 12 (Hageman factor), it will activate 11 and the whole kininogen system. The end product is
bradykinin. ACE degrades bradykinin. Complication of ACE inhibitor is angioedema. Also inhibit metabolism of bradykinin, which
increases vessel permeability, producing the angioedema (swelling of the tissues). How bradykinin produces cough is not really
understood. Bradykinin and PGE2 cause pain (dolor) and is the only one out of the four Latin terms of acute inflammation that is not
due to histamine release.
B. Steps involved in Acute inflammation (this the normal sequence in acute inflammation):
1. Emigration: includes margination, paveenting, rolling, adhesion, and transmigration
Neutrophils in circulation start to become sticky b/c of adhesion molecule synthesis. Endothelial cells begin to synthesize adhesion
molecules. Eventatually, neutrophils will stick to endothelial cells, these steps are called pavmenting or margination. Then neutrophils
look for bare basement membrane on the venules and then they drill a hole through it via type 4 collagenase. Cancer cells also have
type 4 collagenase, thats how they metastasize. Cancer cells attach to endothelial via adhesion molecules, usually against laminin in
BM, and they have collagenase to get through the BM, therefore, cancer cells are pretty much like a neutrophil when invading tissue.
2. Chemotaxis: When they pass BM of small venules, they emigrate but they have to know what direction to go. They get directions
in a process called directed chemotaxis. C5a and LT-B4 (leukotriene B4) are the chemotactic agents. These chemotactic agents are also
involved in making adhesion molecules on neutrophils). Therefore, they make adhesion molecules AND give direction by acting like
chemotactic agents.
3. Phagocytosis via opsonization:
a) Example: in an acute inflammation with staph aureus, the bacteria are being processed by opsonins, which immobilize the particles
on the surface of the phagocyte. The two main opsonins are IgG and C3b. They help with phagocytosis.
b) Example of an opsonization defect: Brutons agammaglobinemia: an x-linked recessive dz, where all the immunoglobulins are
missing, including IgG. Therefore, MCC death in these pts is due to infection b/c cannot opsonize things. It produces hypogammaglobinemia, but the mechanism of infection is due to not having IgG to opsonize bacteria, therefore cannot phagocytose it.
Bacteria are opsonized by IgG and C3b, which means that neutrophils must have receptors for those. In acute inflammation the main
cell is neutrophil and in chronic inflammation the main cell is macrophage/monocyte (monocytes become macrophages). These cells
have to have receptors for these opsonins (IgG and C3b). Then they become phagocytosed or become phagolysomes. When they are
phagocytosed, the lysosomes go to microtubules and empty their enzyme into this.
c) Example: In I-cell disease: in this dz, mannose residues cannot be phosphorylate in golgi apparatus therefore the enzymes are not
marked with phosphorus, and the lysosome are empty.
4. Intracellular microbial killing:
a) Examples:
(1) Staph aureus in hot tub surrounded by enzymes
(2)Chlamydia can get out of phagolysosome, mechanism unknown, but sometimes they have mucous and all kinds of things around
them.
b) O2 dependent myeloperoxidase system is the boards!!
Molecular O2 is converted by NADPH oxidase, which is in the cell membrane of neutrophils and monocytes, but not macrophages.
The most important cofactor is NADPH, which is synthesized in the pentose phosphate shunt. The enzyme responsible is glucose 6
phosphate dehydrogenase, which converts G6P into 6-phosphogluconate, generating NADPH and a neutralizing factor for free
radicals (glutathione).
It is converting O2 into a free radical, superoxide. Superoxide has an unpaired electron giving off energy, which is called a resp burst,
which can be measured by radiation detectors; and by a negative NBT dye test. In the NBT test, you have a test tube, add the colorless
NBT dye; and if neutrophils and monocytes are working normally, they will phagocytose it, will have a respiratory burst, and the free
radical O2 will cause the color to change to blue, indicating that the resp burst is working. If there is no color change, there is not a resp
burst, therefore the pt has chronic granulomatous dz of childhood.
Free radical O2 is converted by SOD (its neutralizer) into peroxide. Peroxide itself could kill bugs, but it is used for another reason.
Within the neutrophils and monocytes are reddish granules which are lysosomes, and are seen in the peripheral blood.
Myeloperoxidase (one of the many enzymes in the granules) will catalyze the rxn. It will combine peroxide with chloride to from
bleach. This is the most potent bactericidal mechanism O2 dep myeloperoxidase system, which is in NEUTROPHILS and
MONOCYTES but NOT in macrophages, b/c macrophages lose the system when they convert from monocytes to macrophages and
they use lysosomes to kill.
Macrophages of the CNS are microglial cells, so the reservoir cell for CNS/ AIDS is the microbial cell. Outside the CNS, it is the
dendritic cell; it is a macrophage located in the lymph nodes.
c) In G6PD deficiency, infection is the MC precipitation of hemolysis b/c there is no NADPH, therefore there is no functioning O 2
dependent myeloperoxidase system, and therefore you are susceptible to infection, which will set of hemolysis of RBCS.
d) Chronic granulomatous dz of childhood = X linked recessive dz where the mom gives the dz to the boy, and is an asymptomatic
carrier, and they will transmit the dz to 50% of their sons. In this dz, there is a deficient activity of NADPH oxidase, and the NBT dye
test is negative (doesnt show color of die), therefore there's no respiratory burst. Do they have superoxide? No. Peroxide? No.
Myeloperoxidase? Yes. Chloride? Yes. Therefore, if they phagocytized a bacteria that could make peroxide, and add it inside the
phagolysosome, this is what the kid would need to kill the bacteria. These kids are missing PEROXIDE b/c there is no NADPH
oxidase. ALL living organisms make peroxide (including ALL bacteria). However, not all bacteria contain catalase, which is an

enzyme that breaks down peroxide. So, in chronic granulomatous dz, what can they and cant they kill? Cannot kill staph, but can kill
strep. Why? B/c staph is Coagulase and CATalase +; so, ie, if its staph. aureus and when it makes peroxide, it will also make
catalase and neutralize it, therefore the child cannot kill staph, and will kill the kid. If it was a streptococcus organism that makes
peroxide (does not have catalase therefore peroxide can be used by the child), it adds what kid really needed to make bleach, and the
bacteria is then wiped out. Therefore, can kill strep and not staph!
e) Myeloperoxidase deficiency: Do they have a resp burst? Yes b/c they have NADPH oxidase. Do they have peroxide? Yes. Do they
have superoxide free radicals? Yes. Do they have chloride? Yes. Do they have myeloperoxidase? No. They have a normal resp burst
and a normal NBT dye test, but they cant kill the bacteria b/c they cannot make bleach. This is called a myeloperoxidase defect. Other
types of defects:
(1) opsonization defects with brutons agammaglobulinemia(missing IgG), C3 defs;
(2) chemotactic defects where cells do not respond to chemotaxis;
(3) microbiocidal defects, the defect in the ablility to kill bacteria, example: chronic granulmatous dz of childhood and
myeloperoxidase deficiency are both microbiocidal dz, in that they cannot kill bacteria, but for different reasons.
In myeloperoxidase def the problem is that they cannot make bleach (b/c of the missing enzyme), but do have resp burst, and is
Autosomal recessive dz. In CGDz the problem is that they cannot make bleach either, but they have an ABSENT resp burst, and is a
X-LINKED recessive dz.
f) Child has an umbilical cord that doesnt fall off when it should. When it was removed and looked at histologically, they did not see
neutrophils in the tissue or neutrophils lining the small vessels. This is an adhesion molecule defect or beta 2 integrin defect.
Umblilcal cord needs to have an inflammatory rxn involving neutrophils; they have to stick in order to get out. Therefore, if the
neutrophils cant stick, they cant get out, and then they cant get rid of your umbilical cord this is a classic adhesion molecule
defect.
C. Chemical mediators:
1. Histamine: the king of chemical mediators of acute inflammation
a) What does it do to arterioles? Vasodilates
b) Venules? Increased vessel permeability
2. Serotonin:
a) What amino acid makes serotonin? Tryptophan
b) Is serotonin a neurotransmitter? Yes
c) In a deficiency, you get depression (also decreased NE)
d) a vasodilator and increases vascular permeability
3. Complement system: Anaphylatoxins C3a, C5a. Function: stimulate mast cells to release histamine, leading to
vasodilation and increased vessel permeablility. They also play a role in shock, b/c when there is inflammation the
compliment system is activated, therefore there will be mast cells and histamine, therefore C3a, and C5a will both be there.
4. Nitric oxide made mainly in endothelial cells, and is a potent vasodilator. It is used for treating pulmonary
hypertension. It has a big time role in septic shock.
5. IL-1 associated with a fever, it is a pyrogen, therefore stimulates the hypothalamus to make PGs, which stimulate thermoregulatory
system to produce fever. Aspirin works by inhibiting the synthesis of prostaglandins thereby reducing the fever.
6. Arachidonic acid metabolites:
a) Corticosteroids inhibits Phospholipase A2, therefore do not release arachidonic acid from phospholipids, therefore not
making PGs or leukotrienes. This is the supreme antiflammatory agent b/c BOTH PGs and leukotrienes are blocked by
blocking phospholipase A2. Arachidonic acids make linoleic acid (omega 3), which is found in fish oils and walnuts. It is
very good for you b/c it acts like aspirin, and blocks platelet aggregation, and thats how omega 3 protects your heart.
b) Lipoxygenase pathway: Zileuton blocks 5-lipoxgenase, other drugs act by blocking the receptors, example:
zafirlukast, etc. Leukotriene (LT) C4, D4, E4 (the slow reactor substances of anaphylaxis) seen in bronchial asthma.
They are potent bronchoconstrictors; therefore it can be seen why zileuton works well in asthma b/c it blocks the
leukotrienes, including these (LT-C4, D4, and E4). LT B4 is an adhesion molecule in chemotaxis.
c) Cyclooxygenase pathway: Aspirin blocks cycoloxygenase, irreversibly in platelets. PGH2: where everything seems to be derived
from. PGI2: derives from endothelial cells, its also called prostacyclin synthase; is a vasodilator and inhibits platelet aggregation
(exact the opposite of TxA2). Thrombaxane A2 (the enemy of PGI2) is made in the platelet; its a vasoconstrictor, a
bronchoconstrictor, and promotes platelet aggregation. What drug blocks thrombaxane synthase and is used to stress testing for CAD?
Dipyridamole blocks the enzyme, TxA2 synthase, therefore does not have to perform a treadmill stress test, all you have to do is use
the drug dipyridamole.
PGE2: vasodilator in kidney; keeps patent ductus patent in baby heart; makes the mucous barrier in GI (stomach) thereby preventing
ulcers; can cause dysmenorrhea woman and increased uterine contractility, and it an abortifactant, to get rid of fetal material.
d) COX 2-make sure you know how this works!
e) Corticosteroids blocks phospholipase A2, and it also decreases adhesion molecule synthesis, along with other steroids like
epinephrine and NE. Decreased adhesion molecule synthesis, will lead to increased neutrophils on CBC; in immuno, 50% neutrophils
are stuck to the endothelial vessels, and the other 50% are circulating, therefore, decreasing adhesion molecule synthesis will lead to

doubled WBC (b/c the 50% of neutrophils that were stuck are now circulating).
Corticosteroids destroy B-cells b/c they are lymphocytotoxic. Mechanism: decrease WBCs (B and T cells) via apoptosis; therefore,
corticosteroids are the signal to activate the caspasases.
Eosinophils, mainly seen in type one HPY rxn, corticosteroids decrease them. When on corticosteroids, the only thing that is increased
is neutrophils, via decreased adhesion molecule synthesis. Lymphocytes and eosinophils are decreased.
Example: If have Addisons, do not have cortisol, therefore the neutrophil count decreases and the eosinophil count will increase.
Example: a person with MI with an 18,000 CBC most of which are neutrophils. Mechanism: Epinephrine decreases adhesion molecule
sythesis and neutrophil count goes up.
D. Electron microscopy of inflammatory cells:
1. In lung, type II pneumocyte (black dots are lysosomes). Lamellar bodies structures where lecithin and phosphotidyl choline is
located; if ask where macrophage, is, will ask which makes surfactant.
2. Monocyte: single nucleus with a grayish cytoplasm has scavenged; can form foam cell in atherosclerotic plaque b/c it has
phagocytized oxidized LDLs (which is a free radical); Vit E neutralizes oxidized LDL.
3. Lymphocyte all nucleus and scant cyptoplasm, prob a T cell (60% of peripheral blood lymphocytes are T cells); ratio of helper to
suppressor: CD4:CD8 is (2:1), therefore, more likely to be a Helper T cell, then a suppressor T-cell, and B cells (20%) are least likely.
4. RER looks like a thumbprint, have ribosomes on it, and likes to make proteins, like Igs (therefore it is a plasma cell). Multiple
myeloma has eccentrically located nucleus, cytoplasm is always sky blue, making plasma cells are easy to recognize.
Plasma cells are derived from B cells, and located in the germinal follicle.
5. Granules eosinophil (have a red color similar to color of RBCs) have crystals in the granules. Eosinophils are the
only inflammatory cell that has crystals in the granules. They are called Charcot-Leiden crystals when its seen in the
sputum of asthmatic patient. They are degenerated eosinophils in sputum of asthmatic, and have formed crystals that look
like spear heads. Basophils have granules that are more purplish and darker, while basophils have darker colors.
6. Mech for killing invasive helminthesType II HPYmajor basic protein is involved. Remember that schistosome eggs are coated by
IgE Abs. Eosinophils have IgE receptors; therefore, eosinophils hook into the IgE receptor and release chemicals; the main one
released is major basic protein, which destroys the helminth, which is type II HPY, b/c it is a cell hooking into an Ab on the target cell.
The effector cell is Type II HPY rxn is the eosinophils; dont get confused with Type I HPY rxn where the effector cell is the MAST
CELL, and they release histamine (an eosinophil chemotactic factor), therefore they are invited to area of type I HPY b/c they have
histaminase and arylsulfatase, which neutralizes leukotrienes. The purpose of eosinophils in type I HPY is to knock off chemical
mediators produced in rxn; however, when an eosinophil kills an invasive helminth, it does so via type II HPY.
E. Cluster designations:
Helper t cell = CD4
Cytotoxic T cell = CD8
Marker for Ag recognition site for all T cells is CD3
Marker for histiocytes (including langerhans cells) is CD1
Marker for MC leukemia in children = CD10 (calla Ag); positive B-cell lymphoma
CD15 and 30 = RS cell
CD21, Only on B cells Epstein barr virus; hooks into CD21 on B cells, and actually the atypical lymphocytes are not B-cells
but T-cells reacting to the infected B-cells.
Burkitts is a B cell lymphoma
CD45 is found on all leukocytes, is a common antigen on everything
F. Fever IL-1 is responsible and PGE2 (this is what the hypothalamus is making) which stimulates the thermoregulatory center.
Fever is good! It right shifts the O2 dissoc curve. Why do we want more O2 in the tissues with an infection? B/c of O2 dependent
myeloperoxidase system. Therefore, with antipyretics its bad b/c thwarting the mechanism of getting O2 to neutrophils and monocytes
to do what they do best. Also, hot temps in the body are not good for reproduction of bacteria/viruses.
II. Types of inflammation (scenarios)
A. post partum woman, with pus coming out of lactiferous duct this is staph aureus suppurative inflammation
B. Bone of child with sepsis, on top of the bone, was a yellowish area, and it was an abscess osteomyelitis staph. aureus; if
the kid had sickle cell, it is salmonella; why at metaphysis of bone? B/c most of blood supply goes here, therefore, mechanism of
spread is hematogenous (therefore comes from another source, and then it gets to bone).
C. Hot, spread over face cellulitis due to strep (play odds!) group A pyogenes (called erysipilis, another name for cellulitis)
D. Diphtheria = pseudomembrane (corynebacterium diphtheria), a gram + rod, that makes an exotoxin, messing up ribosylation of
protiens via elongation factor 2, the toxin damages mucosa/submucosa, producing a pseudomembrane; when bacteria doesnt invade,
produces a toxin that damages the membrane; clostridium difficile also does this. It also produces a pseudomembrane and a toxin,

which we measure in stool to make the dx. Therefore, the answer is C. difficle.
E. Fibrinous pericarditis, usually with increased vessel permeability; seen in (1)lupus, leading to friction rub; also seen in (2) the
first week of MI, and then again 6 weeks later in dresslerss syndrome, (3) seen in Coxsackie
F. MC organism producing infection in third degree burns = pseudomonas aeruginosa. Color of pus: green due to pyocyanin.
G. Basal cell layer on both sides of clot, proliferate, and go underneath it to clot. In a primary wound its usually sealed off in
48 hrs (ie appendectomy). Key to wound healing is presence of granulation tissue.
Fibronectin is a very important proteoglycan and is involved in the healing of the wound. Fibronectin is an important adhesion agent
and chemotactic agent, inviting fibroblast in helping healing process. The granulation tissue starts at day 3 and is on its prime by day
5. If you ever picked at a scar and it bleed like mad and you try to stop it but it still bleed like mad, thats granulation tissue. No
granulation tissue means no healing of a wound. Type of collagen in initial stage of wound repair = type 3;
Type 4 collagen seen in BM;
Type 1 very strong tensile strength; seen in bone, skin, tendons, ligaments.
After a few months, after months, the collagen type 3 is broken down by collagenases, and a metalo- enzyme converts type 3
into type 1. Zinc is part of the metallic enzyme, this is why in a pt with zinc deficiency has poor wound healing b/c it screws up
the collagenase (must replace type 3 with type 1). Max tensile strength after 3 months = 80%. MCC poor wound healing =
infection
H. Ehlers Danlos defect in collagen due to syn/breaking down; have poor wound healing.
I. Marfan defect in fibrilin; also have poor wound healing
J. Pt with scurvy defect in hydroxylation of two aas (proline and lysine) via ascorbic acid. Remember its a triple helix; what
makes the triple helix stick together and increase tensile strength? Crossbridges. When you crossbridge things, they anchor into
areas where you have hydroxylated proline and lysine. Therefore have weak abnormal collagen in scurvy b/c there are no
crossbridges to attach, leading to not being able to heal wounds, hemorrhaging, hemarthroses.collagen has weak tensile strength b/c
cannot crossbridge.

Audio file 5: Fluid and Hemodyn1

K. Granulation tissue with a lot of blood vessels due to lot of fibroblast Growth Factor, with inflammatory cells from plasma cells and
lymphocytes, necessary for wound healing (rich vascular tissue, which is absolutely essential for normal wound healing).
L. Keloid (hypertrophic scar) = excess in type 3 collagen deposition; which causes a tumor looking lesions, esp in blacks. In a
white kid keloid to due to third degree burns.
In another example: in a chronically draining sinus tract of the skin, they tried to put antibiotics on it (didnt work), there was an
ulceration lesion at the orifice of this chronically draining tract, and nothing worked. What is it? The answer is squamous cell
carcinoma due to a lot of turnover; type 3 converted to type 1, and fibroblasts are involved. A lot of cell division occurring, which can
predispose to mutations and cancer, specially squamous cell cancer.
Squamous cancer is important b/c chronically draining sinus tracts, and predisposes to squamous cell carcinoma. Hyperplasia
predisposes to squamous cell carcinoma.
III. Chronic inflammation
A. Difference in Immunoglobulins:
1. Acute Inflammation: IgM = main Ig first, and then IgG
IgM = main Ig; need a lot of complement components in healing process; IgM is the most potent activator, and have
activation of complement pathway (all the way for 1-9); IgM has 10 activating sites (pentamer).
IgG can activate the classical system, but does NOT go passed C3 and stops and does not go onto C5-9.
After 10 days, there is isotype switching, and the mu heavy chain is spliced out (mu chain defies specificity of an Ig); it
splices in a gamma heavy chain, and IgG is made via isotype switching
2. Chronic inflammation: IgG (as main Ig IgM is coverted to IgG immediately)
B. Difference in Cell Types:
1. Acute inflammation = neutrophil
2. Acute allergic reactions= eosinophils (mast cells are in tissues)
3. Viral infections = lymphocytes are the main inflammatory cells
4. Chronic inflammations = monocytes/macrophages are imp. And see a lot of plasma cells and lymphocytes; do not see
pus-exudate (this is in acute inflamm increased vessel permeability, and increased emigration of neutrophils into
interstitial tissue, a protein rich fluid with >3 grams/dL, with a protein rich fluid = pus). Example: Cholecystis.
C. Type IV Hypersensitivity Reaction:
Another example: Granuloma = chronic inflammation (never acute); ie caseious necrosis in someone with TB; roundish,
pink, multinucleated giant cells = granulomas; pathogenesis = type IV hypersentistivity reaction delayed HPY. The main
actors are cytoxic T cells; when they kill neoplastic, virally infected cells, these are also type IV HPY (no Abs involved).
Poison ivy = type IV HPY. Back to TB infection, alveolar macrophage phagocytoses it, and there is lymphohemotogenous
spread; meanwhile the macrophage is processing the Ag. Then after weeks, it presents it to helper T cells. Therefore, the
key players in Type IV hypersensitivity rxn are macrophages which process that Ag and presents that Ag via class II MHC sites to the
helper T cells. These helper T-cells release cytokines: gamma IFN and macrophage inhibitory factor. Gamma IFN will activate the

macrophage to kill the TB, Cryptococcus, histoplasmosis, etc.

Therefore the gamma IFN is the trigger to active the macrophage; macrophage cannot kill without the activation from gamma IFN; b/c
systemic fungi and TB have lipid in the cell wall, this leads to caseous necrosis. All the pink staining cells are epitheloid, which are
activated macrophages (which have been activated by gamma IFN); when they die, they die in style they fuse together and form
multinucleated giant cells (like their gravestone). Therefore, epitheloid cells are fused macrophages; black dots are helper T cells.
There are two types of helper T-cell:
a. Subset 1: involved in Type IV (delayed type) HPY; macrophages have IL-12; when it is secreted, the subset 1 helper T cells are
presented with the antigen; then, subset 1 become MEMORY T cells. IL-12 is involved in activating the memory of subset 1 helper t
cells. Most people in their primary dz usually recover with no problems, but the granulomas can calcify, as seen on x-ray. A calcified
granuloma is not dead b/c they are resistant to dying. Therefore, most cases of secondary TB are due to reactivation TB. Granulomas
necrosis is due to reactivation.
Positive + PPD (purified protein derivative) injected into the skin; the macrophage of the skin is a langerhans cell (histiocyte)
(marker: CD 1) which have birbeck granules-look like tennis rackets on EM. They phagocyotose the Ag (the PPD), and process it
very quickly; they present it to helper subset 1, which has memory of previous exposure. Therefore, it hooks in the MHC class II Ag
sites (as all immune cells do), and once the Ag (PPD processed by the Langerhans cell) is presented, the helper T cell releases the
cytokines producing the inflammatory rxn with induration called the + PPD.
Correlation: older people usually dont host a very good Type IV hypersensitity rxn: they have a less response to + PPD; therefore
have to do a double test on them. In pt with AIDs, may not get any rxn. They dont have enough helper T-cells therefore dont have
granuloma formation. Macrophage inhibitory factor keeps macrophages in that area; therefore, with HIV, b/c the helper t cell count is
decreased, you dont form granulomas at all. Therefore, they will have MAI (organisms) all over the body without granulomas b/c
helper T cells are decreased. When you do + PPD, 5 mm induration is enough to say its positive. .
IV. Tissue Repair
Scar tissue (b/c its permanent tissue); scar tissue (fibrous tissue) does not contract; therefore, if you have more scar tissue to free
wall of left vetricle will lead to decreased ejection fraction (which is stroke volume divided by EDV).
A. Response of Kidneys to Injury: Kidney will form scar tissue; medulla is most susceptible to ischemia (b/c least amount of
blood supply). What part of nephron most susceptible to tissue hypoxia? 2 places:
1. Straight portion of prox tubule b/c most of oxidative metabolism is located there, with brush borders this is where most
of reabsorption of Na, and reclaiming of bicarb is there.
2. Medullary segment of thick ascending limb where the Na/K-2Cl pump is which is where loop diuretics block. The
Na/K-2Cl pump generates free water.
The two type of water in urine: obligated and free. If the water is obligated, then the water is obligated to go out with every Na, K, and
Cl (concentrated urea). Basically 20 mls of obligated water for every Na, K, Cl (its obligated) via Na/K/2Cl pump. The ADH
hormone absorbs free water b/c the pump generates free water.
Lets say you absorb one Na, how much free water is left behind in the urine? 20 mls; then reabsorbed another K, that is another 20,
so its up to 40; another 2 Cls are reabsorbed which is another 40; therefore, for absorbing one Na, one K, and 2 Cls, you have taken
80 mls of free water from the urine this is free water that is generated; its is this pump that loop diuretics block, which is in the thick
ascending limb of the medullary segment.
B. Lung repair cell is type II pneumocyte (can also repair type I pneumocytes); it also synthesizes surfactant.
C. CNS repair cell is the astrocyte; the astrocyte proliferates (b/c its a stable cell, not a neuron), that can proliferate and produces
protoplasmic processes called gliosis (rxn to injury in the brain, which is due to astrocyte proliferation); this is
analogous to fibroblasts laying collagen type 3 in the wound.
D. PNS wallarian degeneration is the mech of axonal regeneration
In PNS, have Schwann cells, while in the CNS, have oligodendrocytes
(both make myelin). Tumor Schwann cell = schwannoma; if it involves CN VIII it is called acoustic neuroma. What genetic dz
that is auto dominant has association? Neurofibromatous.
(Side note: myasthenia gravis tensilon injection will increase Ach in synapses in eyelids, and myasthenic crisis will end)
V. Extra Side notes and Review of Inflammation:
A. ESR putting whole blood into cylinder and see when it settles. The higher the density, or weight, therefore settle pretty
quick and therefore have a increase sedimentation rate. When stuck together and looks like coins = roulouex. When
aggregated together = increased sed rate, which is increased IgG and fibrinogen (includes every acute and chronic inflammation
there is. What causes RBCs to clump IgM, b/c the neg charge normally keeps RBCs from stick to e/o. IgM is a lot bigger;
cold agglutinins are associated with IgM ab, leading to agglutinin. This is why in cold whether, you get Raynauds phenomenon
(lips, nose, ears, toes, fingers turn blue). The IgM ab can cause cold agglutinins, leading to ischemia. Another type of clumping
of IgM are Cryoglobulins Igs congeal in cold weather; IgM abs do the same thing. High assoc of hep C with cryoglobulins.
Mult myleoma = increased esr b/c increased IgG; with waldenstroms, will see increased IgM (Waldenstroms Macroglobemia).
B. Acute appendicitis get CBC, and want to see absolute neutrophilic leukocytosis, meaning that you have an increase of
neutrophils in the peripheral blood; also looking for toxic granulation, and a LEFT SHIFT. Assuming you start from myeloblast on the
left, and eventually form a segmented neutrophil on the right; normally go left to right on maturation; therefore, with a left
shift, its means that we go back to immature neutrophils; the definitions is greater than 10% band neutrophils is considered a
LEFT SHIFT (all the neutrophils are bands); if you have just one metamyelocyte or one myelocyte, its is automatically
considered a LEFT SHIFT. In acute appendicitis, there is an absolute increase in neutrophils, with toxic granulation and a left

shift.
C. Most potent system for killing bugs = O2 dependent myeloperoxidase system;
Myeloperoxidase is located in azurophilic granules, which are lysosomes.
Want a lot of lysosome in an acute inflammatory rxn, b/c therefore there is more myeloperoxidase around for killing bugs this
is what toxic granulation.
Therefore, toxic granulation ensures that there is enough myeloperoxidase to work that potent system to kill bugs (O 2 dep
myeloperoxidase system).

Cell Injury
Post 2: (Dated: Jan 12 - 2009)
Hypoxemia (decrease oxygen partial pressure) is a cause se of hypoxia
Hypoxemia is a cause of hypoxia.
Respiratory acidosis --> Up CO2 --> pO2 ALWAYS (and vice versa)
In case of ARDS and Hyline membrance disease... massive ventilation
defect... 100% cant cure
Hypoxemic patient .... po2 does't increase.... intrapulmanory shunt
increase.
Perfusion defect .... increase in dead space.... treatment ....100%
increases po2
Sarcoidosis or pulmonary edema .... Diffusion deffect.
J receptors acctivated by fluid in lund interstitium irritation ... J reflex
innervated by Tenth Nerve.
Anemia --- normal gas exchange --- Hb low --saturation normal --excertional dyspnea --- excercise intolerance.
CO poisoning --- House fire u get Cyanide poisoning + Co poisoning =
2 bonuses --- saturation dec, cure 100% O2) ---- cyanide n Co inhibits
Cytochrome oxidase.
Cyanosis in Co Poisoning --- decrease in O2 sat --- Red Pigment hides
cyanosis.
MtHb poisoning --- O2 Saturation dec --- chocolate colored blood --Fe3 present not Fe2 (cant carry O2) --- (Question = came from Rocky
Mountain - O2 could't cure ??? what is the reason) --- treatment: IV
methylene blue, Vitamin C.

Sulfa n nitro containing drugs (Oxidizing agents) ---> produce MetHb

---> Hemolytic Anemia in G6Pd deficiency.
MetHbnemia in HIV??? --- Sulfa methoxazole in pneumocystis crini.
Right shift O2 Curve: 2,3BPG Inc, High altitude, Acidosis, Fever.
Left Shift O2 Curve: Co, MetHb, HbF; 2,3 BBG dec, Alkalosis
Cytochrome oxidase delivers electron to O2 --- Inhibited by Co n
Cyanide
Uncoupling Agents (Mitochondrial Membrane permeable protons):
Alcohol, salicylates, dinitrophenol. Compensation of NADH, FAD
producing systems (which produce protons) ---> increase
hyperthermia.
Alcoholics ---> Uncoupling Agent ---> Heatstrokes risk increase
Resp Acidosis --- Hb Normal, O2 Sat dec, Po2 dec
Anemia --- Hb decrease, Saturation Normal, Po2 Normal
Co+ MetHb --- Hb Normal, Saturation dec, Po2 normal
Anaerobic Glycolysis --- all cells can do including. RBC ---> producing
2 ATPs ---> Increase of lactic acidosis ---> acid raised ---> protien
denaturation ---> enzymes denatured as well ---> called coagulation
necrosis.
Therefore Tissue hypoxia ---> Acidosis ---> coagulation necrosis
ultimately
Anaerobic Glycolysis ---> screws all the pumps ---> esp. Na + Water
enter cells ---> cell swell up
No ATP ---> irreversible cell damage ---> Ca AtPase dec --->
Intracellular Ca increase ---> Mitochondrial enzymes activated lead to
Membrane Damage ---> nuclear enzymes leads to pyknosis --->
Phosphilipase damage to cell membrane ---> Pancreatitis.
Cell death: CK, SGOT, ALT, Amylase increase when cell die
Lipofusin ---> when free radical damage ---> wear n tear pigment

---> brown pigment ---> atrophic organs in elderly ---> pigment cant
b digested.
Reperfusion injury is due to O2 Radicals
O2 Radical ---> destroys retina ---> blindness.
O2 Radicals ---> Bronchopulmonary dysplasia (fibrosis)
Iron loves making free radicals ----> cirrhosis, reactive
cardiomyopathy, pancreastic failure ---> Malabsorption n diabetes.
Tylenol (Acetaminophen) ---> produce free radicals ---> #1 cause of
Fulminant hepatitis (around central vein) ---> kidney damage ---->
Treatment : N-Acetyle Cystein (Increases Glutathione)
Superoxide dismutase neutralize superoxide ---> producing peroxide
Pentose phosphate shunt makes Glutathione and NADPH
CCl4 converted in to CCL3 ---> fulminant hepatitis
Acetaminophin (Tylenol) + Aspirin ---> damage kidney (renal medulla)
----> PG dec
Apoptosis ---> genes involved in prog cell death ---> (eg. embryo)
King of our body ---> Y chromosome ---> Mullerian inhibitory factors
---> erase mullerian str ---> caspases wipe them ---> Apoptosis --->
producing lipofusin
Cell Injury
Post 3: (Dated: Jan 13 - 2009)
In women ---> X chromosome ---> wolfian duct structures are
removed by apoptosis
Anterior mediastenum is smaller in adults as compare to children (Due
to thymus) ---> apoptosis in adults
Digeorge syndrome ---> Thymus absent ---> cause tetany
Apoptosis occurs in cancer cells

Apoptotis occurs in neuron cells ---> dec in brain mass ---> pyknotic
bodies.
Caspases involves in Apoptosis
Coagulation necrosis ---> Pale infarct - Heart, kidney, spleen, liver
Hemorrhagic infart: Bowel, testicle (torsion), lungs
Its depends on consistency of tissue whether it goes to coagulation or
hemorrhagic necrosis.
Left side of heart ---> most of the emboli arises
vegetation of acute rheumatic fever rarely embolize ---> Infective
endocarditis does
Clots of emboli or vegetation goes to spleen causing pale infarction
The arrhythmia mostly associated with systemic emboli is atrial
fibrillation ---> pieces of emboli travels out and stuck in vessels
Dry gangrene: no pus ---> Diabetics
Most common cause of non traumatic amputation is diabetes ("ATH of
popliteal artery)
Popliteal artery a most dangerous artery.
Most common cause of bowel infarction: #1: adhesions of previous
surgery, #2: piece of small bowel trapped in an Indirect inguinal hernia
in a sac.
Lung: Hemorhagic infarction ---> wedge shape ---> effusion present
--> neutrophils present ---> plueretic chest pain
Liquefactive necrosis (liquefy) is related to an infection - neutrophils
present - cyctic necrosis - acute inflamation related to neutrophils damaging the tissues.
Gram + = strep auerues ---> abcess ---> cellulitis ---> infetion
spreads thru tissues ---> liquefactive necrosis

Granulomatos necrosis ---> caseous ---> mycobacteria or systemic

fungal infection caseous ---> lipid in cell wall giving cheasy appearance
Non caseous ---> Sarcoidosis
Epigastic distress with pain radiating to back ---> pancreatitis
(retroperitoneal) ---> Enzymatic fat necrosis
Pendulous breast ---> Traumatic Fat Necrosis ---> Calcification --->
painful (not in cancer) ---> Xray looks like cancer ---> Calcium bound
to fatty acid = saponification
Bluish discoloration ---> due to calcium ---> dystrophic calcification
Blue discloration with athromatous plaque = calcium
Lipase specific for pancrease
Alcoholics --> pancrease big time damage
Fibrinoid necrosis ---> immunologic disease (Rheumatoid fever, RA,
glomerulonephritis, SLE, Vasculitis)
Palpable purpura ---> small vessel vasculitis ---> type 3
hypersensitivity
Immune complex ---> activates alternative complement system --->
C5a ---> chemotaxis of neutrophils ---> cause actual damage
Sinusoids = charaterstic gaps bw endothelial cells ---> large cells can
pass thru them
Rt heart failure ---> backup of blood ---> nutmeg liver
Area around central vien of liver most susecptible to injury normaly
---> Zone 1
Yellow fever (Arbovirus) damage the liver zone 2 (Mid-zone necrosis)
Common cause of fatty change is alcoholics ---> Lactic acidosis (inc
NADH shift pyruvate to lactate)
Fasting hypoglycemia ---> ketoacidosis (main ketoacid - B
hydroxybutyrate)

Glycolysis provides glycerol 3 phophate, which is the backbone of TAG

which is incorporated into VLDL ---> Restricting the carbohydrates will
reduce the synthesis of VLDL
Kwashiorkar: reduce protien intake ---> VLDL cant go out of the liver
due to dec apo-protiens - huge fatty liver ---> big prutuberant
abdomen ---> no oncotic pressure ---> Ascites

Cell Injury
Post 4: (Dated: Jan 15 - 2009)
You need proteins around lipids to dissolve in water.
Ferritin: soluble form of iron ---> best marker for diagnosis of iron
dificiency anemia or hemosiderosis, hemochromatosis.
Hemosiderin (Insoluble iron storage), Stored in MP and BM, stained
with Prussian Blue Dystrophic calcification: Calcium loves to calcify
damaged tissue, normal serum calcium.... (Fat necrosis, ATH, aortic
stenosis, hemolytic anemia)

Aortic stenosis: two valves doing job of 3 ---> stenosis ---> Dystrophic
calcification
Primary Hyperparathyroidism most common cause of Hypercalcemia
Metastatic calcification: Hypercalcemia or hyperphosphatemia ---> Ca
deposits in normal tissue.
Cong bicuspid aortic valve most common cause of aortic stenosis in
USA ---> 2 valves instead of 3.
If u cant see a central area of Pallor ---> spherocyte
Spectrin: Needed to keep a bi-concave disc, if its defective --->
spherocytosis.
Ubiquitin: A stress protien
Intermediate filaments: framework of the house ---> when damaged
---> ubiquitin ubiquinate them
A liver with spaces in it ---> fatty liver
Ubiquination: Mallory bodies = alocoholics ---> fatty change
Silver stain Neurofibillary tangles = Alzheimer, Creutzfeld-Jakov
disease.
Tau protein associated with Neurofibillary tangles
Parkinsons: lewy bodies in substantia nigra - dompamine decreased
Cell cycle: Labile cell, division via stem cells (BM, Skin, Intestinal
crypts) are in cell cycle ---> most affected by drugs ---> specific or
non-specific drugs - BM supression, diarrhea, rash on skin (due to
presence of stem cells in these tissues).
Stable cells - G0 phase, stimulated to divide (Liver, spleen, Kidney,
Smooth muscle, endometium) - stimulated by hormone or growth
factor.
Permanent cell can not go in to cell cycle ---> can do hypertrophy
only.

Smooth muscle can undergo hypertrophy and hyperplasia as well

The length of the cell cycle is decided by the length of the G1 stage
Proliferative phase can vary the most in menstrual cycle --->
analogous to G1 stage ---> once ovulated it cannot vary
Kinase always means phosphorylation.
Term: Phosphorylate = Activation (Glucagon - activate protien
kinase) ; Dephosphorylate = De-Activator (Insulin - de-activate protien
kinase)
In-active cyclin-D dependant kinase ---> Activated by cyclin-D ---> G1
phase makes cyclin-D
Once Cyclin-D is made in G1 phase it activates Cyclin Dependant
kinase
The key area in cell cycle to control is going from G1 to Gs Phase --->
Most critical period ---> if mutation in G1 phase and went in to Gs
phase ---> cancer potential
Security check point ---> before going into S phase ---> RB (Ch13)
suppressor gene prevents the cell from going into S phase
When phosphorylated by CDK its inactive
P53 #1 for human cancer (Guardian of the cell ---> gives time to cell
to correct errors ---> if severe DNA damage ---> apoptosis)
HPV- inactivates Rb n P53 gene (either One of the gene gets mutated
---> cell goes from G1 to S phase)
If no Rb protein ---> Retinoblastoma, osteogenic sarcoma, breast
cancer.
Codmans triangle seen in: osteosarcoma, Ewing sarcoma,
subperiosteal abscess.
Vinca Alkaloids works on mitotic spindles(made from periwinkle plant);
Paclitaxel on M Phase (chemotherapy,yew tree); Colchicine (use in
acute gouty arthritis), Griseofulvin ---> M phase
Etoposide ---> G2 phase

MTX, Bleomycin ---> S phase

MTX, used in rheumatoid arthritis, inhibits DHF reductase ---> can
Cause macrocytic anemia.
Atrophy = decrease in tissue mass, decrease cell size, less
mitochondria --- does't have enuff organeles to survive.
Hydronephrosis is mostly caused by renal stones ---> increase
pressure in cortex n medulla---> ischemia ---> atrophy of renal
tubules.
ATH, Alzheimer (B amyloid protein, in layers 3,5,6 destroyed), ALS
---> brain atrophy, neuron degeneration ---> reduction in mass of
brain
Casts --> decrease in muscle mass.
Hypopituitarism ---> adrenal gland atrophy (zona reticularis and
fasiculata ONLY)
ACTH responsible for glucocorticoid (Z. Fasciculata), and sex hormones
(Z. Reticularis); Not aldosterone (zona glumerulosa)
Oral thyroid ---> Natural thyroid goes down ---> thyroid atrophy.
Cystic Fibrosis (defective cystic fibrosis transmembrane regulator at
Chr.7) ---> problems with secretions of exocrine part ---> block lumen
---> pancreas atrophy
Atheromatous plaque in renal vessel --->Renal vascular hypertension
---> Renin high ---> diseased kidney get atrophied, other kidney
hypertrophy.
If you block G2 phase, you have 4n chromosomes (no mitosis) --->
increase in size of cell ---> copies of structures inside cells
1n - sperm
2n - Diploid cell
3n - Cancer cell or some trisomy disease
Hyperplasia left unchecked is predisposing for cancer (EXCEPT

prostate)
Unopposed estrogen (no progesterone) cause endometrial hyperplasia
---> atypical hyperplasia ---> endometrial cancer.
Prostate hyperplasia does not predispose to cancer.

Cell Injury
Post 5: (Dated: Jan 16 - 2009)
Gravid uterus (after delivery): 50% hypertrophy, 50% hyperplasia --->
of smooth muscles.
Normal 3 times many WBC than RBC
RBC hyperplasia in BoneMarrow may be caused by COPD --->
hypoxemia ---> raised Epo
Erythropoetin is made in the endothelial cells of the peri-tubular

capillaries
Psoriasis: Silvery Scales is an unregulated proliferation of squamous
cells in the skin (hyperplasia).
Treatment: MTX (works on the basal cells from proliferating).
All hormone stimulated glands go through hyperplasia, not
hypertrophy.
Urinary bladder goes through hypertrophy of smooth muscle cells
related to afterload caused by urethra narrowing due prostate
hyperplasia.
Barrets esophagus(Metaplasia) = glandular cells, mucus secreting,
goblets cells instead of squamous cells ---> precursor of adeno.ca
Mid esophageal Ca ---> most common Ca in USA
Lining of main stem bronchus ---> psuedost. columnar ---> smoker
---> undergo sq metaplasia
Inc Goblet cells in main stem bronchus ---> hyperplasia
Also smookers have goblet cells in terminal bronchioles --->
metaplasia (normally no goblet cells in this place)
If goblet cells in stomach = abnormal ---> should be present in
s.intestine ---> glandular metaplasia ---> precursor for
adenocarcinoma of stomach
H. Pylori is the most common cause of adenocarcinoma of the stomach
---> produce damage to the pylorus and antral mucosa ---> chronic
atrophic gastritis with intestinal glandular metaplasia ---> precursor
lession for adenocarcinoma
Lung: Cilliated columnar epithelium ---> sq metaplasia ---> sp
dysplasia ---> Cancer Sq Carcinoma
Distal Esophagus: Sq ---> glandular epithelium, mucus secreting --->
defense against acid injury ---> may go into atypical metaplasia --->
adenocarcinoma
Clonorchissinensis (Chinese liver fluke) is associated with cholangio
carcinoma Schistosome Haematubium causes squamus metaplasia

(instead of transitional) in the urinary bladder --->SCC.

Dysplasia = atypical hyperplasia, precursor for cancer.
Actinic (solar) keratosis premalignant to SCC of the skin, related to
chronic sun exposure (UV light) and excess keratin. If scraped off, it
grows back.
No premalignant lesion to basal cell cacinoma. It is more common.
---------------------------------------- END Cell Injury
--------------------------------------------Inflammation
Post 6: (Dated: Jan 16 - 2009)
Histamine is responsible for the rubor, calor (both: vasodilatation on
arterioles) and
tumor ("permeability on venioles) of acute inflammation.
Bradykanin: part of kininogen system which is between Hageman
factor 12 and 11; when u activate intrinsis pathway u automatically
activates the kininogen system ---> end product bradykinin.
Angioadema ---> complication of ACE inhibitor ---> inhibits
metablolism of bradykinin which increases vesel permeability and
producing angioedema , swelling of tissues.
Bradykinin also produces cough ---> mechanism unknown.
Bradykinin degraded by ACE
ACE and PGE2 are responsible for the dolor.
Neutrophils in small vessels gets sticky because of adhesion molecules
synthesis ---> neutrophils stick to endothelial cells (pavementing or
margination) ---> type 4 collegenase ---> drill hole in BM.
Cancer cells also contain Type4 Collegenase like neutrophils---> stick
to endothelial cells through adhesion molecules usually against laminin
in BM ---> pass through the BM by using collegenase ---> Get out of
the vessels dont know the directions because of no chemotaxis
C5A, LTB4 ---> Involves in chemotaxis and make adhesion molecules
in neutrophils.

IgG, C3B ---> opsonization recognized by Neutrophils, monocytes and

macrophages.
Hypogammaglobulinemia: sex linked disease ---> Infections due to
lack of opsonization.
Neutrophils must have receptors for IgG and C3b like monocyte
machrophages.
Neutrophils for acute inflamation; for chronic monocytes and
machrophages.
Monocytes: When get tired becomes machrophages
I-cell disease (lysosomal storage disease): cant add mannose 6
phosphate residues to lysosomal enzymes ---> no proper trafficking
---> empty lysosomes.
Inflammation
Post 7: (Dated: Jan 17 - 2009)
Chlamydia can come out of phagolysosome
C3A, C5A ---> anaphylatoxins (stimulate mast cells to release
histstamine)
Oxygen dependant myeloperoxidase system: O2 is converted by
NADPH oxidase in cell membrane of neutrophils + monocytes (not
Macrophages ---> they loose this system).
NADPH: Synthesized in P.P shunt ---> G6Pd converts G6P in to 6phosphogluconate --> you get NADPH, Glutathione (Neutralizing factor
for free radical).
NADPH converts molecular O2 into superoxide (free radical - having
unpaired electron in its outer orbit), that gives off energy -->
respiratory burst ---> Can be measured by radiation detector or NBT
dye test: if working ok ---> bluish color, if not ---> chronic
granulomatous disease of childhood (X-linked, no NADPH oxidase).
Superoxide is converted to peroxide which together with chloride
(catalyzed by myeloperoxidase) to form bleach (kills bacteria)

Microglial cells are the Macrophages of the CNS ---> reservoirs of CNS
Aids ???
Reservoir of Aids outside CNS are dendritic cells (Macrophages outside
CNS) are re located in lymph nodes.
G6Pd deficiency: Infection prrecipitates hemolysis ---> No NADPH --->
No Functioning O2- dependant Myeloperoxidase system --->
susceptible to infections ---> hemolysis
All females of male dominant disease ---> a-symptomatic carriers of
disease ---> transmit disease to 50% of sons.
CGD of childhood ---> X-linked recessive ---> boy gets from Mom
CGD: NADPH oxidase missing ---> no color in NBT dye test --->
lacking respiratory burst
Superoxide --> No
Peroxide ---> No
Myeloperoxidase ---> yes
Chloride ---> Yes
All living organisms make Peroxide including all bacterias
Not all bacterias contain catalase.
In CGD patients: They cannot kill staph; They can kill strep
Catalase + Coagulase positive (Staph. Aureus) breaks down peroxide
and prevent its utilization in CGD.
Strep doesnt have catalase, so it can be killed even in CGD patient.
In Myeloperoxide deficiency (AR),
Respiratory burst = Yes
Peroxide = Yes
Superoxide Free radicle = Yes
Chloride = Yes
Myeloperoxidase = No,
but no bleach ---> cant kill bacteria.
Opsonization defects (eg. Brutons agamaglobulinemia ---> missing
IgG; C3 deficiency).

CGD of childhood (Cant make bleach + absence of repiratory burst )

and Myeloperoxidase deficiency (cant make bleach + autosomal
recessive disorder) are both microbiocidal defects ---> cant kill
bacteria.
Adhesion/B integrin defect ---> impaired adhesion, phagocytosis --->
umbilical cord doesnt fall off (removed surgically), no neutrophils
lining the small vessels.
Histamine: King of chemical mediators of acute inflamation --->
atrioles: vessodilate ---> Venules: increase vessel permeability.
Serotinin (made by tryphan) ---> a neurotransmitter ---> deficiency
---> depression
Anphylotoxins: C3A and C5a ---> stimulates mast cells to release
histamine ---> vesodilation and increase vessels permeability.
In shock: if you activate complement system ---> anaphylotxins will
be there.
NO: mainly made in endothelial cells ---> potent vesodilator ---> used
in treatment of pulmonary hypertension; big role in septic shock.
IL-1 (pyrogen)---> stimulate hypothalamus to produce PG --->
stimulate thermoregulatory centre to produce fever (reduced by
aspirin ---> inhibits PG).
Corticosteroids (supreme anti-inflamatory agent) inhibit PLA2 ---> no
release of retinoic acid from PL ---> no PG, IL.
Omega-6 ??? fatty acids that can make arachidonic acid (linoleic acid)
in Wallnuts and tissue oils ???: acts like aspirin ---> blocks platelet
aggregation.
Omega 3 (like aspirin) inhibits platelet aggregation ---> protects
heart.
Inflammation
Post 8: (Dated: Jan 18 - 2009)
Zileuton blocks 5-Lipoxygenase.

LTC4, -D4, E4: the slow reacting substance of bronchial asthma --->
potent broncho-constrictors
Zileuton works great in asthma ---> blocks all Leukotrienes --->
including LTB4 (adhesion molecules and chemotaxis)
Aspirin blocks cycloxygenase irreversibly if we are talking about
platelet
TXA2 made in platelets ---> vasoconstrictor, brochconstrictor, platelet
aggregation.
PGI2 made in endothelial cells ---> vasodilator, inhibits platelet
aggregation.
PGE2 ---> vasodilator in kidney, keeps the fetus's patent ductus
patent, mucus barrier in stomach, primary dysmenorrhea, increase
uterine contractility (abortificant to express fetal material).
Dipyridamole inhibits TX synthase, used in stress test in coronary
artery disease.
Coticosteroids: Anti-inflamatory agent ---> block phospholipase A2;
decrease adhesion molecules synthesis along with other steroids like
Epi and N.Epi
White person: 50% of neutrophils already stuck to endothelium of
small vessels; 50%circulate.
Decrease in adhesion molecules synthesis ---> remaining 50% stuck
---> start to circulate ---> Neutrophils count increase in CBC.
Corticosteroids: Stimulate caspases of B-Cells ---> Apoptosis;
Eosinophils decreased; Only neutrophils increase ---> decrease
adhesion molecules.
Addison's disease: Decrease cortisol ---> Neutrophils count decrease;
Eosinophil count increase.
MI: Epinephrine ---> decreases adhesion molecules ---> Raised
adhesion molecules in CBC
Alveolar MP have a lot of lysosomes which are seen as black dots on

EM.
Lamellar bodies (where lechitin is located) are seen in pneumocyte
type 2.
Monocyte grayish cytoplasm, single nucleus, garbage in cytoplasm, on
Em.
Vitamin E neutralizes oxidized LDL
EM: All nucleus with very little cytoplasm = Lymphocyte
T-lymphocytes Vs B-lymphocytes: 60% T-lymphocytes in peripheral
blood
60% of lymphocytes are Th:Tc ratio is 2:1.
Slide: Thumb print ---> RER --> Ribosomes --> immonuglobullins --->
Plasma cells (M.Myeloma)
Plasma cell has a lot of ribosomes, because of Ig production. It is
located in germinal follicle.
Basophils: Granules ---> more purplish and darker
Eosinophils: Granules of color same as RBC
Eosinophils have crystals in their cytoplasm. In asthma: degenerating
eosinophils form Charcot-Leyden crystals seen in sputum.
Major basic proteins are released by eosinophils in type 2
HyperSensitivity to kill helminths.
Shisto ???: Eggs coated by IgE antibodies ---> Eosinophils have
receptors for IgE antibodies --->release chemicals ---> MBP Kill
helminths
T-2 Hypersensitivity: Cell hooking in to antibody on a target cell
(Eosinophils = effector cells).
T-1 Hypersensitivity: Mast cells = effector cells
Mast cells release histamine and eosinophil chemotactic factor in type
1 H-S.(from purple granules) ---> Eosinophils here release

histaminase and leukotriene neutralizing agents.

Eosinophils: T1 hypersensitivity = Knock off mediators producing
hypersensitivity; T2 hypersensitivity = kills helminths.
Inflammation
Post 9: (Dated: Jan 20 - 2009)
CD3 = marker in antigen recognition site for all T cells
CD1 = antigen marker for histiocyte including langerhan cells.
CD10 = CALLA antigen (common ALL antigen), common marker of
leukemia in children
CD15, 30 = Reed Sternberg
CD21 = B cell, EBV hooks on it
CD45 = all leukocytes
Burkits lymphoma is a B cell lymphoma
IL1 responsible for fever most of the time.
Fever right shifts O2 dissociation curve
During fever lots of O2 is needed in inflamation for O2 dependant
myeloperoxidase system.
Antipyretics reduce the oxygen in neutrophils (disturbs O2 dep.
myeloperoxidase system)
Fever is not good for viral and bacterial reproduction.(at 103 - 104 F)
Pus coming out of lactiferous duct in post partum ---> Staph. Aureus.
Osteomyelitis ( yellowish absscess) ---> Staph. Aureus. In Sickle cell
anemia, it is usually cause by Salmonella Typhimurium
--->Hematogenous spread.
Hot ---> spread all over the face ---> Cellulitis ---> Strep. Pyogens
C. dyphteria toxin damages the sub/mucosa ---> psedomembrane
(like ke C. difficile); gram + rod ; exotoxin disturbs riboxylation of
proteins (elongation factor II) ---> damages the mucosa + submucosa
producing a pseudomembrane; does't invades but produces the toxin
that damages the membranes; Endotoxin is for diagnosis in stool.
Bread and butter pericarditis = fibrinous inflammation ---> Usually due

to increase vessel permeability ---> SLE, MI, coxsackie

Dresslers syndrome: pericarditis which develops about 6 weeks after
an MI or heart surgery.
Most common organism causing infection in 3rd degree burn is
Pseudomonas Aeruginosa. Pus color is green due to pyocyanin.
The basal cell layer on both sides of the cut proliferate and go
underneath the clot and seal it; not over the clot.
Appendicectomy: by 48 hours the wound is sealed off because of basal
cells.
The key for the healing of the wound is presence of granulation tissue
+ fibronectin.
Fibronectin is an adhesion molecule and fibroblast chemotactic in
healing process.
Granulation tissue starts at day 3, peak on day 5.
No granulation tissue ---> no healing of wound
Type 4 collagen in basement membrane.
Type 1 collagen is in bone, skin, tendons and ligaments
Typ 3 collagen is in the initial stages of wound repair. Broke by type 3
collagenase.
Metallo enzyme (need zinc) helps turn type 3 into type 1
Maximal tensile strength in a wound by 3 months is 80%.
Most common cause of poor wound healing is infection.
Ehlers danlos syndrome: defect in collagen.
Marfan syndrome: defect in fibriLlin.
Scurvy: defect in hydroxylation of proline and lysine by ascorbic acid ;
Normally triple helix stick together and forms tensile strength by cross
bridges ---> cross bridges anchors into places where hydroxylated
proline and lysine ; No cross bridges ---> cannott attach to anything
---> weak abnormal collagen ---> hemorrhage, no wound healing,

hemoarthrosis.
Keloid: (hypertrophied scar) = excess of type 3 collagen deposition ;
genetic predisposition in blacks.
SCC is common in the setting of scars related to 3rd degree burns or
chronically draining sinus tract (in osteomyelitis).
IgM is the most potent activator of the complement system, because it
has 10 antigen recognition sites (pentamer). Main Ig of Acute
inflammation.
IgG complement activation doesnt go beyond C3 (no C5a and so on).
Main Ig of chronic inflammation. C5a is very important chemotactic
factor.
After 10 days to 2 weeks there is a isotype switching: Same plasma
cell making IgM ---> splice out the "Mu"-Heavy chain (Heavy chain
that defines specificities of an Ig) and it splices in a gamma heavy
chain.
Inflammation
Post 10: (Dated: Jan 21 - 2009)
Acute Allergic reactions: Key cell eosinophil, Mast cell is in tissues.
Viral infection: Key cell Lymphocytes
Chronic inflammation: Key cells Monocytes, macrophages, raised
plasma cells, raised lymphocytes.
Pus is not a characteristic of chronic (only of acute) inflammation:
Increased vessels permeability ---> neutrophils immigration in
interstitial tissue ---> protein rich fluid (exudate: 3gm protein/dl ), cell
rich fluid(exudate) called PUS ---> produces tumor in acute
inflammation.
Granuloma: roundish and pink, multinucleated giant cells. Type 4 H-S.
Sometimes gets calcified. Epitheloid cells are activated MP, when they
die they form multinucleated giant cells which are seen in granulomas.
Killing neoplastic cells or virally infected cells is also Type 4 H-S (no

antibodies)
Poison ivy: Type 4 H-s
MP and TH CD4 are the key cells of TB.
Key actors in delayed reaction H-S ---> Macrophage processes
antigens ---> presents antigen to Th cels ---> Th cells releases
cytokines ---> Gamma interferon and MP inhibitory factor (involved in
granuloma) ---> activates the MP to kill TB, cryptoccocus, Histoplasma
etc.
Subset1 Th cells ---> Type 4 H-S
MP release IL-12 ---> activates and presents antigens to subset1 Th
cells ---> turns into subset1 Cd4 Th cells (memmory T cells of the
event)
Marker of all histiocytes and MP have ---> cluster designation 1 ???
Langerhans cells (EM: birbeck granules looks likes tennis rackets) are
the MP of the skin, phagocytose PPD, proceses it and present it to Th
type 1 that has memory of previous exposure ---> release cytokines
that produce the inflammatory reaction which is part of the positive
PPD.
Old people usually don't have Type4 H-S. they have lesser than brisk
response to PPD. Some times they need double type of PPD, because
of decreased immune response.
HIV: less/no type 4 H-S (Th dec.), no granuloma formation in HIV ; No
Th cells.
PPD of 5 mm induration is enough to say positive in HIV ---> that
would be pretty good immune response.
Reaction to injury in permanent tissues ---> scar tissue (no
contraction)
Scar tissue: heart muscle, kidney (especially straight portion of PT,
TAL)
Damage to free wall of left ventricle ---> fibrous tissues does't contract

---> EF goes down

Kidney Medulla most susceptible to ischemia.
Most susceptible to ishemia of kidney Nephron: 1) straight portion of
proximal tubule (most of oxidative metabolism located, most of the
reabsorption of Na and HCO3) ; (2) Medullary segment of the thick
ascending limb (Na-K-Cl pump located)
Na-K-Cl pump generates free water (80ml for those 4 ions). Blocked
by lasix (Loop diuretic)

Inflammation
Post 11: (Dated: Jan 22 - 2009)
Urine have to kinds of water:
Obligated water: Obligated to go out with every Na, Cl, K ---> 20ml of
water has to go out
Free water: ADH causes Na-K-Cl pump to produce free water
Obligated water: 1 Na reabsorbtion = 20ml + 1 K reabsorbtion = 20ml
+ 2 Cl reabsorbtion = 40ml ---> 80ml of water ; Na-K-Cl pump
Blocked by lasix (Loop diuretic)
Type 2 pneumocytes: 1) Produce surfactant, 2) Repair cells, even
replace type 1.
Astrocytes: can proliferate (stable cell), cause gliosis = increase in
protoplasmic processes (reaction to injury in the brain) ---> analogous
to fibroblast laying down type-3 collagen in wound.
Walerian degeneration: When a big nerve cut into half ---> Schwann
cells myelinate PNS axons.
Oligodendrocytes myelinate CNS axons.
Schwannoma = acoustic neuroma (if involves VIII nerve), seen in
neurofibromatosis (autosomal dominant)
IgG and/or fibrinogen increased ---> ESR Increased (acute and chronic
inflammation)

Negative charge normally keeps RBC away from sticking to each other
together ; IgM, cryoglobulin cause RBC to stick (cold agglutination
---> Raynauds phenomenon).
Raynauds phenomenon: Cold weather ---> nose, tips of finger, ears
turns blue ; warm ---> pink
IgM antibodies produce cold agglutinins causing RBC to agglutinate
---> ishemia ; Blood Warms up ---> IgM cannot work they fell apart.
High association of Hep.C with cryoglobulin.
IgG ---> Multiple Myeloma most common
IgM ---> waldenstrom macroglobulinemia most common
IgG and IgM both increases ESR.
Greater than 10% band neutrophils is left shift.
Acute inflammation: absolute increase in neutrophils, toxic granulation
(azurophilic granules), left shift.
Left shift: assuming myeloblast on the left ---> series of divisions --->
forms segmented neutrophils on the right ; We normally go from left
to right in maturation ; by defination greater than 10% dense ???
neutrophils considered as left shift ; Even presence of 1 myelocyte or 1
metamyelocyte ---> consider it as left shift.
Azurophilic granules: Red granules, lysozomes, increased in acute
inflammation ---> we have more myeloperoxidase to kill bugs (Toxic
granulation).
--------------- The End Inflammation ---------Fluid and hemodynamics
Post 12: (Dated: Jan 22 - 2009) 5 (min30)
Edema: Excess fluid in interstitial fluid (extracellular space)
Non pitting edema: exudate (increase vessel permeability with pus) >
3g/dl protein
Pitting edema: transudate (right heart failure) < 3g/dl protein

Lymphatic fluid: initially pitting, later not.

80% of oncotic pressure is related to serum albumin concentration.
Hypoalbuminemia: leaking of transudate (a protein poor <3 gm/ dl),
cell poor fluid, probably leaks through capilaries and venules in to
interstitial space ---> pitting edema
Hydrostatic pressure: Pushes fluid out of vessels
Normally Oncotic pressure > Hydrostatic pressure
Transudate: Oncotic pressure < Hydrostatic pressure
Low albumin: nephrotic syndrome, malabsorption, cirrhosis, decrease
protein intake (kwashiorkor), 3rd degree burn (ooze out plasma).
Fluid and Hemodynamics
Post 13: (Dated: Jan 24 - 2009)
Thinking about food: Alkaline tide ---> every H2 going into stomach to
make HCL while thinking about food ---> Vagus nerve directly
stimulate parietal cells and G-cells ---> Every H2 combines with
chloride in stomach ---> increase of HCO3 ---> Little bit of Metabolic
Alkalosis ; In gastric phase of digestion ---> H-ions in food reasorbed
and reunite with HCO3 ---> No longer metabolic alkalosis ; Metabolic
alkalosis compensated by respiratory acidosis ---> Po2 goes down --->
O2 curve left shifted ---> PO2 decreased ---> tissue hypoxia --->
Feels Tired ; While sitting still ---> Nutrients used for storage in
different tissues by way of insulin.
A person died 24 hr ago due to MI: fluid comes out of lung
(transudate) ---> increase hydrostatic pressure ---> left heart failure;
As CO decrease, EDV and pressure on left ventricle increases --->
pressure transmitted back in left atrium, pulmonary vein (normally:
8mmHg Hydrostatic pressure and 25 mmHg Oncotic pressure ; 25-8 =
17mmHg) ---> Hydrostatic pressure keeps on going up ---> backs up
of blood in the lung ---> eventually approaches the oncotic pressure
---> Leaking of transudate into the interstitial space ---> activates Jreceptors --->Dyspnea, Kerleys lines (in Xray) ---> fluid in intertitium
goes into alveoli ---> Pulmonary edema.
Bee Sting: Face swelled up due to Exudate ---> Anaphylactic reaction
---> Histamine main player ---> Type 1 H-S ---> Increase vessel

permeability ---> tissue swelling ; Rx: Airway, and aqueous

epinephrine 1:1000 by subcutaneous.
Kerley B lines: usually indicative of interstitial pulmonary edema
(CHF), clinically
present as dyspnea.
Kerley A lines: caused by distension of anastomotic channels between
peripheral and central lymphatics of the lungs (less frequent than B)
Cirrhosis ---> decrease oncotic prssure (decrease albumin synthesis)
+ increase hydrostatic pressure (portal hypertension) ---> ascites.
Pitting edema in the legs can be caused by decreased oncotic pressure
(cirrhosis) or increase in hydrostatic pressure (RHF).
Lymphedema: post radical mastectomy (# 1 cause in USA),
Wuchereria Bancrofti (3rd world countries) and parasitic worms that
damages lymphatics, in lymphogranuloma venerum
(ChlamydiaTrachomatis) there is a tendency of scar tissues in
lymphatics produces lymph edema of scrotum and vulva.
Lymph edema in inflammatory carcinoma of the breast: peu de orange
appearance ---> section of breast --->dermal lymphatic plugged with
tumor ---> lymphatic fluid leaks out in to the intertitium --->
ligaments holding the skin due to excess of fuild produces dimpling like
the surface of orange.
Lymphangiosarcoma is a complication of chronic lymphedema; pt holds
her arm upon her hand, it probably weighs about 50pds due to excess
fluid.
Fluid and Hemodynamics
Post 14: (Dated: Jan 25 - 2009)
ECF: 2 compartment
ICF: 2/3 larger than ECF
How many Litres of isotonic saline u have to infuse in a pt to get 1 lit
in plasma ?
Answer: 3 lit ---> 2 lit will end up in interstitial space and 1 lit end up
in vascular compartment.
In order to keep up the BP ---> Isotonic saline is given which is
equilibrating with the interstitial compartment.

Osmolality is mainly determined by Na (doubled, one for Cl), glucose

and BUN.
Osmolality: Measure of solutes in a fluid.
Normal person Na+ is responsible for plasma osmolality.
Na and glucose are limited to ECF
Urea can equilibriated b/w ECF and ICF when increased ---> equal
amount on both sides.
Since Na and glucose are limited to the ECF ---> changing in there
concentrations ---> movement of H2O from Low to high (Osmosis).
Lungs: 100mmHg O2 in alveoli; 40 mmHg Po2 returning from tissue;
according to the law diffusion O2 dissolves in plasma (up to 95 mmHg
O2)
Diffusion: high ---> low, osmosis: low ---> high.
Hyponatremia ---> osmosis (ICF) ---> brain edema ---> mental status
abnormality
Hypernatremia ---> osmosis (ECF) ---> brain contract ---> mental
status abnormality
Fluid and Hemodynamics
Post 15: (Dated: Jan 27 - 2009)
DK: e.g 1000 mg/dl of sugar ; King of osmosis ---> Na and glucose
are limited to ECF compartment.
Glycolysis: Glucose always goes inside the cell with phosphorus; all
sugars get phosphorylated to trap ---> glucose converted into G6Phosphate and immediately metabolised; Same with Fructose and
galactose ---> F1-Phosphate and Gal1-Phosphate respectively
--->metabolized immediately.
So there is no glucose, fructose or galactose intracellarly ---> it gets
metabolised rapidly
Hyperglycemia ---> osmosis from ICF to ECF ---> Na gets decreased
(dilutional hyponatremia)

Urea is permeable so it can go through the compartments to establish

equilibrium.
Serum Na is reflection of total body Na divided by total body water.
Increase in serum Na can lead to Hypernatremia or by loosing water
Na increases in serum as well.
Isotonic loss of fluid (EC loss, no osmotic gradient): hemorrhage, adult
diarrhea.
Isotonic gain of fluid (EC gain, no osmotic gradient): isotonic saline.
Hypertonic loss of fluid (ECF ---> ICF because of hyponatremia):
diuretics.
Hypotonic loss of fluid: sweat, baby diarrhea (you give back hypotonic
solution).
Hypotonic gain of fluid (EC ECF+ICF expanded): SIADH (treatment:
restrict water).
ADH: Concentrating urine ---> by taking out free water.
ADH absent: loss of free water ---> diluting the urine
SIADH: Free water stays in ECF ----> by osmosis moves into ICF
Serum Na < 120mmol ---> ALWAYS SIADH (at least on boards)
1st generation oral sulphonylureas (chlorpropamide; insulin
secretagogues for DM-II):
SIADH as a side effect in 30% of cases.
Pitting edema (RHF, cirrhosis): gain of both Na and water (but more
water) by kidney.
Rx: will be both Na and water restriction, diuretics.
Total body Na when ever increased ---> always produce pitting
edema ; Most of Na is in interstitial compartment ---> when Na
increase ---> transudate ---> pitting edema.
Glucose or Mannitol in urine ---> hypertonic loss in the urine.
Glucose has to be in the solution with Na, because of the gut Na-Glc
transporter.

Normal saline (0.9%) is plasma without the proteins, it stays in the

ECF.
Baby diarrhea: Hypertonic salt solution; Rota virus infection, baby has
no access to water ---> Na increase ---> more water lost; Rx:
Pedialyte or gatorade ---> hypotonic salt solutions
If you loose hypotonic salt solution ---> replace with hypotonic
solution
Adult Diarhea: Isotonic salt solution loss
Pedialyte & Gatorade (got to have Co-Transport): Reabsorbs Na in GIT
---> Na has to be reabsorbed with Glucose or galatose (Fructose
does't facilitates diffusion).
Cholera: Oral replacement ---> Glucose should be there to be
reabsorbed with Na through Co-transport mechanism
Gatorade ingredients: Fructose + Glucose (for Na reabsorbtion) +
Sucrose (converted in to Glucose and fructose).
Fluid and Hemodynamics
Post 16: (Dated: Jan 28 - 2009)
If any replacement does't have Glucose its worthless.
Hot day in marathon race: in the end there will Hypernatremia.
Effective Arterial blood volume : same thing as Stroke Volume and
Cardiac Output
When C-output decrease ---> all physiologic mechanisms happens in
body to restore volume ---> most serious condition ---> hypovolumia
---> no oxygenated blood to the tissues.
Baroreceptors: Low pressure BReceptors on venous side ; High
pressure BReceptors on arterial like carotid and arch of aorta
(innervated by 9th and 10th nerve).
Decrease in arterial blood volume ---> underfilling of carotid and aorta
---> instead of 9th or 10th nerve response ---> sympathetic nerve
response (catacholamines released) ---> Only one catacholamine
responsible when SV is decreased ---> Venous constriction --->

increased blood to Right heart (We don't want veno-dilation ---> pool
in legs), ---> Increase in force of contraction due to action on BAdrenergic receptors ---> SV increased little bit + increases the heart
rate; Arterioles on the systemic side ---> B-receptors of smooth
muscles gets stimulated.
Diastolic pressure due to amount of blood in arterial system while
heart is filling up in diastole; Peripheral resistance arterioles controls
the amount that is the arterial system ---> maintains the diastolic
pressure; When arterioles constricted ---> very little blood going into
tissues (Compromised) but instead diastolic pressure is up ---> Its
good because coronary arteries get blood by this; All done by
catacholamines ---> stimulates the renin angiotensin aldosterone
system ---> renin ---> angiotensin 2 ---> vasoconstrictor of peripheral
resistance arterioles (helping along the catacholamines); Angiotensin 2
---> stimulates of 18-hydroxylase ---> converts corticosterone in to
aldosterone ---> reabsorbs salt and water ---> raised CO.
SV decreased ---> blood flow to kidney decreased ---> activation of
renin-angiotensin aldosterone system ---> receptors located into JGApparatus in afferent arterioles, have sensors (modified smooth
muscles that sense blood flow); ADH will be released ---> increase in
pure water.
Normal saline (0.9%) is plasma without the proteins, it stays in the
ECF.
CO decreased ---> renal blood flow decreased ---> peritubular
hydrostatic pressure decreases ---> peritubular oncotic pressure
increased ---> reabsorption increased (isotonic solution); Any type of
shock same type of mechanisms.
The tonacity of fluid reabsorbed from proximal tubules ---> roughly
isotonic; ADH contributes pure water ---> adds 2 lit in to ECF; Tonacity
becomes ---> little bit hypotonic; This mechanism normally happens,
kidney reabsorbs when ever there is decrease in CO.
SV and arterial Volume increased: Absolute reverse of above
mechanism; The baroreceptors going to be stretched (innervated by
9th and 10th nerve) ---> parasympathetic system ---> fluid overload
---> ADH or renin-angiotensin aldosterone not activated; Peritubular
hydrostaticpressure is increased in cappilaries ---> even if salt is
reabsorbed ---> it does't get in to blood stream instead it comes out in

urine; So there is loss of hypotonic fluid whenever there is a increase

in arterial blood volume.
Fluid and Hemodynamics
Post 17: (Dated: Jan 30 - 2009)
Decrease in CO: ANP is made in right or left atrium, released on
dilatation of R or L atrium ---> Cuts all ADH + its a naturally uretic
(gets rid of salts); ANP is released in only volume overloaded states
not in hypovolumic conditions.
Dry tongue (dehydration) ---> hyponatremia, skin indentations --->
hypernatremia Normal skin turgor ---> normal Na concentrations
(except in elderly)
When you pinch the skin ---> it goes up and goes down fast--->
shows the total body Na is normal.
Dependant pitting edema ---> Total body Na is absolutely increased.
SIADH: If there is a gain of pure water ---> total body Na is normal,
serum Na concentration is low ---> Rx: Restrict water.
R-Heart Failure: If there is a dependant pitting edema ---> Kidney
reabsorbs Hypotonic salt solution (Little bit more water than salt) --->
Serum Na decrease, (Numerator increase - total body Na /
Denominator - greater increase in water).
Non pharmacological Rx of any of the edema states like heart failure or
cirrhosis ---> restrict salt and water: Diuretics help get rid of water
and little bit of salt.
Diabetes Insipidus CANNOT produce shock (only water loss from ICF,
NOT hypovolemic). No dehydration signs (no salt loss). Treatment: 5%
dextrose water
Tilt test: Lying down (no effective gravity) ---> normal BP + pulse, Sat
up (imposing gravity) ---> BP dec, pulse inc (catecholamine release
from BP dec) ---> sign of volume depletion. Rx: normal saline (0.5%
saline after BP stable)
Marathon Race: Loss of hypotonic salt solution ---> collapsed (100/80)
with pulse 120, lying---> tilt test ---> 70/60 with 150 pulse --->
Hypovolumic ---> Rx Normal Saline (1 Lit NS + 1 Lit NS + 0.5% NS)

DKA: Osmotic diuresis ---> hypotonic urine (little bit more H2O than
salt); hypovolemia --->give normal saline (around 6-8 liters until BP
stable); High Glucose means nothing; After initial Rx ---> 0.5% NS +
Insulin.
When ever Hypovolumic ---> 1st Step in mannagement; NS to get BP
normal then decide according to the cause; if Sweating (hypotonic)--> Hypotonic salt solution; Adult Diarrhea (isotonic) ---> NS.
Diabetes Insipidus: Lets say 165 Serum Na, BP stable, pt is lucid --->
Rx: Water; If there is a problem of aspiration ---> 5% (50 gm of
glucose) Dextrose water I/V which is close to pure water
Loss of salt ---> Hypovolemic shock (CO dec, cold skin, TPR inc, MVOC
dec, BP dec, pulse inc, LVEDP dec)
MI ---> cardiogenic shock (everything like hypovolemic except LVEDP
inc)
E. coli (urinary catheter) ---> septic shock (CO inc, warm skin, TPR
dec, MVOC inc)
Gram negatives: have Endotoxins (lipopolysaccharide) in cell wall;
Gram positive dont have endotoxin.
Fluid and Hemodynamics
Post 18: (Dated: Feb 01 - 2009)
Hypovolumic and Cardiogenic shock: Skin ---> Cold and clamy due to
vasoconstriction of peripheral vessels; EAVD, sV, CO ---> decreased
due to Catacholamines and Angiotensin 2 etc ---> Constricts blood
vessels in skin and redirect the blood flow to more important organs
like brain and kidney; BP decreased, Pulse raised.
Poiseuille law: TPR referred to ur arterioles = viscosity of blood in
numerator / raduis of vessels to the 4th power; Therefore main factor
controlling TPR is radius to 4th power; Viscosity of blood is controlled
by Hb ---> anemia (Viscosity decreased), Polycythemia (Viscosity
increased).
Septic Shock: Endotoxins are released ---> First they activate
alternate system and cause release of C3a and C5a (Anaphylotoxin)
---> stimulate mast cells to release histamine ---> peripheral
resistance arteriolar dilation ---> skin feels warm; Endotoxins also
damage the endothelial cells;histamine ---> vasodilation of arterioles.

Endotoxins ---> damage endothelial cells ---> NO, PG PGI2 release

---> vasodilation --->Diastolic pressure decreases big time.
Water Dam Example: If all the gates of the Dam are opened --->
Similarly when peripheral resistance arterioles are dilated ---> blood
starts gushing through arterioles and goes into cappilaries system,
feeding all the tissues with O2; Disadvantage: Bad day for fishing,
similarly tissues are not able to extract O2; Blood coming faster then
usual to the RT side of the heart ---> CO increased ---> High output
failure.
Endotoxic shock: Skin feels warm.
Swan-Ganz catheter: stuck into RT side of the heart can tell whats
going on in the arterioles; O2 content is 1.34 times the Hb times O2
sat + Po2 ---> measured in Rt atrium ---> Absolute best test for
tissue hypoxia; There are lots of things which can increase lactic acid
and have nothing to do with tissue hypoxia and aerobic glycolysis; But
this catheter measures O2 content returning from tissues.
Hypovolumic and Cardiogenic shock: CO is low ---> There is not lot of
blood but not being pushed ahead with great amount of force --->
Tissues have still lots of time to extract O2 from blood ---> mixed
venous O2 content are very very low.
Mixed venous O2 Content is high in septic shock.
Pulmonary Cappilary Wedge pressure: Its a measure of LVED Volume
and pressure; Catheter in the Rt side of the heart and can tell about
the pressure in LV; LVED is low in Hypovolumic shock.
Kidney medulla suffers the most from shock (BUN + creatinin raised
---> sugar Raised ---> ATN ---> renal tubular casts blocks urine --->
oliguria). Treatment: RBF (Dobutamine and everyting that increased
renal blood flow), we have to prevent the pt to have ATN.
Brain in Shock: Circle of willis distributes blood and saves the brain
during shock for a while.
Renal tubules in shock: Coagulation necrosis ---> dead renal tubules
slough off and produce renal tubular cast in urine and blocks urine flow
---> Oliguria, decrease in GFR.
Fluid and Hemodynamics

Post 19: (Dated: Feb 02 - 2009)

Sickle cell trait can cause micro infarction in kidney medulla (low O2
tension)--->
microhematuria.
Increase in HCO3 ---> PH increase ---> M.Alkalosis
Decrease in HCO3 ---> PH decrease ---> M.Acidosis
Increase in PCO2 ---> PH decrease ---> R.Acidosis
Decrease in PCO2 ---> PH Increase ---> R.Alkalosis
Compensation: Body's attempt to maintain normal PH which it never
does; if there is M.Alkalosis which is an increase in HCO3 in
numerator---> In demonitor PCO2 needs to be increased (R.Acidosis).
If M.Acidosis HCO3 is decreased ---> We need to blowoff PCO2 --->
R.Alkalosis for compensation.
R.Acidosis: Raise the numerator HCO3 ---> M.Alkalosis; By decreasing
the denominator in a primary disease ---> Hyperventilation, blowingoff
CO2 Ventilation is a CO2 term; Hyperventilation - blowing off Co2 --->
R.Alkalosis; Hypoventilation - Retaining Co2 ---> R.Acidosis
Best Rx for R.Alkalosis: Paper bag ---> rebreath of Co2
Full compensation of PH does't exist; Only in Chronic respiratory
alkalosis in high altitude is the only case where pH goes completely
back to normal.
Respiratory center is located in Medulla, controls breathing rate.
If there is a obstruction of upper airways ---> problem in getting rid of
Co2 (Chest Bellows).
Diaphragm is the most important muscle of repiration; It goes down
---> Negative IT.Pressure increased ---> air sucked into lungs, blood
sucked in Rt side of heart (Neck veins collapse on inspiration);
Expiration ---> Positive IT.Pressure ---> It PUSHES THINGS OUT --->
LT heart push blood out, and get rid of air.
Barbiturates, CNS injury ---> damages resp. center in medulla --->
resp. acidosis.

Anxiety, pregnancy ---> respiratory alkalosis ---> tetany (ionized Ca

decreased) signs:
Tourseau sign (compression of the forearm produces spasm in the
hand and wrist)
Chvostek's sign (contraction of the muscles of the eye, mouth or nose,
elicited by tapping along the course of the facial nerve).
Estrogen and progesterone: overstimulate the respiratory system,
cause spider angioma on the skin (normal in pregnancy) and AV fistula
in the lung.
Endotoxins, Salicylate ---> respiratory alkalosis+metabolic acidosis.
Normal pH.
6 year child with inspiratory stridor ---> acute epiglotitis (H.
influenza); Rx, Crash cart, lateral X-Ray (thumb print sign, swollen
epiglottis); Decreasing incidents due to vaccination along with
menningitis.
1m- 8y ---> Nesseria Menningitis; H.Influenza way down the list until
the child is not vaccinated
3 month th baby with inspiratory stridor ---> croup (parainfluenza
virus): tracheal obstruction, stipple sign on X-ray.
Fluid and Hemodynamics
Post 20: (Dated: Feb 04 - 2009)
Cafe Coronary: If a person can talk ---> partial obestruction, leave
them as they can cough out; If cant talk ---> all obstruction.
chest bellows: Diaphragm is innervated by phrenic nerve IV; Erb
duchenne palsy (Brachial plexus paralysis) ---> kid having respiratory
difficulty ---> CXR: diaphragm on the right side elevated ---> Co2
retention.
Lugaric disease, Amyotrohic lateral scelerosis ---> Lower motor
neurons are gone ---> Upper motor neurons activate ---> Diaphragm
and intercostals are paralysed ---> Die
ALS, Guillain-Barr, Polio ---> paralysis of inspiration muscles --->
resp.acidosis.
Guillain-Barr (Demylinating disease): Ascending paralysis, upper resp

infection, spinal fluid shows increase in protein and slight increase in

lymphocytes, gram (-).
Polio: Virus destroys lower motor neurons ---> paralysis of resp.
muscles.
COPD ---> resp. acidosis.
Obs. Lung disease is the problem in getting air out ---> compliance
increased and elasticity decreased ---> Co2 retention ---> R.Acidosis
Restrictive lung disease ---> resp. alkalosis.
08 NUTRITION1
For every 30-33 ft you increase 1 atm pressure underwater;
760 here and its 760x2 when you are down under water 30-33 ft;
Reverse happens like at the top of Mount everest (200 atm pressure),
still breathing 20% O2.
Alveolar O2: 0.21 x Atm.pressure - PCo2 / 0.8
High altitude: atmospheric pressure decrease ---> pCO2 increase --->
pO2 decreased ---> hyperventilation ---> pCO2 decreased ---> resp
alkalosis.
Atm Pressure increase deep under water ---> Nitrogen gas dissolves in
the tissue ---> If get out fast ---> gas comes out as bubbles ---> goes
into tissues and blood vessels.
Caissons disease = the bends = decomppression sickness: Headache,
pain in the arms, legs, joints, and epigastrium, itching of the skin,
vertigo, dyspnea, coughing, choking, vomiting, weakness and
sometimes paralysis, and severe peripheral circulatory collapse.
-----End Fluid and Hemodynamics ----Nutrition
EATING DISORDERS (114pdf/127 )
Main difference b/w Anorexia nervosa and Bulemia Nervosa is distorted
body image.
Women having Anorexia nervosa can be of 60 pds but thinks that they
are fat.

Anorexia nervosa: dec. GnRh, dec.FSH, dec.LH, dec. estrogen,

amenorrhea, osteoporosis; Usually die of cardiac disease, Heart
Failure.
Athelete Women: Amenorrhea ---> Body mass too low for GnRH; Rx,
Convince the person to gain enough wheight to start periods.
First step of treatment for DM-II and hypertension is Weight loss!; DMII ---> Rx, loss of adipose leads to upregulation of insulin receptors.
Bulimia nervosa: They dont have distorted body image but they binge
---> eat a lot and force vomit out; teeth erosion of enamel ---> dentin
showing (brown); Metabolic alkalosis ---> resp. acidosis as
compensation ---> hypoxia ---> Premature Ventricular Contractions
---> Ventricular Fib; May develop Mallory-Weis syndrome (tear in the
distal esophagus and proximal stomach) ---> vomit of blood;
Boerhaave syndrome (rupture of esophagus) ---> air and fluid in the
pleural cavity, air dissects through the subcutaneous tissue comes to
the anterior mediastinum, you have Hammond's crunch.
BMI: Kg / (height in meters)2 => Obesity > 30, morbid obesity > 40.
Obesity: main complication is HTN ---> LVH ---> HF (most common
cause of death). Other complications: 1. Gall bladder diseases. 2. inc.
adipose ---> aromatase ---> inc. estrogen ---> endometrial
adenocarcinoma, breast cancer, colon cancer.
Marasmus: total calorie deprivation, muscle wasting, good survival
chance.
Kwashiorkor: normal calorie intake, protein deprivation, anemia,
cellular immunity problems, edema, ascites, fatty liver, flaky paint
dermatitis, redish area on skin (copper deficiency) more likely to die.
Lipid soluble vit. have greater chance of toxicity (water soluble can be
peed out).
Water soluble vit. are all co-factors of biochemical reactions.
Most common cause bright yellow urine ---> Vitamins pigments of the
pills
Vit. A: Bone and muscle growth; prevents squamous metaplasia --->
eyes are lined by cuboidal epithelium, in case of Sq.Metaplasia --->

white spots ---> becomes extensive and grow over the eye and get
softening of cornea (keratomalacia)---> blindness (2nd most common
cause).
Vit. A deficiency: Eye ---> Bitots spots; Failure to thrive; follicular
hyperkeratosis; night blindness (nictalopia), squamus metaplasia --->
bronchogenic carcinoma.
Number 1 cause of global blindness is trachoma(chlamydia
trachomatis); but in USA DM.
You can be non-smooker, and can get sq.metaplasia of mainstem
bronchus ---> Bronchogenic ca.
Vit A toxicity (bear hunters, who eat bear livers): severe liver toxicity,
cerebral edema with papilledema --->headache.
Retinoic acid: for treatment of Acne and acute progranulocytic
leukemia
A young lady on Isoretinoic acid for cystic Acne, check her Liver
enzymes + any headaches --->may produce papilledema and cerebral
edema.
Vit D: mostly from sunlight, not food (hardly in breast milk).
Cholesterol: is the main component of cell membranes
- is the starting point for bile salts and bile acids
- is the first compound used in the synthesis of steroid hormones in
adrenal cortex
- 7-dihydrocholesterol in skin is photoconverted to Vit.D.
Breast milk: hardly have Vit.K or Vit D ---> needs supplements.
- Vit D. is reabsorbed in jejunum ---> has to go through 2
hydroxylation steps; 1st one in Liver (25-Hydroxylated); 2nd in Kidney
(1-25-Hydroxylated) in proximal tubules by PTH ---> Active Vit D;
- Active vitD, main job is mineralizing bone and cartilage --->
reabsorbs Ca and Phosphorus from jejunum.
PTH is responsible for the synthesis of 1-a-hydroxylase, which is in the
PT.

PTH: is somewhat related to Vit D. metabolism in last hydroxylation

step; Reabsorbtion of Ca mainly from early part of distal tubule
(Blocked by thiazide diuretic for Na reabsorbtion) through a Ca
Channel; Ca has to take turns with Na; Most of the time Na reabsorb
more, Ca has to wait for PTH; When on Thiazides you block Na
reabsorbtion and the channel is totaly open for Ca ---> hypercalcemia.
Ca Stone formers: Majority of the pt have Hypercalcuria ---> absorbs
lots of Ca from GUT; Hydrochlorothiazide sucks the Ca out of the urine,
decreases reabsorbtion of Phosphorus in the proximal tubule and
increase formation of HCO3, also make 1-a-hydroxylase in proximal
tubules and helps Vit.D to get the 2nd hydroxylation.
Vit D: Vit D attaches to Osteoblast receptor's ---> release of Alkaline
Phosphatase.; When ever there is growth of bone while healing of
fracture ---> ALK Phos increase ---> Makes appropriate solubility
products to mineralize cartilage and bone.
The cells that normally breaks bones is osteoclast, which have
receptors for Calcitonin ---> inhibits the osteoclasts and used in Rx of
Hypercalcemia and Osteoporosis.
There is't any receptor on osteoclast for PTH, which is only on
osteoblasts.
ACE is synthesized in endothelial cells and pulmonary capillaries.
Erythropoietin is synthesized in endothelial cells and peritubular
capillaries.
Hypercalcemia is a potential side effect of thiazide (used in stones).
PTH receptor is on osteoblast ---> release IL-1 (osteoclast activating
factor) ---> breakdown bone and increase serum Ca.
Estrogen in females + testosterone in males puts an inhibitory effect
on IL-1 release.
Lack of estrogen in old age ---> osteoporosis.
Vit D mineralizes bone and cartilage (inc. absorption of both P + Ca)
Lack of sunshine, poor diet, liver disease, renal disease (DM) ---> Vit
D deficiency:

Children: Rickets - craniotabes (soft skull), rachitic rosary (excess

osteoids in costochondral junctions), rest like in adult.
Question: A pt on phenytoin and the pt has hypocalcemia --->
Phenytoin, alcohol, barbiturate, rifampin, induces the Cyt-P40 system
which is located in SER ---> SER hyperplasia, increase metabolism of
drugs and other things made in the liver including 25-hydroxy-vit D.
Question: A women that was on Phenytoin and birth control pills got
pregnant ---> Phenytoin Induce P450-sys and increase the metabolism
of estrogen and progesterone in the BC.pills ---> not significant levels
to prevent getting pregnancy.
GammaGlutamilTransferase is the enzyme of SER is increased when
ever P-40 disturbed by drugs (e.g Alcoholics)
DM is the most common cause of Renal disease in USA: Tubular
damage ---> no a-hydroxylation of Vit D; Rx, 1-25 Vit D.
Type 1 Vit D dependant Rickets: 1-a-hydroxylase deficiency,
Type 2 Vit D dependant Rickets: missing the Vit D receptor.
Vit D deficiency in Adults: osteomalacia, you cant mineralize bones and
cartilages soft bones, pathologic fractures.
Vit D toxicity: hypercalcemia ---> stones.
Oral Vit D still has to go through the steps of hydroxylation to work.
1-a-hydroxy-vit D is a prescription drug (can be dangerous).

Vit E: prevent lipid peroxidation of cell membrane (protect from

Phospho Lipase A);
Neutralize oxidized LDL (also Vit C); LDL which is phagocytosed by
macrophages and becomes the part of atherosclerotic process.
Vit E deficiency is mostly seen in Cystic Fibrosis because of
malabsorption, which will cause the deficiency of all ADEK vitamins.
Cause: Hemolytic anemia, neurological diseases (posterior column
disease, spinal cerebellar diseases, related to myelin).
Vit E toxicity: prevent the synthesis of the Vit K dependent coagulation

factor: 2, 7, 9, 10, protein C, protein S ---> synergistic with warfarin

(after MI) ---> INR increases ---> anticoagulant.
MI: Antioxidants and Aspirin (once a day); In case of ant. MI and
along with 3-4 months Rx with warfarin ---> Normal INR , and you go
to drug store, taking vit E, A and C ---> increasing Vit E ---> helping
warfarin (blocks g-carboxylation of vit-k dependant factors)---> over
anticoagulation ---> prevents synthesis of factors; Vit-E works
synergistic with Warfarin.
Vit K: mostly from colonic anaerobe bacteria, less from food (danger in
day 3-5 of newborn, between the end of the mothers contribution and
the beginning of bacteria growth in colon ---> can lead to
hemorrhage); Rx, Vit K at the time of birth.
Bacteria make inactive Vit K (K2), converted to K1 by epoxide
reductase (inhibited by warfarin). Function: g-carboxylation (glutamic
acid residues that get g-carboxylated on the vit k dependant factors)
---> activates them ---> allows Ca to bind those factors---> help
formation of the clot.(if no g-carboxylation, factors are useless as Ca
cannot grab them for the formation of a clot).
Warfarin: inhibits the epoxide reductase ---> all vitamin we have is K2
---> no g-carboxylation ---> anticoagulation
Vit K deficieny: Broad spectrum antibiotics (most common cause in
hospital), poor diet, newborn, and malabsorption.
hemorrhagic diathesis ---> bleed to brain, skin.
Qs: 6 days old child, breast fed and had a bleeding diathesis ---> Not
enough vit K. in breast milk so the kid is Vit K deficient
Treatment of rat poisoning (= warfarin) is intramuscular Vit K.
Qs: A kid lives with his grandparents and developed a hemorrhagic
diathesis ---> elderly are on warfarin ---> took warfarin and ate it.
09. Nutrition2- NEOPLASIA
Water soluble Vitamins:
Old person on tea and toast diet (malnourished and not taking enough

vitamins) ---> gets bleeding gums while brushing his teeth ---> scurvy
(Vit C. defeciency); Vit c. ---> hydroxylates proline and lysine in golgi
apparatus (post translational modification) ---> week tensile strength
of collagen as you cannot form cross bridges ---> blood vessels
rupture, gums bleed (type1 collagen weakens leads to inflammation)
while brushing teeth, hemarthrosis (complications of severe
Hemophilia A).
- Peri-follicular hemorrhage (rupture of vessels around hair follicles
looks like ring around follicles), glossitis (tongue; smoothness and
hurts), kelosis along the angles of mouth.
Ring sideroblasts: Nucleated RBC, has too much iron in mitochondria.
Excess of vit c. common in USA, 6-8 gm/day ---> renal stones (uric
acids and others as well) .
Vit C is theraputic drug for Ancillary treatment of met-Hb Anemia;
reducing agent, a great scavanger hunter for free radicals, knocks of
free radicles.
Water soluble vitamins are mainly co-factors for biochemical reactions;
Vit C. is a co-factor for making catacholomines (converting norepi to
epi.)
Thiamine is a cofactors for many important reaction like; Transketolase
reactions which are involved in the HMP(Pentose Phosphate shunt);
Pyruvate dehydrogenase (all those dehydrogenase reactions in
biochemistry), a-ketoglutrate dehydrogenase, a-ketoacid
dehydrogenase ---> all of these reactions reactions require Thiamine
as a cofactor.
Pyruvate dehydrogenase is the main enzyme that converts pyruvate in
to Acetyl-Coa (pyruvate can also be converted into oxaloacetic acid
with a carboxylase enzyme); when Acetyle-CoA combines with
oxaloacetate ---> citrate forms in TCA cycle; In case of thiamine
defeciency, if its involved in Pyruvate dehydrogenase reaction --->
decreased Acetyl-Coa, decreased Citrate, decreased ATP; so the
problem with Thiamine defeciency is ATP depletion; From Pyruvate to
Acetyl Coa ---> 2 NADH generated in mitochondria and gets 6 ATPs;
TCA-cycle ---> 24 ATPs generated; 6+24 = 30 ATPs; The total ATPs
generated from glucose to metabolised is 38 ATPs; Thiamine
defeciency leads 38 ATP depletions.
Dry Beri-Beri: Peripheral neuropathies (wernicke's and korsakoff

psychosis); A lot of ATP is required to make myelin; in case of ATP

depletion ---> cannot make myelin ---> peripheral neuropathies (foot
drop due to common peroneal palsy; wrist drop due radial nerve; claw
hands due to ulnar nerve);
Wernicke's encephalopathy (confusion, ataxia, nystagmus);
Korsakoff psychosis (cannot remember old and new things), in Qs "I
use to know that but I cannot quite get it during my exam", acquired,
related to stress.
Most common cause of thiamine deficiency in USA is not the outer
whorl of the rise (having nutrients), but instead its Alcohol.
Wet beri-beri: Heart failure (cardiomyopathy); Heart need ATPs to
function, thiamine deficiency ---> Congestive cardiomyopathy --->
biventricular enlargement ---> whole chest is gonna be heart; Both
left and right heart failure; Pitting edema of legs is the sign of RHF,
related to the increase in Hydrostatic pressure behind the failed heart;
Thats why it is called as "WET" ---> Pulmonary edema (LHF) + Pitting
edema (RHF); Rx, IV thiamine to alcoholics and can reverse this
process but unfortunately in some cases of alcoholic cardiomyopathy is
related to direct toxicity of alcohol its not gonna work.
QS: A pt comes in to ER with some kind of thing that requires IV. So IV
is maintained with 5% D/W and Normal Saline. All of the sudden the pt
develops confusion, nystagmus (cannot determine ataxia as pt is lying
down), ophthalmoplegia ---> Ans. Subclinical thiamine deficiency.
The moment you hung up the glucose on him ---> glucose with
pyruvate and pyruvate went into Acetyl CoA ---> used up the rest of
thymine ---> end up Wernike's encephalopathy; Best Rx you give IV
thiamine before you hang up any IV with glucose in it.
When pt comatose or semicomatose ---> Rx 50% glucose (for
hypoglycemia) + Nalaxone (incase of overdose) + IV thiamine.
Rash at Sun exposed area ---> Pellagra due to Niacin deficiency
(diarrhea, dementia, dermatitis) NAD and NADP reactions --->
Nicotinamide derived from Niacin.
All redox reactions Niacin is required.
Tryptophan can be used to synthesize niacin also used in the
synthesizing serotonin thats why its an essential Amino acid.

Nicotinic acid: least expensive lipid lowering drug; Associated with

flushing ---> Rx take Aspirin before Nicotinic acid; Rx of Familial
combine hyperlipidemia ---> when ever elevated cholesterol and
triglyceride, Nicotinic acid is the drug of choice.
Riboflavin: FAD, FMN ---> all those reactions are Riboflavin cofactor.
The first reaction that converts the oxidized glutathione into
glutathione ---> glutathione reductase is the enzyme, Riboflavin is the
co-factor for that.
Pyridoxine: The first reaction in the synthesis of heme involves
succinyl CoA plus glycine, enzyme ALA synthase, Cofactor-B6 --->
most important in synthesis of Hb and heme proteins; Cytochrome
system in liver is the Heme system ; Myoglobin has heme, except
Myoglobin differs from Hb ---> Hb has 4 heme groups where as MyoHb has 1 heme group; So pyridoxine is involved in the synthesis of
heme which is a porphyrin.
Pyridoxine is used in the transaminase reaction The most abundant
substrate for making glucose in fasting state is Alanine came from
muscles; In fasting state you start breaking muscles down to get
substrates to make glucose by gluconeogenisis.
Transaminase:Amino acid is used to make glucose by transamination
(Transaminases: SGOT and SGPT which are liver enzymes, they can
take amino groups out and put amino group into things ---> when
amino group NH2 group out of alanine produces pyruvate which is
alpha-ketoacid); If you take aspartate and takes its amino group out
of it you have oxaloacetate which is substrate for gluconeogenesis;
Pyruvate + aminogroup ---> Alanine;
Oxaloacetate + Aminogroup ---> Aspartate.
B6 also involved in the synthesis of neurotransmitters; B6 deficiency
end up with severe neurological problems, and convulsions.
Most common cause of B6 defeciency is isoniazid ---> Rx give B6 other
wise they can develop neurologic problems, sideroblastic anemia.
Pantothenic acid is involved with FA synthase (16 carbon F: Palmityc
acid); Pantothenic acid also involved in CoA- Reaction (eg, Acetyl CoA,
HMG-CoA)

Biotin is the Co-factor on the other reaction of Pyruvate;

Pyruvate, Acetyl CoA, Pyruvate Dehydrogenase, Thiamine; Pyruvate
Carboxylase, and Oxaloacetate ---> Biotin is the Cofactor.
So you have thiamine on one side forming Acetyl CoA from Pyruvate
and got Biotin on the other side forming Oxaloacetate.
If you are deficient in it which is the ---??? 20 raw eggs a day on a
consistent basis, as the eggs have Avidin in them which binds Biotin so
you become Biotin Deficient. So usually it ends up in rash and Bald.
If you are Biotin deficient you can not form oxaloacetate nor citrate;
Citrate (first step in gluconeogenesis ---> ends up in fasting
hypoglycemia); 2nd you are going to build up pyruvate, and it will
force the reaction to form lactic acid.
Chromium : Glucose tolerance factor ---> helps insulin do its job;
Chromium picolinate everyday helps insulin do its job ---> may feel
hypoglycemic + Oat meal with all its fibers lowers the glucose levels
fast; Rx Type II DM ---> Chromium.
Copper: Lysyl oxidase puts the cross bridges between collagen fibers
and elastic tissues; Copper deficiency leads to weak collagen and
elastic tissues ---> dissecting aneurysm, "flag sign" red hair in
kwashiorkor.
Fluorine: Too much flourine ---> modelled teeths ---> white chalky
teeths like bitots spots (white patch on cornea), calcification of the
ligaments attaching to bones are subject to rupture ; Colorado water
has too much fluorine in it; fluorine poisoning X-rays shows
calcification of ligaments going into the muscles.
Selenium: Co-Factor for glutathione peroxidase forming glutathione
(antioxidant); Selenium given with Vit-E ---> One working on
Glutathione making sure its doing thing, and the other one working on
lipid membrane preventing any free radicle damage to it and knocking
off oxidized LDL.
Zinc: Scenario ---> Old person with dysgeusia (abnormal taste), and
anosmia; The term metalloenzyme (an enzyme that has a trace metal
as a co-factor) points to zinc. Collagenase is a metalloenzyme because
it has zinc in it, breaks down the Type III collagen in order to form
Type I collagen. In case of zinc deficiency = poor wound healing (rash
on the face), anosmia, dysgeusia.
Diabetics all are zinc deficient unless they are taking zinc supplements.

Top 10 causes of morbidity and mortality in USA:

1 - Smoking
2 - Poor Diet / Lack of exercise
3 - Alcohol
Dietary fibers: Soluble fibers lowers cholesterol not insoluble; Oatmeal
contains insoluble fibers ---> suck up water from colon; 95% of bile
acids and bile salts are reabsorbed in terminal ileum, 5% is Lithocholic
acid which is carcinogenic: colon ca; If you are on fiber insoluble or
soluble ---> it sucks lithocholic acid into the interior of the stool and
have no contact with the bound mucosa + you go Poo more often and
that has even less contact.
Women recycles estrogen. The main way of excreting estrogen is in
bile and out into stool, small % of the unwanted estrogen recycles
back into system ---> fibers takes that estrogen and saves from breast
cancer, ovarian cancer or uterine cancer.
Protein restriction:
1. In Chronic Renal failure ---> excess protein broken down into
amonia ---> increase urea cycle ---> increase urea in blood--->
increase load on kidneys;
2. Liver cirrhosis ---> defective urea cycle cannot metabolize amonia.
Most of the amonia comes from bacterias in colon that have urease in
them. H.Pylori and anaerobes have urease ---> break down urea into
amonia in colon ---> amonia gets reabsorbed, goes back to liver and
through urea cycle we get rid of it.
In cirrhosis no urea cycle ---> amonia levels increase in blood --->
hepatic encephalopathy, mental status disturbance, and asterixis. Also
along with amonia ---> octopamine, amino benzoic acid, false
neurotransmitters also cause those.
Neoplasia
Main difference between benign and malignant:
Benign does't metastasize but Malignant has the capacity to
metastasize.
Invasive Mole: Benign tumor which can metastasize to lungs.
Basal cell carcinoma: most common skin cancer which can invade but
doesn't metastasize.
Qs: Most common benign tumor in a women which most commonly
located in which of the following organs -

Ans: uterus and the most common tumor is leimyoma (smooth muscle
tumor).
Term fibroid - "Oid" means looks like fibrous tissue, but its a smooth
muscle. It becomes so hard they look like scar tissues; No
transformation to leimyosarcoma.
The most common benign tumor in a man, "Yellow", around elbow,
Lipoma; Most common in womens, Leimyoma of uterus.
Benign tumors of glands = Adenomas
Adenomas of adrenal: Thinness of adrenal cortex, which must be
functioning, making cortisol (Cushings)---> ACTH suppressed --->
Fasciculata and Reticularis undergo atrophy.
If the tumor is producing mineralocorticoid = Conn syndrome (atrophy
of zona glomerulosa).
GFR = Glomerulosa (salt), Fasciculata (glucocorticoids), Reticularis
(sex hormones)
Tubular adenoma: Precursor lesion for Colon cancer, looks like a
strawberry on a stick.
Carcinoma is the malignancy of epithelial tissues (squamous,
glandular, transitional).
In Squamous Carcinoma: Little swirls of increase redness called as
Squamous Pearls
Glandular carcinoma: Glands, looks like round and have something in
the middle ---> Adenocarcinoma (things inside the glands)
Transitional cell Ca: Comes from genitourinary tract (bladder, ureter, or
renal pelvis)
Malignant Melanoma: Rx Excision; malignancy of melanocytes;
Benign form is Nevus, The most rapidly increasing cancer in USA.
S100-Antigen positive, APUD tumors (A - means precursor of bcarboxylation decarboxylation) which have neurosecretory or
neurocrest origin. On EM, they have neuro secretory granules.
S100 Antigen which is used for staining things with APUD origin or
Neurocrest origin, most of them do not take stain.

Melanoma is an APUD tumor; Small.Cell.Carcinoma of lung also APUD

tumor, its less malignant counterpart called bronchial carcinoid; The
carcinoid tumor at the tip of appendix is APUD tumor; Neuroblastoma
in medulla in a child is APUD neurosecretory tumor.
Qs: 2 year old that has nodules all over the skin. The biopsy showed
small hyperchromatic cells which are s100 antigen positive, where is
the tumor coming from?
Ans - Renal medulla, neuroblastoma - metastatic to skin.
Sarcoma is the malignancy of Mesenchymal tissues, Not epithelial
tissues.
Bone: Metaphysis ---> Split up of periosteum ---> X-ray shows
Codman's triangle. This particular tumor makes bones and on x- ray
shows sunburst appearance ---> diagnosis, Osteogenic sarcoma
(Osteogenic means bone making sarcoma)
Slide: Biopsy of a little girl, that had a necrotic mass coming out of
vagina. Biopsy showed, vimentin negative, keratin negative, desmin
positive ---> Embryonal rhabdomyosarcoma; striations in nucleus can
be seen. Most common sarcoma in childrens, comes out of vagina of
little girls and penis of little boys.
Sarcoma of smooth muscle: Leimyosarcoma
Sarcoma of striated muscle: Rhabdomyosarcoma
Sarcoma of Fat: Liposarcoma
All of these are malignancies of mesenchymal tissues.
Carcinomas are of epithelial tissues.
Qs: Movable at the angle of Jaw: Mixed tumor. The organ affected is
Parotid which is the most common overall salivary gland tumor usually
benign occasionally malignant.
Term Mix means: Two histologic different types of tissues like they
derive in the same cells layers, which is not in teratoma.
Teratoma: Tooth, hair etc. Teratoma derived from all three cell layers;
ectoderm, endoderm and mesoderm.

Cystic teratoma of the ovaries Qs: 16 year old girl with onset of right
lower quadrant pain (always make right lower quadrant pain making
confusion with appendicitis, Crohn disease, ectopic pregnancy or
follicular cysts). X-rays showed some calcification in the pelvic area->
cystic teratoma; calcifications could be bones or teeth.
Germ cell tumors: They have tendency of staying in the mid line.
Ovaries are reasonably in midline. Ant.Mediastinum is right in the
midline. So teratoma is commonly developed there in the Pineal gland,
which is in midline. Therefore these are midline tumors the teratomas
which are Germ cell tumors.
Leukemia and Lymphomas:
Auer rod in a myeloblast ---> Leukemia
Hypersegmented neutrophils ---> B12, folate deficiency
Leukemia: Malignancy of stem cells in bone marrow. Like all cancers
they can metastasize out of it and always do. They have generalized
lymphadenopathy, and hepato splenomegaly.
Malignant Lymphomas arise from lymph nodes. Because they are all
malignant, can metastasize where ever they want including bone
marrow.
The most common site of body where lymphoma are not developing in
the lymph nodes is stomach.
Most of them are extra nodal (outside lymph nodes), primary
lymphomas occurs in stomach; H.Pylori can produce primary
lymphomas. The second most common location is in Peyers patches of
terminal ileum.
Mixed tumors Vs Teratoma
Leukemia Vs Lymphomas
Follicular B-Cell Lymphoma, knocks off apoptosis gene. It is a
translocation(14;18) of a heavy chain, B-Cells makes Bcl2 end product
which inactivates the apoptosis gene in the B-Cell. The cells become
immortal. Therefore it is the inactivation of apoptosis gene, common of
all the lymphomas.
Trophoblastic tumors: We see in pregnancy. Males can get as well
which are non-gestational.
Hydatidiform Mole: Looks like bunch of Grapes. Which presents in 1st

trimester with signs of Pre-Eclampsia. So any patient that has HTN,

proteinuria and edema in 1st trimester, U/S shows uterus too large for
gestational age and "Snow Storm", which is the classic mole (complete
mole). Complete mole has the highest tendency of going into chorio
carcinoma.
A mole is the benign tumor of the chorionic villus. Chorionic villi are
lined by trophoblastic cells; including syncitiotrophoblast on the
outside which is in contact with blood and where O2 is extracted;
Under the syncitiotrophoblast is the cytotrophoblast; then you have
Wharton's jelly in chorionic villus; then there is a little vessel in the
middle of the chorionic villus which eventually becomes umbillical vein
which has the most O2 on the fetus fetus's.
Choriocarcinoma: which is not the malignancy of the chorionic villus
but malignancy of the linning of villus (ie syncytotrophoblast and
cytotrophoblast).
Syncytiotrophoblast makes B-HCG and Human placental lactogen (GH
of pregnancy which gives AA, glucose from mommy to baby).
These are highly malignant but, they are gestationally derived;
Metastatic to lungs; they respond incredibly to chemotherapy like
Methotrexate, chlorambucil and they go away.
All that ends in "OMA" not necessarily benign. Like:
Melanoma - Malignant tumor of melanocytes
Lymphoma - Malignant tumor of lymph nodes.
Hamartoma is a overgrowth of tissue that is normally present in that
area; Like bronchial hamartoma - a benign cartilage which presents as
the solitary coin lesion in the lung which makes you wonder about it is
either granuloma or something of that nature but it is hamartoma, so
they are not neoplasm.
Polyp of Peutz Jagers syndrome is a hamartoma, its not even a
neoplasm. There is no increase risk of colon cancer because the polyps
are not neoplasms.
The Hyperplastic polyps which is the most common polyp of entire GIT
is Hamartoma.
Section of Stomach: In the muscle wall of the stomach presence of
benign pancreatic tissue.

When you have benign tissue in a place where it should't be called

Choristoma or Heterotopic rest.
Meckel's Diverticulum, is the classic example. The most common
complication of M.Diverticulum is bleeding from either ulcerated gastric
mucosae that is ulcerated and sometimes pancreatic tissue causing the
ulceration.
Misconception is that increase mitotic rate means cancer - No.
The thing which really make mitosis malignant is this,an abnormal
mitotic configuration, like 4N cell, more chromosomes in it than
normal. When we have atypical mitotic spindles which is related to the
fact that they are aneuploid and have more than normal 46
chromosome like 63, thats malignant. Syne quanon, which means key
thing: it's ability to metastasize.
Malignant cells have longer cell cycle than the cells they have derived
from.
Qs: How many doubling time as it takes to get a tumor clinically
detected? - Ans. 30 doubling times means 30 times going through the
cell cycle and you get a tumor 1 sonometer (10)-9 (in mass) in size.
Malignant cells are immortal and can live forever.
Burkitts lymphoma cells are used in test for immune complexes. We
can grow Burkitts lymphoma cells in culture.
Malignant cells: They don't like each other so don't stick to each other,
but like adhesion so they can infiltrate the tissues. They have very
simple biochemical system usually anaerobic metabolism. They have
lots of enzymes. They have proteases to break through the tissues,
and Collagenases to break through the basement membranes.
Metastasis: Three modes of metastasis. Lymphatic, hematogenous and
seeding.
We have carcinomas and sarcomas.
Carcinomas: usually, initially metastasize by means of draining into
regional lymph nodes. For breast cancer that's the axillary nodes, they
can also go to internal mammary nodes. Colon cancer, they have
nodes right around them. For esophageal cancers the node is right

around it, so they go to the local lymph node.

What part of the lymph node? Ans. Subcapsular sinus.
Slide: This is showing cancer cells in lymphatic here, and showing a
lymph node that has been partially replaced by malignant tumor.
So the rule is, cancer first goes to the lymph nodes then goes to
efferent lymphatics, drain to the thoracic duct, subclavian :
Hematogenous.
Dont think that carcinoma are not hematogenously spread. When
hematogenous it means they have gone through the lymph nodes. So
they can go to bones, liver, and other places.
This thing is good. We can pick that node in clinical exam. We can pick
cancer in early stage.
Unlike sarcomas which donot like go into the lymph nodes. They just
like, going through the blood vessels, and usually characteristically
metastasize hematogenously. That's why lungs and bones are such
common sites for sarcomas.
If you have angiosarcoma of the breast would you do a radical
dissection of axilla? - Ans. No, because the angiosarcoma does't go to
the lymph nodes, you will do the simple mastectomy. But in case of
carcinoma, you will take out the breast or lumpectomy ---> you
sample a couple of lymph nodes or do a complete dissection, that
would be part of it as carcinomas go there.
Slide: This is lymphatic spread. You can see lymph nodes here. This is
tumor in a vessel.
Slide: As sarcoma likes to go into the blood vessels. Here is the tumor
in the blood vessel.
Actually it is the follicular carcinoma of the thyroid. There are some
carcinomas that don't always like to go to lymph nodes but wanna go
hematogenously. So follicular carcinoma of the thyroid does't like to go
to lymph node (transvestite).
Renal adenocarcinoma: Likes to invade the renal vein. Determines the
prognosis. Goes through the renal veins up to IVC.

Hepatocellular carcinoma always invades the vessels. So there is

always exception in every rule.
In general carcinoma first like to go to lymph nodes, then they have
potential to become hematogenous.
Sarcomas usually dont like lymph nodes and go directly
hematogenous, which makes them dangerous.
Seeding: Is the concept of seeding .... So we have cancers in cavities.
Classic example of ovarian cancers, that have tendency of seeding
little malignant implants. Most ovarian cancers are surface derived
cancers, so it means they derive from the linning around the ovaries.
Its easy for them to seed, through out malignant implants of small
little pieces of cancers, and over the omentum and into the pouch of
Douglas (posterior to the uterus and anterior to rectum and can be felt
by rectal exam).
Pouch of Douglas is to women, as prostate gland to a man. When you
rectal on a man you press forward thats the prostate, but in women
you feel pouch of douglas (most important area as it is the most
dependant part of the womens pelvis ---> things like to go there like
clotted blood in ruptured ectopic, endometrial implants go in
endometriosis, and seeding of ovarian cancers)
Ovarian carcinoma, which is seeded to the omentum, it actually can
invade. It can actually seed into pleural cavity, eg peripherally located
lung cancer, they can get to pleura and seed to the pleural cavity.
Glioblastoma Multiforme: Most common primary malignancy of the
brain in adults. It can seed into the spinal fluid and implant the entire
spinal cord, so do the medulloblastoma in a little child.
Qs: If they ask you about most common cancers stuff. Is metastasis
more common than the primary cancer? Ans - In most cases,
metastasis is the most common cancer in an organ, not a primary
cancer. Exception in Renal adenocarcinoma that is the most common
one, not metastasis to it.
When we talk about lungs, most common is metastasis ---> from
breast cancer; so women are more likely to get the metastasis to
lungs.

Bones, most common cancer is not MM or Osteogenic carcinoma; but

its metastasis. Most common metastasis is from breast because of the
Batson system (its a venous complex that goes through the base of
the skull down to the sacrum, it has no valves in it and little tributaries
communicates with the V.Cava and also to the verterbral bodies and
then they collect all together around the spinal cord area and goes
back up).
A women with breast cancer: May be she got a little plug of tumor in
her intercoastal vein. She goes and pick something of the ground --->
dislodges the little piece of cancer from vein ---> vena cava --->
Batasom plexus ---> vertebral bodies ---> 3 month latter she
complains of back pain. All of a sudden she is staged 4 cancer, just by
bending over due to Batson system. The most common bone getting
breast metastasis is vertebral column. 2nd most common is the head
of femur.
Old person with removal of femoral head, always take sections through
it because its metastasize to it ---> Women with breast cancer, related
to degenerative arthritis.
Most common organ of metastasis ---> lymph nodes. Since
carcinomas are more common then sarcomas. Carcinomas like to go to
lymph nodes, that would be the most common metastasis too.
What's the most common cancer of liver? Ans- Mestastasis;
The most common primary metastasis? Ans- (1)Lung (2)colon because
of the portal vein drainage.
Where would a testicular cancer metastasize first? Ans- Paraortic
lymph nodes.
Why not the inguinal lymph nodes? Ans- Testis derive from the
abdomen and then descend there.
So testicular cancers like a seminomas are malignant, first place not
the inguinal nodes but it would be paraortic nodes.
Left supraclavicular nodes (virchows nodes): Metastasis Scenario Most common primary is stomach.
There is a mass in the left supraclavicular node: Virchows node
Some one with weight loss and epigastric distress ---> stomach cancer
Radionucleotide scan: Best test for bone mets. Everywhere you see

black except that lucency??? down over there ---> its metastasis and
the women is with breast cancer.
Most common bone metastasis is to is vertebral column, higher
vertebral column (acromioclavicular area).
We have metastasis that are lytic and blastic
Lytic: They break bone down.
Multiple myeloma ---> punched out lessions ---> all malignant Plasma
cells have IL-1 (osteoclast activating factor) in them ---> pathologic
fractures + Metabolic abnormality (hypercalcemia).
Some cancers go into bones and induce osteoblastic response. Bone
becomes dense ---> alkaline phos. elevated ---> Males with prostate
cancer which is almost always osteoblastic (which is making bone and
releasing Alk.Phos); Most common location for metastasis is lumbar
vertebrae.
Qs: 80 year old man with lower lumbar pain with point tenderness.
First step in management?
a- Bone scan
b- PSA
c- Transrectal U/S
Ans: Digital Rectal exam. Its stage 4 disease which means that
prostate definitely will be palpable. Then any other test.
X- rays:
Lytic metastasis ---> vertebrae collapse ---> lucencies
Blastic ---> Densities
CT scan of liver: If you see a gross specimen an x ray, CT, MRI etc
---> Multiple lessions in it ---> Ans- metastasis (dont pick abscess or
whatever). Dont pick primary cancer which is usually in one area or
the other but not all over the place. Just find out where that choice
deals with metastasis, never pick benign ever.
Brain: Most common cancer ---> metastasis.
Most common killer in man and women ---> Lung cancer; therefore
the most primary site for cancer in brain ---> lung cancer.
Lung: most common cancer of the lung ---> metastasis; most
common primary ---> breast.

Adrenals: the most common tumor metastasis to adrenals ---> from

Lungs; that's why they always do the CT of Hilar lymph nodes and the
adrenal glands in the staging of all lung cancers as they go so
commonly to adrenal glands.
Bone: Lytic or Blastic? ---> Blastic: most likely cause? Prostate cancer.
Stains:
Desmin: intermediate filaments, wonderful stain for muscles; that's
why used in muscle tumor like embryonal rhabdomyosarcoma.
We have stains for Keratin. Most carcinomas have a keratin in them.
Help identify different kind of tumors
EM:
APUD tumor ---> we see neurosecretory granules
Histiocytic tumor like histiocytosis X ---> Birbek granules; cluster
designation ---> CD1
Muscle ----> Actin and myosin filaments.
Vascular malignancy ---> weibel palade bodies (structures that have
Vw factors in them); we can actually see these things so we know that
they have endothelial origin.
Know gap junctions! which ones communicate & which ones don't
Big picture first, then definitions of different , then study going back to
mechanisms.
Know first: Hypoxia, hypoxia: ischemia, hypoxemia, hb related problems,
uncoupling of oxidative phosphorylation

Oncogenesis:
First step in malignancy is initiation that means mutations.
2nd step - Promotion: you make multiple copies of that mutation;
G1 to S phase, you got a mutation there and cell enter cell cycle --->
bad news ---> cell making multiple copies --->promotion.
Progression: In charged of whole thing ---> progressed --->
3rd step ---> different kinds of cancer cells have different functions
(community of malignant cells that has one purpose --->kill you).
Culturing cancer cells: Like Melanomas ---> tumors placed in the
culture medium and disk with different chemotherapy agents ---> you

can see who kills them ---> they can give you exact chemotherapy
agent that can kill them; Cannot do this for every cancer.
Stage1: Initiation ---> mutation
Stage2: Promotion ---> Dividing (multiple copies)
Stage3: Progression ---> sub specialization
When we have two sets of genes that are involved in cancer. They are
involved in the growth process and involved with cell cycle related
things. Those kind of genes monitor and suppress things, so we have
group of cells that are involved in normal growth cycle and then we
have other types of genes that are involved in suppression called
Suppressor Genes. Those are the two big sets of genes.
Things involved in trying to get cell to divide: Growth factors eg,
Epidermal derived growth factor.
Protoncogenes: these are cancer genes. But normally, when not
activated, they are actually serving normal function in the normal
growth process. Thats why called as protoncogenes. When they
become oncogenes it means that they are bad, they are cancer
producing genes.
So we have certain protoncogenes that are "Co-"??? to growth factors,
eg Cis-protoncogenes whose only function is to make growth factors.
All factors have to hook into receptors just like all hormones have to
hook into receptors like insulin hooks in to tyrosine kinase receptor on
adipose in muscle.
We have certain protoncogenes whose main job is to make receptors.
Erb-2 protoncogene, a classic one from breast cancer who calls for
receptors;
Ret-protocogene, of MENI and MenII.
Therefore protoncogenes are involved in receptors not the growth
hormones, thats their speciality. We have to send the message to the
nucleus.
We have another whole set of protoncogenes whose job is to send the
message like telegraph system.
Some of them are located in the cell membrane ---> Ras

protoncogenes, its messanger is GTP, who sends a phosphorylated

protein message. So its a cell membrane located messenger system.
Abl-protoncogene: Lives in the cytosol very close to the membrane
also is involved in messages as well.
So we have to have some messenger system. The message is sent to
group of protoncogenes located in the nucleus. Once that message is
sent to them, then they stimulate nuclear transcription of that
message, in other words cell divides and makes what ever it is
supposed to make.
The classic protoncogenes are Myc-protoncogene.
We have N-Myc (for neuroblastoma) and C-Myc (for Burkitts
lymphoma).
The protoncogenes are involved in the normal cell process, make
receptors for growth factors ---> those that send messages, lots of
those messages are phosphorylated proteins like tyrosine kinase which
is often attached to the receptors. Eg, Insulin hooks in to receptors on
adipose, it activates tyrosine kinase, right there forms phosphorylated
product which goes into the nucleus, to divide and goes to the Golgi
apparatus ---> Glut4 (glucose transport unit like ...guards) ---> Glut4
goes into the cell membrane of adipose and add receptors for glucose.
So the message goes to the nuclear transcribers (myc-oncogenes) in
the nucleus .
Whose controlling these dudes? Ans - the suppressor genes (Rb and
P53) ---> keeping the cell cycle in G1 phase, so that everything can be
cleaned up a little bit before it goes into S-Phase and gets initiated.
Mechanisms:
Point mutations: like trinucleotides, that could be substituting adenine
for thymine.
The 2 most important genes involved in cancers are both involved in
point mutation ---> P53 suppressor genes and Ras-Oncogenes are
point mutations.
All suppressor genes are point mutations.
Amplifications: its kind of like PCR-reaction which makes multiple

copies of something. The Erb-2 in breast cancer is the amplification

type of system.
Translocation: Take something and put it in some other place. In
translocation things translocated cannot go back.
Classic translocation:
CML: Translocation of the Abl, it has non-receptor tyrosine kinase
activity. Abl gene translocated from chromosome 9 to 22 and where it
fuses with the great cluster region forms its fusion gene (philadelphia
chromosome), and all of a sudden because of its tyrosine activity --->
it sends a message and those stem cells just keeps on dividing.
EBV: Cancer ---> translocation of Myc nuclear transcriber gene from
chromosome 8 and it sticks around the chromosome 14 ---> Burkitts
lymphoma; There is a receptor for EBV in all of our B-Cells (CD 21)
---> when it hooks into CD 21 ---> B-Cells becomes plasma cells and
make antibodies; Because of the fact that it stimulates the B-Cells to
become plasma cells, lots of divisions occurs ---> the more cells
divides ---> more something can happen to it.
t(14:18): B-Cell lymphoma involving the inactivation of suppressor
gene.
t(15:17): Acute progranulocytic leukemia ---> Rx Retinoic acid (Vit A)
---> Matures the blasts, so the malignant cells becomes benign.
Suppressor Gene: Use to suppress; We knock them off ---> what ever
they were suppressing keeps on going.
Familial Adenomatosis polyposis coli:
Suppressor gene - Neurofibramatosis & Wilms tumor - suppressor
gene ---> BRCA-1 (Ch. 13) & BRCA2 (Ch. 17)---> DNA repair.
BRCA-2 totally associated with breast cancer.
BRCA-1 can be breast cancer or ovarian cancer.
Only 15% have genetic relationship and most of the time they are not
genetic.
Suppressor genes and protoncogenes are inhibited by: Chemical,
viruses and radiations. The most common is chemicals (80%)--->
smoking ---> polycyclic hydrocarbons are the carcinogens of smoke
---> not just lungs cancer also of mouth, larynx, pancreas, bladder,
cervical, colon, leukemias.

Pappillary tumor in bladder: most common cause of transitional

cancers is smoking. In dye industry it would be: Amylin.
Qs: If you have Wegeners granulomatosis, you are put on a drug and
ended up with hematuria; you did a cytology which showed some
abnormal cells. Which drug ---> Ans - Cyclophosphamide.
Cyclophosphamide: Causes hemorrhagic cystitis ---> Rx Mesna;
Carcinogen for transitional cell carcinoma.
Lungs: Cancers that are most often associated with smoking are
squamous and small cell.
Non-pruritic raised red lession ---> kaposi's sarcoma (HPV-8)
Burkitt's lymphoma ---> EBV
Nasopharyngeal carcinoma ---> EBV (commonly in Chinese)
Hepatocellular carcinoma ---> HBV (Asians); Combination of HBV +
Cirrhosis + Aflatoxin B (in food) ---> Most common cancer in far-east;
HCV can also produce liver cancers.
Primary senile Lymphoma ---> HIV ; Qs - rapidly increasing incidence
of prim. CNS lymphoma in USA. are directly attributable to? Ans - HIV.
Squamous. Cancers ---> HPV (cervix, Vagina, vulva, Anus in
homosexuals, unprotected intercourse); E6, E7 protein products --->
E6 knocks off the P53, and E7 knocks of Retinoblastoma.
Most common cancer associated with Radiations is Leukemia;
Most common leukemia associated with radiation is Chronic
Myelogenous Leukemia -> t(9;22) of Abl-protoncogene.
Qs: History of radiation in the head and neck area, they have nontender nodular mass in the cervical region - Ans, Metastatic Papillary
carcinoma of thyroid related to ionizing radiation;
Another one is Osteogenic sarcoma.
Qs: Which medical profession is most likely to get Acute leukemia?
Ans, Radiologist.

Qs: Disease with radiation, what would you be? AnsNeuropathologists as they are dealing with brains and the prions.
Basal cell carcinoma: picture: Multifocal; Non ionizing radiation
(ionizing is the bad stuff of radiation); UV-B light (B = Bad).
UV-A: Superficial dermatophytes, shagreen patches in tuberous
sclerosis ---> Rx Black Light (UV-A).
UV-B: Protects from skin cancers like Basal cell Ca. most common, Sq
cell Ca 2nd most common, malignant melonoma; by mechanism of
Thymine dimers.
Precursor lession for certain cancers that are commonly seen in sun
exposed area, which you can scrape it off and it comes black --->
Actinic keratosis (solar keratosis) ---> predisposes to Sq. cancer --->
Pearly grayish white and looks like somebody just scraped it off.
Actinic keratosis: Only 3-4% of Actinic keratosis becomes squamous
cancers;
Heavy metal - Arsenic; Country - Bangladesh (probably water supply
which is contaminated with Arsenic related cancers are increasing).
Arsenic related cancers: Skin cancers, lung cancers, and angiosarcoma
of the liver.
Kid with white eye reflex ---> retinoblastoma, chromosome 13.
Qs - How many mutations does it takes for sporadic to become
retinoblastoma? Ans; 2 separate ones ---> You have to knock one
from One chromosome 13 and from another one.
Qs - How many mutations in autosomal dominant genetic inheritance?
Ans- 1; You are born with one already and activated, so you need one
more mutation on the other chromosome only.
White eye reflex is most commonly caused by congenital cataracts
(congenital infections like CMV or Rubella etc.) ---> shinning a light on
newborn eye ---> its white ---> retinoblastoma.
Qs - Why would a patient with Cushings have cataracts? AnsCorticosteroids, predispose to cataracts
Neoplasia 3

The sun exposed area would be predisposed to all the skin cancers
(basal cells, Sq Cells and melanomas).
Xeroderma pigmentosa: Autosomal recessive disease. Defect in the
DNA repair enzymes.
Group of diseases which are also DNA repair enzyme defects --->
BRCA1, BRCA2, P-53.
Chromosomal Instabillity syndrome: Wiskott aldrich syndrome, Bloom
syndrome, Ataxia telangiectasia, Fanconi's syndrome ---> All of them
have problems with DNA repair.
Upper Lip: Basal cell.
Lower Lip: Squamous cell.
Sq Cell Ca: burns, develops in the draining sinus, also doesn't heals
with antibiotics, constant irritation in the division of cells ---> greater
risk of cancer because you are dealing with squamous epithelium not
glandular epithelium
Lungs: Scar-cancers related to Old TB scar are adenocarcinoma not
squamous (related mostly to skin)
Only bacteria associated with the cancer ---> H.Pylori --->
Adenocarcinoma and Low Grade Malignant lymphoma.
Grade of the cancer ---> what's it look like.
If you can identify what it is because it is doing something like making
keratin, glands and is well differentiated ---> Low Grade.
Its anaplastic and high grade, fully differenciated ---> you cant tell by
looking at it under Microscope what it is. Grade term
Slide: Sq cancer ---> Keratin pearls (you can identify it ---> low
grade)
Slide: Gland like spaces ---> Adenocarcinoma ---> (you can identify it
---> low grade)
Stages of tumor:

T - Toy ---> Size of the Tumor (<2 sonometers it generally has the
chance to metastasize)
N - Nancy ---> Nodes
M - Machine ---> Metastasis outside the nodes.
Most common staging system which goes from least important to most
important.
Scenario: Breast Cancer ---> Low axillary nodes are involved ---> You
think that its the worst part but instead it the end part of TNM --->
Worst part when it is out side the lymph nodes likes bones, lungs, or
liver.
Most important prognostic factor is stage!
In staging the most important thing is Metastasis.
Qs: Which is the worst prognosis in prostate cancer?
a Limited to prostate
b Went into seminal vesicles
c Went into wall of the bladder
d went into lymph nodes around the bladder
e went into the bones (Correct)
Slide: Colon Cancer ---> Lymph nodes. Which one is important size of
the tumor or lymph node involvement? Ans- Lymph node; Simillar
focus of cancer in the liver ---> then liver is the most important
prognostic factor.
Host Defenses: The most important is Cytotoxic CD8-T cells (No 1
most imp. host defense sys. we have got); We have other things --->
Macrophages, NK cells, Antibodies (Type2 HSN).
Cyt-CD8 T cells: They rounds every day looking for altered class I
antigens ---> when ever neoplastic cells those class 1 antigens --->
Cyt CD8 T cells they get interested in that cell to kill that cell ---> put
perforin which is the signal to Caspases (proteases ---> start breaking
down the nucleus, screwing up the mitochondria) to start apoptosis.
Cachexia: Cause is TNF ---> irreversible. Once you see the pt with
disseminated cancer just beginning to go into the catabolic state, you
can get them total parenteral nutrition ---> they will not get their
muscle mass due to TNF-alpha.
Hematologic causes of anemia are present in malignancy. Most
common anemia in malignancy is the anemia of chronic disease.

Colon cancer: Left side obstructs and the right side bleed ---> if you
have the right sided colon cancer ---> then iron deficiency will be more
common; Metastasis to bones and replaced all the bone marrow --->
anemia.
Chemotherapy drugs that are cell cycle specific or non specific --->
you wipe out the marrow.
Autoimmune mechanisms with certain types of cancers; But overall is
the anemia of chronic disease.
Most patients that have the disseminated cancers are hypercoagulable
(tendency of forming clots)
Qs: Pt that has the painless jaundice, left supraclavicular nodes, light
colored stools, he has this peculiar lession in the vein which jumps
from one part of the body to the next? Ans-Trousseau sign, superficial
migratory thrombophelibits of the patient with carcinoma of the head
of the pancreas.
Pancreatic cancers also likes to go to left supraclavicular nodes.
Disseminated cancers - Thrombocytosis: An elevated platelet count.
Labs: We need to work up the cause of thrombocytosis --->
hematology slip; Iron deficiency, scar over here (left abd --->
splenectomy), if TB; No obvious cause of thrombocytosis that rule out
the Myeloproliferative dissease or stuff like that.
40% of all disseminated cancers have thrombocytosis.
Most of the time Colon cancer is missed due to presence of black stool.
Stool guaiac is important
Fever: Most common cause of fever in malignancy is gram (-)
infection. Usually gram (-) is hospital acquired.
E.Coli - Indwelling catheter
Pseudomonas Aeruginosa - Repirator
Staph Aureus (gram +) - Indwelling catheter in vein.
Most common cause of death in cancer is infections.

Paraneoplatic syndromes: These are the signs which shows that there
may be some underlying cancer. They are kind of clues, tells that
something going on in the patient, so you can actually find that cancer
before it get metastasized.
Most common Paraneoplastic syndrome is hypercalcemia.
Qs:There are 2 mechanisms behind hepercalcemia in malignancy.
1) It has metastasized to bones ---> produce some kind of chemical
like IL-1, PGE2 that activates osteoclasts ---> produces lytic lesions in
bones ---> Hypercalcemia.
2) It can be Cal??? cancer like a renal adenocarcinoma or sq.
carcinoma of main stem bronchus which makes paratharmone like
peptide and cause hypercalcemia. It acts like pth
Which one is the paraneoplastic? Ans- 2nd one.
Slide: Two lessions that are black here. Both of these are phenotypic
markers for same cancer, the gastric adenocarcinoma. The black
lession under the arm is acanthosis nigricans; This is called as
seborrheic keratosis (beningn). If they develope all of a sudden, called
Lesser-Trlat sign, you get multiple outcroppings of these things --->
phenotypic marker of gastric adenocarcinoma.
Acanthosis Nigricans: Also associated with other things like Insulin
receptor deficiency related to DM, also with MEN syndromes. So its
phenotypic marker for lots of things but most commonly gastric
adenocarcinoma.
Clubbing: Hypertrophic osteoarthritis ---> Inflammation underlying
bone, periostitis, thats stimulates increase in soft tissues development
producing clubbing; Clubbing also associated with bronchiectasis,
inflammatory bowl disease, but in case of malignancy it would be
mostly associated with primary lung cancer.
Dermatomyositis: Least common collagen vascular disease which is
most commonly associated with underlying cancer, and with elevation
of serum CK, raccoon eyes (heliotrope eyes), inflammation of skin and
muscles. High association with Leukemias, lung cancers, lymphomas
etc, and Goytrans patches over the knuckles.

Marantic endocarditis: Vegetations on mitral valves, sterile which are

associated with mucous producing cancers like colon cancer. Its a
paraneoplastic syndrome, not infected, can embolize (pretty big and
can chip off); Looks similar to Rheumatic fever, looks like right along
the margins of the valve, except the history tells that its related to
colon cancer then rheumatic fever.
In infective-endocarditis: Huge vegetations.
Libman sacs endocarditis: Vegetations are all over the place.
Qs: Hyponatremia or cushings?; Lung ; cancer - Small cell carcinoma;
Harmones - ADH and ACTH.
Small cell cancers are APUD tumors, S100 antigen positive, neural
crest origin and neurosecretory granules on EM.
Qs: Hypercalcemia or Secondary polycythemia?; Renal
adenocarcinoma, can make parato-hormone like peptide and they can
also make erythropoietin (EPO).
Qs: Hypoglycemia or Secondary polycythemia?; Hepatocellular
carcinoma, can make EPO producing polycythemia, can produce insulin
like factor producing hypoglycemia.
Qs: Hypocalcemia or cushings?; Autosomal dominant, rare tumors
where the tumor markers can be converted to amyloid?; Medullary
carcinoma of thyroid; Tumor marker = Calcitonin.
- 2 tumor markers always get in case of Testicular cancer: AFP and
HCG.
AFP: A marker for yolk sac tumor (endodermal sinus tumor).
AFP Sounds young, its the albumin of fetus. So tumors in kids like the
ovaries in girl are most commonly yolk sac tumors. Also associated
with hepatocellular carcinoma, increased open neural tube defects
(have to be on folate before pregnancy to prevent neural tube
defects), and decreased in down syndrome.
BenceJones proteins: Marker for a malignancy of bone that is
associated with mono-clonal spike ---> MM.
BJ protein is the light chain of I-Globulin.

PSA: tumor marker for Prostate cancer. It can be increased in

hyperplasia. It is sensitive but not specific.
PSA: Its not increased during Digital Rectal Exam ---> its not an
enzyme, but an antigen and actually with in the cell and cannot
increase anyways. prostatic acid phosphatase, that would change.
Breast Cancer: CA 15-3
Ovarian Cancer: Surface derived CA-125
Colon Cancer: carcinoembryonic antigen (CEA) ---> also in small cell
and breast; CEA can be part of immune complex ---> CEA - Anti-CEAcomplex, immune complex which is deposited in kidney and can
produce nephrotic syndrome (diffuse membranous
glomerulonephritis).
Over all good percentage of nephrotic syndrome in adults is diffuse
membranous glomerulonephritis, and most of them are related to
malignancy. One of the common malignancy is colon cancer because
CEA could be antigen part of immune complex and end up depositing
into glomeruli.
Women with a trophoblastic tumor or mole: Tumor marker - Beta HCG.
Most common Primary tumor of the brain in kids: Cerebellar cystic
astrocytoma (benign) of astrocytes; not medulloblastoma, its the most
common primary cancer in kids.
Most common childhood cancer: Leukemia (specifically ALL); 2nd
group is CNS tumors; after that neuroblastomas, very common in
renal medulla; Burkitts lymphoma also B-Cells;
Ewings sarcoma, tumor of the bone with "Onion skin" type of
calcification; Embr
yonal rhabdomyosarcoma.
Incidence of cancers in man and women:
Womens:
No 1 Cancer: Breast
No 2 Cancer: Lungs
No 3 Cancer: Colon

Man:
No 1 Cancer: Prostate
No 2 Cancer: Lungs
No 3 Cancer: Colon

2nd most Common cancer and cancer killer in man and women

combined: Colon cancer.

After Age 50 onwards: Should have rectal exam and stool guiac, men
get a flexible sig, endo, or colonoscopy, depending on the risk.
After 50 the most common cause of +stool guiac is colon cancer.
Gyn Cancer: Most common is endometrial; 2nd Ovarian; 3rd Cervix,
because of pap-smear.
Cervical Pap smear: If you pick up the sq. cell dysplasia which is not
the cancer ---> you treat the patient.
Initially mammography the incidence of breast cancer increase.
Same thing with prostate cancer and PSA, they got leveled off. Which
means we need more sensitive techniques to pick them up.
Gyn Cancer killers:
1 - Ovarian 2 - Cervical 3 - Endometrial
The most common has the best prognosis: Endometrial.
Only known existing tumor vaccine: Hepatitis-B
Most common infection in hospital by accidental needle stick in a
hospital: Hepatitis-B ---> the viral burden of Hep-B is more then any
infection.
Once you got vaccinated you will not get: Hepatitis-B, Hepatitis-D
because it need surface antigen, and also HCC related to Hepatitis-B
related cirrhosis.
You can irridicate HCC which is most common cancer in far east by
simple vaccination.
----------End Neoplasia ----------Hematology in Neoplasia 3 (31:50)
Microcytic Anemia: MCV <80
Iron Deficiency: Most common
Macrocytic Anemias: MCV >100 - B12 and Folate deficeincy (Folate

and Alcoholics)
Normocytic Anemias: Low Retic count (Aplastic anemia, Renal
disease).
Corrected Retic count increased: Hemolytic anemia, Spherocytosis,
sickle cell, G6PD deficiency, autoimmune hemolytic anemia,
microangiopathic anemia.
Correcting the Retic count next to Complete blood cell count is your
first step in a work up of any anemia.
Reticulocyte: A young red blood cell. In 24 hours a reticulocyte
becomes a mature RBC with biconcave disc.
In case of anemia the retic count becomes important because it tells
you where the problem is, either in bone marrow in making the RBC or
is it a problem outside the bone marrow causing the problem.
If Bone Marrow was the problem, retic count would not be good --->
inappropriate response ---> you got a marrow that has RBC
hyperplasia ---> BM making lots of RBC and gonna put some of those
reticulocytes out a little bit prematurely ---> that means its working
and doing something, trying to correct the anemia.
In case of blood loss, it takes 5-7 days before it begins getting retic
count increased. Kinda like the kidney dealing with HCO3 in acid base
disorder.
If there is nothing wrong with bone marrow then there should be a
good reticulocyte response (No need of bone marrow exam), if there is
something wrong, it there won't.
You have to correct the retic count to the degree of anemia.
The Corrected retic count is the hematocrit of the patient divided by 45
which is considered as normal (for both male and females) multiply by
retic count that you have been given.
Scenario: The pt hematocrit is 15% (severe anemia). Retic count 9%
(increased, any thing over 3% is considered increased); If you did not
corrected, it looks like bone marrow responding appropriately because
its 9% but you have to correct it according to the degree of anemia;
So 15 over 45 is 1/3 - Divided by 9 = 3, so actually when we correct

the anemia we have a 3%, thats what corrected is.

Its a marker for good response. So 3% or greater - good response.
3% or less - Bad response.
Reticulocyte: Not regular with wright giemsa stain? - Nope, then we do
special stain to see the black filaments which are RNA filaments (looks
like little black worm) ---> showing reticulocyte still synthesizing Hb.
So in 24 hr about 25% of the Hb that normally should be in mature
cell being synthesized.
Wright giemsa stain: Blue color (polychromasia). These are young RBC
then 24 hr old Reticulocytes. These are the cells that still have
basophilia (normally present in cells of marrow not in peripheral blood)
---> If present means BM is really responding and pushing younger
cells out;
If they are talking about Polychromasia, they are talking about these
cells, which takes 2-3 day before they become a mature RBC;
When we are working on anemia, we do a corrected retic count, we
wanna know how the bone marrow responding in this day;
Problem - when we do the reticulocyte stain these dudes (?) takes the
RNA filament in them too, which will be counted and the retic count
becomes falsely elevated, thats not what we want ---> factor them
out, divided by 2. So we make our first correction for the degree of
anemia, that's done automatically, this case was done with 3%. So we
look at the CBC slip and we see no access polychromasia, that's the
corrected retic count. If CBC slip says polychromasia present which
means we have to make an additional correction; So it is arbitrarily
divided by 2 and now all of a sudden our corrected count is 1.5% --->
a bad BM response.
Slide - Reticulocyte: Can you see that with wright giemsa stain? - No;
Ribosomes don't look like threads, but looks like dots (Basophilic
stippling).
Lead poisoning cause Basophilic stippling - those are persistent
ribosomes not RNA filaments (looks like filaments or worms).
CBC Slip: Hb x 3 = Hematocrit; We had a 15% hematocrit of previous
example whats the Hb? Ans - 5.
Transfusion of Packed RBC: For every unit of packed RBC, you increase
the Hb by 1 and Hematocrit by 3%.

Qs: Pt got 5gm of Hb, was given 3 units of Packed RBCs, the following
day Hb is 6, Hematocrit is 18, is that a appropriate response? Ans - Hb
8 with Hematocrit of 24; Why it wasn 't 8? Ans- Pt had GI bleed, the
most common of anemia is iron deficiency and the most cause of iron
deficiency is GI bleeding overall.
Most common reason why the Hb and Hematocrit do not go up after
the transfusion of RBC, you are loosing blood most commonly in GI
tract; If you are thinking Hemolysis - its 1 in 250,000 chance.
Hb Electrophoresis is mainly used to detect different kinds of
Hemoglobinopathies.
MCV: Either Small dude,Normal dude, Big dude. Machine takes
average size of the cells. Its the best way of classifying the anemias.
If normal is 80-100. If average MCV is <80, then it is microcytic --->
play odds its iron deficiency; If its between 80-100 and have an
anemia, then it would be normocytic anemia; If greater >100, then its
Macrocytic anemia.
In case of Small cells and large called Dimorphic RBC population --->
Normal MCV ; Kinda like those blood gases, m.acidosis and m.alkalosis
---> Normal PH.
Iron deficiency anemia and Folate deficiency: They are reabsorbed
---> Iron in duodenum, Folate in Jejunum, B12 in terminal ileum, it
means that you have small bowel disease like celiac disease, you have
malabsorption that effects different areas of small bowel.
Celiac disease: most common cause of Malabsorption ---> duodenum
and Jejunum ---> deficiency iron and folate ---> small cells and large
cells; lets say its involving jejunum and terminal ileum ---> deficiency
of B12 and Folate.
So its possible to have 2 anemias at the same time and normal MCV.
Red Blood Cells Distribution Width (RDW): Its basically, the machine
looking at the RBCs that are coming to the machine, are they
uniformly small, normal, macrocytic or tremendous difference in size.
RDW can detect the change in the size and reports it as a Number.
Qs: Microcytic anemia, RDW increased? Ans- different size in
microcytic cells, difference in the sizes, may be got some small ones

and may be normal ones and RDW is picking that up.

You are normocytic before you become microcytic. So when you are
developing microcytic anemia, you gonna have some normocytic cells
that have't become microcytic yet ---> size variation which is picked
up by RDW.
CBC Slip: Low MCV, Increased RDW ---> Iron deficiency, not
thalassemia (genetic, all microcytic)
Slide: RDW ---> high; Spherocytes (has too little membrane and
cannot hold biconcave disc ---> anorexic), target cells (too much
membrane ---> obese cells ---> bulging in the middle ---> more Hb
can collect in there ---> bulls eye).
Target Cells: Markers for alcoholics (alters the cholesterol
concentration in membranes) and Hemoglobinopathies (eg. Sickle cell,
thalssemia, Hemoglobin-C).
Mature RBC ---> biconcave disc, thin in center having less Hb and
more concentrated at the peripheries ---> central area of pallor in
normal RBC.
Slide: All microcytic anemias have one thing in common, they have
decreased Hb synthesis. If we are not making lot of Hb ---> redness of
the cells markedly decreased and you will see greater area of palor.
Spherocyte: The cell with too little membrane. No area of central palor
and all red---> must be spherocyte.
Best way classifying anemia is by MCV.
You have small cells and large cells, which will come out with normal
MCV.
CBC Slip: When ever you have retic count in percentage ---> you have
to make the correction first to the degree of anemia, hematocrit of the
patient over 45 times the retic count; See for polychromasia, if not
present ---> you correct the anemia and you have the no. --->if it is
3%or higher, bone marrow responding appropriately ---> if 2% or
lower BM not responding; If polychromasia present ---> you divide the
initial correction of anemia, divided by 2, you look at the no. ----> 3%
or higher, good response ---> 2% or lower, bad response.

Signs of anemia:
Spoon nail: Sign of iron defeciency ---> also called as Koilonychia.
Hematology
Post 37: (Dated: March 01 - 2009)
Cheilosis: Cracking (many things produces it like iron deficiency or
riboflavin but not specific).
Palor of conjunctiva: 6 gm or less Hb.
You look in the palmar crease (caucasians): Dont see red in them --->
Anemic.
Slide: Lead line; Discoloration ??? margin ---> lead poisoning.
Neurological Exam is very important in B12 def. because you knock off
the posterior columns and lateral corticospinal tract --->
proprioception abnormalities and decreased vibratory sensation;
Lat.Cort.Sp.Tract have babinski.
Normal Serum Iron = 100 (same with Alveolar O2).
Ferritin: Circulating soluble form of iron storage. It also represents the
amount of iron stored in the bone marrow.
So if you have to pick one test for diagnosing iron deficiency, Anemia
of chronic disease, or iron overload disease ---> it would be serum
Ferritin which is the best screening test.
TIBC: Carrying protein for iron? Ans- Trans = Carry, Ferrin = iron --->
protein carries iron.
All proteins made in liver. Transferrin or TIBC are same.
There is a relationship between the iron stores in the bone marrow
with the transferrin synthesized in the liver. When the iron stores in
bone marrow are difficient ---> iron defeciency ---> it is the signal to
liver to make more transferrin ---> increase TIBC; So low iron stores,
increased transferrin synthesis = increased TIBC ---> kinda like
inverse relationship like hormones ---> T4 increased / Tsh decreased =
iron stores decreased / Transferrin , TIBC increased or vice versa.
Percent sat.: Its a calculation. Serum iron divided by total iron binding
capacity; Normaly serum iron is 100; Normaly TIBC is 300; Normal

%Sat = 100 / 300 = 33%.

Endocrinology: Hormones when they bind to their binding proteins like
Thyroid Hormones or thyroid binding globulin, trancortin or cortisol
---> thats always 1/3 of the binding sites are occupied by what ever is
on the binding protein; 33% = 1/3; Pretty close for albumin, 1/3 of
the binding sites ---> Ca binds to it.
Microcytic anemia have few things in common; One they are
microcytic, Why? Ans- Basically their problem is in making Hb. When a
RBC is developing in a marrow, its the Hb concentration in that
developing RBC that determines the number of cell divisions. Therefore
if the Hb synthesis is decreased thats the signal to the RBC of the
marrow to increase the number of mitosis (when cell mitosed, it goes
from something that was originally big to something small). So
because of the decreased in Hb synthesis in those RBCs ---> there are
extra divisions ---> microcytic.
So all 4 groups of Microcytic anemias have decreased Hb.
Hb Synthesis: Heme + globin; Heme = Iron + protoporphyrin; Globin
---> 2Alpha + 2Beta = HbA,
2alpha + 2 Delta = HbA2, 2alpha + 2 gamma = F.
Iron + protoporphyrin + Globin Chains = Hb.
Iron defeciency: You dont have iron. Therefore there is no iron to put
together with protoporphyrin to form heme. No iron = no heme = No
Hb.
Anemia of Chronic disease: When we have inflammation our body's
responds to inflamation ??? infection ???; Bugs particularly bacteria
increase their reproduction with iron ---> more iron, the more they are
reproduced; When you have anemia of chronic inflamation the body
assumes thats its related to bacterial infection, the object is to keep
the iron away from bacteria.
How is it do that? Ans- Its like safety deposit box and you have the
key. Iron is normally stored in macrophages in bone marrow, thats
where tranferrin goes to pick up the iron to deliver it to the RBCs =
like safety deposit box. Since we dont want bacterias to have access to
iron ---> we gonna lock it away in those macrophages in the BM and
loose the key. So we have lots of iron in those Macrophages in marrow,

but you cant get it out. Good news, you are keeping it away from bugs
so they cannot reproduce. Bad news, keeping it away from the RBC so
you have decreased Hb synthesis. Unlike iron defeciency where there
is no iron in macrophages but in this case piles of iron
in the macrophages but its like a safety deposit box and you are the
only one who have the keys.
Sideroblastic anemia: Sidero means Iron like Ferro.
Reaction Locations:
Biochemical reactions in inner mitochondrial membrane: oxidative
phosphorylation.
Mitochondrial matrix: Beta oxidation of FA (TCA cycle) in Cytosol and
mitochondria.
Gluconeogensis starts in mitochondria and ends ups in cytosol.
Urea synthesis: Starts in mitochondria, goes into cytosol and back into
mitochondria.
Heme synthesis: parts in mitochondria, parts into cytosol and parts
into mitochondria again.
First part of heme or porphyrin synthesis, begins in mitochondria; The
first reaction - succinyl-CoA (in TCA cycle, substrate for
gluconeogensis) ---> put together with glycine.
Glycine: Simplest AA, an inhibitory neurotransmitter of muscles,
blocked by tetnus toxin causing opisthotonus, risus sardonicus, and all
those tetanic contractions of muscles; Every 3rd AA in collagen is
glycine and we can see that its also involved in heme synthesis.
Rate limiting enzyme in heme synthesis, porphyrin synthesis ---> ALA
synthase (cofactor - pyridoxine); delta amino levulinic acid, other
enzymes ---> they go to porphobilinogen, uroporphyrin ??? back into
mitochondria.
Protoporphyrin + iron, put together by chelating agent
(Ferrochelatase) ---> combines iron together with protoporphyrin to
form heme.
Heme has the feedback mechanism as do all rate limmiting enzymes
with ALA-Synthase; heme increased ---> Inhibits ALA-Synthase; Heme
is decreased ---> enhances ALA-Synthase.
Rarest of all microcytic anemias, sideroblastic anemia. Three main
causes:

1- Alcohol ;Mitochondrial poison, it uncouples the Ox-phosprylation,

damages the inner Mitochondrial membrane, allows the protons to go
in there and drain them-on ???; Electron Micrograph of the
mitochondria ---> they are huge called megamitochondria (damaged)
---> So any process that occurs in the mitochondria is screwed up,
which includes Heme synthesis. So Iron gets delivered to the RBC by
transferrin ---> some of it stays there and gets stored as a ferrtin and
most of the times it goes into mitochondria ---> bad news, it can getin
but cannot get out ---> Lots of iron being caught in mitochondria,
stops filling up with iron. Since a mitochondria is located around the
nucleus of the Bone Marrow ---> we get ring sideroblast (marker cells;
also in iron overload disease).
2- B6-Pyridoxine deficiency: Defeciency while Rx with isoniazid for TB.
No B6 ---> No Heme. The very 1st reaction is not gonna happen. The
iron does't know that and it goes right in there ---> ring sideroblast.
3- Lead poisoning: Lead actually produces a sideroblastic anemia. Lead
(all heavy metals) is denaturer of proteins including enzymes --->
mostly ferrochelatase ---> No heme, No Hb, Microcytic anemia.
The most common cause of anemia overall is Anemia of Chronic
disease, followed by Folate deficiency.
Qs: If ferrochelatse is decreased or inhibited ---> heme decreases,
what happens to protoporphyrin before the block? Ans- Increases, not
used to be the screening test of choice for lead poisoning. Increased
RBC protoporphyrin. Not used any more. If you dont have iron present
because you have anemia of chronic disease, we have iron deficiency
---> protoporphyrin increased in mitochondria; Lots of people that had
increased RBC protoporphyrin ---> when they got blood lead levels
were negative ---> so they had iron deficiency or Anemia of chronic
disease ---> not good screen test for lead poisoning anymore.
Thalassemias: Autosomal recessive.
Alpha-thalassemias: Seen in two main groups of people ---> Asian and
black population. Infact all genetic diseases of hematology are seen in
the black population including G6PD, Beta-thal, alpha-thal, sickle cell,
all of them are commonly seen; Alpha-thal, in far-eastern black
population.
Hemoglobin electrophoresis: Is like any other electrophoresis,

separates things out on the basis of size and charge. It clearly

separates Hb-A, Hb-F, Hb-A2 clearly on cellulose acetate, because they
have different migrations. So they phores it, Hb-A, Hb-F, Hb-A2,
settles up. How much is there? Ans- they stain the cellulose acetate
which produce density which correlates with the concentration with
each of those hemoglobins. They gonna know the percentage by
running densitometer right across it and converts the density of the
stain to a percentage.
It turns out that normally Hb-A (2 alphas, 2 betas), is the predominant
hemoglobin in adult (95-96%); Hb-A2 (2 alphas, 2 deltas), may be 12%; Hb-F (2 alphas, 2 gammas), may be 1%. Alpha-thalasemmia:
autosomal recessive is the problem in making alpha-globin chains.
Since all A,A2 or F requires alpha chains ---> so all of them equally
decreased; Electrophoresis shows normal as they are equally
decreased and cannot take it up. There are four genes that control
alpha-globin chain synthesis.
If you have deletion of one the four, you wont have anemia.
2 genes-deletion, is a problem, mild anemia, microcytic since globin
part is gonna be decreased. You will get microcytic anemia --->
decreased Hb concentration. Called as Alpha-thal minor, seen in fareastern population and blacks.
3 gene deletions, is not good. Bad anemia, even have hemolytic
component. Beta-chains get really irrated because there are no alphachains and forms its own hemoglobin. So 4 beta-chains get together
forms Hb-H; Electrophoresis - Hb-H, a different Hb will migrate in
different place then others normally ---> you cannot diagnose with HbElectrophoresis, thats why called as Hb-H disease.
Hematology
Post 38: (Dated: March 04 - 2009)
4 Gene deletion: Should not even born alive. Its spontaneous abortion
usually.
No alpha chains for U-gamma chain, same what Beta-chain did
when it was irritated ---> makes its own Hb ---> 4-gammas (Hb
Barts). Its shown on Electrophoresis, but does't matter because the
baby is dead.
Qs: What is spontaneous abortion rate in Far East? Ans- Very high,
because thats where alpha-thal is most commonly located.

Therefore the most common cancer is choreocarcinoma in Far east, in

the incidence of spontaneous abortion; Perfect logarithmic relationship
---> if there is an increase in abortions like spontaneous or
hydatidiform mole ---> all predispose to choriocarcinoma. Extremely
high incidence of choriocarcinoma in the far east because of alphathal.
Rx of alpha-thal: Leave the patient without any treatment.
Gilbert's disease: 2nd most common cause of jaundice.
Beta-thal: Population ----> Blacks, Greeks and italians.
B : You are making normal amount of beta chain.
B+: You are making but not alot.
B0: You are not making at all.
Beta thal is autosomal recessive, nothing to do with gene deletion. It
deals with splicing defects, stop codons (infact it is the very severe
form ---> terminated before even a start of beta chian).
Mild-Beta chain: Slightly decreased due to splicing defect.
Alpha: Ok
Delta: Ok
Gamma: Ok (fetal Hb-F)
Decrease in Hb-A. Increase in Delta get together ---> HbA2, Gamma
get together ---> HbF. Its shown on electrophoresis ---> reason is
beta chain was decreased and decreased HbA would show up.
So the only way of diagnosing beta-thal is with Hb-Electrophoresis.
Rx: Nothing. But In severe type of beta-thal, hardly any Beta-chain
called Cooley's Anemia --->you are not gonna live past 30. You need
constant transfusion requirement. Infact most of the time they die of
iron-overload disease (eg, HepC, HepB, HIV).
Beta-Delta-Thal: Most commonly seen in Blacks, genetic disease. Hbelectrophoresis shows Hb-F.
Beta chain decreased, Delta chain decreased ---> alpha and gamma
left called as Hb-F disease, hereditary persistence of Hb-F. It is a
NOTHING hemoglobinopathy, you dont have anemia or anything, just

have predominant Hb-f.

Causes of iron defeciency anemias, according to age brackets:
1)Prematurity: Clearcut iron defeciency because everyday a baby is
not in utero is loosing iron. Iron sources are all decreased and need
iron supplements for all preemies.
2)New Born: If iron defeciency ---> check their stool, probably gonna
be positive for THEIR blood ---> you are gonna prove it either their
blood vs mommies blood which it swallows with AP-test???. Most of
the time blood in the stool of the new born when it comes out in
meconium, is the blood which baby swallowed of mommy, so it will
have Hb-A in it. But for some reason if it was Hb-F blood which comes
out in the stool ---> Meckel's diverticulum.
Meckel's diverticulum: Bleeding Ms.D most common cause of iron
defeciency in newborn. Also it might add child in general, but dont put
Mk.D as the cause of iron defeciency in adults because most of them
would have bled by 4 years of age, so you already would have known
that you had it.
3)Women, under 50 yrs ---> clearcut menorrhagia, most common
cause. You are going to get good menstrual history.
4)Under 20 yrs ---> Most common cause is going to be annovulatory
cycles.
5)B/w 20-40 yrs ---> Ovulatory cycles with irregular shedding of
endometrium like inadequate luteal phase, pregnancy related bleeds,
endometrial polyp which are bleeding etc.
6)Men under 50% ---> peptic ulcer disease, play odds, deudenal
ulcers.
7)Over 50 yrs, Men and women ---> Clear cut, Colon cancer.
8)Thallesemia ---> dont do anything, especially dont give them iron as
their iron studies are normal.
Lab test: Serum iron in iron deficiency = low, TIBC = increased, %Sat
= Low (nothing to put on transferrin); Anemia of chronic disease --->
lots of iron in safety deposit box, you cant get it out ---> serum iron is
low ---> TIBC = low (high iron stores, decreased transferrin

synthesis), %Sat. = low, Serum Ferritin = high.

The main difference in lab test that will distinguish chronic disease
anemias from iron deficiency? Ans- Ferritin and the other one TIBC (no
one uses it).
Iron studies in Mild alpha-thal and mild beta-thal: Normal, nothing to
do with iron but with globin chains.
Slide: Smear, decreased appropriate amount of Hb in those cells, more
then likely microcytic anemia (either iron deficiency, anemia of chronic
disease, thalassemia or even lead poisoning).
Slide: This is a ring sideroblast, only way to see ring sideroblast is do
bone marrow ---> stain it prussian blue, which stains iron ---> since
mitochondria are usually around the nucleus ---> they are all filled up
with iron. Here is the nucleus, these are mitochondria that are filled up
with iron, they form a ring around the nucleus and therefore called as
ring sideroblast.
If you think that B6 was producing microcytic anemia: Prove it by
doing bone marrow, and prove that you have those ring sideroblasts.
If you think that alcohol as cause of microcytic anemia ---> rule out
other stuff.
Hematology
Post 39: (Dated: March 08 - 2009)
If you suspect a lead poisoning ---> you wont need bone marrow --->
but simply plain old lead levels.
Lead poisoning: Coarse basophilic stippling (shown on wright giemsa
stain). Thats where you have RBCs, that have micelles, they have lots
of blue spots.
Coarse Basophilic stippling: Lead denatures ribonuclease (enzyme that
breakdowns the ribosomes) ---> ribosomes persist ---> gives marker
in peripheral blood showing lead poisoning (veryspecific).
If its a RNA filament ---> Reticulocyte
Persistent Ribosome ---> lead poisoning.
X-RAY: Epiphysis of the fingers of the child, and thats lead. Any heavy
metal that can deposit in the epiphysis of bone is lead. Mercury or

arsenic cant. Thats why they have failure to grow.

If you screw up the epiphysis of the kid, they are not gonna be able to
grow properly.
Scenario: Little dude that lives in poor area and he is eating paint,
plaster of the wall. In old days the paint had lead in it ---> Lead
poisoning ---> abdominal cholic, cerebral edema, convulsions, severe
microcytic anemia. You can do a flat plate of them and see lead in their
intestine.
Flat plate: three things you can see with it; iron ---> kid who took iron
tablets from mommy taking iron for menorrhagia ---> you can actually
see on x-ray, the iron tablets that are left undigested; You can see lead
and Mercury.
Cerebral Edema: Related to increased vessel permeability in brain, and
relates to the build up of delta amino levulinic acid (if you block
Ferrochelatase and every thing distal??? (proximal*) to that block
increases, like protoporphyrin and including delta amino levulinic acid
---> toxic to neurons, thats what causing it.
Qs: The guy that works in automobile factory with abdominal cholic
and diarhea ---> lead poisoning because they have exposure to
batteries. Usually in automobile factories they incinerate the batteries
to get the lead to use it again.
Moon-shine: Some people make alcohol in old radiators, bad thing
because they are lined by lead. So when you make alcohol, you
automatically get lead poison called as Moon Shine.
Pottery Painters: Pottery is commonly painted with lead based paints.
Lead Poisoning: Adults seems to get neuropathies (slapping gait,
peroneal nerve palsy, wrist drop ---> radial nerve palsy, claw hands
---> ulnar nerve palsy), lead lines in the teeth, abdominal cholic and
diarrhea.
Iron deficiency
Iron: Low
TIBC: High
%Sat: Low
Ferritin: Low

Anemia Of chronic disease

Iron: Low
TIBC: High
%Sat: Low
Ferritin: High
Alpha and Beta Thal
Iron: Normal
TIBC: Normal
%Sat: Normal
Ferritin: Normal
What are you gonna do about it: Nothing
Lead poisoning as well as all the other sideroblastic anemias are iron
overload thing, just like Hemochromatosis and hemosiderosis.
Iron Overload disease
Serum Iron: High
Iron stores: High
Where does the iron stores in Iron Overload disease: ???
TIBC: Low
%Sat: High
Ferritin: High
Slide: B12 and folate. Macrocytic anemia.
B12 and Folate are involved in DNA synthesis. If you are deficient, you
are not able to make DNA, specifically you have a problem in making
deoxythymidine monophosphate (dTMP) ---> you are not going to
mature the nucleus ---> immature nuclei dont have lot of DNA in
them, but as you make DNA, they become more mature and the
nucleus gets more smaller and more condensed. So because of the
fact that you cannot make DNA, then you have big nucleus ???--->
Megaloblastic anemia.
Pathologist: Diagnosis of B12 and Folate deficiency in the cervical
papsmear. when you look at the sq. cells ---> Huge nuclei ---> B12
and Folate deficiency Any cell that has a nucleus, has a DNA in it. So
any cell with the nucleus is big. Not just the hematopoitic cell that are
huge, all the nucleated cells in the body are huge like GIT, sq cells, all
of them.
Another name of B12 is cobalamin because B12 has Cobalt in it.

The Circulating form of Folate is called Methyltetrahydrofolate.

The purpose of cobalamin is to take the methyl group of
Methyltetrahydrofolate ---> called methylcobalamin, and
Methyltetrahydrofolate
now called as tetrahydrofolate.
We dont get the methyl group off from folate ---> not gonna make
DNA. We need both of them.
Cobalamin gives the methyl group and adds to homocysteine --->
methionine.
Methionine: Amino acid which is required for One carbon transfer
reactions. So when ever a carbon is needed, methionine gives its
carbon. Methyl is CH3 (has a carbon). Methionine has one extra carbon
with it that it will give to biochemical reactions that needs extra
carbon.
Qs: If you are B12 or Folate deficient, what would be the serum
Homocystein levels? Ans- High.
High Serum Homocystein: It produces thrombosis including MI,
damages endothelial cells and predisposing them thrombosis.
Most common cause of High serum homocystein levels: Folate
deficiency not Homocysteinuria (rare autosomal recessive).
People with either B12 or Folate defeciency have increased incidence of
thrombosis and MI.
Tetra Hydrofolate seems to be the start of cycle ---> We have got
thymidylate synthetase, so we know here the DNA made. We have
substrate over here, enzyme over here, we convert dUMP to dDTP
which is DNA; so this is the substrate which is necessary to form the
DNA. When it is used to make DNA, it is called as Dihydrofolate.
Dihydrofolate: Dihydrofolate reductase that converts the oxidized
dihydrofolate back to tetrahydrofolate. Lots of drugs blocks
Dihydrofolate reductase like SMX-TMP ---> Decreased DNA synthesis
---> macrocytic anemia.
So the function of B12 is to take the methyl group away from
methytetrahydrofolate and hand it to homocystein to become

methionine; Tetrahydrofolate thats starts of the cycle for making DNA.

B12 is humiliated by just transfering methyl groups. Starts different
thing like taking care of even chain FA (like 2,4,6,8) and metabolise
them with no problem. But we are going to have problem with odd
chain FA, because we are only breaking down the propionyl-CoA and
we cant go further and ending with lots of people with dementia and
problems with proprioception; So B12 is involved in propionate
metabolism which is odd chain FA metabolism.
Priopionate that form methylmalonyl CoA; B12 (co-factor) comes in
converts the methylmalonyl CoA into succinyl CoA (TCA cycle).
B12 deficient: Methylmalonyl Coa, propionate, builds up.
Methylmalonyl Coa becomes Methylmalonic acid which is a very
sensitve and specific test for B12 deficiency ---> it will increased.
Therefore when ever you have a situation with B12 levels or equal in
blood, always get a methylmalonic acid level as it will never fails you.
Hematology
Post 40: (Dated: March 10 - 2009)
The reason why you get neurological problems in B12 deficiency is
because of propionate metabolism ---> you cannot convert odd chain
FA into succinyl CoA ---> so they build up and screws up myelin --->
you cannot synthesize myelin ---> dementia, demyelination of
posterior columns and lateral corticospinal tracts.
In Dorsal or Post. Column disease you have problems with
propioception, vibratory sensations; Lateral Corticospinal tracts
disease ---> problems with upper motor neuron problems --->
spasticity, babinski sign, and dementia; All of these problems are
related to B12 not folate as it is not involved in propionate
metabolism.
Boards: They always tell you that you can have B12 deficiency and you
can correct the anemia with high doses of folate but you cant correct
neurologic disease.
Alzheimer's disease: Pt with with disease improved a little with
injection of B12. They improved because they did't had Alzheimer's
disease, just because they had dementia ---> it was B12 deficiency.
You dont have to have anemia with B12 deficiency but you can have
neurologic disease.

Pt with dementia, must get TSH to rule out hypothyroidism and B12 to
rule out B12 deficiency.
They are reversible causes of dementia.
B12 is an animal product. So you cannot be pure vegan and get B12.
Scenario: Comparing pure vegan to ovo-lacto vegetarian. If you are an
ovo-lacto vegetarian, you are taking dairy products as an animal
products, you wont have to be on B12 supplements. But if you are
pure vegan, you are taking pure vegetable products and no dairy or
meat products, you would require B12.
The very first thing you do when you are chewing, B12 binds to RFactor in saliva. The purpose of R-Factor is to bind the B12 to protect it
from getting distroyed by acid in stomach.
Intrinsic factor is made by parietal cells, located in body fundus (two
thing acid and intrinsic factor).
Intrinsic factor is't distroyed by acid so it does't need anything to
protect it. So the B12-R-factor complex goes into the duodenum where
the intrinsic factor is waiting for it ---> functioning pancrease that
cleave off the R-Factor ---> Intrinsic factor + B12 ---> complex takes
a long route to terminal ileum, where there are receptors for intrinsic
factors and get reabsorbed, its the same place for reabsorbtion of bile
salts and crohns disease.
So when you have crohn disease, you have Bile salts and B12
deficiency.
Duodenum: Iron country
Ligamentum triad - beginning of jejunum: Thats Folate country
The most common cause of all this stuff is pernicious anemia,
autoimmune disease with destruction of the parietal cells. There are
autoantibodies against parietal cells and intrinsic factors. Parietal cells
gets knock off and you get atrophic gastritis of the body andfundus, no
parietal cells no acid (achlorhydria) and no intrinsic factor.
Atrophic gastritis of the body and fundus with no acid ---> predispose
to cancer. Achlorhydria

is the major predisposing cause of adenocarcinoma.

B12 deficiency: You can be pure vegan and develop B12 deficiency,
chronic pancreatitis, Alcoholics (cant cleave off the R-Factor);
diphyllobothrium latum (giant fish tape worm); bacterial overgrowth
that means that you have some peristalsis problem in small intestine
---> may be diverticular pouches and stasis, when ever there is stasis
you get bacterial infection, similarly you can get infection with bladder
that does't Peristalts, small intestine normally does't have bacterias
and if does't peristalts ---> bacterial overgrowth.
Chicago lakes carry diphyllobothrium latum (giant fish tape worm).
Bacterias love B12-intrinsic factor and use it for dessert and adds salts
as bile salts ---> deficiency of them. Terminal ileal that equates with
crohns disease. All of these things can produce B12 dificiency.
Folate is seen in Animals and plant products. So you can not get in
pure vegans infact they have piles of folate.
Folate when you eat it is in polyglutamate form, which means that you
cannot reabsorbs in jejunum, so it has to be convert into a
monoglutamate form by an enzyme in small intestine called intestinal
conjugase (blocked by phenytoin).
So they ask you about some one thats on drug that ends up in
macrocytic anemia, with hypersegmented neutrophils, neurologic
exam normal (B12 excluded). What drug the pt on? Ans-Phenytoin.
Monoglutamate, absorbs folate in the jejunum. There are 2 things that
prevent the absorbtion of monoglutamate form in the jejunum: 1Birth Control Pill, 2- Alcohol.
The most common cause of folate deficiency is alcoholism ---> blocks
the reabsorbtion of folate.
B12 normally have 6-9 years of supply in liver so its very uncommon
to get deficieny. But folate only has 3-4 months.
This is the reason why fOlate deficiency is in STREET people that
drinks all the time and dont eat. You can have an excellent diet but still
unable to reabsorb folate because of alcohol.
Picture: Circulating form of folate after reabsorbtion is

methyltetrahydrofolate, B12 takes the methyl group off, give to

homocystein which becomes methionine. methyltetrahydrofolate
becomes tetrahydrofolate.
Slide: Auer rods, Hypersegmented (more than five lobes) neutrophils,
means B12 or folate deficiency even you dont have anemia. It is the
very first thing even before you have anemia.
If neurological exam normal its folate but if abnormal its B12.
Test for propioception is Rhomberg's Test (RsT): Ask the standing pt,
to close the eyes and open them ---> negative RsT, Pt always able to
keep itself; But in case of posterior column disease you are ok here,
ask to close eyes and open eyes ---> when pt with closed eyes did't
know where were the joints; RsT is not for cerebellar ataxia.
Rene's test or Webers Test: With that tuning fork and move down to
lateral malleolus too, and see for vibratory sensation, you can pick up
B12 by absent vibratory sensation. Those are all posterior column ???
Slide: Bone marrow, huge size of nucleus, they never mature, thats
why called as megaloblastic.
Hematopoietic cells are made outside the sinusoids in bone marrow; It
is analogous to the cords of billroth in the spleen, place where are
fixed macrophages then the RBCs and WBC have to get back into the
sinusoids and circulation through these holes. Same thing happens in
the BM, they have a place which is quivalent to cords of billroth and
thats where they are made, and to get into the circulation, they have
to fit through these little narrow couple microns wide holes, to get into
the sinusoids in a BM to get in to Blood stream.
Something that big (megaloblastic cells) get through those small slits
and get back into the sinusoids ---> No; So you can picture a big
feast, all these macrophages with all megaloblastic cells that cant get
into the sinusoids, including WBCs, RBCs, platelets cant get out.
Macrophages killing all of them ---> nothing in peripheral blood --->
pancytopenia, severe macrocytic anemia, neutropenia,
thrombocytopenia ---> characterstic findings of B12 or folate
deficiency ---> everything too big, and cant get out into the
circulation.
Shillings test: for localizing B12 deficiency. When you know that its

B12 deficiency, you give a radioactive B12 by mouth. They swallow it,
you collect the urine for 24 hrs and see if any of it comes out in the
urine. If Nothing comes out ---> proves they are having a problem
because they are reabsorbing B12.
Shilling Test:
1)Radioactive B12 + Intrinsic factor: Collected urine for 24 hrs --->
piles of B12 in urine = pernicious anemia; if did't work ---> you
exclude pernicious anemia.
2)10 days of broad spectrum antibiotics: Come back in 10 days, you
give radioactive B12 ---> piles of B12 comes out = Bacterial
overgrowth, you have knocked out those bugs that were eating B12; If
that did't worked ---> last thing left, pancreatic extract.
3)Pancreatic Extract: you give couple of pills, you gave radioactive
B12, 24 hrs latter ---> radioactive all over the place = chronic
pancreatitis; If that did't worked could be crohns disease or worms.
Normocytic anemias: When you do the corrections for the anemias,
turns out that its polychromasia, and the correction is <2 % ---> Not
good, normocytic anemia and BM is not responding correctly.
Hematology
Post 41: (Dated: March 15 - 2009)
The first 2 things that you will see here is early iron deficiency and
anemia of chronic disease. You have to have a normotcytic anemia first
before you become microcytic, so you still have to have differential
diagnosis of a normocytic anemia with corrected retic count <2%. You
still have to get a ferritin thats totally ligitimate.
Iron deficiency stages: First thing happens is that ferritin levels goes
down. The next thing iron decreased, TIBC increased, %Sat decreased
---> You still dont have anemia. In fact all the iron studies are
abnormal before you even have any anemia in iron deficiency, then
you get a mild normocytic anemia then eventually microcytic anemia.
Blood loss
Aplastic anemia: No Marrow. All the hematopoietic cells are destroyed
in the marrow ---> in peripheral blood ---> pancytopenia. You have
normocytic anemia, thrombocytopenia, Neutropenia.

You gotta do Bone Marrow.

Slide: Thats the normal marrow, thats the aplastic marrow ---> you
dont see anything, that the spicules there, the rest is plain old fat.
Aplastic anemia Causes: Idiopathic, drugs (chloramphenicol used in
rare situations like Rocky mountain spotted fever, indomethacin,
phenylbutazon, Thyroid related drugs); infections, one of the biggest
infection is Hep-C in which everything is destroyed, if you have purely
an aplasia of RBCs and everyting else is Ok and RBC is totaly
destroyed ---> parvovirus; Radiations.
Mechanism of normocytic anemia <2% corrected retic count in renal
failure ---> decreased EPO.
Do we have EPO available to give to some body? Ans- Yes, its made by
recombinant DNA, treatment of anemia in CRF (no need of blood,
decreasing Hep-B,C and HIV).
Professional Athletes: They are doping, taking EPO to increase amount
of RBC to carry more O2 so that they can last longer.
Mechanisms of Hemolysis:
There are two ways by which you can kill a blood cells. You can kill
intravascular (with in the vessel) or extravascular (outside the vessels)
Extravascular Hemolysis: By macrophages mainly in cords of billroth in
spleen, some times liver sinusoids with fixed macrophages. Every RBC
has to take couple of trips a day through the cords of billroth and
examined by macrophage. Presence of IgG or C3b ---> phagocytosed
and destroyed as the macrophages have receptors for IgG and C3b, if
not IgG and C3b but still RBC die due to abnormal shape (sphere) and
cant fit in a hole of 2 micron to get into the sinusoids. So spherocytes
are removed extravascularly they cant get out neither can a sickle cell.
What else can take RBCs out? Ans - They had got something inside ie
Piece of nucleus called as Howell jolly bodies. Macrophages tries to get
it out like Monkeys. Sometimes Macrophages can take it out or some
times someone not have too much membrane dies.
Those anemias with IgG or C3b on the surface are autoimmune
hemolytic anemias or you have abnormal shape like sphere or sickle
cell ---> cant make out of spleen and removed by macrophages.

End product of phagocytosing an RBC ---> Unconjugated bilirubin.

When RBC is broken down, you have Hb and there is an enzyme that
splits heme from globin and globin is broken in to Aminoacids and goes
into amino acid pool. The heme thing splits open gets the iron, now
you have protoporphyrin and it keeps on breaking it down and
eventually ends up as bilirubin in splenic macrophages ---> goes into
blood stream ---> lipid soluble, unconjugated bilirubin, bind to
albumin, goes to liver and its taken up and conjugated.
Clinical Findings in Extra vascular Hemolytic anemia: Jaundice.
Qs: Is ther any of that bilirubin get into urine? Ans- No because, oneits lipid soluble and, 2- its bound to albumin, dont get into urine. So
you jaundiced but dont have any of it in the urine.
Intravascular Hemolytic anemia: Less common type. When you die
with in the vessel, if you bang into something. Like congenital bicuspid
aortic valve with all Ca+ there, may be bang into while way out
through the aorta.
IgM: Which was on the surface of RBC. Potent activator of complement
system. It will go from I to IX which means that IgM gonna sit on the
blood cell and activate the complement system, makes a hole in that
cell dies intravascularly. So anything thats IgM mediated will be
intravascular hemolysis.
Intravascular hemolysis gonna release Hb in blood. Thats the soluble
commodity in our body. We dont wanna loose Hb in our urine. We
wanna retrieve some of it back so we can get Amino acid out of it and
certainly dont loose the iron. So there is specific protein, haptoglobin
that is made in the liver, also called as suicide protein because when
there intravascular hemolysis ---> all Hb that binds to it forms the
complex which is phagocytosed by macrophage and so it gives its life
in a sense to retrieve the Hb ---> Haptoglobin levels decreased.
Usually you dont have jaundice because if the macrophages
phagocytosing, there is some potential of Hb broken down but usually
not. So the key to intravascular hemolysis is, you have Hb-uria and
low Haptoglobin levels.
Therefore:
Intravascular Hemolysis: Removed by macrophages, unconjugated
bilirubin as end product, clinical manifestation as jaudice. Hb in Urine.
Decreased Haptoglobin.

Intrinsic Vs Extrinsic - When we talk about Hemolytic anemia that is

intrinsic, there is something causing RBCs to hemolyse like no spectrin
in cell membrane, no decay accelerating factor in the cell membrane to
neutralize complement, no G6PD enzyme in PPShunt, abnormal Hb like
HbS; Extrinsic means there is nothing wrong with RBC but it happened
to be in a wrong place and time. It just happens that it smashed into
calcified valve. IgG and C3b sat on RBC, goes into cords of billroth
---> hemolysis.
Something Intrinsically wrong with the RBCs causing it to hemolyse.
There is nothing wrong with the BM but something wrong with RBC. So
the corrected Retic count is >3 % after we correct for everything.
Pneumonic: M.A.D = Membrane defect (spherocytosis, paroxysmal
nocturnal hemoglobinuria), Abnormal hemoglobin (sickle cell trait),
Defecient enzyme (G-6-PD deficiency).
Slide: Absent central area of palor = spherocyte. Removed
extravascularly, cant get out of the spleen. Clinically manifested as
Jaundice (Unconjugated Bilirubin). Defective spectrin, autosomal
dominant. Since spleen is removing all these cells, it gets a little bit
hypertrophied after a while splenomegaly is always seen in these pts
over period of time. Also they get gallbladder disease because,lots of
Unconjugated bilirubin presented to the liver ---> lots of conjugation
---> lot of bilirubin in the bile than usual.
When ever you supersaturate anything thats the liquid, you run the
risk of forming stones.
You supersaturate urine with Ca+, risk of Ca+ stone.
You supersaturate bile with cholesterol ---> cholesterol stones.
You supersaturate with bilirubin ---> Ca+ bilirubinate stones.
So these pts commonly have gallbladder disease at very early age
related to gallstone disease.
The CBC shows Normcytic anemia with a corrected retic count which is
elevated. The smear ??? shows congenital spherocytosis.
Diagnostic test: Osmotic fragility. That put poor RBC that are wall-wall
membrane, very little membrane. They put it into test tubes with
different tonicity salines. They dont last in normal saline because soon
as the get Na+, no room for anything else ---> increase fragility.

Rx Congenital spherocytosis: Splenectomy.

Paroxysmal nocturnal hemoglobinuria: Its a defect in Decay
Accelerating factor. While sleeping there is a mild respiratory acidosis
because of decreased breathing rate (more severe in obs. sleep apnea)
---> predisposes the complement coming and sitting on cells (RBCs,
platelets, WBC) that are circulating in blood streams. We have decay
accelerating factor that causes increased degradation of complement
(does't have opporunity drilling a hole in the membrane) ---> no
neutropenia, Hb-uria, or thrombocytopenia in morning.
If Decay accelerating factor is missing ---> complement is activated
goes from I to IX ---> intravascular hemolysis ---> Paroxysmal
nocturnal hemoglobinuria, occuring at night and wake up in the
morning and pee out Hb.
CBC: Severe normocytic anemia, neutropenia and thrombocytopenia =
Pancytopenia. Very bad disease.
Slide: This is sickle cell. In sickle cell trait you have no anemia and no
sickle cells in peripheral blood. You could have sickle in certain parts of
body like renal medulla and peritubular capillaries but not gonna see in
peripheral blood. The amount of sickle Hb in RBC determines whether
its sickle or not. The magic no. is 60%. If you have 60% or more HbS,
then you can sponatneously sickle also O2 tension in blood. If you
lower the O2 tension lets say hypoxemia thats gonna do sickling.
Sickle cell is an Autosomal Recessive disease ---> both parents have
to have the abnormal gene on their chromosomes . Usually they are
both traits. So you can have person as normal, or person with Trait or
disease, the other partner also has to have the abnormal gene. So its
usually 2 traits. They dont even know that the have trait. So its 25%
chance of totally normal child, 50% chance of sickle cell trait, 25%
chance sickle cell disease when you have an autosomal recessive
inheritance pattern ---> we have 2 asymptomatic carriers to get it.
Same thing with cystic fibrosis. Asymptomatic carrier male +
asymptomatic carrier female ---> 25% chances no CF, 50% chances
asymptomatic carrier, 25% having actual CF (you have to be
homozygous for that abnormal gene).
Sickle cell Trait: You have a black individual whose totally normal on
Physical exam, totally normal CBC, microscopic hematuria ---> First
step in management ---> Sickle cell screen ---> if they have sickle cell

trait it will be positive; A black individual may have sickle cell 1 in 8

people. So thats the first thing you would be thinking about, not renal
stone or IgA glomerulonephritis.
Sickle cell disease: There are 2 things that happens. 1) You have
hemolytic anemia, usually extravascular. 2) You have occlusion of
small blood vessels by these sickle cells. These cells start pilling up in
small capillaries ---> vaso occlusive crisis ---> schemia. Schemia
always produces pain, so its painful crisis. Any organ in body from
lungs to liver, spleen or BM. When it occurs in childrens it begins in the
hands and feet with so called dactylitis.
So 2 things we worry about sickle cell disease is anemia which is very
severe and requires transfusion and, vaso occlusive disease where the
sickle cell just blocking the circulation ---> producing damage to
Kidneys; spleen gets autoinfarcted and gets about the size of thumb,
first 10 years of your life you have splenomegaly because you have all
traped RBC, so dont think that spleen completely autoinfarcted and
disappeared but take atleast take 18-20 years.
But after 2 years it becomes totally non-functional. So you might have
a big spleen but its does't works because its so damaged.
Slide: Thats a piece of nucleus, that should't be there called Howell
Jolly body ---> Thats how you know that the spleen is not working in
sickle cell. If the spleen was working a fixed macrophage in the cords
of billroth would have picked that out removed it. So start seeing these
come up in peripheral blood ---> spleen aint working. Fortunately
actually it happens by 2 years of age because its the time you get
pneumovax. When spleen is non-functional, there is one guaranteed
infection thats Strept pneumoniae sepsis, most common cause of
death in kids with sickle cell disease. So try to cover is antibiotic, and
pneumovax but you cant get pneumovax until 2 years of age, its thats
just about the time when spleen aint working and you start seeing
howell jolly bodies.
First sickle cell crisis: Kid develops, Hands and feet all swollen up and
so painful called dactylitis. It aint gonna occur at birth because HbF
(80-70% normally in newborns) inhibits sickling. In sickle cell disease,
60-70% of RBC have HbF and other one have HbS so enough HbF to
prevent sickling. As those RBC broken down the HbF is replaced, Hbs
increases and HbF decreases by 6-9th month of age, high enough
concentration to induce sickling and there first vaso occlusive crisis.

Slide: So this was the kid with sickle cell disease with dactylitis. They
X-ray the hand and the reason why those bones looked all washed out,
they were all white, and were infarcted.
Because whats happening is, bone infarction occuring due to sickling in
the BM and is infarcting the bone. It hurts so much. X-ray shows, kid
also have lead poisoning with sickle cell.
Dactylitis usually does't come till 6-9 months because HbF inhibits
sickling.
Osteomylitis: Sickle cell pts are very succeptible to osteomyelitis, not
the usually caused by staph aureus but salmonella. One reason for
that is dysfunctional spleen. Salmonella is destroyed by macrophages,
not by other mechanism. Thats why salmonella (75% of the times its
salmonella species) is the more common cause of osteomyelitis in
sickle cell disease. Next most common one is staph aureus.
Rx: Hydroxyurea ---> decrease in the incidence of vaso occlusive crisis
---> increases HbF synthesis.
Slide: Howell jolly body. G6PD deficiency. Sex linked recessive; Inborn
errors of metabolism like PKU, albinism, homocysteinuria ---> majority
of those are autosomal recessive, so that means that you gotta 1 in 4
chance with carriers having a kid with the disease.
Sex Link recessive: G6PD deficiency and lesch nyhan syndrome.
Lesch nyhan syndrome: Purine metabolism problem. Kids are mentaly
retarded, self mutilation, increase in uric acid, HGPRT deficient.
G-6-Phosphate: Use to make glutathione, and also Ribose 5-Carbon
sugars for making DNA from this pathway. Also you can make
glycogen from G-6-P, which is converted to G-1-P ---> UDP-Glucose
and glycogen; G-6-P can be the substrate used for making glutathione
and other substrates.
Here is an enzyme, you are gonna be able to make NADPH, which is
the major factor for anabolic types of biochemical reactions in our
body like steroid synthesis etc. NADPH will reduce oxidized-glutathione
to glutathione ---> neutralizes peroxides into H2O (Catalyzed by
Vitamin Riboflavin, enzyme - glutathione peroxidase, trace metal selenium).

Every living cell makes peroxide as an end product, just normal end
product to normal metabolism. Thats why every living cell has to have
some way of handling it. Catalase is present in all cells except RBCs
and it can neutralize peroxide, stored in peroxisomes. The other way of
neutralizing peroxide is with glutathione which is the only thing
available to RBCs which dont have catalase. So when you are deficient
in glutathione, peroxide increases to a point where you start
hemolyzing like you have infection, certain oxidizing drug (sulfa or
nitro drug) ---> you will be getting lots of peroxide ---> not gonna be
neutralized if we are deficient in that enzyme ---> peroxide gonna do a
job on Hb ---> causes it clump up and called Heinz bodies + damages
the RBC membrane so much that the primary mechanism for
destruction is intravascular (little bit extravascular as well).
Hematology
Post 42: (Dated: March 16 - 2009)
Two drugs most important: Primaquine and Dapsone.
Primaquine: Pt got Malaria, recieved a drug, 2-3 days later developed
Hb-Uria, chills and Hemolytic anemia.
Dapsone: For Rx of leprosy. Every person thats in the leprosarium,
before they put him on Dapsone they do a screen for G-6-PD because
of high incidence of producing hemolysis. Its a normal screen test for
pts of leprosy before they put them on Dapsone; Pretty much same
with Beta-thal, gotta be black, greek or italian population. So BetaThal and G-6-PD deficiency are two things in same group of people.
Heinz bodies: This is what a smear look like when someone is actively
hemolysing your RBC. Special stain ---> Blue clumps all over the
place, some ones are right on the membrane, called heinz bodies. This
goes into the cords of billroth and the macrophages will see this big
thing and will take a big bite out of the membrane and some times its
just a small bite, so cell can get out in the peripheral blood and just a
piece of its membrane missing like some thing took a bite out of it and
hence the term Bite Cells. Very characterstic finding in peripheral blood
in G6PD deficiency.
You need special stains to find out these Hienz bodies thats why its
called Hienz body anemia.
The pts that are greeks or italians have the most severe forms of
G6PD deficiency. They can eat just Fava beans and precipitates
hemolysis of cells. Fava beans present in salads. Also called as Favism.

Diagnosis of G6PD deficiency: In case of acute hemolytic episode, last

thing you wanna do for diagnosis is get an enzyme essay because the
only cells that are hemolysed are the ones that are missing the
enzyme. The one which have G6PD are still gonna be there --->
normal essay. You never use enzyme essays in active hemolysis, you
do the special stains to identify the heinz bodies. When the hemolytic
episode is over, thats when you confirm your diagnosis with G6PD
essay.
Autoimmune Hemolytic anemias: Warm reacting antibodies = IgG;
Cold Reacting antibodies = IgM.
The most common autoimmune (AI) anemia is WARM and the most
common cause of it is Lupus. When you have autoimmune disease in
you family, you have certain HLA types that predispose you to
autoimmune disease so you can have one autoimmune disease and
another. Pts with lupus will not only have lupus but also they
commonly have AI hemolytic anemia, AI thrombocytopenia, AI
neutropenia, and AI lymphopenia.
Pts who have hashimotos thyroiditis, the most common cause of
Hypothyroidism ---> very commonly have other endocrine diseases
like pernicious anemia, vetligo, AI destruction of melonocytes.
So if you have one autoimmune disease its very likely that if you have
some hemotologic problems, is also autoimmune related, because of
the HLA relation.
Qs: If you have a family, that has an AI disease. What would be the
single best screening test? Ans- HLA. Find out if the have the HLA-Type
thats specific for lupus, or hashimoto ---> they have specific HLA
relationship, thats would be the best screen. Its not all AI diseases
have positive serum ANAs.
So lupus would be the most common cause of AI hemolytic anemia
---> IgG and C3b on the surface of RBC ---> removal of RBC by
macrophages (extravascular). Direct coombs test detects directly the
presence of IgG and/or C3b on the surface of RBCs.
Indirects Coombs the womens are pregnant and in first visit they do
an antibody screen to see the antibody in serum but not on RBC, so its
another name is antibody screen.

You cant do direct coombs on platelets or neutrophils, only on RBC.

There are three types of drug induced Hemolytic anemias, and its the
second most common cause of AI hemolytic anemia:
1) Penicillin: benzylpenicilloyl (BPO) group of penicillin attaches to
RBCs ---> may develope IgG antibodies against that ---> attaches to
BPO group on the surface of RBC ---> removed extravascular in
spleen. Type-II-HSV.
Qs: Person on penicllin develops a rash, what type of hypersensitivity?
Ans- Type-I; develops ahemolytic anemia , what type of
hypersensitivity? Ans- Type-II.
2) METHYLDOPA - ORAL (Aldomet): used in HTN. One of those drugs
that can be given to preganant women with HTN. Its only basically 2
---> thats Hydralazine and Methyldopa. Both have their complications;
Methyldopa could produce a hemolytic anemia; Hydralazine can
precipitate drug induced lupus, second to procainamide.
Mehtyldopa works different then penicillin. It screws with Rh antigen
on the surface of RBC and alters it. It screws so bad that you make
IgG antibodies against own Rh antigen ---> removed by macrophages
---> type-II-HSV.
3) Innocent bystander, thats immune complex, classic drug Quinidine:
Quinidine acting as the hapten and an IgM antibody attaches to the
drug and forms immune complex. So we have the drug and IgM
attached together and cirulating in blood stream. Type-III-HSV; Igm,
immune complex.
Hematology
Post 43: (Dated: March 17 - 2009)
So we have the drug + IgM attached together in the blood stream --->
sits on the RBC and activates the classical pathway, you are gonna
stop at C3 and wanna go to C9 ???---> intravascular hemolysis --->
decreased haptoglobin, and Hb in urine.
Slide: Microangiopathic hemolytic anemia, fragmented RBCs called
shistocytes. These have hit something. Most common cause of this
hemolytic anemia and that is Aortic stenosis, RBCs hit it and are totally
destroyed ---> Intravascular hemolysis, Hb concentration goes down,
Haptoglobin is lost in the urine ---> Chronic Intravascular hemolysis.
Gonna loose lots of Hb in urine and since Hb have iron attached --->

another potential of getting iron deficiency anemia.

Scenario of Aortic stenosis: Sys.ej.Murmur, rt 2nd intercoastal space,
radiating into the carotids, S4 heart sound, increases in intensity on
expiration, prominant PMI ???, they have the following CBC findings
---> you see low MCV, fragmented RBCs present? AnsMicroangiopathic hemolytic anemia related to aortic stenosis.
DIC: RBC are very fragile. There are little fibrin strands in DIC ???
(screw them in half???). You have platelet plugs scattered through out
all the small blood vessels in the body, you gonna have a big time
problem in banging into these things ---> shistocytes and
microangiopathic hemolytic anemia.
Those of you who are long distance runners, this is runners anemia.
When you do a long distance you smashed little crap out of your RBC
when you hit the pavement. After marathon you see Hb in pee.
???
Slide: Malaria, falciparum. Why? Ans- 1) Ring form, 2) you have super
infection, and got more then one ring form. The other form that could
potentially be in the falciparum ---> the comma??? shaped thing. The
gametocytes and the ring form, these produce a hemolytic anemia.
The hemolytic anemia correlates with the fever when cell ruptures.
Fever pattern called tirtian, which means it can come up any time Vs
the other types.
Slide: WBC, conglomeration of different things over here. Beningn
changes that occur with different type of cells.
Neutrophils: In acute inflammation, especially appendicitis etc, we
have absolute neutrophilic leukocytosis ---> left shift and toxic
granulations.
Leukemoid reactions: "OID" means sounds like but it is't. So they are
saying it looks like leukemia but it is't, something thats benign. Usually
leukemoid reaction can involve any of the cell lines. You can get
leukemoid reaction in lymphocytes, neutrophils, eosinophils.
Leukemoid reaction is caused by serious reaction like TB, sepsis and
you get >30,000 or >50,000 cells in the peripheral blood. Benign or
over exagerated response to an infection. Kids get this like in otitis
media ---> CBC with 30,000 neutrophils count. In case of adult otitis

media ---> 12000.

Pertussis: If you have a whooping cough, you have lymphocytosis
60,000 (not uncommon) --->pediatrician worried about acute
lymphoblastic leukemia accept the problem is they dont have anemia
or thrombocytopenia ---> comes in PALE ---> lymphocytes are totally
mature, they are not atypical, there is no anemia, no
thrombocytopenia, its pertusis ---> leukemoid reaction.
Slide: Here are lots of lymphocytes. Kids with viral infections they get
lymphocytosis or with pertusis they get lymphocytosis.
Atypical lymphocytes: Basically its a lymphocyte thats doing what is
supposed to do, its presenting antigen. Its responding to antigen by
dividing and getting bigger. So basically antigenically its stimulated
lymphocyte. So atypical lymphocyte the first thing comes in mind is
"MONO".
Hematology
Post 44: (Dated: March 22 - 2009)
Atypical lymphocytes: Basically its a lymphocyte thats doing what is
supposed to do, its presenting antigen. Its responding to antigen by
dividing and getting bigger. So basically antigenically its stimulated
lymphocyte. So atypical lymphocyte the first thing comes in mind is
"MONO".
Mono is't the only that can produce these large, bluish staining cells.
CMV can do it, toxoplasmosis, any cause of Hepatitis, Phenytoin
(produces macrocytic anemia; blocks intestinal conjugase) --->
Produces atypical lymphocytosis.
This pt that had Infectious Mono, due to EBV, usually transmitted by
kissing as the virus holds up in the salivary glands and infects B-cells,
and CD21 receptor.
Mononucleosis: Viremia, generalized painful lymphadenopathy,
exudative tonsillitis very commonly which is most of the time, is't by
Group A strep. but most of the time the Virus itself. They all have
hepatitis but never have jaundice. Tansaminase is off the map, 2000 or
3000 SGPTs and increased SGOTs. Never goes to the chronic disease
but they always have heptatis, they have spleen that have the
tendency to rupture, usually not spontaneously but some kid thats in
high school with MONO, told not to wrestle or play football ---> tackled

and rupture their spleen.

Downy cells are big cells with lots of cytoplasm, many things can
cause.
Mononucleosis: Hepatits with out jaundice, does't become chronic. Test
for diagnosis, Monospot.
Monospot test: detects heterophile antibodies. Hetero = Different, and
Phile = Loving ---> Different loving antibodies; Anti-horse RBC
antibodies, absolutely unique to Mono. Chances of recurrent disease
any time in life 3-4 times.
EBV lives in B-Cells, actually these are Tcells. The atypical Tlymphocytes in mono are Tcells that are reacting against the infected
Bcells.
Slide: This is the monocytes. Its is the king of chronic inflammation.
So we would expect monocytosis in pts that have chronic infections
like RA, Crohns disease & UC, Lupus, and malignancy.
Eosinophilia: Hay fever, Rash in the pt with penicillin.
Why does creatine gives you energy? Ans- this would binds phosphate,
thats the phosphate that you get from making ATP. Thats the only
thing cretine does. If some one taking creatine for muscles Serum
creatinine elevated because the end product of creatine metabolism is
creatinine ---> Creatinine high, BUN normal.
Scenario: Lots of people take creatine. Horrendously big time
creatinine level in body builder.
The urea level is normal ---> due to cretine supplements.
Amebiasis; pinworm, strongyloides; Malaria. But no protozoa ---> but
this is the eosinophilia.
Thats rule out amebeasis, malaria, giardia.
Pinworm is not invasive. You donot have eosinophilia; Perverted worms
---> male and female mates in anus and lay eggs and causes itching
and due to scratching ends up going into the mouth ---> reinfection
with own eggs. But, no invasion in muscosa.

So protozoal infections only invasive helminths, strongyloides.

Not adult ascariasis, all they do is get together and obstruct the bowl,
except the larval form that goes accross the lung (transmigration route
it take there, you swallow it) ---> when you are going accross the
lungs, which is invassive ---> eosinophilia; but adult ascariasis, non
invassive ---> no esinophilia.
Any thing Type I-HSV ---> Yes
Any thing protozoa ---> No
Worms (not adult ascariasis, no pinworms) ---> No, but
All the other worms ---> Yes they invade like ??? worms
Difference b/w Serum Na+ and total body Na+:
Serum Na+ ---> M eq/ lit plasma.
TB Na+ ---> M lit/ Kg of body weight the total amount that you have.
RBC mass is the total number of RBCs you have in entire body in M
lit/Kg of your body weight. So all you have can be measured by
radioactive technique.
RBC count is the number of RBCs you have in Micro lit of your blood,
so how many you have in a certain volume of blood thats the RBC
count.
Scenario: During lunch break you are out and ran and you got volume
depleted ---> RBC count will be high because if you are volume
depleted and you will be hemoconcentrating your RBC, because little
less plasma volume when you were running ---> more RBCs /
microlitres of blood. RBC masswill be normal.
Relative Polycythemia: You have decrease in plasma volume, causing
an increase in RBC count but the RBC mass is normal. Most common
cause of Polycythemia.
Absolute Polycythemia: Absolute increase in RBCs. Next question is, is
it appropriate or inappropriate?
Appropriate: Increase in actual synthesis of RBCs ---> tissue hypoxia
like; lung disease, you have hypoxemia, COPDs always have high RBC
count, High altitude.
Inappropriate: Perfectly normal blood gases, no tissue hypoxia but
increase in RBC mass:

1)Polycythemia rubravera which is an example of myeloproliferative

disease, stem cell disease in the BM, means that stem cells are kinda
like dictator, non responsive to check and balances on them ---> will
make what ever they want, so its a neoplastic disease of stem cell and
there is a propensity for going in to leukemias.
2)You have some tumor, cyst ---> excess production EPO; Renal
adenocarcinoma making EPO ---> Increase in RBCs mass.
Myeloproliferative: Its a stem cell disease, its neoplastic where the
stem cell has lost all its regulation, nothing can inhibit it any more. 5
diseases fit under this definition:
1) Polycythemia rubravera
2) CML ---> only leukemia thats put under this category.
3) Agnogenic myeloid metaplasia ---> BM is replaced by fibrous tissue.
4) Essential thrombocythemia ---> stem cells makes platelets, ??? you
make one million six hundred (1000600) platelets / micro lit.
5) Myelodysplastic syndrome ---> preleukemia type of syndrome.
Polycythemia rubravera
: "4Hs"
1H) Hyperviscosity ---> Poiseuille law, total peripheral resistance =
viscosity / radius to 4th power; Polycythemia gonna increase viscosity
---> increased peripheral resistance ---> predisposes to thrombosis.
Its thrombosis that can kill you in any polycythemic state and
particularly polycythemia rubravera. Thrombosis can occur in anything
like dural sinuses, hepatic vein (e.g,budd chiari syndrome), coronary
artery, superior messenteric vein.
Rx: Phlebotomy to reduce viscosity so you dont thrombose. Another
reason for phlebotomy is iron deficiency ---> longer time to make
more RBCs because of low iron stores.
2H) Hypervolumia: its the only Polycythemia, where there is also
increase in plasma volume, that matches the increase in RBC mass.
None of the other causes of Polycythemia have increase in Plasma
volume.
Both RBC mass and plasma volume can be measured by radioactive
techniques.
So its very unique for polycythemia rubravera to have an increase in
Plasma volume.

Myeloproliferative diseases takes years to develope ---> because of

slow process the plasma volume, is able to keep pace with RBC mass
and so they both kinda go up together.
3H) Histaminemia: All cells are increased, RBC, WBC and Platelets,
including mast cells and basophils.
Pts with polycythemia very commonly will come to you with history of
overall body itching during shower ---> When mast cells which are
usually in skin and they are increased ---> temperature changes
causes mast cells to degranulate and releases histamine ---> gen.
itching, also face red-looking due to vasodilation, headaches.
Causes of itching: Bile salts in deposition in skin of pt with obs.
jaundice and second is Mast cells degranulation.
4H) Hyperuricemia: Since Nucleated hematopoietic cells are elevated
like neutrophils or stuff like that ---> when they die, nuclei have
purines in them ---> purine goes into purine metabolism ---> end
product is uric acid.
Tumor lysis syndrome (TLS):When you have cancers and when you
treat them with chemotherapy drug ---> lots of cancer cells gonna die
---> always have to put on drugs like allopurinol to prevent them into
going renal failure from urate nephropathy. You have to block xanthine
oxidase because you are gonna release millions of purines when you
kill those nucleated cells ---> forms uric acids ---> tubules gonna build
up uric acid ---> renal failure.
Same thing happens when in polycythemia rubravera, such an increase
in no. of cells that eventually die, you run the risk of hyperuricemia.
Scenarios: RBC Mass, Plasma Volume, O2 Sat and EPO
I'= Increased
D'= Decreased
Polycythmia Rubra vera: RBC Mass=I', Plasma Volume=I', O2 Sat=N
(its an inappropriate polycythemia); O2 content= 1.34 time the Hb,
times the O2 sat + PO2 ---> EPO=D', since you have piles of O2 and
RBCs.
COPD, Tetralogy of fallot (TOF), some one living in colorado: RBC
Mass=I', Plasma Volume=N, O2 Sat=D' and EPO=I'. So its an
appropriate polycythemia because it related to hypoxic stimulus.

Renal Adenocarcinoma: RBC Mass=I', Plasma Volume=N, O2 Sat=N

and EPO=I'. EPO being produced ectopically.
Its not always neoplasms where you can get ectopic secretion of EPO.
It can be anything like renal cyst, hydronephrosis, and wilms tumor.
Relative Polycythemia: RBC Mass=N, Plasma Volume=D', O2 Sat=N
and EPO=N.
Slide: This chronic myelogenous leukemia.
Findings in leukemia: Remember the age brackets to leukemia.
Its the malignancy of stem cells in Marrow and it matastisize anywhere
it wants. So you always have gen. lymphadenopathy and
hepatoslenomegaly.
Second you are going to have abnormal cells in the blood ---> blasts,
that could be myeloblasts, lymphoblasts, monoblast, megakaryoblast
or any blast.
3rd, because its rising in the Bone marrow, its gonna crowd all the
normal hematopoietic cells ---> always gonna have anemia usually
normocytic. 99% of the time, thrombocytopenia because you are
crowding out the normal megakaryocytes making platelets. Usually
increase in the WBC count with abnormal cells.
What separates the acute leukemia from chronic? Ans- simply BM. We
count blasts. When the no. of blasts is lesser then 30% of the WBC of
the marrow ---> chronic. If the greater then 30% its acute.
Age brackets [ ] of leukemia:
[0-14] ALL
[15-39] Acute myelogenous leukemia (AML). A myeloblast with Auer
Rods.
[40-59] Acute myelogenous leukemia and chronic Myelogenous
leukemia.
[60 and over] Chronic lymphocytic leukemia.
CLL is the most common leukemia regardless of the age; Most
common cause of Gen. non-tender lymphadenopathy ???. Because it
metastasize to lymph nodes.

Slide: This is peripheral smear from a 49 year old man. 150,000 WBC
count, 1% myeloblast in peripheral blood and BM, Gen. non-tender
lymphadenopathy, hepatosplenomegaly, thrombocytopenia,normocytic
anemia: Diagnosis - Chronic myelogneous leukemia.
Hematology
Post 45: (Dated: March 23 - 2009)
Right age bracket, right % of blasts ---> what test? Ans- Philadelphia
chromosomes study; Philadelphia chromosome t(9 ABL; 22 BCR). ABL
has non-receptor tyrosine kinase activity.
Translocation from 9 to 22 fuses with great cluster region on the fusion
gene thats the Philadelphia chromosome.
CML test: Leukocyte alkaline phosphatase, which is a Stain; We will
take the smear and overlay the stain on it and see which neutrophils in
the smear gonna take up the stain for alkaline phosphatase. Mature
neutrophils all have alkaline phosphatase in them but neoplastic
neutrophils donot. So in this test we look for staining ---> segmented
neutrophil with out stain (if it was benign it would have taken up the
stain). So you grade from 0 to 4 by counting the neutrophils --->
Score called Leukocyte Alkaline phosphatase score ---> always low in
Chronic Myelogneous leukemia.
Therefore confirmatory test for CML: Philadelphia chromosomes study
and Leukocytes alkaline phosphatase score which is low, usualy "0".
Slide: Tear drop; Hematopoeitic cells moves from BM to spleen.
Extramedullary Hematopoiesis ---> in which hematopoiesis takes place
other then bone marrow usually spleen. Spleen is huge, some of the
biggest spleen you will ever feel in disease called Agnogenic myeloid
metaplasia.
Some of the hematopoeitic cells wants to go back to marrow. While
some of the megakaryocytes lay down collagen through out the
marrow so nobody can go back ---> Fibrosis of entire BM, old term to
this is Myelofibrosis Myeloid Metaplasia and now called as Agnogenic
myeloid metaplasia.
10% of the cells never get the message and donot move to spleen
---> hang around even in the fibrotic marrow and do their things; like
RBCs, to get out into sinusoids they have to move through the strands
of fibrous tissues which damages their membranes. Plus it hurts --->
they cry! ---> while coming through all the barbwires (fibrous tissues)

and getting into the sinusoids ---> finally makes their way to
peripheral blood ---> they cry and become identifiable cells the "Tear
Drop".
Slide: Too many platelets. This is the myeloproliferative disease. This is
essential thrombocythemia. Thats a neoplastic stem cell that wants to
make too many platelets.
Slide: This is the pt 4 years old that presents with sternal tenderness,
fever, gen.non-tender lymphadenopathy, hepatpsplenomegaly,
normocytic anemia, 50000 WBC many of which are abnormal
appearing cells like these. Diagnosis? Ans- Acute Lymphoblastic
leukemia (ALL), the most common cancer in kids.
ALL: Most common type. Common ALL antigen, Bcell leukemia --->
the "cALLa"-antigen. The cluster designation of CALLA antigen = 10.
So its CD10+, CALLA antigen positive, B-Cell= ALL.
Slide: This is the peripheral blood from 65 year old man, gen.nontender lymphadenopathy,hepatpsplenomegaly, normocytic anemia,
thrombocytopenia and 90000 WBC almost all those cells resembling
these cells. There are couple of "Smudge cells". This pt also have
hypogammaglobinemia, because these are neoplastic B-Cell and
cannot tranformed into plasma cells to make the gammaglobulin --->
death due to infections related to hypogammaglobulinemia.
Slide: This is the 62 yrs old pt, hepatosplenomegaly, huge spleen.
These are Weird old cells with projections of cytoplasm, stained by
tartrate resistant acid phosphatase (TRAP).
Hematology
Post 46: (Dated: March 24 - 2009)
Slide: Continue... And wat cancer? Ans- Hairy cell leukemia.
Slide: Thats the Auer rods. This is a peripheral smear from a pt that is
35 who has 50000 WBC count with many abnormal cells, 70% blast in
BM, Anemia, thrombocytopenia ---> Acute Myelogenous leukemia.
Auer rods: Abnormal lysosomes. Looks like little red splinters in the
BM.
All you need to know is How Auer rods looks like, leukemia likes to
infiltrate gums (Acute monocytic leukemia - M5), and this one you
need to know:

This one over here is so full of them (Auer rods) does't have any
cytoplasm left. Some may even get into the blood ---> Acute
progranulocytic leukemia, M3, they always have DIC. So in all the
leukemia this is the numero ono in DIC. It has translocation t(15;17).
You treat it with retinoic acid (vit.A) ---> it causes blasts to mature
into benign cells.
Slide: This is the lymph node. If you have a lymphadenopathy that
hurts its never malignant, means you have some kind of inflamation.
Does't always means infection. You have gen. lymphadenopathy in
lupus but its painful adenopathy becasuse you are stretching the
capsule ---> its an inflammatory condition that produces pain.
When you have nontender lymphadenopathy, always think malignant.
The first thing is metastatis and 2nd primary lymphoma.
You have localized and generalized lymphadenopathy.
Generalized painful lymphadenopathy means systemic inflamatory
disease. So in HIV, EBV, SLE, they all have gen.lymphadenopathy. But
exudative tonsillitis, goes into local nodes and gonna hurt. Breast
cancer goes into local regional nodes and gonna hurt.
Slide: This is the lymph node:
Bruton's Agammaglobulinemia: The area would be ABSENT, the
germinal follicle (B-Cells gone).
Digeorge Syndrome: Paratrabecular got screwed up which is the Tcell
country.
Histiocytosis X: which means Hand-Schuller-Christian Disease,
Letterer-Siwe Disease, which is a true histiocytic CD1+ tumor. Seen in
sinuses.
Severe Combined Immunodeficiency: due to adenine deaminase
deficiency. You would have histiocytes, thats a combine B and T
lymphocytes.
When macrophages process antigens, they deliver it to Bcells that
what causes these germinal follicles. These are Bcells that are in the
process of division ---> the end product come out of the follicle is

Plasma cells making antigen ---> this is called reactive

lymphadenopathy.
This could be lupus, or some thing draining your tonsillitis but where it
is benign.
Slide: These look like follicles. Different demarcations like light stain,
dark stain, a lil bit of difference in types of cell population. Every thing
looks like the same, forming in follicles ---> malignant lymphoma,
origin of this is Follicular lymphoma ---> B cell ---> most common
Non-Hodgkins malignant lymphoma, t(14;18), apoptosis genes
knocked off.
Slide: This is with little cartilage there, elastic cartilages, its the
trachea, these are branches of elastic arteries. This is lymphoma looks
like fish flesh.
What two cells are resistant to invasion by cancer cells? Ans - Cartilage
and elastic tissue.
Slide: Burkitts lymphoma; EPV, translocation of A-14, translocates
myc-oncogene. Morphology of cells is "Stary Sky appearance", normal
benign macrophages looks like the stars in the black night of sky.
These cells are Burkit lymphoma cells. The most common cancer in
kids. We have French chemotherapy system, we can cure this disease.
In USA burkitts lymphoma is the most common lymphoma in kids ???
usualy payers patches, paraortic lymph nodes. Burkitts lymphoma
which looks like this is more common than africa, kids usually have in
abdominal cavity, paraortic nodes, payers patches, and even testicle.
Hematology
Post 47: (Dated: March 25 - 2009)
Slide: Plaque like lessions. Looks like fungal infection because sections
shows inflammatory cells in the epidermis, but they dont find any
fungus, and called it Mycosis Fungoides. It turns out that those cells
were Neoplastic cells ---> Th-Cells. The neoplastic cells in Mycosis
fungoides is the Th-Cells and since these cells helping every body but
does't help this dude a lot so its the key cell malignancy and usualy
involves skin, and lymph nodes.
Slide: Thats Szary cell ---> In mycosis fungoides, one of those
malignant Th-Cells gets into the peripheral blood.

Electron Micrograph: A child that has a eczematous rash on the skin. A

gen. nontender lymphadenopathy, hepatosplenomegaly. A biopsy was
done of the rash and there was a monomorphic infiltrate of cells that
was CD1+. So they did electron microscopy of those monomorphic
apearing cells ---> Malignant histiocytic lession, and in this case
Letterer-Siwe Disease. This is called as a birbeck granule, looks like a
tennis racket.
There is a bacteria thats a spore former, with a terminal end-spore,
also looks like a tennis racket ---> Clostridium tetany. Spores dont
take up the stains because they are with in the Bascillus ???.
So a birbeck granule that looks like a tennis racket in a histiocyte the
very next thing to be associated is Clostridium tetany spore.
Hodgkins disease: It is called as a disease because any one with fever,
night sweats and weight loss has TB. So these pt coming with localized
nontender lymphadenopathy. Biopsy showed ---> benign, little dudes
over there which are the malignant cells ---> Reed Sternberg cells
looks like Owl eyes (so is CMV, giardia, aschoff nodules of Rheumatic
fever).
Less no. of RS.cells ---> better the prognosis but more is worst.
Painful lymphadenopathy ---> some inflammatory condition.
Pain less lymphadenopathy ---> Malignant.
Most common malignancy of lymph node ---> metastasis
Most common primary cancer of lymph node ---> non-hodgkins
malignant lymphoma. Its the follicular B-cell lymphoma. t(14;18) --->
you knocked off the apoptosis gene and the cell become immortal.
Hogkins disease: Four types, you need to know one which is most
common and most common in women other types are more common
in men then women. Its called Nodular sclerosing Hodkins. Nodular
means a low power of the lymph node with the nodular sclerosing, you
will get a nodular appearance. Sclerosis means lots of collagen
deposition which is shown as PINK Crap. Seems like hard non-painful
node.
To recognize Hogkins: usualy women. Lymph node involvement in 2
places, One in ant.
mediastinum. And the second is some where above the diaphragm, it
could be cervical nodes, or supraclavicular nodes; So they ask Mass in

ant. mediastinum and non-painful lymphnode in neck ---> nodular

sclerosing Hodkins.
Serum protein electrophoresis: Albumin is the one that migrates the
furthest because it has the most negative charge where as the Gama
globulin kinda like ??? where they apply the serum, it just sits there.
polyclonal: Many clones - of plasma cells. The gamma globulin region
has the gamma globulins; "GAM" from gamma ---> letters order of
greatest amount G, 2nd most A, 3rd most M, and D and E down there.
When we do P.Elecp. we look at this gamma globulin region, when we
see a little peek we know that it has to be increase in IgG, thats the
most abundant immunoglobulin. Since in chronic inflamation the
primary immunoglobulin was IgG. In acute inflamation the primary
immuoglobulin was IgM.
So you have chronic inflamation like RA, Crohns disease, UC --->
increase in IgG, thats gonna cause the gamma globulin region to show
this big diffuse elevation like round mountain. This is called polyclonal
gammopathy, thats because many benign plasma cells are making IgG
and Igm.
But lots of different clones of plasma cells are making there things.
So the polycolonal gammopathy means: benign and chronic
inflammation.
Hematology
Post 48: (Dated: March 26 - 2009)
So you get this diffuse elevation of that Peak. So polyclonal
gammopathy means benign and chronic inflammation. You are not
gonna have polyclonal gammopathy in acute inflammation. You have
acute appendicitis ---> not gonna happen to gamma globulin region,
as main immunoglobulin is IgM.
When you have chronic inflammation, you have got all that IgG thats
being made, causes diffuse elevation of all gammaglobulin peak, called
polyclonal gammopathy.
Monoclonal gammopathy means one clone of plasma cells making
immunoglobulin. Monoclonal peak almost always means malignancy of
plasma cells and all other plasma cells are supressed by immunologic
mechanism. So there is one malignant clone of Plasma cells makes its
immunoglobulin.

Because its just one clone of plasma cells, you get most of the time
IgG. It makes lots of immunoglobulin, lots of light chains and the light
chains get into the urine ---> bence jones proteins.
Scenario: A person 25 yrs, non-smoker, emphysema of lower lobes
and protein electrophoresis showed, this peak was gone, no alpha-1
peaks. Diagnosis? Ans- Alpha-1 antitrypsin.
Multiple myeloma is a horrible disease, usualy incurable unless BM
transplant. Over 50 yr, Women>men. Most common type is Ig-Kappa
type of MM. Remember that Plasma cells have IL-1 (osteoclast
activating factor).
Slide: Skull, lots of lytic lessions. Pretty much round. Pagets disease of
bone also have lytic areas but very fussy looking.
IL-1 activates osteoclasts, they bore hole through the BM and produces
lytic areas. If this lytic lession is in ribs and when you cough --->
pathologic fractures, extremely common.
Scenario: Elderly women, who coughs and develops severe pain. She
comes in and you see there is a point tenderness over the Rib. Xray
showed a lytic lession with pathological fracture ---> MM.
Slide plasma Cells: Bright blue cytoplasm, nucleus eccentrically
located, right next to nucleus is clear area. Electron microgroscopy - in
cytosol shows, layers of RER, sheaths and sheaths as constantly
making proteins. Important to know how Plasma cells looks on WrightGiemsa stain, and EM.
EM: This is amyloid, non-branching linear compound that has a hole in
center of it.
Amyloidosis: Always seems to end up in the DD, for multisystem
disease. Amyloid is a protein, and many different kinds of proteins are
converted into it. So its a unique protein and many different kinds of
proteins are transformed in it. eg. Pre-albumin can be converted into
amyloid. Calcitonin (tumor marker for meduallary Ca. of thyroid) can
be converted into amyloid.
Light chains in MM can be converted. Trisomy 21, chromosome 21
codes for beta-amyloid. So if you have 2 chromosome-21 ---> gonna
make little bit more beta-amyloid (toxic to neurons).

Scenario: A person died at age 40 and a autopsy is done and reveals

atrophy in brain and reveals senile plaques in frontal and temporal
lobes. Who is the pt? Ans- Down Syndrome.
Down Syndrome: All gets alzheimers disease if they happened to live
that long, either die one of two thing ---> childhood from cardiac
disease (endocardial cushion defects - combination of ASD and VSD),
but if they have managed to live ---> all gets alzheimers, because of
excess of chromosome 21 making excess beta-amyloid.
Macrophage: Wrinkle, paper like apearance of cytoplasm --->
lysosomes are filled with glucocerebroside ---> gauchers disease,
Autosomal recessive disease with missing glucocerebrosidase.
Slide: Bubbly cytoplasm, this pt has severe mental retardation. The
build up product in lysosomes is sphingomyelin ---> neiman pick's
disease, missing sphigomyelinase.
Cherry Red Macula ---> tay sachs disease.
Only Glycogen storage disease that is lysosomal? Ans- Pompes
disease. Missing an enzyme that to break glycogen down in the
lysosomes, excess deposition of normal glycogen in the heart --->
they die.
Hematology
Post 49: (Dated: March 30 - 2009)
Hemostasis: Things in our body, that prevents little clots from
developing in our small blood vessels. You probably had DIC,
thrombotic thrombocytopenic purpura, hemolytic anemic syndrome.
Small blood vessels include, arterioles, venules, & capillaries.
Small airways: Terminal bronchioles, respiratory bronchioles, alveolar
ducts, & alveoli.
How come we dont form clots? Ans- We have heparin which is a
glycosaminoglycan. Its a "GAG", mucopolysaccaride. It enhances antithrombin III, made in liver.
Heparin gets all the credit for anticoagulating you, but its actually
antithrombin III that do all the work. Antithrombin III basically
neutralizes most of the coagulation factors. So we have a little bit of

heparin in our small vessels that prevents clotting from occuring. We

have PGI2 (prostacyclin), made by endothelial cells, its a vesodilator.
When you vesodilate a small vessel, blood flow is increased ---> hard
for things to stick and hard for thrombus as it is blown away so fast.
So vesodilatation is very antagonistic in forming thrombi any ways, as
its too fast and every thing moving too quickly. It also prevents
platelets aggregation.
We also have protein C and S. These are actually Vit.K dependant
factors ---> inactivates or neutralizes factor V and VIII in our
circulation. Antithrombin cant inhibit protein C and S, as it can only
inhibit serine proteases (factor V and VIII are not serine proease).
We have protein C and S that take care of V and VIII because
antithrombin-III cant.
Tissue plasminogen activator (TPA): Which is used to dissolve a clot
with a pt with coronary thrombosis. It activates plasminogen to
plasmin ---> eats everything inside.
Qs: What if all/any of these things (heparin, protein C and S, TPA)
were deficient. Whats gonna happen? Ans- You form clots.
Birth Control pills (BCPs): Increases factor V and VIII synthesis,
increases fibrinogen, and inhibits antithrombin III ---> in sense acting
like antagonist of heparin ---> blocking or inhibiting ant.thrombin III
for doing its job.
So any women on BCPs ---> estrogen ---> producing lil bit of
inhibiting things and increasing synthesis of other things that
potentiates formation of clots.
BCPs have less estrogen than once in the past. Risk is lil bit less but its
still there.
Scenario: You are a women on BCPs, smoking ---> Thrombogenic.
Smoking is itself thrombogenic ---> damage the endothelial cells and
along with BCPs ---> you are asking for it. (Highly contraindicated,
BCPs + smoking).
Scenario: While shaving in morning, cut itself. Whats gonna stop the
bleeding from small vessels (arteriole, cappilary, venule) not talking
about arteries?

Bleeding time: Used for evaluating platelet fuctions.

Hemophilia A and have zero factor VIII ---> normal bleeding time --->
absolutely nothing to do with coagulation. Its purely aint (? VIII)
platelet thing that controls the bleeding time.
The test is done by cleaning off an area usually volar aspect of the
forearm. The have template (?) with blades in it which are hidden --->
inflict wound ---> start a stop watch, get a piece of filter paper --->
every 30 seconds you ??? that wound and no blood comes off on filter
paper ---> stop the stopwatch, ends bleeding time. Usually its about
7-9 minutes.
So We cut the vessel that gonna release tissue thromboplsatin --->
activates the extrinsic coagulation system. But it has nothing to do
with bleeding time but it starts the coagulation system. Also collagen is
exposed ---> factor XII (Hageman factor) is activated ---> activates
intrinsic system, also nothing to do with the bleeding time.
Endothelial cells as well as megakaryocytes makes certain adhesion
product. In other words a glue whose especial purpose is to stick to
platelets ---> the glue is Von Willebrand factor (vWF) which is the part
of the factor VIII molecule, actually made in two places; its made in
megakaryocytes in BM and its also made in the endothelial cells
normally.
Hematology
Post 50: (Dated: March 31 - 2009)
So whats made from Megakaryocytes? Ans- Platelets. So platelets
carry a little bit of glue with them in granules and also made in the
endothelial cells. So when you damage the small blood vessels vWF is
exposed.
Platelets have receptors just like neutrophils have receptors for
adhesion molecules made by endothelial cells, so do platelets have
receptors for vWF which is basically adhesion molecule.
If neutrophils cant stick to venules, how will they be able to get out
where they are supposed to go to kill the bug?. They cant!
They have to stick before getting out of the vessels. Therefore
platelets have to stick before they can do their things. So vWF is that
adhesion molecule that allows it to do that.

So now the platelets sticks called platelets adhesion ---> it causes the
platelets to release chemicals ---> most important chemical is
Adenosine diphosphate (ADP) ---> potent aggregating agent --->
causes platelets to begin sticking together ---> forms a thrombus in
little injured vessel ---> begins to stop the bleeding ---> but its not
enough to do the whole thing. So this is called the Release Reaction.
We need one more chemical to stop the bleeding. ASA that platelet has
that release reaction, it begins synthesizing its own unique substance
---> Thromboxane A2 (TXA2). Its the only cell in the entire body that
has Thromboxane synthase. It converts PGH2 ---> TXA2.
TXA2: Potent vasoconstrictor. It is important to stop bleeding because
when you slow up the rate of blood flow it makes easier for platelets to
stick together. They dont get washed away.
PGE2: Vasodilator. Platelets cant stick.
TxA2, as a matter of fact it causes vasoconstriction of coronary artery
in prinzmetal angina.
Its also a bronchoconstrictor ---> has some activity in asthmatics --->
gonna help LT- C4,D4,E4 alot. So its a vasoconstrictor,
bronchoconstrictor and platelets aggregator; It block up the lumen of
injured vessels ---> bleeding time has just ended.
TXA2 synthesis: Platelets have 2 interesting things; First platelets have
release reaction for the chemicals, that were already made in it, were
released; Second it makes its own unique chemical called TXA2 a lil bit
latter.
Mast Cells: 2 IGEs, next juxta-post to each other in polen kinda bridge
the gap like an electrical circuit ---> mast cells have release reaction
of preformed chemicals like histamine, serotinin, eosinophil
chemotactic factor ---> start the process of inflammatory reaction in
TypeI-HSR ---> mast cells (? in-)activated the released arachidonic
acid from its membrane, we ended up making PGs and leukotrienes,
they were released 30 minz to an Hour latter ---> gonna further
enhance that inflammatory reaction, which we associate with TypeIHSR.
So release reaction of preformed elements ---> make you ??? PGs and
leukotrienes as a latter effect. The platelets kinda do the same thing.

They have a release reaction too. They make TxA2 a lil bit latter.
That little plug is very temporary. Its a bunch of platelets stuck
together and held together by fibrinogen ---> enough to stop &
prevent bleeding ---> Stops bleeding.
Prolong bleeding time: Most common cause is thrombocytopenia. You
have low platelet count, <90,000 platelets ---> prolong bleeding time.
vWF Adhesion molecule disease: Most common genetic hereditary
disease ---> Autosomal dominant. 1 in 250 people have vWF disease.
Aspirin: Most common cause of prolong bleeding time ---> Aspirin
blocks platelets cyclooxygenase (COX) (TX-synthase is blocked by
dipyramidole); Endothelial cells have COX too.
Aspirin did't inhibit endothelial COX from making PGI2; The platelet
COX Vs endothelial cells COX reacts differently with aspirin --->
basically different compounds reacts differently to non-steroidals. Its a
9:1 ratio, with 9 times inhibition of platelets COX when you take
aspirin and non-steroidal Vs inhibition of the endothelial cells COX.
Therefore Aspirin and NSAIds inhibits platelets COX predominantly not
COX of endothelial cells.
Aspirin: Irreversible
NSAIDs: Reversible, 48 hrs.
You took one Aspirin for any reason: Gonna work on every single
platelet ---> if you cut yourself shaving this morning ---> not gonna
stop bleeding in 9 minutes, may be 15-20 minutes.
So aspirin works by blocking platelets COX and preventing them from
aggregating. If There is no TXA2 there ---> Its not gonna work and
you continue bleeding.
It also helps in understanding the signs and symptoms of a platelets
deficiency vs coagulation factor deficiency.
Reminder: We release tissue thromboplastin and activated the
extrinsic system ---> activate the Hageman factor XII because the
collagen being exposed ---> activates the intrinsic system ---> end
product of coagulation system ---> Thrombin, converts the fibrinogen

to fibrin.
We have piles of platelets stuck together and draped over them is
fibrinogen ---> these things gonna happen just a little bit latter after
the bleeding time is over; Thrombin which is generated from ext. & int.
sytem will convert the fibrinogen thats holding the platelets together
loosely into fibrin ---> makes a stable platelet plug in there that it
wont be able to dislodge.
Whose gonna remove the platelet plug from the vessel? AnsPlasminogen will be activated.
Plasmin will be formed, drill a hole through it ---> recanalize, and our
vessels looks normal.
Hematology
Post 51: (Dated: April 01 - 2009)
So in other words we do the bleeding time, the bleeding time goes up
to the formation of temporary hemostatic plug. We have piles of
platelets stuck together with fibrinogen ---> stops the bleeding time
but it very unstable. But when the coagulation system makes its
thrombin or converts the fibrinogen, thats draping it together,
converted to fibrin ---> strong platelet plug forms.
Platelet problem: Bleeding time = Prolong. If cut small vessels --->
continue to bleed.
Bleeding from superficial scratches or cuts. You cant form the
temporary hemostatic plug. In addition you screw up the integrity of
the small vessels when ever you screw around with platelets ---> you
get petechia (pinpoint areas of hemorrhage; only seen in platelets
abnormality), echymoses or purpura (little greater area of hemorrhage
in to the tissues), epistaxis (nose bleed).
None of the things like petechia, echymoses or purpura, epistaxis or
bleeding from superficial scratches, occurs in coagulation deficiencies.
Hemophilia A: Deficient in Factor-A, Bleeding time = Normal. Run into
late rebleeding. eg, Appendectomy, you woke up and start to move
around and the massive amounts of blood starts to come out ---> you
bled to death. The only thing that was really holding in small vessels
together were sutures and temporary hemostatic plugs.
If you have a coagulation factor deficiency, you cant convert the

fibrinogen into fibrin and that little platelet things gonna fall away. So
you get late rebleeding.
You can handle superficial scratches and superficial cuts with no
problems. But they are not gonna hold that vessel closed for too long,
they gonna be dislodged ---> rebleeding.
Scenario: Best question to ask a person to see, if they have
coagulation factor deficiency.
Q- Do you have ever molar tooth removal or wisdom tooth removal?
A: yes they have.
Gonna find out whether she has a coagulation factor deficiency.
Q- Do you have any problem with bleeding with it?
A: No
Just checked off a coagulation factor deficiency.
If you dont have a bleeding problem after extracting a wisdom tooth,
that actually imposes to greatest hemostatic stress on your system
that exist. Its even worst than thoracotomy, or other types of surgical
procedures.
Scenario: If you had your wisdom tooth extraction today. A dude over
there and got numbed up, and got epinephrine to help vasoconstrict.
They gonna pack a little bit. If you have Hemophilia-A, mild case. No
problem in hemostasis control. The only thing holding little vessels,
little temporary platelet plugs held together by fibrinogen. They always
tells you to rinse your mouth out. Preferably little salt and bit of
peroxide there ---> all those temporary hemostatic plugs are gone
---> bleed to death, lots of people choke to death on their own blood.
Factors deficiency: Menorrhagia - more of a feature of coagulation
deficiency than platelet problem; Potentential for hemarthrosis
depends on how severe the factor deficiency is. Hemarthrosis is the
bleeding in close spaces. Totally different from platelet problems.
Epistaxis, petechia, echymosis, bleeding from sperficial scratches vs.
late rebleeding, menorrhagia, GI bleeds and potential for
hemarthrosis; So both of them are different in terms of sign and
symptoms. All based on knowing what normally happens when you
screw up small vessels when you are injured.
Test for platelets abnormalities: Platelets count, bleeding time and vWF
test.

How many Platelets we have?. You took an aspirin or NSAIDs, you still
have normal number of platelets, but they dont work.
Bleeding time: Good test for platelet function.
vWF test: Called ristocetin co-factor assay. If you are missing vWF,
ristocetin cant cause the platelets to clump. Most sensitive test for
diagnosis of vWF disease.
Qs: Old Pt with chronic headaches, osteoarthritis went into prostate
transurethral resection surgery. Bleeding to death after that. PT
normal, PTT normal, platelet count normal. Whats your treatment?
Ans- You have osteoarthritis, you probably on pain medication like
NAIDs. Since PT, PTT are coagulation factors test. Platelets are also
normal but due to NSAIDs, stops them to clump (?). Rx- Platelet
packed transfusion. When you gave them platelets from a donor they
are able to work, the pt's platelet cant work but donor units of
platelets can work and it will stop the bleeding.
Case: Pt had 20 units of blood. PT normal , PTT normal, bleeding time
normal. Guy was bleeding to death. He was on NSAIDs. Rx- 5 units of
platelets.
In case of Major surgery, you are bleeding to death. The only Rx is
normal platelet.
Extrinsic system has Factor VII.
Intrinsic system: Four dudes in it, XII, XI, IX and VIII.
Both systems share the same final common pathway.
Common pathway also shared by other systems like complement
system. You have classical pathway, alternative pathway and they
have final common pathway (C3), what you call MAC - Membrane
Attack complex, unit.
Very similar with this, you have extrinsic and intrinsic. They both uses
the final common pathway except it has "factor-X", not "C3".
So what we have left, we have used VII and we have used XII, XI, IX,
VIII. We have X, V, II (prothrombin), I (fibrinogen) ---> clot.

Prothrombin time (PT): Detects, extrinsic system. We have VII, X, V,

II, I. The end stage of the test is the clot in test tube.
Hematology
Post 52: (Dated: April 02 - 2009)
International normalized ratio (INR): Is a standardized way of dealing
PT. No matter what type of reagent we use, what type of instrument,
we always come with the same answer.
You go to mozambique on vacation and you are on warfarin. You have
to get a test done to get INR, it would be same, no matter where ever
in the world you go.
Partial thromboplastin time (PTT): Its the test of intrinsic system,
down to the formation of clot. So that would be XII, XI, IX, VIII, X, V,
II and I.
Scenario:
PT-Prolong, PTT-normal = VII deficiency; abnormal PT means VII
abnormal, and PTT normal means XII, XI, IX, VIII, X, V, II and I all are
normal.
PT-Normal, PTT-abnormal = VIII deficiency; abnormal PTT means XII,
XI, IX, VIII, X, V, II and I. But since PT was normal, that means VII, X,
V, II, I are normal.
That means that one of these 4 coagulation factors is deficient. Since
Hemophilia-A next to vWF disease is the most common factor
deficiency and you play odds it would be factor VIII deficiency.
Warfarin blocks epoxide reductase ---> prevents the gamma
carboxylation of II, VII, IX, X. You usually follows PT for warfarin. The
only factor that you are not evaluating here while you do the PT to
evaluate the person on warfarin is IX and thats the intrinsic system.
Since two factors X and II (which is the final common pathway), are
vit.K dependant factors in the final common pathway ---> the PTT of
person on warfarin will be prolong; So both PT, and PTT are prolong.
Warfarin: PT does a better job at evaluating it than the PTT because 3
out 4 things that its involved in are in the PT.
Heparin: We follow PTT. All of the factors that antithromnbin III knocks
off ---> XII, XI, VII, X, prothrombin and thrombin ---> they are all
neutralized by antithrombin III.

Qs: Patient on heparin, obviously PTT is prolong because of the pile of

factors that inhibited by antithrombin. Whats the PT? Ans- Prolong.
PTT does a better job of evaluating a pt on heparin than PT does.
So both PT and PTT are prolong whether they are on warfarin or
heparin. But Warfarin is better followed by PT, and heparin by PTT.
Fibrinolytic system: Plasmin breaks down fibrinogen, fibrin, and
coagulation factors. It loves especially fibrin. While it breaks there are
lots of different pieces that are left over when they breaks over a clot,
breaks down the fibrin ---> called as fibrin degradation products.
Qs: Whats the single best screening test for DIC? Ans- D-dimers;
di=two. When you form a fibrin clot, fibrin stabilizing factor (factor
XIII) stabilizes the strands by linking them and makes them stronger
(Similarly collagen is made stronger by linking as well ---> Increases
the tensile strength). So XIII puts little cross bridge in it. The D-dimer
is detecting only those fibrin fragments that it has linked, its means
that two of them are held together, thats what test picks up. It proves
there was a fibrin clot. It would be present in DIC.
D-dimers: If you break a platelet thrombus in a coronary artery. Since
paltelet was bunch of platelet held together by fibrin ---> D-dimer
assay would be increased. This test also commonly used in pulmonary
embolus.
Therefore D-dimer is a single best test for DIC. Wonderful test for
picking up a P.E along with ventilation/perfusion scans. Excellent test
to see reperfusion after you have been given tissue plasminogen
activator. Because it proves that if D-dimer present, a fibrin clot was
there.
Slide: Back of the hand of old pt. This is called senile purpura. Every
one gonna get it in old age as the vessels get unstable. The
subcutaneous tissues get thin. When you hit yourself the small blood
vessels get rupture and produces extensive areas of echymoses. Its an
age dependant finding. Present in only places that hits things like
chins, back of the hands.
Qs: These hands were the only abnormality in the pt, trying to make a
case for litigation because a mommy that was in old age home. They
were, gonna sue the old age home for abusing their mommy. AnsNothing to do with abuse. Its normal age dependant find; They can

change the scenario by saying echymoses on buttocks and back (not

normal place to get trauma by just bumping into things).
Slide: This person and many people in his family had chronic iron
deficiency anemia related to persistent GI bleeds. Physical exam
shows, on fingers they have little small red dots called telengectasias,
also red dots in tounge and endoscopy shows red dots in GI as well
---> osler weber rendu disease (hereditary telengectasias). Most
common genetic vascular disease. So you get chronic iron deficiency
because you are always bleeding because of these telengectasias
rupture. Kinda like angiodysplasia of the skin.
Hematology
Post 53: (Dated: April 03 - 2009)
So most important vascular diseases: senile purpura, osler weber
rendu disease and scurvy.
Platelets disorders: Epistaxis (nosebleeds most common), petechia,
echymoses and bleeding from superficial scratches.
Scenario: 12 yrs old kid, URI a week ago. Now presents with epistaxis,
you do physical exam and you see these lessions over there. You press
on them, they dont blanch (petechia=blanch, dont go away when you
press on it as they are bleeding into tissues; Spider angioma go away
when you press on it, an AV fistula). Rest of the exam normal. Platelet
count 20,000. Diagnosis? Ans. Idiopathic thrombocytopenic purpura
(ITP).
ITP: IgG antibodies against the platelets. Type II-HSV. Platelets being
removed by macrophages in spleen as they are covered by IgG --->
kinda similar to Autoimmune Hemolytic anemia except its Autoimmune
thrombocytopenia. Rx: Corticosteroids.
Scenario: This is a women with positive serum ANA test. Epistaxis,
petechia, splenomegaly, gen.tender lymphadenopathy ---> SLE. So its
a Autoimmune thrombocytopenia in pt, has lupus. Same mechanism,
IgG antibodies against platelets. Type II-HSV, macrophage related
removal.
Thrombotic thrombocytopenic purpura - Hemolytic uremic syndrome
(TTP-HUS): Similar pathophysiology. Disclaimer - Its not DIC, you are
not consuming coagulation factors, the PT and PTT are normal.
Reminder: Bleeding time - we had small vessel injuries. A temporary

hemostatic plug. The coagulation system converted fibrinogen to fibrin

and made a strong platelet plug ---> Thats what you see in TTP-HUS.
Somethings in the plasma damages small vessels through out your
body. So platelet stick and aggregate and eventually for firm paltelet
plugs in all the small vessels in entire body. When you consume all the
platelets ---> thrombocytopenia, gonna bleed. Peripheral blood shows
little platelet thrombi, nice and strong in every small vessels ---> RBC
gonna smashed into oblivion (?) ---> Shistocytes. So we have
microangiopathic hemolytic anemia.
So they have thrombocytopenia, fever, renal failure (glomerular
cappilaries may have those platelet plugs in them). You have to have
shistocytes in you peripheral blood with hemolytic anemia.
HUS: There are 2 causes:
1) E. coli serotype O157:H7 - Toxin produced by ecoli that it can be
present in beef. If you are eating hamburger that is undercooked, and
got this ecoli with particular toxin ---> damages the vessels and
produces HUS ---> with shistocytes, uremic (renal failure parts), or
brain problems.
One of the most common cause of acute renal failure in children is
HUS.
2) Shigela toxin: Causing shigellosis ---> causing HUS.
What we should see in TTP-HUS: Low platelet count, bleeding time =
prolong, PT and PTT normal (we are not consuming coagulation
factors).
Reminder: In coagulation deficiencies, there are totally different
symptoms and signs then in platelet abnormalities; We dont have
epistaxis, petechia, echymoses, or bleeding superficial scratches in a
coagulation factor deficiency. What we do have is delayed bleeding.
Means you can go through entire operation with out any problem. But
when you start moving around, all of a sudden, all held literally breaks
loose and you bleed to death.
When you have operation and you start bleeding out of the wound.
The common cause is not a coagulation factor deficiency but most
common cause is, your suture slipped or you just have a bleed. But
when you have coagulation problem, its not a little bit of bleeding.

Scenario: Molar extraction in this pt. Constant oozing of blood. Nothing

holding those small vessels together. There are just temporary
hemostatic plugs, they did't have that fibrin bonds to hold them
together.
Scenario: Hemorrhage into fascia compartment of the thigh, you can
see how big this thigh is. It can be also seen by looking at this kid's
knee vs that one, that kid has repeated hemarthrosis due severe
Hemophilia-A.
You dont see hemarthrosis or bleeding into spaces in platelet
abnormalities. You only see in coagulation factor deficiencies.
Difference bw Hemophilia-A vs vWF disease: Key coagulation factors
you must need to know.
vWF disease: There is a missing vWF, so they have platelets adhesion
defects. Which automatically says that they get all the signs and
symptoms that are usually seen with platelet problems. But they have
also another problem. They have factor VIII deficiency, but very mild.
abnormalities. So they have got two abnormalities, a platelet defect
and a coagulation factor defect. Thats why they have menorrhagia
(done all the D&Cs, but cant figure out) , GI bleeds, epistaxis, and
easy bruisability.
There are 3 parts of factor VIII molecule. You already know about the
two of them, one is vWF and VIII-coagulant (intrinsic system). The
third one is VIII-antigen, its just an antigen that carries vWF and VIIIcoagulant around the blood. Its only function is a carrier protein. All 3
of these things can be measured.
A pt that have Hemophilia-A, its a sex-linked recessive. Which means
Males. Classical vWF disease is autosomal dominant so there is
difference of genetics. Dominant conditions means only one of the
parent has to have the abnormality, the other parent can be totally
normal and 50% have the potential to be involved.
Hemophilia-A, has only one thing deficient, thats VIII-coagulant. They
have normal VIII-antigen levels and normal vWF. But vWF all 3 things
are decreased ---> VIII-antigen decreased, VIII-coagulant is mildly
decreased and certainly vWF is decreased.

Rx: Desmopressin - increase the synthesis of all the factor-VIII

molecules. You dont have to give blood component. It help treat mild
hemophilia-A and treatment of choice for vWF.
Hematology
Post 54: (Dated: April 04 - 2009)
Women: Menorrhagia, been studied, dont have an-ovulatory bleeding.
Found nothing in D&C---> Guaranteed vWF. They put you on BCPs and
the bleeding went away. But when you wanted to get pregnant, you
went off the BCPs, you start bleeding big time again; PT and PTT =
Normal, Bleeding time = normal ---> the sensitivity of PTT and
bleeding time being abnormal in vWF is 50% ---> the test should be
done is ristocetin cofactor assay = abnormal.
Estrogen increase the synthesis of all the factor VIII molecules. When
you are on BCPs, you got much great significant relieve because you
are basically treating vWF disease.
Two things can increase the synthesis of all factor VIII molecules,
desmopressin and BCPs. The DOC in women would be BCPs not
desmopressin.
Antiphospholipid - One of the causes of spontaneous abortion.
Antiphospholipid syndrome includes lupus anticoagulant, and the
anticardiolipin antibodies.
Both of the antibodies have one thing in common ---> cause vessel
thrombosis.
Lupus anticoagulant: Means thrombogenic. Its not anticoagulant, its a
part of a syndrome that produces vessel thrombosis. Not just seen in
Lupus but seen in HIV.
Anticardiolipin Antibodies: Produces biological false +ve syphilis
serology. So you have VDRL or RPR +ve; Double check it. Fluorescent
treponemal antibody absorption test , FTA-ABS will be -ve ---> makes
the RPR and VDRL = False +ve because the test antigen is beef
cardiolipin and the syphilis antibodies react against beef cardiolipin and
produces a +ve reaction and so do the anticardiolipin antibodies.
Scenario: Women, with Biological false +ve syphilis serology. The very
first test you get after FTA-ABS is Serum-ANA because she will develop
lupus. Anti-cardiolipin antibodies are very commonly seen in lupus

infact a biological false +ve syphilis serology is one of the criteria of

the diagnosis of lupus because of that antibody.
DIC: Easy to diagnose clinically but hard to diagnose Lab-wise.
Disseminated = All over the body
Intravascular = With in the vessel
Coagulation = We are forming clots in small vessels. Consuming
fibrinogen, V, VIII, prothrombin (thats forms thrombin), and paltelets.
Clot tube: At the top is serum. So serum is missing and all the things
are consumed in clots which are fibrinogen, V, VIII, prothrombin, and
paltelets. So when you spin that tube down, you get serum ---> thats
what you have in DIC. You are consuming those coagulation factors
along with platelets in those clots through out your body ---> you have
two diseases in one. You have got thrombi in your vessels and at the
same time you are anticoagulated because all you have circulating
around is serum. You dont have plasma because you consumed the
coagulation factors ---> also called Hemorrhagic thrombosis
syndrome.
Intravascular coagulation is responsible for consuming all those
coagulation factors. Other factors include, septic shock and the most
commonly caused by E.Coli; Snake bite, not neurotoxin types like
cobra, or coral snake but the rattle snakes.
Biggest cause of DIC is septic shock. Easy to recognize. A person thats
in shock that does have a rattle snake bite ---> bleeds from every
orfice (mouth, penis, anus), any place with puncture wound, or any
scratch.
DIC: PT and PTT should be prolong, Platelet = decreased, D-Dimers =
Positive ---> classic DIC; The D-dimers is the test of choice.
Amniotic fluid embolism: A complication of pregnancy usually abruptio
placenta ---> they die.
The true amniotic fluid does gets into the circulation of the mommy
but the amniotic fuid contains thromboplastin ---> DIC.
Hereditary thrombosis: A young person that has DVT in a leg. Its not
normal. Talking about genetic disease. Most common factor V, the
protein C and S cant break down ---> increase in factro V leads you to
thrombosis.

Antithrombin III deficiency: MCC is a women on BCPs.

Scenario: A pt with DVT, you put him on warfarin, heparin; PTT =
normal after you gave him heparin. You gave a little bit of more
heparin and still the PTT is normal ---> Antirhombin III deficiency.
Heparin is anticoagulase which enhances what antithrombin does --->
not causing the PTT to prolong.
Hematology
Post 55: (Dated: April 05 - 2009)
Platelet count, PT, PTT, bleeding time ---> basic tests to evaluate
general hemostasis.
Aspirin:
Platelet count = N
Bleeding time = P
PT & PTT = N
Idiopathic Thrombocytopenic Purpura: MCC of thrombocytopenia in
kids.
Platelet count = L
Bleeding time = P
PT & PTT = N
Hemolytic Uremic syndrome:
Platelet count = L
Bleeding time = P
PT & PTT = N
Hemophilia A:
Platelet count = N
Bleeding time = N
PT = N
PTT = P
VWF disease:
Platelet count = N
Bleeding time = P
PT = N
PTT = P
Main difference bw vWF disease and Hemophilia in terms of Lab tests
---> Bleeding time, as they are missing vWF which is a platelet
adhesion factor.

Warfarin or Heparin:
Platelet count = N
Bleeding time = N
PT & PTT = P
For warfarin ---> PT
For Heparin ---> PTT
Blood group-O: Most common one. You have anti-A IgM and anti-B
IgM, antibodies. Also anti-AB IgG.
Blood group-A: Anti-B IgM
Blood group-B: Anti-A IgM
Blood group-AB: Nothing
New Born: Nothing. Dont begin synthesizing IgG until they are born.
Those are IgM antibodies.
After 2-3 months they begin synthesizing IgG, so dont have isohemaglutinins.
Old Men or Women: Hardly any.
Scenario: An old person. Who is blood group-A and by mistake recieve
group-B blood and did't develope the hemolytic transfusion reaction.
Why? Ans - Their levels of antibodies are so low when you get older
that they don't have anything around to attack those cells.
Associations:
Gastric cancer ---> group-A
Duodenal ulcers ---> group-O
Universal donor ---> group-O; they have no A or B antigen. Can get
only from group-O.
Universal recepient ---> group-AB; No antibodies to attack those cells.
Rh +ve: There are five Rh antigens ---> D, C, c, E, e. When you say
you are Rh+, you are +ve to one of them ---> ie. D = Dork.
Rh -ve: D-Antigen -ve.
Duffy antigen: Is missing in Black population. Not likely to get
plasmodium vivax malaria ---> antigen that p.vivax needs to parasitize

the RBC with Duffy antigen. So if you dont have it on your RBC --->
p.vivax cant get into it.
Alphas, Beta-thals, sickle cells, G6PD: Protects black population from
Falciparum ---> all of those anemias have RBCs that have shorter life
span ---> malaria parasites cant live out their cycles in RBCs --->
protected from getting Falciparum.
Cross Match: While giving blood, the Major cross match ---> gonna
take the pt's blood-serum in a test tube with the blood of the donor
unit that they are supposed to get and mix the two together ---> So
its the pt serum with the donors RBCs, mix them together to see if
they are compatible. Any thing in pt serum gonna attack antigens in
the donor RBC ---> basic purpose of Major Cross match.
Antibodies in a pt serum, is another part of the work up for cross
matching people is to do the antibody screen ---> Indirect coomb test
---> thats -ve 99.99% of the time. When you do the major cross thats
compatible because what it really detecting is whether there is an
antibody in the pt serum, thats gonna attack the donor RBCs. So they
have to do a SEPARATE cross match for every unit of blood.
Its that gonna prevent you from getting hemolytic transfusion reaction
= No
Its that gonna protect you from developing antibodies ??? = No
There is zero chance of having same antigenic makeup on RBC in
different individuals.
So if a Group-O person , gave blood to Group-O person---> dont have
all the same antigens ---> gonna develope antibodies against it --->
every unit of blood that you give a person ---> increase the risk of
developing antibodies. Thats means thats when times comes up to get
the another transfusion, they have to find units of blood that are -ve to
that antigen to which you have antibodies which increases cost and
time it takes to cross match you.
Moral of the story: Dont transfuse unless its absolutely necessary.
Answer to some kinda Question:
Because they are only involved in IgG antibodies against those
particular cells. Everything in Lupus is not Type III.
Post streptococcal disease is not type III either. eg. post streptococcal

disease produce the Rheumatic fever ---> Type II, a non-immune

complex; Where as post streptococcal glomerulonephritis is type III.
Its certainly not true thrombocytopenia and hemolytic anemia which
are type II.
Penicillin Rash = Type I, Hypersensitivity reaction.
Penicillin hemolytic anemia = Type II. IgG antibody against penicillin
groups thats attached to RBC membrane.
Every person in USA has been exposed to CMV in some part of their
live and has antibodies against it. So its the most common antibody in
USA.
At this stay (?) in age that you are safest from getting HIV from blood
transfusion of all infections. Its 1 in 600,25000 chances of getting HIV
per unit of blood ---> very uncommon, because of the screening
mechanisms ---> they do the ELISA test, checking for anti-gp120
antibodies, which is gp120 antigen that attaches to Th-Cell, CD4
molecules. So they do the Western blot assay ---> measuring 3-4
different antibodies, so they all have to present before you call it a
positive western blot, that makes it more specific. So if you have all
those 4 antibodies ---> definitely have true +ve HIV, from ELISA
screening.
Hematology
Post 56: (Dated: April 06 - 2009)
The most common infection transmitted by blood transfusion is CMV.
The most common cause of post-transfusion hepatitis is Hep-C. Got
1/3000 chances of getting Hep-C/unit of blood.
CMV: So every one have CMV antibodies in their blood.
In case of newborn: They wanna prevent graft vs host reaction, in
other words donor lymphocytes from attacking the baby. Also they
wanna prevent it from getting CMV as they have no immune defences
against it. So they usually irradiate the blood. Any blood that a new
born gets, is being irradiated by certain amount of radiation ---> kills
lymphocytes ---> no way they can get graft vs host reaction, diarrhea,
rash or jaundice. Plus CMV lives in the lymphocytes and its destroys
that too.
Accidental needle stick from a pt, that you know nothing about. Whats
the most common infection? Ans- Hep-B.

A pt with HIV and you accidentally stick your finger with a needle.
Chances of getting HIV +ve? Ans- 1/300. Rx- You go on a therapy as if
you were HIV +ve ---> Triple therapy, 2 reverse transcriptase
inhibitors, AZT and protease inhibitors for 6 months. You get constant
checks, may be PCR test looking for RNA virus (Most sensitive test),
and ELISA screen.
In fact the most common mechanism for medical personal to get HIV
is accidental needle stick.
Reminder: Dont transfuse anything into a person unless they are
symptomatic from what ever they are deficient of.
If a person have 10 gm of Hb and it has no symptoms ---> dont
transfuse.
If 10 gm of Hb + COPD, starting to have angina related to that 10gm
of Hb ---> transfusion.
If you have 50,000 platelets count. If you are not having epistaxis --->
Dont treat. But if they have, treat them.
Every blood product is dangerous. As You can get infections from it.
FFPs: Should never be used like Isotonic saline, raising the pt BP. You
run the risk of transmitting disease. (Extremely contraindicated)
We use FFPs predominantly for multiple coagulation factors
deficiencies. eg, DIC, Warfarin over anti-coagulation but they were
bleeding to death we wont be using I/M Vit.K as it take 6-8 hrs to
reverse it ---> but FFPs reverses immediately.
Heparin overdose: Protamine Sulphate ---> works immediately.
So FFPs are pretty much limited to multiple factor deficiencies; Like
Cirrhosis, as most of the factors are made in liver so they are deficient
in factors ---> bleeding significantly.
Allergic reaction: Most common Transfusion reaction. With Itching like
Hives, potentially get anaphylaxis related to it and it would be Type IHSR.
You have got a unit of blood and in the plasma of that person, he has
something to which you are allergic to, may be it was penicillin --->

When they ask that you been on any medications - NO. They got your
blood and you are allergic to penicillins, and you got that pts blood and
you end up with allergic reaction.
Hematology
Post 57: (Dated: April 08 - 2009)
You just treat with benadryl (antihistamine) in most of the cases.
2nd most common one is the febrile reaction, which is due to HLAAntibodies. The pt has HLA-antibodies against leukocytes from the
donor units. So when that unit of blood is transfused in pt --->pt's
antibodies will react against it ---> destroy those cells and release the
pyrogens from the neutrophils ---> Fever.
Qs: If a person never been transfused, should he have anti-HLA
antibodies against any of them? Ans- No.
Qs: Who is most at risk for having a febrile reaction with transfusion?
Ans- A women because she has been pregnant. So every women that
has given birth to a baby, that had a feto-maternal bleed. So of the the
baby's leukocytes goes into the mommys blood stream and develope
anti-HLA antibodies.
So the more pregnancies a women has, the more anti-HLA antibodies
she is gonna develope because of her previous pregnancies. Thats also
true for spontaneous abortions, you can still get HLA-Antibodies of that
baby.
We should not have anti-HLA antibodies in our blood stream unless we
been exposed to human blood.
So its Type II-HSR. Thats IgG antibody-anti ALA antibody.
Where as the allergic reaction is type-I.
Transfusion reactions are very rare. A person who is group-A and got
group-B blood ---> got anti-B IgM. Since IgM is the most potent
compliment activator. That RBC gonna last for a millisecond.
ASA that RBC hits the circulation the anti-B IgM gonna attack it --->
CI to CIX, intravascular hemolysis, anaphylotoxins released --->
shock.
A pt that has antibody against an antigen on the RBC in unit. Instead

of major cross match thats compatible and means that there are't any
antibodies ---> unfortunately some antibodies are not present; but
you have been exposed to (antigen), and you have memmory B-cell.
If a person got blood 30 years ago from a car accident, say there were
anti-CALLA antibodies ---> probably after 30 years there would be no
antibodies, what so ever ---> because they would have gone away, but
do have memmory B-Cells of the event ---> so the person will be have
normal cross match and -ve antibody-screen. On transfuion of CALLA
+ve unit ---> The memmory B-Cells who were sleeping for 30 years
---> wakes up, start dividing in germinal follicles and eventually turn
into plasma cells ---> gonna make anti-CALLA IgG antibodies. Some
times it can occur in few hours or take a week or so, depends on the
antibody ---> delayed hemolytic transfusion reaction.
Scenario: A women postpartem, had very difficult delivery with
abruptio placenta ---> she was transfused 3 units of blood. When she
left the hospital her Hb=10, and she was fine. One week latter she
looked into the mirror and sees jaundice and feeling little tired and
week. She goes to doctor ---> she has an unconjugated
hyperbillirubinemia and Hb=8 ---> Delayed hemolytic transfusion
reaction. You will get Coombs test ---> prove that antibodies are
coating the pts RBCs.
Moral of story: You have been transfused, you have a certain level of
Hb. A week latter you have jaundice and a drop in Hb ---> delayed
hemolytic transfusion reaction.
ABO-Rh incompatibility: Babies only compatibility are Rh-compatibility.
Blood group-O women: If they have baby, they will be the one gonna
have problem with ABO-incompatibility because they already have an
antibody that can cross the placenta.
Reminder: Old people are anti-A IgM and anti-B IgM and anti-AB IgG
normaly ---> if there was placenta ---> it would cross it and attack A
or B RBCs.
So ABO-incompatibility, the very first pregnancy you can have a
problem.
Scenario: Mommy Blood group-O -ve, Baby blood group-A -ve.
Incompatibility of blood groups = Yes
RH groups = No

Mommy gonna have anti-AB IgG antibody ---> cross the placenta. The
A-part of mommy's IgG antibody gonna attach to baby's A-Cells --->
baby's macrophages in spleen destroys it ---> Type II-HSR, mild
anemia, unconjugated bilirubin derived from that macrophages ---> in
utero, mommy's liver take care of it and no problem with kernicterus,
or jaundice; Baby is born ---> mild anemia and in first 24 hrs they will
develop jaundice.
The MCC of jaundice in newborn baby is ABO incompatibility. Not
physiologic jaundice thats day 3.
The baby developed jaundice because its liver system for conjugating
is't good as adults --->has to handle all that unconjugated bilirubin on
its own now ---> bilirubin builds up.
UVB-Light: Its converts the bilirubin into di-pyrol, which is water
soluble, harmless and they pee it out.
The hemolytic anemia is very mild. Mainly because its not strong
antigen, and does't host a very brisk hemolytic anemia by antibodies
---> little problem with jaundice but with no problem. The coomb test
on baby's RBC would be +ve, as some of the RBC are covered by IgG
antibodies.
Always old mommys with blood group-A and with group-A or B baby.
There could be problem from very first pregnancy. Its not like RHsensitization with the first pregnancy, but it can be from any pregancy.
So you are group-O, your baby is A = problem, B = problem, and O =
no problem.
Rh-Incompatiblilty: Mommy is Rh -ve, and baby is Rh +ve ---> or
comparatively Mommy is group-O -ve and Baby is group-O +ve. So
they are not ABO-incompatible but Rh-incompatible.
First pregnancy: Mommy delivers the baby there is a feto-maternal
bleed. Some of the baby's O- +ve cells goes into the blood stream
---> not good and develop anti-D antibodies against it ---> The
mommy is sensitsized, got antibody against that D-Antigen; An year
later mommy is preganant (O-negative, anti-D,), with O-postive baby
---> as its IgG antibody gonna cross the placenta and attach to baby's
D-Antigen +ve cells ---> worst hemolytic anemias ---> baby will be
more severely anemia with Rh than ABO-incompatibility.
Baby's macrophage start phagocytosis ---> Anemia, mommys liver

gonna work little bit harder ---> when the baby is born ---> bilirubin
levels will be way higher, anemia will be way worst ---> 99% chances
of exchange transfusion ---> gonna take all of their blood out and so
getting rid of all the bilirubin and sensitized RBCs and also do the
transfusion because they are anemic.
Remember: In first pregnancy the baby is not affected that when you
get sensitized. Future pregnancies the baby gonna have problem.
Prevention: Mommy Rh-negative ---> when she comes in she will have
antibody screen = negative.
Around 28th week they are gonna give Rh-Immunoglobulin (anti-D)
thats a prophylactic; The anti-D comes from women that was
sensitized and was re-treated (?), cant cross the placenta ---> staying
inside the mommy ---> given on 28th week because often time
mommy get feto-maternal bleed before you actual delivery ---> may
get into car accident or fall and some baby blood can get into
circulation and you have some anti-D antibodies there that sits on DPositive cells and destroy it, so the mommy dont get sensitized (thats
probably the reason); Now at birth the baby is Rh-positive, they have
to do ??? test ---> take some of the mommy's blood and do a special
stain ---> can identify the fetal RBCs, if there are any in her circulation
---> they can count them and can accurately say that there is 10 ml,
or 20 ml of bleed from baby to mommy ---> depending on that, gonna
count how many vials of Rh-immunoglobulins should be given to
protect her further.
So anti-D from Rh-immunoglobulins are up to 3 months ---> gonna
give more at birth if you find the baby Rh-postive.
If the mommy is O-negative and the baby is A-positive. Two problems
---> ABO-imcompatible and Rh-Incompatible ---> no problem with
sensitization because while delivery some of the baby's A-cells gonna
enter the blood of mommy ---> gonna live for millisecond because
mommy is bood group-O and have anti-A IgM antibodies ---> gonna
destroy those cells so fast and in majority of cases (not all), they are
all gone ---> no oppotunity for the mother to develope antibodies
against D-Antigen.
Literature says: ABO-incompatibility protects against Rh-sensitization.
Slide: This is a kid with Erythroblastosis fetalis and has Rhincompatibility. They are died by heart failure. Severe anemia

decreases viscosity of blood and so that get a high out put failure, LHF
first and RHF 2nd. Actually we dont get the pitting edema but there
would be pitting edema in this pt. The liver is huge because they have
extramedullary hematopoiesis in it---> they are severely anemic --->
so basically they die of heart failure and secondary to severe anemia.
Slide: CS of brainstem from kid. What was the cause of color change.
These are kinda yellowish, its kernicterus. The baby probably had RhIncompatibility. Its Unconjugated hyperbilirubinemia because its a
hemolytic anemia and it realtes to unconjugated which is lipid soluble.
The baby's blood brain barrier is immature, so this lipid soluble
unconjugated bilirubin gets into the lipid rich brain ---> basal ganglia,
or other areas of the mid brain and its very toxic and you end with
severe debiltating disease or death from kerniterus.
---------------End Hematology ----------Cardiovascular
Post 58: (Dated: April 10 - 2009)
Jugular venous pulse: Its usually on the right side where we examine
the pt. The best way of finding out is when systole occurs ---> when
1st heart sound occurs, then you can clearly identify the waves. The CWave corresponds with the first Heart sound, which is the begining of
systole.
There are 3 positive waves: A, C, V
Two Negative waves: X and Y
A = Rt atrial contraction in late diastole. That is to get the last bit of
blood out to fill up that Rt ventrical. When it does that the last
contraction, lots of the blood goes into the Rt ventricle, little bit backs
up and the venous pulse creates a +ve A-wave. So A-wave due to late
atrial contraction and the ventricle.
As the tricuspid valve closes in systole and there is contraction --->
blood goes up to PA, and some of it will hit against the Tricuspid valve
and bulge it out a little bit into the Rt atrium ---> Creates a C-Wave.
Make a picture: Systole occured, Rt ventricle contracted and triscup
valve is closed and bulge out initially. Blood going right up to PA an
creates a little negative pressure behind it and sux the valves down a
little bit ---> x-waves which is negative.
V-Wave: Is the filling up of Rt atrium with blood in systole. The

tricuspid valve is still closed, systole occuring, blood going out the PA
but your Rt atrium has to fill up again. So v-waves actually
corresponding with the actual begining of Diastole, the S2 heart sound.
Regular-Irregular Pulse: Its Mitral stenosis ---> A-wave is disappeared,
because thats atrial contraction. Whats been discribed here is atrial
fibrillation.
If this heart sound was present but usually it is't. What heart sound
would be absent? Ans- S4.
It relates to atrial contraction against the increase resistance. So you
will have an absent A-Wave if you have A-Fib and if you have S4, you
will loose it because it deals with atrial contraction.
Tricuspid stenosis (TS): The atrium had to contract against a valve that
did't wanted to open ---> A-wave become huge called Giant A-wave.
Tricuspid regurgitation (TR): Systole occured and lots of blood went
into the Rt atrium and some went up to PA --->you will get Giant C-Vwave.
So giant A-wave is TS and giant C-V-wave is TR.
When you have turbidity of plasma ---> its due to only triglyceride not
cholesterol.
There are 2 fractions that carry triglycerides:
Chylomicrons from the triglyceride you eat at Mc Donalds which is
saturated fat, which are long chain fatty acids and they are being
broken down in your gut with the help of lipases and reassembled in
small intestine and stuck in chylomicrons. So its exogenous or diet
drived triglycerides. In order to find the acurate triglyceride levels
thats telling you about the pts real triglyceride level, you must fast for
12 hrs otherwise any kind of fatty food, that would be in chylomicron
---> falsely increase the triglyceride.
You dont fast for an accurate cholesterol and you can go to Mc Donalds
if you want ---> get HDL and cholesterol level and it wont be affected
by it at all ---> <3% cholesterol present in chylomicrons ---> you dont
have to fast to get an accurate cholesterol and HDL (for cholesterol
measuring).

But you have to fast to get triglycerides levels because there will be
chylomicrons related to the crap that you ate.
What is it called that the triglyceride we make ---> VLDL, what we
make in liver from glyerol 3 phosphate which came from glucose and
its increased among all alcoholics, because of all that NADH, pushing
the DHAP to glycerol 3 phosphate.
VLDL are more dense than chylomicrons because of little protein in it.
Chylomicrons hardly have any proteins so it floats.
So you see this kinda white with yellow, its chylomicron. When you see
this pinkish turbidity below thats called the Infernate, thats VLDL.
1. In the respiratory lectures, during the fungal infections, he says that
Crypto looks like a "mickey mouse" and is a narrow based bud. He
then says the treatment for it is Actynomycin. I think he confused
crypto with blasto.
He apologized for this last statement in the renal section the next day,
saying the treatment is Anphotericin B.
2. Still in respiratory, while describing Sarcoidosis as a common cause
for Restrictive Lung Disease, he says it's the 2nd MCC of
Pneumoconiosis.
3. In heme or cardio, I don't exactly recall, he says that Chagas
disease is a Leishmanial disease, when in fact, the agent is
Trypanosoma.
4. When describing chronic renal failure, he says the definition is a
BUN/Cr ratio of 10:1 for more than 3 months. (Normally, we should
always have that ratio)...He forgot to mention that it's actually the
BUN and Cr being elevated for more than 3 months what defines the
disease, while keeping the normal BUN/Cr ratio.
So far it's the one's I've found. I'm still going through day 5, so I'll
check for more and post up.
KEEP ROCKIN' GIK!
Cardiovascular
Post 59: (Dated: April 12 - 2009)
So a simple tube placed in the refrigerator at 4 degrees and you can
tell what lipid fractions are responsible for your elevated triglycerides.
So this pt is combination of excess chylomicrons probably because he
did't fast and increase in VLDL.

Look at this tube thats perfectly normal. Cholesterol could be elevated

but it wont produce turbity.
This one: High chylomicrons, VLDL-none. The pt was't fasting.
What if there was no supernate (chylomicrons) but you have turbit
infernate ---> increase in VLDL ---> Type IV hyperlipoproteinemia.
So you fast to decrease the triglycerides derived from diet. We dont
need fast, to get accurate cholesterol and HDL.
Slide: Xanthalesma ---> Xanth = Yellow , alesma = Eyelid; Cholesterol
causing the yellow ---> you somebody with this get lipid profile. It
wont be triglycerides but it would be cholesterol.
Slide: Xanthoma of the Achilles Tendon, in a pt who have a family
history of death by coronary artery disease by 20 years of age --->
familial hypercholesterolemia, autosomal dominant disease with
absent LDL receptor. Achilles Tendon xanthoma is pathognomonic for
that genetic disease.
All that LDL thats supposed to be going into cells cant go there, so it
builds up and at 18 you get your first coronary and usually you are
dead very shortly thereafter.
Probably at birth they put you on HMG-COA reductase inhibitor, in
order to keep your cholesterol down. They are also doing gene therapy
on this, trying to figure out whats the code for LDL receptor ---> they
take that code and make a copy and stick into some virus or
something to put into the host genome.
Severe combined immunodeficiencies (SCID): They found the code for
missing enzyme adenine deaminase. They copied it and stuck in Adeno
virus which is a DNA virus ---> they stuck into the genome of that
virus ---> they infected the kid with adeno virus ---> virus replicates
itself and put its DNA into the host DNA ---> carried along with it the
code for adenine deaminase ---> Kid is alive.
Slide: Atherosclerosis in Aorta.
Atherosclerosis: Some thing injuring the endothelial cells lining the
elastic arteries and muscular arteries.

Inurious things: Component of cigarette smoke ---> amonia, CO, and

other horrible things that damage the endothelial cells; LDL ---> if
oxidized its really bad; Viral infections like clamydia pneumoniae (2nd
MCC of atypical pneumonia)---> most of the pts that have MI, most of
them had antibodies against C.pneumoniae ---> may be an infection
with that atypical clamydia and potentially may be something in it
causing vascular damage and predisposing to atherosclerosis; and
homocysteine.
When you damage endothelial cells, platelets stick to it. So platelets
have PDGF in it and they release that into the artery ---> smooth
mucles cells in the media of the vessel ---> starts proliferating,
undergo hyperplasia ---> they start chemotactically migrating like a
school of fish to the sub-intimal level, they move from media to right
underneath the intima of the vessel; The monocytes now have access
into the vessels because its been injured, monocytes also have growth
factors that do the same thing ---> if you have increase in LDL --->
smooth mucles and macrophages phagocytize the LDL ---> produces
the fatty streak.
So its basically, macrophages and smooth muscle cells that have LDL
in them that produces the yellowish discoloration. Over time there is
an injury that occurs, there is a release of fibroblast that developed in
there ---> you end up with a fibrofatty plaque which is the
pathognomonic lession of atherosclerosis ---> it can become
complicated by dystrophic calfication, fissuring, and thrombosis.
Atherosclerosis: There are lots of cells involved like platelets,
monocytes and macrophages, even Cytotoxic T-Cells are involved with
cytokines. Not neutrophils.
Its a primary factor for certain diseases like coronary artery disease
mainly because of atherosclerosis we get thrombus; Stroke --->
atherosclerotic plaques; Abdominal aortic aneurysm is purely an
atherosclerotic problem with weakening of vessels; non-traumatic
amputation of lower extremities, peripheral vascular disease;
Mesentric angina, small bowel infarction; renal vascular HTN,
atherosclerotic plaque at the begining of renal artery.
Can small vessels like arterioles get hardened? Ans- Yes.
Slide: These are arterioles, they are not normal. This is called hyaline
arteriolosclerosis ---> looks like Onion, C.S its called Hyperplastic
arteriolosclerosis.

The Lumen is very narrow. When ever we have lots of pink staining
stuff with some tissue, we always use the term Hyaline.
Hyaline arteriolosclerosis: its a small vessel disease. Diabetes and HTN
produces this kind of small vessel disease but with different
mechanisms.
Diabetes is by non-enzymatic glycosylation; Hb-A1c = glycosylated
Hb; So glycosylation is glucose attaching to Amino acids and proteins.
In terms Hb-A, it is glucose attaching to Amino acids in Hb-A, it means
that it gets glycosylated. Hb-A1c levels correlates with 6-8 weeks what
your blood glucose levels were. So its the absolute best way of seeing
long term glucose management.
So if <6%, you are diabetic ---> you are in normal glucose range.
All the damgage due to diabetes is purely related to glucose and
nothing else. So you have two pathologic processes ---> nonenzymatic glycosylation of small blood vessels including cappilaries in
kidney, and osmotic damage.
Osmotic damage: Those tissues that contains aldose reductase (lens,
pericytes in the retina, schwann cells) ---> convert glucose into
sorbitol, which is osmotically active ---> sucks the water into it and
those cells die ---> you get cataracts, micro-aneuryms in the eyes
because the pericytes are destroyed and they are weakened so the
retinal vessels get aneuryms and you get peripheral neuropathy
because your shwann cells are destroyed.
Non-enzymatic glycosylation: Causes the BM of the small vessels,
becomes permeable to proteins ---> so the proteins in the plasma
kinda leaks into the BM and goes into the vessels wall and produces
the hyaline change and narrows that lumen; Similarly in nonenzymatic glycosylation of glomerular BM ---> render it permeable to
proteins ---> proteins in urine called microalbuminuria, which is the
first change that one sees in diabetic nephropathy, a little bit trace
amount of albumin that should't be there.
HTN: Does't use that system to produce this disease, it just uses brute
(?) force ---> it just drives because of the increase in diastolic
pressures ---> it just the proteins right through the BM there and
produces that effect.

When we look at the kidneys in HTN, its shrunken and got the
cobblestone appearance on the surface ---> because they have hyaline
arteriolosclerosis of the little arterioles in the cortex ---> the schemia
and basically its just wasting away with fibrosis and atrophy of tissue.
So it has a significant component to the pathology of HTN ---> lacunar
strokes, with tiny areas of infarction that occured in internal capsular
area, its a hyaline arteriolosclerosis problem related to HTN. So much
of the pathology of HTN and diabetes are related to that disease.
Slide: Hyperplastic arteriolosclerosis ---> We see this with malignant
HTN. blacks > whites, mainly because HTN is more common in blacks
than whites. The BP- 240/160, you have papilledema, this is the kinda
vessel changes you see in kidney. Mainly its the vessels disease we see
in malignant HTN.
Slide: You see Two kidneys, Aorta, bifurcation and you see the
aneurym.
Aneurysm: Its an area of out pouching of a vessel due to weakening of
a vessel wall.
Whats causing the weakening the vessel wall causing it to out pouch?
Ans- Atherosclerosis.
Terms related to Weakening and Outpouching:
In lungs ---> bronchietasis, its due to cystic fibrosis with infection,
destruction of elastic tissue. You get out pouching and dilatation of the
bronchi.
GI ---> Divertucular disease, you have a weakening and outpouching
of mucosa and submucosa through the area of weakening.
Physio: law of Laplace, wall stress increases when radius increases. It
means that ones you start dilating it, it does't stops because when you
dilate someting and increase the radius ---> increases the wall stress
---> it just keeps on getting. So in other words all aneuryms will
rupture, its just a matter of when.
Why its the most common location for aneuryms? Ans- No vasavasorum ---> blood supply to the aorta below the renal arteries. So
That means that aorta can only get O2 and nutrients from the blood
thats in its lumen ---> so the peripheral part furthest from it, gets
screwed. So because of the fact that its not getting enough O2 and

nutrients, it would be little bit more succeptible to injury,

atherosclerosis, weakening of the walls ---> aneurysms.
Dogs have vasa vassorum below the renal arteries ---> never get
aneurysms.
Aneurysms: Most common thing is rupture.
Scenario: Sudden onset of severe left flank pain because the aorta is
retroperitoneal (so the bleeder is not in the peritoneal cavity but its
present in retroperitoneal tissue); Hypotension , because you can put
25% of your blood supply in your retroperitoneum; pulsatile mass on
physical exam ---> Those 3 things = rupture of abdominal aortic
aneurym.
Aneurysm of the arch of aorta: MCC is tertiary syphilis.
The pathology of syphilis is vasculitis of arterioles, painless chancre.
Painless chancre: CS ---> shows little arterioles surrounded by plasma
cells and the lumen of the vessel is totally shut, so its schemic
necrosis. In other words its the ischemia of the overlying tissue and
under goes the necrosis. Because the nerves are right next to vessels
---> knocks them off too ---> painless.
Cardiovascular
Post 60: (Dated: April 13 - 2009)
All of syphillis is vasculitis. Thats what the treponeme infects --->
small vessels and arterioles. They are infecting the vasavasorum in the
arch of aorta. The richest supply of vasa vasorum is in the arch.
So its logical the treponemes will pick it, so what happens is you get
End arteritis obliterans ---> obliterating the lumen, ischemia,
weakening under systolic pressures ---> looks like a catcher smith ?,
looks like that you can catch your heart ball in there ---> aneurysm.
The aortic valve ring going to stretch ---> Aortic regurgitation murmur.
A murmur gonna occur because of valvular damage, or valve ring is
stretched ---> so you can have stretching of the ring and have nothing
wrong with the vavlves and have a murmur.
Scenario: The aorta should be closing in diastole. So you pump the
blood out ---> stroke volume out, because the aortic valve cant close

properly ---> some of the blood gonna drip back. So you gonna have
more volume of blood in your Lt ventricle, some one with Aortic
regurgitation ---> Frank starling gonna be working, since you strectch
cardiac muscles, you increase the force of contraction. So you have a
120 ml of blood in Lt ventricle and get out 80 ml normally. So the E.F
is 80/120 = 0.66.
Lets say you have 200 mls of blood in here because of the blood
drifting back in ---> Frank starling ---> they get out 100. Actually its
not all that efficient because a normal person gets out 80/120 = 0.66;
This is a 100/200 = 0.5 ---> the frank starling is not a normal
physiologic process, it occurs in pathologic conditions.
So when you have 100 ml of blood coming out of aorta ---> your
heads gonna be going like this (?) ---> the mouth shows the uvula
pulsating. The nails have underneath pulsating vessels. stethoscope
over the femoral artery, press down ---> Duroziez's sign. They have
water hammer pulse; All of this because of increased stroke volume
coming out related to the fact that there is more blood in the left
ventricle; Classics ones of syphillitic aneurysm in the aorta.The left
recurrent laryngeal nerve goes around this arch ---> it streches it --->
hoarseness.
Most common complication of aneyrysm ---> rupture.
Slide: This is syphilitic aortitis. This is the dissecting aortic aneurysm.
Article says: The key factor that causing the tear in the aorta is HTN.
This imposes stress on the wall of the vessel. There is a weakening of
the elastic artery as well ---> elastic tissue fragmentation. Plus there
is a cystic medial necrosis, that kinda where glycosaminoglycans
mixed together and have muciny crap there, little cystic pockets.
You can almost see the walls of the aorta rubbing on itself and the
middle is like nothing in there ---> fragmented elastic tissue ---> little
bit of HTN ---> tears.
Cardiovascular
Post 61: (Dated: April 15 - 2009)
Slide: This is where the tear was in this person. This is the aortic
valve, the tear is right over here near the arch of vessel. So what
happens is, where ever the area of weakness is in the elastic artery,
the blood will dissect. In this pt you can see that it was't distally, but
its proximally, its out side of the aorta - thats the linning of aorta. Here

is blood ---> the paricardial sac attaches to it ---> blood goes into the
heart (pericardium) ---> pt dies of cardiac tamponade. This is called a
Proximal dissection which happens to be the most common one.
Because of the fact that most of the tears are up in the arched vessel
---> absent pulse; Very common in dissection thats proximal when
that dissect close off the lumen of the subclavian artery, usually on the
left ---> absent pulse.
Pain: You will have tearing pain, retrosternal, and radiating to back.
The pulse on the left diminished vs the one the right. Tropinin -ve, EKG
not shows any signs of acute changes. CXR ---> widening of the aortic
knob ---> dissecting aortic aneurysm.
CXR: Excess blood in here, you do the chest xray. The diameter of the
proximal aorta is gonna be expanded ---> 85% sensitive so its the
screening test of choice.
Confirmation: Trans-esophageal ultrasound, and angiography.
Lots of diseases can predispose to dissection.
Slide: This is Marfans syndrome. The height from the pelvic rim to the
feet > pelvic rim to the head. Arms span > height. This guy had an
appendectomy, this pt already had operation for his dissection.
In marfans which Autosomal dominant, chromosome 15, defect in
fibrillin which is the component in elastic tissue ---> lens dislocation,
and dissecting aortic aneurysm. The MCC of death in marfans is MVprolapse or TCV-prolapse ---> sudden death because of conduction
defects.
More Causes: Ehler Danlos, defects in collagen ---> the MCC of death
Pregnancy: The most common catastrophic disease of aorta in
pregnancy ---> dissecting aortic aneurysm ---> because there is twice
the plasma volume during pregnancy (2 RBC mass by 1) ---> Hb
concentration decrease; Normally all pregnant women have 11.5 as
cutoff point for anemia and for non-pregnant women its 12.5 ---> in
pregnancy usually its due to dilutional effect of excess of plasma
volume.
Excess of plasma volume for 9 months ---> in some women can cause
weakening and you get dissections.

Slide: This guy was smoker with primary lung cancer. Now complaining
of headache and blurry vision. So you are looking at his retina, he has
retinal vein engorgement, its congested ---> superior vana caval
syndrome ---> Its usually due to primary lung cancer knocking off the
superior vena cava and you get back up of venous blood into the
jugular system into the dural sinuses ---> the pt usually dies. Rx with
radiation to shrink down the amount of tumor so that they can get
some good blood flowing here.
Superior vena caval syndromes confusing with pancoast tumors which
are associated with Horner syndrome. SVC syndrome is just knocking
off the SVC and nothing to do with horner syndrome.
Slide: This is sturge weber syndrome. Its vascular malformation in the
face. This is in the trigeminal distribution. On the same side of brain
there is a AV malformation there as well ---> predisposes to bleeding.
Also these pts are little bit mentally retarded.
Slide: This is the osler weber rendu disease showing some of the
telengectasia in the GI tract.
If you press this end, these little tentacles will go away ---> Spider
angiomas; Normal in pregnant women, due hyperestrinism. Other
ther than pregnant women, spider angioma means cirrhosis ---> MCC
of cirrhosis is alcohol --->can't metabolize estrogen and it builds up
---> gynecomastia, gonna have warm skin - palmar erythema and
gonna have spider angiomas related to hyperestrinism.
Hyperestinism: No metabolism of 17-keto-steroids ---> gonna
aromatize those in adipose into estrogen. So there are 2 ways that you
get hyperestrenism in cirrhosis.
Qs: How does this looks different from a petechia? Ans- It looks
different for one but if you press that in, this would blanch because its
an AV-fistula, in other words you are going from arteriole directly to a
venule and bypassing capillaries.
Slide: Picture of a child with red lession, B/L white eye reflex, This kid
does't have retinoblastoma.
They show you a kid with a red lession on the face. They are gonna
say:
A- Surgically removed
E- Leave that alone ---> Yes

Capillary hemangioma ---> leave them alone.

Slide: kaposi's sarcoma, HPV-8.
There is a lession which is only seen in AIDs pts that looks like kaposi's
but its due to a bacteria ---> Bacillary angiomatosis due to bartonella
henselae ---> seen by Silver stain. Rx with Sulfa drug and it goes
away. Also the cause of cat-scratch disease.
Slide: This is a angiosarcoma of the liver. Pneumonic - VAT (Vinyl
chloride, Arsenic and thorotrast).
Vinyl chloride: Present in people doing work with plastics and rubber.
Arsenic: Part of pesticides.
Vasculitis: there is a vasculitis of musclar arteries, and elastic arteries
just like platelet disorder have different signs symptoms from
coagulation disorders.
Small vessel vasculitis: 99% of the time its Type-III HSV, which means
it involves immune deposition ---> in small vessel and activates
complement C5a, attracts neutrophils ---> fibrinoid necrosis and
damage to that small vessel + you will have palpable purpura.
The hand of an old person, not palpable but thats just hemorrhage in
skin and there was no inflammatory problem. But if it was palpable
---> it would have been small vessel vasculitis, not a platelet one.
Leukocytoclastic vasculitis - nuclear dust ??? ---> they have fibrinoid
and they are all immune complex diseases.
Muscular arteries: You get a vasculitis like PAN, wegener's
granulomatosis ---> you are gonna get vessel thrombosis, not
palpable purpura so you gonna have an infarction.
Kawasaki's disease: In children, they are gonna get coronary artery
vasculitis. In fact MCC of MI in children is Kawasaki's disease, because
part of the syndrome in addition to the mucocutaneous inflammation,
desquamation of skin and lymphadenopathy its coronary artery
vasculitis. So when you get a thrombosis in poor little dude got an
infarction.

So infarction is what you see with muscular artery vasculitis like PAN,
W.Granulomatosis, Kawasaki's.
When you knock off elastic arteries then you start dealing with Arched
vessels and you are gonna get pulseless disease thats takayasu
arteritis. The vasculitis will block off the lumen of one of the arch
vessel ---> you get strokes, because it may knock off the part of
internal carotid.
Palpable purpura = small vessel vasculitis Infarction = Muscular
vasculitis
Pulseless or stroke = Elastic arteries (far east young lady with absent
pulse = Takayasu's arteritis)
Slide: This guy has headache; History ---> It hurts right here doc, i
cant see at this side. I have aches and pain all over my body. When I
chew it hurts ---> Dx- Temporal arteritis.
Temporal arteritis slide: Its a granulomatous (multinucleated giant
cells). It can involve other portions of the artery including the
opthalmic branch and produce blindness. Thats sedimentation rate is
the only screen from temporal arteritis, its not specific for this but if
this is an arteritis (an inflammation), Sed.rate should be elevated but
if it was not then you can think about TIA or some other thing; Since
screen takes time, to take a biopsy and look for these things and the
pt can go blind, so you have to put them on corticosteroid on just
history alone.
Cardiovascular
Post 62: (Dated: April 17 - 2009)
Polymyalgia rheumatica: Muscle aches and pains. Commonly
associated with this as well. There is no elevation serum CK where as
polymyositis is the inflammation of muscle and you have elevated
serum CK.
Slide: This pt smoked. Buergers disease, also called as
thromboangiitis obliterans or smokers disease. Usually males, young,
they get digital vessels thrombosis. They get autoinfarction of their
fingers and toes. Does't go away usually by quitting smoking.
Story: Stuffy nose ---> look for amputated finger.???
Scenario: 14 year old boy. URTI 1 week ago, presents with
polyarthritis, joint pain, hematuria, RBC casts, and palpable purpura of

buttocks and lower extremity ---> Dx- henoch schonlein purpura. The
most common vasculitis in children. Its an immune-complex, as are all
small vessel vasculitides, its an anti-IgA immunecomplex and the RBC
cast is glomerulonephritis.
Scenario: This pt with saddle nose deformity and it aint congenital
syphillis. Also have problems with sinus infections and problems with
URTI, lungs problems with nodular masses and also even a rib ???
glomerular disease ---> Dx - Wegener's granulomatosis. MCC of saddle
nose deformity in USA. Its a granulomatous inflammation and
vasculitis involving U.airways, lungs, kidneys and its an antibody thats
associated with it, highly specific antineutrophil cytoplasmic antibody
(c-ANCA). TOC: cyclophosphamide ---> C = C (c-ANCA).
cyclophosphamide can cause hemorrhagic cystitis and blader cancer.
Hemorrhagic cystitis is prevented by Mesna.
Polyarteritis nodosa (PAN): A male dominant disease and involves
musclar arteries so infarction is part of this thing. Also have antineutrophil cytoplasmic antibody but its p-ANCA. PAN is highly
associated with Hbs-Ag.
Scenario: IV drug abuser with chronic Hep.B who has a nodular
inflammed mass on the lower extremity, hematuria (kidney infarct).
Diagnosis? Ans- PAN.
Slide: This is vessel in Rocky mountain spotted fever. Rickettsial
organism infects endothelial cells. The spots are in fact petechia.
Unlike other Rikettsial diseases with rash, this starts on extremities
and goes to the trunk where as the other ones goes from the trunk to
the extremities. The vector is Tick.
Tick borne diseases:
Lyme disease = Borrelia burgdorferi; where as Borrelia recurrentis =
relapsing fever with antigenic shifts (means it can shifts in terms of
antigenicity).
Spirochetes: Leptospira, also Syphillis, Borrelia, and Treponema
pallidium.
Slide: This is a fungus. Its wide angle non-septate. This pt with DKA
and there is cerebral abcess related to this fungus. Dx? Ansmucormycosis.

Strong relation b/w DKA and mucormycosis.

Diabetics commonly have Mucor in their frontal sinuses. So when the
pt goes in DKA ---> It starts proliferating and goes right through
cribriform plate and they invade the frontal lobes ---> infarct it and
infects it with the disease.
Slide: Raynaud's Phenomenon. Many things can do this. Causes
include:
Cold reacting antibodies and cold reacting globulins ---> people going
outside in cold wheather ---> gets raynaud's, cyanosis of the nose and
ears ---> they come inside and it goes away.
Either it can be some kind of IgM cold agglutinin disease or
cryoglobulinemia, and Hep-C.
Other diseases that are collagen vascular where the first manifestation
often Raynauds. This involves the digital vasculitis and eventually a
fibrosis ---> progressive systemic sclerosis or scleroderma and its
counter part CREST syndrome.
CREST syndrome: little bit variation of scleroderma and the first
manifestation is Raynauds but its a different mechanism. Its a natural
vasculitis of the digit and eventually you will fibrose the finger ---> like
the smoker got their autoamputation of fingers.
C = 2Cs - calcinosis thats dystrophic calcification and centromere
antibody (specific).
R = Raynauds
E = Esophageal dysmotility
S = Sclerodactyly
T = Telengectasias - pinpoint areas of hemorrhage looks like osler
weber rendu.
Other causes are due to just vasoconstriction. Its common with people
with migraine headache who takes Cafergot types of drugs because
migraines thats due to dilatation of vessels ---> the medications cause
the vasoconstriction ---> some times you can get Raynauds
phenomenon after you take cafergot derivatives; beurger's disease
also have raynauds associated with it as well.
So vasoconstriction, vasculitis (scleroderma, CREST), Cold reacting
antibodies and globulins is another group of diseases.

HTN: Main organs that HTN affects and most common cause of death
in HTN:
1- MI
2- Stroke
3- Renal failure
Essential HTN: highest incidence in HTN in black population. The
genetic thing associated with it is Multifactorial inheritance or Polygenic
inheritance.
Gout is multiple factorial inheritance.
When you ask people if they have family histroy of a coronary disease
they say YES. So the coronary artery disease is mulifactorial.
Multifactorial: Diabetes-II, affective disorder, congenital pyloric
stenosis, Essential HTN It means that you have a tendency but not
necessarily get it.
So you are black and have family history ---> to prevent it from
getting E.HTN ---> cant change the genetics like cant get rid of salts in
urine ---> retaining too much salts which is the basic mechanism of
E.HTN in black population + old people. But can control 2 things like
weight (since there is a direct correlation with HTN) and reduce salt
intake + excercise ---> reduces risks for developing HTN because
those are the other factors which can produce the disease.
Gout: If there is a family history of Gout. Prevention ---> avoid red
meat, and absolutely no alcohol which keeps the purine metabolism
down.
Type II diabetes Prevention: Weight ---> lean and mean. When you
loose adipose you upregulate insulin receptors synthesis.
Some thing you cant do, that will decrease the chance that you can
get the multifactorial inheritance:
HTN: like You retain salt ---> retained in ECF ---> plasma volume
increases ---> stroke volume increase. So excess salt which likes to go
into smooth muscle cells in peripheral resistance arterioles ---> Na+
enter muscles it opens up certain channels for Ca+, which goes in --->
causes the contraction of smooth muscles ---> peripheral resistance
arterioles, constricted.

Since peripheral resistance equals to viscosity / radius to 4th power

---> decrease in radius causes increase in peripheral resistance; We
are retaining more blood in our arterial system in diastole while the
heart is filling up ---> increase in diastolic pressure.
Rx of choice: in blacks or old people is Hydrochlorothiazide ---> you
get rid of salts and water ---> drops BP. In hyperlipidemia we cant use
beta blocker or Hydrochlorothiazide because these drugs can produce
it so we use ACE-inhibitors.
Its a Low renin type of HTN: Because you have increased plasma
volume, thats increased blood flow to the renal artery ---> decreased
renin.
Complications: MI, and stroke.
Slide: blood is located in globus palidus, putamen area. Thats where
almost all HTN bleeds occurs in the brain. Thats because lenticulo
striate vessels which are small little branches from the middle cerebral
artery ---> under increased pressures forms aneuryms (charcot
bouchard) ---> they rupture; So this is not an infarct but its a
hematoma. Its a blood clot right there.
Cardiovascular
Post 63: (Dated: April 18 - 2009)
Not good place to have a blood clot. The neurosurgeon can go to silent
areas of the brain and suck these out and improve the prognosis.
Slide: This is kidney. The surface is kinda like pebbly ---> hyaline
arteriolosclerosis ---> small vessels disease which is causing the
ischemia in that kidney ---> atrophy of tubules, destruction of
glumeruli, kidney is shrinking ---> Renal failure eventually; Its 3rd
MCC of death in HTN.
LVH is the most common overall abnormality in HTN. Its afterload
problem ---> left ventricle contracts against an increase resistance
---> LVH and if its long enough ---> heart failure.
Slide: Its normal heart. On the left we have got hypertrophied heart
and on the right we have hypertrophied heart but for different reasons.
If you look at this heart its thick and hypertrophied, its called
concentric hypertrophy. Over here we have a dilated and
hypertrophied heart ---> it involves work.

It will require a lot of work to contract and push blood against an

increased afterload like an stenotic aortic valve, and increase TPR from
HTN ---> increase in afterload and gonna produce this kind of
hypertrophy (?concentric).
In case of valvular problem and you have excess volume of blood in
your ventricles, increased preload ---> gonna increase work (Frank
starlings) ---> hypertrophy (?dilated).
Concentric hypertrophy is afterload problem.
Dilatation and hypertrophy ---> volume overload and preload problem.
Things make noises when they close.
Systole: mitral and tricupid valve are closing ---> S1 heart sound.
Mitral close before the tricuspid because of the higher pressures.
S2: Aortic and pulmonary valves are closing ---> variation with
respiration, thats because the diaphragm goes down and increase the
intrathoracic pressure ---> blood is being sucked into the right side of
the heart and because of that pulmonic valve gonna close latter then
the aortic valve. So P2 (pulmonic component of the second heart
sound) separates away from A2 on inspiration and comes back on
expiration.
So as the second heart sound has the variation with inspiration. The P2
separates away from A2 because there is more blood coming into the
right side of the heart so the valves closes a little bit latter.
S3: It may be normal in someone of 30-35 years of age. Over that its
usually pathologic.
S1 - begining of systole
S2 - begining of diastole
S3 - in early diastole ---> its due to blood in diastole thats going into a
chamber thats volume overloaded ---> so when diastole was occuring,
blood from the left atrium was going into this chamber that was
already filled with blood ---> makes turbulance and makes a sound
called S3 heart sound. So you only hear the S3 in volume overloaded
chamber.
S3 can be from left ventricle is volume overloaded in left heart failure,

or in right heart failure you have right ventricle volume overloaded so

you can have left sided S3 and right sided S3 heart sound.
Analogy: lots of rivers going into the ocean ---> great turbulance in
that area as there is one body of water emptying into large body.
Similarly the ocean is the ventricle with lots of fluid in it and the river
is the blood coming in diastole and hits this large mass of fluid and
there is turbulance ---> S3.
S4: Its in late diastole. When the atrium is contracting, there is a last
bit of blood out in to the ventricles.
S4 sound means there is a problem with compliance. The compliance
is a filling term ---> its ability to fill up.
When you have a ventricle this thick and you have left atrium
contracting and trying to get blood into a thick ventricle and is noncompliant ---> gonna meet some resistance ---> creates vibration and
produces the S4 heart sound. So S4 sound is due to problem with
compliance. Left atrium is encountering some problem including that
blood in late diastole in to that ventricle that does't wanna fill up any
more ---> it can be due to 2 reasons ---> one, its so hypertrophied
like or it could't be because its already filled up and it has to put blood
in already over filled chamber.
Slide: This is volume overloaded it will have S4; In case of HTN you
will have S4; We will have S3 there because it has already volume
overloaded but also have S4 because it cant fill up any more.
Analogy: Turkey dinner ---> full tummy ---> apple pie ---> hard to put
in stomach which is already filled ---> little vibration there called S4
heart sound.
S3-S4: "budup,budup,budup,budup" gallop rythm thats because they
have S1,S2,S3,S4.
Differentiate b/w the left or right ---> breathing.
Breath IN: You breath in ---> suck blood into the right side of the
heart. All right sided heart murmurs and abnormal heart sounds ie. S3
and S4 ---> increases in intensity on inspiration on the right side.
Breath Out: When you have positive intrathrocic pressures that are

helping the left ventricle push blood out of the heart ---> abnormal
Heart sounds and murmurs increases in expiration.
Scenarios: Left, Right or middle. Heart sounds
E.HTN ---> Left
MR ---> Right
MS ---> Middle
Stenosis means problem in opening the valves.
Regurgitation or insufficiency means that there is a problem in closing
the valves.
In stenosis murmurs when the vavle is opening, thats when the
murmur gonna occur.
For Regurgitation murmur all you have to know when the valve is
closing.
Who is opening in systole? Ans- Aortic and Pulmonic valve ---> so the
murmurs of AS and PS occur in systole. They have to push the blood
through a narrow orifice.
Picture of aortic stenosis: Left ventricle contracts, it encountering some
great resistance ---> the intensity of the murmur initially going up
---> "Shhhheeeeeeeeee" pushing pushing pushing ---> goes to a peak
and "Shheewww" ---> diamond shape configuration thats why its
called an ejection murmur.

When you get to bone pathology, he says the most common B9 tumor of the cartilage/
Exostosis (osteochondroma) and then he says that the multiple form of it is Ollier's dis
When in fact Ollier's is the multiple form of Enchondromas.
Side note: Marfucci's is Ollier's + hemangiomas.

So basically, he's saying that Osteochondromas and Enchondromas are the same thing
Cardiovascular
Post 64: (Dated: May 20th - 2009)
So E.Murmur like Aortic stenoisis has crescendo decrescendo
appearance.
Valves heard best:

Aortic valve = Rt second intercoastal space.

Pulmonic valve = Lt second intercoastal space
TCV = Lt parasternal border.
MV = Apex
That does't necessarily means thats where the valve is. Its just where
the noise is heard.
Aortic stenosis: You have an Ejection type of murmur in systole. Heard
best in the right second intercoastal space. Radiates into the carotids
and the murmur intensity increases on expiration and you hear S4.
Pulmonic stenosis: Mainly on the left. Ejection type murmur. Increase
on expiration.
Diastole: Stenosis murmurs; Mitral and triscupid valves are opening.
Mitral: Stenosis ---> problem in opening it. Left atrium has problem in
opening the MV. This valve does't wanna open, and LA has to get it
open to get blood in it ---> its gonna get pretty strong because it has
an afterload to deal with ---> gets dilated and hypertrophied;
Predisposes to Atrial fibrillation with stasis of blood, thrombus and all
kind of things.
The left atrium has to force the blood into the ventricle in a milisecond
---> MV snaps open ---> all that blood that was built up behind --->
gushing in ---> mid diastolic rumble; So you have an opening snap
followed by a rumbling sound.
In MS there is a problem in opening the valve ---> you are underfilling
the LV ---> no hypertrophy at all since all the work done by LA.
The murmur gonna be heard at apex and will increase in intensity on
expiration.
Regurgitation: Problem in closing the valve; in systole Mitral and
tricuspids are closing. You certainly dont want the mitral, aortic and
pulmonic valve to close on systole ---> you wanna make sure that the
blood does't go back in to the atrium. So MV and TCV are closing in
systole so if they are incompetent and they cant close properly --->
systole occurs ---> because the MV cant close properly and lets say 30
ml goes back into the LA and 50 ml goes out of the aorta ---> there is
even more blood in the LA than normal now.

You just put 30 ml of stroke of the Stroke volume in it + its already

been trying to fill up ---> you have excess blood there ---> volume
overloaded.
Murmur: Since its the problem in closing the valve ---> gonna be
"sheeeeeeewwwwwwwww" ---> as the blood all the way through
systole is going through incompetent valve into the LA ---> so its
pansystolic murmurs; More of a striaght line; Some times obliterating
S1 and S2. (not cresendo decresendo)
So again Apical murmur, pansystolic, S3 and S4 heart sound because
we have a problem with compliance as well as volume overload,
increases in intensity on expiration.
You can figure out the TCR ---> pansystolic, S3 and S4, left
parasternal border, increases in intensity on inspiration.
Scenario: IV drug abuser with fever, pansystolic murmur along the
parasternal border, S3 and S4, accentuation of the neck veins. Dx?
Ans- Infective endocarditis of TCV. Most common infection of IV drug
abuser.
The Murmur and heart sounds increase on inspiration ---> Rt sided.
Changed Scenario: They said that the murmur intensity increased on
expiration, it would have been infective endocarditis of MV.
Diastole: Closing of Aortic and pulmonic ---> what you just pump out
does't comes back in.
Aortic Regurgitation: You have systole ---> the blood goes out ---> the
valves should be closing properly but it does't ---> some blood will be
trickling back ---> let say 80 cc went out initially and 30 cc of blood
drift back in ---> at the begining of diastole you have volume
overloaded chamber and frank starling gonna invalve ---> end diastolic
volume gonna be 200 ml which is supposed to be 120 ml.
The murmur of AR is heard after the second heart sound because its
not closing and the blood is dripping back in ---> makes a sound, high
pitch diastolic blowing murmur right in second intercoastal space --->
increases in intensity on expiration, S3 and S4 heart sounds because
its a volume overloaded chamber + all those bounding pulse.

The ant. leaflet of M.V ---> is actually one side of the outflow tract out
into the aorta ---> the murmur called Austin flint murmur; When you
have AR and you have austin flint murmur ---> you call you cardiac
surgeon, thats the time to remove the valve because if you have that
murmur then you are significantly dripping back in here, that valve has
to be replaced.
Scenarios: Left and Right sided heart failure.
This is section through lungs ---> Lf
Liver ---> Rt
Paroxysmal nocturnal dyspnea ---> Rt
Left Heart Failure: Its forward failure or your left ventricle is failed. It
has to push against and after load, it fails; it has to deal with an
excess volume it fails; you have so many infarcts that the left ventricle
no longer muscle and its fibrous tissue so the contractility is
decreased.
Cardiovascular
Post 65: (Dated: May 29 - 2009)
So that means that your EDV gonna increased because you cant get all
the blood out or you cant push it out. With that pressure the volume
gonna go back in to the LA and back into the Pulmonary Vessels --->
increase the hydrostatic pressure ---> Pulmonary Edema.
When you have chronic LHF ---> you have hemmorhage with alveolar
macrophages that phagocytose the RBC ---> rusty colored sputum
---> you do cytology and see Heart failure cells, those are alveolar
macrophages that have phagocytose the RBC and its broken down into
hemosiderin.
LHF is the diagnosis of symptoms ---> "Doc 'm having trouble in
breathing"
RHF is the diagnosis of signs ---> Since its the problem in the RT heart
getting blood through the Pulmonary vessels to the left heart. So if it
fails ---> blood builts behind it ---> its backward failure --->
hydrostatic pressure will increase in the venous circuit ---> you have
neck vein distension; painful hepatomegaly called as Nutmeg liver
because the increased pressures in the vena cava gonna be
transmitted to the hepatic vein which empties into it and back into the
liver into the central vein and you are gonna get the little dots all
around it and looks like a Nutmeg.

Most common cause of the congested hepatomegaly is RHF. The

increase in hydrostatic pressure also gonna produce pitting edema and
possibility of even ascities.
So neck vein distension, hepatomegaly, pitting edema, ascities ---> all
right heart failure.
When you lie down and go to sleep ---> you can reasorb upto about a
litre fluid from interstitium goes into the venous side of circulation
because there is no effective gravity any more ---> little bit of extra
blood going into the right heart and into the left heart; if you have left
heart failure ---> you have all that excess blood that was't there when
you were standing up is now coming back and this left heart is having
big time problem to get it out and you have more coming in ---> blood
goes back into the lungs ---> windows goes up ---> paroxysmal
nocturnal dyspnea.
Cardiovascular
Post 66: (Dated: June 02 - 2009)
Eventually it settles down and you go to sleep this stincky thing
happens again. If there is one pillow othropnea its not too bad but if
you have to sit up ---> serious left heart failure.
You are imposing gravity. Just placing only one pillow decreases your
venous return to the right side of your heart. You put two pillows that
decreases even more. You sit up it decreases even more. So pillow
orthopnea and PND are signs of LHF not right.
Rx of LHF or RHF ---> best non-pharmacological treatment --->
restrict water and salt.
The king of the Rx of heart failure: Its king because it decreases
afterload and decreasespreload at the same time ---> ACE inhibitor
---> decreases preload (decrease in aldosterone, decreases salt and
water reabsorbtion) and by blocking ATII you decreases
vasoconstrictive effect on PRA so you decreasing the afterload.
Article: People that were on ACE-inhibitors and spironolactone did
better than those who were on ACE-inhibitors alone. The reason to
that was, aldosterone got elevated again even you are on ACE inhibitor
so its not a permanent suppression. So giving aldosterone and ACE
inhibitor increases prognosis.
High Output failure (HOF): In Endotoxic shock ---> PRA were dilated,

C3a, C5a, Nitric oxide ---> increases venous return in the heart.
Poiseles Law: Viscosity over radius to the 4th power. So if you vasso
dilate the PRA ---> decreased TPR ---> more blood comes back to the
right heart, left heart has to deal with it ---> you run the risk of high
output failure.
Beside septic shock another cause of vassodilatation is thiamine
deficiency.
Since the problem in thiamine deficiency is ATP depletion ---> smooth
mucle cells in the PRA need ATP ---> decreased ATP ---> vassodilation
of the PRA ---> HOF.
Graves disease: Thyroid hormone increases synthesis of Beta
receptors in the heart ---> increased in force of contraction ---> there
is more blood, systolic pressure are higher ---> HOF.
AV-Fistulas: If you are stabbed in leg ---> develop AV-malformation
---> arterial blood bypassing microcirculation goes directly in the
venous circulation ---> blood will be coming faster than normal --->
bruit over the mass, pulsatile, if you press the proximal portion of it
the heart rate will slow (branham sign).
Fetal circulation: Baby is not exchanging blood with O2 in our lungs.
The Pulmonary vessels in fetus look like they have P.Hyp ---> they are
so thick that is extremely hard to get blood through the P.A into the
left ventricle. Therefore you need PDA in order to get it out of there.
The O2 in fetus is coming from the chorionic villous dipping into the
lake of blood which drives from mommy's spiral arterioles. Its not a
good O2 source as lungs. So you need high affinity hemoglobin to able
to get O2 ---> HbF which has high affinity for O2. The bad thing is that
it does't wanna give it up. This produces tissue Hypoxia so EPO is
released ---> 18 gm hemoglobin is present normaly. Newborns have
polycythemia.
Therefore HbF has high affinity ---> you have more RBCs with more
Hb in it.
Cardiovascular
Post 67: (Dated: July 17 - 2009)
So the blood O2 goes through syncytiotrophoblast of chorionic villous
---> cytotrophoblast ---> myxomatous stroma of the chorionic villous

---> goes into the blood vessels of the chorionic villi ---> umbilical
vein which has the highest O2 concentration ---> goes up to liver and
there are 2 ways it can go ---> (1) In to hepatic sinusoids, and
through hepatic vein and gets dumped into IVC or (2) They can select
the ductus venosus and goes into right IVC, ---> Right side of the
heart.
Picture this: Foramen ovale is opened. Oxygenated blood is coming up
from IVC ---> right atrium ---> foramen ovale ---> left atrium --->
left ventricle ---> aorta.
The SVC blood goes through tricuspid valve ---> right ventricle --->
since pulmonary vessels are too thick, blood goes through the patent
ductus arteriosus (kept opened by PGE2 made by placenta, a
vasodilator) ---> Right-left-shunt ---> dumped into the aorta.
When the baby is born: baby breaths ---> pulmonary vessels gets
opened in milli seconds ---> blood goes through them; Patent ductus
begins functionally closing and eventually closes and forms the
ligamentum arteriosum.
When the blood goes out the Aorta: it goes into 2 umbilical arteries;
there is one umbilical vein. The vessels with the least amount of O2
are the umbilical arteries, where as the most O2 is in the umbilical
vein.
If you have left-right-shunt and you have Oxygenated blood going into
un-oxygenated blood ---> Step up of O2 saturation on the right side.
If you have right-left-shunt with unoxygenated blood going into left
side ---> step down.
The O2 saturation of the blood on the right side of the heart, returning
from the body is 75%.
The O2 saturation on the left side is 95%.
Slide ASD: Normally there is a membrane in this portion of the
septum. Its not just all muscles going straight up there; Notice the
close relationship of aortic valve leaflet in that septum.
The left ventricle is stronger then right ---> direction of shunt is leftright ---> Oxygenated blood dumped into the right ventricle ---> Step
up; also its gonna pumped out of the pulmonary artery ---> step up.

So you have step up of O2 in the right ventricle and pulmonary artery.

If this is not corrected: Since you are volume overloading the right
side of the heart by all this blood coming over here ---> pulmonary
arteries have to deal with more blood ???---> pulmonary hypertension
---> right ventricle having problem in contracting, get bads --->
hypertrophied ---> risk of reversal of shunt because the right ventricle
could become stronger than left ventricle ---> eisenmenger syndrome
---> cyanosis (also called as cyanosis tardive).
Most of the VSD close spontaneously, some need to be patched.
Atrial septal defect: It is normal for the fetus to have patent foramen
ovale, but its not normal once they are born. The flow of blood is from
left to right as left is always stronger than the right ---> step up in R.A
---> goes from 75-85% ---> step up in R.V ---> step up in P.A.
Difference bw ASD vs VSD: Step up of O2 also in right atrium.
Since there is a volume overloading in the right side of the heart --->
risk for Eisenmenger syndrome.
Also there is a risk of paradoxical embolisation.
If there is a DVT in leg ---> embolized up, the pressures in the right
side of the heart are increasing ---> patent foramen ovale --->
embolus goes into right atrium ---> left atrium ---> a venous clot in
your arterial system.
Fetal alcohol syndrome: Most commonly has ASD associated with it. 2
out of 1000 kids with Fetal alcohol syndrome have ASD.
Patent ductus arteriosus: Normal in fetus but is't when they are born.
Slide: there is a connection bw aorta and the P.A; Aortic pressures are
higher ---> Oxygenated blood goes from left and get dumped in to the
PA before it goes into the lungs ---> step up in PA about 80%; Since
there is an opening bw these, the blood switching back and forth
persistently in diastole ---> pheeeeesshhhhh ooooo pheeeeesshhhhh
ooooo pheeeeesshhhhh ooooo ---> machinery murmur ---> gonna
hear bw the shoulder blades.
PDA: Left-right-shunt ---> volume overload at the Right side of the
heart ---> P.HTN. The shunt will be directed like the fetal one. There

will be unoxygenated blood dumping in to the aorta. Since the ductus

empties distal to subclavian artery ---> babies gonna have pink on top
and blue on the bottom because you are dumping unoxygenated blood
below the subclavian artery (differential syanosis).
Cardiovascular
Post 68: (Dated: July 22 - 2009)
Congenital Rubella is associated with patent ductus.
PDA with out any other heart defects dependant on it ---> closed with
indomethacin, a potent non-steroidal which inhibits PGE2 ---> PDA
start to constrict on its own.
tetralogy of fallot: Most common cyanotic congenital heart disease.
1) Over riding Aorta
2) Membranous septal defect
3) Pulmonic stenosis below the valve.
4) R.V hypertrophy.
The degree of Pulmonic stenosis determines the cyanosis.
Not all babies with TOF have cyanosis. They are called Acyanotictetrology; The degree of P.Stenosis is't all that bad. When the right
ventricle contracts, there would be lots of blood goes up in P.A and
gets oxygenated and much less blood will go and get dumped into left
ventricle ---> wont have cyanosis at birth.
In case of very severe stenosis: When right ventricle contracts, very
little get up there and most of it will be shunted from right to left --->
step down of O2 in left ventricle may from 95-80% ---> cyanosis.
Cardioprotective groups of shunts: PDA and ASD
ASD: the blood will go from left-right ---> step up
PDA: From aorta-Pulmonary artery ---> some of unoxygenated blood
also gets oxygenated ---> pulmonary vein is 95% oxygenated.
Its good to have a PDA and patent foramen ovale in TOF.
Abnormalities in right-left shunting: Polycythemia; risk for infective
endocarditis, because you have shunt going from right side going into
systemic circulation ---> risk for vegetations spreading to brain, and
multiple cerebral abcesses any where they want.

All congenital heart diseases have risk for infective endocarditis.

Kartagener's syndrome ---> normal heart on the right side of chest.
Transposition of great vessels: Right atrium is still getting
unoxygenated blood; left atrium still getting 95% O2 saturated blood
from pulmonary vein; the problem is in the ventricles.
Right ventricle is being emptied by Aorta. Left ventricle is emptied by
Pulmonary artery.
So the things thats transposed are venticles while atria are fine.
Incompatible with life unless you have shunts.
Three shunts are working: Patent foramen ovale, septal defect and
PDA.
Since 95% O2.sat in left atrium ---> thats going from left-right
atrium---> step up of O2 in right atrium ---> step up in right ventricle
---> some of it, gonna go out the aorta, some of its gonna go in left
ventricle.
Since left ventricle is being emptied by P.A ---> blood goes into lungs
to get oxygenated.
The blood wont by 95% saturated but may be 80% ---> cyanosis in
these patients.
Coarctation of aorta: Pre means before ductus; Post means after
ductus.
Pre-ductal occurs in turner syndrome. Most common congenital
disease in turners.
Post-ductal are't present at birth; Actually occurs any time in adult life.
Its important to recognize because there is a surgically cause of
HTN ???
Slide: We have stenosis over here in the aorta. Proximally there is a
problem with getting blood through that, you will hear a systolic
murmur there which probably be heard between the shoulder blades.
There will be lots of pressure build up proximally and this would dilate

the proximal aorta ---> lots of pressure going up to those branched

vessels like the subclavian and internal carotids; so the BP in upper
extremities gonna be higher and certainly than the lower (limb). There
is increased blood flow going into the brain right at the junction where
the communicating branches hit the main branch of the cerebral
vessels, we have no internal elastic lamina and no smooth muscles
---> its a weak area ---> all of us have potential for developing berry
aneurysms and HTN will exacerbate it.
In APKD ---> 20-25% cases develope berry aneurysm; Also increase
incidence in essential HTN, coarctation or any cause of HTN can
produce the berry aneurysm.