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Table of Contents
Table of Contents
Table of Contents........................................................................................................................2
Cardiovascular............................................................................................................................4
Introduction..................................................................................................................................4
Classification...........................................................................................................................4
Vasculitis................................................................................................................................4
Abnormalities of Veins.............................................................................................................4
Abnormalities of Arteries..........................................................................................................4
Tumours and Malformations of Blood Vessels...........................................................................5
Heart Disease...............................................................................................................................6
Pathophysiology......................................................................................................................6
Ischaemic Heart Disease (IHD)................................................................................................7
Rheumatic Fever.....................................................................................................................8
Endocarditis............................................................................................................................9
Mechanical Disturbances of Valve Function.............................................................................10
Cardiac Failure......................................................................................................................10
Arterial Disease...........................................................................................................................11
Hypertension.........................................................................................................................11
Respiratory...............................................................................................................................13
Respiratory Failure................................................................................................................13
Obstructive Disease.....................................................................................................................13
Emphysema..........................................................................................................................13
Chronic Bronchitis..................................................................................................................14
Asthma.................................................................................................................................14
Bronchiectasis.......................................................................................................................14
Infection.....................................................................................................................................15
Pneumonia............................................................................................................................15
Tuberculosis..........................................................................................................................17
Restrictive Disease......................................................................................................................20
Adult Respiratory Distress Syndrome......................................................................................20
Pneumoconiosis.....................................................................................................................21
Solid Tumours...........................................................................................................................24
Lung Cancer...............................................................................................................................24
Colon Cancer..............................................................................................................................25
Adenocarcinoma....................................................................................................................25
Other....................................................................................................................................26
Skin Cancer.................................................................................................................................26
Malignant Melanoma..............................................................................................................26
Musculoskeletal........................................................................................................................28
Bone..........................................................................................................................................28
Bone Tumours.......................................................................................................................28
Osteosarcoma.......................................................................................................................28
Osteomyelitis........................................................................................................................29
Paget’s Disease (osteitis deformans).............................................................................................30
Osteoarthritis (OA)................................................................................................................30
Gastrointestinal........................................................................................................................32
Oesophagus + Stomach...............................................................................................................32
Large Intestine............................................................................................................................34
Infections/Infestations...........................................................................................................34
Idiopathic Chronic Inflammatory Bowel Disease (IBD).............................................................34
Ischaemic Colitis....................................................................................................................35
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Diverticular Disease...............................................................................................................36
Diversion Colitis.....................................................................................................................36
Radiation Colitis.....................................................................................................................36
Collagenous Colitis.................................................................................................................36
Drug Induced Colitis..............................................................................................................36
Liver...........................................................................................................................................37
Hepatitis...............................................................................................................................37
Hepatocellular Carcinoma.......................................................................................................39
Cirrhosis...............................................................................................................................39
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Cardiovascular
Introduction
Classification
can be based on pathological mechanisms, type of blood vessel, or component of vessel wall
none are entirely satisfactory because many disease (e.g. hypertension) affect many elements
Vasculitis
Hypersensitivity Vasculitis
most common pattern
affects capillaries and venules
causes skin rashes
may reflect allergy to drug or as manifestation of bacteraemia
antibody-antigen complexes become trapped within vessel walls and initiate acute inflammation
Systemic Vasculitides
show various patterns of vessel wall destruction
although “systemic” usually only some regions are affects
causes fibrinoid necrosis, loss of smooth muscle and elastic laminae, vessel obstruction and
ischaemia
Abnormalities of Veins
Structural Abnormalities
dilatation and congestion relatively common in certain sites: varicose vv., haemorrhoids,
varicocoele, oesophageal varices and caput medusae
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Abnormalities of Arteries
arteriosclerosis
medial sclerosi
arteriolosclerosis (see hypertension)
aneurysms
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Heart Disease
Pathophysiology
Myocyte Injury
response of myocardial cells to sudden severe ischaemia is rapid and ATP production leads to
cessation of contraction within seconds
however, energy generation (by anaerobic glycolysis) is sufficient to maintain membrane stability
for some time
susceptibility to ischaemic injury is greater near endocardium and least near epicardium, leading to
transmural “wave front” progression of injury
irreversible injury in severe ischaemia develops within one hour in endocardium, and becomes full
thickness within 12 hours
reversible ischaemic injury has interesting effects on function of myocytes
brief period of ischaemia (e.g. 15 minutes) does not compromise long-term viability, but recovery
of normal activity is gradual and may take 24 hours – this is called myocardial stunning
ischaemia preconditioning is where several very brief intervals of ischaemia (e.g. 4 x 5
minutes) markedly increases tolerance to a subsequent longer period
used in cardiac surgery to allow longer operation times
thought to occur through two mechanisms: alteration of ATP metabolism through activation of
adenosine receptors and PKC (short-term) and production of heat-shock proteins
Microvascular Injury
contrary to expectation that vasodilatation, hyperaemia, and capillary recruitment in response to
ischaemia would be associated with increased blood flow when restored, reperfusion is associated
with diminished blood flow
virtually impossible to reperfuse infarct because of no-reflow phenomenon
develops in all tissues about time of irreversible ischaemia injury (e.g. brain 3-4 min, heart 1-12
hours, muscle 6-8 hours)
thought to prevent haemorrhage into infarcts
even brief (e.g. 15 minutes) ischaemia injury followed by ~50% reduction in competent capillaries
= microvascular stunning
caused by ischaemia and (mostly) injury due to oxygen-derived free radical damage
Reperfusion Injury
paradoxically, restoration of blood flow necessary to salvage tissue may cause further injury
through generation of oxygen-derived free radicals
hydroxyl radical (OH*) is extremely reactive and can initiate chain of lipid peroxidation and
irreversible cell membrane damage
normally, free radicals are rapidly eliminated by enzymes (SOD, catalase), or mopped up (Vit E,
glutathione)
during period of ischaemia: antioxidants are used up, xanthine dehydrogenase (XDH) is converted
to xanthine oxidase (XO) (by proteases) and pH falls (accumulation of H+ from anaerobic glycolysis)
adding oxygen by reperfusion rapidly generates reaction oxygen species and cause damage
ATP
Ischa
ADP
AMP
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Adenosine
Inosine
SO
XO catalase
D
Xanthine +
Hypoxanthine H2O2 H2O
O2*
OH* + OH- + O2
Reperfusion
clinically significant question is whether reperfusion injury per se produces irreversible injury in undamaged
cells
if so, reoxygenation should be preceded by anoxic perfusion (to remove accumulated substrates)
or administration of free radical scavengers
Epidemiology
most common type of cardiac disease and leading cause of death in Western world
30% of and 23% of deaths
predominantly due to coronary atherosclerosis and complications
l heart more commonly affected than r because of greater work load (i.e. oxygen demand)
Pathogenesis
Coronary Atherosclerosis
low flow in coronary aa. causes angina pectoris with increased demand
associated with >50% occlusion of major coronary aa.
if plaque is eccentric vasodilator drugs may be useful, but if concentric surgical therapy is required
myocardium has some capacity to develop collateral circulation but often as atheroma progresses
individual myocytes succumb producing a diffuse fibrosis
Acute IHD
usually arises from complications (usually thrombotic) of atheromatous lesion
25% caused by ulceration (altering flow and exposing collagen) and 75% caused by rupture (with
bleeding into lesion which balloons into lumen)
changes can occur in small, previously innocuous, symptomless lesions
sudden onset angina with frequency and severity is called unstable angina and has high risk of
death from total thrombotic occlusion
Myocardial Infarction
regional in 90% of case due to coronary thrombosis
if thrombus persists will lead to transmural progression and full thickness infarct
if thrombus lyses (either spontaneously or therapeutically) outer layers will be spared
circumferential subendocardial infarction causes remaining 10%, due to generalised
hypoperfusion of coronary circulation
Response to Infarction
necrosis stimulates inflammatory response with neutrophil infiltration evident within 12 hours, and
loss of oxidative enzymes can be shown with NBT staining
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subsequently infarct becomes pale (12-24 hours), softens (24-72 hours), develops a hyperaemic
border (3-10 days) and gradually is replaced by whitish collagenous scar
Subsequent Complications
Complication Notes
Cardiac arrhythmia especially if infarct involves AV node
Ventricular failure with large volumes of infarction and cardiac dilatation
Myocardial rupture can occur at any time, but most common after 2-10 days haemopericardium
cardiac tamponade
rarely intraventricular rupture causes l to r shunt and LV failure
Papillary muscle dysfunction may lead to valvular incompetence
Mural thrombosis due to endothelial cell loss and inflammation of endocardium and altered blood
flow to myocardium
risk of system embolism and further infarct
Pericarditis due to inflammation over infarct
Chronic left heart failure due to extensive loss (<40%) of contractile tissue
Aneurysm 10% of long-term survivors
due to dilatation of scars, laminated thrombosis may occur with risk of embolism
Recurrent MI risk due to underlying coronary a. disease
Rheumatic Fever
Epidemiology
incidence and complication of rheumatic fever are high in NZ, especially among Maori (6.5/year/100,000)
similar incidence to developing countries (e.g. India, Pakistan)
Pathogenesis
immune disorder that follows infection in children, usually streptococcal tonsillitis or pharyngitis
some strains of group A β-haemolytic streptococci induce production of antibodies which in some patients
cross react with 20 antigens that are components of c.t., including the heart
acute RF manifests as systemic “flu-like” illness with fever, malaise and muscle and joint pains
pain caused by development of inflammatory lesions (Aschoff’s nodules) composed of
degenerated collagen, activated macrophages, lymphocytes and fibroblasts
other manifestations that may occur are due to similar lesions in brain (Sydenham’s chorea), skin
(subcutaneous necrosis and erythematous rashes) and arteries (fibrinoid arteritis)
however, heart is most important target organ of RF
Aschoff nodules may develop in:
myocardium (rheumatic myocarditis, usually mild)
pericardium (rheumatic pericarditis) - often producing copious serous exudates which may
distend the pericardium (pericardial effusion) or be partially reabsorbed (fibrinous pericarditis)
endocardium (rheumatic endocarditis)
aortic and mitral valves most commonly affected due to higher pressures on left side
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Endocarditis
Pathogenesis
Non-Infective Endocarditis
any structural abnormality of heart valve will be associated with abnormal blood flow over it
leads to predisposition to platelet activation and formation of thrombus and risk of embolism
Infective Endocarditis
bactaraemias are relatively common during chewing (if oral hygiene is poor), from bowel, during
ENT, oral GI or GU surgery, or from unhygienic IV drug use
if thrombosis is occurring during such “bacterial showers” circulating micro-organisms will be
incorporated into vegetations where they may proliferate, invade, inflame and destroy valve tissue
microbial species infecting valve are usually of low virulence and members of resident flora
called sub-acute bacterial endocarditis (SABE) when such organisms colonise structurally
abnormal heart valves
sub-acute indicates that condition may persist longer than would justify term acute but still poses
substantial risk to patient
duration of disease depends of virulence of infecting organism, frequency and distribution of
emboli, capacity of host to mount effective inflammatory/immune response and effectiveness of
antibiotic therapy
when bactaraemias involve pathogenic organism of high virulence derived from sites of infection,
organisms may directly infect valves with normal anatomy
antibiotic therapy needs to be prolonged and high dose to be effective against organisms
protected within vegetations and antibiotic prophylaxis may be advised if predisposing factors are
present
surgical replacement of diseased valves with allograft or xenograft or prosthetic valves will restore
valve function but any replacement valve will have abnormal anatomy and risks of thrombosis and
recurrent bacterial endocarditis will remain
Clinical Sequelae
Complication Features
Infection and toxaemia weight loss
anaemia
café au lait skin pigmentation
splenomegaly
Large emboli infarcts (brain, spleen, kidney)
splinter haemorrhages (longitudinal under nails)
metastatic abscesses
mycotic aneurysms
Microemboli petechial skin rash
Osler’s nodes (tender cutaneous nodules)
retinal haemorrhage
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Cardiac Failure
disorder) failure)
Right Left heart failure (usual) Liver – congestion, may progress to
Cor pulmonale centrilobular necrosis
Kidney – congestion and oedema
Venous pressure
Peripheral oedema
Congestive End point of all types of serious disease dilatation and hypertrophy of heart
Arterial Disease
Hypertension
Classification
Aetiology
primary (90%)
secondary (10%)
renal (vascular, renal failure)
endocrine (Cushing’s, acromegaly, phaeo, myxoedema)
neurogenic (ICP )
miscellaneous (coarctation, polycythaemia)
Severity
benign
malignant (diastolic > 120 mmHg, papilloedema present)
Pathogenesis
Normal Regulation of Blood Pressure
baroreceptors in arteries
kidney secretes renin Ag II (constricts arterioles, Na+ retention)
Hypertension
Renal
renal blood flow , renin secretion
renal function , salt and water retention , hypertension
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Primary
mechanism unknown
hereditary and environmental (smoking, stress, obesity, inactivity, salt intake, oestrogens) factors
possible mechanisms:
role of renin
role of Na+ and Cl-
role of Ca2+
cell membrane defect
insulin resistance
Morphology
microscopically: arterioles show hyalinisation (arteriosclerosis) in many organs, especially kidney
kidney: slightly shrunken, surface shows fine granularity
heart: LV hypertrophy, may cause ventricular failure, increase risk of MI
eye changes: arteriolosclerosis, flame-shaped haemorrhages, cotton wool “exudates” (swollen nerve fibres),
papilloedema
Clinical Features
Benign
usually asymptomatic
increased risk of MI, HF, cerebral haemorrhage
Malignant
symptoms: headache, confusion, convulsion, visual blurring, scotomata
complications: heart failure, renal failure
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Respiratory
Respiratory Failure
causes:
failure of ventilatory drive (e.g. depression of respiratory centre)
upper airways obstruction
lung diseases
mechanical impairment (e.g. rib fractures)
effects:
pulmonary hypertension RV hypertrophy
polycythaemia (due to stimulation of erythropoeitin release) blood viscosity
Obstructive Disease
characterised by increased resistance to airflow
e.g. asthma, chronic bronchitis, emphysema, bronchiectasis
Emphysema
abnormal permanent enlargement of air spaces distal to terminal bronchiole, with destruction of walls
emphysema and chronic bronchitis are best viewed as spectrum with patients with α-1 antitrypsin deficiency
(with almost pure emphysema) at one end, and pure bronchitis at the other
Morphology
Type Areas Affected Notes
Centriacinar respiratory bronchiole affected, distal alveoli spared associated with smoking
more common in upper lobes
Panacinar acini uniformly enlarge from level of respiratory bronchiole associated with α-1 antitrypsin deficiency
more common at bases
Paraseptal proximal acini normal, distal portion affected probably cause of spontaneous
more striking adjacent to pleura next to areas of scarring pneumothorax
Irregular acini irregularly involved associated with scarring (e.g. old Tb)
Pathogenesis
protease-antiprotease theory: alveolar wall destruction results from imbalance between proteases (e.g.
elastase) and antiproteases (e.g. α-1 antitrypsin) in lung
smoking inhibits antiproteases, recruits leukocytes (which secrete proteases) and promotes
protease release
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Clinical Course
symptoms appear once 1/3 lung tissue affected
dyspnoea
cough ± sputum
significant weight loss
prolonged expiration
panacinar form most disabling because all alveolar affected
Secondary Complications
right-sided heart failure
respiratory acidosis ( coma)
pneumothorax ( massive collapse of lungs)
COAD
Chronic Bronchitis
persistent cough with sputum production for at least 3 consecutive months in at least 2 consecutive years
common among habitual smokers and inhabitants of smoggy city
Morphology
Macroscopic
redness, oedema
excess mucinous or mucopurulent secretion
Microscopic
hyperplasia of mucus glands
goblet cells ± squamous meta/dysplasia
mucus plugging
inflammation
Pathogenesis
chronic inhalation of irritants causes bronchiolar and bronchial injury
bronchospasm and infections (viral & bacterial) cause hypersecretion of mucus leading to reversible
obstruction
continued injury and infection leads to chronic bronchitis
Asthma
Bronchiectasis
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Infection
Pneumonia
Classification
location (alveolar/interstitial)
extent (lobar/bronchopneumonia)
aetiology (bacterial/fungal/viral)
duration (acute/chronic)
clinical (community acquired/hospital acquired/special environment/immunosuppressed/aspiration)
Epidemiology
important cause of morbidity and mortality in all age groups
result of complex interaction between patient, environment, and infecting organism
important factors include age, community or hospital acquired, concurrent disease, severity of illness
Age of Patient
Age Commonest cause(s)
< 6 months usually viral (e.g. respiratory syncitial virus (RSV), adenoviruses, influenza, parainfluenza)
Chlamydia tracomitis may transmitted to infant from mother’s genital tract during birth
6 months – 5 years Haemophilus influenzae
older children and adults Streptococcus pneumoniae
young adults chlamydia, mycoplasma, strep. pneumoniae
elderly incidence and frequency of concomitant disease is associated with mortality
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Concurrent Disease
alcohol misuse, malnutrition, diabetes and underlying cardio-respiratory disease predispose and
are associated with mortality
patients with COPD have mucociliary clearance and organism of low virulence may spread from
bronchi into lung tissue causing bronchopneumonia
mortality from influenza infection (either 10 or 20) is highest in elderly
aspiration pneumonia can occur with neuromuscular disease or impaired consciousness
pneumonia in immunocompromised (e.g. with AIDS) associated with unusual pathogens (e.g.
Pneumocystis carinii, Tb, H. influenzae)
Pathogenesis
Protective Mechanisms
nasal clearance (filtration etc.)
tracheobronchial clearance (mucus trap)
alveolar clearance (macrophages etc.)
Transmission
aspiration from oropharynx
inhalation of infectious aerosols
haematogenous dissemination
direct inoculation + contiguous spread
Lobar Pneumonia
inhalation of micro-organisms initiates inflammatory reaction initially centre in large bronchi but
spreads rapidly through lobe
classically pathological features are described in four stages:
Stage Microscopically Macroscopically
Acute congestion local vasodilatation followed by out-pouring of exudate causing heavy, dark red and firm
congestion
alveolar capillaries are engorged with RBCs and alveolar spaces filled
with eosinophilic oedema fluid containing bacteria and neutrophils
Red hepatisation capillary engorgement persists brick red, dry, firm and airless
alveolar exudate contains fine network of fibrin, large numbers of
RBCs, and neutrophils
Grey hepatisation reduction in vasodilatation and congestion fibrinous pleurisy, dry, airless
macrophage recruited into alveolar spaces, which are distended and and grey
consolidated by dense network of fibrin and dead and dying neutrophils
and lysed red cells
Resolution by 8-10 days in untreated cases exudate is gradually liquefied by
fibrinolytic enzymes
if no tissue damage, lung parenchyma returns to normal
Bronchopneumonia
patchy consolidation centred around inflamed bronchi
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usually multifocal and bilateral, caused by large number of organisms of varying pathogenicity (but
often commensuals or relatively avirulent)
very young, old and debilitated most at risk
inflammatory consolidation is distributed patchily while suppurative exudate fills terminal
bronchi, bronchioles an adjacent alveoli
neutrophils are dominant and usually only small amounts of fibrin are present
clinically poorly defined, frequently overshadowed by predisposing condition
complications (especially abscess formation) are more frequent
Aspiration Pneumonia
usually associated with regurgitation during episodes of unconscious or during impaired swallowing
gastric acid causes chemical pneumonitis with intense oedema
patients develop increasing respiratory dysfunction with pacification of lungs
food excites foreign body response and bacteria from oropharynx cause infection
development of abscess may complicate
Viral Pneumonia
influenza, CMV, measles and varicella may all cause interstitial pneumonia
loss of damaged cells causes defects that are covered with fibrin
fibrin exudates contributes to formation of hyaline membranes
Clinical Presentation
Typical Atypical
(mycoplasma, Legionella, viral)
sudden onset chills, fever
rigors, fever, sweating dry cough
cough, purulent rusty sputum predominance of extrapulmonary
pleuritic pain symptoms (headaches, myalgia, n/v,
diarrhoea)
dyspnoea
localised chest signs
Morphology (Microscopic)
Atypical
usually interstitial
often proteinaceous intra-alveolar spaces
low mortality
may be complicated by 20 bacterial infection
Tuberculosis
Aetiology
inflammation caused by Mycobacterium tuberculosis (and other species of mycobacteria)
slender, rod-shaped bacterium (1-5 μm)
can only be stained with some difficulty (Ziehl-Neelson method)
aerobic, grow very slowly in culture
very robust and extremely resistant to drying (can remain active <8 months)
destroyed by sunlight
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organism excites from of cell mediated immunity involving T-cells and macrophages
entry of bacillus into body not necessarily followed by illness (1.7 billion infected, 20 million ill, 3 million
deaths/year)
spread by ‘open case’ by coughing, sneezing, talking etc.
affected by age, natural resistance and immune state
can also be infected by drinking unpasteurised milk
Pathology
Primary Lesion
usually seen in non-immune children with first contact
infection begin as localised inflammation usually in subpleural midzone of lung (called the Ghon
focus)
essential lesion is granuloma, characterised by central caseous necrosis
extends almost invariably to bronchial and mediastinal lymph nodes, sometimes replaced by large
caseous masses
Ghon focus + hilar node involvement = Ghon complex
Subsequent Developments
Healing (90%)
small Ghon focus may undergo complete fibrosis, larger focus may be encapsulated and calcified
same changes occur in hilar nodes
bacilli may still be present in scarred foci and persist for years
Spread
inflammatory reaction in adjacent tissue may induce effusion in pleural space
infection may be carried by lymphatics from lymph nodes to pleura or pericardium with
development of tuberculous pleurisy or pericarditis
Invasion of blood vessels
will lead to dissemination associated with generalised military tuberculosis
if tuberculous infection invades one or more branches of pulmonary a., numerous military
tubercles form in lung tissue only
any form of immunocompromise (e.g. AIDS, cancer, DM) may allow endogenous reactivation
post-primary infection may also result from gradual extension of Ghon foci or reinfection by bacilli
lesions tend to appear in characteristic sites:
upper lobes
apical segments of lower lobes
sensitised T-cell recognise new threat and recruit macrophages to form large granulomas with
extensive caseous necrosis (liquefaction, cavitation, CD8 + + CD4+ lymphocytes)
easily dislodged and coughed up in sputum
extension of lesion is usually slow and hilar nodes aren’t affected
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granulation tissue heavily infiltrated by lymphocytes and macrophages forms at edges with fibrosis
at this stage lesion may:
heal, leaving dense grey scar often with central calcification
become encysted mass of caseous material and cease to spread
slowly extend by formation of new tubercles and necrosis of fibrous barriers
extent and coalesce with caseous material dislodge via small bronchus leaving cavity
disseminate via blood or bronchi
Clinical Fevers
Primary
usually asymptomatic (± fever, erythematous nodosum, phlycentular conjunctivitis, lassitude,
cough or sputum)
tuberculin test may be positive
Post-Primary
usually symptomatic (weight loss, night sweats, cough, haemoptysis, dyspnoea, malaise, organ
specific damage)
any other site may become main clinical problem
Complication Notes
Meningitis aseptic with insidious onset, increasing neck stiffness, headache, drowsiness, cranial n. palsies, choroidal
tubercle (50%), ± papilloedema
Genitourinary dysuria, haematuria, frequency
Bone usually affects adjacent vertebrae causing collapse (Potts disease) with paravertebral abscess
tuberculous osteomyelitis usually associated with arthritis or adjacent joints
Peritonitis associated with abdominal pain and GI upset
Pericarditis may present with effusion, tamponade, constrictive pericarditis or calcification
Scrofula tuberculous lymph adenitis of cervical lymph nodes that may drain onto overlying skin
in untreated case pulmonary Tb tends to be progressive disease with spread via bloodstream or
bronchi possible
however, modern antibiotic treatment chemotherapy usually prevent progression and
complications
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Restrictive Disease
characterised by expansion of lung parenchyma with total capacity
e.g. interstitial lung disease, pneumoconiosis, chest wall disorders (e.g. obesity, kyphoscoliosis)
characterised by acute onset of dyspnoea, progressive hypoxia, bilateral radiographic lung infiltrates and rapid
development of respiratory failure
severity varies but can require ventilation, 50-60% mortality
pathologically changes = diffuse alveolar disease (DAD)
descriptive term for pathologic sequence of event that follow severe acute lung injury due to
variety of causes
“diffuse” indicates that all part of alveolus are affected by process
usually widespread change in both lungs, but sometimes can be localised
Causes
Agent Example(s)
Infectious agents any infection in immunocompromised
Inhalants O2
Drugs chemoterapeutic agents
Ingestants
Shock traumatic, haemorrhage
Sepsis
Radiation
Miscellaneous acute massive aspiration, acute pancreatitis
Unknown
Pathogenesis
Lung Toxin
Epithelial Injury + Endothelial Injury
Necrosis of Type I cells Leaky capillaries
Oedema
Hyaline membranes
Alveolar collapse/coalescence
Fibrosis
Honeycomb lung
Initial Damage
mechanism depends on cause:
Cause Mechanism
Direct damage lung infection, aspiration, noxious gas
Septicaemia endotoxin activates complement cascade, stimulates platelet aggregation, intrinsic clotting pathway,
stimulates macrophages to release cytokines
Shock and trauma release of proteolytic agents from damaged tissue
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Inflammatory Response
can worsen or continue tissue damage
cell damage PG, LT, cytokine release
stimulates platelet aggregation, coagulation pathway, neutrophil chemotaxis, increased
permeability
increased leakiness leads to exudation and pulmonary oedema
hyaline membranes (fibrin + necrotic alveolar cells) form
Management
treat underling cause
ventilation, oxygen
circulatory support
renal support
Clinical Outcome
if survive, most have good recovery, although some have permanent severe lung scarring (honeycomb lung)
Pneumoconiosis
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Disease Morphology Clinical Pathogenesis Complications
Simple CWP coal macules (accumulation within macrophages little or no respiratory deficit fibrosis result of damage to macrophages by cor pulmonale
Coal Dust
with minimal fibrosis) or nodules (larger than chest x-ray may be normal coal dust leading to (1) release of enzymes Caplan’s syndrome
macules) + focal emphysema and free radicals causing damage and (2)
precursor lesion to complicated CWP cytokines which induce scarring
Complicated large areas of fibrosis (round, oval or stellate) respiratory function compromised (obstructive,
CWP which may cross septae and have central cavity restrictive or diffusing)
most common in upper lobes
Asbestos
Asbestosis diffuse interstitial fibrosis, most marked in periphery insidious condition, may be discovered incidentally on three possible mechanisms: (1) release of emphysema
of lower lobes chest x-ray in asymptomatic patient or as slow damaging enzymes from m-phages, (2) bronchiectasis
uncoated asbestos fibres and bodies (ferruginous development of SOB and cough release of fibroblast stimulating factors from
m-phages, (3) direct stimulation of fibroblasts Caplan’s syndrome
body) within areas of scarring
by asbestos pulmonary
hypertension, cor
pulmonale
Malignant effusion tend to disappear as tumour obliterates 3x > , 40-60 years, v. latency between presence of asbestos fibres in vicinity of may also invade
mesothelioma pleural cavity exposure and development of cancer serosal surface appears to crucial pathogenic pericardium and
radiology: pleural thickening, possible extending factor mediastinum
chest pain, SOB + weakness, fatigue, weight loss
into fissures and lungs carcinogenic potential enhanced by smoking metastases to lymph
average survival: 15 months, no treatment effective
nodes and liver
Benign pleural effusions
Visceral pleural fibrosis
Fibrocalcific parietal pleural plaques
Bronchogenic carcinoma
Silicon
Acute silicosis intra-alveolar granular proteinaceous material due to heavy exposure over short time period
variable interstitial fibrosis
Chronic silicosis tiny nodules throughout lungs (initially upper lobes) insidious, slowly progressing deterioration of macrophages activated releasing cytokines cor pulmonale
which enlarge and coalesce forming hard black respiratory function which activate neutrophils, fibroblasts and tuberculosis
scars lymphocytes
Caplan’s syndrome
adjacent compression of lung or emphysema vicious cycle of activation
eventually honeycombing ± calcification
radiology: “snow storm”
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Solid Tumours
Lung Cancer
Classification
papilloma
benign
adenoma
Epithelial
carcinoma (95%)
malignant
carcinoid
Lymphoma
benign hamartoma
Mesenchymal
malignant sarcoma
Unclassified
Metastatic
differentiated cells in epithelium though to all arise by differentiation from basal stem cells
lung tumours probably also arise from these stem cells and show a particular pattern because tumour cells
differentiate along one particular line
population of neuroendocrine cells in lung called Kulchitsky cells, scattered among epithelium
produce various peptide hormones acting in a paracrine fashion
function uncertain but appear to have some chemoreceptor function, e.g. ventilation/perfusion
matching
may also have role in growth and repair as much more prevalent in foetal lung
neuroendocrine tumours include small cell carcinoma and carcinoid (5 year survival 95%)
atypical carcinoid tumours are intermediate between SCC and carcinoid tumours
Epidemiology
530, 280 deaths/million
most aggressive type (SCC) has 5 year survival rate < 5%
others have 5 year survival rate <20%
most important prognostic feature is stage at presentation
Aetiology
smoking
environmental factors (asbestos, air pollutants, radiation, metal refining)
others (pulmonary fibrosis and scars)
genetic
Diagnosis
suggested by chronic cough with blood in sputum
chest x-ray
bronchoscopy (biopsy/bronchial wash)
fine needle aspirate
sputum cytology
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Types
Tumour Type % Identifying Features
Squamous cell carcinoma 35% keratin ± intercellular bridging
Adenocarcinoma 35% glands ± intracellular mucin
Large cell carcinoma 10% absence of other features
Small cell carcinoma 20% neuroendocrine
occasionally get mixed lung tumours with small cell admixed with squamous or adenocarcinoma
Adenocarcinoma
one variant is bronchioalveolar carcinoma where cell line up along alveolar walls, can present
like pneumonia on chest x-ray
Metastatic
most commonly adenocarcinoma (breast, pancreas, GIT)
metastatic adenocarcinoma usually present with one or more mass lesions, but occasional presents
as lymphangitis carcinomatosa (wide-spread permeation of lymphatic vessels) with fine
shadowing of chest x-ray
2nd most common body site to be involved in metastatic disease
Pathological Diagnosis
carcinoma or not
if carcinoma, SCC or NSCC
SCC – chemotherapy
NSCC – resection ± radiotherapy
Colon Cancer
>95% are adenocarcinoma
Adenocarcinoma
Epidemiology
one of commonest causes of death (2nd highest cause of death by cancer in USA)
affects middle aged/elderly, mainly in left colon and shows predominance
however, right-sided carcinomas show predominance
both genetic and environmental factors play a role in pathogenesis
specific gene defects have been identified in case of familial adenomatous polyposis (FAP) and
hereditary non-polyposis carcinoma of the colon (HNPCC)
familial component also seen in sporadic cases, with family history of 1 0 relative giving 3x risk
environmental factors include meat and fibre
chronic ulcerative colitis and Crohn’s disease also risk factors
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Morphology
15% are mucinous
sometimes residual polyp is present at edge of tumour
most moderately differentiated
morphology and symptomatology of r- and l-sided carcinomas may vary
L-sided
70-75% found in rectum, rectosigmoid and sigmoid colon
grow as plaques which gradual encircle bowel, may have fungating edges
tumours ulcerate and cause obstruction and/or haemorrhage
R-sided
may cause late symptoms because greater capacity to accommodate tumour
anaemia may be presenting symptom
Classification/Prognosis
classified by Duke:
Stage Description 5 year survival Chemotherapy
A confined to wall 99.8%
B spread beyond wall but not to lymph nodes 70% if obstructed or perforated
C tumour present in lymph nodes 30%
(C1 = region, C2= apical)
Other
Skin Cancer
Malignant Melanoma
Epidemiology
incidence: 541 (4th) 491 (4th)
deaths: 83 (6th) 99 (6th)
14% of all melanomas found on non skin sites (e.g. eye, vulva, rectum)
Risk Factors
personal or family history
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Warning Signs
A asymmetry
appearance of new lesion
B irregular borders
C colour variable
change in shape, size or colour
concern
D diameter >6 mm
E elevated
Classification
malignant melanoma types:
Type Features
superf spreading
nodular
acral lentiginous feet, hands, under nails
lentigo maligna on face as large pale mole
desmoplastic (<1%) spreads along nerves
Clarke’s classification:
Growth Phase Level Description
in situ in epidermis only
Radial
2
growth into papillary dermis
2
Vertical 3 growth into reticular dermis
4 growth into subcutaneous tissue
Prognosis
prognostic features:
Feature Prognosis
thickness <1 mm few die, >4 mm almost all die
Clark’s level (stage)
site back, arm, neck, scalp (BANS)
sex
amelanocytic
node involvement
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Musculoskeletal
Bone
Disease Example
Neoplasm osteosarcoma
Infectious bone disorders osteomyelitis
tuberculosis
Metabolic bone disorders Paget’s disease
osteoporosis
osteomalacia
hyperparathyroidism
Developmental disorders achondroplasia
Fractures
Bone Tumours
Osteosarcoma
Clinical Presentation
clinical signs (e.g. pain and swelling) present relatively late (i.e. when cortex destroyed)
often associated with Paget’s disease in elderly (50%)
vertebrae, pelvis and skull often affected
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Morphology
Macroscopic
haemorrhagic, variegated tumour expanding bone and destroying both medulla and cortex
spicules of bone may be palpable
periosteum frequency raised to produce “Codman’s triangle” at junction of periosteum and cortex
(non-specific)
Microscopic (variable)
essential feature is presence of malignant osteoblasts which lay down spicules of irregular osteoid
may or may not calcify – can be osteolytic or osteosclerotic
tumour osteoblasts are atypical, bizarre, show mitotic activity and frequency giant cell forms
small areas of cartilage may be present and 20 necrosis and haemorrhage frequent
common to find evidence of vascular invasion within tumour
Osteomyelitis
Pathogenesis
organism reaches bone via blood stream (10 bacteraemia usually subclinical)
site of infection usually adjacent to metaphyses of long bone
20 bacteraemia occurs
untreated infection extends into marrow cavity and through cortex in periosteum
pus between periosteum and cortex causes interruption of blood supply to cortex into periosteum
pus may penetrate skin forming draining sinus
periosteal new bone formation may be extensive and new bones sheath around necrotic sequestrum, giving
rise to involucrum
Clinical Features
sudden onset in children with high fever and tachycardia
localised pain, heat, redness, swelling
exquisite bone tenderness
radiological changes may not be apparent for 2-3 weeks
adult may have more insidious illness
occasionally involves vertebral bodies – infection invades intervertebral discs, pus destroys disc, vertebral
collapse, cord compression and neurological deficits
unless treatment is started promptly, expanding inflammatory process within rigid bone is seriously
compromised
with large sequestra, natural methods are inadequate so that surgical treatment is necessary
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at late chronic stage, in addition to local disability and disturbance of bone growth, amyloid disease may
supervene and occasionally squamous carcinoma arises
common bone disorder (10% of 65+) of unknown cause characterised by bone formation and reabsorption
Pathogenesis
three phases:
osteolytic
mixed osteolytic and osteoblastic
osteosclerotic (fracture and haemorrhage common)
irregular trabeculae (mosaic)
unmineralised osteoid
marrow space fibrotic
1-2% develop osteosarcoma
occasionally high output heart failure
Clinical Features
may be asymptomatic
enlarge of bones (e.g. skull, femur, clavicle, spine)
nerve deafness from bone overgrowth
20% in one bone only
joint degeneration (bowed tibia, kyphosis)
pathological fractures
Osteoarthritis (OA)
heterogeneous group of conditions that lead to joint symptoms and signs associated with defective integrity of
articular cartilage, in addition to related changes in underlying bone at joint margins
commonest form of arthritis, disorder of joints and chronic disability after middle age
Type Age Aetiology Affect Joint(s)
Primary 60+ (85% of 80+) idiopathic, although familial pattern evident knees, hips, spine, DIP
Secondary younger associated with predisposing condition single predisposed joint
(e.g. trauma, rheumatoid arthritis, gout, etc.)
Pathogenesis
oedema and softening of cartilage (susceptibility to injury )
thin cartilage (e.g. DIP) osseous proliferation
thick cartilage (e.g. knee) cartilaginous and synovial proliferation
flaking and fibrillation (cracks and clefts in surface cartilage)
chondrocyte proliferation and death (necrosis/apoptosis?) matrix disorganisation
blood vessels penetrate through subchondral bone bringing fibrocytes
fibrocartilage repair tissue fills cracks in cartilage
remodelling of bone
loss of cartilage with eburnation of bone surface
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Epidemiology
sport
occupation
minor injury ABNORMAL STRESS
abnormal biomechanics
heredity
NOT age
Ageing OA
Tissue water content
Glycosaminoglycans
Proteoglycans
Link protein fragmented normal
Degenerative enzymes normal
Clinical Features
crepitus
tender
pain usually present and commonly severe
stiff and functionally impaired joint (e.g. gait changes)
loss of cartilage results in radiological narrowing of joint space
osteophytes also prominent radiologically
bony swellings
deformity
muscle wasting
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Gastrointestinal
commonest pathological lesion of GI tract are inflammatory and neoplasia
clinical presentation:
abdominal pain
dyspepsia
GI bleeding
diarrhoea
obstruction
Oesophagus + Stomach
Helicobacteria Pylori
microaerophilic, spiral, gram –ve bacteria
natural habitat is gastric mucus, congregating at or around intercellular junction of gastric surface
also found attached to some cells on tissue surface through formation of adhesion pedicles
high urease activity
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Disease Morphology Pathogenesis Epidemiology Clinical Signs
O Reflux oesophagitis inflammation, peptic ulceration ± haemorrhage associated with increase in intra-abdominal
e sometimes fibrous strictures, Barrett’s oesophagus pressure
s
o
p Carcinoma squamous cell carcinoma in upper may present as fungating ulcerative lesions >, 50’s dysphagia
h adenocarcinoma in lower dietary nitrosamines, Fe , alcohol, haemorrhage
a tobacco, hot coffee
g
u
s
S G Acute superficial ulceration, infiltration of mucosa by neutrophils acid secretion chronic NSAIDS nausea, vomiting, abdominal pain,
t a deeper ulcers involving whole thickness seen in stress ulcers damage or alteration of mucosal protective excess alcohol haematamesis, melaena
o s barrier
m t uraemia
a r smoking, shock, stress, chemotherapy,
c i infection, gastric irradiation, ICP
h t Chronic (A) body probably autoimmune affects elderly other autoimmune phenomena
i
s antibodies to parietal cells (90%) and IF (50%) > gastric carcinoma
vit B12 malabsorption
Chronic (B) involves antrum H. pylori
associated with peptic ulceration and duodenitis
Peptic ulceration duodenum (1st part), gastric antrum, Barrett’s acute - burns, stress, drugs haemorrhage/perforation
oesophagus, Meckel’s diverticulum, small intestine chronic - age , > obstruction
round or oval, punched out edges, may erode full thickness carcinoma (1%)
microscopic – necrotic & inflammatory damage, granulation
deep vessels show endarteritis obliterans
N Benign stromal tumour SM, submucosa or serosa, small (~2cm) and asymptomatic
e regenerative polyp associated with inflammation, small, sometimes multiple
o
p neoplastic polyp much less common, >2 cm, sessile or pedunculated
l Malignant carcinoma (90-95%) usually adenocarcinoma genetic usually diagnosed late
a macroscopic – early gastric carcinoma confined to mucosa environmental (SES, H. pylori) weight loss, abdominal pain, v&n,
s and submucosa (5YS 75%), but usually fungating, bleeding
i abnormalities in gastric mucosa
ulcerative or diffusely infiltrative (5YS 10%) lymph node metastases usually
a dietary – nitrates/nitrites?
microscopic – glandular or diffuse present
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Large Intestine
Infections/Infestations
Agent Examples
Bacterial E. coli, shigella salmonella, campylobacter, mycobacteria, yersinia, vibrios, clostridia
Fungal candida
Protozoal entamoeba, schistosoma, balantidia, cryptosporidia
Viral rotovirus, adenovirus, calicivirus, astovirus, CMV
Bacterial Enterocolitis
Disease Process Description
Ingestion of preformed toxins explosive diarrhoea and acute abdominal distress (hours days)
systemic toxins (e.g. botulinim) may cause rapid fatal respiratory failure
Infection with enteric pathogens incubation (hours-days) followed by:
diarrhoea and dehydration (secretory enterotoxin) or dysentery (cytotoxin or enteroinvasive)
Insidious infection may present as subacute diarrhoeal illness (e.g. yersinia, mycobacteria)
complications are logical consequences of massive fluid loss of destruction of intestinal mucosal barrier
include dehydration, sepsis and perforation
without intervention in severe cases death ensues rapidly, especially in very young
Agent Disease Type Notes
E. coli enterotoxigenic food poisoning
enterhaemorrhahic Shigella-like toxin
enterpathogenic effacement of enterocytes but no invasion
enterinvasive
Salmonella typhoid fever multiplies in lymphoid tissue of small bowel
some gain access to blood and are taken up by reticuloendotrial system
headache, prostration, nose bleeding, bronchitis, constipation, abdominal tenderness and high
fever, ‘rose spots’ on skin, splenomegaly
ulcerative inflammation of Peyer’s patches causes diarrhoea and later haemorrhage and perforation
characteristically ulcers contain histiocytes showing erythrophagocytosis and paucity of neutrophils
food poisoing
septicaemia (without
bowel involvement)
Clostridium pseudomembranous aka antibiotic precipitated diarrhoea
colitis mild and self-limiting, or fulminant
necrosis of mucosa
Amoebiasis pass unharmed through stomach, vegetative forms released in small intestine
invade crypts and submucosa in caecum and asc. colon
Epidemiology
both common in Western world (4-6/100,000) >
peak age 20’s-30’s
Aetiology
cause unknown, theories:
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Toxic Megacolon
usually affects transverse colon making it dilated and thin-walled
becomes prone to perforation (peritonits and shock, with high mortality)
deep ulcerations (may be confused with Crohn’s), hyperaemia and transmural inflammation
associated with muscle necrosis
septicaemia may also supervene
caused by number of inflammatory bowel diseases
Ischaemic Colitis
Epidemiology
usually in elderly patients with atheroma
Clinical Presentation
may present as colitis with bleeding
Morphology
segmental, usually affecting splenic flexure
radiological: thumb printing sign (due to oedema and haemorrhage)
macroscopic: oedema with linear ulcers, sometimes mucosa becomes necrotic and prone to perforation
microscopic: mucosal ulceration, submucosal oedema and haemorrhage, focal muscle necrosis
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strictures due to fibrosis, haemosiderin laden macrophages, thickened fibrotic submucosa, ulcerated and
irregularly healed mucosa seen in chronic ischaemia
Diverticular Disease
Epidemiology
common condition in Western world (30-50% in routine autopsies)
uncommon before 30, with age
Morphology
affects particularly recto-sigmoid but also l. colon
hard cartilaginous consistency with prominent taenia coli and circular muscles
diverticula occur in two rows between mesocolon and taenia and open out in lumen through small openings
microscopic: invaginations through vessel openings by mucosa, muscle wall between openings attenuate
and fibrotic
Complications
80% asymptomatic
abdominal pain, diarrhoea/constipation
inflammation/fibrosis
abscess/perforation/peritonitis
bleeding
Pathogenesis
low fibre diet low stool bulk, abnormal peristalsis, hypertrophied muscle, intraluminal pressure
focal weakness in colonic wall at site of vascular entry
Diversion Colitis
inflammatory changes in mucosa of excluded large intetion after diversion of faecal stream
may be asymptomatic or lead to discharge/bleeding
lymphoid hyperplasia and surface ep degeneration
may be caused by change in bacterial flora leading to loss of ep trophic factors
Radiation Colitis
mucosal necrosis with ulceration, atypia or nuclei, obliterating endarteritis, necrosis and strictures
Collagenous Colitis
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Liver
Hepatitis
Pathogenesis
either infectious or non-infectious
Infectious
liver almost always involved in all blood-born infections
needle biopsy of used to diagnose occult infections, especially when military Tb suspected
number of specifically hepatropic virus (hepetatis A, B, C, D, E, etc) which cause significant global
mortality and morbidity
all cause virtually same clinicomorphological pattern of acute hepatitis, but vary in ability to
produce chronic, carrier state and fulminant hepatitis
Clinical Epidemiology
A 99% acute 3 world, homosexuals, overseas travellers
rd
Non-Infectious
Agent Notes
Alcohol single largest cause of liver failure in US
degree of damage determined by duration, quantity and genetic makeup
pathological liver show fatty change, portal and lobular PMN infiltrates, hepatocellular necrosis and
eventual cirrhosis
Drugs/toxins toxic (dose-dependent) or idiosyncratic (unpredictable)
can cause almost any type of hepatitis
Auto-immune >, similar to viral but -ve serology and +ve autoantibodies
often presents as acute hepatitis and characterised by plasma cells
responds to steroids
1 biliary
0
brunt of insult borne by biliary system rather than parenchyma
10 sclerosing cholangitis eventual expansion of portal tracts with piecemeal necrosis and cirrhosis occurs
Ascending cholangitis
α-1 antitrypsin deficiency can all mimic viral hepatitis and progress to cirrhosis
Wilson’s disease major extrahepatic manifestations and specific histological findings on biopsy
Haemochromatosis
Cryptogenic small number of cases have unknown cause
Clinical Syndromes
Acute Hepatitis
only hep A causes solely acute hepatitis
mainly parenchymal changes
lobular lymphocytic infiltration
ballooning degeneration of hepatocytes
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patchy necrosis
± cholestasis
can be divided into four phases:
Phase Features
Incubation period Hep A 15-45 days
Hep B 30-180 days
Hep C 14 days-many years
Hep D 15-90 days
Symptomatic pre-icteric phase non-specific constitutional symptoms (malaise, fatigue, fever, nausea, headaches)
circulating immune complexes (esp in Hep B) may create serum sickness-like syndrome with
fever, rash and arthralgia
elevated ALT & AST indicate hepatocyte damage
Symptomatic icteric phase caused mainly by conjugated hyperbilirubinaemia
dark urine, light stools, severe itching, hepatomegaly
ballooning degeneration of hepatocytes, focal necrosis, lobular inflammation and disarry with
fatty change and portal inflammation
Convalescence
not all acute attacks proceed through all phase (e.g. hep A in young children or hep C in adults
may be virtually asymptomatic)
Chronic Hepatitis
symptomatic, biochemical or serological evidence of continuing inflammatory hepatic disease for
more than 6 months
mainly portal tract changes
lobular inflammation in flares of activity
variable degree of fibrosis
necroinflammatory lesions represented by focal parenchymal necrosis and dropout, larger lobular
areas of confluent necrosis and periportal or periseptal piecemeal necrosis
inflammatory cells predominantly lymphocytic
serology determines cause, histology of biopsy determines grade and staging
most widely used grading system is histological activity index (HAI), which scores grade of
necroinflammatory activity and stage of fibrosis
final report includes aetiology, grade (mild/moderate/severe) and stage
(none/portal/periportal/bridging/cirrhosis)
Carrier State
individual without manifest symptoms who harbours and can transmit organism
two types: healthy carrier and carrier with chronic hepatitis
Hepatitis Carrier State
A none
B 1-10%
C 2-3%
D low
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He p C
30%
He p B (only)
30%
He p B/ D (c o)
He p A He p B
3%
0.01% 40%
He p B/ D (supe r)
7%
Drugs/ Che mic a ls
30%
25-90% mortality
if patient survives, liver may completely regenerate or cirrhose
macroscopic: red/green liver with wrinkled capsule
microscopic: lobular necrosis with sparing of periphery and little inflammation
Complications
hepatocellular carcinoma
cirrhosis
Hepatocellular Carcinoma
Pathogenesis
virtually any condition associated with chronic hepatic injury predisposes towards hepatocellular carcinoma
Hep B and alcohol related cirrhosis appear to two most important factors
recent data also indicate important pathogenic role of Hep C
hypothesised that chronic liver injury leads to sustained hepatocyte hyperplasia, susceptibility to carcinogens
and greater risk of chromosomal damage
proto-oncogenes may be activated and/or tumour suppressor genes inactivated
to date neither Hep B or Hep C found to be directly carcinogenic
Cirrhosis
diffuse process characterised by fibrosis and conversion of normal liver architecture into structurally abnormal
nodules
Morphology
fibrous scars formed in response to hepatocyte injury and loss, causing disorganisation of hepatic structure
fibrosis may take form of delicate bands (portal central, portal portal, or both) or broad scars
replacing multiple adjacent lobes
parenchymal nodules created by regenerative activity and network of scars
classically divided into micronodular (<3mm) and macronodular (>3mm)
vascular architecture reorganised by parenchymal damage and scarring forming abnormal a-v junctions
once developed no evidence that fibrosis can regress
may be clinically silent but often is anorexia, weight loss, weakness, spider angiomas,
gynaecomastia, and impaired synthesis of albumin, fibrinogen, prothrombin and other clotting factors
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Aetiology
P ost -ne c r ot ic
10.00%
S yphilis
2%
Ha e moc hr oma t osis
5%
Ot he r Ca rc inoma
40% 2%
Ot he r
10%
Ca rdia c Wilsons
Alc oholic
2% 2%
65%
Bilia ry
10%
Epidemiology
in most Western countries, cirrhosis is one of 10 leading causes of death, mainly due to alcohol
Complications
portal hypertension is important complication of cirrhosis
occurs mainly because of portal resistance at level of sinusoids due to parasinusoidal deposition
of collagen and compression of central veins by perivenluar fibrosis and parenchymal nodules
a-v junctions in fibrous scars may also play a role
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Major Differences
High degree of localisation of inherently vulnerable to focal lesions
function markedly different symptoms of same pathology depending on site
selective vulnerability of types of neurons or specific regions
Peculiar anatomical and skull – protects against injury, essential component in ICP
physiologyical features CSF – protects against trauma, agent for development of
hydrocephalus and dissemination of infection
BBB - stabilises intraparenchymal interior milieu
No lymphatics – with BBB makes brain immunologically privileged
site, renders brain susceptible to oedema
Disease Types
nervous system disease fall into two groups:
common – e.g. infections, trauma, neoplasm
unique – e.g. demyelination, system degeneration
Normal Cells
Cell Description
Neuron basic communicating unit of CNS
high metabolic rate, obligate aerobic
Astrocyte found throughout nervous system
physical and biochemical support of neurons
processes end on blood vessels, forms BBB, act as fibroblast during
repair
Oligodendrocyte found through brain (surround neurons in grey matter, line up along
myelinated fibres in white matter)
production and maintenance of CNS myelin
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Infection
brain and spinal cord relatively well protected from infection by bone and dura
haematogenous spread more common than direct
once infection established local defence mechanisms relatively deficient
dissemination through subarachnoid pace and ventricular system can be rapid
Bacterial Infection
CSF Changes
Normal Acute Subacute Viral
Colour clear and colourless
Cell count <5 x 106/L MNM , neutrophils MNMs lymphocytes
no neutrophils or RBCs
Glucose 60-70% plasma normal
Lactate (mM) 1-3
Protein (g/L) 0.2 – 0.5
Pyogenic Infection
Pachymenigitis
usually spread from focus of chronic suppuration (e.g. chronic otitis media, mastoiditis, frontal
sinusitis)
small extradural abscesses spread through dura to become subdural abscess or empyema
can spread from leptomeninges to subdural space especially in children
Leptomeningitis
spread of pyogenic organisms through subarachnoid space
occurs most commonly at extremes of life
medical emergency
Causative Agent
vary with age of patient
neonatal: E. coli, group B streptococci
other: N. menigitidis, H. influenzae, Strep. pneumoniae
Route of Infection
haematogenous (most common route in acute pyogenic meningitis)
bacteraemic phase (may be dominant clinical feature)
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Morphology
Macroscopic
intense congestion
purulent exudate, most marked about base and sulci
hydrocephalus may develop
necrosis of superficial cortex
Microscopic
neutrophil exudate in subarachnoid space + lymphocytes + macrophages
vasculitis
adhesions
Brain Abscess
Pathogenesis
Route of Infection Notes
Secondary to osteitis chronic otitis media or chronic mastoiditis commonest source in countries
where they are common
spread from bone, through meninges without causing significant subdural
empyema or purulent meningitis
Haematogenous associated with bronchiectasis, pneumonia, empyema, acute infective
endocarditis, congenital heart disease
Penetrating head injury
Morphology
chronic abscess has 2-3mm capsule, purulent contents and associated oedema
inner zone contains neutrophils and necrotic debris
capsule shows collagen, gliosis and mixed inflammatory cells
outer shows gliosis and oedema
acts as mass lesion because of oedema
other complications: meningitis, ventriculitis, suppurative cerebritis
Tuberculous Meningitis
almost always haematogenous, occasionally direct spread (e.g. from vertebrae) or military
Morphology (Macroscopic)
exudate gelatinous or caseous, most abundant in basal cisterns
almost always some degree of hydrocephalus
Morphology (Microscopic)
fibrinocaseous, diffusely permeated by lymphocytes, histiocytes and plasma cells
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Tuberculoma
encapsuleated caseous mass in brain
adults - cerebral hemispheres
children - cerebellum
convential tuberculous abscess
Viral Infections
clinically evident infections are uncommon (most individuals have antibodies to viruses known to cause CNS
infections but have never had any symptoms)
many viruses have diverse effects on CNS
different cell populations have different susceptibilities and viruses may affect different cells differently
host cell must possess specific receptor in order to be susceptible to infection
Pathogenesis
most gain access via mucous members of GI and respiratory tracts
most replicate outside of CNS
viraemia carries virus to CNS (some travel along nerves, e.g. radies, HSV)
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Infarction
brain very susceptible to oxygen deprivation, i.e. dependent on cerebral blood flow
cerebral perfusion pressure = mean system arterial pressure - intracranial pressure
autoregulation maintains blood flow at constant level between 50 and 160 mmHg
neurons most sensitive, followed by oligodendrocytes, astrocytes, microglia and blood vessels
distribution of hypoxic damage probably due to local metabolic factors rather than anatomy of blood supply
Cerebral Infarction
Morphology
Selective Neuronal Necrosis
neuron becomes shrunken, cytoplasm eosinophilic and nucleus pyknotic
glial reaction varies with degree of insult
Frank Infarction
usually centred on particular arterial territory
may involve entire arterial territory or just central regions depending on collateral circulation
three stages:
swelling and softening with coagulative necrosis
early reactive changes, inflammatory cells and phagocytosis
glial scar
Pathogenesis
Embolism
causes 30-60% of ischaemia stroke
sources include cardiac (mural, valvular disease) and atherosclerotic plaque ulceration
Atheroma
found in extracranial, internal carotid (especially prox) and cervical vertebral aa.
stenosis or occlusion of vertebral aa. may lead to infarction in hindbrain
anatomical distribution of aa. within brain remarkably constant
middle cerebral a. is most commonly affected
Hypertension
aggravates atherosclerosis
also produces change in walls of arteries and arterioles (hyaline arteriolosclerosis)
lacunes (small cavities in pons and basal ganglia) frequently found
commonest cause of spontaneous intracranial haemorrhage
Cardiac Arrest
characterised by widespread selective neuronal necrosis
hippocampus, post cerebral cortex, caudate nucleus and cerebellar Purkinje cell particularly
vulnerable
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Hypotension
commonest type of damage are ischaemic changes in boundary zones between cerebral and
cerebellar aa.
may occur in absence of, but is potentiated by, occlusive arterial disease
Tumours
Epidemiology
3-4/100,000 (2% of all tumours)
~50% neuroepithelial, ~30% metastatic
Clinical Features
histologically benign tumours may demonstrate biological malignancy
usually have diffusely infiltration borders making resection difficult or impossible
symptoms depend more on size and location than tumour type
Classification
Cell Tumour
Astrocyte astrocytoma
anaplastic astrocytoma
glioblastoma
Oligodendrocyte oligodendroglioma
Ependymal ependymoma
Undifferentiated/primitive medulloblastoma
Meninges mengioma
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Raised ICP
once fontanelles have closed, intracranial contents enclosed in rigid container:
Brain 70%
CSF 15%
Blood 15%
Pathogenesis
four stages:
Stage Notes
Spatial compensation increased in one component compensated by decrease in another
Slow rise in ICP systemic arterial pressure rises to maintain cerebral perfusion
pressure
Rapid rise in ICP cerebral perfusion pressure may fall
Cerebral vasomotor paralysis intrinsic vasomotor control lost in cerebral arterioles (ICP=systemic
arterial pressure, perfusion ceases, brain stem death occurs)
Clinical Features
headache
vomiting
consciousness
papilloedema
wide variety of pathological processes (e.g. neoplasm, haematoma, abscess, swollen infarct, granuloma)
Morphology
local distortion
displacement and herniation
ICP
Pathogenesis
Spatial Compensation
CSF volume decreases (ventricle size , subarachnoid space partly obliterated)
compression of venous sinuses reduces blood volume
local loss of brain tissue (especially with slowly growing lesions)
Contributing Factors
pressure volume curve
rate of expansion
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pre-existing atrophy
other factors (respiratory, anaesthetic agents)
Alterations in Brain
focal epilepsy, paralysis, haemianopia
shifts
Location
Supratentorial lesion enlargement of cerebral hemispheres with convolutional flattering
CSF displaced, ipsilateral ventricle shrinks, contralateral ventricle may dilate
lateral sift of midline structures, internal herniae
cingular gyrus herniates under free edge of falx
Tentorial herniation herniation of uncus and med ipsilateral parahippocampal gyrus through tentorial incisura
midbrain narrowed transversely
ipsilateral oculomotor nerve compressed
compression of ipsilateral posterior cerebral a. with infarction of occipital love
caudal movement of brain
haemorrhage and infarction midline midbrain and pons
Tonsillar herniation caudal displacement of cerebellar tonsils through foramen magnum
compression of medulla apnoea
Infratentorial hydrocephalus
enlargement of cerebral hemispheres with convolutional flattering
Other effects bone erosion
separation of sutures in children
in many expanding lesions effective size increased by associated oedema and vasodilatation
Cerebral Oedema
Cause Notes
Vasogenic BBB defective
cytotoxic oedema, essentially intracellular caused by energy failure
commonest cause is ischaemia
Hydrostatic sudden increase in intravascular pressure
Interstitial increase in periventricular water content associated with hydrocephalus
Hypo-osmotic serum osmolality
no evidence to suggest that brain water content directly interferes with patients neurological state
effects due to ICP
Hydrocephalus
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Pathogenesis
commonest cause in cerebral atrophy
acute hydrocephalus most often due to obstruction
ventricles enlarge, white matter
disruption of ependyma
Acute Hydrocephalus
causes include:
mass lesion at strategic point (foramen, aqueduct)
obliteration of subarachnoid space
congenital lesions
increased production
decreased absorption
Clinical Features
acute – symptoms from high ICP
children – spreading of sutures, enlargement of head
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Neurodegenerative Diseases
normal aging:
Macroscopic brain volume + gyral atrophy
(2-3% weight loss/decade > 50)
Microscopic number of neurons (especially cortical)
accumulation of pigment within neurons
senile plaques (predominantly amyloid)
Dementia
Causes
Type Examples
Neurodegenerative Alzheimer’s (65%)
Lewy body disease (10%)
Pick’s disease (2%)
Parkinson’s
Huntington’s
Prion CJD
Other cerebro-vascular (15%)
infections/inflammatory
toxic/metabolic
tumours
hydrocephalus
trauma
Diseases
Disease Epidemiology Macroscopic Microscopic
Alzheimer’s after 60 size (especially med temporal neurofibrillary tangles (temporal)
10% familial, several loci identified lobe) plaques (frontal & temporal)
history of head injury atrophy of grey matter neuronal loss
Parkinson’s idiopathic loss of dopaminergic neurons from
drug induced substantia nigra with Lewy bodies
multiple system atrophy
Lewy Body dementia ± late onset paranoia, lewy bodies in cortex (temporal + frontal)
may have parkinsonianism sometimes also Alzheimer’s pathology
Vascular confusion with other types infarcts (large areas) microscopic infarcts (basal ganglia,
often associated with Alzheimer’s smaller foci of ischaemia necrosis thalamus, usually multiple)
sudden onset, fluctuating course diffuse periventricular white matter diffuse white matter atrophy with
injury demyelinisation
history of TIA
Term Definition
Neurofibrillary tangles thickened and tortuous fibrils within neuronal cytoplasm
Plaques amyloid cores, neuritic (core of amyloid surrounded by abnormal neurons) or non-neuritic
Lewy body accumulation of filaments with dense granular material
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Endocrine
functions:
respond to stress
growth and development
reproduction
ionic homeostasis
energy metabolism
basic principles:
close relationship with CNS
hormones and target cells
feedback control mechanisms
intermittent release
other sources of hormones (e.g. kidney, tumours, drugs)
mechanisms of disease
disturbance of hormone concentration (/)
disturbance of hormone function
disturbance of organ
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