Pathophysiology

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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

Central Nervous System...........................................................................................................41

Introduction................................................................................................................................41
Overview..............................................................................................................................41
Infection.....................................................................................................................................42
Bacterial Infection.................................................................................................................42
Brain Abscess........................................................................................................................43
Non-Pyogenic Infection (Tuberculosis)....................................................................................43
Viral Infections......................................................................................................................44
Infarction....................................................................................................................................45
Cerebral Infarction................................................................................................................45
Tumours.....................................................................................................................................46
Raised ICP..................................................................................................................................47
Intracranial Expanding Lesion.................................................................................................47
Oedema and Brain Swelling....................................................................................................48
Hydrocephalus......................................................................................................................48
Neurodegenerative Diseases........................................................................................................50
Dementia..............................................................................................................................50

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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

 group of diseases characterised by inflammation and damage to vessel walls

 may be mild and transient (marked only cellular infiltration of vessel wall and leakage of RBCs) or severe
(leading to destruction of affected vessels)
 three main groups of vasculitis syndromes: hypersensitivity, element of multiorgan autoimmune disease or
systemic vasculitides
 diagnosis based on resolution when cause is removed or nature of perivascular infiltrate

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

Element of Multiorgan Autoimmune Disease

 e.g. system lupus erythematosis, rheumatoid disease
 lymphocytes prominent in perivascular infiltration

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

Deep Vein Thrombosis

 see general pathology lectures

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

Tumours and Malformations of Blood Vessels

 developmental abnormalities relatively common and are called angiomas or haemangiomas

 contain small (capillary) or larger venous (cavernous) vessels or both
 sometimes lymphatics involved (cystic hygroma)
 brain may have venous malformations which may produce neurological signs due to compression
or haemorrhage
 vascular tumours are rare but AIDS related Kaposi’s sarcoma is becoming more common
Benign
Capillary haemangioma contain small channels (e.g. birthmarks)
Cavernous haemangioma include large channels (e.g. port wine stain)
Glomus tumour painful tumour arising from glomus bodies (a-v shunts with neural elements)
Borderline
Haemangioendothelioma contains endothelial cells with some vascular intima
Malignant
Angiosarcoma rare but very malignant, consists of masses of malignant endothelial cells
may be associated with environmental carcinogens when found in liver
Haemangiopericytoma rare, presumed to arise from pericytes
Kaposi sarcoma contains vascular intima and masses of poorly differentiated endothelial cells, originally described as
sporadic tumour in 6th or 7th decade of life, now mainly found associated with AIDS
appears as widespread multifocal lesions and painful purple/brown nodules in skin

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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

Ischaemic Heart Disease (IHD)

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

Sudden Cardiac Death

 most deaths from IHD occur outside hospital due either to infarction or arrhythmias
 many patients die without warning symptoms or shortly after onset
 usually due to VF
 patients with previous symptoms can develop rhythm abnormalities arising from muscle adjacent
to scar or from new thrombotic incidents

Subsequent Complications
Complication
Cardiac arrhythmia
Ventricular failure
Myocardial rupture
Papillary muscle dysfunction
Mural thrombosis
Pericarditis
Chronic left heart failure
Aneurysm
Recurrent MI
Notes
especially if infarct involves AV node
with large volumes of infarction and cardiac dilatation
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
may lead to valvular incompetence
due to endothelial cell loss and inflammation of endocardium and altered blood
flow to myocardium
risk of system embolism and further infarct
due to inflammation over infarct
due to extensive loss (<40%) of contractile tissue
10% of long-term survivors
due to dilatation of scars, laminated thrombosis may occur with risk of embolism
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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Rheumatic Heart Disease

 when present in heart value, Aschoff nodules can produce irregularity and sometimes ulceration of surface
 occurs particularly along lines of closure where platelets and fibrin accumulate to form small
vegetations of thrombus
 during acute RF the greatest risk is chronic or repeated immune damage which leads to progressive scarring
and distortion of heart vales, so that valves become stenotic and incompetent
 best prevented by prophylactic antibiotic therapy to rapidly treat streptococcal sore throat

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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Immune complex deposition focal glomerulonephritis

focal encephalitis
cerebral arteritis

 causes of death from bacterial endocarditis include

 acute valve perforation
 embolism
 ruptured mycotic aneurysm
 renal failure

Mechanical Disturbances of Valve Function

 two main types are stenosis and incompetence

 principle causes are:
 congenital abnormality
 post-inflammatory scarring
 age-related degeneration
 dilatation of valve ring
 destruction by inflammatory necrosis
Valve Disease Causes Consequences
Stenosis post-inflammatory scarring often with history of RF left atrium fails to empty, becomes dilated and
valve cusp thickened and fused, orifice narrowed, chordae hypertrophic
tendinae thickened, fused and maybe shortened back pressure causes pulmonary hypertension and
vascular congestion
left sided heart failure develops often with atrial
fibrillation and thrombosis
Mitral Incompetence post-inflammatory scarring acute: acute pulmonary oedema
post MI papillary muscle dysfunction chronic: develops with regurgitation with atrial
LV dilatation enlargement and progressive heart failure
cusp destruction
“floppy valve” syndrome (excessive glycoprotein softens
cusps)
Stenosis calcification of congenital bicuspid valve LV hypertrophy
(post-inflammatory scarring) angina
(senile calcific degeneration) sudden cardiac death due to arrhythmias
Aortic Incompetence post-inflammatory scarring LV hypertrophy
cusp destruction LV failure
senile calcification
dilatation of aortic wall

Cardiac Failure

 failure of heart to pump at rate required to maintain normal metabolism

 low output = majority output is low in respect to body requirements (e.g. IHD)
 high output = output is not sufficient for body needs but still higher than normal (e.g. chronic
anaemia)
 three types: left, right and congestive heart failure
Type Cause(s) Effects
Heart Organs
Left ischaemia heart disease LV dilatation Lungs – pulmonary congestion with
systemic hypotension LV hypertrophy (with restrictive oedema
aortic/mitral valve disease outflow lesion) Kidneys – function 
myocardial disease (e.g. cardiomyopathy) Mitral dilatation (with LV restrictive Brain – cerebral hypoxia (advanced
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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

 three mechanisms of compensation:

Mechanism Description Pathological Physiological
Rate of pumping   
Dilatation occurs to accommodate regurgitated blood (e.g. valve incompetence)  
Hypertrophy increase in muscle fibre bulk in order to deal with increase pressure load 
(e.g. hypertension)

 can also be described in terms of acute and chronic:

Acute Chronic
myocardial infarct hypertension
valve rupture cardiomyopathy
arrhythmia chronic valve disease
myocarditis chronic myocardial ischaemia
trauma

Arterial Disease
Hypertension

 definitions of raised blood pressure range from 140

/90 to 160
/95 mmHg

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

 PaO2 < 8 Kpa (normally 10.7 – 13.3)

Type Characteristic
Diffusion (type 1) PO2 low
PCO2 normal
Ventilation (type 2) PO2 
PCO2 

 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

 get notes of Poornima

Bronchiectasis

 get notes of Poornima

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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

Community Acquired Pneumonia

 may be 10 infection in otherwise healthy individual or associated with concomitant disease
 Streptococcus pneumoniae accounts for majority and gram -ve organisms are rare
 most patients are treated at home, with only ~25% requiring admission
Pathogen Frequency
Streptococcus pneumoniae 60%
Mycoplasma pneumoniae 10%
Staph. aureus, Legionella pneumoniae 5%
Others 5%

Hospital Acquired (Nosocomial)

 defined as pneumonia developing 2+ days after admission for some other reason (i.e. 2 0 infection
in patient with other illnesses)
 Gram -ve organisms are most important
 variety of factors (including use of broad spectrum antibiotics and impaired host defences)
promote colonisation of nasopharynx
 aspiration of infected nasopharyngeal secretions into lower respiratory tract facilitated by factors
which compromise defence mechanisms of lung (e.g. endotracheal intubation, impaired cough)
Pathogen Frequency
Gram -ve bacteria 50%
Staphylococcus aureus 20%
Streptococcus pneumoniae 15%
Anaerobes and fungi 10%

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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

Lost Defence Mechanisms

 loss or suppression of cough reflex
 injury to mucociliary system (e.g. cilia damage)
 interference of alveolar macrophage bactericidal and phagocytic ability
 pulmonary congestion + oedema
 accumulation of secretions

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

Hilar node involvement/Pulmonary Complications

 pressure of enlarged lymph nodes on bronchi may cause obstruction and lead to collapse,
retention of secretions and pneumonia
 bronchiectasis may develop

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

Secondary Tuberculosis (post-primary pulmonary infection)

 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

Tuberculin Skin Testing

 infection produced sensitivity to antigenic components called tuberculins
 when tuberculin is injected into skin a local mild inflammatory reaction occurs
 in non-sensitive subjects soon stops
 in sensitive subjects, hyperaemia and oedema continue to increase and is an intense perivascular
neutrophils infiltration, visible to naked eye as erythema and induration
 tests include Mantoux, Heaf and Tine
 positive test indicates of presence of hypersensitivity from either previous infection or BCG vaccination
 negative test makes active tuberculosis unlikely

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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)

Adult Respiratory Distress Syndrome

 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

 often multiple contributing causes in particular case

 e.g. severe trauma and shock  DAD  O2 therapy and may be later sepsis

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

Organisation and Repair

 stimulation of fibroblasts to proliferate, migrate and lay down matrix
 hyaline membrane organised then lined by type 2 alveolar cells, reabsorbed then differentiate with
type 1 cells

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

 group of lung disease cause by inhalation of dust and/or aerosol

 include both occupational and environmental related conditions
Agent Disease Exposure
Mineral Dusts
Coal dust progressive massive fibrosis coal mining
Caplan’s syndrome
Silica silicosis foundry work, sandblasting, hard-
Caplan’s syndrome rock mining, stone cutting

Asbestos asbesotsis mining, milling & fabrication,

pleural plaques insulation work
Caplan’s syndrome
mesothelioma
carcinoma of lung, larynx, stomach, colon
Beryllium acute berylliosis mining, fabrication
beryllium granulomatosis
Organic dusts that induce extrinsic allergic alveolitis
Mouldy hay farmer’s lung farming
Bagasse bagassosis manufacturing wallboard, paper
Bird droppings bird-breeder’s lung bird handling
Organic dusts that induce asthma
cotton, flax, hemp byssinosis textile manufacturing
red cedar dust asthma lumbering, capacity
Chemical fumes and vapours
NO, sulphur dioxide, bronchitis occupational and accidental
ammonia, asthma exposure
insecticides
pulmonary oedema
respiratory distress syndrome

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Important Factors in Development

 amount of dust retained
 concentration of substance in air
 duration of exposure
 effectiveness of clearance mechanisms
 shape and size of particles (1-5 μm most important)
 chemical nature and solubility

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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

Small Cell Carcinoma (SCC)

 cells not necessarily small
 have hyperchromatic nuclei and scanty cytoplasm
 numerous mitoses and extensive necrosis
 sometimes produce ectopic hormones

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 prognostic features include:

Feature Prognosis
extramural venous invasion 
perforation of tumour 
number of lymph nodes invaded more 
lymphocytic infiltration at edge 
nature of advancing edge pushing , infiltrative 

Other

 rare but include:

 stromal tumours
 endocrine tumours (carcinoid)
 lymphoma (rarer than in stomach and small intestine)

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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 large numbers of moles

 clinically atypical moles
 sun burning in childhood/adolescence
 acute/intermittent exposure to sunlight
 light skin type, eyes, hair
 N. European ancestry living in high sunlight

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

 80% in axial skeleton

 70% osteolytic, 20% osteoblastic
Name Incidence Common Sites Behaviour
(Age)
Osteoid osteoma adolescent lower limb benign, osteosclerotic, painful
Giant cell tumour 20-40 around knee benign, may recur
Chordoma 40+ axial (sacrum, speno-occipital) local bone destruction and invasion
Osteosarcoma 10-25, 65+ around knee (young) highly malignant, early metastases to lungs
at site of Paget’s (elderly, 50%)
Chondrosarcoma 40-70 limb girdle malignant
Fibrosarcoma 20-60 long bones (under peri- or endosteum) malignant
Ewing’s tumour 5-15 midshaft of long bones (esp. fibula) malignant

 all more common in males than females

 adenocarcinoma of breast, kidney, thyroid & prostate and carcinoma of bronchus often metastasise to bone
 may result in:
 pathological fractures
 bone pain
 replacement of bone marrow
 hypercalcaemia
 compression of structure

Osteosarcoma

 commonest 10 tumour of bone (excluding myeloma)

 highly variable but two fundamental groups: central and peripheral

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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 tumours may be multicentric

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

 acute infection caused by variety of organisms but 90% staph. aureus

 also Strep. pyogenes, Haemophilus influenzae, Neisseria gonorrhoea, Escherichia coli
 may occur with generalised septicaemia, infection of surrounding tissues or following fracture
 haematogenous osteomyelitis common in childhood, particularly with Polynesians
 can also occur in immunocompromised

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

Paget’s Disease (osteitis deformans)

 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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 subchondral bone cysts form in osteoporotic domains from microfractures

 osteophyte formation on joint margin (Herberden’s nodes = osteophytes at DIP)
 synovitis cause by fragments of cartilage in joint space

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 

 OA is not simply result of biological ageing of articular cartilage

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

Prevalence in developed countries children 

Prevalence in disease states
Evidence of pathogenicity
age 
ethnic/racial differences
large family  overcrowding 
low SEC 
chronic gastritis - >90%
duodenal ulcer - >95%
gastric ulcer - ~70%
volunteer studies
endoscope transmission
animal models
immunological response
antibiotic treatment

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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

Idiopathic Chronic Inflammatory Bowel Disease (IBD)

 has come to mean ulcerative colitis (UC) and Crohn’s disease

 grouped together because of many similarities (e.g. aetiology, epidemiology, familial tendency,  cancer risk)
 chronic diseases characterised by remission and exacerbations or almost continuous inflammation

Epidemiology
 both common in Western world (4-6/100,000) >
 peak age 20’s-30’s

Aetiology
 cause unknown, theories:
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 infection: virus have been implicated, but data ambiguous

 immunological: 10 disease results in inappropriate exposure of intestinal immune system to
antigens
 genetic predisposition: suggested by familial aggregations
Disease Morphology Complications
U affects mucosa only (except in fulminant colitis) toxic megacolon
C starts in rectum and l. colon, may move prox to involve whole colon adenocarcinoma (5%) risks: early onset, 10
skipped areas not seen years+, extensive, continuous, dysplasia

Acute deeply congested hyperaemic mucosa (+ plasma cells, lymphocyrtes, extraintestinal:

eosinophils, neutrophils) liver disease (common, non-specific, portal
crypitis and crypt abscesses with loss of mucus duct inflammation, sometimes sclerosing
cholangitis or cirrhosis)
ulceration usually superficial
skin (erythema nodosum, pyoderm
surviving islands of mucosa undergo regeneration  inflammatory gangrenosum, papulonecrotic lesions)
psedopolyposis
joints (polyarthritis)
Chronic in recovery of mucus, inflammatory cells , branching and shortening of
remission crypts
Chronic with mild patchy inflammation in background of regenerative mucosal changes
activity mucosal atrophy, Paneth cell metaplasia, hypertrophy of muscularis
mucosae
loss of haustral folds
Crohn’s affects entire wall malabsorption
affects any part of GI tract, affected segments may increase with time fistulae (internal, entercutaneous,
(small intestine with colonic involvement most common) anal/rectal)
skipped areas seen toxic megacolon
oedema + longitudinal fissures (cobblestoning) obstruction
patchy lymphoid infiltration, crypt abscesses, goblet cells preserved
thickened submucosa with lymphoid aggregations and epithelioid
granulomas
lymphoid aggregation and inflammation also seen in muscle wall and
serosa  fibrosis

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

 drug induced or idiopathic

 elderly, >
 watery diarrhoea (weeks  years) and normal endoscopic appearance
 deposition of thick layer of collage (10-100 μm) beneath epithelium

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Drug Induced Colitis

 NSAIDS, gold, methotrexate, methyldopa

 non-specific inflammation, ulceration, strictures and diaphragm formation in small intestine

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Liver
Hepatitis

 inflammation of hepatic parenchyma

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

B 60% subclinical, 30% acute, 3rd world, homosexuals, IDU, prostitutes

10% chronic, 1% fulminant
C usually chronic (10+ years)
D usually coinfection with B
frequently fulminant or chronic
E usually acute
Africa (10%)
rare in NZ, drug users, Mediterraneans
Asia, overseas travellers

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
Wilson’s disease
Haemochromatosis
Cryptogenic
can all mimic viral hepatitis and progress to cirrhosis
major extrahepatic manifestations and specific histological findings on biopsy
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
Incubation period
Symptomatic pre-icteric phase
Symptomatic icteric phase
Convalescence
Features
Hep A 15-45 days
Hep B 30-180 days
Hep C 14 days-many years
Hep D 15-90 days
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
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

 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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Fulminant Hepatitis (massive or sub-massive necrosis)

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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Central Nervous System

Introduction
Overview

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

 6 potential sites of infection (either singly or in combination):

 bone (osteitis, mastoiditis, otitis media, osteomyelitis)
 extradural space (pachymeningitis)
 subdural space (pachymeningitis)
 subarachnoid space (leptomeningitis)
 intracerebral
 intraventricular
 dura, arachnoid and pia appear to be relatively effective barriers to spread

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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 spread from skull (compound fracture, iatrogenic)

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

 can be caused by organisms of low pathogenicity

 mixed infections (including anaerobes) common

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

Non-Pyogenic Infection (Tuberculosis)

 always 20 to infection elsewhere

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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 Langhans cells sparse

 obliterative endarteritis
 superifical infarcts

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)

Acute Aseptic usually not severe

caused by enteroviruses (e.g. polio, Coxsackie, mumps)
lymphocytes, plasma cells and macrophages in subarachnoid space
Acute viral inflammatory reactions similar in all types of viral encephalitis
infiltration by lymphocytes, plasma cells and macrophages in subarachnoid space,
hyperplasia of microglia, reactive astrocytes followed by progressive fibrillary gliosis
abnormalities in neurons (chromatolysis, necrosis, neuronophagia)
inclusion bodes (in neurons, astrocytes, oligodendrocytes, round/oval, eosinophilic)
necrosis (selective neuronal  frank infarction)
Subacute Persistent sclerosing multifocal demyelination with lipid laden macrophages, abnormal oligodendrocytes and
panencephalitis large bizarre astrocytes
Progressive multifocal middle aged patients with immune deficiency
leukoencephalopathy

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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%

 normal ICP <20 mmHg (<3 kPa)

 moderate elevation 20-40 mmHg (3-5 kPa)
 marked elevated >40 mmHg (>5 kPa)
 commonest cause of  ICP is intracranial expanding lesion

Pathogenesis
 four stages:
Stage
Spatial compensation
Slow rise in ICP
Rapid rise in ICP
Cerebral vasomotor paralysis
Notes
increased in one component compensated by decrease in another
systemic arterial pressure rises to maintain cerebral perfusion
pressure
cerebral perfusion pressure may fall
intrinsic vasomotor control lost in cerebral arterioles (ICP=systemic
arterial pressure, perfusion ceases, brain stem death occurs)

 transient increases in pressure common during stages 2 & 3

 pressure gradients between compartments also important

Clinical Features
 headache
 vomiting
 consciousness 
 papilloedema

Intracranial Expanding Lesion

 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

Oedema and Brain Swelling

Normal Oedema
White matter 70% 75%
Grey matter 80% 81%

 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

Congestive Brain Swelling

 can occur rapidly particular in children with head injury
 arterioles dilate, capillaries flood with stagnant blood (i.e. some vasomotor paralysis)
 can rapidly lead to  ICP

Hydrocephalus

 total volume of CSF changed 3-5x/day

Type Notes
Internal within ventricular system
External in subarachnoid space

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Communicating ventricles can communicate with subarachnoid space

Non-communicating ventricles can’t communicated with subarachnoid space
Active progressive enlargement and  ICP
Arrested ventricular enlargement ceases
Compensatory increased CSF volume compensated by loss of brain tissue

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

Pituitary Anterior pituitary disease

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