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..............................................................................................5 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............................................................................................................11 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................................................................................................................18 Restrictive Disease..........................................................................................................21 Adult Respiratory Distress Syndrome.........................................................................21 Pneumoconiosis.........................................................................................................22 Solid Tumours..................................................................................................25 Lung Cancer.....................................................................................................................25 Colon Cancer...................................................................................................................26 Adenocarcinoma........................................................................................................26 Other..........................................................................................................................27 Skin Cancer......................................................................................................................28 Malignant Melanoma..................................................................................................28 Musculoskeletal...............................................................................................30 Bone................................................................................................................................30 Bone Tumours............................................................................................................30 Osteosarcoma............................................................................................................30 Osteomyelitis.............................................................................................................31 Pagets Disease (osteitis deformans)..........................................................................32 Osteoarthritis (OA).....................................................................................................32 Gastrointestinal...............................................................................................34 Oesophagus + Stomach..................................................................................................34 Large Intestine.................................................................................................................36 Infections/Infestations................................................................................................36 Idiopathic Chronic Inflammatory Bowel Disease (IBD)................................................36 Ischaemic Colitis........................................................................................................37 Diverticular Disease...................................................................................................38 Diversion Colitis.........................................................................................................38
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Radiation Colitis.........................................................................................................38 Collagenous Colitis.....................................................................................................39 Drug Induced Colitis...................................................................................................39 Liver................................................................................................................................40 Hepatitis.....................................................................................................................40 Hepatocellular Carcinoma..........................................................................................42 Cirrhosis.....................................................................................................................42 Central Nervous System...................................................................................44 Introduction.....................................................................................................................44 Overview....................................................................................................................44 Infection...........................................................................................................................45 Bacterial Infection......................................................................................................45 Brain Abscess.............................................................................................................46 Non-Pyogenic Infection (Tuberculosis)........................................................................46 Viral Infections...........................................................................................................47 Infarction.........................................................................................................................48 Cerebral Infarction......................................................................................................48 Tumours...........................................................................................................................49 Raised ICP........................................................................................................................50 Intracranial Expanding Lesion....................................................................................50 Oedema and Brain Swelling.......................................................................................51 Hydrocephalus...........................................................................................................52 Neurodegenerative Diseases...........................................................................................53 Dementia...................................................................................................................53 Endocrine .......................................................................................................54

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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: haemorrhoids, varicocoele, oesophageal varices and caput medusae
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varicose

vv.,

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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 Kaposis sarcoma is becoming more common
Benign Capillary haemangioma Cavernous haemangioma Glomus tumour Borderline Haemangioendothelio ma Malignant Angiosarcoma Haemangiopericytom a Kaposi sarcoma rare but very malignant, consists of masses of malignant endothelial cells may be associated with environmental carcinogens when found in liver rare, presumed to arise from pericytes 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 contains endothelial cells with some vascular intima contain small channels (e.g. birthmarks) include large channels (e.g. port wine stain) painful tumour arising from glomus bodies (a-v shunts with neural elements)

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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 heatshock 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
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Table of Contents ATP ADP AMP Adenosine Inosine Hypoxanthin e X O Xanthine + O2* OH* + OH- + O2 Reperfusion SO D H2O2 catalase H2O Ischaemia

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 causes remaining 10%, due to

circumferential subendocardial infarction generalised hypoperfusion of coronary circulation

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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 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 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 Papillary dysfunction Mural thrombosis muscle 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 Pericarditis Chronic left heart failure Aneurysm 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 Recurrent MI risk due to underlying coronary a. disease

Rheumatic Fever Epidemiology

incidence and complication of rheumatic fever are high in NZ, especially among Maori (6.5/year/100,000) similar incidence to developing countries (e.g. India, Pakistan)

Pathogenesis
immune disorder that follows infection in children, usually streptococcal tonsillitis or pharyngitis some strains of group A -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 (Aschoffs nodules) composed of degenerated collagen, activated macrophages, lymphocytes and fibroblasts other manifestations that may occur are due to similar lesions in brain (Sydenhams chorea), skin (subcutaneous necrosis and erythematous rashes) and arteries (fibrinoid arteritis) Aschoff nodules may develop in:

however, heart is most important target organ of RF

myocardium (rheumatic myocarditis, usually mild)

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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

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

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Clinical Sequelae
Complication Infection and toxaemia weight loss anaemia caf au lait skin pigmentation splenomegaly Large emboli infarcts (brain, spleen, kidney) splinter haemorrhages (longitudinal under nails) metastatic abscesses mycotic aneurysms Microemboli petechial skin rash Oslers nodes (tender cutaneous nodules) retinal haemorrhage Immune deposition complex focal glomerulonephritis focal encephalitis cerebral arteritis Features

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
Causes post-inflammatory scarring often with history of RF valve cusp thickened and fused, orifice narrowed, chordae tendinae thickened, fused and maybe shortened Consequences left atrium fails to empty, becomes dilated and hypertrophic back pressure causes pulmonary hypertension and vascular congestion left sided heart failure develops often with atrial fibrillation and thrombosis

Valve Disease Stenosis

Mitral

Incompetenc e

post-inflammatory scarring post MI papillary muscle dysfunction LV dilatation cusp destruction floppy valve syndrome (excessive glycoprotein softens cusps)

acute: acute pulmonary oedema chronic: develops with regurgitation with atrial enlargement and progressive heart failure

Stenosis

calcification of congenital bicuspid valve (post-inflammatory scarring) (senile calcific degeneration)

LV hypertrophy angina sudden cardiac death due to arrhythmias LV hypertrophy LV failure

Aortic

Incompetenc e

post-inflammatory scarring cusp destruction senile calcification dilatation of aortic wall

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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)
Cause(s) Heart ischaemia heart disease systemic hypotension aortic/mitral valve disease myocardial disease cardiomyopathy) (e.g. LV dilatation LV hypertrophy (with restrictive outflow lesion) Mitral dilatation (with restrictive disorder) LV Effects Organs Lungs pulmonary congestion with oedema Kidneys function Brain cerebral (advanced failure) hypoxia

three types: left, right and congestive heart failure

Type Left

Right

Left heart failure (usual) Cor pulmonale

Liver congestion, may progress to centrilobular necrosis Kidney congestion and oedema Venous pressure Peripheral oedema

Congestiv e

End point of all types of serious disease

dilatation and hypertrophy of heart

three mechanisms of compensation:

Mechanism Rate of pumping Dilatation Hypertrophy occurs to accommodate incompetence) regurgitated blood (e.g. valve Description Pathologica l Physiologica l

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

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 (Cushings, acromegaly, phaeo, myxoedema) neurogenic (ICP ) miscellaneous (coarctation, polycythaemia)
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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 , mechanism unknown hereditary and environmental (smoking, stress, obesity, inactivity, salt intake, oestrogens) factors possible mechanisms:

Primary

role of renin role of Na+ and Clrole 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 Diffusion (type 1) Ventilation 2) (type Characteristi c PO2 low PCO2 normal PO2 PCO2

causes:

effects:

failure of ventilatory drive (e.g. depression of respiratory centre) upper airways obstruction lung diseases mechanical impairment (e.g. rib fractures) 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 -1 antitrypsin deficiency (with almost pure emphysema) at one end, and pure bronchitis at the other

Morphology
Type Centriacina r Panacinar Areas Affected respiratory bronchiole affected, distal alveoli spared more common in upper lobes acini uniformly enlarge from level of respiratory bronchiole more common at bases Paraseptal proximal acini normal, distal portion affected more striking adjacent to pleura next to areas of scarring Irregular acini irregularly involved probably cause pneumothorax of spontaneous associated deficiency with -1 antitrypsin Notes associated with smoking

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. -1 antitrypsin) in lung

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smoking inhibits antiproteases, recruits leukocytes (which secrete proteases) and promotes protease release

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 environment/immunosuppressed/aspiration) acquired/hospital acquired/special

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 < 6 months Commonest cause(s) usually viral (e.g. respiratory syncitial virus (RSV), adenoviruses, influenza, parainfluenza) Chlamydia tracomitis may transmitted to infant from mothers genital tract during birth 6 months 5 years older children adults young adults elderly and Haemophilus influenzae Streptococcus pneumoniae chlamydia, mycoplasma, strep. pneumoniae incidence and mortality frequency of concomitant disease is associated with

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 Streptococcus pneumoniae Mycoplasma pneumoniae Staph. aureus, pneumoniae Others Legionella Frequency 60% 10% 5% 5%

Hospital Acquired (Nosocomial)

defined as pneumonia developing 2+ days after admission for some other reason (i.e. 2 infection in patient with other illnesses)
0

Gram -ve organisms are most important variety of factors (including use of broad spectrum antibiotics and impaired host defences) promote colonisation of nasopharynx

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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 Gram -ve bacteria Staphylococcus aureus Streptococcus pneumoniae Anaerobes and fungi Frequency 50% 20% 15% 10%

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 consciousness can occur with neuromuscular disease or impaired

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 Acute congestion local vasodilatation causing congestion Microscopically followed by out-pouring of exudate Macroscopically heavy, dark red and firm

alveolar capillaries are engorged with RBCs and alveolar spaces filled with eosinophilic oedema fluid containing bacteria and neutrophils Red hepatisation capillary engorgement persists alveolar exudate contains fine network of fibrin, large numbers 16 brick red, dry, firm and airless

Table of Contents of RBCs, and neutrophils Grey hepatisation reduction in vasodilatation and congestion macrophage recruited into alveolar spaces, which are distended and consolidated by dense network of fibrin and dead and dying neutrophils and lysed red cells by 8-10 days in untreated cases exudate is gradually liquefied by fibrinolytic enzymes if no tissue damage, lung parenchyma returns to normal fibrinous pleurisy, airless and grey dry,

Resolution

Bronchopneumonia

patchy consolidation centred around inflamed bronchi 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 sudden onset rigors, fever, sweating cough, purulent rusty sputum pleuritic pain dyspnoea localised chest signs Atypical (mycoplasma, Legionella, viral) chills, fever dry cough predominance of extrapulmonary symptoms (headaches, myalgia, n/v, diarrhoea)

Morphology (Microscopic)
Atypical

usually interstitial often proteinaceous intra-alveolar spaces low mortality may be complicated by 20 bacterial infection

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Tuberculosis Aetiology

inflammation caused by Mycobacterium tuberculosis (and other species of mycobacteria)

slender, rod-shaped bacterium (1-5 m) 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

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 pressure of enlarged lymph nodes on bronchi may cause obstruction and lead to collapse, retention of secretions and pneumonia bronchiectasis may develop 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 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
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Hilar node involvement/Pulmonary Complications

Spread

Invasion of blood vessels

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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 arent affected 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
Complicatio n Meningitis Genitourinary Bone Notes aseptic with insidious onset, increasing neck stiffness, headache, drowsiness, cranial n. palsies, choroidal tubercle (50%), papilloedema dysuria, haematuria, frequency usually affects adjacent vertebrae causing collapse (Potts disease) with paravertebral abscess tuberculous osteomyelitis usually associated with arthritis or adjacent joints Peritonitis Pericarditis Scrofula associated with abdominal pain and GI upset may present with effusion, tamponade, constrictive pericarditis or calcification tuberculous lymph adenitis of cervical lymph nodes that may drain onto overlying skin

in untreated case pulmonary Tb tends to be progressive disease with spread via bloodstream or bronchi possible however, modern antibiotic treatment chemotherapy usually prevent progression and complications

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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 Infectious agents Inhalants Drugs Ingestants Shock Sepsis Radiation Miscellaneous Unknown acute massive pancreatitis aspiration, acute traumatic, haemorrhage Example(s) any infection in immunocompromised O2 chemoterapeutic agents

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 Oedema Hyaline membranes Alveolar collapse/coalescence Fibrosis Honeycomb lung Leaky capillaries

Initial Damage

mechanism depends on cause:

Cause Direct damage Septicaemia lung infection, aspiration, noxious gas endotoxin activates complement cascade, stimulates platelet aggregation, intrinsic 21 Mechanism

Table of Contents clotting pathway, stimulates macrophages to release cytokines Shock trauma and release of proteolytic agents from damaged tissue

Inflammatory Response

can worsen or continue tissue damage cell damage PG, LT, cytokine release stimulates platelet increased permeability aggregation, coagulation pathway, neutrophil chemotaxis,

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 Coal dust Silica Disease Mineral Dusts progressive massive fibrosis Caplans syndrome silicosis Caplans syndrome Asbestos asbesotsis pleural plaques Caplans syndrome mesothelioma carcinoma of lung, larynx, stomach, colon Beryllium acute berylliosis beryllium granulomatosis Organic dusts that induce extrinsic allergic alveolitis Mouldy hay Bagasse Bird droppings cotton, flax, hemp red cedar dust farmers lung bagassosis bird-breeders lung byssinosis asthma 22 farming manufacturing paper bird handling textile manufacturing lumbering, capacity wallboard, mining, fabrication foundry work, sandblasting, hard-rock mining, stone cutting mining, milling & fabrication, insulation work coal mining Exposure

Organic dusts that induce asthma

Table of Contents Chemical fumes and vapours NO, sulphur dioxide, ammonia, insecticides bronchitis asthma pulmonary oedema respiratory distress syndrome occupational exposure and accidental

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 m most important) chemical nature and solubility

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Table of Contents Disease Coal Dust Simple CWP Morphology coal macules (accumulation within macrophages with minimal fibrosis) or nodules (larger than macules) + focal emphysema precursor lesion to complicated CWP Complicated CWP large areas of fibrosis (round, oval or stellate) which may cross septae and have central cavity most common in upper lobes Asbestos Asbestosis diffuse interstitial fibrosis, most marked in periphery of lower lobes uncoated asbestos fibres and bodies (ferruginous body) within areas of scarring insidious condition, may be discovered incidentally on chest x-ray in asymptomatic patient or as slow development of SOB and cough three possible mechanisms: (1) release of damaging enzymes from m-phages, (2) release of fibroblast stimulating factors from m-phages, (3) direct stimulation of fibroblasts by asbestos emphysema bronchiectasis Caplans syndrome pulmonary hypertension, pulmonale cor respiratory function compromised (obstructive, restrictive or diffusing) Clinical little or no respiratory deficit chest x-ray may be normal Pathogenesis fibrosis result of damage to macrophages by coal dust leading to (1) release of enzymes and free radicals causing damage and (2) cytokines which induce scarring Complications cor pulmonale Caplans syndrome

Malignant mesothelioma

effusion tend to disappear obliterates pleural cavity

as

tumour possible

3x > , 40-60 years, v. latency between exposure and development of cancer chest pain, SOB + weakness, fatigue, weight loss average survival: 15 months, no treatment effective

radiology: pleural thickening, extending into fissures and lungs

presence of asbestos fibres in vicinity of serosal surface appears to crucial pathogenic factor carcinogenic smoking potential enhanced by

may also invade pericardium and mediastinum metastases lymph nodes liver to and

Benign pleural effusions Visceral pleural fibrosis Fibrocalcific plaques Silicon Acute silicosis parietal pleural

Bronchogenic carcinoma intra-alveolar material granular proteinaceous due to heavy exposure over short time period

variable interstitial fibrosis

Chronic silicosis

tiny nodules throughout lungs (initially upper lobes) which enlarge and coalesce forming hard black scars adjacent compression of lung or emphysema eventually honeycombing calcification radiology: snow storm

insidious, slowly progressing deterioration of respiratory function

macrophages activated releasing cytokines which activate neutrophils, fibroblasts and lymphocytes vicious cycle of activation

cor pulmonale tuberculosis Caplans syndrome

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Solid Tumours
Lung Cancer
Classification
benign Epithelial malignan t papilloma adenoma carcinoma (95%) carcinoid hamartoma sarcoma

Lymphoma Mesenchym al Unclassified Metastatic benign malignan t

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 ventilation/perfusion matching to have some chemoreceptor function, e.g.

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
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sputum cytology

Types
Tumour Type Squamous carcinoma Adenocarcinoma Large cell carcinoma Small cell carcinoma cell % 35% 35% 10% 20% Identifying Features keratin bridging glands mucin intercellular intracellular

absence of other features 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 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 10 relative giving 3x risk
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both genetic and environmental factors play a role in pathogenesis

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environmental factors include meat and fibre chronic ulcerative colitis and Crohns disease also risk factors

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:
Stag e A B C Description confined to wall spread beyond wall but not to lymph nodes tumour present in lymph nodes (C1 = region, C2= apical) 5 year survival 99.8% 70% 30% Chemotherapy if obstructed perforated or

other prognostic features include:

Feature extramural venous invasion perforation of tumour number invaded of lymph nodes at more pushing infiltrative , Prognosis

lymphocytic edge

infiltration

nature of advancing edge

Other

rare but include:

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

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Skin Cancer
Malignant Melanoma Epidemiology

incidence: deaths:

541 (4th) 83 (6th)

491 (4th) 99 (6th)

14% of all melanomas found on non skin sites (e.g. eye, vulva, rectum)

Risk Factors

A B C

personal or family history 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
asymmetry appearance of new lesion irregular borders colour variable change in shape, size or colour concern D E diameter >6 mm elevated

Classification

malignant melanoma types:

Type superf spreading nodular acral lentiginous lentigo maligna desmoplastic (<1%) feet, hands, under nails on face as large pale mole spreads along nerves Features

Clarkes classification:
Growth Phase Radial Level in situ 2 2 Vertical 3 4 Description in epidermis only growth into papillary dermis growth into reticular dermis growth into subcutaneous tissue

Prognosis

prognostic features:
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Table of Contents Feature thickness Clarks (stage) site sex amelanocytic node involvement level back, arm, neck, scalp (BANS) Prognosis <1 mm few die, >4 mm almost all die

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Musculoskeletal
Bone
Disease Neoplasm Infectious disorders Metabolic disorders bone bone osteosarcoma osteomyelitis tuberculosis Pagets disease osteoporosis osteomalacia hyperparathyroidism Developmental disorders Fractures achondroplasia Example

Bone Tumours

80% in axial skeleton 70% osteolytic, 20% osteoblastic

Name Incidence (Age) adolescent cell 20-40 40+ 10-25, 65+ 40-70 20-60 5-15 Common Sites lower limb around knee axial (sacrum, speno-occipital) around knee (young) at site of Pagets (elderly, 50%) limb girdle long bones endosteum) midshaft fibula) of (under long perior (esp. Behaviour benign, osteosclerotic, painful benign, may recur local bone destruction and invasion highly malignant, early metastases to lungs malignant malignant malignant

Osteoid osteoma Giant tumour Chordoma Osteosarcoma Chondrosarcom a Fibrosarcoma Ewings tumour

bones

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

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Clinical Presentation

clinical signs (e.g. pain and swelling) present relatively late (i.e. when cortex destroyed) often associated with Pagets disease in elderly (50%) vertebrae, pelvis and skull often affected 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 Codmans triangle at junction of periosteum and cortex (non-specific)
(variable)

Microscopic

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
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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 at late chronic stage, in addition to local disability and disturbance of bone growth, amyloid disease may supervene and occasionally squamous carcinoma arises
(osteitis deformans)

Pagets Disease

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 Primary Secondar y 60+ 80+) Age (85% of idiopathic, evident Aetiology although familial pattern Affect Joint(s) knees, DIP single joint hips, spine,

younger

associated with predisposing condition (e.g. trauma, rheumatoid arthritis, gout, etc.)

predisposed

Pathogenesis

oedema and softening of cartilage (susceptibility to injury )

thin cartilage (e.g. DIP)

osseous proliferation
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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 subchondral bone cysts form in osteoporotic domains from microfractures osteophyte formation on joint margin (Herberdens nodes = osteophytes at DIP) synovitis cause by fragments of cartilage in joint space

Epidemiology
sport occupation minor injury abnormal biomechanics heredity NOT age ABNORMAL STRESS

Ageing Tissue water content Glycosaminoglycans Proteoglycans Link protein Degenerative enzymes fragmente d normal

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

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Table of Contents Disease O Reflux e oesophagitis s o p Carcinoma h a g u s S t o m a c h G a s t r i t i s Acute Morphology inflammation, peptic ulceration haemorrhage sometimes fibrous strictures, Barretts oesophagus squamous cell carcinoma in upper adenocarcinoma in lower Pathogenesis associated with increase abdominal pressure in intraEpidemiology Clinical Signs

may present as fungating ulcerative lesions

>, 50s
dietary nitrosamines, Fe alcohol, , tobacco, hot coffee

dysphagia haemorrhage

superficial ulceration, infiltration neutrophils

of mucosa by

acid secretion damage or alteration protective barrier of mucosal

chronic NSAIDS excess alcohol uraemia smoking, shock, chemotherapy, infection, irradiation, ICP stress, gastric

nausea, vomiting, abdominal pain, haematamesis, melaena

deeper ulcers involving whole thickness seen in stress ulcers

Chronic (A)

body antibodies to parietal cells (90%) and IF (50%)

probably autoimmune

affects elderly

other autoimmune phenomena gastric carcinoma vit B12 malabsorption

>
H. pylori

Chronic (B)

involves antrum associated with peptic ulceration and duodenitis

Peptic ulceration

duodenum (1st part), gastric antrum, Barretts oesophagus, Meckels diverticulum, small intestine round or oval, punched out edges, may erode full thickness microscopic necrotic & inflammatory damage, granulation deep vessels show endarteritis obliterans

acute - burns, stress, drugs chronic - age > ,

haemorrhage/perforation obstruction carcinoma (1%)

N e o p l a s i a

Benign

stromal tumour

SM, submucosa or serosa, small (~2cm) and asymptomatic associated with inflammation, small, sometimes multiple genetic environmental (SES, H. pylori) abnormalities in gastric mucosa dietary nitrates/nitrites? usually diagnosed late weight loss, abdominal v&n, bleeding pain,

regenerative polyp Malignant

neoplastic polyp much less common, >2 cm, sessile or pedunculated carcinoma (90-95%) usually adenocarcinoma macroscopic early gastric carcinoma confined to mucosa and submucosa (5YS 75%), but usually fungating, ulcerative or diffusely infiltrative (5YS 10%) microscopic glandular or diffuse

lymph node metastases usually present

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Large Intestine
Infections/Infestations
Agent Bacterial Fungal Protozoal Viral Examples E. coli, shigella salmonella, campylobacter, mycobacteria, yersinia, vibrios, clostridia candida entamoeba, schistosoma, balantidia, cryptosporidia rotovirus, adenovirus, calicivirus, astovirus, CMV

Bacterial Enterocolitis
Disease Process Ingestion of preformed toxins Infection pathogens with enteric Description explosive diarrhoea and acute abdominal distress (hours days) systemic toxins (e.g. botulinim) may cause rapid fatal respiratory failure incubation (hours-days) followed by: diarrhoea and dehydration (secretory enterotoxin) or dysentery (cytotoxin or enteroinvasive) may present as subacute diarrhoeal illness (e.g. yersinia, mycobacteria)

Insidious infection

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 E. coli Disease Type enterotoxigenic enterhaemorrhahic enterpathogenic enterinvasive Salmonell a 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 Peyers patches causes diarrhoea and later haemorrhage and perforation characteristically ulcers contain histiocytes showing erythrophagocytosis and paucity of neutrophils food poisoing septicaemia (without bowel involvement) Clostridiu m Amoebiasi s pseudomembranou s colitis aka antibiotic precipitated diarrhoea mild and self-limiting, or fulminant necrosis of mucosa pass unharmed through stomach, vegetative forms released in small intestine invade crypts and submucosa in caecum and asc. colon food poisoning Shigella-like toxin effacement of enterocytes but no invasion Notes

Idiopathic Chronic Inflammatory Bowel Disease (IBD)

has come to mean ulcerative colitis (UC) and Crohns disease grouped together because of many similarities (e.g. aetiology, epidemiology, familial tendency, cancer risk) chronic diseases inflammation characterised by remission and exacerbations or almost continuous

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Epidemiology

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

Aetiology
cause unknown, theories:

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
Morphology affects mucosa only (except in fulminant colitis) starts in rectum and l. colon, may move prox to involve whole colon skipped areas not seen Complications toxic megacolon adenocarcinoma (5%) risks: early onset, 10 years+, extensive, continuous, dysplasia extraintestinal: liver disease (common, non-specific, portal duct inflammation, sometimes sclerosing cholangitis or cirrhosis) skin (erythema nodosum, pyoderm gangrenosum, papulonecrotic lesions) joints (polyarthritis)

Disease U C

Acute

deeply congested hyperaemic mucosa lymphocyrtes, eosinophils, neutrophils) ulceration usually superficial surviving islands of mucosa inflammatory psedopolyposis undergo cells

(+

plasma

cells,

crypitis and crypt abscesses with loss of mucus regeneration , branching and

Chronic remission

in

recovery of mucus, shortening of crypts

inflammatory

Chronic with mild activity

patchy inflammation in background of regenerative mucosal changes mucosal atrophy, Paneth muscularis mucosae loss of haustral folds cell metaplasia, hypertrophy of

Crohns

affects entire wall affects any part of GI tract, affected segments may increase with time (small intestine with colonic involvement most common) skipped areas seen oedema + longitudinal fissures (cobblestoning) patchy lymphoid preserved infiltration, crypt abscesses, goblet cells

malabsorption fistulae (internal, anal/rectal) toxic megacolon obstruction entercutaneous,

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 Crohns), hyperaemia inflammation associated with muscle necrosis septicaemia may also supervene caused by number of inflammatory bowel diseases and transmural

Ischaemic Colitis Epidemiology

usually in elderly patients with atheroma

Clinical Presentation
may present as colitis with bleeding
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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 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

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Collagenous Colitis

drug induced or idiopathic elderly, > watery diarrhoea (weeks years) and normal endoscopic appearance deposition of thick layer of collage (10-100 m) beneath epithelium

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

A B

all cause virtually same clinicomorphological pattern of acute hepatitis, but vary in ability to produce chronic, carrier state and fulminant hepatitis
Clinical 99% acute 60% subclinical, 30% acute, 10% chronic, 1% fulminant 3rd world, travellers 3rd world, prostitutes Africa (10%) rare in NZ, drug users, Mediterraneans or Asia, overseas travellers Epidemiology homosexuals, overseas IDU,

homosexuals,

C D

usually chronic (10+ years) usually coinfection with B frequently chronic fulminant

usually acute

Non-Infectious
Agent 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 Auto-immune toxic (dose-dependent) or idiosyncratic (unpredictable) can cause almost any type of hepatitis >, similar to viral but -ve serology and +ve autoantibodies often presents as acute hepatitis and characterised by plasma cells responds to steroids 10 biliary 10 cholangitis -1 deficiency sclerosing brunt of insult borne by biliary system rather than parenchyma eventual expansion of portal tracts with piecemeal necrosis and cirrhosis occurs Notes

Ascending cholangitis antitrypsin can all mimic viral hepatitis and progress to cirrhosis major extrahepatic manifestations and specific histological findings on biopsy

Wilsons disease Haemochromatosis Cryptogenic small number of cases have unknown cause

Clinical Syndromes
Acute Hepatitis

only hep A causes solely acute hepatitis mainly parenchymal changes

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lobular lymphocytic infiltration ballooning degeneration of hepatocytes patchy necrosis cholestasis can be divided into four phases:
Phase Features Hep A 15-45 days Hep B 30-180 days Hep C 14 days-many years Hep D 15-90 days

Incubation period

Symptomatic phase

pre-icteric

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

Symptomatic icteric phase

Convalescence

not all acute attacks proceed through all phase (e.g. hep A in young children or hep C in adults may be virtually asymptomatic)

Chronic Hepatitis
symptomatic, biochemical or serological evidence of continuing inflammatory hepatic disease for more than 6 months mainly portal tract changes lobular inflammation in flares of activity variable degree of fibrosis necroinflammatory lesions represented by focal parenchymal necrosis and dropout, larger lobular areas of confluent necrosis and periportal or periseptal piecemeal necrosis inflammatory cells predominantly lymphocytic serology determines cause, histology of biopsy determines grade and staging

most widely used grading system is histological activity index (HAI), which scores grade of necroinflammatory activity and stage of fibrosis (mild/moderate/severe) and stage

final report includes aetiology, grade (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 A B C D Carrier State none 1-10% 2-3% low

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Fulminant Hepatitis
Hep C 30%

(massive or sub-massive necrosis)

Hep B (only) 30% Hep B/ D (co) 3%

Hep A 0.01%

Hep B 40%

Hep B/D (super) 7% Drugs/ Chemicals 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 classically divided into micronodular (<3mm) and macronodular (>3mm)

parenchymal nodules created by regenerative activity and network of scars vascular architecture reorganised by parenchymal damage and scarring forming abnormal a-v junctions once developed no evidence that fibrosis can regress

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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

Aetiology
Post-necrotic 10.00% Syphilis 2% Haemochromatosis 5% Other 10% Other 40% Carcinoma 2%

Alcoholic 65% Biliary 10%

Cardiac 2%

Wilsons 2%

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 function inherently vulnerable to focal lesions markedly different symptoms of same pathology depending on site selective vulnerability of types of neurons or specific regions Peculiar anatomical physiologyical features and skull protects against injury, essential component in ICP 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:

Cell Neuron Astrocyte

common e.g. infections, trauma, neoplasm unique e.g. demyelination, system degeneration

Normal Cells
Description basic communicating unit of CNS high metabolic rate, obligate aerobic found throughout nervous system physical and biochemical support of neurons processes end on blood vessels, forms BBB, act as fibroblast during repair Oligodendrocyt e 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) (pachymeningitis) (pachymeningitis)

extradural space subdural space intracerebral intraventricular

subarachnoid space (leptomeningitis)

dura, arachnoid and pia appear to be relatively effective barriers to spread

CSF Changes
Normal Colour Cell count clear and colourless <5 x 106/L MNM no neutrophils RBCs Glucose Lactate (mM) Protein (g/L) 60-70% plasma 1-3 0.2 0.5 or neutrophils , MNMs lymphocytes normal Acute Subacute Viral

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: other: E. coli, group B streptococci N. menigitidis, H. influenzae, Strep. pneumoniae

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Route of Infection

haematogenous

(most common route in acute pyogenic meningitis) (compound fracture, iatrogenic)

bacteraemic phase (may be dominant clinical feature) spread from skull

Morphology
Macroscopic

intense congestion purulent exudate, most marked about base and sulci hydrocephalus may develop necrosis of superficial cortex neutrophil exudate in subarachnoid space + lymphocytes + macrophages vasculitis adhesions

Microscopic

Brain Abscess

can be caused by organisms of low pathogenicity mixed infections (including anaerobes) common

Pathogenesis
Route of Infection Secondary to osteitis Notes 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 Penetrating injury head associated with bronchiectasis, pneumonia, empyema, acute infective endocarditis, congenital heart disease

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
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Morphology (Microscopic)

fibrinocaseous, diffusely permeated by lymphocytes, histiocytes and plasma cells Langhans cells sparse obliterative endarteritis superifical infarcts

Tuberculoma
encapsuleated caseous mass in brain

adults children -

cerebral hemispheres 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 eosinophilic) Subacu te Persistent sclerosing panencephalitis Progressive multifocal leukoencephalopath y (in neurons, astrocytes, oligodendrocytes, round/oval,

necrosis (selective neuronal frank infarction) multifocal demyelination with lipid laden oligodendrocytes and large bizarre astrocytes middle aged patients with immune deficiency macrophages, abnormal

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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

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hippocampus, post cerebral cortex, caudate nucleus and cerebellar Purkinje cell particularly vulnerable

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 Astrocyte Tumour astrocytoma anaplastic astrocytoma glioblastoma Oligodendrocyte Ependymal Undifferentiated/primiti ve Meninges oligodendroglioma ependymoma medulloblastoma mengioma

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Raised ICP

once fontanelles have closed, intracranial contents enclosed in rigid container:

Brain CSF Blood 70% 15% 15%

normal ICP

<20 mmHg

(<3 kPa) (3-5 kPa) (>5 kPa)

moderate elevation 20-40 mmHg marked elevated >40 mmHg

commonest cause of ICP is intracranial expanding lesion

Pathogenesis
four stages:
Stage Spatial compensation Slow rise in ICP Rapid rise in ICP Cerebral paralysis vasomotor Notes increased in one component compensated by decrease in another systemic arterial pressure perfusion pressure rises to maintain cerebral

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
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rate of expansion 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 Infratentorial Other effects caudal displacement of cerebellar tonsils through foramen magnum compression of medulla apnoea hydrocephalus enlargement of cerebral hemispheres with convolutional flattering bone erosion separation of sutures in children

Oedema and Brain Swelling

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

in many expanding lesions effective size increased by associated oedema and vasodilatation

Cerebral Oedema
Cause Vasogenic BBB defective cytotoxic oedema, essentially intracellular caused by energy failure commonest cause is ischaemia Hydrostatic Interstitial Hypoosmotic sudden increase in intravascular pressure increase in periventricular water content associated with hydrocephalus serum osmolality Notes

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

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Hydrocephalus

total volume of CSF changed 3-5x/day

Type Internal External Communicating Noncommunicating Active Arrested Compensatory in subarachnoid space ventricles space can communicate with subarachnoid Notes within ventricular system

ventricles cant communicated with subarachnoid space progressive enlargement and ICP ventricular enlargement ceases 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:
Macroscopi c Microscopic brain volume + gyral atrophy (2-3% weight loss/decade > 50) number of cortical) accumulation neurons neurons of (especially within

pigment

senile plaques amyloid)

(predominantly

Dementia Causes
Type Neurodegenerati ve Lewy (10%) Examples Alzheimers (65%) body disease

Picks disease (2%) Parkinsons Huntingtons Prion Other CJD cerebro-vascular (15%) infections/inflammatory toxic/metabolic tumours hydrocephalus trauma

Diseases
Disease Alzheimer s Epidemiology after 60 10% familial, identified idiopathic drug induced multiple system atrophy Lewy Body dementia late paranoia, may parkinsonianism often associated Alzheimers sudden course onset, onset have infarcts (large areas) with smaller foci necrosis of ischaemia white lewy bodies in cortex (temporal + frontal) sometimes also Alzheimers pathology microscopic infarcts (basal ganglia, thalamus, usually multiple) diffuse white matter demyelinisation atrophy with several loci Macroscopic size (especially temporal lobe) atrophy of grey matter med Microscopic neurofibrillary tangles (temporal) plaques (frontal & temporal) neuronal loss loss of dopaminergic neurons from substantia nigra with Lewy bodies

history of head injury Parkinsons

Vascular

confusion with other types

fluctuating

diffuse periventricular matter injury

history of TIA Term Neurofibrillary tangles Plaques Lewy body Definition thickened and tortuous fibrils within neuronal cytoplasm amyloid cores, neuritic (core of amyloid surrounded by abnormal neurons) or non-neuritic accumulation of filaments with dense granular material

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Endocrine

functions:

respond to stress growth and development reproduction ionic homeostasis energy metabolism close relationship with CNS hormones and target cells feedback control mechanisms intermittent release other sources of hormones (e.g. kidney, tumours, drugs) disturbance of hormone concentration (/ ) disturbance of hormone function disturbance of organ

basic principles:

mechanisms of disease

Pituitary

Anterior disease

pituitary

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