Pathophysiology
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Table of Contents
Table of Contents
Table of Contents ....................................................................................................................... 2
Cardiovascular ........................................................................................................................... 4
Introduction ................................................................................................................................. 4
Classification .......................................................................................................................... 4
Vasculitis ................................................................................................................................ 4
Abnormalities of Veins ............................................................................................................. 4
Abnormalities of Arteries ......................................................................................................... 4
Tumours and Malformations of Blood Vessels ........................................................................... 5
Heart Disease ............................................................................................................................... 6
Pathophysiology ...................................................................................................................... 6
Ischaemic Heart Disease (IHD) ................................................................................................ 7
Rheumatic Fever ..................................................................................................................... 8
Endocarditis ............................................................................................................................ 9
Mechanical Disturbances of Valve Function ............................................................................. 10
Cardiac Failure ...................................................................................................................... 10
Arterial Disease........................................................................................................................... 11
Hypertension ........................................................................................................................ 11
Respiratory .............................................................................................................................. 13
Respiratory Failure ................................................................................................................ 13
Obstructive Disease .................................................................................................................... 13
Emphysema .......................................................................................................................... 13
Chronic Bronchitis ................................................................................................................. 14
Asthma................................................................................................................................. 14
Bronchiectasis ....................................................................................................................... 14
Infection .................................................................................................................................... 15
Pneumonia ........................................................................................................................... 15
Tuberculosis.......................................................................................................................... 17
Restrictive Disease ...................................................................................................................... 20
Adult Respiratory Distress Syndrome ...................................................................................... 20
Pneumoconiosis .................................................................................................................... 21
Solid Tumours .......................................................................................................................... 24
Lung Cancer ............................................................................................................................... 24
Colon Cancer .............................................................................................................................. 25
Adenocarcinoma ................................................................................................................... 25
Other ................................................................................................................................... 26
Skin Cancer ................................................................................................................................ 26
Malignant Melanoma ............................................................................................................. 26
Musculoskeletal ....................................................................................................................... 28
Bone .......................................................................................................................................... 28
Bone Tumours ...................................................................................................................... 28
Osteosarcoma ....................................................................................................................... 28
Osteomyelitis ........................................................................................................................ 29
Paget’s Disease (osteitis deformans) ............................................................................................ 30
Osteoarthritis (OA) ................................................................................................................ 30
Gastrointestinal ....................................................................................................................... 32
Oesophagus + Stomach .............................................................................................................. 32
Large Intestine ........................................................................................................................... 34
Infections/Infestations........................................................................................................... 34
Idiopathic Chronic Inflammatory Bowel Disease (IBD) ............................................................. 34
Ischaemic Colitis ................................................................................................................... 35
2
Table of Contents
Diverticular Disease ............................................................................................................... 36
Diversion Colitis .................................................................................................................... 36
Radiation Colitis .................................................................................................................... 36
Collagenous Colitis ................................................................................................................ 36
Drug Induced Colitis .............................................................................................................. 36
Liver .......................................................................................................................................... 37
Hepatitis ............................................................................................................................... 37
Hepatocellular Carcinoma ...................................................................................................... 39
Cirrhosis ............................................................................................................................... 39
Central Nervous System .......................................................................................................... 41
Introduction ............................................................................................................................... 41
Overview .............................................................................................................................. 41
Infection .................................................................................................................................... 42
Bacterial Infection ................................................................................................................. 42
Brain Abscess ....................................................................................................................... 43
Non-Pyogenic Infection (Tuberculosis) .................................................................................... 43
Viral Infections ...................................................................................................................... 44
Infarction ................................................................................................................................... 45
Cerebral Infarction ................................................................................................................ 45
Tumours ..................................................................................................................................... 46
Raised ICP .................................................................................................................................. 47
Intracranial Expanding Lesion ................................................................................................ 47
Oedema and Brain Swelling ................................................................................................... 48
Hydrocephalus ...................................................................................................................... 48
Neurodegenerative Diseases ........................................................................................................ 50
Dementia ............................................................................................................................. 50
3
Cardiovascular
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

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
may be mild and transient (marked only cellular infiltration of vessel wall and leakage of RBCs) or severe
(leading to destruction of affected vessels)
Hypersensitivity Vasculitis





most common pattern
affects capillaries and venules
causes skin rashes
may reflect allergy to drug or as manifestation of bacteraemia
antibody-antigen complexes become trapped within vessel walls and initiate acute inflammation
Element of Multiorgan Autoimmune Disease


e.g. system lupus erythematosis, rheumatoid disease
lymphocytes prominent in perivascular infiltration
Systemic Vasculitides



show various patterns of vessel wall destruction
although “systemic” usually only some regions are affects
causes fibrinoid necrosis, loss of smooth muscle and elastic laminae, vessel obstruction and ischaemia
Abnormalities of Veins
Deep Vein Thrombosis

see general pathology lectures
Structural Abnormalities

dilatation and congestion relatively common in certain sites: varicose vv., haemorrhoids, varicocoele,
oesophageal varices and caput medusae
Abnormalities of Arteries

arteriosclerosis
4
Cardiovascular



medial sclerosi
arteriolosclerosis (see hypertension)
aneurysms
Tumours and Malformations of Blood Vessels

developmental abnormalities relatively common and are called angiomas or haemangiomas




contain small (capillary) or larger venous (cavernous) vessels or both
sometimes lymphatics involved (cystic hygroma)
brain may have venous malformations which may produce neurological signs due to compression or
haemorrhage
vascular tumours are rare but AIDS related Kaposi’s sarcoma is becoming more common
Benign
Capillary haemangioma
contain small channels (e.g. birthmarks)
Cavernous haemangioma
include large channels (e.g. port wine stain)
Glomus tumour
painful tumour arising from glomus bodies (a-v shunts with neural elements)
Borderline
Haemangioendothelioma
contains endothelial cells with some vascular intima
Malignant
Angiosarcoma
rare but very malignant, consists of masses of malignant endothelial cells
may be associated with environmental carcinogens when found in liver
Haemangiopericytoma
rare, presumed to arise from pericytes
Kaposi sarcoma
contains vascular intima and masses of poorly differentiated endothelial cells, originally described as
sporadic tumour in 6th or 7th decade of life, now mainly found associated with AIDS
appears as widespread multifocal lesions and painful purple/brown nodules in skin
5
Cardiovascular
Heart Disease
Pathophysiology
Myocyte Injury

response of myocardial cells to sudden severe ischaemia is rapid and  ATP production leads to
cessation of contraction within seconds

however, energy generation (by anaerobic glycolysis) is sufficient to maintain membrane stability for
some time

susceptibility to ischaemic injury is greater near endocardium and least near epicardium, leading to
transmural “wave front” progression of injury

irreversible injury in severe ischaemia develops within one hour in endocardium, and becomes full
thickness within 12 hours

reversible ischaemic injury has interesting effects on function of myocytes

brief period of ischaemia (e.g. 15 minutes) does not compromise long-term viability, but recovery
of normal activity is gradual and may take 24 hours – this is called myocardial stunning

ischaemia preconditioning is where several very brief intervals of ischaemia (e.g. 4 x 5
minutes) markedly increases tolerance to a subsequent longer period


used in cardiac surgery to allow longer operation times
thought to occur through two mechanisms: alteration of ATP metabolism through activation of
adenosine receptors and PKC (short-term) and production of heat-shock proteins
Microvascular Injury

contrary to expectation that vasodilatation, hyperaemia, and capillary recruitment in response to
ischaemia would be associated with increased blood flow when restored, reperfusion is associated
with diminished blood flow

virtually impossible to reperfuse infarct because of no-reflow phenomenon



develops in all tissues about time of irreversible ischaemia injury (e.g. brain 3-4 min, heart 1-12
hours, muscle 6-8 hours)

thought to prevent haemorrhage into infarcts
even brief (e.g. 15 minutes) ischaemia injury followed by ~50% reduction in competent capillaries =
microvascular stunning
caused by ischaemia and (mostly) injury due to oxygen-derived free radical damage
Reperfusion Injury

paradoxically, restoration of blood flow necessary to salvage tissue may cause further injury through
generation of oxygen-derived free radicals

hydroxyl radical (OH*) is extremely reactive and can initiate chain of lipid peroxidation and
irreversible cell membrane damage

normally, free radicals are rapidly eliminated by enzymes (SOD, catalase), or mopped up (Vit E,
glutathione)

during period of ischaemia: antioxidants are used up, xanthine dehydrogenase (XDH) is converted to
xanthine oxidase (XO) (by proteases) and pH falls (accumulation of H+ from anaerobic glycolysis)

adding oxygen by reperfusion rapidly generates reaction oxygen species and cause damage
Ischaemi
a
ATP
ADP
AMP

6
Cardiovascular
Adenosine
Inosine

XO
Hypoxanthine

SOD
Xanthine +
O2*
catalase

H2O2

H2O

OH* + OH- + O2
Reperfusion 

clinically significant question is whether reperfusion injury per se produces irreversible injury in undamaged
cells

if so, reoxygenation should be preceded by anoxic perfusion (to remove accumulated substrates) or
administration of free radical scavengers
Ischaemic Heart Disease (IHD)
Epidemiology




most common type of cardiac disease and leading cause of death in Western world
30% of  and 23% of  deaths
predominantly due to coronary atherosclerosis and complications
l heart more commonly affected than r because of greater work load (i.e. oxygen demand)
Pathogenesis
Coronary Atherosclerosis




low flow in coronary aa. causes angina pectoris with increased demand
associated with >50% occlusion of major coronary aa.
if plaque is eccentric vasodilator drugs may be useful, but if concentric surgical therapy is required
myocardium has some capacity to develop collateral circulation but often as atheroma progresses
individual myocytes succumb producing a diffuse fibrosis
Acute IHD


usually arises from complications (usually thrombotic) of atheromatous lesion


changes can occur in small, previously innocuous, symptomless lesions
25% caused by ulceration (altering flow and exposing collagen) and 75% caused by rupture (with
bleeding into lesion which balloons into lumen)
sudden onset angina with  frequency and severity is called unstable angina and has high risk of
death from total thrombotic occlusion
Myocardial Infarction

regional in 90% of case due to coronary thrombosis



if thrombus persists will lead to transmural progression and full thickness infarct
if thrombus lyses (either spontaneously or therapeutically) outer layers will be spared
circumferential subendocardial infarction
hypoperfusion of coronary circulation
causes remaining
10%, due
to generalised
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
7
Cardiovascular
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
Notes
Cardiac arrhythmia
especially if infarct involves AV node
Ventricular failure
with large volumes of infarction and cardiac dilatation
Myocardial rupture
can occur at any time, but most common after 2-10 days  haemopericardium
 cardiac tamponade
rarely intraventricular rupture causes l to r shunt and LV failure
Papillary muscle dysfunction
may lead to valvular incompetence
Mural thrombosis
due to endothelial cell loss and inflammation of endocardium and altered blood
flow to myocardium
risk of system embolism and further infarct
Pericarditis
due to inflammation over infarct
Chronic left heart failure
due to extensive loss (<40%) of contractile tissue
Aneurysm
10% of long-term survivors
due to dilatation of scars, laminated thrombosis may occur with risk of embolism
Recurrent MI
risk due to underlying coronary a. disease
Rheumatic Fever
Epidemiology


incidence and complication of rheumatic fever are high in NZ, especially among Maori (6.5/year/100,000)
similar incidence to developing countries (e.g. India, Pakistan)
Pathogenesis


immune disorder that follows infection in children, usually streptococcal tonsillitis or pharyngitis

acute RF manifests as systemic “flu-like” illness with fever, malaise and muscle and joint pains

some strains of group A β-haemolytic streptococci induce production of antibodies which in some patients
cross react with 20 antigens that are components of c.t., including the heart

pain caused by development of inflammatory lesions (Aschoff’s nodules) composed of degenerated
collagen, activated macrophages, lymphocytes and fibroblasts

other manifestations that may occur are due to similar lesions in brain (Sydenham’s chorea), skin
(subcutaneous necrosis and erythematous rashes) and arteries (fibrinoid arteritis)
however, heart is most important target organ of RF


Aschoff nodules may develop in:


myocardium (rheumatic myocarditis, usually mild)

endocardium (rheumatic endocarditis)
pericardium (rheumatic pericarditis) - often producing copious serous exudates which may
distend the pericardium (pericardial effusion) or be partially reabsorbed (fibrinous pericarditis)
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
8
Cardiovascular

during acute RF the greatest risk is chronic or repeated immune damage which leads to progressive scarring
and distortion of heart vales, so that valves become stenotic and incompetent

best prevented by prophylactic antibiotic therapy to rapidly treat streptococcal sore throat
Endocarditis
Pathogenesis
Non-Infective Endocarditis


any structural abnormality of heart valve will be associated with abnormal blood flow over it
leads to predisposition to platelet activation and formation of thrombus and risk of embolism
Infective Endocarditis

bactaraemias are relatively common during chewing (if oral hygiene is poor), from bowel, during ENT,
oral GI or GU surgery, or from unhygienic IV drug use

if thrombosis is occurring during such “bacterial showers” circulating micro-organisms will be
incorporated into vegetations where they may proliferate, invade, inflame and destroy valve tissue

microbial species infecting valve are usually of low virulence and members of resident flora

called sub-acute bacterial endocarditis (SABE) when such organisms colonise structurally
abnormal heart valves

sub-acute indicates that condition may persist longer than would justify term acute but still poses
substantial risk to patient

duration of disease depends of virulence of infecting organism, frequency and distribution of
emboli, capacity of host to mount effective inflammatory/immune response and effectiveness of
antibiotic therapy

when bactaraemias involve pathogenic organism of high virulence derived from sites of infection,
organisms may directly infect valves with normal anatomy

antibiotic therapy needs to be prolonged and high dose to be effective against organisms protected
within vegetations and antibiotic prophylaxis may be advised if predisposing factors are present

surgical replacement of diseased valves with allograft or xenograft or prosthetic valves will restore
valve function but any replacement valve will have abnormal anatomy and risks of thrombosis and
recurrent bacterial endocarditis will remain
Clinical Sequelae
Complication
Infection and toxaemia
Features
weight loss
anaemia
café au lait skin pigmentation
splenomegaly
Large emboli
infarcts (brain, spleen, kidney)
splinter haemorrhages (longitudinal under nails)
metastatic abscesses
mycotic aneurysms
Microemboli
petechial skin rash
Osler’s nodes (tender cutaneous nodules)
retinal haemorrhage
Immune complex deposition
focal glomerulonephritis
focal encephalitis
cerebral arteritis

causes of death from bacterial endocarditis include


acute valve perforation
embolism
9
Cardiovascular


ruptured mycotic aneurysm
renal failure
Mechanical Disturbances of Valve Function


two main types are stenosis and incompetence
principle causes are:





congenital abnormality
post-inflammatory scarring
age-related degeneration
dilatation of valve ring
destruction by inflammatory necrosis
Valve Disease
Causes
Stenosis
Consequences
post-inflammatory scarring often with history of RF
valve cusp thickened and fused, orifice narrowed, chordae
tendinae thickened, fused and maybe shortened
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
Mitral
Incompetence
post-inflammatory scarring
acute: acute pulmonary oedema
post MI papillary muscle dysfunction
chronic: develops with regurgitation with atrial
enlargement and progressive heart failure
LV dilatation
cusp destruction
“floppy valve” syndrome (excessive glycoprotein softens
cusps)
Stenosis
Aortic
Incompetence
calcification of congenital bicuspid valve
LV hypertrophy
(post-inflammatory scarring)
angina
(senile calcific degeneration)
sudden cardiac death due to arrhythmias
post-inflammatory scarring
LV hypertrophy
cusp destruction
LV failure
senile calcification
dilatation of aortic wall
Cardiac Failure

failure of heart to pump at rate required to maintain normal metabolism



low output = majority output is low in respect to body requirements (e.g. IHD)
high output = output is not sufficient for body needs but still higher than normal (e.g. chronic
anaemia)
three types: left, right and congestive heart failure
Type
Cause(s)
Effects
Heart
Left
ischaemia heart disease
LV dilatation
systemic hypotension
LV hypertrophy (with restrictive
outflow lesion)
aortic/mitral valve disease
myocardial disease (e.g. cardiomyopathy)
Right
Mitral dilatation (with LV restrictive
disorder)
Left heart failure (usual)
Organs
Lungs – pulmonary congestion with
oedema
Kidneys – function 
Brain – cerebral hypoxia (advanced
failure)
Liver – congestion, may progress to
centrilobular necrosis
Cor pulmonale
Kidney – congestion and oedema
Venous pressure 
Peripheral oedema
Congestive

End point of all types of serious disease
dilatation and hypertrophy of heart
three mechanisms of compensation:
10
Cardiovascular
Mechanism
Description
Rate of pumping 

Pathological

Physiological


Dilatation
occurs to accommodate regurgitated blood (e.g. valve incompetence)

Hypertrophy
increase in muscle fibre bulk in order to deal with increase pressure load
(e.g. hypertension)

can also be described in terms of acute and chronic:
Acute
Chronic
myocardial infarct
hypertension
valve rupture
cardiomyopathy
arrhythmia
chronic valve disease
myocarditis
chronic myocardial ischaemia
trauma
Arterial Disease
Hypertension

definitions of raised blood pressure range from
140
/90 to
160
/95 mmHg
Classification
Aetiology


primary (90%)
secondary (10%)




renal (vascular, renal failure)
endocrine (Cushing’s, acromegaly, phaeo, myxoedema)
neurogenic (ICP )
miscellaneous (coarctation, polycythaemia)
Severity


benign
malignant (diastolic > 120 mmHg, papilloedema present)
Pathogenesis
Normal Regulation of Blood Pressure


baroreceptors in arteries
kidney secretes renin  Ag II (constricts arterioles, Na+ retention)
Hypertension
Renal


renal blood flow , renin secretion 
renal function , salt and water retention , hypertension
Primary



mechanism unknown
hereditary and environmental (smoking, stress, obesity, inactivity, salt intake, oestrogens) factors
possible mechanisms:



role of renin
role of Na+ and Clrole of Ca2+
11
Cardiovascular


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
12
Respiratory
Respiratory
Respiratory Failure

PaO2 < 8 Kpa (normally 10.7 – 13.3)
Type
Characteristic
Diffusion (type 1)
PO2 low
PCO2 normal
Ventilation (type 2)
PO2 
PCO2 


causes:




failure of ventilatory drive (e.g. depression of respiratory centre)
upper airways obstruction
lung diseases
mechanical impairment (e.g. rib fractures)
effects:


pulmonary hypertension  RV hypertrophy
polycythaemia (due to stimulation of erythropoeitin release)  blood viscosity 
Obstructive Disease

characterised by increased resistance to airflow

e.g. asthma, chronic bronchitis, emphysema, bronchiectasis
Emphysema


abnormal permanent enlargement of air spaces distal to terminal bronchiole, with destruction of walls
emphysema and chronic bronchitis are best viewed as spectrum with patients with α-1 antitrypsin deficiency
(with almost pure emphysema) at one end, and pure bronchitis at the other
Morphology
Type
Centriacinar
Areas Affected
Notes
respiratory bronchiole affected, distal alveoli spared
associated with smoking
more common in upper lobes
Panacinar
acini uniformly enlarge from level of respiratory bronchiole
associated with α-1 antitrypsin deficiency
more common at bases
Paraseptal
Irregular
proximal acini normal, distal portion affected
more striking adjacent to pleura next to areas of scarring
probably
cause
pneumothorax
of
spontaneous
acini irregularly involved
associated with scarring (e.g. old Tb)
Pathogenesis

protease-antiprotease theory: alveolar wall destruction results from imbalance between proteases (e.g.
elastase) and antiproteases (e.g. α-1 antitrypsin) in lung

smoking inhibits antiproteases, recruits leukocytes (which secrete proteases) and promotes protease
release
Clinical Course

symptoms appear once 1/3 lung tissue affected
13
Respiratory





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

continued injury and infection leads to chronic bronchitis
bronchospasm and infections (viral & bacterial) cause hypersecretion of mucus leading to reversible
obstruction
Asthma

get notes of Poornima
Bronchiectasis

get notes of Poornima
14
Respiratory
Infection
Pneumonia
Classification





location (alveolar/interstitial)
extent (lobar/bronchopneumonia)
aetiology (bacterial/fungal/viral)
duration (acute/chronic)
clinical (community acquired/hospital acquired/special environment/immunosuppressed/aspiration)
Epidemiology



important cause of morbidity and mortality in all age groups
result of complex interaction between patient, environment, and infecting organism
important factors include age, community or hospital acquired, concurrent disease, severity of illness
Age of Patient
Age
Commonest cause(s)
< 6 months
usually viral (e.g. respiratory syncitial virus (RSV), adenoviruses, influenza, parainfluenza)
Chlamydia tracomitis may transmitted to infant from mother’s genital tract during birth
6 months – 5 years
Haemophilus influenzae
older children and adults
Streptococcus pneumoniae
young adults
chlamydia, mycoplasma, strep. pneumoniae
elderly
incidence  and  frequency of concomitant disease is associated with  mortality
Community Acquired Pneumonia



may be 10 infection in otherwise healthy individual or associated with concomitant disease
Streptococcus pneumoniae accounts for majority and gram -ve organisms are rare
most patients are treated at home, with only ~25% requiring admission
Pathogen
Frequency
Streptococcus pneumoniae
60%
Mycoplasma pneumoniae
10%
Staph. aureus, Legionella pneumoniae
5%
Others
5%
Hospital Acquired (Nosocomial)

defined as pneumonia developing 2+ days after admission for some other reason (i.e. 20 infection in
patient with other illnesses)


Gram -ve organisms are most important

aspiration of infected nasopharyngeal secretions into lower respiratory tract facilitated by factors
which compromise defence mechanisms of lung (e.g. endotracheal intubation, impaired cough)
variety of factors (including use of broad spectrum antibiotics and impaired host defences) promote
colonisation of nasopharynx
Pathogen
Frequency
Gram -ve bacteria
50%
Staphylococcus aureus
20%
Streptococcus pneumoniae
15%
Anaerobes and fungi
10%
15
Respiratory
Concurrent Disease

alcohol misuse, malnutrition, diabetes and underlying cardio-respiratory disease predispose and are
associated with  mortality

patients with COPD have  mucociliary clearance and organism of low virulence may spread from
bronchi into lung tissue causing bronchopneumonia



mortality from influenza infection (either 10 or 20) is highest in elderly
aspiration pneumonia can occur with neuromuscular disease or impaired consciousness
pneumonia in immunocompromised (e.g. with AIDS) associated with unusual pathogens (e.g.
Pneumocystis carinii, Tb, H. influenzae)
Pathogenesis
Protective Mechanisms



nasal clearance (filtration etc.)
tracheobronchial clearance (mucus trap)
alveolar clearance (macrophages etc.)
Transmission




aspiration from oropharynx
inhalation of infectious aerosols
haematogenous dissemination
direct inoculation + contiguous spread
Lost Defence Mechanisms





loss or suppression of cough reflex
injury to mucociliary system (e.g. cilia damage)
interference of alveolar macrophage bactericidal and phagocytic ability
pulmonary congestion + oedema
accumulation of secretions
Lobar Pneumonia

inhalation of micro-organisms initiates inflammatory reaction initially centre in large bronchi but
spreads rapidly through lobe

classically pathological features are described in four stages:
Stage
Acute congestion
Microscopically
local vasodilatation followed by out-pouring of exudate causing
congestion
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
brick red, dry, firm and airless
alveolar exudate contains fine network of fibrin, large numbers of
RBCs, and neutrophils
Grey hepatisation
reduction in vasodilatation and congestion
macrophage recruited into alveolar spaces, which are distended and
consolidated by dense network of fibrin and dead and dying neutrophils
and lysed red cells
Resolution
by 8-10 days in untreated cases exudate is gradually liquefied by
fibrinolytic enzymes
if no tissue damage, lung parenchyma returns to normal
Bronchopneumonia

patchy consolidation centred around inflamed bronchi
16
fibrinous pleurisy, dry, airless
and grey
Respiratory

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



neutrophils are dominant and usually only small amounts of fibrin are present
inflammatory consolidation is distributed patchily while suppurative exudate fills terminal bronchi,
bronchioles an adjacent alveoli
clinically poorly defined, frequently overshadowed by predisposing condition
complications (especially abscess formation) are more frequent
Aspiration Pneumonia





usually associated with regurgitation during episodes of unconscious or during impaired swallowing
gastric acid causes chemical pneumonitis with intense oedema
patients develop increasing respiratory dysfunction with pacification of lungs
food excites foreign body response and bacteria from oropharynx cause infection
development of abscess may complicate
Viral Pneumonia



influenza, CMV, measles and varicella may all cause interstitial pneumonia
loss of damaged cells causes defects that are covered with fibrin
fibrin exudates contributes to formation of hyaline membranes
Clinical Presentation
Typical
Atypical
(mycoplasma, Legionella, viral)
sudden onset
chills, fever
rigors, fever, sweating
dry cough
cough, purulent rusty sputum
predominance
of
extrapulmonary
symptoms (headaches, myalgia, n/v,
diarrhoea)
pleuritic pain
dyspnoea
localised chest signs
Morphology (Microscopic)
Atypical




usually interstitial
often proteinaceous intra-alveolar spaces
low mortality
may be complicated by 20 bacterial infection
Tuberculosis
Aetiology

inflammation caused by Mycobacterium tuberculosis (and other species of mycobacteria)






slender, rod-shaped bacterium (1-5 μm)
can only be stained with some difficulty (Ziehl-Neelson method)
aerobic, grow very slowly in culture
very robust and extremely resistant to drying (can remain active <8 months)
destroyed by sunlight
organism excites from of cell mediated immunity involving T-cells and macrophages
17
Respiratory

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


essential lesion is granuloma, characterised by central caseous necrosis

Ghon focus + hilar node involvement = Ghon complex
infection begin as localised inflammation usually in subpleural midzone of lung (called the Ghon
focus)
extends almost invariably to bronchial and mediastinal lymph nodes, sometimes replaced by large
caseous masses
Subsequent Developments
Healing (90%)



small Ghon focus may undergo complete fibrosis, larger focus may be encapsulated and calcified
same changes occur in hilar nodes
bacilli may still be present in scarred foci and persist for years
Hilar node involvement/Pulmonary Complications

pressure of enlarged lymph nodes on bronchi may cause obstruction and lead to collapse, retention
of secretions and pneumonia

bronchiectasis may develop
Spread


inflammatory reaction in adjacent tissue may induce effusion in pleural space
infection may be carried by lymphatics from lymph nodes to pleura or pericardium with
development of tuberculous pleurisy or pericarditis
Invasion of blood vessels


will lead to dissemination associated with generalised military tuberculosis
if tuberculous infection invades one or more branches of pulmonary a., numerous military tubercles
form in lung tissue only
Secondary Tuberculosis (post-primary pulmonary infection)



any form of immunocompromise (e.g. AIDS, cancer, DM) may allow endogenous reactivation
post-primary infection may also result from gradual extension of Ghon foci or reinfection by bacilli
lesions tend to appear in characteristic sites:


upper lobes
apical segments of lower lobes

sensitised T-cell recognise new threat and recruit macrophages to form large granulomas with
extensive caseous necrosis (liquefaction, cavitation, CD8+ + CD4+ lymphocytes)




easily dislodged and coughed up in sputum
extension of lesion is usually slow and hilar nodes aren’t affected
granulation tissue heavily infiltrated by lymphocytes and macrophages forms at edges with fibrosis
at this stage lesion may:
18
Respiratory





heal, leaving dense grey scar often with central calcification
become encysted mass of caseous material and cease to spread
slowly extend by formation of new tubercles and necrosis of fibrous barriers
extent and coalesce with caseous material dislodge via small bronchus leaving cavity
disseminate via blood or bronchi
Clinical Fevers
Primary

usually asymptomatic (± fever, erythematous nodosum, phlycentular conjunctivitis, lassitude, cough
or sputum)

tuberculin test may be positive
Post-Primary

usually symptomatic (weight loss, night sweats, cough, haemoptysis, dyspnoea, malaise, organ
specific damage)

any other site may become main clinical problem
Complication
Notes
Meningitis
aseptic with insidious onset, increasing neck stiffness, headache, drowsiness, cranial n. palsies, choroidal
tubercle (50%), ± papilloedema
Genitourinary
dysuria, haematuria, frequency 
Bone
usually affects adjacent vertebrae causing collapse (Potts disease) with paravertebral abscess
tuberculous osteomyelitis usually associated with arthritis or adjacent joints
Peritonitis
associated with abdominal pain and GI upset
Pericarditis
may present with effusion, tamponade, constrictive pericarditis or calcification
Scrofula
tuberculous lymph adenitis of cervical lymph nodes that may drain onto overlying skin

in untreated case pulmonary Tb tends to be progressive disease with spread via bloodstream or
bronchi possible

however, modern antibiotic treatment chemotherapy usually prevent progression and complications
Tuberculin Skin Testing


infection produced sensitivity to antigenic components called tuberculins
when tuberculin is injected into skin a local mild inflammatory reaction occurs





in non-sensitive subjects soon stops
in sensitive subjects, hyperaemia and oedema continue to increase and is an intense perivascular
neutrophils infiltration, visible to naked eye as erythema and induration
tests include Mantoux, Heaf and Tine
positive test indicates of presence of hypersensitivity from either previous infection or BCG vaccination
negative test makes active tuberculosis unlikely
19
Respiratory
Restrictive Disease

characterised by  expansion of lung parenchyma with  total capacity

e.g. interstitial lung disease, pneumoconiosis, chest wall disorders (e.g. obesity, kyphoscoliosis)
Adult Respiratory Distress Syndrome

characterised by acute onset of dyspnoea, progressive hypoxia, bilateral radiographic lung infiltrates and
rapid development of respiratory failure


severity varies but can require ventilation, 50-60% mortality
pathologically changes = diffuse alveolar disease (DAD)

descriptive term for pathologic sequence of event that follow severe acute lung injury due to variety of
causes


“diffuse” indicates that all part of alveolus are affected by process
usually widespread change in both lungs, but sometimes can be localised
Causes
Agent
Example(s)
Infectious agents
any infection in immunocompromised
Inhalants
O2
Drugs
chemoterapeutic agents
Ingestants
Shock
traumatic, haemorrhage
Sepsis
Radiation
Miscellaneous
acute massive aspiration, acute pancreatitis
Unknown

often multiple contributing causes in particular case

e.g. severe trauma and shock  DAD  O2 therapy and may be later sepsis
Pathogenesis
Lung Toxin

Epithelial Injury + Endothelial Injury


Necrosis of Type I cells
Leaky capillaries
Oedema
Hyaline membranes

Alveolar collapse/coalescence
Fibrosis
Honeycomb lung
Initial Damage

mechanism depends on cause:
Cause
Mechanism
Direct damage
lung infection, aspiration, noxious gas
Septicaemia
endotoxin activates complement cascade, stimulates platelet aggregation, intrinsic clotting pathway,
stimulates macrophages to release cytokines
Shock and trauma
release of proteolytic agents from damaged tissue
20
Respiratory
Inflammatory Response





can worsen or continue tissue damage
cell damage  PG, LT, cytokine release
stimulates platelet aggregation, coagulation pathway, neutrophil chemotaxis, increased permeability
increased leakiness leads to exudation and pulmonary oedema
hyaline membranes (fibrin + necrotic alveolar cells) form
Organisation and Repair


stimulation of fibroblasts to proliferate, migrate and lay down matrix
hyaline membrane organised then lined by type 2 alveolar cells, reabsorbed then differentiate with
type 1 cells
Management




treat underling cause
ventilation, oxygen
circulatory support
renal support
Clinical Outcome

if survive, most have good recovery, although some have permanent severe lung scarring (honeycomb lung)
Pneumoconiosis


group of lung disease cause by inhalation of dust and/or aerosol
include both occupational and environmental related conditions
Agent
Disease
Exposure
Mineral Dusts
Coal dust
progressive massive fibrosis
coal mining
Caplan’s syndrome
Silica
silicosis
foundry work, sandblasting, hardrock mining, stone cutting
Caplan’s syndrome
Asbestos
asbesotsis
mining, milling
insulation work
pleural plaques
&
fabrication,
Caplan’s syndrome
mesothelioma
carcinoma of lung, larynx, stomach, colon
Beryllium
acute berylliosis
mining, fabrication
beryllium granulomatosis
Organic dusts that induce extrinsic allergic alveolitis
Mouldy hay
farmer’s lung
farming
Bagasse
bagassosis
manufacturing wallboard, paper
Bird droppings
bird-breeder’s lung
bird handling
Organic dusts that induce asthma
cotton, flax, hemp
byssinosis
red cedar dust
asthma
textile manufacturing
lumbering, capacity
Chemical fumes and vapours
NO, sulphur dioxide,
ammonia,
insecticides
bronchitis
occupational
exposure
asthma
pulmonary oedema
respiratory distress syndrome
Important Factors in Development

amount of dust retained
21
and
accidental
Respiratory





concentration of substance in air
duration of exposure
effectiveness of clearance mechanisms
shape and size of particles (1-5 μm most important)
chemical nature and solubility
22
Respiratory
Disease
Coal Dust
Simple CWP
Morphology
Clinical
coal macules (accumulation within macrophages
with minimal fibrosis) or nodules (larger than
macules) + focal emphysema
Pathogenesis
little or no respiratory deficit
chest x-ray may be normal
precursor lesion to complicated CWP
Complicated
CWP
large areas of fibrosis (round, oval or stellate)
which may cross septae and have central cavity
respiratory function
restrictive or diffusing)
compromised
Complications
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
cor pulmonale
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
presence of asbestos fibres in vicinity of
serosal surface appears to crucial pathogenic
factor
may
also
pericardium
mediastinum
carcinogenic potential enhanced by smoking
metastases to lymph
nodes and liver
Caplan’s syndrome
(obstructive,
most common in upper lobes
Asbestosis
diffuse interstitial fibrosis, most marked in periphery
of lower lobes
Asbestos
uncoated asbestos fibres and bodies (ferruginous
body) within areas of scarring
Malignant
mesothelioma
insidious condition, may be discovered incidentally on
chest x-ray in asymptomatic patient or as slow
development of SOB and cough
effusion tend to disappear as tumour obliterates
pleural cavity
3x  > , 40-60 years, v. latency between
exposure and development of cancer
radiology: pleural thickening, possible extending
into fissures and lungs
chest pain, SOB + weakness, fatigue, weight loss
average survival: 15 months, no treatment effective
bronchiectasis
Caplan’s syndrome
pulmonary
hypertension,
pulmonale
cor
invade
and
Benign pleural effusions
Visceral pleural fibrosis
Fibrocalcific parietal pleural plaques
Bronchogenic carcinoma
Acute silicosis
intra-alveolar granular proteinaceous material
due to heavy exposure over short time period
Silicon
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”
23
insidious, slowly progressing
respiratory function
deterioration
of
macrophages activated releasing cytokines
which activate neutrophils, fibroblasts and
lymphocytes
vicious cycle of activation
cor pulmonale
tuberculosis
Caplan’s syndrome
Solid Tumours
Solid Tumours
Lung Cancer
Classification
benign
Epithelial
malignant
papilloma
adenoma
carcinoma (95%)
carcinoid
Lymphoma
Mesenchymal
benign
hamartoma
malignant
sarcoma
Unclassified
Metastatic


differentiated cells in epithelium though to all arise by differentiation from basal stem cells

population of neuroendocrine cells in lung called Kulchitsky cells, scattered among epithelium
lung tumours probably also arise from these stem cells and show a particular pattern because tumour cells
differentiate along one particular line


produce various peptide hormones acting in a paracrine fashion



may also have role in growth and repair as much more prevalent in foetal lung
function uncertain but appear to have some chemoreceptor function, e.g. ventilation/perfusion
matching
neuroendocrine tumours include small cell carcinoma and carcinoid (5 year survival 95%)
atypical carcinoid tumours are intermediate between SCC and carcinoid tumours
Epidemiology




 530,  280 deaths/million
most aggressive type (SCC) has 5 year survival rate < 5%
others have 5 year survival rate <20%
most important prognostic feature is stage at presentation
Aetiology




smoking
environmental factors (asbestos, air pollutants, radiation, metal refining)
others (pulmonary fibrosis and scars)
genetic
Diagnosis





suggested by chronic cough with blood in sputum
chest x-ray
bronchoscopy (biopsy/bronchial wash)
fine needle aspirate
sputum cytology
24
Solid Tumours
Types

Tumour Type
%
Identifying Features
Squamous cell carcinoma
35%
keratin ± intercellular bridging
Adenocarcinoma
35%
glands ± intracellular mucin
Large cell carcinoma
10%
absence of other features
Small cell carcinoma
20%
neuroendocrine
occasionally get mixed lung tumours with small cell admixed with squamous or adenocarcinoma
Adenocarcinoma

one variant is bronchioalveolar carcinoma where cell line up along alveolar walls, can present like
pneumonia on chest x-ray
Small Cell Carcinoma (SCC)




cells not necessarily small
have hyperchromatic nuclei and scanty cytoplasm
numerous mitoses and extensive necrosis
sometimes produce ectopic hormones
Metastatic


most commonly adenocarcinoma (breast, pancreas, GIT)

2nd most common body site to be involved in metastatic disease
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
Pathological Diagnosis


carcinoma or not
if carcinoma, SCC or NSCC


SCC – chemotherapy
NSCC – resection ± radiotherapy
Colon Cancer

>95% are adenocarcinoma
Adenocarcinoma
Epidemiology


one of commonest causes of death (2nd highest cause of death by cancer in USA)
affects middle aged/elderly, mainly in left colon and shows  predominance


however, right-sided carcinomas show  predominance
both genetic and environmental factors play a role in pathogenesis

specific gene defects have been identified in case of familial adenomatous polyposis (FAP) and
hereditary non-polyposis carcinoma of the colon (HNPCC)



familial component also seen in sporadic cases, with family history of 1 0 relative giving 3x  risk
environmental factors include  meat and  fibre
chronic ulcerative colitis and Crohn’s disease also risk factors
25
Solid Tumours
Morphology




15% are mucinous
sometimes residual polyp is present at edge of tumour
most moderately differentiated
morphology and symptomatology of r- and l-sided carcinomas may vary
L-sided



70-75% found in rectum, rectosigmoid and sigmoid colon
grow as plaques which gradual encircle bowel, may have fungating edges
tumours ulcerate and cause obstruction and/or haemorrhage
R-sided


may cause late symptoms because greater capacity to accommodate tumour
anaemia may be presenting symptom
Classification/Prognosis

classified by Duke:
Stage
Description
5 year survival
Chemotherapy

A
confined to wall
99.8%
B
spread beyond wall but not to lymph nodes
70%
if obstructed or perforated
C
tumour present in lymph nodes
30%

(C1 = region, C2= apical)

other prognostic features include:
Feature
Prognosis
extramural venous invasion

perforation of tumour

number of lymph nodes invaded
more 
lymphocytic infiltration at edge

nature of advancing edge
pushing , infiltrative 
Other

rare but include:



stromal tumours
endocrine tumours (carcinoid)
lymphoma (rarer than in stomach and small intestine)
Skin Cancer
Malignant Melanoma
Epidemiology



incidence:
 541 (4th)
 491 (4th)
deaths:
 83 (6th)
 99 (6th)
14% of all melanomas found on non skin sites (e.g. eye, vulva, rectum)
Risk Factors


personal or family history
large numbers of moles
26
Solid Tumours





clinically atypical moles
sun burning in childhood/adolescence
acute/intermittent exposure to sunlight
light skin type, eyes, hair
N. European ancestry living in high sunlight
Warning Signs
A
asymmetry
appearance of new lesion
B
irregular borders
C
colour variable
change in shape, size or colour
concern
D
diameter >6 mm
E
elevated
Classification

malignant melanoma types:
Type
Features
superf spreading
nodular

acral lentiginous
feet, hands, under nails
lentigo maligna
on face as large pale mole
desmoplastic (<1%)
spreads along nerves
Clarke’s classification:
Growth Phase
Radial
Level
in situ
2
growth into papillary dermis
2
Vertical
Description
in epidermis only
3
growth into reticular dermis
4
growth into subcutaneous tissue
Prognosis

prognostic features:
Feature
thickness
Prognosis
<1 mm few die, >4 mm almost all die
Clark’s level (stage)
site
back, arm, neck, scalp (BANS) 
sex

amelanocytic

node involvement

27
Musculoskeletal
Musculoskeletal
Bone
Disease
Example
Neoplasm
osteosarcoma
Infectious bone disorders
osteomyelitis
tuberculosis
Metabolic bone disorders
Paget’s disease
osteoporosis
osteomalacia
hyperparathyroidism
Developmental disorders
achondroplasia
Fractures
Bone Tumours


80% in axial skeleton
70% osteolytic, 20% osteoblastic
Name
Incidence
Common Sites
Behaviour
(Age)
Osteoid osteoma
adolescent
lower limb
benign, osteosclerotic, painful
Giant cell tumour
20-40
around knee
benign, may recur
Chordoma
40+
axial (sacrum, speno-occipital)
local bone destruction and invasion
around knee (young)
highly malignant, early metastases to lungs
Osteosarcoma
+
10-25, 65
at site of Paget’s (elderly, 50%)
Chondrosarcoma
40-70
limb girdle
malignant
Fibrosarcoma
20-60
long bones (under peri- or endosteum)
malignant
Ewing’s tumour
5-15
midshaft of long bones (esp. fibula)
malignant



all more common in males than females
adenocarcinoma of breast, kidney, thyroid & prostate and carcinoma of bronchus often metastasise to bone
may result in:





pathological fractures
bone pain
replacement of bone marrow
hypercalcaemia
compression of structure
Osteosarcoma


commonest 10 tumour of bone (excluding myeloma)
highly variable but two fundamental groups: central and peripheral
Clinical Presentation




clinical signs (e.g. pain and swelling) present relatively late (i.e. when cortex destroyed)
often associated with Paget’s disease in elderly (50%)
vertebrae, pelvis and skull often affected
tumours may be multicentric
28
Musculoskeletal
Morphology
Macroscopic



haemorrhagic, variegated tumour expanding bone and destroying both medulla and cortex
spicules of bone may be palpable
periosteum frequency raised to produce “Codman’s triangle” at junction of periosteum and cortex
(non-specific)
Microscopic





(variable)
essential feature is presence of malignant osteoblasts which lay down spicules of irregular osteoid
may or may not calcify – can be osteolytic or osteosclerotic
tumour osteoblasts are atypical, bizarre, show mitotic activity and frequency giant cell forms
small areas of cartilage may be present and 20 necrosis and haemorrhage frequent
common to find evidence of vascular invasion within tumour
Osteomyelitis

acute infection caused by variety of organisms but 90% staph. aureus



also Strep. pyogenes, Haemophilus influenzae, Neisseria gonorrhoea, Escherichia coli
may occur with generalised septicaemia, infection of surrounding tissues or following fracture
haematogenous osteomyelitis common in childhood, particularly with Polynesians

can also occur in immunocompromised
Pathogenesis







organism reaches bone via blood stream (10 bacteraemia usually subclinical)
site of infection usually adjacent to metaphyses of long bone
20 bacteraemia occurs
untreated infection extends into marrow cavity and through cortex in periosteum
pus between periosteum and cortex causes interruption of blood supply to cortex into periosteum
pus may penetrate skin forming draining sinus
periosteal new bone formation may be extensive and new bones sheath around necrotic sequestrum, giving
rise to involucrum
Clinical Features






sudden onset in children with high fever and tachycardia

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
localised pain, heat, redness, swelling
exquisite bone tenderness
radiological changes may not be apparent for 2-3 weeks
adult may have more insidious illness
occasionally involves vertebral bodies – infection invades intervertebral discs, pus destroys disc, vertebral
collapse, cord compression and neurological deficits
at late chronic stage, in addition to local disability and disturbance of bone growth, amyloid disease may
supervene and occasionally squamous carcinoma arises
29
Musculoskeletal
Paget’s Disease (osteitis deformans)

common bone disorder (10% of 65+) of unknown cause characterised by bone formation and reabsorption
Pathogenesis

three phases:



osteolytic
mixed osteolytic and osteoblastic
osteosclerotic (fracture and haemorrhage common)





irregular trabeculae (mosaic)
unmineralised osteoid
marrow space fibrotic
1-2% develop osteosarcoma
occasionally high output heart failure
Clinical Features


may be asymptomatic
enlarge of bones (e.g. skull, femur, clavicle, spine)




nerve deafness from bone overgrowth
20% in one bone only
joint degeneration (bowed tibia, kyphosis)
pathological fractures
Osteoarthritis (OA)

heterogeneous group of conditions that lead to joint symptoms and signs associated with defective integrity
of articular cartilage, in addition to related changes in underlying bone at joint margins

commonest form of arthritis, disorder of joints and chronic disability after middle age
Type
Age
Aetiology
Affect Joint(s)
Primary
60+ (85% of 80+)
idiopathic, although familial pattern evident
knees, hips, spine, DIP
Secondary
younger
associated
with
predisposing
condition
(e.g. trauma, rheumatoid arthritis, gout, etc.)
single predisposed joint
Pathogenesis

oedema and softening of cartilage (susceptibility to injury )











thin cartilage (e.g. DIP)
 osseous proliferation
thick cartilage (e.g. knee)  cartilaginous and synovial proliferation
flaking and fibrillation (cracks and clefts in surface cartilage)
chondrocyte proliferation and death (necrosis/apoptosis?)  matrix disorganisation
blood vessels penetrate through subchondral bone bringing fibrocytes
fibrocartilage repair tissue fills cracks in cartilage
remodelling of bone
loss of cartilage with eburnation of bone surface
subchondral bone cysts form in osteoporotic domains from microfractures
osteophyte formation on joint margin (Herberden’s nodes = osteophytes at DIP)
synovitis cause by fragments of cartilage in joint space
30
Musculoskeletal
Epidemiology
sport
occupation
minor injury
ABNORMAL STRESS
abnormal biomechanics
heredity
NOT age
Ageing
OA
Tissue water content


Glycosaminoglycans


Proteoglycans


fragmented
normal
normal

Link protein
Degenerative enzymes

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
31
Gastrointestinal
Gastrointestinal


commonest pathological lesion of GI tract are inflammatory and neoplasia
clinical presentation:





abdominal pain
dyspepsia
GI bleeding
diarrhoea
obstruction
Oesophagus + Stomach
Helicobacteria Pylori




microaerophilic, spiral, gram –ve bacteria
natural habitat is gastric mucus, congregating at or around intercellular junction of gastric surface
also found attached to some cells on tissue surface through formation of adhesion pedicles
high urease activity
Prevalence in developed countries
children 
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
32
Gastrointestinal
Disease
O
e
s
o
p
h
a
g
u
s
Reflux oesophagitis
S
t
o
m
a
c
h
G
a
s
t
r
i
t
i
s
Carcinoma
Morphology
Pathogenesis
inflammation, peptic ulceration ± haemorrhage
sometimes fibrous strictures, Barrett’s oesophagus
associated with increase in intra-abdominal
pressure
squamous cell carcinoma in upper
may present as fungating ulcerative lesions
adenocarcinoma in lower
Acute
Epidemiology
Clinical Signs
dysphagia
>, 50’s
dietary nitrosamines,
tobacco, hot coffee
superficial ulceration, infiltration of mucosa by neutrophils
acid secretion 
chronic NSAIDS
deeper ulcers involving whole thickness seen in stress ulcers
damage or alteration of mucosal protective
barrier
excess alcohol
Fe
,
alcohol,
haemorrhage
nausea, vomiting, abdominal pain,
haematamesis, melaena
uraemia
smoking, shock, stress, chemotherapy,
infection, gastric irradiation, ICP 
Chronic (A)
body
probably autoimmune
antibodies to parietal cells (90%) and IF (50%)
affects elderly
other autoimmune phenomena
> 
gastric carcinoma 
vit B12 malabsorption
Chronic (B)
involves antrum
H. pylori
associated with peptic ulceration and duodenitis
Peptic ulceration
duodenum (1st part), gastric antrum, Barrett’s
oesophagus, Meckel’s diverticulum, small intestine
round or oval, punched out edges, may erode full thickness
acute - burns, stress, drugs
haemorrhage/perforation
chronic - age ,  > 
obstruction
carcinoma (1%)
microscopic – necrotic & inflammatory damage, granulation
deep vessels show endarteritis obliterans
N
e
o
p
l
a
s
i
a
Benign
stromal tumour
SM, submucosa or serosa, small (~2cm) and asymptomatic
regenerative polyp associated with inflammation, small, sometimes multiple
neoplastic polyp
Malignant
much less common, >2 cm, sessile or pedunculated
carcinoma (90-95%) usually adenocarcinoma
genetic
usually diagnosed late
macroscopic – early gastric carcinoma confined to mucosa
and submucosa (5YS 75%), but usually fungating,
ulcerative or diffusely infiltrative (5YS 10%)
environmental (SES, H. pylori)
weight loss, abdominal pain, v&n,
bleeding
microscopic – glandular or diffuse
33
abnormalities in gastric mucosa
dietary – nitrates/nitrites?
lymph node
present
metastases
usually
Gastrointestinal
Large Intestine
Infections/Infestations
Agent
Examples
Bacterial
E. coli, shigella salmonella, campylobacter, mycobacteria, yersinia, vibrios, clostridia
Fungal
candida
Protozoal
entamoeba, schistosoma, balantidia, cryptosporidia
Viral
rotovirus, adenovirus, calicivirus, astovirus, CMV
Bacterial Enterocolitis
Disease Process
Ingestion of preformed toxins
Description
explosive diarrhoea and acute abdominal distress (hours  days)
systemic toxins (e.g. botulinim) may cause rapid fatal respiratory failure



Infection with enteric pathogens
incubation
(hours-days)
followed
by:
diarrhoea and dehydration (secretory enterotoxin) or dysentery (cytotoxin or enteroinvasive)
Insidious infection
may present as subacute diarrhoeal illness (e.g. yersinia, mycobacteria)
complications are logical consequences of massive fluid loss of destruction of intestinal mucosal barrier
include dehydration, sepsis and perforation
without intervention in severe cases death ensues rapidly, especially in very young
Agent
E. coli
Disease Type
Notes
enterotoxigenic
food poisoning
enterhaemorrhahic
Shigella-like toxin
enterpathogenic
effacement of enterocytes but no invasion
enterinvasive
Salmonella
typhoid fever
multiplies in lymphoid tissue of small bowel
some gain access to blood and are taken up by reticuloendotrial system
headache, prostration, nose bleeding, bronchitis, constipation, abdominal tenderness and high
fever, ‘rose spots’ on skin, splenomegaly
ulcerative inflammation of Peyer’s patches causes diarrhoea and later haemorrhage and perforation
characteristically ulcers contain histiocytes showing erythrophagocytosis and paucity of neutrophils
food poisoing
septicaemia (without
bowel involvement)
Clostridium
pseudomembranous
colitis
aka antibiotic precipitated diarrhoea
mild and self-limiting, or fulminant
necrosis of mucosa
Amoebiasis
pass unharmed through stomach, vegetative forms released in small intestine
invade crypts and submucosa in caecum and asc. colon
Idiopathic Chronic Inflammatory Bowel Disease (IBD)



has come to mean ulcerative colitis (UC) and Crohn’s disease
grouped together because of many similarities (e.g. aetiology, epidemiology, familial tendency,  cancer risk)
chronic diseases characterised by remission and exacerbations or almost continuous inflammation
Epidemiology


both common in Western world (4-6/100,000) >
peak age 20’s-30’s
Aetiology

cause unknown, theories:
34
Gastrointestinal



infection: virus have been implicated, but data ambiguous
immunological: 10 disease results in inappropriate exposure of intestinal immune system to antigens
genetic predisposition: suggested by familial aggregations
Disease
Morphology
U
C
Complications
affects mucosa only (except in fulminant colitis)
toxic megacolon
starts in rectum and l. colon, may move prox to involve whole colon
adenocarcinoma (5%) risks: early onset, 10
years+, extensive, continuous, dysplasia
skipped areas not seen
Acute
deeply congested hyperaemic mucosa (+ plasma cells, lymphocyrtes,
eosinophils, neutrophils)
crypitis and crypt abscesses with loss of mucus
ulceration usually superficial
surviving islands of mucosa undergo regeneration  inflammatory
psedopolyposis
Chronic
remission
in
Chronic with mild
activity
recovery of mucus, inflammatory cells , branching and shortening of
crypts
extraintestinal:
liver disease (common, non-specific, portal
duct inflammation, sometimes sclerosing
cholangitis or cirrhosis)
skin
(erythema
nodosum,
pyoderm
gangrenosum, papulonecrotic lesions)
joints (polyarthritis)
patchy inflammation in background of regenerative mucosal changes
mucosal atrophy, Paneth cell metaplasia, hypertrophy of muscularis
mucosae
loss of haustral folds
Crohn’s
affects entire wall
malabsorption
affects any part of GI tract, affected segments may increase with time
(small intestine with colonic involvement most common)
fistulae
anal/rectal)
skipped areas seen
toxic megacolon
oedema + longitudinal fissures (cobblestoning)
obstruction
(internal,
entercutaneous,
patchy lymphoid infiltration, crypt abscesses, goblet cells preserved
thickened submucosa
granulomas
with
lymphoid
aggregations
and
epithelioid
lymphoid aggregation and inflammation also seen in muscle wall and
serosa  fibrosis
Toxic Megacolon



usually affects transverse colon making it dilated and thin-walled


septicaemia may also supervene
becomes prone to perforation (peritonits and shock, with high mortality)
deep ulcerations (may be confused with Crohn’s), hyperaemia
associated with muscle necrosis
and transmural inflammation
caused by number of inflammatory bowel diseases
Ischaemic Colitis
Epidemiology

usually in elderly patients with atheroma
Clinical Presentation

may present as colitis with bleeding
Morphology





segmental, usually affecting splenic flexure
radiological: thumb printing sign (due to oedema and haemorrhage)
macroscopic: oedema with linear ulcers, sometimes mucosa becomes necrotic and prone to perforation
microscopic: mucosal ulceration, submucosal oedema and haemorrhage, focal muscle necrosis
strictures due to fibrosis, haemosiderin laden macrophages, thickened fibrotic submucosa, ulcerated and
irregularly healed mucosa seen in chronic ischaemia
35
Gastrointestinal
Diverticular Disease
Epidemiology


common condition in Western world (30-50% in routine autopsies)
uncommon before 30,  with age
Morphology




affects particularly recto-sigmoid but also l. colon
hard cartilaginous consistency with prominent taenia coli and circular muscles
diverticula occur in two rows between mesocolon and taenia and open out in lumen through small openings
microscopic: invaginations through vessel openings by mucosa, muscle wall between openings attenuate
and fibrotic
Complications





80% asymptomatic
abdominal pain, diarrhoea/constipation
inflammation/fibrosis
abscess/perforation/peritonitis
bleeding
Pathogenesis


low fibre diet  low stool bulk, abnormal peristalsis, hypertrophied muscle, intraluminal pressure 
focal weakness in colonic wall at site of vascular entry
Diversion Colitis




inflammatory changes in mucosa of excluded large intetion after diversion of faecal stream
may be asymptomatic or lead to discharge/bleeding
lymphoid hyperplasia and surface ep degeneration
may be caused by change in bacterial flora leading to loss of ep trophic factors
Radiation Colitis

mucosal necrosis with ulceration, atypia or nuclei, obliterating endarteritis, necrosis and strictures
Collagenous Colitis




drug induced or idiopathic
elderly, >
watery diarrhoea (weeks  years) and normal endoscopic appearance
deposition of thick layer of collage (10-100 μm) beneath epithelium
Drug Induced Colitis


NSAIDS, gold, methotrexate, methyldopa
non-specific inflammation, ulceration, strictures and diaphragm formation in small intestine
36
Gastrointestinal
Liver
Hepatitis

inflammation of hepatic parenchyma
Pathogenesis

either infectious or non-infectious
Infectious



liver almost always involved in all blood-born infections
needle biopsy of used to diagnose occult infections, especially when military Tb suspected
number of specifically hepatropic virus (hepetatis A, B, C, D, E, etc) which cause significant global
mortality and morbidity

all cause virtually same clinicomorphological pattern of acute hepatitis, but vary in ability to
produce chronic, carrier state and fulminant hepatitis
Clinical
Epidemiology
A
99% acute
3rd world, homosexuals, overseas travellers
B
60% subclinical, 30% acute,
10% chronic, 1% fulminant
3rd world, homosexuals, IDU, prostitutes
C
usually chronic (10+ years)
Africa (10%)
D
usually coinfection with B
rare in NZ, drug users, Mediterraneans
frequently fulminant or chronic
E
usually acute
Asia, overseas travellers
Non-Infectious
Agent
Alcohol
Notes
single largest cause of liver failure in US
degree of damage determined by duration, quantity and genetic makeup
pathological liver show fatty change, portal and lobular PMN infiltrates, hepatocellular necrosis and
eventual cirrhosis
Drugs/toxins
toxic (dose-dependent) or idiosyncratic (unpredictable)
can cause almost any type of hepatitis
Auto-immune
>, similar to viral but -ve serology and +ve autoantibodies
often presents as acute hepatitis and characterised by  plasma cells
responds to steroids
10 biliary
0
1 sclerosing cholangitis
brunt of insult borne by biliary system rather than parenchyma
eventual expansion of portal tracts with piecemeal necrosis and cirrhosis occurs
Ascending cholangitis
α-1 antitrypsin deficiency
can all mimic viral hepatitis and progress to cirrhosis
Wilson’s disease
major extrahepatic manifestations and specific histological findings on biopsy
Haemochromatosis
Cryptogenic
small number of cases have unknown cause
Clinical Syndromes
Acute Hepatitis


only hep A causes solely acute hepatitis
mainly parenchymal changes



lobular lymphocytic infiltration
ballooning degeneration of hepatocytes
patchy necrosis
37
Gastrointestinal


± cholestasis
can be divided into four phases:
Phase
Incubation period
Features
Hep A 15-45 days
Hep B 30-180 days
Hep C 14 days-many years
Hep D 15-90 days
Symptomatic pre-icteric phase
non-specific constitutional symptoms (malaise, fatigue, fever, nausea, headaches)
circulating immune complexes (esp in Hep B) may create serum sickness-like syndrome with
fever, rash and arthralgia
elevated ALT & AST indicate hepatocyte damage
Symptomatic icteric phase
caused mainly by conjugated hyperbilirubinaemia
dark urine, light stools, severe itching, hepatomegaly
ballooning degeneration of hepatocytes, focal necrosis, lobular inflammation and disarry with
fatty change and portal inflammation
Convalescence

not all acute attacks proceed through all phase (e.g. hep A in young children or hep C in adults may
be virtually asymptomatic)
Chronic Hepatitis

symptomatic, biochemical or serological evidence of continuing inflammatory hepatic disease for more
than 6 months




mainly portal tract changes


inflammatory cells predominantly lymphocytic
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
serology determines cause, histology of biopsy determines grade and staging


most widely used grading system is histological activity index (HAI), which scores grade of
necroinflammatory activity and stage of fibrosis
final
report
includes
aetiology,
(none/portal/periportal/bridging/cirrhosis)
grade
(mild/moderate/severe)
Carrier State


individual without manifest symptoms who harbours and can transmit organism
two types: healthy carrier and carrier with chronic hepatitis
Hepatitis
Carrier State
A
none
B
1-10%
C
2-3%
D
low
38
and
stage
Gastrointestinal
Fulminant Hepatitis (massive or sub-massive necrosis)
Hep C
30%
Hep B (only)
30%
Hep A
0.01%
Hep B/D (co)
3%
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


parenchymal nodules created by regenerative activity and network of scars



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)
vascular architecture reorganised by parenchymal damage and scarring forming abnormal a-v junctions
once developed no evidence that fibrosis can regress

may be clinically silent but often is anorexia, weight loss, weakness, spider angiomas, gynaecomastia,
and impaired synthesis of albumin, fibrinogen, prothrombin and other clotting factors
39
Gastrointestinal
Aetiology
Post-necrotic
10.00%
Syphilis
2%
Haemochromatosis
5%
Other
40%
Other
10%
Alcoholic
65%
Cardiac
2%
Carcinoma
2%
Wilsons
2%
Biliary
10%
Epidemiology

in most Western countries, cirrhosis is one of 10 leading causes of death, mainly due to  alcohol
Complications

portal hypertension is important complication of cirrhosis

occurs mainly because of  portal resistance at level of sinusoids due to parasinusoidal deposition of
collagen and compression of central veins by perivenluar fibrosis and parenchymal nodules

a-v junctions in fibrous scars may also play a role
40
Central Nervous System
Central Nervous System
Introduction
Overview
Major Differences
High degree
function
of
localisation
of
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:


common – e.g. infections, trauma, neoplasm
unique – e.g. demyelination, system degeneration
Normal Cells
Cell
Neuron
Description
basic communicating unit of CNS
high metabolic rate, obligate aerobic
Astrocyte
found throughout nervous system
physical and biochemical support of neurons
processes end on blood vessels, forms BBB, act as fibroblast during
repair
Oligodendrocyte
found through brain (surround neurons in grey matter, line up along
myelinated fibres in white matter)
production and maintenance of CNS myelin
41
Central Nervous System
Infection



brain and spinal cord relatively well protected from infection by bone and dura

 haematogenous spread more common than direct
once infection established local defence mechanisms relatively deficient
dissemination through subarachnoid pace and ventricular system can be rapid
Bacterial Infection

6 potential sites of infection (either singly or in combination):







bone
(osteitis, mastoiditis, otitis media, osteomyelitis)
extradural space
(pachymeningitis)
subdural space
(pachymeningitis)
subarachnoid space (leptomeningitis)
intracerebral
intraventricular
dura, arachnoid and pia appear to be relatively effective barriers to spread
CSF Changes
Normal
Colour
clear and colourless
Cell count
<5 x 106/L MNM
Acute
Subacute
Viral
, neutrophils
 MNMs
 lymphocytes


normal


no neutrophils or RBCs
Glucose
60-70% plasma
Lactate (mM)
1-3
Protein (g/L)
0.2 – 0.5
Pyogenic Infection
Pachymenigitis

usually spread from focus of chronic suppuration (e.g. chronic otitis media, mastoiditis, frontal
sinusitis)


small extradural abscesses spread through dura to become subdural abscess or empyema
can spread from leptomeninges to subdural space especially in children
Leptomeningitis



spread of pyogenic organisms through subarachnoid space
occurs most commonly at extremes of life
medical emergency
Causative Agent



vary with age of patient
neonatal: E. coli, group B streptococci
other:
N. menigitidis, H. influenzae, Strep. pneumoniae
Route of Infection

haematogenous


(most common route in acute pyogenic meningitis)
bacteraemic phase (may be dominant clinical feature)
spread from skull
(compound fracture, iatrogenic)
42
Central Nervous System
Morphology
Macroscopic




intense congestion
purulent exudate, most marked about base and sulci
hydrocephalus may develop
necrosis of superficial cortex
Microscopic



neutrophil exudate in subarachnoid space + lymphocytes + macrophages
vasculitis
adhesions
Brain Abscess


can be caused by organisms of low pathogenicity
mixed infections (including anaerobes) common
Pathogenesis
Route of Infection
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
associated with bronchiectasis, pneumonia, empyema, acute infective
endocarditis, congenital heart disease
Penetrating head injury
Morphology

chronic abscess has 2-3mm capsule, purulent contents and associated oedema





inner zone contains neutrophils and necrotic debris
capsule shows collagen, gliosis and mixed inflammatory cells
outer shows gliosis and oedema
acts as mass lesion because of oedema
other complications: meningitis, ventriculitis, suppurative cerebritis
Non-Pyogenic Infection (Tuberculosis)

always 20 to infection elsewhere
Tuberculous Meningitis

almost always haematogenous, occasionally direct spread (e.g. from vertebrae) or military
Morphology (Macroscopic)


exudate gelatinous or caseous, most abundant in basal cisterns
almost always some degree of hydrocephalus
Morphology (Microscopic)




fibrinocaseous, diffusely permeated by lymphocytes, histiocytes and plasma cells
Langhans cells sparse
obliterative endarteritis
superifical infarcts
43
Central Nervous System
Tuberculoma

encapsuleated caseous mass in brain



adults -
cerebral hemispheres
children - cerebellum
convential tuberculous abscess
Viral Infections

clinically evident infections are uncommon (most individuals have antibodies to viruses known to cause CNS
infections but have never had any symptoms)



many viruses have diverse effects on CNS
different cell populations have different susceptibilities and viruses may affect different cells differently
host cell must possess specific receptor in order to be susceptible to infection
Pathogenesis



most gain access via mucous members of GI and respiratory tracts
most replicate outside of CNS
viraemia carries virus to CNS (some travel along nerves, e.g. radies, HSV)
Acute
Aseptic
usually not severe
caused by enteroviruses (e.g. polio, Coxsackie, mumps)
lymphocytes, plasma cells and macrophages in subarachnoid space
Acute viral
inflammatory reactions similar in all types of viral encephalitis
infiltration by lymphocytes, plasma cells and macrophages in subarachnoid space,
hyperplasia of microglia, reactive astrocytes followed by progressive fibrillary gliosis
abnormalities in neurons (chromatolysis, necrosis, neuronophagia)
inclusion bodes (in neurons, astrocytes, oligodendrocytes, round/oval, eosinophilic)
necrosis (selective neuronal  frank infarction)
Subacute
Persistent
sclerosing
panencephalitis
multifocal demyelination with lipid laden macrophages, abnormal oligodendrocytes and
large bizarre astrocytes
Progressive multifocal
leukoencephalopathy
middle aged patients with immune deficiency
44
Central Nervous System
Infarction





brain very susceptible to oxygen deprivation, i.e. dependent on cerebral blood flow
cerebral perfusion pressure = mean system arterial pressure - intracranial pressure
autoregulation maintains blood flow at constant level between 50 and 160 mmHg
neurons most sensitive, followed by oligodendrocytes, astrocytes, microglia and blood vessels
distribution of hypoxic damage probably due to local metabolic factors rather than anatomy of blood supply
Cerebral Infarction
Morphology
Selective Neuronal Necrosis


neuron becomes shrunken, cytoplasm eosinophilic and nucleus pyknotic
glial reaction varies with degree of insult
Frank Infarction



usually centred on particular arterial territory
may involve entire arterial territory or just central regions depending on collateral circulation
three stages:



swelling and softening with coagulative necrosis
early reactive changes, inflammatory cells and phagocytosis
glial scar
Pathogenesis
Embolism


causes 30-60% of ischaemia stroke
sources include cardiac (mural, valvular disease) and atherosclerotic plaque ulceration
Atheroma




found in extracranial, internal carotid (especially prox) and cervical vertebral aa.
stenosis or occlusion of vertebral aa. may lead to infarction in hindbrain
anatomical distribution of aa. within brain remarkably constant
middle cerebral a. is most commonly affected
Hypertension




aggravates atherosclerosis
also produces change in walls of arteries and arterioles (hyaline arteriolosclerosis)
lacunes (small cavities in pons and basal ganglia) frequently found
commonest cause of spontaneous intracranial haemorrhage
Cardiac Arrest


characterised by widespread selective neuronal necrosis
hippocampus, post cerebral cortex, caudate nucleus and cerebellar Purkinje cell particularly vulnerable
45
Central Nervous System
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
oligodendroglioma
Ependymal
ependymoma
Undifferentiated/primitive
medulloblastoma
Meninges
mengioma
46
Central Nervous System
Raised ICP





once fontanelles have closed, intracranial contents enclosed in rigid container:
Brain
70%
CSF
15%
Blood
15%
normal ICP
<20 mmHg
(<3 kPa)
moderate elevation 20-40 mmHg (3-5 kPa)
marked elevated
>40 mmHg
(>5 kPa)
commonest cause of  ICP is intracranial expanding lesion
Pathogenesis

four stages:
Stage


Notes
Spatial compensation
increased in one component compensated by decrease in another
Slow rise in ICP
systemic arterial pressure rises to maintain cerebral perfusion
pressure
Rapid rise in ICP
cerebral perfusion pressure may fall
Cerebral vasomotor paralysis
intrinsic vasomotor control lost in cerebral arterioles (ICP=systemic
arterial pressure, perfusion ceases, brain stem death occurs)
transient increases in pressure common during stages 2 & 3
pressure gradients between compartments also important
Clinical Features




headache
vomiting
consciousness 
papilloedema
Intracranial Expanding Lesion

wide variety of pathological processes (e.g. neoplasm, haematoma, abscess, swollen infarct, granuloma)
Morphology



local distortion
displacement and herniation
 ICP
Pathogenesis
Spatial Compensation



CSF volume decreases  (ventricle size , subarachnoid space partly obliterated)
compression of venous sinuses reduces blood volume
local loss of brain tissue (especially with slowly growing lesions)
Contributing Factors




pressure volume curve
rate of expansion
pre-existing atrophy
other factors (respiratory, anaesthetic agents)
47
Central Nervous System
Alterations in Brain


focal epilepsy, paralysis, haemianopia
shifts
Location
Supratentorial lesion
enlargement of cerebral hemispheres with convolutional flattering
CSF displaced, ipsilateral ventricle shrinks, contralateral ventricle may dilate
lateral sift of midline structures, internal herniae
cingular gyrus herniates under free edge of falx
Tentorial herniation
herniation of uncus and med ipsilateral parahippocampal gyrus through tentorial incisura
midbrain narrowed transversely
ipsilateral oculomotor nerve compressed
compression of ipsilateral posterior cerebral a. with infarction of occipital love
caudal movement of brain
haemorrhage and infarction midline midbrain and pons
Tonsillar herniation
caudal displacement of cerebellar tonsils through foramen magnum
compression of medulla  apnoea
Infratentorial
hydrocephalus
enlargement of cerebral hemispheres with convolutional flattering
Other effects
bone erosion
separation of sutures in children
Oedema and Brain Swelling
Normal

Oedema
White matter
70%
75%
Grey matter
80%
81%
in many expanding lesions effective size increased by associated oedema and vasodilatation
Cerebral Oedema
Cause
Vasogenic
Notes
BBB defective
cytotoxic oedema, essentially intracellular caused by energy failure
commonest cause is ischaemia


Hydrostatic
sudden increase in intravascular pressure
Interstitial
increase in periventricular water content associated with hydrocephalus
Hypo-osmotic
serum osmolality 
no evidence to suggest that  brain water content directly interferes with patients neurological state
effects due to  ICP
Congestive Brain Swelling



can occur rapidly particular in children with head injury
arterioles dilate, capillaries flood with stagnant blood (i.e. some vasomotor paralysis)
can rapidly lead to  ICP
Hydrocephalus

total volume of CSF changed 3-5x/day
Type
Notes
Internal
within ventricular system
External
in subarachnoid space
Communicating
ventricles can communicate with subarachnoid space
Non-communicating
ventricles can’t communicated with subarachnoid space
Active
progressive enlargement and  ICP
Arrested
ventricular enlargement ceases
48
Central Nervous System
Compensatory
increased CSF volume compensated by loss of brain tissue
Pathogenesis




commonest cause in cerebral atrophy
acute hydrocephalus most often due to obstruction
ventricles enlarge, white matter 
disruption of ependyma
Acute Hydrocephalus

causes include:





mass lesion at strategic point (foramen, aqueduct)
obliteration of subarachnoid space
congenital lesions
increased production
decreased absorption
Clinical Features


acute – symptoms from high ICP
children – spreading of sutures, enlargement of head
49
Central Nervous System
Neurodegenerative Diseases

normal aging:
Macroscopic
brain volume  + gyral atrophy
(2-3% weight loss/decade > 50)
Microscopic
number of neurons  (especially cortical)
accumulation of pigment within neurons
senile plaques (predominantly amyloid)
Dementia
Causes
Type
Examples
Neurodegenerative
Alzheimer’s (65%)
Lewy body disease (10%)
Pick’s disease (2%)
Parkinson’s
Huntington’s
Prion
CJD
Other
cerebro-vascular (15%)
infections/inflammatory
toxic/metabolic
tumours
hydrocephalus
trauma
Diseases
Disease
Alzheimer’s
Epidemiology
Macroscopic
neurofibrillary tangles (temporal)
10% familial, several loci identified
size  (especially med temporal
lobe)
atrophy of grey matter
neuronal loss
 after 60
history of head injury
Parkinson’s
idiopathic
Microscopic
plaques (frontal & temporal)
loss of dopaminergic neurons
substantia nigra with Lewy bodies
drug induced
from
multiple system atrophy
Lewy Body
Vascular
dementia ± late onset paranoia,
may have parkinsonianism
lewy bodies in cortex (temporal + frontal)
sometimes also Alzheimer’s pathology
confusion with other types
infarcts (large areas)
often associated with Alzheimer’s
smaller foci of ischaemia necrosis
sudden onset, fluctuating course
diffuse periventricular white matter
injury
history of TIA
Term
microscopic
infarcts
(basal
thalamus, usually multiple)
diffuse white
demyelinisation
matter
Definition
Neurofibrillary tangles
thickened and tortuous fibrils within neuronal cytoplasm
Plaques
amyloid cores, neuritic (core of amyloid surrounded by abnormal neurons) or non-neuritic
Lewy body
accumulation of filaments with dense granular material
50
ganglia,
atrophy
with
Endocrine
Endocrine

functions:






growth and development
reproduction
ionic homeostasis
energy metabolism
basic principles:






respond to stress
close relationship with CNS
hormones and target cells
feedback control mechanisms
intermittent release
other sources of hormones (e.g. kidney, tumours, drugs)
mechanisms of disease



Pituitary
disturbance of hormone concentration (/)
disturbance of hormone function
disturbance of organ
Anterior pituitary disease
51