LOM 1

Andrea Tonelli
MBChB (UCT)
2018

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Anatomical Pathology

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Anatomical Pathology
Glossary

• Aetiology ® the cause of a disease, may involve multiple factors

• Complications and sequelae ® secondary, long-term consequences of
disease
• Epidemiology ® frequency and distribution of disease, deals with multiple
factors
• Iatrogenic ® Any condition occurring in a patient, result of
surgeon/physician treatment
• Idiopathic ® unknown causation
• Lesion ® any structural/functional abnormality, responsible for ill health
• Pathogenesis ® step-by-step, MECHANISM of development of disease
• Pathognomonic ® feature specific for one disease, not other
• Morphology ® the form/appearance of something
Surgical Sieve
• Most common classification, via aetiology:
o Congenital
o Acquired
§ Vascular
§ Inflammatory
• Infective
• Non-infective
§ Toxic
§ Traumatic
§ Autoimmune
§ Metabolic
§ Idiopathic
§ Neoplastic
§ Endocrine

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Cell Injury ® Basis of All Disease
• Characteristics of a Normal Cell
o “Steady state” ® copes with normal physiological demands
o Produces energy
o Functionally adaptive
o Has barrier between internal and external environment
• Requirements for “Steady State”
o Intact genome ® preservation of normal DNA templates
o Stable metabolic pathways \ normal enzyme content
o Intact membrane + transmembrane proteins
o Adequate metabolites ® oxygen, substrates

• Mechanisms of Cellular Injury

o Acquired (NIITPRIH)
§ Hypoxia ® deficiency of oxygen at site of tissues
§ Ischemia ® reduced blood supply
§ Reoxygenation injury ® formation of free radicals
§ Physical agents ® trauma, thermal injury, electric shock, radiation
§ Toxins ® drugs, chemicals, poisons
§ Immunological reactions ® allergic reactions, autoimmune
responses, inflammatory reactions
§ Infectious agents ® pathogens \ viruses, fungi, bacteria
§ Nutritional imbalances ® obesity, kwashiorkor etc.

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 o Congenital
§ Genetic abnormalities
• Inborn errors in metabolism
• Chromosomal abnormalities
• Deficiency of functional proteins

• Sites of Injury ® Relate to Steady State Characteristics

o Cell Membranes
§ Transport defects
§ Receptor defects
§ Membrane damage
§ Mechanical disruption ® trauma
o Nucleus
§ Irradiation
§ Cytotoxic agents
§ Free radicals
§ Inherited/congenital abnormalities
o Metabolic pathways
§ Respiratory toxins/poisons
§ Disruption of protein abnormalities
o Essential metabolites
§ Glucose deprivation
§ Hormones
§ Oxygen supply

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• Cellular Responses to Injury
o Excessive physiological/pathological stresses result in ® cell
adaptations
o Continued/heightened stress ® adaptive threshold exceeded ® cell
injury (no more adaptive mechanisms)
o Injury = reversible or irreversible

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• Cellular Adaptations to Stresses
o Hypertrophy ® increase in size of cells
o Hyperplasia ® increase in number of cells
o Atrophy ® acquired decrease in size of organ or tissue owing to
decrease in number/size of cells
o Metaplasia ® reversible change, one adult cell type
(epithelial/mesenchymal) to another
o Reversible cellular injury
§ Stage of cell injury at which deranged function and morphology of
injured cells may return to normal, injurious stimuli removed
o Intracellular accumulations ® water, fat, glycogen
o Irreversible cellular injury ® cell death
o Subcellular alterations ® ultrastructural
• Reversible vs. Irreversible?
o Type of injurious agent
o Duration/severity of injury
o Number/type of cells involved
o Regenerative potential of cell

• Reversible Injury
o Cellular accumulations
§ Hydropic/Vacuolar Degeneration
• Cytoplasm becomes swollen + pale, minor cloudy swelling
• Failure of Na-K pump ® accumulation of H2O and Na
within cell
• ­ in fluid, small/clear cytoplasmic vacuoles form

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§ Fatty change
• Abnormal accumulation of triglyceride fat within parenchymal cells,
commonest form of degeneration
o Parenchymal = functional tissue of organ

• Fatty change in liver

o Causes
§ Alcoholism
§ Protein calorie deficiency
§ Starvation
§ Obesity
§ Diabetes mellitus
§ Hepato-toxins
§ Drugs
§ Inborn errors
§ Hypoxia
o Pathology
§ Macro ® Mild, may not affect gross
appearance/Progressive accumulation =
enlarged, yellow + soft and greasy
§ Micro ® begins with tiny membrane bound
cytoplasmic inclusions \ liposomes = micro
vesicular fatty change
• Micro-vesicles coalesce, form larger
vesicles
§ Sever fatty change ® maybe not reversible

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 § Lipoid degeneration/deposition
• Intracellular accumulations of cholesterol + cholesterol ester in histiocyte
• Foci of cell injury/inflammation
• Foamy macrophages ® phagocytosis of lipid in
injured/necrotic cells

• Strawberry gallbladder/cholesterosis
o Ä increase in serum cholesterol
o Results from reabsorption of lipids from bile
o Focal accumulation of cholesterol in macrophages in
tips of mucosal folds

§ Proteins
• Examples
o Reabsorption droplets in PCT in proteinuria
o Immunoglobulins in plasma cells
§ Glycogen
• Storage diseases
• Diabetes mellitus

o Other
§ Hyaline Degeneration
• Any alteration within cell or in extracellular space, which results in a
translucent, homogenous, structureless, glassy, pink appearance in
routine H&E stains
• Hyalinisation ® CT origin
o Walls of blood vessels ® atherosclerosis
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 o Atrophic organs/aging
o Neoplasms ® degeneration of uterine tubes
• Epithelial origin
o Mallory’s hyaline ® hepatocytes of alcoholics
o Crooke’s hyaline ® pituitary basophils, caused by
Cushing’s syndrome

§ Myxoid Degeneration
• Accumulation of extracellular mucopolysaccharides or ground substance
• CT Myxoid appearance in neoplasms
• Myxoedema

§ Fatty Loading
• Accumulation of adipocytes in tissue, not normally
associated with them ® myocardium tissue

• Irreversible Cell Injury Definitions

o Necrosis
§ Death of cells in living organisms due to
• Denaturation of cellular proteins
• Enzymatic digestion of the cell

§ Gangrene
• Necrosis with putrefaction of a number of tissues in a body part of a
living organism

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 o Putrefaction = anaerobic decomposition of organic
matter by bacteria and fungi, strong odour
o Apoptosis
§ Individual cell deletion of defective cells induced by physiological/pathological
stimuli
• Form of programmed cell death
• Involves protein synthesis
• Energy dependant fragmentation of DNA by endogenous endonucleases
o Necroptosis
§ Cell death, shares aspects of necrosis + apoptosis
§ Morphologically resembles necrosis
§ Mechanistically resembles apoptosis ® triggered by genetically programmed
signal transduction
§ Independent of caspase
o Pyroptosis
§ Form of programmed cell death
§ IL-1 released \ characterized by fever
o Autophagy
§ Cell eats own contents ® starved, cannibalizes own components
§ Occurs from exercise + aging
§ Roles in cancer, neurodegenerative disorders. Infectious diseases
• Necrosis
o Autolysis ® cellular enzymatic degradation by catalytic enzymes derived from the
lysosomes of dead cells
o Heterolysis ® cellular enzymatic degradation by catalytic enzymes derived from
immigrant leukocytes + other cells e.g. macrophages
o Recognition of necrosis
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 § Cytoplasm
• Swells
• Increased eosinophilia ® high level of eosinophils present
• Loss of RNA
• ­ Binding of eosin (red, fluorescent dye) to denatured
protein
• Glassy appearance
• Loss of glycogen + striations in striated muscle
§ Nucleus
• Pyknosis ® Small, dense, wrinkled mass, tightly packed
chromatin
• Karyorrhexis ® fragmentation of chromatin material
• Karyolysis ® progressive dissolution of DNAases
o Causes
§ Ischaemia
• Centre of tumour, infarct (small, localized area of dead
tissue, arises from failure of blood supply)
• Different tissues = different abilities to withstand hypoxia

§ Toxins
• Venom
• Bacterial toxins
§ Infections
• Virus
o Poliomyelitis (Polio)
o Hepatitis
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 • Bacteria
o Diphtheria ® acute bacterial disease
o Typhoid
§ Hypersensitivity reactions
• Caseative necrosis in TB
§ Chemical poisons
• Acids ® char
• Alkalis ® liquefy
• Phenols ® coagulate
§ Physical factors
• Heat ® 45oC
• Freezing ® vasospasm. Ice crystals
• Irradiation ® block mitosis + DNA synthesis

o Types of necrosis (morphology)

§ Coagulative necrosis
• Due to denaturation of structural + enzymatic proteins, Ä
proteolysis of cell
• Commonest
• Ghost outlines under microscope due to
o Preservation of cellular shape
o Loss of nucleus
o Acidophilic opaque cytoplasm
• Removed by fragmentation + phagocytosis by leucocytes
• All tissues except brain

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§ Colliquative (Liquefactive) necrosis
• Due to hydrolytic enzymes (autolysis + heterolysis)
• Liquefaction of tissues
• Characteristic ® ischaemic destruction of brain
• Bacterial infections (neutrophils) \ rapid stimulus of
inflammatory cells, leukocyte enzymes liquefy

§ Caseous necrosis
• Combination of liquefactive + coagulative necrosis
• Cellular outlines Ä discernible (vs. coagulative)
• Fragmented, coagulative cells ® surrounded by a
granulomatous reaction
• Soft, friable, white grey debris ® cheese
• Typically, in TB
§ Fat necrosis
• Enzymatic
o Acute pancreatitis
§ Patchy necrosis of pancreas + abdominal fat,
activated by pancreas enzymes
§ Liquefy cell membranes
§ Lipases catalyse triglyceride fatty acids ®
complex with calcium to form soaps
§ Macro appearance
• Chalky, opaque foci
§ Micro appearance
• Necrotic fat cells = shadowy outline

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 • Amorphous granular basophilic deposits
§ Caused
• Alcohol
• Bile reflux
• Enzymatic lysis of fat owing to lipase
trauma (injections) to fatty tissue
• Trauma
o Injury to fatty tissue
§ Breast
§ Buttock
§ Extracellular liberation of fat
o Appearance ® foam cells, giant cells, granulation
tissue, hemosiderin deposits \ formation of hard mass
• Infections

• Gangrene
o Necrosis with putrefaction of a number of tissues in a body part
o Primary ® Gangrene owing to infection with pathogenic bacteria which
kill tissue (exotoxins) then invade + digest dead tissue
o Secondary ® necrosis owing to another cause e.g. ischaemia and then
saprophytic bacteria digest dead tissue (incapable of invading living
tissue)

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o Primary/infective gangrene
§ Gas gangrene
• Caused by a group of anaerobic, gram-positive sporulating
bacilli ® Clostridia, esp. C. perfringens (Intestinal
commensal)
• Spores in soil, contaminates wounds + flourishes in dead
tissue
• Anaerobic environment, produces exotoxins, diffuse into +
kill adjacent tissue and invade, process spreads rapidly
• Ferments sugars ® \ H2 + CO2 collect as bubbles in
tissues, feel crepitant upon palpation
o Secondary/ischaemic gangrene
§ Lower limbs, ischaemia result in coagulative necrosis, modified by
liquefactive action of bacteria + leukocytes

o Causes
§ Vascular disease
• Atherosclerosis
• Diabetes ® atheroma (degeneration of walls of arteries)
§ Embolism
• Atria of left heart
• Valves ® infective endocarditis
• Ventricle ® infarct
• Cardiomyopathy
• Aorta-aneurysm
• Atheroma

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§ Trauma
• Injury to major vessels + invasion of saprophytic bacteria
§ Frostbite
• Vascular spasm ® thrombosis
§ Chemicals
• Carbolic acid ® thrombosis
• Ergot (fungal disease) ® vasospasm
§ Visceral gangrene
• Mechanical
o Strangulated hernia
o Volvulus ® loop of intestine twists around itself
o Intussusception ® part of an intestine slides into an
adjacent part of an intestine
• Vascular
o Embolism (obstruction of an artery)
o Thrombosis
o Arteritis

§ Pressure sore
• Localised area of ischaemic gangrene over pressure points
• Pressure ® ischaemia ® necrosis ® putrefaction
(decomposition of dead material)
• Seen in paraplegics, the elderly and the debilitated

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• Apoptosis
o Individual cell deletion of defective cells induced by pathological/physiological
mechanisms
o Involves energy dependant fragmentation of DNA by endogenous endonucleases
o Programmed cell death
o Involves protein synthesis

o Physiological importance
§ Embryogenesis ® e.g. hormone dependant involution in adults
• Endometrial cell breakdown ® menstruation
• Ovarian follicular atresia ® menopause
• Regression of lactation during weaning
§ Cell deletion in proliferating tissue ® intestines
§ Prevent genome instability

o Pathological functioning
§ Cell death in tumours
§ Death of immune cells ® T and B cells
§ Atrophy of hormone dependant organs ® thymus + prostate
§ Atrophy of organs, after obstruction ® pancreas, parotid, kidney
§ Cell death, induced by cytotoxic T-cell (perforin ® protein release
by T cells, destroys target cells, create lesions in membranes
§ Cell injury by viruses ® hepatitis

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o Morphology
§ Lysosomes intact + cell integrity maintained
§ Cell shrinkage + separation from adjacent cells
§ Cytoplasm becomes intensely dense + eosinophilic and peripheral
chromatin condenses ® results in dense nuclear mass of various
shapes + sizes
§ Nucleus may fragment into 2 or more fragments
§ Formation of extensive cytoplasmic blebs + number of membrane
bound apoptotic bodies, some with nuclear fragments, form
§ Adjacent macrophages + parenchymal cells phagocytose bodies
§ Adjacent cells migrate/proliferate to fill space
§ Ä ILLICT A INFLAMMATORY RESPONSE

o Disease associations
§ Reduced apoptosis ® cell accumulation
• Causes
o Absent/mutate p53 function ® neoplasia
o Excessive bcl-2 expression
o Autoimmune disease ® Systemic Lupus
Erythematosus
§ Increased apoptosis ® excess cell loss
• AIDS
• Neurodegenerative disorders

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 • Necrosis vs. Apoptosis

Acute Inflammation
• Local response by living tissue to tissue injury
• Results in the formation of a fluid rich in:
o Protein
o Cells ® polymorphs and later macrophages

• Terminology
o -itis ® inflammation, acute or chronic
o Specify by stating acute/chronic
o Specify site if inflammation via anatomical terms
§ Acute appendicitis
§ Acute cholecystitis ® inflammation of gallbladder
o Cerebritis ® acute inflammation of brain parenchyma
o Encephalitis ® viral infection, illicts chronic inflammatory response

• Fluid rich in protein and cells (breakdown of definition

o Accumulated material derived from precursors/material/cells in blood
o \ these substances must accumulate at site of AI by:
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 § An increase in blood flow to area
§ An increase in permeability of BM of vessel
o Achieved through chemical mediators released when injury occurs ®
response \ limited to area of injury

• Phases of acute inflammation

o Vascular phase
§ Increased blood flow to area
§ Slowing of blood flow in distended vessel by:
• Increased permeability of vessels
• Loss of axial flow (central leaning flow of cells in vessels,
avoids peripheral resistance within vessels)
§ Allows egress of cells
§ ­ molecular weight proteins leak out of vessel
o Cellular phase
§ Attachment of neutrophils + later macrophages to walls of vessels
§ Movement of cells through wall
§ Phagocytosis of debris/organisms by neutrophils
§ Intracellular killing/digestion by neutrophils ® fusion of
phagocytic vacuoles with membrane bound packets of enzymes in
neutrophil cytoplasm
• Tissue injury
o Revise causes listed above
o Note ® inflammation Ä always mean infection, other causes of tissue
injury will result in AI
o Note ® infection does not always cause inflammation, if patient
severely immunocompromised + ¯ polymorph count = not present
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 o Classify infective agents! ® need to know what kind of inflammatory
process will be incited
§ Bacteria
• Pyogenic ® results in the formation of pus
• Granulomatous ® inflammation, collection of immune cells
§ Viral etc.

• Local response (breakdown of definition) ® ways to induce dissemination

o Attempts to contain infectious insult as far as possible ® if insult
spreads, can be fatal. Containment can be modified by:

o By therapeutic intervention
§ i.e. in peritoneal cavity
• Acute inflammatory response results in fibrin precipitating
out to surfaces of bowels
• Bowels become sticky + adhere together \ seal of process,
prevent spread
• Surgeon separates loops during early stages of peritonitis ®
adherence broken down + insult disseminates
o By toxins
§ i.e. in gas gangrene
• Organism only lives in anaerobic conditions but produce
toxins which diffuse into living tissue
• Results in necrosis of vessels ® further anaerobic conditions
® spread of gangrene

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• Living tissue (breakdown of definition)
o Characteristic of tissue here is BLOOD vessels ® some tissues are
predominately made of acellular CT (valves of heart or cornea)

o Tissue with few vessels = limited AI response

§ If infective process here, organism easily takes hold \ life-
threatening
§ Difficult to treat ® antibiotics delivered by way of blood
o Dead tissue
§ No active blood vessels, \ no active flow to area
§ Bacteria sets up focus of infection
§ Ä be eradicated until dead tissue removed (cannot deliver protein
+ cell rich fluid
§ Can tell if tissue was alive at time of injury as dead tissue would
not mount AI response
o Infarcts
§ Area of infarct = no AI, but living at peripheral will
§ Process is self-limited as enzymatic destruction will stop once all
enzymes are released
§ Bacterial infections continue as they proliferate and produce a
continuous supply of enzymes
• Cardinal Signs of AI
o RUBOR ® redness ® increased blood flow + vasodilation
o CALOR ® heat ® increased blood flow + vasodilation
o TUMOUR ® swelling ® protein + cells
o DOLOR ® pain ® activation of nerves
o LOSS OF FUNCTION
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 o All AI processes will show these signs to different degrees
o BUT infections may modify \ allows for distinction of causative
organism by macroscopic lesion produced
o \ skin infections with AI macroscopically differ depending on:
§ Which organism is involved
§ Site of infection

• Tissues and acute inflammation ® various tissues have different responses to

AI owing to anatomy + physiology:

o Tissue must be able to expand! (increased volume)

§ Brain
• Fixed volume in skull, no room for expansion owing to
calcification
• Dangerous ® brain squeezed out like toothpaste to
compensate space
• Differs in neonates ® fibrous connections of cranial bones
may expand \ skull enlarges
§ Bone
• Fixed volume in medullary cavity in bone
• AI ® increased volume ® increased pressure
• When pressure out = pressure of blood, supply stops ®
infarction of bone marrow

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o Tissue will produce a fluid rich exudate over its surface area
§ Surface is large ® amount of fluid formed
§ May cause ­ fluid loss ® patient into shock (peritoneal cavity)

o Tissue may release substances that cause further chemical damage ®

results in further AI/metabolic upset
§ Pancreas
• Release of lipase ® chemically breaks down fat in adipocytes
• Results in fat necrosis
• Release of insulin if islets destroyed, drop blood sugar
§ Stomach
• Release of hydrochloric acid ® chemical peritonitis if
perforation of wall
§ Extensive tissue damage
• Induces release of potassium ® neuro dysfunction
• K+ in cell >>> K+ outside

o Tissue itself physiologically responds differently

§ Lungs ® pneumonia (acute inflammation of alveoli) has 2 phases:
• Red hepatisation
o Congestion + dilation of vessels in area
o Results in red colour in area ® typical of AI
• Grey hepatisation
o Accumulation of cells + fluid in alveoli ® hypoxia
o Effect on pulmonary vessels = opposite of systemic
vessels

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 o Vessels contract, cutting supply to abnormal lobe
(cross-reference to autoregulation in physiology)
o \ grey colour rather than expected red

• Beneficial effects of AI
o Fluid dilutes toxins
o Fluid contains antibodies circulating in bloodstream
o Fluid contains soluble fibrinogen, converts to fibrin (an insoluble,
delicate, strand-like protein, forms barrier to spread of infection,
localizes area
o Fluid contains polymorphs ® ingest + destroy pyogenic organisms
o Fluid contains macrophages, phagocytose proteins, first phase of
immunity

• Possible outcome of acute inflammation

o Resolution
o Suppuration (pus in acute inflammation)
o Healing by fibrosis
o Progression to chronic inflammation
o Spread ® direct, blood vessels, etc.
o Death

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• Neutrophils
o Live
§ 24-48 hours when circulating in blood
§ 9 hours after leaving vessel
o \ Must be continuously replaced by bone marrow
o Can release harmful enzymes
o \ Chemical attacks by polymorphs = intracytoplasmic (occurring within
the cytoplasm of the cell)
o Contents of granules of dead/dying polymorphs = inactivated!
o Alpha-1-antitrypsin circulated to destroy these enzymes

• Alpha-1-antitrypsin
o In basal area of lung (polymorphs accumulate, increased flow)
o Polymorphs that die ® release elastase
o A1A destroys, if not present ® elastase persists, acts on lung
parenchyma (contain ­ elastic tissue)
o Causes irreversible distension of air spaces ® emphysema

• Anti-neutrophilic-cytoplasmic-antibodies
o Various forms of circulating antibodies against antigens in the cytoplasm
of neutrophils
o May be identified in vasculitic syndromes (pANCA + cANCA)
o Produce either green or yellow puss
§ Green ® presence of myeloperoxidase (enzymes, produce
hypohalous acid
§ Yellow ® lipid from breakdown of cell membranes

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• Glossary
o Exudate ® fluid rich in proteins
o Pus ® yellow/green fluid collection containing dead and dying cells,
polymorphs + organisms
o Pyogenic bacteria ® pus forming bacteria, usually Streps/Staphs, not
TB/syphilis ® result in chronic inflammation
o Abscess ® a localized collection of pus from colliquative necrosis
o Bacteraemia ® bacteria circulating in blood stream, Ä dividing, may be
ingested by polymorphs + is not life threatening
o Septicaemia ® bacteria circulating in the blood, actively dividing, have
overcome host defences (present where neutrophils are most present)
§ Not localized \ life-threatening

• Detailed Mechanism of AI
o Definitions
§ Passive hyperaemia ® relative stasis of blood arising from increase
venous pressure (congestion)
§ Exudate ® excess fluid in tissues which contain plasma proteins
e.g. fibrinogen
§ Transudate ® fluid in tissues, ultra-filtrate \ Ä or little protein

o Vascular phase ® cardinal signs result from this phase

§ Transient, brief vasoconstriction ® neuronal reflex
§ Dilation of blood vessels
§ Increased blood flow (active hyperaemia)
§ Loss of exudate into tissues
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 § Increased lymphatic flow
§ Vascular permeability adjusted by:
• Kinin + histamine ® immediate, transient ­ vascular
permeability (Venules only!)
• Endothelial cell injury ® delayed but persistent ­ vascular
permeability (Capillaries + venules)

o Cellular phase
§ 2 main cell types in AI:
• Neutrophils
o Polymorphonuclear neutrophilic granulocytes
o Definitive cell of AI, polymorphs (including
eosinophil) owing to lobated nuclei
o Cytoplasm = ­ no. of lysosomes
o Primary ® phagocytose particles + microorganisms
• Macrophages
o Mononuclear phagocyte, part of extensive
mononuclear phagocyte system (monocytes)
o Functions
§ Phagocytosis of small + large debris
§ AP to lymphocytes for antibody synthesis
§ Secrete factors ® stimulate fibrosis
§ Produce some components of complement

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§ 7 sub phases:
• Slowing of blood flow ® loss of fluid

• Margination of leukocytes ® results in tethering, selectins

seen in venules owing to loss of axial flow

• Triggering

• Strong adhesion ® integrins

• Motility and emigration via intercellular junctions, move to

sight of injury

o Movement facilitated via chemotactic factors

§ Bacterial products
§ Leukotriene LTB4
§ Complement system by-products
§ C567 complex
o Neutrophils can attract others via lysosomal enzyme
cleavage, forming chemotactic factors
o Biphasic cellular response ® polymorphs then
monocytes because:
§ ­­­ polymorphs in circulating blood
§ Polymorphs migrate faster
§ Polymorphs = much ¯¯ life span
§ Monocytes can proliferate in tissue

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 • Phagocytosis
o Process whereby particles = ingested + destroyed
o 2 steps:
§ Opsonization ® some instances, prior coating
required for phagocytosis
• \ Certain opsinins opsonize cells
o Particle specific opsinins ® IgG
antibodies
o Particle non-specific ® C3
component of complement
§ Phagocytosis ® pseudopods of cytoplasm
surround phagosome
• Phagosome incorporated into cell

• Intracellular killing ® superoxide, halides

o Cytoplasmic lysosome fuse with phagosome, enzyme
digestion of particle aided by:
§ Low pH inside vacuole
§ Hydrogen peroxide
§ Respiratory burst
o Results of phagocytosis
§ Removal + destruction of causative agent
§ Ingestion + digestion of cell debris
§ Release of lysosomal enzymes, help digest debris
§ Carriage of cells through lymphatic, may contain viable bacteria,
initiate immune response

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o Third phase ® consequences of AI

§ Resolution
• Return to normal, Ä morphological change
• Ä change to supporting structures
• Superficial epithelium may be repaired
• Stroma Ä be repaired, if so = fibrosis and scar formation

§ Suppuration
• Purulent ® pus forming ® septic
• Severe, local toxic injury with tissue necrosis by pyogenic
organisms
• Intense emigration of polymorphs ® inflammatory exudate
called pus
• Contains
o Dead tissue cells
o Dead + dying, polymorphs + macrophages
o Bacteria
o Fibrin rich fluid, with cholesterol, fats, nucleic acids
• Abscess ® when occurs in solid tissue
o Necrosis + abscess formation ® favour bacterial
proliferation
o Abscess ­ in size or forces itself along tissue planes
(low resistance)
o May rupture, pus release ® ¯ pressure, free flow of
exudate \ bacteria eliminated

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 o If not drained, become walled off by:
§ Granulation tissue + fibrin = pyogenic
membrane
§ Fibrous tissue

§ Fibrosis
• Part of repair process of necrosis
• Organize excessive fibrin in exudate ® part of chronic
inflammation (Vive infra)

§ Progression ® if unstopped, to chronic inflammation

§ Death

• Systemic Effects of Acute Inflammation

o Fever
§ Elevation of internal body temperature above normal value of 37oC
§ Caused by action of pyrogens on thermo-regulatory centre of
hypothalamus ® acts via prostaglandin E
§ Endogenous pyrogens ® release by polymorphs + macrophages
• Ag-Ab complexes
• Bacterial endotoxins
• Certain viruses
• Pyrogenic lymphokine from lymphocytes

§ Exogenous pyrogens ® include containments in IV infusions

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 § Ill effects include:
• General malaise (general feeling of discomfort) and anorexia
• Increased metabolism
• Thermal injury to neurons (>41.5oC)

o Leucocytosis
§ Increase in the number of leukocytes in the bloodstream
§ Mature neutrophils are available:
• Attached to the endothelium
o Polymorphs released from ‘marginated pool’ during
exercise + epinephrine
• As a proportion from bone marrow
o Involves release from polymorph reserve in bone
marrow ® stimulated by neutrophil releasing factor,
including C3 fragments
§ Immature neutrophils are available:
• Stimulation of proliferation of precursors in marrow, may
result in release of immature forms in circulation = right-
shifted

o Alterations in serum proteins

§ ­ in gamma globulins + fibrinogen

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• Beneficial Effects of AI
o Dilution of toxins
o Delivery of antibodies
o Fibrin barrier, controlling spread
o Promotion of immunity ® introduction to APC + macrophages for
antigen presentation
o Phagocytosis

• Specific Patterns of AI
o Suppuration
§ Pus formation ® usually an acute inflammatory response
§ May be chronic suppuration, resulting in:
• Continued tissue destruction
• Pus formation
• Fibrosis
§ Suppuration in solid tissue ® abscesses forming
§ Pus accumulates in pre-formed spaces also ® peritoneum

o Cellulitis
§ Diffuse inflammation of CT, by bacteria that produce factors,
allow spread
§ E.g. haemolytic streptococci, produce hyaluronidase, breakdown
BM of CT

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o Pseudomembranous inflammation
§ Caused by organisms that:
• Grow on surface of mucous membranes, little ability to
invade
• Produce exotoxins, cause superficial necrosis
§ Exudate of AI mixed with dead cells ® formation of false
membrane containing:
• Fibrin + necrotic tissue cells
• Causal bacteria
• Neutrophils + RBC
§ E.g. Bacillary dysentery in colon ® membrane engorged to to
vessels produced

o Serous inflammation
§ Manifests via excess fluid exudate
§ Involves inflammation of serous membrane of cavity + fluid
accumulation
§ Results in deposition of fibrin on serous surface
§ Serous inflammation may be acute or chronic

o Catarrhal inflammation
§ Acute inflammation of mucous membranes
§ Results in an excess secretion from mucous glands
§ E.g. influenza (bronchi), common cold (upper respiratory tract)

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 o Ulceration
§ Loss of surface epithelium
§ As on surface = necrotic tissue lost
§ Inflammatory response appears in underlying stroma, acute or
chronic

Treatment of Inflammation
• Successful healing
o Scar tissue formation
o Removal of necrotic tissue
• \ Therapeutic approaches to healing process aim to reduce inflammation

• Evolution of an Abscess (under skin)

o Bacteria cause tissue damage + necrosis
o Bacteria multiply, polymorphs pack into central zone
§ Hyperaemia + oedema occur
o Delineation (action of portraying) of abscess by pyogenic bacteria ®
new capillaries, polymorphs + few fibroblasts at edge
§ Thinning of epidermis
§ Pus tracks towards surface
§ Pus formation in centre
o Abscess ‘points’ + ruptures ® discharging pus + pyogenic membrane
becomes more pronounced
o Swelling subsides, cavity collapses ® organisation + fibrosis proceed
o Final small scar forms

37
• Available Treatment modalities
o Surgical therapy

o Temperature therapy
§ Cold-therapy (cryotherapy)
• Ice packs applied for intervals of 15-20 minutes
• Effects include:
o Decrease in blood flow ® ¯ hyperaemia + ¯
exudation
o Inhibition of spinal neurons ® reduce pain
o Localised decrease in metabolic demand

38
 § Heat-therapy
• Every 1oC increase in tissue temp. = 13% ­ in metabolic
demand
• Effects include
o Increase in cellular metabolism
§ Increase in oxygen + nutrient demand
§ ­ production of metabolites + waste products
o Local vasodilation \ increase in blood flow
o Enhance oxygen + nutrient supply
• BEWARE ® heat-induced injury + tissue damage occurs at
45oC

o Ultrasound therapy
§ Ultrasonic waves = thermal effects on tissue
§ Effects include:
• Enhance cell metabolism
• Enhance histamine release in surrounding tissue
• ­ in blood flow
§ Owing to effects on collagen + protein synthesis ® also used to
treat injury of ligaments + tendons

o Drug therapy
§ Non-steroidal anti-inflammatory drugs (NSAIDs)
• Anti-inflammatory, antipyretic, analgesic properties
• Aspirin, ibuprofen, naproxen

39
 • Mechanism of action:
o Influence cyto-oxygenase, block conversion of
arachidonic acid to prostaglandins
o Mediators not available to enhance inflammatory
response
§ Corticosteroids
• Include Prednisolone, dexamethasone, methylcortisone
• Effects on inflammatory process:
o Reduce production of adhesion molecules
o Suppress activated macrophages
o Reduce/prevent antigen presentation
o Other effects
§ Anti-histamines
• Act as histamine receptor antagonists, prevent following
actions:
o Vasodilation
o Increased capillary permeability ® oedema
o Increased secretions ® salivary, nasal
o Stimulation of nerve endings ® pain
• Ä Prevent histamine release
§ Immune modulating agents ® gold, biological agents,
methotrexate
• Biologicals ® antibodies to the chemical mediators of
inflammation, prevent action or destroy (block anti-IL1)
§ Antibiotics
o Plasmapheresis ® filtration of autoantibodies + drugs + toxins from
plasma of patient
40
• Suppuative inflammation + abscess formation
o Suppuration ® formation of pus (thick, creamy, yellow exudate cased
by pyogenic bacteria)
o Abscess ® accumulation of pus within solid tissues, surrounded by a
pyogenic membrane composed of sprouting capillaries, neutrophils +
occasional fibroblasts (in granulation tissue) and fibrosis

o Diagnostic features of abscess ® think of cardinal signs of AI

§ Swollen
§ Painful + tender
§ Hot
§ Red/erythematous
§ Fluctuant

o Evolution of abscess

• Treatment ® abscess incision + drainage (I&D)

o Preparing for I&D
§ Local anaesthetic ® acidic environment around abscess, \ might
reduce effect of anaesthetic
§ Skin preparation
• Sterile environment ® prevention of contamination
• Shave hair
• Skin cleanser ® chlorhexidine

41
o I&D
§ Incision into abscess ® removal of pus + infective agent (sample
for microbiological culture)
§ Blunt dissection ® breakdown of loculations to disrupt pyogenic
membrane
§ Debridement of non-viable tissue
§ Wound irrigation ® saline + peroxide (mimic function of
lysosomal enzymes
§ Wound packing ® prevent collapse of abscess wall + re-
accumulation of bacteria
• Promotes free-drainage of abscess cavity

o After-care ® control cardinal signs!

§ Wound dressings + ointments
§ Antibiotics
§ Analgesics ® painkillers
§ Antipyretics
§ Anti-inflammatories (NSAIDs)

42
Gangrene and its Treatment
• Classification
o Primary/Gas gangrene
§ Damage to tissue ® deep anaerobic nidus (place where something
is formed) into which spores are inoculated
§ Anaerobic condition ® allow proliferation
§ Produce extracellular toxin ® diffuse into adjacent tissue
§ Particularly toxic to blood vessels ® damage ® thrombosis
§ Destruction of vessel ® infarction with further anaerobic
conditions
§ Organism spreads \ so does infection
§ Also produce H2S gas ® crepitus + swelling
o Secondary gangrene
§ Tissues undergo ischaemic necrosis ® e.g. thromboembolism
(formation of a clot in blood vessels that that are carried, causing
blockage elsewhere) in right leg
§ Tissue dies ® secondary putrefaction occurs, tissue turns black
§ Border, living and dead tissue ® clearly demarcated
§ During surgery
• Level of amputation = ABOVE interface between black and
living tissue
• Extra blood flow is required to effect healing + repair of the
surgical bed

43
 • Treatment of gas gangrene
o Surgical
§ Dead zone with anaerobic conditions = fully excised
§ Usually on periphery \ amputation is performed
§ Level of amputation = ABOVE zone where toxins have diffused
o Antibiotics
§ Ä Antibiotics can penetrate into infracted necrotic tissue (no
blood vessels)
§ Give though to raise level in still viable tissue, assists in destruction
if further spread occurs
o Anti-toxins
§ Toxin spread into local tissue + systemic blood stream
§ Systemically, can be devastating \ used to neutralize + protect
o Hyperbaric oxygen
§ O2 delivered at ­­ conc. to penetrate into tissue
§ Prevents organisms from growing
§ Toxin itself may be harmful at ­­ conc.

Chronic Inflammation (LOM)

• Definition ® immunologic + fibrotic (AI: vascular + phagocytic)
o Process in which there is continuing inflammation and fibrosis at the same time as
attempts at healing, resulting from persistence of the injurious agent
o Injurious agent normally perceived as foreign by body, almost always
infection, also occurs when body fails to recognize as ‘self’
(autoimmune)

44
o Persistence may be due to:
§ Defective/frustrated acute inflammatory response
• Poor circulation
• Poor nutrition
• Anti-inflammatory drugs
• Immunodeficiency etc.
§ Resistance of injurious agent to phagocytosis
• Agent capable of evading defence mechanism by ‘hiding’
within host cells ® TB, viruses
§ Agent being ‘altered self’
• Immune system = tolerant of molecules recognized as ‘self’
• May be altered by disease (autoimmune diseases) or altered
by attachment of foreign molecules
• Tolerance may cease, and body auto-reacts
o CI may be secondary to AI, but can be primary (not preceded by AI,
seen in viral disease, autoimmune responses etc.)
o Often CI is non-specific to agent, yet some agent may produce
suggestive characteristics
o AI and CI represent ends of a dynamic continuum, may overlap
o Features
§ Phagocytosis by macrophages, especially in granulomatous
inflammation
§ Infiltration by CI cells ® lymphocytes + plasma cells
§ Attempts at healing ® regeneration + repair
§ Variable/absent AI ® if present, inflammation deemed as sub-
acute inflammation

45
• The Immune System
o Humoral immunity ® antibodies
§ Proteins (immunoglobulins), produced by B-lymphocytes in
response to ­ molecular weight antigens/APC
§ Ags perceived as non-self ® matching Abs produced to neutralise
§ Abs = very specific, fit to form neutralized Ag-Ab complex
§ Coating the Abs form on some pathogens (bacteria), enhance
phagocytosis of that organism
§ Forming of Ag-Ab complex, activate complement!
o Cellular immunity ® cytokines
§ Cytokines ® form signalling network between cells
• Lymphokines ® cytokines secreted by T-helper lymphocytes
that have been sensitized by Ab
• Interleukins ® Mediate local reactions between leukocytes
§ Produced by many cells, most prominently:
• Macrophages
• T-lymphocytes
§ Cytokine classes include:
• Chemokines ® attract other cells (chemotaxins)
• Growth factors ® stimulate growth of cell populations
• Interferons ® activate macrophages + fibroblasts = antiviral
• Tumour necrosis factor ® stimulates vessel growth +
inhibits tumour growth

46
• Complement
o Proteins that circulate as part of the acute phase reactants ® produced
by the liver
o Stable, unless encountered by micro- organisms or Ag-Ab complexes
o Contact results in cleavage of a small fragments and conversion into an
enzyme capable of cleaving other small fragments from other members
o Results in a cascading effect
o Fragments are responsible for activities of complement, which is to
facilitate effects of Ab:
§ Activation of macrophages
§ Opsonizing bacteria
§ Lysing cell membranes
§ Modulating co-agulation
§ Act as chemotaxins for leukocytes

• Cells associated with CI ® predominantly mononuclear leukocytes

o B lymphocytes + plasma cells
§ Mature in the bone marrow
§ Transform ® plasma cells and produce specific antigens upon
antigen presentation
§ Memory cells persist ® can produce same Ab upon future
challenges
§ Plasma cells predominate in CI

47
o T-lymphocytes
§ Mature in thymus
§ Antigen receptors on membrane occupied ® proliferation
§ Suppressor T-cells ® inhibit B-cells, protect against autoimmune
§ Cytotoxic T-cells ® destroy cells
§ Helper T-cells ® produce cytokines
§ T & B-cells indistinguishable microscopically
o Macrophages
§ Derive from bone marrow monocytes
§ Upon exit into tissue = macrophages/histiocytes
§ Always components of CI
§ Bigger vs lymphocytes, pale nuclei, voluminous cytoplasm
§ When elongated ® epithelioid histiocytes
§ Functions
• Phagocytosis
• Antigen handling
• Synthesis ® cytokines, interferons etc.
• Enzyme release ® elastase, collagenase
§ Multinucleated giant cells
• Fusion of several macrophages
• Seen in characteristic CI conditions, usually within vicinity of
poorly digestible exogenous + endogenous material:
o Infections ® TB, fungi, syphilis
o Foreign body reactions ® nuclei dispersed
o Phagocytosis of lipid ® Touton giant cells
o Collagen diseases ® rheumatic fever
48
 o Fibroblasts
§ Develop from stem cells circulating in vessels +
mesodermal/parenchymal tissue
§ Give rise to cells that comprise mesodermal tissue:
• Osteocytes
• Chondrocytes
• Myocytes
• Adipocytes

• Patterns of CI
o General ® hard to identify cause from histological patterns
§ Continuing fibrinopurulent exudate ® persistent attempts at
healing, sometimes in presence of tissue necrosis
§ Tissue damage + impairment that is progressive + occurs at a
fast/slow rate, depending on:
• Severity of inflammation
• Efficiency of healing process
• Damage + healing = dynamic processes

o Granulomatous
§ Granuloma results ® substances provoking inflammation Ä be
digested by neutrophils
§ \ Are digested by macrophages ® prevent perpetual stimulation
of AI + tissue damage
§ If not killed, macrophages sequester noxious agent in cytoplasm,
resulting in:
• Loss of motility
49
 • Accumulation
• Epithelioid appearance
§ Epithelioid macrophages form nodular collection ® \
granulomas
§ Usually surrounded by lymphocytes + fibroblasts
§ Multinucleate giant cells + necrosis are frequently present
§ Commonest causes of granulomatous infection:
• Foreign bodies ® exogenous (suture), endogenous (keratin)
• Bacterial infections ® TB, leprosy, syphilis
• Fungal + parasitic infections ® histoplasmosis,
schistosomiasis
• Idiopathic diseases ® sarcoidosis, Crohn’s disease
• Certain drugs

Chronic Inflammation
• Endarteritis obliterans
o Obliteration of arterial lumina by intimal (Tunica) proliferation of fibrous tissue
induced by external inflammation
o May arise in longstanding CI
o In syphilis, may cause:
§ Local infarction, particularly in brain
50
 § Syphilitic gummas (soft, non-cancerous growths) ® necrotic mass
lesions (tertiary syphilis)
o In cases of chronic gastric ulcers, deep erosion in wall with medium
artery present:
§ Severe haemorrhage
§ Ä be shut off via muscular contraction as fibrosis hold lumen
open

• CAUSES OF CI
o Following AI
§ Acute osteomyelitis ® chronic osteomyelitis
§ Ascending pyelonephritis ® chronic pyelonephritis

o Persistent infections
§ Mycobacterium
§ Spirochetes ® syphilis
§ Viral infections ® chronic hepatitis B & C
§ Fungi ® Cryptococcus, histoplasmosis
§ Parasitic infections ® schistosomiasis
o Foreign bodies/foreign material
§ Exogenous agents
• Silicosis ® inhaled silica particles
• Talc (clay mineral) ® IV drug users
• Silicone ® breast augmentation
§ Endogenous
• Keratin

51
 • Necrotic bone
• Cholesterol crystals

o Autoimmune diseases + hypersensitivity reactions

§ Systemic Lupus Erythematosus (SLE)
§ Rheumatoid arthritis
§ Hypersensitivity reactions

• Cell population of CI ® mostly mononuclear cells

o Lymphocytes ® associated with immune response
o Plasma cells ® associated with immune response
o Monocytes ® AP + phagocytic, presence of giant cells in some CI
o Foreign body giant cells ® Numerous nuclei, dispersed in cytoplasm or
clustered in centre, close vicinity to poorly digestible exogenous +
endogenous material
o Langhan’s giant cell ® multiple nuclei, around periphery of cell,
associated with granulomatous infection
o Eosinophils ® particularly associated with parasites
o Neutrophils ® small numbers, particularly with fungi
• Types of CI

o Chronic non-specific inflammation

§ Follows acute inflammation ® lymphocytes, plasma cells +
macrophages, Ä granulomas
§ Morphology ® chronic gastric ulcer
• Severe infection of the skin by a pyogenic organism

52
 • Central necrotic cavity forms with several organisms persist
• Failure of polymorphs in control, organisms persist and
cause further damage
• Wall of cavity shows organisation of fibrin ® fibrous tissue
via process of healing and repair
• Macrophages secrete substances, further stimulate formation
of fibrous tissue
• Adaptive immune system is activated, resulting in
lymphocytes migrating to the area:
o Ab producing B-lymphocytes and T-cells
• Insult persists, resulting in fibrosis (required for diagnosis
of CI) and pus persists further
§ Antibiotics fail owing to insufficient vasculature and dense fibrosis
§ Will show surface ulceration with fibrin + acute inflammatory
response
§ In its bed ® chronic inflammatory cells + fibrous tissue
§ Edges will continue to attempt to re-epithelialize
§ Ulcer \ shows attempts at repair (required for diagnosis of
CI)

o Granulomatous
§ Defining feature = granuloma formation
§ Morphology of a granuloma
• Often a rim of surrounding lymphocytes
• Giant cells may be present
• May be necrosis present
• Outer rim of fibroblasts
53
 • Macrophages have abundant cytoplasm and resemble
epithelial cells \ epithelioid
§ Causes
• Mycobacterial infections
o Tuberculosis
§ Langhans type giant cells
§ Caseous necrosis
§ Acid-fast bacilli on Ziehl-neelsen stain
o Leprosy
§ Lepromatous leprosy ® poor immune response
§ Tuberculoid leprosy ® good immune response
o BCG adenitis
§ Following BCG vaccination in neonates
o MOTT infection
§ Mycobacteria, other than TB

• Fungal infections
o Histoplasmosis
o Cryptococcus

• Parasitic infections
o Schistosomiasis

• Foreign bodies
o Talc
o Silicone
o Silica
54
 o Keratin

• Autoimmune diseases
o Sarcoidosis
§ Non-necrotizing granulomas
§ Discrete + well-formed
§ Asteroid bodies + Scheuermann bodies
o Crohn’s disease
§ Inflammatory bowel disease

• Bacterial + Spirochaete infections

o Cat-scratch disease ® Bartonella henslae
o Tertiary syphilis ® Treponema pallidum

§ From appearance of granuloma, may determine cause:

• TB = granuloma with caseous necrosis
• Syphilis ® central coagulative necrosis, endarteritis
obliterans occlude bloody supply to area
• Fungi ® collections of polymorphs in granuloma
• Parasites ® eosinophils associated with them
• MAIN FEATURES OF CI
o Mononuclear cell infiltrate
§ Lymphocytes
§ Plasma cells
§ Macrophages/histiocyte (± granulomas)
o Tissue destruction
o Angiogenesis
55
 o Healing by fibrosis

• Recticulo-endothelial system
o Involved in innate immunity
o Has roles in:
§ Phagocytosis
§ Blood monocytes
§ Tissue macrophages
§ Kupffer cells (liver) ® specialized macrophages
§ Alveolar macrophages
§ Sinus histiocytes (lymph nodes + spleen)

• Infection by micro-organisms

o Routes of entry
§ Inhalation
§ Ingestion
§ Innoculation ® artificial introduction
§ Sexual transmission
56
 § Transplacental

o Body Defences Against Infection

§ Mechanical
• Barriers
o Squamous epithelial covered surfaces
o Include ® skin, mouth, pharynx, oesophagus etc.
• Movement of body fluid ® moves organisms towards sights
that can deal with them
o Backwards flow of saliva + swallowing
o Upwards flow of mucous in respiratory tract + cough
reflex
• Washing of conjunctiva by tears
• Voiding of urine + emptying of bladder
§ Non-specific chemical action + enzymes
• Sweat ® acidic
• Unsaturated fatty acid in sebaceous secretions
• Hydrochloric acid in stomach
• Acidic pH environment in vagina, arises from commensals

§ Competition from resident commensals

• Particularly on skin, in colon + lower female genital tract
§ Immunoglobulin mechanisms
• IgA antibody in GIT
• Mucosal-associated lymphoid tissue

o Spread of infection in body

57
§ Local
• Flow of fluid exudate through tissues
• Muscle action may ­ flow
• Fibrin in exudate ® barrier to spread
• Viable organisms carried in macrophages
§ Natural spaces
• Serous cavities
• Bronchi
• Gut
• Joints etc.
§ Lymphatics
• Fluid exudate + macrophages carried to draining lymph
nodes
§ Nerves
• Certain viruses ® CNS via nerves
§ Bloodstream
• Bacteraemia ® ¯ no. of non-multiplying bacteria in blood
stream, caused by minor trauma, may seed out into abnormal
tissue
o Endocarditis ® damaged heart valves
o Osteitis ® traumatized bone
• Septicaemia
o Presence + MULTIPLICATION of bacteria in blood
o Begins as a focus of infection somewhere in the body
o May cause multiple foci of infection

58
 • Pyaemia
o Presence of infected particles (emboli) in blood
o Local infection ® changes in endothelial cells ®
thrombosis
o Bacteria multiply in thrombus ® infiltration by
polymorphs ® partial digestion of thrombus by
polymorph enzymes
o Bits of infected thrombus break off + are carried by
blood ® impaction in small vessels ® formation of
new abscesses (Pyaemic abscesses)

• Tuberculosis ® brief example of chronic disease which can cause back pain
o Primary TB
§ First exposure to TB antigen ® no previous exposure!
§ May occur in lung/gut, depending on site of inoculation
§ In the lung:
• Produces small lesions in upper portion of middle lobe or
lower portion of lower lobe ® acute inflammatory response
occurs
• Polymorphs unable to control ® infection persists
• Owing to Ä previous exposure ® 10-14 days for cell-
mediated immunity
• Meanwhile, macrophages engulf, emigrate to draining lymph
nodes in hilum of the lung
• \ Cell-mediated immunity develops ® macrophages:
o Develop into epithelioid forms

59
 o Pulled into area
o Granulomas develop
• Presence of lipoproteins from SCANTY organisms ®
release of IL1 + TNF from epithelioid macrophages
• Caseous necrosis in enlarged hilar LNs occur
• Lesion of primary tuberculosis ® THE GHON COMPLEX

§ The Ghon Complex

• Consists of:
o The Ghon focus
§ Subpleural focus in base of upper lobe/top of
lower lobe
§ Dry, firm lesion with central cottage cheese
appearance
§ \ Necrotizing granulomas with caseous necrosis
o Enlarged hilar + trachea-bronchial lymph nodes
(kidneys also)
§ Necrotising granulomatous inflammation
§ Granulomas in lymphatics
• Granulomas break through anatomic structures
o Bronchus ® bronchopneumonia
o Vessels ® miliary blood spread throughout body
o Secondary TB
§ Patient recovers from TB \ memory immunity to TB
§ 2 cases:
• There is a second infection
• There is re-activation
60
 o Organism remained within macrophages, unable to
proliferate
o Blind to immune system \ considered ‘outside’ the
body
o Immune system weakens ® organism re-activates ®
kill macrophage + re-appears to immune system
o Occurs:
§ Upper lobes of lung ® higher O2 conc.
§ IMMEDIATE activation of adaptive immune
system
§ Development of granulomas + caseous necrosis
where present (parenchyma of lungs)
§ Caseous bits coughed up ® apical (apex) cavities
develop
§ Organism spreads haematogenously
• Very few organisms in TB = hypersensitivity reaction to
AFB (acid-fast bacilli)
• ¯ no. = very hard to isolate
• In AIDS ® adaptive immunity profoundly reduced:
o Reduced granulomatous reaction
o ­­ organisms

61
Autoimmune Diseases (CI)
• Tissue damage (disease) from excessive immune reactions against self-proteins, involving both
genetic + environmental risk factors
• 2 types
o Systemic ® SLE, rheumatoid arthritis
o Organ specific ® diabetes mellitus, Grave’s disease
• Aetiology
o Idiopathic
o Thought to be a combination of genetic susceptibility + environmental
influence
• Pathogenesis
o Examples of genetic susceptibility
§ HLA B27 in ankylosing spondylitis
§ HLA DQ2 in coeliac disease
o Examples of environmental susceptibility
§ UV light ® apoptosis
§ Oestrogen in SLE
o Combination results in defective antigen presentation ® loss of
tolerance ® results in hypersensitivity reaction
o \ Damage and disease
• Pathology
o Depends on type of hypersensitivity reaction and shows:
§ Chronic inflammation ® lymphoid follicles, vasculitis,
granulomas, infiltration by CD8+ T-cells
§ Tissue injury, associated with growth + repair

62
• Complications
o Local complications ® ankylosis (stiffness of joint owing to abnormal
adhesion and rigidity of bone) of joint
o Systemic complications
o Iatrogenic ® infections from immune suppression

• MHC
o Cell surface proteins
o In humans = HLA (human leukocyte antigen)
o Highly diverse!
§ Immune individuality
§ Mismatch in transplant = rejection
o Cell surface proteins
o Present antigens to lymphocytes
o \ immune response if recognised as non-self
• Defective antigen presentation
o Associated with auto-immunity
§ HLA B27 in ankylosing

• Immune tolerance
o Phenomenon in which the body does not initiate an immune response
upon presentation of a certain antigen

• Immunity ® protection against pathogens

o Innate
o Adaptive

63
• Hypersensitivity ® excessive, pre-sensitized reaction to antigen
o Type 1
§ Mediated by IgE, mast cells, Th2 cells, eosinophils
§ Allergy, asthma, anaphylaxis

o Type 2
§ Local, antibody-mediated
§ Antibody binds to antigen ®
§ Opsonization ® phagocytosis
§ Stimulate/inhibit receptors ® activate complement \
inflammation
§ E.g. Grave’s disease
• Most common cause of hyperthyroidism
• Due to antibodies against TSH receptor
• Stimulates release of TSH
§ E.g. Non-insulin dependent diabetes

o Type 3
§ Systemic, circulating Ag-Ab complexes
§ Cause damage when deposited (vasculitis)
§ Cause blockages in epithelial lining

o Type 4
§ Cell-mediated, delayed ® CD4+ T-cells release cytokines
§ Recruit macrophages + WBCs
§ Prolonged ® granuloma
§ CD8+ T-cell ® cytotoxic death
64
• Auto-immune diseases

65
• Systemic Lupus Erythematosus (SLE)
o Definition
§ Multi-system autoimmune disease characterised by production of a vast array
on antibodies
§ Numerous manifestations
66
 § Smokers
§ Asian/Blacks > Whites
§ 9 females : 1 male

o Pathology
§ Lymphoid follicular hyperplasia + small vessel vasculitis
§ Thrombosis of vessels (anti-phospholipid antibodies)
§ Tissue damage + necrosis
§ Libman-Sacks endocarditis (non-bacterial verrucous endocarditis)
• Small to medium sized vegetations on either or both sides of
valve leaflets
o Diagnosis
§ Biopsy-proven lupus nephritis with ANA or anti-dsDNA
antibodies
§ Or 4 diagnostic criteria, 1 clinical and 1 immunological:
• Discoid rash
• Oral ulcer ® nonerosive, 2+ peripheral joints,
tender/swelling/effusion
• Photosensitivity
• Arthritis
• Malar rash
• Immunological
o antiSm
o anti-dsDNA
o antiphospholipid
67
 • Neurologic ® seizures/psychosis
• Renal ® cellular casts, proteinuria>0.5g/d/3+
• ANA ® non-drug induced
• Serositis ® pleuritic, pericarditis
• Haematological ® haemolytic anaemia, leucopoenia,
lymphonaemia, thrombocytopenia

o Antibodies in SLE
§ Anti-nuclear antigen
§ Antihistone
§ Anti-dsDNA
§ Anti-sm

o Management + prognosis
§ Analgesia
§ Sunscreen
§ Immune suppression

o CASUE OF DEATH
§ Renal failure ® \ renal biopsy + renal function tests to monitor
kidneys
§ Inter-current infections
§ CAD
• Immune complex endothelial damage
• Hyperlipidaemia ® cortisol treatment

68
• Rheumatoid arthritis
o Definition
§ Chronic, multi-system disease characterized by poly-articular erosive synovitis
§ Rheumatoid factor (IgM antibody against Fc portion of IgG) associate with
progression
§ Type IV hypersensitivity reaction, predominant mechanism of injury
§ 3 female : 1 male
§ Smokers
§ Whites > Asians/blacks

o Systemic juvenile idiopathic arthritis/Still’s disease

§ More acute
§ Oligoarticular
§ Rheumatoid factor = -ve.

o Joint pathology
§ Pannus
• Overgrowth of inflamed granular tissue covering articular
surfaces
• Erodes bone ® bone destruction from periphery inwards
§ Hypertrophic villous synovitis with lymphoid follicles
§ Rice bodies ® fibrin with inflammatory cells
§ Articular cartilage loss ® fibrous + bony union = ankylosis

o Systemic manifestations
§ Cardinal symptoms of AI
69
 § Rheumatoid nodule
• Subcut/juxtaarticular (near a joint) ® rarely visceral nodules
• Central fibrinoid necrosis
• Surrounding palisade (close-off) of macrophages + fibrosis
• Rheumatoid factor invariably +ve
§ Vasculitis
§ Nodular scleritis (white outer-coating of the eye)
§ Pulmonary fibrosis
§ Fetty syndrome
§ Caplan syndrome

o Complications
§ Local
• Carpal tunnel syndrome (numbness/tingling in the hand,
caused by pinched median nerve)
• Subluxation ® partial dislocation
§ Systemic
• Anaemia, lung, spleen
• Amyloidosis
• Lymphoma
• Other auto-immune
§ Iatrogenic
• NSAID ® ulcer
• Steroid ® infections, osteoporosis, CAD ® hyperlipidaemia
• Disease modifying anti-rheumatic drugs ® nephritis, hep.

70
 o Management + prognosis
§ Analgesia
§ Night splitting + physiotherapy
§ Immune modulating drugs ® methotrexate

Vertebral (Spinal) Tuberculosis (CI)

• Aetiology
o Caused by ® M. tuberculosis

• Pathogenesis
o Haematogenous dissemination from multiple, small granulomas in lungs
® to spread to spinal column
§ Progressive primary TB
§ Secondary TB
o Gain access to spine via blood, tend to locate towards the epiphysis of
bones/vertebral bodies
o Necrotizing granulomatous infection ensues
o Pott’s disease

• Macroscopic findings
o Narrowing of intervertebral of disk
o Destruction of anterior parts of adjacent vertebrae
o Collapse of vertebral body
o Paravertebral abscesses = misnomer ® not true abscesses, collections
of caseous material (Psoas/cold abscesses)
o Angular deformity (kyphosis)

71
• Microscopic findings
o Granulomatous inflammation ® collections of epithelioid macrophages
o Central, caseous necrosis
o Langhans giant cells may be present
o Fragments ® necrotic bone + cartilage
o AFB on Ziehl-neelsen

• Radiologic Findings
o Narrowing of disk space
o Vertebral collapse ® several may be involved
o Paravertebral shadow
o Apical cavities + fibrosis ® ± lymph node ­ in chest

• Complications
o Spinal cord compression ® paresis (condition of muscle weakness) and
paralysis
o Kyphosis (abnormal curvature of spinal cord) ® cardiorespiratory
compromise, arises from weakening of intercostal muscles
o TB meningitis (very rare)

• Psoas abscesses
o Cold abscess = fluctuant swelling beneath the inguinal ligament,
represents necrotising granulomatous infection (caseous), tracked down
from spine, ÄÄÄ true abscess ® no cardinal signs of AI
o Extends beneath fascia of psoas muscle, to below inguinal ligament
o Present ® pelvic mass/hip pain,
o Release IL-1 + TNF = pyrexia \ night sweats + weight loss
72
CNS Tuberculosis ® TB meningitis
• Aetiology
o M. tuberculosis

• Pathogenesis
o Haematogenous dissemination, results in necrotizing granulomatous
inflammation in Rich’s focus (paraventricular tuberculosis focus) ®
bacilli enter CSF ® TB meningitis

• Macroscopic
o Lesions at base of brain
o Grey-white discolouration of brain, bacterial induced ® pus (yellow or
green)
o Small tubercles
o Turbid cerebro-spinal fluid ® spider web appearance

• Microscopic
o Lymphocytes, granulomas, caseous necrosis, fibrin
o Obliterate vessels (endarteritis obliterans)

• Complications
o Hydrocephalus (build-up of cerebro-spinal fluid in the brain)
§ From obstruction of 4th ventricle
§ Cranial = non-expansionary structure \ deadly
o Cerebral infarct owing to occlusion of blood vessels

73
 o Tuberculosis encephalitis
§ Multiple small nodules/ single large tuberculoma in parenchyma of
brain
§ Haematogenous spread
§ Mass lesions
§ Raised intracranial pressure ® brain to move
§ Complications
• Seizures ® abnormal firing of CNS nerves
• Space occupying lesion + brain herniation

Syphilis
• Aetiology
o Bacterial infection ® Treponema pallidum (Spirochaete)

• Pathogenesis
o Sexually transmitted
o Transplacental spread
o Main cell of infection ® plasma cells
o Often characteristic fibrosis
o Warthin-Starry stain ® identify bacteria in syphilis
o 3 phases of syphilis:

74
o Primary syphilis
§ Any area of sexual contact ® vagina, penis, anus, mouth
§ 3 weeks after infection
§ Main features
• Chancre ® PAINLESS ulcers
• Regional lymphadenopathy (swollen lymph nodes)
• Spirochaetemia ® present in blood

o Secondary syphilis
§ Condylomata lata ® moist, large, smooth warts ® perianal,
vaginal, penile
§ Alopecia ® patchy hair loss
§ Snail tract ulcers in mouth
§ Lymphadenopathy + maculopapular rash (flat, red are on skin)

o Tertiary
§ Cardiovascular syphilis
• Aortitis = Occlusion of vaso vasorum (supply outer 2/3 of
aorta) ® loss of elastin ® fibrosis ® tree bark appearance
(death of peripheral tissue)
• Aortic arch aneurysms ® loss of elasticity of proximal
aortal wall (characteristic to syphilis)
• Aortic regurgitation (excessive blood volume)
• Left ventricular hypertrophy and globular dilatation
o Cor bovinum (Cow’s heart)
• Coronary artery stenosis (narrowing of vessels resulting
from local fibrosis) ® ischaemia + infarction
75
 § Neurosyphilis
• Tabes dorsalis ® tertiary syphilis
o Degeneration of posterior columns of spinal cord
• Meningovascular (meninges = membranes that line skull +
vertebral canal) syphilis
o Meningeal and parenchymal arteritis with occlusion
o ® secondary area of infarction
o Meningeal fibrosis ® block CSF ® hydrocephalus
• General paresis
o Grey matter degeneration ® dementia + paresis

§ Gumma
• Liver, testis and bone
• Firm, rubbery masses
o Granuloma with central coagulative necrosis!

• Congenital syphilis
o Large, pale placenta ® > 50% of foetus’ weight
o Hydrops fetalis (abnormal accumulation of fluid in 2 or more foetal
compartments) ® cardiac failure
o Fibrosis ® lungs, pancreas, liver, spleen
o Osteochondritis ® rat bitten metaphysis, jagged, rough “bite-outs”
§ Syphilis= propensity towards head and necrosis

76
Amyloidosis and Sarcoidosis
• Amyloidosis
o Excessive accumulation of inert, amorphous, eosinophilic material
o Composed of b-pleated sheets of misfolded fibrillary proteins

o Pathogenesis
§ Production abnormal proteins ® misfold ® soluble ® deposition
in tissue

o Classification
§ Systemic (generalised)
• Primary amyloidosis (AL) ® myeloma (cancer of plasma
cells) + other monoclonal B cell proliferations
• Secondary amyloidosis (AA) ® chronic inflammatory
conditions (TB, autoimmune etc.)
• Haemodialysis associated
§ Localized
• Alzheimer
• Type 2 diabetes mellitus
§ Hereditary
• Familial Mediterranean fever
• Familial amyloidotic neuropathies
• Senile amyloidosis

77
 o Morphology
§ Macroscopic
• Waxy + enlarged organ
§ Microscopic
• Amorphous eosinophilic deposit between atrophic cells
• Congo red stain
o Salmon pink colour
o Green birefringence (refraction of light) on light
polarisation

o Complications
§ Restrictive cardiomyopathy
§ Arrhythmia
§ Nephrotic syndrome
§ Carpal tunnel syndrome
§ Diarrhoea

• Sarcoidosis
o Non-caseating granulomatous inflammatory disease
o Idiopathic (Ä autoimmune) + multi-system
o Manifestations
§ Lungs
• 90% of cases = peribronchial + lymphagitic granulomas
• Hilar LN ® interstitial fibrosis
§ Skin ® erythema nodosum (painful lumps under skin) + lupus
pernio (growth of inflammatory cells, all over body)
§ Eye, lacrimal gland, parotid, heart
78
 o Pathological findings
§ ‘Naked’ granulomas
§ Schaumann bodies ® laminated calcifications (protein + calcium
inclusion with Langhans giant cells)
§ Asteroid bodies (stellate (radiating pattern like star) inclusion in
giant cells)

Wound Healing + Repair

• “Healing” ® refers to the reformation of structure
• 2 methods:
o Regeneration
o Repair
• Ability of tissues to heal/repair themselves, determined, in part by intrinsic
proliferative capacity
• Based on this, 3 groups of cells:
o Permanent cells
§ Neurones, skeletal + cardiac muscle
§ Cannot regenerate \ repair via organisation
§ ® Gliosis (proliferation of glial cells which are supportive cells of
the CNS Microglia are phagocytic and astrocytes provide
framework analogous to fibrous tissue, CNS scars) or Scarring
(fibrosis)
o Stable cells
§ Most parenchymal ® liver, pancreas, kidney
§ Regenerate under stimulus
§ CT framework intact ® regeneration
§ CT framework not intact ® repair or organisation
79
 o Labile cells
§ All mucosal surfaces, skin, bone marrow
§ Continuously dividing + regenerating
§ \ Good capacity to regenerate ® healing via regeneration

• Regeneration
o Definition ® replacement of damaged cells by cells of the same type
o Conditions
§ Only labile + stable cells
§ CT framework must be intact

• Repair/Organisation
o Definition ® repair by the formation of fibrous tissue (fibrosis)
o Conditions
§ Permanent cell damage
§ Labile with Ä CT framework intact
o Occurs via ® granulation tissue formation
§ Angiogenesis
§ Fibroblastic proliferation

• Types of injury
o Trauma
o Ischaemia
o Toxins
o Physical agents

80
• Wound Healing

o Inflammatory phase
§ Injury ® platelet adhesion ® clot formation ® inflammation
§ Migration/proliferation of CT cells + angiogenesis ® granulation
tissue formation ® Re-epithelialization of wound surface
§ Extracellular matrix deposition ® tissue remodelling ® wound
contraction

• Growth Factors in Wound Healing

• Contact adhesion molecules ® integrins

o Laminin ® cells to basement membrane
o Fibronectin ® cells to collagen

81
• Examples of Wound Healing

o Skin
§ Primary Union
• Occurs ® edges of cleanly incised wounds are kept together
(sutures)
• Ä Occur if
o Poor approximation
o Haematoma/blood clot in wound
o Sepsis

• Process
o Immediately
§ Haemorrhage ® blood + fibrin cleft in wound
o 1-3 Hours
§ Mild acute inflammation at edges
§ Migration of epithelial cells begin beneath surface
of blood clot
o 2-3 Days
§ Macrophages remove blood clot
§ Epithelial covering continuous but thin
§ Granulation tissue + fibroblast activity
§ Wound contraction ® myofibroblasts
o 10-14 days
§ Epithelial covering complete
§ Scab loosens
§ Weak fibrous union present

82
 o Late
§ Strengthening of fibrous union
§ Devascularisation
§ Remodelling of collagen

• How long for skin to achieve maximum strength?

o Wound strength at end of first week ® 10% of normal
o Wound strength after 12 weeks ® 70-80% of normal

§ Secondary union
• Occurs in open wound when:
o Loss of tissue/large defect
o Skin edges kept apart
o Infection/sepsis

• Process:
o Immediately
§ Cavity fills with blood
o 1-3 hours
§ AI ® adjacent active tissue
o 2-3 days
§ Epithelial growth at edges, down in crater
§ New capillary loops in base of wound
§ Macrophages remove clot, necrotic tissue, debris
§ Wound contraction

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 o 10-14 days
§ Granulation tissue + fibrosis in base
§ Surface debris cleared
o Late
§ Full thickness epithelium restored
§ Collagenous scar in dermis

• Factors that Impair Wound Healing

o Systemic
§ Age ® immune senescence
§ Nutrition ® Vit C deficiency, protein
§ Metabolic status ® Diabetes Mellitus
§ Hormones ® glucocorticoids
§ Renal failure
§ Smoking

o Local
§ Circulatory status ® arteriosclerosis
§ Infection ® persistent injury
§ Mechanical factors ® early mobilization, poor apposition
§ Foreign bodies ® suture material, steel, glass, bone
§ Presence of tumour
§ Previous scarring

84
 o Complications in Skin Healing
§ Contractures
§ Pyogenic granuloma ® ‘proud flesh’, unchecked granulation of
tissue
§ Keloid formation ® excessive collagen deposition
§ Infections ® wound sepsis
§ Wound dehiscence ® wound rupture
§ Malignant change ® Marjolin’s ulcer (aggressive, ulcerating
squamous carcinoma)

Bone Injury
• Aetiological Classification of Bone Fractures
o Traumatic fractures
§ Sudden exposure to intolerable amounts of energy
o Stress fractures
§ Repetitive mechanical force on a bone ® accumulation results in
breakages
o Pathological fractures
§ Causes
• Local bone disease
o Infection ® chronic osteomyelitis, resulting in the
weakening of the bone
o Benign neoplasms ® giant cell tumour
o Malignant neoplasm ® metastatic lung carcinoma
o Mechanical ® bone atrophy in paralysis

85
 • General skeletal disease
o Congenital ® Osteogenesis imperfecta
o Metabolic ® Senile osteoporosis
o Disseminated neoplasia ® multiple myeloma (cancer
of plasma cells)
o Mechanical ® Paget disease (increased bone
deposition, bone produced = brittle + weak)

• Open/Closed Fractures
o Closed/simple fracture
§ No communication between fractured bone and skin
o Open/compound fracture
§ Wound leading down to the sight of fracture
§ \ Communication between bone + skin

• Fracture patterns
o Transverse fracture
o Oblique fracture
o Butterfly fracture
o Spiral fracture
o Comminuted fracture
o Segmental fracture

86
o Children
§ Greenstick fractures
• Force applied to one side of long bone
• Opposite site cracks, side closest to force remain intact
§ Growth plate fractures
• Type 1
o Fracture through epiphysis only
• Type 2
o Fracture travels through physis (growth plate)
o Part of metaphysis involved
o Most common
• Type 3
o Fracture across part of physis
o Part of metaphysis involved
o Common in older children
• Type 4
o Break through metaphysis + physis at end of bone
• Type 5
o Crushing injury to physis
o Owing to compression force
o Rare

87
• Stages of Fracture Healing
o Week 0 ® haematoma + bone necrosis
§ Bleeding around fractures, normally contained by periosteum

o Week 1 ® Stage of inflammation

§ Macrophages digest haematoma via phagocytosis
§ Osteoclasts become active
§ Formation of granulation tissue
§ Proliferation of subperiosteal osteoblasts

o Week 2-4 ® Provisional/Soft callus formation

§ Osteoid (precursor to bone matrix) + cartilage laid down at the
end of the fractured bone
§ Mineralisation ® calcium deposited in bone
§ Woven bone (disorganised deposition of bone) laid down in callus
(temporary bone, weaker than normal)

o Weeks 5-12 ® Definitive callus formation

§ Cartilage + woven bone removed
§ Lamellar (parallel rows of bone) bone deposited, much stronger
then woven bone
§ May remove cast, maintains structural integrity

o Months ® Remodelling to stress

§ Definitive callus is strong, yet incorrect shape owing to bulging
§ Normal stress on bone + muscle ® callus to take on normal
shape of bone
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• Complications of Fracture Healing
o Osteitis ® inflammation of cortical bone
o Osteomyelitis ® inflammation of bone = bone marrow
o Related to Fracture Itself
§ Associated Injury ® bone pushing into adjacent structures
• Major Blood Vessels
• Nerves
• Viscera
• Tendons
• Joints
• Fat embolism ® fat cells within bone marrow ® squeezed
into damaged vessels ® to lungs
§ Infection ® much longer to heal
• Compound fractures
• Surgical intervention
• Chronic osteomyelitis ® infection of the bone
o Sinus discharging pus
• Retards union

o Delayed union
§ Bone fragments still freely mobile ® 3 months after fracture, takes
longer to unite
§ Causes
• Poor blood supply ® damaged, vascular disease
• Infection
• Malalignment ® incorrect alignment
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 • Site devoid or periosteum
• Pathological fracture
o Non-union
§ Radiological changes of aborted healing process
• False joint ® pseudo appearance of joint on X-rays
§ Causes
• Same as delayed union
• Interposition of soft tissue

o Fibrous union
§ Weakened, fibrous connections between bones
§ Causes
• Failure of immobilisation

o Mal-union
§ Union in an abnormal position
§ Shortening ® bone shorter vs. original
• Causes
o Mal-union with overlap, angulation
o Crushing or loss of bone
o Interference with growth plate of children
o Avascular necrosis
§ Fracture interrupts blood supply to articular end of bone ®
devoid of vascular soft tissue
§ Bone dies ® osteoarthritis
§ Common sites
• Head of femur
90
Pathological Calcification
• Dystrophic calcification
o Deposition of calcium in dead or degenerate tissue
o Serum calcium + phosphate levels normal
o Deposition = usually localized

o Sites
§ Caseous necrosis
§ Dead parasite
§ Fat necrosis
§ Infarcts
§ Thrombi
§ Scar tissue ® valves in chronic rheumatic heart disease
§ Atherosclerotic vessels
§ Degenerate/necrotic tumours

• Metastatic calcification
o Deposition of calcium in otherwise normal tissue
o Serum hypercalcaemia + hypophosphatemia present
o Deposition ® widespread

o Causes
§ Primary, secondary, tertiary hyperthyroidism
§ Vitamin D intoxication
§ Disseminated bone disease
§ Sarcoidosis

91
 o Sites
§ Visceral tissue
§ Vascular tissue
§ Soft tissue

Classification and Treatment of Burns

• Classification ® correlate with depth of skin + likelihood of repair
o First degree
§ Present in epidermis
§ Germinal layer affected, but focally
§ \ Skin will repair
o Second degree
§ Superficial
• Into upper portion of dermis (Papillary)
• Little circlets of adnexal structures (hair + sweat glands)
remain viable
• Fairly rapid regeneration of epidermal surface
§ Deep
• Into lower portion of dermis (Reticular)
o Several adnexal structures are destroyed, some remain
o Time + wound care = regeneration
o Third degree
§ Into hypodermis, level of pain receptors
§ Painless
§ Below deepest portions of adnexal structures \ no regeneration

92
• Treatment
o Aim
§ Achieve epithelial regeneration
§ Shortest time possible
§ Least possible scarring

o Historically
§ Thought that granulation tissue maximal after 10 days
§ \ Best time for graft (maximal O2 + nutrients)
§ \ Wound closed + kept clean ® 10 days

§ But!
• Sepsis of wound would occur, resulting in tissue damage + ­
likelihood of systemic + specific infections by S. pyogenes
• \ Granulation tissue capillaries = Ä support for proper
capillary bed
• \ Graft did not take:
o Albumin dropped, needed for repair
o Fibrosis was increased ® more scarring

o Modern Treatment
§ Graft second degree + deeper as soon as possible
§ \ Patient must be stabilized
§ Graft bed adequate enough to support graft, despite granulation Ä
being maximal

93
 § Losses
• Fluid ® hypovolemic shock
• Albumin
• \ must replace

§ Given colloids/crystalloids depending on:

• Surface area of burn
• Age of patient (Palm = 1% of SA in adults, Rule of 7’s ®
kids)

o Split skin grafts

§ Very thin layer of skin, comprising of superficial part of epidermis
+ as little dermis as possible, is taken
§ Means:
• Graft origin can repair quickly
• Graft is thin \ less O2 + energy requirements
§ Graft = small holes + compressed into burn site
§ Burn site = rubbed up until bleeding, crust is removed
§ Then sutured into place

o Optimization of grafts
§ Patient must be in optimum condition
• Hb must be adequate, if not ® give blood
• Albumin must be adequate (healing and repair)

§ Patient must be over initial shock

• Must be stable before undergoing anaesthesia
94
 § Graft site must be non-infected
• NB! ® S. pyogenes = absolute contraindication to grafting
• All wounds over joint must be grafted (danger of fibrosis ®
contractures)
• General principles of healing + repair ® must be followed
o Graft Ä move
o Wound must be clean
o Adequate diet!

Congestion and Oedema

• Congestion
o Definition
§ ­ Content of blood to an organ or tissue, active or passive:
• Active
o Arteriolar dilation + recruitment of
inactive/latent capillaries
o Hyperaemia in area of AI
o Hyperaemia in response to increased metabolic
activity of cell
• Passive
o Owing to venous obstruction
o Heart
§ Congestive heart failure

95
 o Lung
§ Chronic LV failure ® ­ alveolar capillary
failure ® rupture + blood in alveolar ®
iron laden alveolar macrophages
§ Brown induration ® hemosiderin
pigmentation + fibrosis in lungs from
chronic passive congestion of lungs
o Liver
§ Budd-Chiari syndrome (hepatic vein
thrombosis ® ¯ hepatic venous drainage
® centrolobular congestion ‘nutmeg liver”
• Oedema
o Excess of interstitial fluid ® applies to all sites except brain
o Brain
§ Excess fluid within the brain (extracellular or interstitial
spaces)
§ Anomaly present ® advent of radiological techniques,
allow accumulation in interstitial or intracellular
compartments to be shown
o Anasarca ® severe generalized oedema, frequently with
effusions into serous cavities
§ Ascites ® accumulation of fluid in peritoneal cavity
§ Pleural effusion ® accumulation of fluid in pleural cavity

96
 § Pericardial effusion ® accumulation of fluid in pericardial
cavity

• Types of capillaries
o Same general structure in all sites, except brain
§ Continuous
§ Fenestrated
§ Sinusoidal/discontinued

• Determinants of Intercompartmental Movement

o Starling’s Parameters
§ Hydrostatic pressure
• Capillary vessel
• Interstitial space
§ Osmotic pressure
• Capillary vessel
• Interstitial space
§ Endothelial permeability
§ Lymphatic drainage

97
• Type of oedema fluid
o Exudate
§ Specific gravity ® >1,020 (protein >3g/dl)
§ Contains inflammatory cells
§ Associated with ® increased vascular permeability
o Transudate
§ SG < 1,020
§ Associated ® imbalance of equilibrating fluid
o Chyolus
§ Lymphatic fluid ® contain chylomicrons + is fatty on
inspection
§ Rupture of thoracic duct in surgery + tumour

98
• Classification of oedema
o Localised ® to leg/arm etc.
§ Increased hydrostatic pressure of blood
• Venous thrombosis
• Pressure on veins from outside
• Cirrhosis (normal liver cells replaced by scar tissue) of
liver + portal hypertension
§ Increased vascular permeability
• Any cause ® AI
§ Abnormality in lymphatics
• Congenital absence of lymphatics (Milroy’s disease)
• Obstruction of lymphatics
• Carcinoma
• Irradiation ® fibrous scarring of lymphatics
• Surgical removal of lymphatics ® dissection of lymph
nodes
• Filarial worms ® elephantitis
o Generalised
§ Increased hydrostatic pressure
• Cardiac failure
§ Decreased osmotic pressure
• Loss of protein in urine
• Reduced synthesis of protein in liver ® cirrhosis

99
 • Inadequate intake/absorption
§ Na+ and water retention
• May be primary cause of oedema
• Diminished renal perfusion + glomerular filtration ®
salt retention, may be caused by primary disorders of
the kidney + other that = decreased renal perfusion
o Glomerulonephritis
o Nephrotic syndrome
o Renal failure
o Cardiac failure
o Cushing’s syndrome ® excess ACTH/cortisone
produced/administered
• Activation of renin-angiotensin-aldosterone axis
• ­ salt retention + obligate associated water
• ® increased hydrostatic pressure + diminished
vascular colloid osmotic pressure
§ Increased vascular permeability
• Systemic hypoxia + prolonged ischaemia
• Bactericidal toxins
• Sepsis
• Generalised fluid movement ® interstitium

100
• Organ failure causing generalised oedema
o Cardiac failure (“pump failure”)
§ Types
• LV failure
• RV failure
• Biventricular failure
• Backward failure ® increased backward venous
pressure ® oedema
• Forward failure ® inadequate output
§ Mechanisms of oedema formation
• Renin-angiotensin-aldosterone mechanism
• Atrial natriuretic factor depletion (from atrial walls)
• ­ Venous pressure
§ Pathology of RV failure
• Liver
o Hepatomegaly ® swelling of liver beyond
normal size
o Nutmeg congestion
o Centrolobular necrosis ® fibrosis of prolonged
(Ä cirrhosis)
• Spleen
o Splenomegaly
o Fibrosis of sinusoidal walls

101
 • Kidneys
o Congestion
o Altered blood flow ® shunting to glomerular
glomeruli ® Na+ retention
• Dependant areas (maximally affected by gravity)
o Ankle/sacral pitting oedema
• Peritoneum
o Ascites
• Brain
o Congestion/hypoxia
§ Pathology of LV failure
• Lung
o Chronic passive venous congestion
o Pulmonary oedema
o Pleural effusions
• Systemic organs
o Hypo-perfusion
o Shock, infracts etc.

102
• Liver ® usually due to cirrhosis
o Mechanisms of oedema formation
§ Fibrous scarring ® obstruction of portal flow
§ Impaired albumin synthesis
§ Decreased renin degradation in liver
§ Renin-angiotensin-aldosterone mechanism
o Pathology
§ Ascites + pleural effusions
§ Dependant areas ® pitting oedema
§ Spleen ® as for RV failure

• Kidney ® nephrotic syndrome

o Mechanisms of oedema formation
§ ­ Protein loss in urine ® decreased colloid osmotic
pressure
§ Renin-angiotensin-aldosterone mechanism
§ Superimposed renal vein thrombosis
o Pathology
§ Periorbital oedema (accumulation in eyelid + areas around
eye)
§ Ascites + pleural effusions
§ Dependant area ® pitting oedema
o Acute renal failure ® glomerulonephritis
§ Mechanisms of oedema formation
103
 • No renal perfusion
• ® No Na+/H2O lost in urine

• Fluid accumulation in body cavities

o Localised processes ® exudates
§ Peritonitis/pleuritis/pericarditis
• Pyogenic bacteria
• TB
• Response ® underlying infarct
§ Tumour
§ Trauma
o Generalised oedema ® transudates
o Cerebral oedema
§ Cerebral capillary vessels
• No fenestrate
• Thick basal lamina
• Unique enzyme structures
• Tight junctions ® complete ring
§ Blood-brain barrier ® intercellular fluid accumulation =
differs

104
• Classification
o Cytotoxic oedema
§ Hypoxia in brain + endothelial cells ® Na+ + H2O move
into:
• Endothelial cells
• Neurones + glial cells ® intracellular oedema (­­­ in
cortex)
§ Blood-brain barrier intact \ no ring enhancement on CT
o Vasogenic oedema
§ Frank infarction of brain ® vascular disease
• Atheroma ® degeneration of walls of arteries owing
to accumulation of fatty deposits + scar tissue
• Embolus
• Hypotension
• Abscess
§ Blood-brain barrier breeched ® \ ring enhancement on
CT
§ Fluid = extracellular, maximal in white matter
o Hydrocephalic oedema
§ Obstruction to CSF flow
§ Fluid accumulates ® adjacent to ventricles in extracellular
place
§ Blood-brain intact

105
o Other
§ Poisoning
§ Congestive
§ Hypo-osmolar

106
Thrombosis + Embolism: Introduction
• Definitions
o Thrombosis
§ Formation of a solid/semi-solid mass from constituents of circulating
blood
o Thrombus
§ The mass so formed
o Clot
§ Formation of a solid mass in blood which is not circulating ® test
tube/after death

• Evolution of a thrombus
o Primary platelet thrombus (porous platelet plug)
§ Collection of platelets ® adhere to vessel wall
§ Relative stasis induced ® accumulation of clotting factors
o Corraline thrombus (haemostatic plug)
§ Superadded (add to something that has already been
added) ® coagulation + further platelet deposition
§ Cycle of alternating fibrin + platelet deposition
§ Aggregations of platelets alternating with fibrin +
enmeshed blood cells
§ Lines of Zahn ® parallel arrays of alternating fibrin +
platelets = macroscopically identifiable, fibrin = contractile
\ surface rippling
107
 o Occlusive thrombus
§ Further slowing of blood from enlarging luminal thrombus
§ ® extension of thrombus results in occlusion of vessel
lumen
o Propagation of thrombus
§ Blood flow ceases ® red, friable clot is formed in
continuity with thrombus
§ Clot consist of:
• Monomorphous aggregations of platelets
• Fibrin
• Enmeshed blood cells
§ Trails for some distance ® free-floating tail

• Macroscopic appearance of thrombus

o Adherent to wall
o Pale, friable + dry (platelet component)
o Lines of Zahn ® surface papillation + parallel linear streaks
• Microscopic appearance
o Line of Zahn
o Platelets
o Fibrin + enmeshed cells

108
• Thrombus vs. Clot
o Thrombus distinguishable:
§ Firmer, drier consistency
§ Paler colour
§ Greater tendency to adherence
o Clots show:
§ Even plum red colour
§ Postmortem clots ® surface of yellow ‘chicken fat’ owing
to lower sedimentation of white cells vs. red, prior to
formation)

• Classification of thrombi
o Venous thrombosis
o Arterial thrombosis
o Cardiac thrombosis

• Factors predisposing to thrombosis

o Changes resulting ® thrombosis, occur in:
§ Vessel wall
§ Blood flow
§ Constituents of blood

109
o Vessel wall
§ Venous
• Inflammation
o Thrombophlebitis (inflammation of vein, caused
by blood clot)® inflammation results in
thrombosis
• Mechanical damage
o IV lines, CVP lines, fracture of long bones
• Chemical damage
o IV fluids, sclerosants (used to treat varicose
veins, induce thrombus formation)
• Bacterial damage
o Extension of infective process to wall of vessel
§ Arterial
• Atherosclerosis
• Mechanical damage
o Surgery
o Intra-arterial catheters
• Chemical damage
o IV pentothal ® intra-arterially error
o IV drug abuse
• Bacterial damage
o Extension of infection into arterial wall

110
 • Autoimmune vasculitis
o Polyarthritis nodosa

§ Cardiac
• Infarctive damage ® post-myocardial infarction
• Mechanical damage
o Post-surgery
• Bacterial damage
o Direct
§ Bacterial endocarditis (valve cusps)
§ Incites florid inflammatory reaction
o Indirect
§ Rheumatic fever
§ Sterile, no organisms on valves
§ Thought to be causes by cross-reaction
between bacterial antigens + tissue proteins

o Blood-flow changes
§ Venous
• Direct pressure ® plaster of paris, splints, occlusive
bandages
• Lack of muscle pump ® bedrest
• Poor general circulation

111
§ Arterial
• Atherosclerosis plaques
• Aneurysms (localized, blood-filled balloon) ®
dilation of walls of vessel, slower flow in distended
portion
• Spasm ® aggregation of platelets ® formation of TX
A2 = powerful vasoconstrictor
§ Cardiac
• Conduction defects
o Atrial fibrillation ® no regular ejection of blood
from atrial chambers (mitral stenosis
complicating rheumatic fever + thyrotoxicosis)
• Contraction defects
o Ventricular aneurysms ® post myocardial
infarction (lost muscle replaced by fibrous =
non-contractile
o Dilated cardiomyopathy
§ Primary myocardial disease ® weakening
of muscular contraction ® dilated flabby
heart \ poor blood ejection
o Prosthetic valves
§ Relative stasis around struts of artificial
valves

112
o Blood-constituent changes
§ Increased viscosity
• Dehydration ® fluid loss owing to
vomiting/diarrhoea
• Polycythaemia (­­­ RBC)
o Primary ® Polycythaemia rubra vera
o Secondary ® cyanotic congenital heart disease
+ chronic bronchitis
• ­ plasma proteins ® multiple myeloma
§ Hypercoagulable states
• ­ Platelets ® leukaemia, post-splenectomy
• ­ Hepatic synthesis of clotting factors
• ­ Steroids ® oral contraceptives, pregnancy, anabolic
steroids
• ­ Nephratic syndrome ® excessive loss of protein,
causing ­ hepatic synthesis ® excessive production
of clotting factor in liver
• Coagulative activation
o Malignancies ® pancreatic carcinoma,
promeylotic leukaemia
• Shock

113
• Effects of thrombi
o Local
§ Venous
• Stagnation of blood flow \ congestion + oedema
• Complete cessation of flow from organ ® arterial
perfusion ceases
§ Arterial
• Complete arterial occlusion: ischaemia ® infarction
o Distant
§ Thrombus may detach, form embolism

• Important sites of thrombi

o Deep veins ® commonest
§ Clinical presentation
• At risk ® poor circulation
• Often silent
• Homan’s sign
• Oedema + congestion
§ Sites
• Deep veins in calves
• Ileofemoral veins
• Pelvic veins ® esp. after surgery

114
o Superficial veins
§ Clinical presentation ® cord-like painful swelling
§ Sites
• Superficial veins of limb + chest
o Renal veins
§ Seen in patients ® nephrotic syndrome, owing to:
• ¯ Blood flow in renal vein (protein loss in urine)
• ­ synthesis of hepatic proteins ® coagulation factors
o Intracranial veins
§ Superior sagittal sinus thrombosis ® severe dehydration +
sever cyanotic congenital heart disease
§ Cavernous sinus thrombosis ® thrombophlebitis of veins
in face with distal propagation of clot ® cavernous sinus
o Portal mesenteric veins
§ Portal hypertension ® blood flow ¯¯
§ Veins in portal system ® origin of small septic emboli to
liver
§ Mesenteric thrombosis ® sever intestinal ischaemia
o Hepatic veins
§ Budd-Chari syndrome ® outflow of venous blood from
liver compromised ® hepatomegaly

115
• Fate of Thrombi
o Resolution
§ Fibrin component = capability to contract \ decrease
thrombosis volume, re-establish blood flow to area
§ Lysis of components
• Platelets undergo autolysis
• Breakdown of fibrin
• Binding plasminogen (circulating pro-enzyme) +
plasminogen activator to fibrin
• Production of plasmin, if in excess ® inactivated by
a2-antiplasmin
• Plasmin degradation of fibrin ® fibrin degradation
products
o Organisation
§ Endothelial cells, fibroblasts + smooth muscle ® grow
into thrombus = granulation tissue. Depending where,
Results:
• Re-canalization
o Capillary vessels coalesce + allow partial
restoration of flow
• OR Re-endothelialisation
o Endothelial cells grow over surface of thrombus,
incorporating thrombus into vein walls,
thrombus ® fibrous plaque
116
 o Detachment
§ Portions of thrombus/propagated clot break off ®
embolus!!!!!

Embolism
• Definition
o Impaction in part of the vascular tree by any undissolved material carried
there by the blood stream

• Classification
o Origin of embolic material
§ Sources of venous embolic material
• Infected venous catheter
• Injections ® air, foreign material
• Tumour emboli ® renal cancer carcinoma
• Amniotic fluid embolism
• Thrombophlebitis thrombosis
• Fracture with fat embolism
§ Sources of arterial thrombi
• Atheroma ® Carotid artery
• Mural thrombosis ® left atrium/left ventricle/aortic
aneurysm ® atrial fibrillation
• Mitral/aortic endocarditis

117
o Type of material embolized
§ Thrombus ® thromboembolus
• Venous thromboemboli
o Usually originate in calf/leg/pelvic veins
o Mobilize + impact in pulmonary arteries
o Access of thrombi ® systemic circulation Ä
occur (filtration of pulmonary capillary bed)
o Unless! ® septal heart defect present
(paradoxical embolism)
o Effects
§ Sudden death
• Occlusion of major pulmonary artery
(bifurcation (division into two parts) =
saddle embolism)
• Acute, severe systemic anoxia
• Acute RV failure
§ Pulmonary infarction
• Small vessel affected \ acute death Ä
occur
• Lung = dual blood supply (pulmonary
+ systemic circulation\ infarct =
haemorrhagic

118
 § Pulmonary hypertension
• Multiple small embolisms obliterate
large proportion of capillary bed ®
pressure in pulmonary trunk + RV
­­­
• Arterial = cardiac thromboemboli
o Main sites of OG thrombus:
§ Atheromatous lesions in aorta + major
branches
§ Vegetations on valve cusps
§ Mural thrombus in LV
§ Atrial thrombus
o Effects
§ Infarction ® release into systemic
circulation = infarcts of ­ organs (brain,
spleen, kidney)
§ Gangrene
• Occlusion of arterial supply to limb

119
§ Fat
• Impaction of fat globules ® small arteries +
capillaries
• Trauma to tissue ­ fat ® mechanically release
globules into systemic venous circulation, caused:
o Fracture of long bone
o Operative manipulation of fractures
o Trauma to fatty tissue ® fatty liver
• Effects
o Pulmonary fat embolism
§ Globules filtered in pulmonary capillary bed
§ Patient = dyspnoeic (poor O2 in lungs)
§ ® ­ in pulmonary capillary pressure ®
rupture ® occluding fat into alveolar \
coughed up
§ Sputum = haemorrhagic + fatty layer on
surface
§ Pressure ® distort fat, force into venous
drainage
§ Access to systemic achieved!
o Systemic fat embolism
§ Impacted molecules ® haemorrhagic
infarcts in brain (confusion), skin +
mucous membranes
120
§ Gas
• Air
o 100-200ml enter circulation ® foamy cushion in
RV = prevent outflow
o Owing to:
§ Mismanaged venous infusions
§ Stabs/operations to large veins of
neck/cerebral tissues (negative pressure vs.
RV draws air in)
§ Insufflation (blow) of fallopian tubes with
CO2 to test pregnancy
§ Tension
pneumothorax/pneumoperitoneum
• Nitrogen (Caisson disease/compression sickness)
o High external pressure ® nitrogen dissolves into
tissues (esp. high fat)
o Pressure ¯, gas reforms, rid through lungs
o Too quick ® accumulation in tissues +
circulation
o Owing to:
§ Divers returning to surface rapidly
§ Rapid decompression ® jets

121
 o Effects
§ CNS ® confusion, come, hallucinations
§ Joints + ends of long bones ® necrosis +
osteoarthritis
§ Lungs ® dyspnoea, coughing, hypoxia
§ Vestibular apparatus ® disturbed balance

§ Tumour
• Malignant growths ® grow into vessels \ metastasis
• Some, a large plug of intravascular tumour breaks off
• ® vascular occlusion + ischaemia
• Examples
o Renal cell carcinoma
o Hepatoma
o Wilms tumour in children

§ Bacteria
• Clusters of bacteria OG from infective
endocarditis/abscess (appendiceal mass) may cause:
o Pyaemic abscesses
o Mycotic aneurysm ® occluded vessel wall =
weekend by inflammation ® dilation

122
§ Atheroma
• Rupture of thin fibrous cap, covering atheromatous
deposit ® release granular lipid debris
• ® distal part of artery
• Common cause ® focal myocardial necrosis in
coronary vessel

§ Amniotic fluid
• Escape amniotic fluid ® placental bed ® maternal
circulation during labour, esp. obstructed
• May cause
o Acute respiratory distress
o Fatal shock
o Disseminated intravascular coagulation
• Owing to action of thromboplastin in fluid or
afibrinogenaemia (inherited blood disorder) owing to
activation of plasmin

§ Foreign body
• Catheters in intravenous infusions ® heart
• Talcum powder (IV abusers) ® lungs
• Bullets

123
Ischaemia
• Definition
o Impaired blood supply to an organ resulting in hypoxic damage:
o Ischaemia ® impaired oxygen delivery ® failed energy production ®
functional changes ® morphological changes
o To susceptible cells

• Functional changes
o Lack of oxygen ® cessation of mitochondrial oxidative
phosphorylation ® depletion of creatine phosphate + ATP
o Anaerobic glycolysis commences
o Stores of glycogen + glucose depleted ® cannot be replenished
owing to interrupted blood supply
o Anaerobic glycolysis ceases ® inhibited owing to ¯ levels of
ATP
o Na+/K+ pumps fail ® Na+ ions meter cell ® water enters

• Morphological changes
o Mitochondrial swelling
§ Formation of mitochondrial permeability transition pore
124
 § Mitochondria swell + lipid protein complexes flocculate
within
§ Seen on EM within 40-60 minutes, heralds irreversible
damage
o Intracellular oedema (failure of Na+/K+ pump)
§ Water enters cell, cytoplasm becomes pale + swollen
o Cell necrosis ® death of cells in living organisms
§ Total depletion of ATP ® failure of ATP pump
§ Leakage of proteins + enzymes from cells
§ Denaturation of cellular proteins
§ Failure of protein synthesis + altered membrane structure
§ Activation + release of lysosomes
§ Auto digestion of cells
§ Cytoplasm = homogenous + eosinophilic
(hypereosinophilia)
§ Nucleus ® Pyknosis, Karyorrhexis, Karyolysis
§ Cell detail lost, only debris remain

§ Ischaemic necrosis ® limited to scattered individual cells,

either no residual effect or atrophy of areas or reactive
changes leading to fibrosis + scarring
o Inflammatory response
§ Stimulated by necrotic debris
§ Inflammatory cells ® infiltrate edges of ischaemic area
125
• Types of ischaemia
o Generalised, temporary
§ Owing to shock, myocardial arrest, fibrillation
§ Felt in organs susceptible to ¯ oxygen tension ® heart and
brain

o Local chronic
§ Cardiac
• Cause
o Incomplete occlusion of coronary arteries owing
to atheroma
o Spasm of vessels
o Arteritis
• Clinical effects ® angina pectoris
• Macroscopy ® smaller, involuted organ
• Microscopy ® loss of myocytes, replaced by fibrous
tissue

§ Limb ischaemia
• Causes
o Atheroma (degeneration of vessel walls owing to
accumulated fatty deposits)
o Burger’s disease
126
 • Clinical effects ® intermittent claudication (pain,
during exercise)
• Macro/microscopy
o Ä until frank infarction = pain, limits continued
exercise
§ Bedsores ® mechanical compression of blood vessels \
compromised flow over bony prominences

• Ischameia-repurfusion injury
o Restoration of blood flow
o Reversible injury ® cells recover
o Irreversible injury ® cells do not recover

o Depending on intensity + duration ischaemic injury ® cells may

go on to die ® necrosis, apoptosis, neutrophilic infiltrates

o Mechanisms
§ Reperfusion results in formation of free radicals
§ Reactive oxygen species ® further promote mitochondrial
permeability transition
§ Inflammatory cells recruited ® further injury
§ Activation of the complement pathway
127
Infarction
• Definition
o A localized area of ischaemic necrosis in an organ/tissue resulting from
either arterial or venous occlusion

• Pathogenesis
o Arterial occlusion
§ Owing to:
• Embolism
• Thrombosis
§ Effect of occlusion ® dependent on anatomic pattern of
arterial supply
o Arterial narrowing
§ May cause frank infarction/ischaemic effect
§ Owing to:
• Endarteritis obliterans
• Atheromatous deposition in wall
o Venous occlusion
§ Outflow of blood ¯ ® ­ in pressure
• If organ drains out of 1 vein, pressure ­ is ­­­ so as
to prevent arterial inflow ® infraction of organ

128
 • If organ drains from multiple veins, ­ in pressure ¯¯
as increase distends unoccluded veins ® ­ venous
outflow
§ Owing to:
• Thrombosis
• Torsion of pedicle (small, stalk-like structure
connecting an organ) of organ e.g. ovary

• Types of infarcts ® classified according to colour (reflection of

arterial supply) + presence/absence of bacterial contamination

o White/pale infarcts
§ Complete occlusion of arterial supply, organ with an end
arterial supply (only 1 artery supplying area ® heart, brain)
§ Initially ® small haemorrhagic area, destruction of vessel
walls in necrotic area releases RBCs
§ Lysis of RBCs occur within 24-48 hours = infarct becomes
pale

o Red/haemorrhagic infarcts
§ Macro = features of markedly swollen necrotic tissue, red
due to number RBCs present
§ Occurs:
• Tissue has double circulation (liver, lung)
129
 • Tissue = rich anastomotic (connections between
vessels) blood supply (small bowel)
• Re-perfusion of infarcted tissues
• Venous occlusion
• Previously congested tissue ® torsion (twisting)

o Septic infarcts
§ Bacterial contamination of infarct may be caused by:
• Prior bacterial infection (pneumonia)
• Septic embolus
• Bacteraemic seeding (bacteria seed out edge of
necrotic tissue)
• Proliferation of normal commensals ® small bowel
infarct

• Macroscopic
o Wedge-shaped
§ Apex towards vascular occlusion
§ Base = edge of organ
§ Outline variable, map-like
o Early-infarct
§ Dark (contained blood) + firmer than surrounding tissue
§ Vague outline

130
 o Later lesions (>24 hours)
§ White/pale infarcts
• Become better defined, colour changes
o Better defined owing to rim of hyperaemia from
adjacent viable tissue
• Firm consistency ® inflammatory cell infiltrate
• Inflammatory fibrinous exudate on involved serosa
§ Red/haemorrhagic
• Better defined as colour changes
• Develop red-blue colour
• Ill-defined edge ® dual/anastomotic blood supply

• Microscopic
o Cloud swelling
§ Earliest change, 40-60 mins ® on EM only =
mitochondrial swelling + lipid-protein complexes
deposited
§ 12-18 hours ® no LM change
§ >18 hours ® cells lyse + pale staining
o Coagulative cell necrosis
§ Cytoplasm = homogenous + intensely eosinophilic
§ Nucleus = pyknotic ® dark + shrunken
§ Then undergoes Karyorrhexis + Karyolysis ® detail gone

131
 o Haemorrhage
§ May mask above

o Inflammation + repair
§ Commences within a few hours
§ Apparent at edges of infarct, cells migrate from adjacent
micro-vasculature
§ Used to estimate time since infarct
§ Results in fibrosis at margins + progressively moving
inwards, ultimately = scar
§ Residual necrotic debris in some large infarcts

o Liquefaction
§ Liquefaction + phagocytosis of necrotic debris ® cyst
§ Surrounding glial proliferation ® reparative scar

o Abscess formation
§ In septic infarcts
§ Ä recognize underlying infarct later
• Factors affecting severity of vascular occlusion + its effects
o General status of blood and CVS
§ Infarcts = more extensive if:
• ¯ O2 carrying capacity ® anaemia
• ¯ oxygenation of blood ® chronic respiratory disease
132
 • Abnormal RBC morphology, cause sludging vessels
® sickle cell diseases
• Acute ¯ in perfusion of tissue with already ¯ blood
supply ® sudden hypotension in conjunction with
coronary atheroma
• Poor tissue perfusion ® shock

o Anatomic pattern of blood supply

§ Double blood supply
• Reduce effect on infarct + minimal parenchyma lost
• Lungs, liver
§ Parallel blood supply
• Similar effect, ¯¯ effect of vascular occlusion
• Ulna + radial arteries, circle of Willis
§ Single blood supply, rich in anastomoses
• Allows distal occlusion to be by passed
• Small bowel arcade arrangement

§ Single blood supply, poor in anastomoses (cross-

connection between adjacent channels ® cross-link before
capillary bed)
• Organs most at risk
• Kidney

133
 o Rate of occlusion
§ Slow occlusion = better toleration ® more time for
collaterals (side branch) to be developed

o Vulnerability of tissue
§ Neurones of brain, renal tubules, myocardial cells ®
exquisitely sensitive to ischaemia
§ Fibroblasts = persistent, may continue even when
parenchyma = necrotic

DIC
• Definition
o Profound systemic circulatory failure resulting in life-threatening
hypoperfusion of vital organs
o Perfusion ® delivery of substrates + oxygen to the capillary bed
• Classification of Shock
o Hypovolemic shock ® reduced blood flow
§ Overt blood/fluid/plasma loss
§ Internal blood/plasma/fluid loss ® haemorrhage, burns,
diarrhoea, acute peritonitis
o Cardiogenic failure (may not have tachycardia, will have
raised jugular + bradycardia) ® pump failure
§ Intrinsic myocardial damage ® infarction

134
 § Extrinsic interference in function ® cardiac tamponade
(fluid build-up in pericardium), pulmonary saddle embolus

o Distributive ® vasodilation (warm peripheries, low BP) ®

reduced systemic vascular resistance + venous pooling
§ Septic ® septicaemia + bacterial (esp. gram -ve,
lipopolysaccharide binds + activates macrophages)
endotoxins
§ Anaphylactic ® mast cells release ­­­ of vasoactive amine
(bee sting)
§ Neurogenic ® vasovagal reflex (faint), high spinal
anaesthesia
§ Other ® heat stroke

o Metabolic/endocrine ® hypoadrenalism, pituitary infarct, ­/¯

insulin, hyper/hypothyroidism

• Pathogenesis
o Insult ® microbial toxins, bleeding etc.
o ® ­­­ inflammatory mediators
o ® endothelial damage
o ® hypoperfusion
o ® cellular swelling, ­­ inflammatory mediators secreted

135
 o ® eventual organ damage (e.g. decreased myocardial
contractility)
o ® further shock ® irreversible tissue necrosis ® death

• Stages of shock
o Stage 1 ® Compensated shock
§ Tachycardia
§ Peripheral vasoconstriction (Ä coronary + cerebral) +
vasodilation in distributive
§ BP normal + CNS function maintained
§ Vasoconstriction:
• Cold, clammy skin
• Pale/peripheral cyanosis (cardiogenic)
• Hypoperfused bowel ® nausea
• Kidney ® oliguria (reduced output)
• Delayed capillary refill

o Stage 2 ® Decompensated (progressive) shock

§ ®¯ BP, ¯ CO2 = tissue dysfunction

• Heart ® tachyarrhythmia/bradycardia/weak thread
pulse
• Lung ® pulmonary oedema/crackles
• CNS ® confusion/¯ consciousness
136
 • Metabolic acidosis ® tachypnoea
• Capillaries ® leaky ® peripheral oedema
• Kidney ® oliguria/anuria (non-passage of urine)

o Stage 3 ® Irreversible (refractory) shock

§ Tissue necrosis ® multi-organ failure, severe acidosis,
hypotension, bradycardia
§ ÄÄÄ respond to treatment
§ Death

Disseminated Intravascular Coagulation

• Widespread microthrombi in micro-circulation, causes:
o Consumptive coagulopathy ® consumption of platelets,
clotting factors + fibrin, result in bleeding tendency
o Microangiopathic haemolytic anaemia ® shearing of fibrin
strands of RBC passing through kidneys
o Mechanism = thrombosis, patient will present with paradoxical
bleeding

• Aetiology
o Release of inappropriate tissue coagulation factors
§ Obstetric ® amniotic fluid, placental abruption, eclampsia
(convulsion, pregnant women with high BP)

137
 § Fat embolism
§ Malignancy ® mucin-secreting adenocarcinomas, acute
promeylotic leukaemia (abnormal accumulation of
immature granulocytes)
§ Bacterial endotoxins ® gram-ve in meningococcal
septicaemia: macrophages release TNF in response to
lipopolysaccharide, activate clotting
o Endothelial injury
§ Streptococcal, staphylococcal, malarial, virus
§ Shock
§ Vasculitis
§ Acute haemolysis (burns, Ä transfusion, snake bites)
§ Deposition of antigen/antibody complexes
§ Massive tissue injury ® trauma/surgery
o Miscellaneous
§ Liver disease

• Pathogenesis
o Underlying disorder ® systemic activation of coagulation
§ Widespread intravascular coagulation
o Consumptive coagulopathy
§ Microthrombi form
• Depletion of clotting factors

138
 • Activation of fibrinolysis ® inhibit platelets +
thrombin
• Ischaemia ® injury ® inflammation
• Easy skin/mucosal petichae

• Laboratory finding
o Decreased fibrinogen + platelets
o Increased:
§ Fibrin degradation products
§ Partial thromboplastin time ® activation of intrinsic
pathway
§ Prothrombin time ® activation of extrinsic pathways

Pathology of Shock
• Sites most vulnerable to shock
o High metabolic need
§ Brain
§ Myocardium
§ PCT
§ Liver + GIT mucosa

139
o Low flow sites
§ Watershed (boundary) zones ® brain
• Boundary zones between two arterial territories ®
furthest away from perfusions
• \ drop in BP affects here first
• Cortical watershed areas ® between cortical areas of
anterior, middle (these 2 most) + posterior cerebral
arteries
• Internal watershed areas ® white matter between
superficial + deep arterial systems of the
MCA/Superficial systems of the MCA + ACA
• Bowel watershed areas
o Splenic flexure ® junction of superior
mesenteric, bend of transverse ® descending
colon
o Recto-sigmoid junction
o Ileocecal region
• Subendocardial myocardium ® between blood in
ventricles + coronary arteries

140
 § Secondary capillary beds
• Anterior pituitary
• PCT
• Parts of exocrine pancreas
• Liver ® oxygenated from hepatic, deoxy from portal
vein

o Toxic sites
§ Stomach ® gastric acid
§ Pancreas ® enzymes
§ Small bowel ® enzymes
§ Gallbladder ® bile

o Capillary rich sites ® prone to DIC

§ Prone to coagulopathy
§ Adrenals
§ Kidneys
§ Lungs
§ Skin

141
• Shock and Kidney
o Renin-angiotensin system and shock
§ Reduced perfusion of juxtaglomerular apparatus ®
activates renin-angio(blood vessel)tensin(­ BP) system
§ Angiotensin II ® arteriolar vasoconstriction (efferent
more than afferent)
• Glomerulus spared
• PCT, supplied via capillaries distal to efferent
arteriole = more effected
• Sustained ® acute tubular necrosis (ATN)/acute
kidney injury

o Prolonged/severe shock
§ Thrombosis ® reduced flow + endothelial damage, ±
pre-existing atheroma ® DIC)
§ Afferent arterioles thrombosed ® necrosis of glomeruli
and tubules = acute cortical necrosis
§ Macroscopic Morphology
• ATN ® bigger kidney, pale + thickened cortex
owing to oedema from leaky vessels (oedema)
• ACN ® smaller kidney, thin, pale cortex with
dystrophic calcification

142
 § Outcome
• ATN ® tubular cells regenerate, patient survives
shock ® tubules recover function
• ACN ® glomerulus Ä regenerate as podocytes =
specialized cells ® fibrous scar if patient survives.
o Life-long dialysis/renal transplant

§ Papillary necrosis
• Distal + poorly vascularized
• Papilla can occlude ureters

• Shock and Brain

o Brain = target organ of shock
§ Permanent neurologic damage despite ‘successful’
resuscitation (sub-acute irreversible shock)
§ High metabolic needs
§ Poor energy reserves
§ Glucose dependent
§ Watershed zones

o Ischaemic changes (initially) ® low flow infarcts

§ General ® convulsion, amnesia, stroke, persistent
vegetative state, coma, brain death

143
§ Selective neuronal necrosis
• Ischaemia lasting 4-5 minutes ® damage,
irreversibly:
o Hippocampal + neocortical pyramid cells
o Striatal neurons
o Purkinje cells (cortex of cerebellum)
• May cause apoptosis of granule cells ® cerebellum
• More protracted ® brainstem + thalamic neurons

§ Watershed infarcts
• Boundary zones ® between anterior, posterior +
middle cerebral arteries = most affected by
hypoperfusion
• ® sickle shaped areas of infarct
• Often symmetrical + bilateral

§ Cortical Pseudolaminar Necrosis

• Band-like necrosis in cortex
• Owing to vulnerability of neurons in cortical layer 3
to hypoxia

144
 § Hypoxic Ischaemic Encephalopathy
• Widespread hypoxia + hypoglycaemia
• ® neuronal damage from toxins (lactic acid) + free
radicals (reperfusion)
o Anoxic neurons ® shrunken eosinophilic
neurons with condensed nuclei
o Cerebral oedema ® initially cytotoxic (hypoxia),
later vasogenic (vascular damage)
• Fatal if severe = brain death. Mild = survive with
gliosis, atrophy
• Can occur in birth asphyxia ® cerebral palsy

• Pathological lesions
o Global hypoperfusion ® ischaemic changes ® low flow infarct
® endothelial damage ® DIC

• Shock and Heart ® arrhythmia to sudden death

o Fatty change
o Sub-endothelial haemorrhage + infarct
o Contraction band necrosis
§ Hypercontraction of cells ® sarcolemmal rupture
§ Associate with reperfusion injury + adrenalin

145
 o Subendocardial infarct ® sub-endocardium furthest from coronary
artery
o Transmural infarct ® if pre-existing atherosclerosis

• Shock and Lungs

o Epithelial + endothelial damage
§ ­ permeability
o Pulmonary oedema, late exudate of fibrin line alveolar surfaces
o ® Diffuse alveolar damage
§ Acute respiratory distress syndrome
§ Hyaline membrane disease
§ ® diffuse pulmonary fibrosis (organisation) ® chronic
lung disease

• Shock and liver

o Centre of lobule = distal to portal supply ® centrolobular
congestion ® stasis + hypoxia
o ® fatty change (hypoxia) ® = centrolobular haemorrhagic
necrosis

146
• Shock and pituitary
o Infarcts ® Simmonds disease/Sheehan syndrome (when
postpartum = first 6 weeks after birth)
§ Empty sella turcica
§ Esp. posterior pituitary (second capillary bed)
§ ® panhypopituitarism:
• ¯ GSH ® Dwarfism in children
• ¯ FSH, ¯ LH ® amenorrhoea (absence of
menstruation)
• ¯ ACTH ® Addison disease (abdo pain, weakness,
weight loss)
• ¯ TSH ® hypothyroidism
• ¯ ADH ® diabetes insipidus

• Shock and GIT

o Stomach
§ Ischaemia ® ¯ mucosal defences
• Mucosal haemorrhages
• Cushing ulcers ® stress (shock only)
• Curling ulcers ® burn
§ Systemic hypoperfusion = multiple ulcers

147
 o Shock and colon
§ Mucosal haemorrhages
§ Watershed infarcts
• Splenic flexures
• Transverse colon
§ Perforation

• Shock and pancreas

o Initially oedema + distal pancreatitis (acute interstitial
pancreatitis)
o Ischaemia ® cell injury ® zymogens released ® activation of
lipase, elastase, proteases ® fat necrosis, vasculitis
o Acute haemorrhagic pancreatitis ® fat necrosis

• Shock and adrenals

o Compact cell changes in cortex ® depletion of steroid
o Focal necrosis of cortical cells
o ® adrenal medullary haemorrhage = Waterhouse-Friderichsen
syndrome

• Shock and Placenta

o Abruptio placentae
o Intra-uterine growth retardation (IUGR)/IU death

148
• DIC manifestations
o Bleeding
§ Easy skin/mucosal petechiae

• Venepuncture + surgical sites

§ Visceral haemorrhages
•
• Serosa, adrenal, GIT
o Waterhouse-Friderichsen syndrome
§ Bilateral adrenal medullary haemorrhage
§ Classically meningococcemia ® septic shock + DIC
§ Occasionally other highly virulent pathogens ®
Pseudomonas species, Pneumococci, Haemophilus
influenzae, ± Staphylococci
• Multi-organ failure!
o Downward spiral affect with all organs
o Shock induces organ damage + failure which in turns worsens
invigorates shock and so forth

• Treatment of Shock + DIC

o Treat cause ® anti-histamine for anaphylaxis, stop bleeding etc.
o Treat underlying mechanisms ® vasopressors for distributive
shock, frozen plasma for DIC

149
 o Prevent complications ® proton pump inhibitors, prevent HCl

• SHOCK = LOW-FLOW INFARCTS

o Low-flow infarcts ® different shape + distribution vs. occlusive
infarcts
o Low flow infarcts:
§ Often at the periphery of arterial territory (sickle shaped)
§ Or affect only vulnerable area + are bilateral/symmetric
o Occlusive infarcts
§ Caused by thromboembolic events
§ Affect entire arterial area ® (wedge shape)
§ Usually localized

150
Chemical Pathology

151
Introduction to Chemical Pathology
• Definition
o Aims to describe in molecular terms the derangement of
normal chemical processes = how they are related to disease
o Every spontaneous endogenous disease ® roots in
biochemistry, and eventually all will be described in logical,
biochemical terms
o Run clinical chemistry laboratories
§ Provide accurate + relevant biochemical information
§ Aids in management of patient
§ Guides clinical decision making
o Functions
§ Screen
§ Diagnose
§ Monitor
§ Prognosticate ® determine possible outcome, path
forward

• Measure
o Genome
o Transcriptome
o Proteome
o Metabolome ® super-biochemical = inorganic, tiny molecules
® Na+, K+

152
• Use Physical Characteristics to Elicit and Measure Small Molecules
o All conjugated organic matter absorbs UV(190-400nm)/visible
light (400-700nm)
o More conjugated compounds ® absorb in visible spectrum
(Hb)
o Less conjugated ® absorb in UB spectrum
o UV/visible ® excites electrons into higher energy orbits
o Electrons return + emit light at lower energy (­ wavelength) =
fluorescence

• Colorimetric Assays
o Used to measure how many small molecules are present in
sample + used to measure enzyme activity
o Measure rate of colour change to determine enzymatic activity
o Common assays
§ Ca, Mg, ALP
§ Albumin, Total protein
§ Bilirubin
§ Cholesterol
§ Glucose etc.
o 1IU/L = means there is enough enzyme present in 1L of plasma
to convert 1umol of substrate to product/minute

153
• Antibodies
o Very useful for measuring low abundance molecules
o Labels ® use technologies that amplify a small signal into a
detectable measure (fluorophores, chemiluminescent molecules,
radio-active lables)

o Non-competitive immunoassay
§ Process
• Antibody coated onto solid support
• Binding of analyte (substance whose chemical
constituents are being identified/measured) +
washing
• Binding of second, labelled antibody + washing
• Reading of label activity + relating signal to analyte
concentration
• Graph created (Conc. vs. signal)
§ Great for large molecules (proteins) ® enough space for 2
antibodies to bind ® TSH, FSH, LH, Prolactin, Insulin

154
 o Competitive immunoassay
§ Process
• Antibody coated onto solid support
• Addition of unmarked analyte in sample + marked
analyte (Eu) + specific Ab ® compete for binding to
secondary Ab
• Add DELFIA inducer ® caused Eu to dissociate
• \ Florescence measurement, inverse as more Eu = ¯
previous analyte (compete-out)
§ Used for smaller molecules, Ä have space for 2 Abs to
bind but can be labelled ® T4, T3, Vit D, Cortisol,
Testosterone etc.

• What is abnormal? ® dealing with probabilities

o Reference ranges
§ Derived of what is thought to be normal in a healthy
population
§ Most ranges = values within 2 standard deviations of the
mean \ = NORMAL RANGE for particular substance
o Sensitive test ® will detect all patients who have the disease
(few false negative)
o Specific test ® will not mislabel a person as diseased (few false
positives)

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 o No test is 100% sensitive or 100% specific ® usually set cutoff
values to reach compromise between the 2 using:
§ Receiver Operating Characteristic Curve

o Approach
§ Treat individuals long before they fall outside the ‘norm’,
goal is to prevent ever leaving in the first place

• Interesting cases
o Causes of Cushing’s syndrome ® excessive glucocorticoid
steroids
§ Exogenous corticosteroids
• Most common
• ¯ACTH
• Bilateral adrenal atrophy

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§ Primary adrenal adenoma (benign tumor of epithelial tissue
with glandular origin)
• ¯ ACTH
• Unilateral adrenal atrophy

§ ACTH secreting pituitary adenoma ® Cushing’s

syndrome!
• ­ ACTH
• Bilateral adrenal hyperplasia
• Dexamethasone (acts on adrenal glands) ® suppress

§ Paraneoplastic ACTH secretion (Small-lung cell carcinoma)

• ­ ACTH
• Bilateral adrenal hyperplasia
• Dexamethasone ® failure to suppress

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Biostatistics

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Biostatistics

• Science which deals with the development and application of most

appropriate methods
o Collection of data
o Presentation of data
o Analysis and interpretation
o Making decisions on the basis of analysis
o Biostats = statistics applied to medicine

• Role of the biostatician

o Guide the design of an experiment/survey prior to data
collection
o Analyze data using proper techniques/procedures
o Report, present + interpret results relevant to decision markers

• Data
o Raw material of statistics
o Data = measurements or responses
o Examples
§ HIV status
§ CD4 count etc.

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• Types of studies
o Observational
§ Simply observe what happens without interference
§ 2 types
• Cross-sectional
o All subjects observed at one specific time
• Longitudinal
o All subjects are observed at different point in
time/intervals

o Experimental
§ Intervention on part of researcher
§ Researcher deliberately imposes different treatments on
different groups + compares groups to determine any
difference in outcome
§ Randomized control trials

• Population
o Entire group of individuals having certain common
characteristics
o Sample ® subset of individuals selected from a population

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• Sampling
o Less time to collect + analyze
o Greater flexibility in data management
o Reduce cost
o Probability sampling
§ Every individual has an equal chance of being selected
o Convenience sampling
§ Selectively choose who you want in your study
§ Need to test a specific population
§ Location of research etc.

o Sampling error
§ Discrepancy between a sample statistic + actual population
parameter
§ \ Statistical error that occurs when selected sample Ä
represent entire population
§ \ Value in sample Ä value that would be found in
population
§ Defining + measuring sampling error = large part of
inferential statistics

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 § Reducing sampling error
• Increase sample size
• Select a representative sample
o Randomization in homogenous population
o Stratification in heterogeneous population

o Variables
§ Numerical
• Continuous ® infinitely divisible into whatever
research is being done (time)
• Discrete ® indivisible categories (class size)

§ Categorical
• Ordinal ® ordered set of categories
o Direction of difference between individuals
• Nominal ® unordered set of categories identified
only by name
o Permit you to determine whether two individuals
are the same/different
§ Scale
• Interval scale ® ordered series of equal sized
categories
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 o Identify direction and magnitude of difference
o Zero point located arbitrarily
• Ratio scale
o Interval, value of zero indicates none of the
variable
o Identify direction + magnitude of difference,
allow ratio comparisons of measurements

• Types of statistics
o Descriptive statistics
§ Summarizing + describing data
§ Use numerical + graphical summaries to characterize
sample data
o Inferential statistics
§ Use sample data ® make conclusions about a broader
range of individuals than just those who are observed

• Presentation of data
o Data presentation methods
§ Tabulations, graphs, diagrams
• Frequency tables
• Cross tabulation
• Graphical representation

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 o Bar graph ® categorical data
§ Bars are plotted for different categories in
the categorical variable
§ Length of bars represent
percentages/frequencies
o Pie graph ® categorical data
o Line graph ® numerical data
o Histogram ® continuous numerical data

§ Descriptive statistics, measures of location, measure of

dispersion, measures of skewness

§ Inferential statistics, hypothesis testing, point estimates,

interval estimates

§ Univariate/multivariate analysis

• Central tendency
o Mean ® average of numerical data only
o Median ® middle value
o Mode ® most often, numerical or categorical data only

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• Measures of position
o Percentiles ® 60th percentile = value at which 60% of data is
less than or equal to
o Quartiles
§ 25th percentile = 1st quartile
§ 50th percentile = 2nd quartile
§ 75th percentile = 3rd quartile

• Dispersion
o Rand
o Standard deviation
o Interquartile range

• Symmetrical distribution
o Several numerical variables tend to approximately follow a bell-
shaped curve ® normal distribution
o Symmetrical about its mean

• Left skewed distributions

o Mean is pulled by low extreme points \ mean is lower the
median
• Right skewed distributions
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 o Mean is pulled by high extreme points ® mean is much higher
than the median
• Hypothesis testing
o Hypothesis ® statement of the research question that sets forth
the appropriate statistical evaluation
o Test a claim about a parameter using evidence
§ Null hypothesis ® statement of no differences or
association between variables
§ Alternative hypothesis ® statement of differences or
association between variables
o Mutually exclusive, only one can be true!!

o Point estimate ® single number

o Interval estimate

§ ­­ Information about a population characteristic va. A

point estimates
§ Provides confidence level for estimate
§ = Confidence intervals

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o Confidence intervals

§ 95% confidence interval = if we were to take 100 different

samples from population and compute a 95% confidence
interval for each sample, approx. 95% of confidence
interval will contain true mean value
• Ä reflect variability
• Reflects how likely true value falls within interval

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