LOM 1 PDF - Anatomical Pathology

LOM 1 Andrea Tonelli MBChB (UCT) 2018 1 Anatomical Pathology 2 Anatomical Pathology Glossary Aetiology ® the cause of a disease, may involve multiple factors Complications and sequelae ® secondary, long-term consequences of disease Epidem...

LOM 1 Andrea Tonelli MBChB (UCT) 2018 1 Anatomical Pathology 2 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 3 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. 4  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 5  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 6  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 7 § 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 8  § 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 9  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 10  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 11  § 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 12  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 13 § 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 14  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) 15 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 16 § 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 17  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 18 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 19  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: 20  § 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 21  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 22  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 23  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 24 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 25  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 26  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 27  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 28  § 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 29 § 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 30  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 31 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 32  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 33  § 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 34  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 35 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) 36  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 83  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 88  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 89  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 + ­