Veterinary · Para-clinical · also MSVE VPP-211
The general responses of tissue to injury: circulatory disturbances, degeneration and necrosis, inflammation and repair, immunopathology and neoplasia.
In the exams: ICAR AICE-JRF core group 06; ICAR AIEEA-PG 13 (Pathology); PRC 10%; Nepal NLEV 6; China basic paper 20; BCSE 20-23 items; AVE Paper 1 at least 8 (with clinical pathology); SAVC diagnostic pathology 25
General veterinary pathology is the study of the basic ways in which cells and tissues of animals respond to injury: how cells adapt, degenerate and die; how blood flow and fluid balance fail; how tissue becomes inflamed and heals; how the immune system can itself cause disease; how genes and the uterine environment produce defects; and how cells escape growth control to form tumours. These responses are common to all tissues and all species, so the subject is the grammar of the whole of veterinary medicine. Systemic pathology, clinical pathology, infectious disease, toxicology and oncology all use its vocabulary.
In practice the subject is used every day. A clinician who reads a biopsy report, interprets an effusion as a transudate or an exudate, recognises a nutmeg liver or a wedge-shaped renal infarct at necropsy, explains why a cow with chronic mastitis is losing protein in her urine, or decides whether a skin mass is likely to be benign is applying general pathology.
This manual follows the sequence used in most veterinary curricula worldwide, including the Indian MSVE course VPP-211 and the general pathology blocks of North American, European, Australasian, African and Asian schools. It gives species examples throughout, because examiners everywhere ask for them. The subject is examined as definitions and mechanisms in Indian postgraduate and PhD entrance tests and state service papers, as clinicopathological scenarios in NAVLE, BCSE, the RCVS examination and the Australasian examination, and as a defined block in the licensing examinations of the Philippines, Nepal, China and South Africa. Reference values and incidence figures vary by laboratory, country and population; where a number is given it is a widely taught teaching value, not a universal constant.
Pathology is the study of disease through the structural and functional changes it causes in cells, tissues and organs. Aetiology is the cause of a disease; pathogenesis is the sequence of events from the first contact with the cause to the final lesion. A lesion is any structural abnormality produced by disease, visible grossly or microscopically. A lesion is pathognomonic when it is so characteristic that it identifies one disease on its own, for example Negri bodies in neurons for rabies. Most lesions are not pathognomonic, so the pathologist builds a morphological diagnosis that names the organ, the process, and modifiers of distribution, duration and severity: for example, 'lung: bronchopneumonia, fibrinosuppurative, cranioventral, acute, severe'.
Almost every aetiological agent injures cells through a limited set of mechanisms. The main categories are: oxygen deprivation (hypoxia, reduced oxygen, and ischaemia, reduced blood flow, which is more damaging because it also removes nutrients and allows metabolites to accumulate); physical agents (trauma, heat, cold, radiation, electricity, pressure); chemicals and toxins (heavy metals such as lead and copper, plant toxins, mycotoxins, drugs at toxic doses, and even water and salt in excess); infectious agents (prions, viruses, bacteria, fungi, protozoa and metazoan parasites); immunological reactions (hypersensitivity and autoimmunity); genetic defects (enzyme deficiencies, structural protein defects); nutritional imbalances (deficiencies of energy, protein, vitamins and trace elements, or excesses such as vitamin D); and ageing. Neurons and cardiac myocytes are the most sensitive cells to hypoxia, fibroblasts and adipocytes among the least; within the kidney, the proximal tubule is more sensitive than the glomerulus, and within the liver, the centrilobular (zone 3) hepatocytes, which receive the least oxygenated blood, are injured first.
Four biochemical targets explain most cell injury. First, ATP depletion: with hypoxia, oxidative phosphorylation stops, the sodium-potassium pump fails, sodium and water enter the cell and it swells; anaerobic glycolysis produces lactic acid, pH falls and chromatin clumps; ribosomes detach from the rough endoplasmic reticulum and protein synthesis falls. Second, mitochondrial damage opens the mitochondrial permeability transition pore, collapses the membrane potential and releases cytochrome c, which can trigger apoptosis. Third, loss of calcium homeostasis: calcium floods the cytosol and activates phospholipases, proteases, endonucleases and ATPases, which destroy membranes, cytoskeleton and DNA. Fourth, oxygen-derived free radicals (superoxide, hydrogen peroxide, the hydroxyl radical) cause lipid peroxidation of membranes, protein oxidation and DNA breaks; defences include superoxide dismutase, catalase, glutathione peroxidase (which requires selenium) and vitamin E. This is why selenium and vitamin E deficiency produces nutritional myopathy (white muscle disease) in lambs and calves and mulberry heart disease in pigs. Reversible injury is recognised by cell swelling, fatty change, membrane blebs, swollen mitochondria and dilated endoplasmic reticulum; if the cause is removed the cell recovers. Two findings mark the point of no return: the inability to restore mitochondrial function and profound disturbance of membrane function.
Hyperaemia is active: arterioles dilate and more blood flows in, as in exercising muscle, the digestive tract after a meal, and acute inflammation. Congestion is passive: outflow of venous blood is impeded, so blood accumulates, the tissue is dark red to blue-red (cyanotic) and cooler, and it may swell. Congestion may be local, from obstruction of a vein (for example, torsion of a lung lobe, splenic torsion or intestinal volvulus), or generalised, from heart failure. Left-sided heart failure causes pulmonary congestion; with chronicity, red cells leak into alveoli and are phagocytosed by alveolar macrophages, which convert haemoglobin to haemosiderin and are then called heart failure cells. Right-sided heart failure causes congestion of the systemic venous system, most visibly the liver. Chronic passive congestion of the liver gives the cut surface a pattern of dark red centrilobular areas alternating with paler, often fatty, periportal tissue: the so-called nutmeg liver. In cattle, right-sided failure from traumatic reticulopericarditis, brisket disease (high-altitude pulmonary hypertension) or endocarditis produces brisket oedema, ascites and nutmeg liver.
Oedema is an excess of fluid in the interstitial tissue or body cavities. Fluid exchange across capillaries follows Starling's principle: net filtration equals the filtration coefficient multiplied by [(capillary hydrostatic pressure minus interstitial hydrostatic pressure) minus the reflection coefficient multiplied by (plasma oncotic pressure minus interstitial oncotic pressure)]. Oedema therefore arises by four mechanisms. First, increased hydrostatic pressure, as in heart failure, venous obstruction, or overzealous intravenous fluids. Second, reduced plasma oncotic pressure from hypoalbuminaemia; albumin provides most of the plasma oncotic pressure, and it falls in protein-losing enteropathy, protein-losing nephropathy (for example, glomerular amyloidosis or glomerulonephritis), chronic liver failure and starvation. Heavy gastrointestinal parasitism with Haemonchus contortus in sheep and goats or Fasciola hepatica causes the classic submandibular 'bottle jaw'. Third, increased vascular permeability, as in inflammation; the fluid is then an exudate, rich in protein and cells. Fourth, lymphatic obstruction by tumour, inflammation, surgery or congenital lymphatic hypoplasia. Oedema from the first, second and fourth mechanisms is a transudate: clear, low in protein and cells, and it does not clot.
Haemorrhage is the escape of blood from vessels. Haemorrhage by rhexis follows rupture of a vessel wall (trauma, erosion by inflammation or tumour, aneurysm rupture); haemorrhage by diapedesis is the passage of red cells through intact but damaged endothelium, as in congestion, septicaemia and some viral diseases. Size determines the name: petechiae are pinpoint haemorrhages of about 1 to 2 millimetres, typical of thrombocytopenia, vasculitis and septicaemia; ecchymoses are larger blotches up to a few centimetres; suffusive (paintbrush) haemorrhage covers a large continuous area, as on serosal surfaces in acute septicaemia; a haematoma is a localised mass of blood within tissue, such as the aural haematoma of dogs and the splenic haematoma. Blood in body cavities is named haemothorax, haemopericardium and haemoperitoneum; haemoperitoneum in an older large-breed dog should prompt a search for ruptured splenic haemangiosarcoma. Haemorrhagic diatheses are tendencies to bleed. Platelet defects (thrombocytopenia or thrombocytopathia) tend to give petechiae and mucosal bleeding; coagulation factor defects tend to give haematomas and bleeding into joints and cavities. Examples: haemophilia A (factor VIII deficiency) in dogs, von Willebrand disease (the commonest inherited bleeding disorder of dogs, for example in Dobermanns), anticoagulant rodenticide poisoning (vitamin K antagonism affecting factors II, VII, IX and X), sweet clover poisoning in cattle (dicoumarol from mouldy sweet clover), and bracken fern poisoning in cattle (bone marrow suppression causing thrombocytopenia).
A thrombus is a solid mass formed within the vascular system during life from the constituents of blood. Virchow's triad names the three predisposing factors: endothelial injury, abnormal blood flow (stasis or turbulence) and hypercoagulability. Endothelial injury is the most important on its own; examples are the verminous arteritis of the cranial mesenteric artery in horses caused by larvae of Strongylus vulgaris, and the vasculitis of many septicaemias. Arterial thrombi form in fast-flowing blood, are pale and layered, and show the lines of Zahn (alternating pale platelet-fibrin layers and darker red-cell layers); they are firmly attached to the wall. Venous thrombi form in stagnant blood, are dark red and contain many trapped red cells. A thrombus must be distinguished from a post-mortem clot: post-mortem clots are rubbery, moist and shiny, not attached to the wall, and often separated into a dark red 'currant jelly' lower part and a yellow 'chicken fat' upper part where red cells settled before clotting. The fates of a thrombus are propagation, resolution by fibrinolysis, organisation (ingrowth of granulation tissue) with recanalisation, and embolisation. Cats with hypertrophic cardiomyopathy form thrombi in a dilated left atrium; these commonly embolise to the aortic trifurcation ('saddle thrombus'), causing acute painful hindlimb paralysis with cold pads and absent femoral pulses.
An embolus is a detached intravascular solid, liquid or gaseous mass carried by blood to a site distant from its origin. Most emboli are thromboemboli. Others are fat emboli (after fractures of long bones or crushing of fat), air or gas emboli (after careless intravenous injection or decompression), bacterial and septic emboli (from endocarditis or abscesses; in cattle, a ruptured liver abscess into the caudal vena cava sends septic emboli to the lungs, producing the caudal vena cava thrombosis syndrome with haemoptysis), tumour cell emboli (the route of haematogenous metastasis), parasitic emboli (Dirofilaria immitis in the pulmonary arteries of dogs, especially after adulticide treatment), and fibrocartilaginous emboli from the nucleus pulposus that cause acute ischaemic myelopathy in dogs. An infarct is a localised area of ischaemic necrosis caused by occlusion of the arterial supply or, less often, the venous drainage. Infarcts in organs with an end-arterial supply, such as the kidney, are wedge- or cone-shaped with the base at the capsule and the apex pointing at the occluded vessel. Red (haemorrhagic) infarcts occur with venous occlusion (for example, intestinal volvulus or torsion), in loose tissues, in organs with dual circulation such as the lung, and where blood re-enters after reperfusion. White (anaemic) infarcts occur with arterial occlusion in solid organs with end-arteries, such as the kidney and heart. The brain is an exception: its infarcts undergo liquefactive necrosis and leave a cyst. Septic infarcts become abscesses.
Shock is circulatory failure leading to inadequate perfusion and oxygen delivery to tissues, with cellular hypoxia. It is classified as hypovolaemic (haemorrhage, severe diarrhoea as in neonatal calves with enterotoxigenic Escherichia coli, burns), cardiogenic (myocardial failure, arrhythmia, tamponade), obstructive (pulmonary embolism, gastric dilatation-volvulus compressing the caudal vena cava), and distributive, in which vessels dilate and leak: septic or endotoxic shock (lipopolysaccharide from Gram-negative bacteria, for example in equine colic with strangulated bowel or in coliform mastitis), anaphylactic shock and neurogenic shock. The organ that shows the most striking lesions differs by species: the gastrointestinal tract is usually cited as the shock organ of the dog, and the lung as the shock organ of the cat and of ruminants, while in all species renal tubular necrosis, centrilobular hepatic necrosis, and adrenal and cardiac haemorrhages may be found. Disseminated intravascular coagulation (DIC) is a secondary acquired syndrome, never a primary disease, in which widespread activation of coagulation forms microthrombi in small vessels, consuming platelets and clotting factors and activating fibrinolysis, so the animal paradoxically both thromboses and bleeds. Triggers include sepsis, endotoxaemia, heat stroke, extensive tissue injury, snake envenomation, haemangiosarcoma, acute pancreatitis, immune-mediated haemolysis and gastric dilatation-volvulus. Laboratory findings are thrombocytopenia, prolonged clotting times, low fibrinogen or antithrombin, and raised fibrin degradation products or D-dimers; histology shows fibrin microthrombi in glomeruli, lungs and other capillary beds.
Acute cell swelling (cloudy swelling, hydropic degeneration or vacuolar degeneration) is the first and most common response to injury: failure of membrane ion pumps lets water enter, organs are pale, swollen and heavier, and the cytoplasm is pale and finely granular or contains clear vacuoles. Ballooning degeneration is extreme swelling of epithelial cells, typical of poxvirus and some herpesvirus infections of stratified squamous epithelium; the ballooned cells separate and form vesicles, as in foot-and-mouth disease. Fatty change (lipidosis, steatosis) is the accumulation of triglyceride within parenchymal cells, most often hepatocytes. It occurs when the supply of free fatty acids to the liver exceeds the hepatocyte's ability to oxidise them or export them as very-low-density lipoprotein. Causes include negative energy balance with fat mobilisation (fatty liver of high-yielding dairy cows in early lactation, pregnancy toxaemia of ewes and goats, hyperlipaemia of ponies and miniature horses, and idiopathic hepatic lipidosis of obese cats that stop eating), toxins that block protein synthesis and so lipoprotein export (for example, carbon tetrachloride, aflatoxin), diabetes mellitus and hypoxia. Grossly the fatty liver is enlarged, yellow, greasy, soft and friable with rounded edges, and slices may float in water or formalin. Because lipid is dissolved by the solvents of routine paraffin processing, its presence is confirmed on frozen sections with stains such as Oil Red O or Sudan dyes, which colour lipid red to orange.
Excess glycogen accumulates in hepatocytes of dogs given corticosteroids or with hyperadrenocorticism (steroid hepatopathy, with feathery, poorly defined cytoplasmic vacuoles), in diabetes mellitus, and in inherited glycogen storage diseases such as the lysosomal alpha-glucosidase deficiency (Pompe disease) described in Brahman and Shorthorn cattle and Lapland dogs. Glycogen is dissolved by aqueous fixatives to some degree and is best shown by the periodic acid-Schiff (PAS) reaction, abolished by prior diastase digestion. Some plants cause acquired storage disease by inhibiting lysosomal enzymes: swainsonine in locoweeds (Astragalus and Oxytropis species) and Swainsona species inhibits alpha-mannosidase. Proteins accumulate as hyaline droplets in renal tubular cells when protein leaks through damaged glomeruli and is reabsorbed. 'Hyaline' is a descriptive word for any homogeneous, glassy, eosinophilic material in haematoxylin and eosin sections; it is not a single substance.
Amyloid is an extracellular, proteinaceous material made of fibrils folded into a beta-pleated sheet structure. It is homogeneous and pale eosinophilic in haematoxylin and eosin sections; stained with Congo red it is orange-red and shows apple-green birefringence under polarised light, which is the diagnostic test. The two main types in animals are AA (reactive, secondary) amyloid, derived from serum amyloid A, an acute phase protein produced by the liver during chronic inflammation; and AL (immunoglobulin light chain) amyloid, derived from plasma cell dyscrasias such as plasmacytoma. AA amyloidosis is by far the commonest systemic form in domestic animals. It follows chronic infections and inflammation: chronic mastitis, traumatic reticuloperitonitis and other chronic suppurative diseases of cattle, repeated immunisation of horses used to produce antisera, and chronic inflammation in ducks and other birds. Familial forms occur in Shar-Pei dogs (with episodic fever and swollen hocks, and amyloid mainly in the renal medulla and liver) and Abyssinian and Siamese cats; in Siamese and Oriental cats hepatic amyloid can cause hepatic rupture and haemoperitoneum. The main clinical consequence in cattle and dogs is renal: glomerular amyloid causes heavy proteinuria, hypoalbuminaemia, oedema and eventually renal failure, the nephrotic syndrome.
Haemosiderin is a golden-brown, granular, iron-containing pigment formed when macrophages break down haemoglobin; it represents aggregated ferritin. It stains blue with Perls' Prussian blue reaction. Local haemosiderosis follows any haemorrhage (a bruise, heart failure cells in the lung); generalised haemosiderosis follows increased red cell destruction (haemolytic anaemias, repeated transfusions) or excess iron uptake. Haematoidin is an iron-free yellow-brown crystalline pigment formed in the anoxic centre of large haemorrhages; it is chemically similar to bilirubin and does not stain with Perls. Bilirubin is the end product of haem breakdown in macrophages. Unconjugated bilirubin travels bound to albumin to the liver, is conjugated with glucuronic acid and excreted in bile. Icterus (jaundice) is yellow staining of tissues, most obvious in the sclera, mucous membranes, intima of blood vessels and fat, by an excess of bilirubin in blood. It is classified as pre-hepatic (haemolytic: excessive red cell destruction, as in babesiosis, anaplasmosis, leptospirosis, chronic copper poisoning in sheep, neonatal isoerythrolysis and immune-mediated haemolytic anaemia), hepatic (impaired uptake, conjugation or excretion by diseased hepatocytes, as in toxic hepatitis or infectious canine hepatitis), and post-hepatic (obstruction to bile outflow, as by choledocholiths, pancreatic tumours or liver fluke). Horses become mildly icteric during anorexia (fasting hyperbilirubinaemia) without liver disease, and normal horses have relatively high plasma bilirubin, so a yellow sclera in a horse is interpreted with caution. Plasma of cattle and horses may also be yellow from carotenoids.
Melanin is a brown-black pigment formed by melanocytes from tyrosine by the enzyme tyrosinase and transferred to keratinocytes. Melanosis is the congenital presence of melanin in abnormal sites, such as black spots in the lungs, aorta or meninges of calves, lambs and pigs; it is of no clinical significance but leads to trimming at meat inspection. Melanomas arise from melanocytes and are especially common in grey horses. Lipofuscin is the 'wear-and-tear' or ageing pigment: a yellow-brown, finely granular pigment of lipid and protein residues left after peroxidation of membranes, accumulating in long-lived cells such as neurons and cardiac myocytes of old animals. When it accumulates rapidly from vitamin E deficiency or chronic injury it is often called ceroid; both are autofluorescent, and ceroid is often acid-fast. Brown atrophy of the heart is atrophy with lipofuscin accumulation. 'Brown dog gut', lipofuscin accumulation in the intestinal smooth muscle of dogs, is linked to vitamin E deficiency. Porphyrins are intermediates of haem synthesis. Bovine congenital erythropoietic porphyria, an autosomal recessive defect in Holstein and other breeds, causes reddish-brown discolouration of teeth and bones ('pink tooth'), porphyrins that fluoresce red under ultraviolet light, haemolytic anaemia and photosensitisation. Photosensitisation, whether primary (plant pigments such as hypericin from St John's wort) or hepatogenous (phylloerythrin, a chlorophyll breakdown product that accumulates when the liver fails, as in facial eczema from the mycotoxin sporidesmin), causes dermatitis of unpigmented, sun-exposed skin.
Necrosis is the death of cells or tissues in a living animal, together with the changes that follow from enzymatic digestion and denaturation of proteins. It always affects groups of cells and usually provokes inflammation, because contents leak from ruptured membranes. The dead cell has increased eosinophilia (from denatured cytoplasmic protein and loss of RNA), and the nucleus shows one of three changes: pyknosis (shrinkage and dark condensation), karyorrhexis (fragmentation) and karyolysis (fading as DNA is digested). Necrosis must be distinguished from autolysis, which is self-digestion after death of the whole animal, without an inflammatory reaction. Post-mortem changes begin immediately and include algor mortis (cooling), rigor mortis (stiffening from ATP depletion in muscle, later passing off), livor mortis (hypostatic congestion), autolysis (most rapid in the gastrointestinal mucosa, pancreas, kidney tubules and adrenal medulla), pseudomelanosis (green-black discolouration from iron sulphide formed by bacterial hydrogen sulphide and haemoglobin iron), bile imbibition (green-yellow staining around the gall bladder), emphysema of putrefaction, and post-mortem displacement or rupture of the stomach and intestines.
Coagulative necrosis is the typical pattern produced by ischaemia in solid organs other than the brain. The architecture of the tissue is preserved for some days because both structural proteins and enzymes are denatured; outlines of dead cells remain as 'ghost cells'. Liquefactive necrosis occurs where enzymatic digestion dominates: in the central nervous system, which has little supporting stroma and a high lipid content, and in bacterial infections that attract neutrophils, which release hydrolytic enzymes to form pus. Examples include polioencephalomalacia (cerebrocortical necrosis) of ruminants, associated with thiamine deficiency or high dietary sulphur, and equine leukoencephalomalacia caused by fumonisin B1 from Fusarium verticillioides on mouldy maize. Caseous necrosis is a cheese-like, crumbly, white to yellow dead tissue in which the architecture is lost but the debris is not liquefied; it is typical of tuberculosis in mammals, caseous lymphadenitis caused by Corynebacterium pseudotuberculosis in sheep and goats (with its concentric onion-ring lamination in sheep), and many chronic abscesses of cattle. Fat necrosis includes enzymatic fat necrosis (lipases released in acute pancreatitis split triglyceride in peripancreatic fat; the released fatty acids combine with calcium to form chalky white soaps, saponification), traumatic fat necrosis, and abdominal fat necrosis (lipomatosis) of cattle, in which hard masses of necrotic fat in the mesentery can constrict the intestine; the last has been linked to grazing endophyte-infected fescue.
Apoptosis is programmed cell death: an active, energy-dependent pathway in which a cell activates caspases that dismantle it from within. The cell shrinks, the chromatin condenses against the nuclear envelope, the nucleus fragments, and the cell buds into membrane-bound apoptotic bodies that expose phosphatidylserine and are eaten by neighbouring cells or macrophages without inflammation. DNA is cut at internucleosomal sites into fragments of about 180 to 200 base pairs, giving a 'ladder' on gel electrophoresis, unlike the smear of necrosis. The intrinsic (mitochondrial) pathway is controlled by the BCL-2 family and triggered by DNA damage, growth factor withdrawal or cell stress, releasing cytochrome c; the extrinsic (death receptor) pathway is triggered by Fas ligand or tumour necrosis factor binding their receptors. Apoptosis is physiological in embryonic development, involution of hormone-dependent tissue (for example, the regressing corpus luteum and mammary gland), deletion of self-reactive lymphocytes in the thymus, and removal of cells killed by cytotoxic T cells. Gangrene is necrosis of a large area of tissue, usually from loss of blood supply, followed by further change. Dry gangrene is coagulative necrosis in which the tissue dries, shrinks and turns dark, with a clear line of demarcation; examples are the tail and ear tips in ergotism (vasoconstriction by ergot alkaloids from Claviceps purpurea), fescue foot in cattle, and frostbite. Moist (wet) gangrene is necrosis invaded by saprophytic putrefactive bacteria, making it soft, swollen, foul-smelling and dark, without a clear demarcation, and toxaemic; examples are gangrenous mastitis caused by Staphylococcus aureus or Clostridium species in ewes and cows, intestinal gangrene after volvulus, and aspiration pneumonia after drenching. Gas gangrene is caused by histotoxic clostridia, for example Clostridium chauvoei in blackleg and Clostridium septicum in malignant oedema; the muscle is dark, crepitant and smells of rancid butter.
Pathological calcification is the abnormal deposition of calcium salts, mainly calcium phosphate as hydroxyapatite, in soft tissues. In haematoxylin and eosin sections calcium is deep blue-purple and granular; it is confirmed with the von Kossa method (black) or alizarin red S (red-orange). Dystrophic calcification occurs in dead or degenerate tissue while blood calcium and phosphate are normal. It is common and is a local marker of previous injury: caseous foci of tuberculosis and caseous lymphadenitis, necrotic muscle in nutritional myopathy (the chalky white streaks of white muscle disease in lambs and calves), dead parasites (for example, calcified cysticerci or the migration tracts of Strongylus larvae), thrombi (phleboliths), old infarcts, fat necrosis, and damaged heart valves. Metastatic calcification occurs in previously normal tissues because blood calcium, phosphate or both are persistently raised, so that their product exceeds solubility. Its targets are tissues that lose acid and so have an internal alkaline compartment: the gastric mucosa (fundic glands, which secrete hydrochloric acid), the kidney (which excretes acid), the lung (which excretes carbon dioxide), and the walls of arteries and pulmonary veins; the endocardium, pleura and intercostal muscles are also affected.
Vitamin D toxicity is the leading cause in practice. It may be iatrogenic (excessive dietary supplementation or injection of cattle to prevent milk fever), follow ingestion of rodenticides containing cholecalciferol, or follow ingestion of calcinogenic plants that contain vitamin D-like glycosides of 1,25-dihydroxycholecalciferol: Solanum malacoxylon (enteque seco of cattle in South America), Cestrum diurnum (day-blooming jessamine in Florida and elsewhere), and Trisetum flavescens (yellow oat grass causing enzootic calcinosis of cattle in the Alps). Chronic kidney disease, especially in dogs, produces a high phosphate level and renal secondary hyperparathyroidism; the characteristic lesions include calcification of the gastric mucosa, the intercostal pleura (subpleural mineralisation), and the kidney itself, while demineralisation of the skull bones and replacement by fibrous tissue produce 'rubber jaw' (fibrous osteodystrophy).
Not every white deposit is calcium. Gout is the deposition of urate crystals in tissues when blood uric acid is high. It is important in birds and reptiles, which excrete nitrogen mainly as uric acid. Visceral gout, a white chalky coating of urates on the pericardium, liver capsule and other serosae and within the kidney, follows renal failure or dehydration; in chickens it has been associated with infectious bronchitis virus nephropathogenic strains, excess dietary protein or calcium, vitamin A deficiency and water deprivation. Urates dissolve in aqueous fixatives, so tissues suspected of gout are fixed in alcohol, and the crystals are birefringent needle shapes under polarised light. Calculi (stones, uroliths) are concretions formed in hollow organs from precipitated salts on an organic matrix. Urolithiasis is common in castrated male ruminants on high-grain diets, where the stones (commonly struvite, that is magnesium ammonium phosphate, or calcium phosphate) lodge in the sigmoid flexure or urethral process; silica calculi occur in cattle and sheep grazing silica-rich pastures; calcium oxalate and struvite are the common uroliths of dogs and cats; urate uroliths are typical of Dalmatian dogs, which have an inherited defect in hepatic uric acid transport, and of dogs with portosystemic shunts.
Inflammation is the response of vascularised tissue to injury, aimed at diluting, destroying or walling off the injurious agent and preparing for repair. The cardinal signs are redness (rubor), heat (calor), swelling (tumor), pain (dolor) and loss of function (functio laesa, added by Virchow). Vascular changes begin with transient arteriolar constriction, followed by vasodilatation that causes heat and redness, and increased permeability that lets a protein-rich exudate leak out. Permeability rises by endothelial cell contraction in postcapillary venules (the immediate transient response to histamine), by direct endothelial injury (burns, toxins), by leukocyte-mediated injury and by leakage from new vessels. As fluid leaves, blood concentrates and slows (stasis), allowing leukocytes to move to the edge of the flow (margination). Leukocytes then roll along the endothelium through selectins, adhere firmly through integrins binding endothelial adhesion molecules such as ICAM-1, migrate between endothelial cells (diapedesis) and follow chemotactic gradients (bacterial peptides, C5a, leukotriene B4, interleukin-8) to the site. Neutrophils dominate the first 6 to 24 hours and are replaced by macrophages from monocytes over 24 to 48 hours. Phagocytes recognise microbes through pattern recognition receptors and opsonins (IgG and C3b), engulf them and kill them with reactive oxygen species (the NADPH oxidase respiratory burst and, in mammalian neutrophils, myeloperoxidase producing hypochlorite) and granule enzymes.
Mediators come from cells or from plasma proteins. Vasoactive amines, histamine from mast cells and platelets and serotonin from platelets (and from mast cells in rodents and cattle), cause vasodilatation and increased venular permeability within seconds. Arachidonic acid, released from membrane phospholipids by phospholipase A2, is converted by cyclooxygenases to prostaglandins and thromboxane, and by 5-lipoxygenase to leukotrienes. Prostaglandin E2 causes vasodilatation, pain and fever; thromboxane A2 aggregates platelets and constricts vessels; prostacyclin does the opposite; leukotriene B4 is chemotactic, and the cysteinyl leukotrienes C4, D4 and E4 cause bronchoconstriction and permeability. Glucocorticoids reduce arachidonic acid release and cytokine gene expression; non-steroidal anti-inflammatory drugs inhibit cyclooxygenase. Plasma protein systems include complement (C3a and C5a as anaphylatoxins causing mast cell degranulation, C5a as a chemoattractant, C3b as an opsonin and C5b-9 as the membrane attack complex), the kinin system (bradykinin, which increases permeability and causes pain), and the coagulation and fibrinolytic systems (thrombin, fibrinopeptides, plasmin). Systemic effects of inflammation, the acute phase response, are driven mainly by interleukin-1, interleukin-6 and tumour necrosis factor: fever (via prostaglandin E2 in the hypothalamus), anorexia, lethargy, leukocytosis with a left shift (or, in cattle, often a leukopenia and neutropenia early in severe acute infection because the bovine marrow neutrophil reserve is small), and hepatic production of acute phase proteins. The major acute phase proteins differ by species: C-reactive protein and serum amyloid A in dogs, serum amyloid A and alpha-1 acid glycoprotein in cats, haptoglobin and serum amyloid A in cattle, serum amyloid A in horses, and C-reactive protein, haptoglobin and pig-major acute phase protein in pigs.
Serous inflammation produces a thin, clear, protein-poor fluid, as in blisters, early inflammation of serosal surfaces and the vesicles of foot-and-mouth disease. Catarrhal (mucous) inflammation affects mucous membranes, where goblet cells produce excess mucus, as in the nasal discharge of an early upper respiratory infection. Fibrinous inflammation follows marked permeability that lets fibrinogen escape and polymerise into yellow, friable strands and sheets on serosal surfaces; it is especially common in cattle and pigs. Examples are fibrinous pericarditis and pleuritis in pigs with Glaesser's disease (Glaesserella parasuis), fibrinous pleuropneumonia in cattle with Mannheimia haemolytica or contagious bovine pleuropneumonia (Mycoplasma mycoides subsp. mycoides), and the diphtheritic (fibrinonecrotic) membranes of calf diphtheria or salmonellosis in the intestine. Fibrin may be removed by fibrinolysis or organised into fibrous adhesions, as in the 'bread and butter' pericarditis of traumatic reticulopericarditis. Purulent (suppurative) inflammation produces pus, a mixture of living and dead neutrophils, liquefied tissue and bacteria; pyogenic bacteria include Staphylococcus, Streptococcus, Trueperella pyogenes and Pasteurella species. A localised collection of pus surrounded by a fibrous capsule is an abscess; pus in a pre-existing cavity is an empyema (for example, of the guttural pouch in horses with strangles); diffuse suppurative inflammation spreading along tissue planes is cellulitis (or phlegmon). Birds and reptiles have heterophils that lack the myeloperoxidase of mammalian neutrophils and so rarely form liquid pus; their inflammatory exudate is typically caseous and dry. Haemorrhagic inflammation contains many red cells from severe vascular damage, as in anthrax, acute clostridial enterotoxaemia and canine parvovirus enteritis.
Chronic inflammation lasts weeks to years and is characterised by infiltration of mononuclear cells (lymphocytes, plasma cells and macrophages), continuing tissue destruction, and attempts at repair by fibrosis and angiogenesis. Macrophages are the central cell: they phagocytose and secrete cytokines, growth factors (for fibroblasts and new vessels) and enzymes, and they present antigen to T cells. Granulomatous inflammation is a distinctive form of chronic inflammation in which activated macrophages called epithelioid cells, with abundant pale pink cytoplasm and indistinct borders, cluster together and often fuse into multinucleated giant cells. Langhans giant cells have nuclei arranged in a horseshoe at the periphery; foreign body giant cells have nuclei scattered through the cytoplasm. A granuloma is a nodular aggregate of epithelioid macrophages, usually surrounded by lymphocytes and plasma cells and a fibrous capsule, sometimes with central caseous necrosis. Causes include mycobacteria (Mycobacterium bovis tuberculosis; Johne's disease caused by Mycobacterium avium subsp. paratuberculosis, which produces diffuse granulomatous enteritis with thickened, corrugated ileal mucosa rather than discrete granulomas), fungi (Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Aspergillus), Actinomyces bovis (lumpy jaw, with sulphur granules and club colonies, the Splendore-Hoeppli reaction), Actinobacillus lignieresii (wooden tongue), Rhodococcus equi in foals, feline infectious peritonitis (pyogranulomatous vasculitis), migrating parasites, and foreign bodies such as suture material, plant awns and hair (as in canine interdigital furunculosis).
Repair restores tissue after injury in two ways: regeneration, the replacement of lost cells by the same type so that structure and function return, and replacement by connective tissue (fibrosis, scar), which restores continuity but not specialised function. Which occurs depends on the proliferative capacity of the cells and on whether the supporting stroma, especially the basement membrane and reticulin framework, survives. Cells are classified by their capacity to divide. Labile (continuously dividing) cells include surface epithelia of skin, gastrointestinal tract and urinary tract, and haematopoietic cells; they regenerate readily from stem cells. Stable (quiescent) cells normally divide little but can enter the cell cycle when stimulated: hepatocytes, renal tubular cells, fibroblasts, endothelium, smooth muscle and pancreatic acinar cells. Permanent cells cannot divide in adult life: most neurons and cardiac myocytes; skeletal muscle has limited regeneration from satellite cells when the basal lamina survives, as in nutritional myopathy, but heals by scar after extensive destruction. The liver shows both paths. After loss of hepatocytes with an intact framework, as after partial hepatectomy or a single toxic insult, it regenerates completely. When injury is repeated and the framework collapses, regenerating hepatocytes form nodules separated by bands of fibrous tissue; the end stage is cirrhosis, a diffuse, irreversible change of the liver into regenerative nodules and fibrous septa, seen for example in pyrrolizidine alkaloid poisoning of horses and cattle from Senecio species, chronic aflatoxicosis and copper-associated hepatitis of Bedlington terriers and other breeds.
Healing by connective tissue follows a predictable sequence. Within 24 hours of injury a clot fills the defect and neutrophils arrive. From about 3 to 5 days granulation tissue forms: a pink, soft, granular tissue named for its surface, made of new capillaries (angiogenesis) growing into the defect, proliferating fibroblasts and a loose, oedematous matrix with inflammatory cells. Granulation tissue bleeds easily, resists infection and is the hallmark of healing. Fibroblasts then lay down collagen, first type III and later type I; some become myofibroblasts, which contract the wound. Over weeks to months the scar is remodelled by matrix metalloproteinases, becomes pale and avascular, and gains strength, although a skin wound usually recovers only about 70 to 80 per cent of the tensile strength of intact skin. Healing by first intention (primary union) occurs in a clean, closely apposed surgical incision with little tissue loss: epithelium bridges the gap within a day or two and only a thin scar forms. Healing by second intention (secondary union) occurs in wounds with tissue loss, infection or separated edges: the defect fills with abundant granulation tissue, wound contraction by myofibroblasts reduces its size, and epithelium migrates across the surface from the edges. Species matter. Horses, particularly on the distal limb, tend to form exuberant granulation tissue ('proud flesh') that protrudes above the skin and blocks epithelialisation; wounds contract less on the distal limb, and horses heal more slowly than ponies, which have a stronger early inflammatory response.
Local factors that delay healing include infection (the most important), foreign bodies, movement, poor blood supply, repeated trauma, necrotic tissue, excessive pressure and the site itself. Systemic factors include poor nutrition (protein deficiency and vitamin C deficiency, the latter relevant to guinea pigs, which cannot synthesise vitamin C, and which then make defective collagen), glucocorticoid excess (which reduces inflammation, fibroblast activity and collagen synthesis), diabetes mellitus, old age, anaemia and hypoproteinaemia. Bone heals by a specialised sequence: haematoma, inflammation, a soft (fibrocartilaginous) callus, a hard (bony) callus of woven bone, and remodelling to lamellar bone. In the central nervous system, neurons are not replaced; astrocytes proliferate to form a glial scar (gliosis), and phagocytic microglia and macrophages (gitter cells) remove debris after necrosis.
Type I (immediate) hypersensitivity is mediated by IgE bound to mast cells and basophils; re-exposure cross-links the IgE, releasing histamine, leukotrienes and other mediators within minutes. Systemic anaphylaxis is its most severe form, and the target ('shock') organ differs by species: in dogs the liver and gastrointestinal tract (hepatic venous congestion and portal hypertension), in cattle, sheep, horses and cats the lungs and respiratory tract. Localised type I diseases include canine atopic dermatitis, flea allergy dermatitis, insect bite hypersensitivity of horses (sweet itch, caused by Culicoides midges), recurrent airway obstruction of horses in part, and milk allergy in cows sensitised to their own alpha-casein. Type II (cytotoxic) hypersensitivity is antibody against antigens on cells, destroying them by complement, phagocytosis or antibody-dependent cytotoxicity: neonatal isoerythrolysis in foals, mules, kittens (type A kittens born to type B queens) and piglets; immune-mediated haemolytic anaemia and thrombocytopenia of dogs; incompatible transfusions; and drug-induced haemolysis. Type III (immune complex) hypersensitivity follows deposition of antigen-antibody complexes in vessel walls, glomeruli and joints, where they fix complement and attract neutrophils. The local form is the Arthus reaction; systemic forms include glomerulonephritis in chronic infections (canine pyometra, dirofilariasis, feline leukaemia virus, equine infectious anaemia), the uveitis ('blue eye') caused by canine adenovirus 1 infection or vaccination, purpura haemorrhagica of horses after Streptococcus equi infection, and hypersensitivity pneumonitis (farmer's lung) in cattle exposed to mouldy hay. Type IV (delayed-type) hypersensitivity is mediated by T cells and macrophages and peaks 24 to 72 hours after exposure: the tuberculin skin test, allergic contact dermatitis and the granulomas of tuberculosis are examples.
Autoimmune disease results from failure of self-tolerance, so that antibodies or T cells attack the host's own tissues. Organ-specific examples in animals include lymphocytic thyroiditis, the commonest cause of hypothyroidism in dogs; acquired myasthenia gravis, with antibodies against the acetylcholine receptor, often with megaoesophagus and sometimes associated with thymoma; the pemphigus complex, of which pemphigus foliaceus is the commonest autoimmune skin disease of dogs and cats, with antibodies against desmosomal proteins (desmocollin-1 in dogs) causing acantholysis and superficial pustules; immune-mediated haemolytic anaemia with spherocytes and a positive Coombs test; and hypoadrenocorticism caused by immune destruction of the adrenal cortex. Immunodeficiencies are primary (inherited) or secondary (acquired). Primary examples include severe combined immunodeficiency of Arabian foals (a DNA-dependent protein kinase catalytic subunit defect, leaving foals without functional T and B lymphocytes, so they die of infections such as adenovirus pneumonia and cryptosporidiosis within months once maternal antibody wanes); Chediak-Higashi syndrome (giant granules in leukocytes and melanocytes, partial albinism and bleeding) in Hereford and Japanese Black cattle, Persian cats, mink and other species; and cyclic haematopoiesis (cyclic neutropenia) of grey Collies. Secondary immunodeficiencies are far more common: failure of passive transfer of colostral antibody in foals, calves, lambs and piglets; viral destruction of lymphoid tissue (infectious bursal disease in chickens, Marek's disease, feline immunodeficiency virus and feline leukaemia virus, bovine viral diarrhoea virus, canine distemper and parvovirus); malnutrition; and glucocorticoid or cytotoxic drug therapy.
Genetic diseases arise from changes in DNA: single-gene (Mendelian) defects, chromosomal abnormalities, and polygenic or multifactorial traits in which several genes and the environment interact, such as hip dysplasia in dogs. Most single-gene diseases of livestock are autosomal recessive: carriers are clinically normal, and the disease appears when a popular sire used widely by artificial insemination spreads the allele, so that inbreeding brings two copies together. Well-known examples in Holstein cattle are bovine leukocyte adhesion deficiency (BLAD, CD18 mutation), deficiency of uridine monophosphate synthase (DUMPS, embryonic death), complex vertebral malformation (CVM, a SLC35A3 defect causing abortion and calves with vertebral malformations and arthrogryposis), and brachyspina. Others include bovine citrullinaemia (argininosuccinate synthetase deficiency) in Holstein-Friesians and alpha-mannosidosis in Angus and Galloway cattle; hereditary chondrodysplasia ('bulldog' calves) in Dexter cattle; porcine stress syndrome and malignant hyperthermia, caused by a mutation in the ryanodine receptor (RYR1) calcium channel of skeletal muscle and producing pale, soft, exudative pork; and hyperkalaemic periodic paralysis (HYPP) of Quarter Horses descended from one stallion, an autosomal dominant sodium channel (SCN4A) mutation. In dogs, examples include the ABCB1 (MDR1) mutation in Collies and related herding breeds, which makes them sensitive to ivermectin and some other drugs; collie eye anomaly; progressive retinal atrophy; von Willebrand disease; and haemophilia A and B, which are X-linked recessive and so seen mostly in males.
Chromosomal abnormalities are changes in number (aneuploidy) or structure. The 1/29 Robertsonian translocation, a fusion of chromosomes 1 and 29, is the best known structural abnormality in cattle; carriers are normal but have reduced fertility because of unbalanced gametes. The freemartin is a sterile heifer born co-twin to a bull. Placental vascular anastomoses allow the exchange of blood cells and hormones between the twins, so the heifer is an XX/XY blood chimera, and anti-Mullerian hormone and other male factors from the male twin suppress her reproductive tract: she has a small vulva, a short blind vagina and underdeveloped or absent uterus and ovaries. More than 90 per cent of heifers born twin to a bull are freemartins; the condition is also recorded in sheep, goats and pigs. Congenital anomalies (birth defects) may be inherited, or caused in utero by teratogens, which act during a critical window of organogenesis. Viral teratogens include bovine viral diarrhoea virus (cerebellar hypoplasia, cataracts and retinal atrophy after infection in mid-gestation, and persistently infected immunotolerant calves after early infection), Akabane and Schmallenberg viruses (arthrogryposis and hydranencephaly), bluetongue virus vaccine strains and field strains (hydranencephaly in lambs), border disease virus ('hairy shaker' lambs), and feline panleukopenia virus (cerebellar hypoplasia in kittens infected late in gestation or neonatally). Plant teratogens include Veratrum californicum (cyclopia in lambs whose dams ate it on about day 14 of gestation, through cyclopamine blocking the Sonic hedgehog pathway) and Lupinus species (crooked calf disease).
Failure of development gives agenesis (complete absence of an organ, including its primordium), aplasia (failure of an organ primordium to develop, so the organ is absent or rudimentary), and hypoplasia (incomplete development, so the organ is smaller than normal but functional to some degree), such as cerebellar hypoplasia from bovine viral diarrhoea or feline panleukopenia infection, renal hypoplasia and segmental aplasia of the Mullerian ducts in white Shorthorn heifers ('white heifer disease'). Atrophy is a decrease in the size of an organ or tissue after it has reached normal size, through loss of cell size or number. Causes are reduced workload (disuse atrophy of limb muscle in a cast), loss of innervation (denervation atrophy, as in laryngeal hemiplegia of horses, in which the left recurrent laryngeal nerve fails and the cricoarytenoideus dorsalis muscle atrophies), reduced blood supply, inadequate nutrition (serous atrophy of fat, in which fat depots, including those of the coronary groove and bone marrow, become gelatinous, translucent and grey, a key sign of starvation or cachexia), loss of endocrine stimulation (for example, testicular atrophy) and pressure. Hypertrophy is an increase in size of cells and so of the organ, without new cells, as in the heart muscle of animals with pressure overload (left ventricular hypertrophy with aortic stenosis, right ventricular hypertrophy in brisket disease), in the pregnant uterus (where hyperplasia also contributes), and in the remaining kidney after loss of the other (compensatory). Hyperplasia is an increase in the number of cells: physiological (the lactating mammary gland) or pathological, such as benign prostatic hyperplasia of older intact dogs, driven by dihydrotestosterone; cystic endometrial hyperplasia of bitches under progesterone; thyroid hyperplasia (goitre) from iodine deficiency or goitrogens; and hyperplasia of the gastric mucosa. Metaplasia is the reversible replacement of one differentiated cell type by another of the same germ layer, usually better able to withstand stress: squamous metaplasia of glandular and respiratory epithelium in vitamin A deficiency, and squamous metaplasia of the prostate in dogs with oestrogen-secreting Sertoli cell tumours. Dysplasia, in the cellular sense, is disordered growth and maturation with cellular atypia, often preneoplastic; the word is also used in its developmental sense for abnormal formation of a tissue, as in hip and elbow dysplasia. Anaplasia is the loss of differentiation seen in malignant tumours.
A neoplasm (tumour) is an abnormal mass of tissue whose growth exceeds and is uncoordinated with that of normal tissue, and persists after the stimulus that caused it has stopped. Benign tumours usually take the suffix -oma: from surface epithelium a papilloma, from glandular epithelium an adenoma, from fibrous tissue a fibroma, from fat a lipoma, from smooth muscle a leiomyoma, from blood vessels a haemangioma. Malignant tumours of epithelium are carcinomas (squamous cell carcinoma, adenocarcinoma, transitional cell or urothelial carcinoma) and those of mesenchymal tissue are sarcomas (fibrosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, haemangiosarcoma). Tumours of blood-forming and lymphoid cells are leukaemias (in the blood and marrow) and lymphomas (solid lymphoid masses). Several names break the rule and must be learned: lymphoma, melanoma, mesothelioma and seminoma are malignant despite the -oma suffix (melanomas and seminomas in animals include benign-behaving examples, so behaviour is judged case by case), and a hamartoma is a disorganised but non-neoplastic mass of tissues normal to the site, whereas a choristoma is normal tissue in an abnormal site. Mixed tumours contain more than one neoplastic cell type from one germ layer, such as the canine mammary mixed tumour with epithelial, myoepithelial and cartilaginous or bony elements. Teratomas contain tissues from more than one germ layer and arise from germ cells, especially in the ovary and testis. Round cell tumours of dogs, recognised on cytology as discrete individual cells, are lymphoma, mast cell tumour, histiocytoma, plasmacytoma and transmissible venereal tumour (melanoma may resemble them).
Benign tumours are usually well differentiated, grow slowly and expansively, are often encapsulated, compress rather than invade neighbouring tissue, and do not metastasise; they cause harm by their position (a meningioma in the skull), by hormone production (an insulinoma causing hypoglycaemia) or by ulceration. Malignant tumours show variable differentiation up to anaplasia (loss of differentiation), with pleomorphism, large nuclei with a high nuclear-to-cytoplasmic ratio, prominent nucleoli, numerous and atypical mitoses and loss of polarity; they grow faster, invade locally and metastasise. Invasion and metastasis are the most reliable criteria of malignancy. Metastasis occurs by three routes: lymphatic spread, typical of carcinomas, to regional lymph nodes first; haematogenous spread, typical of sarcomas, most often to the lungs (via systemic veins) or liver (via the portal vein); and transcoelomic spread by seeding across body cavities, as in ovarian and mesothelial tumours and carcinomatosis. Grading describes the degree of differentiation and mitotic activity of the tumour cells under the microscope; staging describes the extent of spread in the patient, usually with the TNM system (T for the size and extent of the primary tumour, N for regional node involvement, M for distant metastasis) and, for lymphoma in dogs, the World Health Organization stages I to V with substages a (no systemic signs) and b (systemic signs). Stage generally predicts outcome better than grade. Mitotic count is now expressed per 2.37 square millimetres, the area traditionally covered by 10 high-power fields of a standard microscope, so that counts can be compared between microscopes. The canine cutaneous mast cell tumour is graded by the three-tier Patnaik system (grades I to III) and by the two-tier Kiupel system (low or high grade); in the Kiupel system a tumour is high grade if it has at least 7 mitotic figures in 10 high-power fields, at least 3 multinucleated cells in 10 high-power fields, at least 3 bizarre nuclei in 10 high-power fields, or karyomegaly.
Mutations accumulate in proto-oncogenes, which become activated oncogenes that drive growth (for example, the KIT receptor tyrosine kinase mutated in a proportion of canine mast cell tumours and gastrointestinal stromal tumours, which is the target of tyrosine kinase inhibitors), in tumour suppressor genes that normally brake the cell cycle or trigger apoptosis (TP53 and RB), and in DNA repair genes. Carcinogens are chemical (for example, aflatoxin B1 as a hepatocarcinogen, ptaquiloside in bracken fern associated with bladder and upper alimentary tumours in cattle), physical (ultraviolet light, which causes squamous cell carcinoma of unpigmented skin on the ear tips and nose of white cats and of the eyelid and eye of cattle with unpigmented periocular skin, such as Herefords; and ionising radiation), and biological. Oncogenic viruses are especially important in animals: retroviruses such as bovine leukaemia virus (enzootic bovine leukosis, B-cell lymphoma in adult cattle), feline leukaemia virus (lymphoma and leukaemia), avian leukosis virus, reticuloendotheliosis virus and Jaagsiekte sheep retrovirus (ovine pulmonary adenocarcinoma, with copious lung fluid that pours from the nostrils when the hindquarters are lifted, the 'wheelbarrow test'); the herpesvirus of Marek's disease, which causes T-cell lymphoma and peripheral nerve enlargement in chickens; and papillomaviruses causing warts in cattle, dogs and horses, and bovine papillomavirus types 1 and 2 associated with equine sarcoid. Paraneoplastic syndromes are effects of a tumour at a distance from it, produced by its products rather than by its mass or metastases: hypercalcaemia of malignancy (lymphoma, anal sac apocrine gland adenocarcinoma, multiple myeloma), hypoglycaemia (insulinoma, some large hepatic and smooth-muscle tumours), feminisation with alopecia, gynaecomastia and bone marrow suppression by oestrogen (Sertoli cell tumour of the canine testis), hypertrophic osteopathy (periosteal new bone on the distal limbs, usually with a thoracic mass), cancer cachexia, anaemia, hypergammaglobulinaemia and hyperviscosity (myeloma), erythrocytosis (renal tumours) and gastric ulcers from histamine release (mast cell tumours).
Dogs: the cutaneous mast cell tumour, often in Boxers and other brachycephalic breeds, can mimic any skin lesion and may release histamine and heparin when handled (Darier's sign); the histiocytoma, a benign tumour of Langerhans cells in young dogs, often on the head and limbs, usually regresses spontaneously; lipomas are common in older and overweight dogs; the perianal (hepatoid) gland adenoma occurs in older intact males and is androgen-dependent, so castration is part of treatment; mammary tumours are the commonest tumour of intact bitches, and roughly half are malignant, while ovariohysterectomy before the first or second oestrus greatly reduces the risk; osteosarcoma affects the metaphyses of long bones of large and giant breeds, classically 'away from the elbow, towards the knee' (distal radius, proximal humerus, distal femur, proximal tibia), and metastasises to the lungs early; haemangiosarcoma, especially in German Shepherds and Golden Retrievers, arises in the spleen, right atrium and skin and presents as haemoperitoneum or pericardial tamponade; multicentric lymphoma presents with generalised lymphadenopathy; oral malignant melanoma is aggressive; transitional cell carcinoma of the bladder trigone is overrepresented in Scottish Terriers; the canine transmissible venereal tumour is a naturally transplanted tumour spread by coitus and licking, in which the tumour cells themselves are the infectious agent, and it responds well to vincristine chemotherapy. Cats: lymphoma is the commonest tumour, with alimentary lymphoma now predominating where feline leukaemia virus has been controlled; mammary tumours are mostly (in the order of 80 to 90 per cent) malignant adenocarcinomas; squamous cell carcinoma of white ears and nose, and oral squamous cell carcinoma; and feline injection-site sarcoma, an aggressive fibrosarcoma that arises at sites of injections, including vaccines. Horses: sarcoid is the commonest skin tumour and does not metastasise but recurs locally; melanomas are very common in older grey horses, around the perineum, tail base and parotid region, and many are slow-growing for years before some become malignant; squamous cell carcinoma of the eye, penis and vulva. Cattle: ocular squamous cell carcinoma ('cancer eye'), enzootic bovine leukosis (bovine leukaemia virus) and sporadic bovine lymphoma forms (calf, thymic and cutaneous), papillomas, and bladder tumours with enzootic haematuria in bracken-grazing cattle. Sheep: ovine pulmonary adenocarcinoma, enzootic nasal adenocarcinoma (a separate retrovirus), and squamous cell carcinoma of the ears and vulva in sunny climates. Chickens: Marek's disease and avian leukosis; Marek's affects young birds with nerve and visceral lymphomas, whereas lymphoid leukosis affects older birds and involves the bursa of Fabricius, a distinction used on necropsy. Incidence figures vary widely by population, country, neutering practice and breed, so they are given here only in rough terms.
As a student you need the vocabulary before anything else: learn to describe a lesion by organ, process, distribution, duration and severity, and to name each process correctly (hyperaemia or congestion, transudate or exudate, dystrophic or metastatic calcification, atrophy or hypoplasia, hyperplasia or neoplasia). Make one example per species for every process, because exam questions and later clinical teaching hang on them: white muscle disease, nutmeg liver, bread-and-butter pericarditis, caseous lymphadenitis, freemartin, cancer eye, proud flesh. Learn which stain shows which substance. When you attend necropsies, practise telling post-mortem change from lesion and a clot from a thrombus. Keep a notebook of the gross photographs you see, labelled with the morphological diagnosis you would write.
Five years into practice you apply general pathology at the table and in the report. You decide whether an abdominal fluid is a transudate or an exudate before you send it; you recognise that jaundice in a sheep on copper-rich feed is haemolytic; you submit a mass in formalin at ten parts fixative to one part tissue, with margins inked, because grade and margin decide the next step. You read a mast cell tumour report and know what a high-grade Kiupel result means for the owner, and why stage matters more than grade. You know when to fix tissue in alcohol (suspected gout) and when to keep a fresh sample for culture. You recognise when a herd problem, such as calves with arthrogryposis or lambs with cerebellar signs, points to a teratogen or an inherited defect, and you collect the dam history and the sire identity.
With twenty-five years' experience you use general pathology to lead investigations and to teach. You set up necropsy protocols for outbreak work, decide which tissues go for histology, toxicology and molecular testing, and interpret findings across a herd rather than one animal. You advise breed societies and artificial insemination centres on carrier testing for inherited defects and on how quickly a popular sire can spread a recessive allele. At a slaughterhouse or in government service you judge whether melanosis, calcified parasites or serous atrophy of fat mean trimming or condemnation, under your national meat inspection rules. You mentor younger vets to write precise morphological diagnoses, to distinguish reactive lymph node hyperplasia from lymphoma, and to explain prognosis honestly using grade, stage and the limits of published data.
At PhD and research level with long experience, general pathology is the basis of mechanistic and comparative work. You design animal models and pathology endpoints for toxicology and drug safety studies under good laboratory practice, using standardised nomenclature and severity grading, and you validate image analysis and immunohistochemistry against pathologist scoring. You study species differences in acute phase proteins, amyloid fibril proteins, apoptosis pathways and oncogenic retroviruses, and you use spontaneous animal tumours such as canine osteosarcoma and lymphoma as comparative models for human cancer. You understand the reproducibility problems of mitotic counts and grading schemes, publish agreement statistics between pathologists, and contribute to consensus classification systems and to open datasets of annotated whole-slide images.
This manual does not yet cover: systemic (organ-by-organ) pathology, the special pathology of individual infectious and toxic diseases, necropsy technique, and clinical pathology (haematology, biochemistry, cytology, urinalysis), which belong to other subjects; the pathology of fish, reptiles, laboratory rodents and wildlife beyond passing examples; molecular diagnostic methods such as PCR for clonality, immunohistochemistry panels and next-generation sequencing; and tumour-specific treatment protocols, drug doses and survival figures, which vary by study and must be taken from current oncology sources. Incidence and malignancy percentages for tumours are given only as widely taught approximations and vary by country, breed and neutering practice. Species lists for shock organs and acute phase proteins follow common textbook teaching; individual papers differ, and exam setters may follow a particular national textbook. Detailed WHO tumour classification tables and all grading schemes other than the canine mast cell tumour schemes are left out.
Original practice questions written to the syllabus and pattern of the exams named in each question's examTags. They are not past papers and do not reproduce any board's questions.
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