Pathogenesis of Veterinary DiseaseGeneral  Icterus Prehepatic - increased production of circulating bilirubin d/t lysis of erythrocytes

Hepatic - impaired scavenging/processing of bilirubin d/t hepatocellular insufficiencyPosthepatic - impaired excretion of bilirubin d/t biliary disease

Mechanisms of neoplastic transformation

Mesothelioma: 1) direct irritation by asbestos, 2) disruption of mitotic spindle by asbestos fibres-aneuploidy, chromosomal damage, 3) generation of iron-dependent ROS; 4) induces MAPK and ERK-1/2 signaling - stimulation of c-Jun and AP-1 protooncogenes Growth advantage - produce/respond to many growth factors (PDGF-A/B, EGF, TGF-B); may have abnormal Wnt/Frizzled pathway signalling Immortalization - telomerase activity increased in 90% of mesotheliomas Absence of Tumor Suppressor Genes - loss of p14, p16 (involved in P53/Rb signaling); loss of NF2-merlin Apoptotic Avoidance - increased expression of antiapoptotic Bcl-xL Angiogenesis - produce VEGF Matrix interactions - express collagens, matrix metalloproteinases

Carney Complex Protein kinase A regulator gene (PKRAR1A) mutation???Amyloidosis Reactive Amyloidosis - Chronic inflammation > release of IL1& 6 by macrophages > synthesis of SAA by hepatocytes > limited

proteolysis > amyloid deposited as -pleated sheets in glomeruli, interstitium and/or tubular basement membrane > protein leakage βthrough damaged glomeruli > proteinuria.

Type I Hypersensitivity Production of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells; recruitment of inflammatory cells (late-phase reaction)

Type II Hypersensitivity Production of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes

Type III Hypersensitivity Deposition of antigen-antibody complexes → complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules

Type IV Hypersensitivity Activated T lymphocytes → i) release of cytokines and macrophage activation; ii) T cell-mediated cytotoxicityTh1 responses T-helper-1 (TH1) subset synthesizes and secretes IL-2 and interferon- (IFN- ) but not IL-4 or IL-5γ γ delayed hypersensitivity,

macrophage activation, and synthesis of opsonizing and complement-fixing antibodies, such as IgG2a in mice, all of which are actions of IFN-γ

Th2 responses  TH2 cells produce IL-4, IL-5 and IL-13 but not IL-2 or IFN-γ synthesis of other classes of antibodies, notably IgE (mediated by IL-4 and IL-13), activation of eosinophils (mediated by IL-5)

Haptenization Adsorption of a small, nonimmunogenic molecule to a large carrier molecule (such as a protein) to produce an immunogenic complex, inducing an immune response

Acquired Melanosis (pigs) - ingestion of acorns by genetically predisposed pigs swine tyrosinase acts on phenolic substances found in acorns increase the biosynthesis and the anomalous storage of melanin?

Cancer BiologyCachexia  Paraneoplastic hypercalcemia ectopic production of Parathyroid-related protein (PTH-rP) - mobilization of Acute Tumor Lysis syndrome in mice rapid and widespread lysis of tumor cells massive release of intracellular components such as nucleic acids, potassium, and

phosphorus disseminated microemboli composed of nuclear and cytoplasmic debris derived from lysed tumor cells mechanical obstruction of capillary beds death

Mechanisms of viral malignant transformation

Subgroup J Avian Leukosis virus – associated histiocytic sarcoma – in ovo/neonatal infection  persistent viremia ChL5 (myelomonocytic cells and activated T Lymphocytes), CD45 (hematopoietic except erythoid, platelets), and MHC class II – positive tumors arising from splenic ellipsoids and red pulp metastasis to liver, kidney, and other organsEquine Sarcoid – Bovine Papillomaviruses 1/2 express E5 major transforming oncoprotein binds PDGF-BR activating PI3K-AKT-cyclinD pathway proliferation ; also activation of activation of phosphor-JNK and phosphor-JUN

Self-sufficiency in growth signals (Oncogenes)

Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation - protooncogenes - constitutively expressed oncoproteins endow cell with self-sufficiency in growth Growth Factors (PDGF-B/SIS; FGF/HST-1; INT-1; TGF-B/TGF-a; HGF) Growth Factor Receptors (EGF-R family/ERB-1/2; CSF-1R/FMS; neurotropic factors receptor/RET; PDGFR; stem cell factor receptor/KIT) Proteins involved in Signal Transduction (GTP-binding proteins/K-RAS, HRAS, N-RAS; nonreceptor tyrosine kinase/ABL; Ras signal transduction/BRAF; WNT signal transduction/B-catenin) nuclear regulatory proteins (C-MYC, N-MYC, L-MYC) cell cycle regulators (cyclins/cyclin-D, cyclin-E; cyclin-dependent kinase/CDK4)

Insensitivity to growth-inhibitory signals (tumor suppressor genes)

Tumors may not respond to molecules that are inhibitory to the proliferation of normal cells such as transforming growth factor- β(TGF- ), and direct inhibitors of cyclin-dependent kinases. β - TGF-βreceptor, E-cadherin SMAD 2 and SMAD 4 Growth inhibition, Cell adhesion

Failure of TGF-B signalling (inactive TGF-B receptor, diminished SMAD-2/4) diminished CDK inhibitors (Cip/Kip, INK4a) uncontrolled CDK4 complex formation failure of brake mechanisms on cell cycle progression from G1/S(diminished B-catenin expression) Diminished E-cadherin expression disaggregation of cells

- NF-1 Inhibition of RAS signal transduction and of p21 cell-cycle inhibitorLoss of NF-1 diminished neurofibromin uncontrolled RAS-GTP binding and activation continuous cell proliferation signalling

- NF-2 Cytoskeletal stabilityLoss of NF-2 diminished merlin diminished actin-CD44 binding unstable cell-matrix interactions abnormal contact inhibition

- APC/ β-catenin Inhibition of signal transductionDiminished APC failure of downregulation of B-catenin, increased translocation to nucleus forms complex with TCF upregulation of cMYC, cyclin D1, etc upregulated cell proliferation Altered B-catenin - E-cadherin interaction altered cell adhesiveness

- PTEN PI-3 kinase signal transductionDiminished PTEN activity diminished transcription of p27 Kip/Kip cell-cycle inhibitor and stabilizing protein uncontrolled CDK4 complex formation failure of brake mechanisms on cell cycle progression from G1/S

- RB Regulation of cell cycleRB mutation (knock-out or abnormal E2F binding site) failure of transcription of E2F transcription factors uncontrolled CDK4 complex formation failure of brake mechanisms on cell cycle progression from G1/S

- p53 Cell-cycle arrest and apoptosis in response to DNA damage

- Failure of p53 signalling diminished CDK inhibitors (Cip/Kip, INK4a) uncontrolled CDK4 complex formation failure of brake mechanisms on cell cycle progression from G1/S - DNA damage DNA-dependent protein kinase and ATM (ataxia-telangectasia mutated) activation lack of phosphorylation of p53 and protein unfolding unable able to bind to DNA fails to stimulate transcription of several genes that mediate cell-cycle arrest and apoptosis

- WT-1 p16(INK4a) Nuclear transcription; Regulation of cell cycle by inhibition of cyclin-dependent kinasesDiminished p16(Ink4a) activity lost capacity to block cyclin D-CDK4 activity and to prevent RB phosphorylation during the cell cycle

- BRCA-1 and BRCA-2 DNA repair - KLF6 Transcription factor

Diminished KLF6 decreased transcription of Cip/Kip cell-cycle inhibitor p21Evasion of apoptosis Tumors may be resistant to programmed cell death, as a consequence of inactivation of p53 or other changes

- BCL-2Overexpression of BCL-2 accentuated protection from mitochondrial pathway of apoptosis

- P53Diminished expression of p53 diminished transcription of proapoptotic genes (BAX, BID)

Defects in DNA repair Tumors may fail to repair DNA damage caused by carcinogens or unregulated cellular proliferation - DNA mismatch Repair Abnormalities: MSH2(2p16), MLH1 (3p21) genes

Failure of nucleotide mismatch repair progressive accumulation of abnormalities in various genes (protooncogenes, TSGs) microsatellite instability

- nucleotide excision repair – failure of repair of pyrimidine crosslinks impaired DNA replication - recombination repair - ATM gene

Diminished expression of ATM (ataxia-telangiectasis) gene impaired dectection of DNA double-strand breaks (ionizing radiation, O2 free radicals) diminished phosphorylation of p53 failure of cell cycle arrest and apoptosis

- BRCA genes (BRCA-1/2)Diminished BRCA-1/2 expression diminished RAD51 binding impaired repair of double-strand DNA breaks, chromatin remodelling

Limitless replicative potential – Telomerase

Tumor cells have unrestricted proliferative capacity, associated with maintenance of telomere length and functionEnhanced telomerase expression loss of normal telomere shortening with cell replication failure of telomere-mediated, p53-dependent proliferative arrest/apoptosis

Sustained angiogenesis Tumors are not able to grow without formation of a vascular supply, which is induced by various factors, the most important being vascular endothelial growth factor (VEGF) - production of angiogenic factors (HIF-1a-mediated expression of VEGF) - loss of angiogenesis inhibitors – mutation of p53 diminished thrombospondin-1 expression, accentuated VEGF, HIF-1a

Mechanisms of metastasis/invasion Tumor metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue environment 1) Invasion of Extracellular Matrix: detachment of cells from one another - (diminished catenin expression ) - downregulation of E-cadherin diminished homotypic adhesions between cells 2) attachment ot matrix components - Atypical expression/distribution of laminin and fibronectin receptors, increased/atypical expression of integrins invasion of basement membrane, attachment to ECM components3) degradation of ECM - abnormal/enhanced expression of serine, cysteine, matrix metaloproteinases (particularly Type IV collagenases MMP2, MMP9) - matrix degradation releases growth promoting, angiogenic/antiangiogenic, chemotactic factors4) migration of tumor cells5) Vascular dissemination and homing of tumor cells - homotypic adhesions between tumor cells, heterotypic adhesions with platelets (promotes survival and implantability) - Degradation of ECM (as above) - CD44 expression (a normal Tcell adhesion molecule used to migrate to selective sites through interactions with high endothelial venules) – expression may favour metastasis - tumor metastasis homing mediated by: - adhesion molecule-ligand interactions in endothelium of target tissues - chemokine receptor expression on tumor cells – homing to tissues in which chemokine ligand is expressed

Sialyl-Lea – E-selectin ligand - T and Tn antigens -

Cyclooxygenase activity in cancer

Alimentary  

Palatoschisis (Cleft Palate) genetic abnormalities (inherited?); excessive administration of Vit A during gestation (dogs); administration of cortisone during gestation (Dogs) --> Failure of fusion of lateral palatine processes --> Aspiration pneumonia, emaciation

Cheiloschisis (Hare Lip) Failure of fusion of maxillae along midline (philtrum) --> Aspiration pneumonia, emaciationOdontoma hamartoma of enamel organ --> mix of fully-differentiated dental components: Complex - do not form dental structures; Compound -

form numerous differentiated but abnormal dental structures ("denticles")Dentigerous Cyst dental dysgenesis - abnormal proliferation of cell rests of Malassez --> epithelial-lined cyst; may contain rudimentary/malformed teeth

--> may become impacted with keratin; may cause fistula formationDiarrhea four major mechanisms by which diarrhea may occur:

1) Malabsorption with or without bacterial fermentation osmotic diarrhea. Generally, this is a problem of the small intestine, but secondary colonic malfunctions can occur because of malabsorption of bile salts and fatty acids that stimulate fluid secretion in the large intestine.2) Hypersecretion by a structurally intact mucosa. This activity results in a net efflux of fluid and electrolytes independent of permeability changes, absorptive capacity, or exogenously generated osmotic gradients.3) Exudation caused by increased capillary or epithelial permeability (protein-losing enteropathy).4) Hypermotility (increased rate, intensity, or frequency of peristalsis) decreased mucosal contact time, digestion and absorption

of nutrients should be less efficient decreased motility in some diseases allows for increased bacterial proliferation; some enterotoxins can stimulate intestinal motility

Segmental intestinal/colonic/anal aplasia (Atresia coli/ani)

- segmental ischemia - peritonitis - failure of development of luminal epithelial primordium

Meckel's Diverticulum - retention of stalk of yolk sac omphalomesenteric duct remnant (blind-ended sac near termination of ileum)Colonic Aganglionosis (Lethal White Foal Syndrome)

White patterned horses (esp. vero foals). Ile118Lys endothelin receptor B (EDNRB) mutation --> failure of migration of neuroblasts from neural crest - congenital lack of myenteric and/or submucosal plexuses in distal colon/anus - contracted/nonperistaltic distal colon - proximal megacolon (Model for the Hirschprung aganglionosis of humans).

Equine Dysautonomia (Grass Sickness)

Unknown pasture toxin > Toxic intestinal ganglion cell necrosis > progressive craniocaudal impaction. Seasonal. Hares also affected.

Mycotic Rumenitis Grain overload > rumenal acidosis > mucosal damage > opportunistic fungal inf > vasculitis > ischemia & mucosal ulcerationRumenal Tympany (Bloat) Bloat, Primary or frothy - ingestion of legumes > stable foam formation > foam obstructs cardia and inhibits normal eructation >

rumenal distention > respiratory distress > death from anoxiaBloat, Secondary - Failure of eructation (vagal indigestion) > distention of rumen > respiratory distress > death due to anoxiaBloat line - Bloat > elevated intra thoracic pressure > decreased venous return (passive congestion) > cyanosis of extra-thoracic (cervical) esophageal mucosa and pallor of intra-thoracic esophageal mucosa

MCT-associated duodenal ulceration Mast Cell Tumor somewhere in body > histamine release > ↑ gastric parietal cell HCl secretion > pyloric mucosal damage & ulceration

Cardiovascular  

Vitamin D-related metastatic mineralization

Chronic granulomatous disease (M. avium paratuberculosis) - Macrophages Produce Vit D Analog > Aortic Mineralization

Atherosclerosis Hypothyroidism or DM > ↓ lipoprotein lipase activity > ↑ cholesterol > atherosclerosisScurvy Guinea pig, P, red-vented bulbul bird, northern shrike, Indian pipstrels, channel catfish, & primates normally lack L-Gulonolactone

Oxidase necessary for Vit C synthesisPathogenesis: Lack L-Gulonolactone Oxidase > dietary Vit C defic > ↓ lysine & proline hydroxylation > impaired Type 1 & 4 collagen synthesis > weakened vessel walls (physeal cartilage deformity) > periarticular hemorrhage (&/or osteochondrodysplasia)

Ionophore Toxicosis Toxic exposure to Lasalocid/Monensin > Exchange of cations for protons across cell membranes without using ion channels > decreased ATP production, increased ATP utilization (to maintain cation concentrations) > cell death > Myocardium necrosis and fibrosis

E. coli-associated Edema Disease Edema of Eyelids, Mesocolon, Gallbladder, Glandular Portion of Stomach, Mesenteric LNs, Larynx, & Lungs; Hydrothorax & Hydropericardium; Bilaterally Symmetric Brainstem MalaciaE. coli Inf > Shiga-like toxin prod > endothelial damage > ↑ vascular permeability > edema (various tissues)In brain: Shiga like toxin type IIe > Necrosis of smooth muscle cells in the arteriole and arteries > vascular compromise > infarction

Fibrinosuppurative pericarditis Traumatic Reticuloperitonitis/Pericarditis (Hardware Dz) - Ingest wire foreign body > penetrates reticulum wall & diaphragm into pericardium > fibrinous pericarditis & epicarditis

High-Altitude Disease High altitude > chronic hypoxia > pulmonary artery vasoconstriction > right ventricular hypertrophy & failure > chronic passive congestion > edema

Viral Vascular Disease Bluetongue - Culicoides (midge, gnat) bites sheep > hematopoietic cell viral replication > viremia > widespread endothelial cell viral replication & damage > hemorrhage, edema, thrombosis, & infarction - Hemorrhage at the Base of the Pulmonary Artery; Rumenal Pillar Hemorrhage & NecrosisNon-effusive FIP - Coronaviral inf of møs > weak cell-mediated immune response > virus persists in møs > pyogranulomatous inflam (non-effusive form)

Type III Hypersensitivity Vasculitis Purpura Hemorhagica - Streptococcus equi equi Ag/Ab complexes. Ag/ab complex vasculitis.Aleutian Mink Disease - Parvoviral inf of lymphocytes >viral release > immune complex deposition in vessels, glomeruli, & other tissues > plasmacytic vasculitis, GN, splenomegaly/hepatomegaly, & hypergammaglobulinemiaEffusive FIP - Coronaviral inf of møs > no cell mediated response > viremia > non-neutralizing antibodies deposited in vessel walls > fibrinonecrotic peritonitis & vasculitis (effusive form)

Parasitic Vascular Disease Strongylus vulgaris infarcts - Ingestion of L3 larvae of Strongylus vulgaris > larvae enter wall of cecum and colon and molt to L4 larvae > penetrate arterioles > migrate up the vessel along the intima > localize in cranial mesenteric artery and its branches along the aorta > arteritis, thrombosis + aneurysm > + emboli to small and large intestine > intestinal infarction and abdominal pain (colic).

Human Familial hypertrophic cardiomyopathy

AD; various mutations involving sarcomeric proteins of cardiac myocytes (Cardiac B-myosin heavy chain; Cardiac troponin T; Cardiac troponin I; A-tropomyosin; Ventricular myosin essential light chain; Cardiac myosin-binding protein C)

Human familial dilated cardiomyopathy

Documented mutations in dystrophin, myosin

Boxer arrhythmogenic right ventricular cardiomyopathy

AD; humans – mutations in ryanodine receptor 2 gene and desmoplakin gene

Marfan Syndrome Mutation in Fibrillin Gene abnormal collagen crosslinking? megaloglobus, ectopia lentis; degeneration of elastic laminae aortic, pulmonary arterial, coronary arterial dissecting aneurysm and rupture

Coagulation  Vitamin K-deficient hemorrhagic diathesis

Ingest rodenticide/clover > coumarin toxicity > ↓ Vit K > ↓ Vit K-dep coag factors (II, VII, IX, & X) > hemorrhage

Saddle Thrombus Feline - HCM --> left atrial enlargement>blood turbulence/stasis > thromboembolism formation > distal aortic and ilial thrombosis (Note: Sometimes assoc w/ hyperthyroidism)

Simmental Thrombopathia Calcium diacylglycerol guanine nucleotide exchange factor I mutation ????Rambouillet Sheep Coagulopathy Mutations in g-glutamyl carboxylase deficient?? diminished vitamin K-dependent coagulation parametersDisseminated Intravascular Coagulation

 

Hepatobiliary-associated hemorrhagic diatheses

1) failure of metabolism of vitamin K2) failure of synthesis of coagulation factors (all but Factor 8), anticoagulant factors, fibrinolytic factors3) failure of scavenging of activated coagulation factors, anticoagulant factors (such as FDPs), fibrinolytic factors

Uremic coagulopathy  Hemophilias  Inherited Thrombasthenia  Hypercoagulability of glomerular disease

Protein-losing nephropathy loss of antithrombin III in the urine hypercoagulable state( atrial thrombosis (hamsters))

Endocrine  

Mature onset diabetes for the Young Inactivating mutations for Beta cell function (human):

(MODY) - glucokinase rate-limiting step for glucose metabolism in beta cells - insulin gene transcriptional regulators PDX1, HNF1a, HNF4a

Ferret Hyperadrenocorticism Adrenal cortical hyperplasia/adenoma/carcinoma > estrogenic hormone secretion > swollen vulva, hypocellular marrow, nonregen anemia, & alopeciacytochrome b5 (cyt b5) allosteric regulator that selectively enhances the 17,20-lyase activity of P450c17 androgen synthesis

Primary Hyperparathyroidism Functional parathyroid adenoma/adenomatous hyperplasia > excessive PTH secretionClinicopathologic Findings: Hypercalcemia, hypophosphatemia, elevated alkaline phosphatase due to bone resorption.

Hyperplastic Goiter Iodine Defic, Goiterogenic Agents (Brassica sp., Sulfonamides, Thiouracil, etc.), Iodine Excess, or Congenital Enzyme Defect Affect Hormone Synthesis (Corriedale, Dorset Horn, Merino, & Romney Sheep, Afrikander Cattle, & Saanen Dwarf Goats)Pathogenesis: Any of the above causes >inadequate thyroxine synthesis > ↓ free T4 & T3 > stim TSH secretion > follicular cell hypertrophy & hyperplasia

Thyroid peroxidase deficiency in Rat Terriers, Toy Fox Terrier

AR Thyroid peroxidase deficiency congenital hypothyroidism CNS hypomyelination

Multiple Endocrine Neoplasia Syndrome in cats, humans

Menin gene mutations development of multiple tumors in parathyroid, pituitary, pancreatic endocrine tumors

Diabetes Mellitus  Diabetes Insipidus  Cushing's Disease  Hypothyroidism  Hyperthryoidism  

Haemolymphatic  

Congential Erythrocytic Porphyria Shorthorns, Holsteins – AR hereditary deficiency of uroporphyrinogen III cosynthase > Defective heme synthesis > accumulation of porphyrin pigment in bone or teeth, porphyrinuria, epidermolysis and exudative dermatitis (photosensitization), and hemolytic anemia

Protoporphyria Limousins - deficiency of ferrochelatase > accumulation of protoporphyrin in the skin > absorption of UV light energy by protoporphyrin > epidermolysis and exudative dermatitis (photosensitization) (NO discoloration of teeth, urine, or anemia)

Pyruvate Kinase Deficiency Pyruvate kinase deficiency Diminished ability to synthesize ATP diminished erythrocyte lifespan osteosclerosis, hemochromatosis, myelofibrosis

Phosphofructokinase deficiency Point mutation in M gene for erythrocyte/muscle phosphofructokinase deficiency haemolytic anemia, hemosiderosis, EMH, slowly-progressive myodegeneration with myocyte vacuolation and PAS-positive, diastase-resistant inclusions

Estrogen Myelotoxicosis Ferret - prolonged estrus - prolonged Hyperestrogenism – bone marrow suppression/toxicosis – thrombocytopenia, anemia – hemorrhages

Anemia of Chronic Disease Increase in IL-1, IL-10, TNF-a, IFN-g --> increased production of Ferritin, Transferrin, Divalent Metal Trasporter 1 --> increased iron storage in RES inhibition of erythropoiesis (reduced EPO receptors, secretion; reduced Stem Cell Factor; apoptosis)Increase in IL-6, action of LPS --> increased production of hepcidin --> decreased iron absorption, increased sequestration in RES (inhibition of Ferroportin)Increase in TNF-a, erythrophagocytosis --> decreased RBC half-life

Acute intravascular hemolysis Equine Lentivirus (EIA) - Virus adsorbed on erythrocytes > IgM, IgG attachment to virus > complement activation > hemolysis; bone marrow hyperplasia and then atrophy; ag-ab membranous glomerulonephritis; virus within macrophage cytoplasm (ISH)

Hemolytic anemia in Japanese Black Cattle

Lack band 3 integral protein (necessary to link lipid bilayer of erythrocyte membrane to cytoskeleton) haemolytic anemia, stunted growth

Neonatal isoerythrolysis Mare sensitized to fetal RBC sire inherited-antigens in utero > foal ingests anti-RBC antibodies in colostrum > IV hemolysis > icterus, hemoglobinemia, hemoglobinuria, splenomegaly, & anemia w/ erythroid marrow hyperplasia

Severe Combined Immunodeficiency (SCID)

Arab foals - V(D)J gene defect > blocked development of B & T lymphocytes > Immunosuppression > Opportunistic adenovirus and Pneumocystis carinii pneumonia

Bovine Leukocyte Adhesion Deficiency

Holstein calves – AR inherited single point mutation (adenine to guanine) at position 383 of the CD18 gene impaired expression of the beta2 integrin (CD11a,b,c/CD18) of the leukocyte adhesion molecule on neutrophils failure of extravasation of neutrophils persistent marked neutrophilia bacterial infections, delayed wound healing and stunted growth ulcers on oral mucous membranes, severe periodontitis, loss of teeth, chronic pneumonia and recurrent or chronic diarrhea

Hepatobiliary  

Hepatic Lipidosis Guinea Pigs, Rabbit, Cow, Ferret, Cat, Horse, Sheep, Macaque, & Camelids: Obese animal > anorexia (after parturition in dairy cattle, before parturition in beef cattle, during preg & lactation in horses, during preg in rabbits & GPs, & with Vit B12 & cobalt defic in sheep) > ↑ adipose tissue lipid mobilization > overwhelms hepatocellular FA oxidation & VLDL formation > hepatocellular lipid accum Watanabe rabbits - genetic defect in low-density lipoprotein receptor gene causing hypercholesterolemia, hepatic lipidosisDiabetes Mellitus - Reduced insulin-dependent glucose uptake by cells accelerated lipolysis from adipose tissue

Hepatic Glycogenosis Hyperglycemia secondary to diabetes mellitus > glucose uptake by the liver (not insulin-dependent as in in muscle, fat, fibroblasts) > excess intrahepatocellular glucose stored as glycogen.

Pyrrolizidine Alkaloid Toxicosis Crotalaria, Senecio, Cynoglossum, Heliotropium, Echium,, Amsinckia, Symphytum ingestion > Cytopathic effect and mitosis inhibition causing hepatic portal fibrosis with bile duct hyperplasia and megalocytes. (Also photosensitivity dermatitis).

Corriedale sheep hyperbilirubinemia Mutation in canalicular multispecific organic anion transporter (cMOAT) accumulation of black pigment in hepatocyte lysosomesCongenital Erythrocytic Protoporphyria in Limousin, Blonde d’Aquitaine cattle

Ferrochelatase deficiency accumulation of protoporphyrin pigments in portal regions, Kupffer cells, sinusoidal endothelium, hepatocytes

Glycogen storage disease type Ia (Maltese)

Hepatic and renal G-6-Pase deficiency accumulation of glycogen and lipid in hepatocytes, RTE; hypoglycemia

Familial AA Amyloidosis (Familial Mediterranean Fever)

Mutation of Pyrin gene expression inadequate inhibition of IL-1B activity (human)

Human Wilson Disease AR mutation of WD gene dysfunction of ATP7B cationic transport protein abnormal secretion and excretion of copperBedlington terrier copper-associated hepatopathy

AR abnormality in MURR1 gene abnormal segregation of copper in hepatocytes

Copper Storage Disease Sheep - simple Cu excess in diet OR Mb deficiency OR pyrollizidine alkaloid ingestion > chronic accumulation of copper in liver >

sudden release of copper into vasculature > intravascular hemolysis with release of hemoglobin > acute tubular necrosis, hemoglobinuria, hepatic necrosis

Human Hemochromatosis AR abnormality in HFE gene diminished hepcidin activity? enhanced absorption from GIT iron accumulation

A1 antitrypsin deficiency Deficient secretion of a1 antitrypsin cirrhosis, accumulation of PAS-positive, diastase-resistant material (altered forms of a1-antitrypsin) in hepatocytes

Biliary Toxicosis Facial Eczema of Sheep - ingestion of dead rye grass (Lolium) infected with Pithomyces chartarum fungi that produces sporodesmin toxin > necrotizing cholangiohepatitis > cholestasis > increased phylloerythrin due to decrease excretion > UV light activation > cutaneous free radical production > facial eczema

Hemosiderosis/haemochromatosis AR abnormality in HFE gene diminished hepcidin activity? enhanced absorption from GIT iron accumulation (human)Hepatosis Dietetica Vit E/Selenium defic > peroxidative damage of capillary membranes > ↑ vascular permeability, thrombosis, & ischemia > tissue necrosisClostridial Necrotizing Hepatitis Bacillary Hemoglobinuria (Red Water) - Dormant Clostridium haemolyticum spores in Kupffer cells > hepatic injury from Fasciola

hepatica migration > ↓ oxygen tension > spore germination > Phospholipase C toxin prod > hepatocellular necrosis & IV hemolysis > icterus, hemoglobinemia, & hemoglobinuriaBlack Dz (Infectious Necrotic Hepatitis) - Dormant Clostridium novyi (usually Type B) spores in liver> hepatic injury from Fasciola hepatica migration > ↓ oxygen tension > spore germination > toxin prod > hepatocellular necrosis

Hepatic Fusobacteriosis/Actinomycosis

Damaged rumenal mucosa > bacterial invasion > spread to liver via portal vein > hepatic necrosis

Ascites Mechanical and dynamic influences on blood flow through a damaged liver (fibrosis and nodular expansion impede blood flow, dynamic influences of stellate cell contraction and hepatic vein smooth muscle that affect portal venous pressure) portal hypertension + Increased generation/impaired clearance of Various factors that regulate splanchnic blood flow (including histamine, nitric oxide, endothelins, atrial natriuretic peptide (ANP), calcitonin gene regulated peptide (CGRP), TNF- , substance P and vasoactive αintestinal peptide (VIP), produced locally in splanchnic circulation, normally cleared by liver)

Increased splanchnic arteriolar blood flow increased hydrostatic pressure in splanchnic capillaries over-production of splanchnic lymph increased portal pressure, sodium retention, increased cardiac output, induced contraction of stellate cells and intrahepatic vascular smooth muscle, could restrict venous outflow through established portosystemic collateral veins

+ Reduced synthesis of albumin and globulins by failing liver reduced vascular oncotic pressure + Dysregulation of autonomic regulation of splanchnic blood flow

Ductal Plate malformations Disruption or failure of the epithelial-mesenchymal interaction during fetal development of the liver

congenital hepatic fibrosis (CHF; calf), Caroli disease, von Meyenburg complexes, Caroli syndrome (dogs, rats), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic kidney disease (ADPKD; mice, pck strain), biliary atresia (dog,foal)

Cytochrome P450-related intoxicationDirect HepatotoxicitySmooth Endoplasmic Reticulum InductionDNA adduct formation  Toxic Induction of Autoimmunity  RNA interference  Hepatic Arteriovenous Fistula Acquired (subsequent to abdominal trauma, rupture of hepatic artery aneurysms, secondary to hepatic vein obstruction or cirrhosis

with extreme portal hypertension) Mixing of higher pressure arterial blood with venous blood retrograde flow into portal vein, arterialization of portal circulation, development of portal hypertension opening of vestigial, low-resistance collateral extrahepatic portosystemic communications (acquired extrahepatic shunts).

   

Glycogen storage disease type Ia(von Gierke's disease)

Loss-of-function mutations in hepatic and renal glucose-6-phosphatase (G6Pase) increased hepatic glycogen storage, diminished blood glucose

Metabolic Diseases

Hypoglycemia - hypoglycaemia of hepatic insufficiency: severe diffuse hepatic necrosis 1) inadequate gluconeogenic enzyme activity for conversion of amino acids to glucose2) reduced functional hepatic mass for sufficient gluconeogenesis3) insufficient storage of glycogen to sustain euglycemia between interdigestive intervals4) abnormal response to glucagon - dogs with large hepatic tumors (hypoinsulinemia) - beta cell tumors, rare non-beta cell tumors - rare congenital enzyme deficiencies; usually suggested by abnormal glycogen retention:

- glucose-6-phosphatase deficiency – impaired hydrolysis of glucose-6-phosphate to glucose; accumulation of glycogen in liver - amylo-1,6-glucosidase deficiency (debrancher enzyme) – impaired conversion of glycogen to glucose-6-phosphate - lysosomal acid alpha-glucosidase deficiency – glycogen accumulation

Hyperglycemia - hyperglycemia of hepatic insufficiency - defective insulin metabolism peripheral hyperinsulinemia overcompensation of catecholamines, glucocorticoids, glucagon hyperglycemia during fasting period

Lactic Acidosis - Inadequate delivery of O2 to tissues - stagnant hypoxia (shock, vascular occlusion) - demand hypoxia (strenuous exercise) - repiratory hypoxemia

- hemoglobic hypoxia (anemia, methemoglobinemia) - Increased production by metabolic pathways

- grain overload - defective metabolic pathways for aerobic glycolysis

- Hyperammonemia – urea toxicosis, , ammoniated forage toxicosis - pyruvate dehydrogenase deficiency

- lactic acidosis of hepatic insufficiency - metabolism of lactate to glucose may be compromised with severe liver disease

- others - sepsis, canine babesiosis, transfusion of stored blood or packed RBCs

Integumentary  

Epitheliogenesis Imperfecta  AR or spontaneous mutationEhlers-Danlos syndrome Deficiency of enzyme amino procollagen peptidase (which is required for oxidative deamination of terminal lysine residue on

procollagen > defective cross-linkage of collagen > weak abnormal collagenIchthyosis Failure of dissolution of desmosomes > retention of keratinized cells > icthyosis > death from septicemia in calves and dogsPemphigus complex diseases Pemphigus foliaceus - Autoimmune breakdown of intercellular attachments via IgG attach of desmoglein 1 intracorneal pustular

(and acantholytic) dermatitis with alopecia and crustsBullous Pemphigoid - IgG bind to the bullous pemphigoid antigen II, a collagen type 17 present within hemidesmosomes of the lamina lucida of the basement membrane zone > subepidermal cleftingPemphigus Vegetans - Autoimmune breakdown of intercellular attachments via IgG attach of desmoglein 3 (dogs – desmoglein-1) suprabasilar pustular (and acantholytic) dermatitis with mucosal ulceration

Mechanobullous Disease Defective development and / or deficiency of hemidesmosomes > mild mechanical trauma leads to detachment of basal cells from basement membrane > bulla formation > sloughing of skin, foals slough hooves. Seen in foals, sheep, dogs.

Photosensitization Primary (St. John's Wart, Buckwheat, phenothiazine, tetracycline, thiazides, sulfonamides), Secondary (hepatogenous), & Inherited (Bovine Congenital Porphyria in Holsteins & Shorthorns & Bovine Erythropoietic Protoporphyria in Limousins)Photosensitization, primary, type I - ingestion of Hypericum/Fagopyrum à ultraviolet light exposure à activation of photodynamic compounds deposited in skin à free radical production à cutaneous necrosis (non-pigmented areas)Photosensitization, sedondary/hepatogenous, (type III) - ingestion of Brachiaria decumbens/Senecia/Crotalaria à liver damage with cholestasis à Accumulation of phylloerythrin > UV light exposure > activation of the photodynamic agent à ulcerative photodynamic dermatitisInherited: Defect in Uroporphyrinogen III Cosynthetase (Bovine Congenital Porphyria) or Ferrochelatase (Bovine Erythropoietic Protoporphyria) > defective heme synthesis > photodynamic agent accum (porphyrin) > photosensitization

Necrotizing Steatitis Vit E/Selenium defic > peroxidative damage of capillary membranes > ↑ vascular permeability, thrombosis, & ischemia > tissue necrosisCutaneous Infarction Ergotamine Toxicosis - Ingestion of plant containing Claviceps purpura > Ergotamine toxin > vasoconstriction & thrombosis of pedal

vessels > gangrenous pododermatitisFrostbite - Cold temp > vasoconstriction > ischemia & necrosisErysipelothrix rhusiopathiae inf > septicemia > dermal vasculitis, thrombosis, & necrosis > cutaneous infarctsOther Causes of Gangrenous Pododermatitis: Fescue Toxicity

Epidermolysis bullosa simplex Mutations in basal cell keratins 5 and 14 abnormal assembly of keratin intermediate filaments cytolysis of basal cells intraepidermal clefting

Junctional epidermolysis bullosa Deficiency or abnormality in one of the hemidesmosome-associated proteins (laminin-5, collagen 17(aka BPAG2 or BP180), integrin a6B4, LAD-1) subepidermal clefting at lamina lucida in BM

Dystrophic epidermolysis bullosa Mutation in the anchoring fibril protein type 7 collagen (COL7A1 in cats) subepidermal clefting in superficial dermis, below lamina densa

Epidermolysis Bullosa Acquisita production of autoantibodies against collagen VII (normally forms the fibrous 2-dimensional network of lamina densa) in sublamina densa anchoring fibrils autoimmune subepidermal blistering disease(collagen IV IHC - detected more commonly above subepidermal vesicles than below)

Bovine Collagen dysplasia Mutation in gene for procollagen I N-proteinase (excises amino-propeptide of type I and II procollagens) abnormal collagen precursor molecules abnormal assembly of collagen fibers (ribbon-shaped) with diminished tensile strength dermatosparaxis

Proteoglycan deficiency Mutation of gene that codes proteoglycan core moleculeWaardenburg syndrome Cats - AD mutation with complete penetrance melanocytopenic hypomelanosis; incomplete penetrance for deafness

Horses (Waardenburg Type 4 (Hirschprung disease)) White patterned horses (esp. vero foals). Ile118Lys endothelin receptor B (EDNRB) mutation --> failure of migration of neuroblasts from neural crest - congenital lack of myenteric and/or submucosal plexuses in distal colon/anus - contracted/nonperistaltic distal colon - proximal megacolon (Model for the Hirschprung aganglionosis of humans).

Peibaldism Mutations in gene excoding c-kin TKR, gene for stem cell factor (receptor ligand) diminished proliferation and survival of malenoblasts localized melanocytopenic hypomelanosis

Albinism Mutation in tyrosinase gene lack of activity absent melanin synthesisChediak-Higashi syndrome Mutation in beige gene (involved in generating cellular organelles) formation of giant melanosomes diminished secretion to

keratinocytes color dilution Uveodermatologic Syndrome (Vogt-Koyanagi-Harada-like syndrome

immune-mediated attack against melanin or melanocytes

Laminitis - two basic hypotheses, vascular and toxic-metabolic: - vascular hypothesis digital ischemia is the primary event - toxic-metabolic hypothesis direct damage to epithelial cells of the laminae or to the basement membrane, and that the vascular lesions are secondary

Muscular  

Ischemic Myopathy Downer Cow Syndrome - hypocalcemia – weak cow – downer cow – pressure-induced muscle ischemia – necrosisDeep Pectoral Myopathy of Turkeys, Chickens - excessive exercise > swelling of supracoracoid and pectoralis profundus muscles >

compression of muscle within tight osteofascial compartment > vascular occlusion > ischemia > coagulative necrosis of muscle (Zenker’s necrosis).

Malignant Hyperthermia/PSS Ryr-1 (ranitidine) gene mutation (encodes Ca release channel) > defective ryanodine receptor > Halothane anesthesia or stress > ↑ Ca release & muscle contraction > ↑ O2 & glycogen consumption & ATP depletion> necrosis & hyperthermia

Clostridial myositis Blackleg - Ingestion of spores of Clostridium chauvoei > deposition in muscle > trauma or transient ischemia to muscle > anaerobic environment > growth of latent spores > secretion of cytolytic exotoxins (lecithinases, hemolysin, deoxyribonuclease, hyaluronidase) > necrosis of endothelium and myofibers

Masticatory Myositis Circulating antibody to Type IIM myofibers in masticatory muscles (masseter, temporal, & pterygoid muscles) > immune complex deposition > myositis & myofiber atrophy

White Muscle Disease Vit E/Selenium defic > peroxidative damage of capillary membranes > ↑ vascular permeability, thrombosis, & ischemia > tissue necrosisContagious Foot Rot epidermal maceration > invasion of F. necrophorum > induction of interdigital dermatitis > secondary infection with B. nodusus >

necrosuppurative digital dermatitis +/- extension to underlying tissues with osteomyelitis, tenosynovitis, and arthritisCaprine Myotonia AD mutation in skeletal muscle voltage-dependent chloride channel ClC-1 causes decreased skeletal muscle chloride channel

conductance ionic instability of sarcolemmal membrane myotoniaMiniature Schnauzer myotonia AR mutation in skeletal muscle voltage-dependent chloride chanel (ClC-1) (see Malignant Hyperthermia below)Malignant Hyperthermia Mutation in gene encoding skeletal muscle calcium release channel (RYR1) hypersensitive and heightened ligand-gating of the Ca-

release channel sustained increase in cytoplasmic Ca levels and subsequent activation of the actin-myosin contractile proteins depletion of glycogen stores, hypoxemia, and accumulation of heat, hyperkalemia, lactic acid, and metabolic and respiratory acidosis

X-linked Muscular Dystrophy X-linked mutation in genes (xmd) encoding Dystrophin progressive myodegenerationNemaline Myopathy Three mutations (slow alpha tropomyosin 3, nebulin, actin) contractile dysfunction and rod formation (composed of a-actinin)

progressive myodegeneration Hyperkalemic Periodic Paralysis AD mutation in muscle sodium channel increased open time and sodium influx compensatory loss of muscle potassium may

further activate sodium channels altered resting muscle membrane potential increased muscle action potentials – muscle fasciculations and spasms

Congenital Muscular Hyperplasia Deficient activity of myostatin unregulated skeletal musclePolysaccharide Storage Myopathy AD mutation in glycogen synthase I gene (GYS1) accumulation of polysaccharide within skeletal myocytesKnockdown Syndrome Myopathy in Turkeys

monensin in feed induce lower hepatic concentrations of vitamin E predispose the turkeys to skeletal myopathy 

  

Nervous  

Coup-contrecoup Cerebral contusions

1.Head freely movable.2.Head accelerated rapidly (by being struck by a broad object, such as an automobile) or decelerated rapidly (head strikes pavement after a fall from a standing position).3.Because the brain does not fill the cranial vault, it may lag behind the movement of the cranium when the head is accelerated or decelerated rapidly.4.As a result, the inside of the cranial vault may strike the stationary brain at the point of impact (coup injury), or the lesion may occur on the opposite side (contrecoup), either from the stretching and tearing of vessels at that site or by the brain being struck by the inside of the cranial vault on the opposite side when there is reduced amount of cerebrospinal fluid buffer present.

Cerebellar Hypoplasia Cerebellar hypoplasia, BVD: In utero viral inf > inf & necrosis of cerebellar external germinal cells > defective Purkinje cell localization & maturation > cerebellar hypoplasiaBovine- in utero infection of Bovine Pesti Virus (BVD), Akabane virus; Cat- Feline panleukopenia virus (in utero); Sheep- Border disease (Pestivirus),Cache valley fever virus; Dog- Segmental hypoplasia - canine herepes virus, canine Parvo virus; Pig- Hog cholera virus (Pestivirus),sows treated with organophosphate during pregnancy; Goat- Cache valley fever virus, copper deficiency; Birds- Fowl glioma- inducing virus (avian leucosis virus group A)

Hydranencephaly/Porencephaly Bluetongue In utero viral inf around 40-75 days gestation > inf & necrosis of undiff cerebral subventricular cells > cerebral cavitationCyclopia ingestion of Veratrum californicum by dam between 9-14 d gestation > steroidal alkaloids (Cyclopamine and jervine, potent

teratogens) > inhibit Sonic hedgehog (Shh) signaling during gastrulation-stage embryonic development) > inhibit neural tube development > cyclopia, CNS malformations, arrhinencephalia

Spina bifida Separation Defect in fusion site I of neural tubeLeukoencephalomalacia Ingest moldy corn w/ Fusarium moniliforme > Fumonisin B1 toxin > inhibition of ceramide synthesis > cytotoxic sphinganine &

sphingosine accum > vascular and direct cellular toxicity > leukoencephalomalacia Focal Symmetric Encephalomalacia Lambs - Fed on lush pasture or high grain diet > Clostridium perfringens Type D intestinal overgrowth > epsilon toxin activated by

trypsin > endothelial damage > ↑ vascular permeability & edema > focal brain hypoxia & necrosisNigropallidal encephalomalacia in horses - Centaurea solstitialis (Yellow star thistle) OR Centaurea repens (Russian knapweed) chronic ingestion (repin, a sesquiterpene lactone) > gluthatione depletion > increase of reactive oxygen species (ROS) > bilaterally symmetric necrosis of the globus pallidus and substantia nigra

Polioencephalomalacia Dietary deficiency of thiamine OR thiamine destruction by sulfites OR diet containing thiamine antagonists OR grain overload w/reduction in number of microorganisms that synthesize thiamine and an increase in microorganisms that produce thiaminase > reduction in thiamine > decreased thiamine pyrophosphate > low ATP (Thiamine is a cofactor in the hexose monophosphate shunt, the metabolic pathway for glucose in the brain, and the Krebs cycle) > reduction in sodium-potassium pump > loss of osmotic control > cell swelling and necrosis of neurons > increased intracranial pressure and laminar cortical necrosis (CCN)In canine ,fox,cat,mink – chastek paralysis (absolute dietery requirement) CAUDAL COLLICULI (mid brain)In ruminants- 1, Thiamine deficiency 2. Water depriviation –Na+ toxicosis 3. High S intake 4. high CHO diet – acidosis –Rumen microflora alteration

Feline Ischemic Encephalopathy Aberrant cerebral Cuterebra larva migration > thrombosis & occlusion of middle cerebral artery > cerebral ischemia & necrosisBotulism zinc-binding metalloprotease - cleaves specific proteins on synaptic vesicles - prevents release of acetylcholine from vesicles at nerve

terminals - flaccid paralysisTetanus wound - innoculation of bacteria into tissue - proliferation and death of bacteria - production of toxin Tetanospasmin - absorbed by

local motor nerves zinc-binding metalloprotease - cleaves synaptobrevin on synaptic vesicles - inhibition of glycine, GABA release by inhibitory neurons ("Renshaw cells") - extensor spasm, hyperesthesia

Bovine Citrullinaemia Abnormal activity of arginosuccinate synthetase accumulation of citrulline CNS – astroglial swelling; Liver – hepatocellular hydropic swelling

Maple Syrup Urine Disease Branched chain ketoacid decarboxylase deficiency elevated leucine, isoleucine, valine Myelin sheath splitting (status spongiosis)Ceroid Lipofuschinosis Recessive defect in lysosomal or mitochondrial function; deficiency in palmitoyl protein thioesterase in some accumulatioof

sphinoglipid activating proteins A and D, subunit c of mitochondrial ATPase Cerebral atrophy, lipofuschin accumulationPrimary Hyperoxaluria in the cat Deficient activity of D-glycerate dehydrogenase L-glyceric aciduria, hyperoxaluria, heavy deposition of oxalate crystals in renal

tubules; neurofilamentous accumulations and Wallerian degeneration in proximal axons of spinal motor neurons, ventral roots, intramuscular nerves and dorsal root ganglia

Lafora Disease Mutations of EPM2A (Laforin) and EPM2B (Malin) (humans)Feline Toxic Peripheral neuropathy Inherited deficiency of D-glycerate dehydrogenase focal swelling and accumulation of neurofilaments in axons and motor nerves

Wallerian degenerationRosenthal Fiber Encephalopathy AD mutations in genes encoding GFAP cytoskeletal protein accumulation of disorganized fibers in axons formation of

eosinophilic deposits (Rosenthal Fibers) neurologic dysfunctionPolyarteritis nodosa  Hepatoencephalopathy Ammonia toxicity - shunting or hepatic failure dietary ammonia that bypasses removal on first pass through hepatic portal

circulation accumulates in general circulation, crosses blood-brain barrier encephalopathy: decreased expression of microsomal Na-K-dependent ATPase in brain ATP consumption in glutamine production - ATP availability excitability (mild in NH3) disturbed malate-aspartate shuttle glycolysis brain edema (acute liver failure) glutamate, altered glutamate receptors BBB transport of glutamate, tryptophan, octopamine CNS tissue lacks mechanisms for urea cycle – metabolizes ammonia via astrocytic enzymes glutamine synthetase and

dehydrogenase to form glutamine – toxic? Elevated blood ammonia is postulated accumulation of glutamine in astrocytes osmotic stress and

astrocyte swelling consequences of which include altered gene expression, changes in multiple neurotransmitter systems, and brain edema

Ammonia can be directly neurotoxic altering neurotransmission potentially contributing to cerebral energy failure - inhibition of -ketoglutarate dehydrogenase,

a rate-limiting enzyme in TCA cycle alpha-ketoglutarate Diversion from Urea Cycle for NH3 detoxification ATP availabilityGlutamine altered BBB amino acid transportAromatic Amino Acids neurotransmitter synthesis; DOPA; Altered neuroreceptors; production of false neurotransmittersShort-chain Fatty Acids decreased expression of microsomal Na-K-dependent ATPase in brain; uncouples oxidative phophorylation impairs oxygen utilization; displaces tryptophan from albumin - free tryptophanFalse Neurotransmitters - Tyrosine Octopamine impairs norepinephrine action; Phenylalanine Phenylethylamine impairs norepinephrine action; Methionine Mercaptans; synergistic with other toxins (NH3, SCFA); gut-derived fetor hepaticus; microsomal Na-K-dependent ATPase in brainTryptophan Directly neurotoxic; serotonin inhibitionPhenol (derived from Phenylalanine, Tyrosine) Synergistic with other toxins; a multitude of cellular enzymes neurotoxic and hepatotoxicBile Acids Membranocytolytic effects alter cell/membrane permeability BBB more permeable to other HE toxins impaired cellular metabolism due to cytotoxicityGABA hyperpolarize neuronal membrane neural inhibition; BBB permeability to GABA in HEEndogenous Benzodiazepines: hyperpolarize neuronal membranes neural inhibitionHypoglycemia: severe diffuse hepatic necrosis hypoglycaemia (below) convulsions1) inadequate gluconeogenic enzyme activity for conversion of amino acids to glucose2) reduced functional hepatic mass for sufficient gluconeogenesis3) insufficient storage of glycogen to sustain euglycemia between interdigestive intervals4) abnormal response to glucagon

Salt Intoxication Initial dehydration phase (osmotic loss of water from brain secondary to an increased blood sodium concentration) influx of ionic sodium, potassium, chloride into brain inhibits anaerobic glycolysis influx or production of organic molecules (amino acids, polyols, methylamines) osmoles result in cell swelling upon rehydration osmotic differential cannot be equalized quickly enough to prevent edema of the brain clinical signs and typical lesions result

Status spongiosus  Neuroexcitotoxicity  Metabolic Polyneuropathy  Domoic Acid -

- degenerative cardiomyopathy (proposed pathogenesis) - primary or at least initial direct interaction of domoic acid with receptors that are suspected to exist in the heart myocardiocyte apoptosis

STORAGE DISEASESSphigolipidosesGM1 Gangliosidosis AR B-galactosidase deficiency accumulation of GM1 ganglioside Neurons have foamy or granular cytoplasmGM2 Gangliosidosis AR B-hexosaminidase deficiency accumulation of GM2 ganglioside Neurons have foamy or granular cytoplasmGlucocerebrosidosis Deficiency of glucocerebrosidase (catalyzes conversion of glucocerebroside to ceramide) accumulation eosinophilic cytoplasmic

vacuoles in cytoplasm of neurons (PAS-), hepatic Kupffer cells (PAS+)Type A and B Sphinogomyelinoses Deficient activity of sphinomyelinase accumulation of Gangliosides, cholesterol, shingomyelin in neurons, macrophages in liver,

spleen, lymph node, adrenal, bone marrow, lung – expansion of organs by foamy macrophagesNiemann-Pick type c disease (Type C Sphingomyelinosis)

Deficient activity of a cholesterol transporter, NPC1 protein, or a soluble lysosomal cholesterol-binding NPC2 protein accumulation of Gangliosides, cholesterol, shingomyelin in neurons, macrophages in liver, spleen, lymph node, adrenal, bone marrow, lung – expansion of organs by foamy macrophages

Galactosialidosis Combined deficiency of B-galactosidase and a-neuraminidase activityGalactocerebrosidosis (Globoid cell leukodystrophy)

AR Galactosylceramidase deficiency abnormal myelination, accumulation of Galactosylceramide and Galactosysphongosine toxic to oligodendroglia Hypomyelination, globoid cell accumulation (macrophages)inherited galactocerebrosidase deficiency > accumulation of psychosine in the lysosomes of macrophages (globoid cells) and necrosis of oligodendrocytes > demyelination

Glycoproteinosesa-mannosidosis Deficiency in a-mannosidase accumulation of mannose-containing oligosaccharide in secretor epithelial neurons, endothelia, mixed

macrophages, fibrocytes; +/- hypomyelinationAcquired a-mannosidosis Ingestion of swainsonine in Astralagus/Oxytropis/Swainsona > inhibition of lysosomal alpha-mannosidase > accumulation of alpha-

mannosidose within lysosomes > acquired alpha-mannosidosisB-mannosidosis Deficiency in B-mannosidase accumulation of mannose-containing oligosaccharide; hypomyelination a-L-fucosidosis in English Springer Spaniels

AR deficiency of a-L-fucosidase accumulation of fucose-containing compounds as glycosylasparagines in neurons, astrocytes, microglia, perivascular macrophages; accumulation of macrophages and myxoid perineureal ground substance in nerves

MucopolysaccharidosesN-acetylglucosamine-6-sulfatase deficiency (Nubian Goat) (Sanfillipo Disease, MPSIII)

N-acetylglucosamine-6-sulfatase deficiency accumulation of heparin sulphate as lucent flocculent material in lysosomes in arterial smooth muscle, cardiac myocytes, fibroblasts, macrophages, hepatocytes, Kupffer cells, chondrocytes; accumulate of PAS+ gangliosides in neurons (interference with neuraminidase activity)

Arylsulfatase-B deficiency (Siamese and shorthairs) (Maroteaux-Lamy syndrome, MPSIV)

Arylsulfatase-B deficiency accumulation of heparin sulphate as lucent flocculent material in lysosomes in arterial smooth muscle, cardiac myocytes, fibroblasts, macrophages, hepatocytes, Kupffer cells, chondrocytes

B-glucuronidase-deficient mucopolysaccharidosis (Sly disease, MPSVII)

B-glucuronidase deficiency widespread neurovisceral storage, cytoplasmic inclusions appear empty or with sparse granular-lamellar material; excrete excess chondroitin-6-sulfate and chondroitin-4-sulfate in urine

Glycogenosesa-1,4-glucosidase deficiency AR deficiency in a-1,4-glucosidase glycogen accumulation in skeletal and cardiac muscle, neurons, glia, liver, elsewhereAmylo-1,6-glucosidase deficiency (glycogen storage disease type III)

Amylo-1,6-glucosidase deficiency glycogen accumulation in liver, muscle, myocardium, neurons, glia

Polyglucosan body disease (glycogen storage disease type IV)

Deficiency of glycogen-branching enzyme polyglucosan bodies in neurons, liver, myocardium

Myophosporylase Deficiency (Type V glycogenosis)

Deficient myophosphorylase activity Accumulation of glycogen in muscle, neurons

Acid Maltase Deficiency Deficient Acid maltase activity accumulation of glycogen in skeletal muscle, myocardium, neuronsMucolipidosesMucolipidosis II AR Amylo-1,6-glucosidase deficiency retinal degeneration, accumulation of oligosaccharides, mucopolysaccharides, lipids in bone,

cartilage, skin, connective tissues; occasional lipid inclusions in cerebrocortical neurons, sciatic nerve axons Murine Mucolipidosis Type II Mutation in gene encoding a/B subunit precursor for ClcNAc-1-Phosphotransferase retinal degeneration, accumulation of

oligosaccharides, mucopolysaccharides, lipids in bone, cartilage, skin, connective tissues; occasional lipid inclusions in cerebrocortical neurons, sciatic nerve axons

Murine Mucolipidosis Type II Mutation in gene encoding g subunit precursor for ClcNAc-1-Phosphotransferase retinal degeneration, accumulation of oligosaccharides, mucopolysaccharides, lipids in bone, cartilage, skin, connective tissues; occasional lipid inclusions in cerebrocortical neurons, sciatic nerve axons

Ophthalmic  

Primary Glaucoma absence or underdeveloped outflow tracts with incomplete cleavage of iridocorneal angle.NZW rabbits: autosomal recessive with incomplete peneterance

Secondary Glaucoma Lens Luxation - may involve several factors including anterior dislocation of the vitreous causing pupillary block and accumulation of degenerate zonular material within the trabecular meshworkNeovascular Galucoma Tissue Hypoxia (retinal detachment, iridociliary tumor) evolution of angiogenic factors into vitreous/aqueous humor angiogenesis within anterior iris formation of fibrovascular memebrane over anterior surface of iris and drainage angle

Cataract Diabetic Cataract - Excess glucose due to hypoinsulinemia or insulin insensitivity > shunts to sorbitol synthesis > excess sorbitol increases lens osmotic pressure > increased uptake of water > hydropic degeneration and rupture of lens fibers > diabetes cataract

Marfan Syndrome Mutation in Fibrillin Gene abnormal collagen crosslinking? megaloglobus, ectopia lentis; degeneration of elastic laminae aortic, pulmonary arterial, coronary arterial dissecting aneurysm and rupture

Retinal Atrophy of Irish Setters (Rod-Cone dysplasia type 1/rcd1)

AR mutation in cGMP phosphodiesterase beta-subunit gene (PDE6B) diminished hydrolysis of cGMP toxic effecs to outer retinal segments

Rod-Cone degeneration in miniature poodles, cocker spaniels, others

Diminished incorporation of docoshexaenoic acid into outer rod segments?

Ocular albinism and hypopigmentation

Mutation of SLC24a5 cation carrier hypopigmentation of iris, ciliary body, RPE, reduced size and pigmentation of melanosomes in melanocytes, other neural crest-derived cell lines

Coloboma      

Otic  

Waardenburg syndrome Cats - AD mutation with complete penetrance melanocytopenic hypomelanosis; incomplete penetrance for deafness

Pancreatic  

Zollinger-Ellison Syndrome Function gastrin-producing beta cell tumor > hypergastrinemia > hypersecretion of gastric acid > severe gastric ulcerationPancreatitis, acute meal high in fat > intrapancreatic activation of phospholipase and elastase > pancreatic damage > release of inflammatory mediators >

necrotizing pancreatitis with hemorrhage and fat saponification

Reproductive - Male  

Freemartinism Female fetus co-twin w/ male > placental vascular anastomoses & shared hormones (anti-Müllerian hormone) > masculinization of female genital tract

Acquired Feminization Sertoli Cell Tumor > Hyperestrogenism, Elevated Inhibin > Gynecomastia, Myelotoxicosis (Non regenerative anemia, Thrombocytopenia, Granulocytopenia), Squamous metaplasia of Prostate gland acini

Cystic Prostatic Hyperplasia Ferret - Hyperestrogenism (adrenocortical tumor) - squamous metaplasia of glandular prostate epithelium + keratin & pus filled cystSpermatic Granuloma Release of spermatozoa into interstitium (trauma, necrosis) > highly sulfated amino acid content (similar to keratins) + immune-

privileged tissue niche > immune recognition and Th1 response - granuloma formation

Reproductive - Female  

Pyometra Persistant corpus luteum – Increase Progesterone- Increase endometrial gland activity, decrease myometrial activity – colonization of bacteria from urinary tract, decrease uterine leukocyte response and maintains closed cervix,glandular secretions enhance bacterial growth

XXY syndrome XXY karyotype male phenotypeMale Pseudohermaphroditism (Androgen Insensitivity)

Tfm mutation – deficiency in intracellular androgen receptors insensitive to masculinising effects of normal androgens female external genitalia (blind-ended vagina), nor female internal genital structures, testes in ovarian position, no male accessory sex glands

XX sex reversal Abnormal masculinising gene (Sxr, SOX9; polled gene)XY sex reversal AD or Y chromosomal mutation XY karyotype with female phenotypeOvarian/Parovarian CystsCystic Uterine/Vaginal Structures  Persistent Estrus  Mastitis  Cystic Endometrial Hyperplasia  

Respiratory  

Familial Neonatal Respiratory Distress

- SP-A deficiency is associated with bronchopulmonary dysplasia and/or increased susceptibility to bacterial infection - SP-B mutations result in alveolar proteinosis, failure of formation of tubular myelin, and/or diffuse alveolar damage - SP-C mutations in humans cause fibrosis of alveolar septa with infiltration of mononuclear cells (similar to idiopathic pulmonary fibrosis) - SP-D deficient mice develop alveolar lipidosis with type II pneumocyte proliferation

Atrophic Rhinitis Bordetella bronchiseptica inf allows Pasteurella multocida inf > Type A & D toxin prod > degen of osteoblasts & chondroblasts > turbinate bone resorption (osteopenia)

Guttural Pouch Mycosis Aspergillus nidulans guttural pouch infection> erosion of int. carotid artery > hemorrhage Laryngeal Hemiplegia (horses) Trauma to the left recurrent laryngeal nerve. (e.g. pressure by abscesses in strangles due to Streptococcus equi, idiopathic) >

demyelinization and axonal degeneration in nerve > neurogenic atrophy of left cricoarytenoideus dorsalis muscle > lack of laryngeal dilatation on inspiration > distension of lateral ventricles of larynx > roaring

Toxic Pneumonitis Cattle - Ingest L-Tryptophan (in lush pasture (rape, kale & turnip tops) or foggage) > converted to 3 methylindole in rumen >carried in blood to lung > further metabolized by Clara cells > free oxygen radical formation > Type I pneumocyte injury & necrosis > edema, hyaline membranes, & emphysema > Type II pneumocyte hyperplasia(Ingestion of stinkwood (unidentified toxins), Perilla mint (Perilla mint ketone), & moldy sweet potatoes (4 ipomeanol), Micropolyspora faeni spore hypersensitivity (bovine farmer's lung), smog, pit gases, BRSV infection, & reinf w/ Dictiocaulus viviparus cause similar lesions)

Primary Ciliary Diskinesia AR inherited defects in one of hundreds of proteins that comprise the structural or functional (motile) components of cilia/flagella impaired motility of respiratory, urogenital, otic, retinal, ventricular, embryonal cilia, sperm flagella respiratory infections, inner ear infections, situs inversus, hydrocephalus

Ectodyplasin-1 deficiency X-linked mutation of ED-1 gene (TNF-related signalling molecule involved in ectodermal development) hypotrichosis, hypodontia, reduced eccrine glands, respiratory squamous metaplasia with rhinotracheitis, lack of respiratory mucous glands

Bronchiectasis  Bronchiolitis obliterans  Emphysema Various factors that increases the recruitment of macrophages and leukocytes in the lungs (cigarette smoking, pollution, or defects in

the synthesis of antiproteases, such as homozygous α1-antitrypsin deficiency) imbalance between proteases released by phagocytes and antiproteases produced in the lung as a defense mechanism (the protease-antiprotease theory) proteolytic destruction of alveolar walls

Pulmonary Dysmaturity  Recurrent airway obstruction (horse)

 induced by persistent/repeatedexpsoure to allergens (dust, molds, pollens, bacterial components mucus hyperproduction, neutrophilic inflammation, bronchoconstriction; smooth muscle hyperplasia, fibrosis, lymphoid hyperplasia; diminished expression of Clara cell secretory protein with disease diminished anti-inflammatory activity

  

Skeletal  

Osteogenesis Imperfecta COL1A1 or COL1A2 gene mutations > defective Type I collagen > impaired lamellar bone formation & osteopeniaArthrogryposis Cause: Akabane virus > Loss of ventral motor neurons- Denervation muscle atrophy- arthogryposis (fixation of hind limb joints)

Blue tongue, Lupine (Anmodendrine), Poison HemlockAutosomal Recessive (Charolais Breed)

Metaphyseal Growth Arrest Lines Malnutrition > ↓ cartilage growth > ossification > improved nutrition > resumption of cartilage growth & growth arrest line formationRickets P or vit D deficiency > inadequate mineralization of physeal cartilage > blood vessels cannot penetrate the maturing cartilage and

primary spongiosa (spicules of cartilage) cannot be resorbed > persistence of primary spongiosa and cartilage cores within secondary spongiosa > osteoid fails to be mineralized > osteodystrophy with osteopenia

Reptile Metabolic Bone Disease Dietary vitamin D3 deficiency &/or lack of UVB light > ↓ intestinal Ca absorption > ↓ plasma Ca > ↑ PTH > ↑ Ca resorption from bone >↓ bone density > replacement by fibrous CT (fibrous osteodystrophy)

Articular Gout metabolic defect in the secretion of urates by the kidney tubules due to genetics or high protein diet > chronic hyperuricemia > deposition of urates in synovium and periarticular tissues > urate granuloma formation > articular swelling

Fibrous Osteodystrophy Renal dz/nutritional defic > Ca/P imbalance > ↑ PTH > ↑ Ca resorption from bone >↓ bone density > replacement by fibrous CTHuman Achondroplasia Mutation in cartilage fibroblast growth factor receptor 3 diminished response to growth signals. Spider Lamb syndrome (Ovine Chondrodysplasia)

AR point mutation in FGFR3 gene + mechanical stress abnormal development of ossification centers in bones developing by endochondral ossification postnatally

Osteogenesis imperfecta AD (rarely AR) mutations in collagen I genes (COL1A1 and COL1A2) abnormal Type I collagen synthesis diminished osteoid matrix synthesis excessive bone/dental fragility, joint laxity, blue sclera

Porcine Scurvy Spontaneous AR mutation in L-gulonolactone oxidase diminished synthesis of ascorbic acid deficiency in hydroxylysine diminished synthesis/deposition of collagen, diminished intermolecular cross-links between collagen fibers; also impaired differentiation of osteoblasts, hypertrophy of chondrocytes impaired endochondral ossification metaphyseal subperiosteal hemorrhage, osteopenia; diminished ossification of zone of provisional calcification, increased medullary mesenchyme

Complex Vertebral Malformation monogenic autosomal recessive hereditary defect; point mutation from G to T at nucleotide position 559 in bovine solute carrier family 35, member 3 gene (SLC35A3) changes amino acid sequence of uridine 5'-diphosphate-N-acetylglucosamine transporter protein from a valine to a phenylalanine in position 180 proportional dwarfism, symmetrical arthrogryposis, multiple malformations of cervical and thoracic parts of vertebral column

Pituitary Dwarfism  Osteochondrosis  

Urinary  

Chronic Renal Failure Stage 1 (Diminished Renal Reserve) – progressive renal disease acute loss of nephrons diminished GFR without loss of urea/creat clearance or loss of concentrating abilityStage 2 (Renal Insufficiency) – sufficient loss of nephrons loss of concentrating ability (polyuria, isosthenuria), urea/creat excretion (azotemia)Stage 3 (Renal Failure) – persistent poly/isosthenuria, azotemia, inadequate control of water/electrolyte balance uremia, electrolyte imbalancesStage 4 (End-stage renal failure, oliguric or anuric renal disease) – few nephrons filter plasma marked azotemia, oliguria/anuria with isosthenuria

Azotemia Def’n – intravascular increase in nitrogenous wastes (normally excreted by kidneys)Prerenal azotemia – functional hypovolemia, anemia diminished renal perfusion reduced renal filtration + ischemic injury to RTE azotemia

Azotemia of hypoadrenocorticism – Aldosterone deficiency impaired renal excretion of K+ bradycardia decreased cardiac output; diminished renal retention of Na+ diminished renal retention of H2O functional hypovolemia prerenal azotemia Azotemia of protein-losing nephropathy – glomerular loss of albumin hypoalbuminemia decreased plasma colloidal osmotic pressure functional hypovolemia prerenal azotemia

Renal azotemia – injury to nephrons (loss, hypoperfusion, diminished glomerular permeability, increased renal interstitial pressure, increased intratubular pressure) decreased GFR azotemiaPostrenal azotemia – obstruction of flow of urine within lower urinary tract (ureters, bladder, urethra) release of vasoactive substances (angiotensin, prostaglandins) constriction of glomerular arterioles decreased GFR; transient increase in tubular hydrostatic pressure decreased GFR

Nonobstructive postrenal azotemia - accumulation of urine in abnormal body spaces (peritoneum, soft tissues) passive absorption of urea, creatinine into blood (in peritoneum, urea equilibrates faster than creatinine)

Uremia Def’n – “urine in the blood”; clinical signs reflecting renal failureUlcerative and necrotic stomatitis – ammonia concentration and secretion in saliva physicochemical injury to oral mucosa and blood vessels necrosisAtrial and aortic thrombosis – endothelial and subendothelial injuryHypoplastic anemia – increased erythrocyte fragility increased turnover; diminished renal EPO secretion diminished BM erythropoiesisSoft tissue mineralization – Altered Ca-Ph metabolism mineralization of blood vessels in lungs, stomach, pleura, kidneysUremic gastric ulceration – Renal secondary Hyperparathyroidism - Chronic renal disease > decreased production of calcitriol by kidney and hyperphosphatemia > decreased intestinal absorption of Ca, hypocalcemia due to systemic precipitation, decreased inhibition of PTH secretion > increased PTH secretion > bilateral parathyroid hyperplasia; Clinicopathologic findings: Hypo- to normocalcemia, hyperphosphatemia, nonregenerative anemiaFibrous Osteodystrophy – Chronic Renal dz/nutritional defic > Ca/P imbalance > ↑ PTH > ↑ Ca resorption from bone >↓ bone density > replacement by fibrous CTOther lesions – myocardial necrosis, ulcerative endocarditis, ileus,

Visceral Gout renal failure due to infectious/nutritional/toxic> decreased urate excretion > hyperuricemia > urate deposition on visceral organs such as liver/myocardium/spleen or serosal surfaces like pleura/pericardium/air sacs

Emphyematous Cystitis Glucosuria due to Diabetes Mellitus or Fluid Administration > Infection of Urinary Bladder with Glucose-Fermenting Bacteria > Emphysema in the Bladder Wall

Hemoglobinuria/Hemoglobinuric nephrosis

Bacillary Hemoglobinuria (Red Water) - Dormant Clostridium haemolyticum spores in Kupffer cells > hepatic injury from Fasciola hepatica migration > ↓ oxygen tension > spore germination > Phospholipase C toxin prod > hepatocellular necrosis & IV hemolysis > icterus, hemoglobinemia, & hemoglobinuriaCopper Toxicosis (sheep) - High copper &/or low molybdenum diet > hepatocellular copper accum > hepatocellular insult > copper release > lipid peroxidation of RBCs > IV hemolysis & hemoglobinuriaRed Maple (Acer rubrum) Toxicosis (horses)- Ingestion of wilted red maple leaves > oxidative damage > methemoglobinemia, formation of Heinz bodies, and hemolysis > renal hemoglobin casts and tubular degeneration due to vasoconstriction, hypoxia, direct toxic effects of bilirubin

NSAID-induced Renal Papillary Necrosis

NSAID admin > inhibits COX 1 & 2 > inhibits prostacyclin (PGI2) > renal vessel vasoconstriction > renal papillary ischemia & necrosis

Glomerulonephritis  Protein-losing Nephropathy  

Hypercoagulability of glomerular disease

Protein-losing nephropathy loss of antithrombin III in the urine hypercoagulable state( atrial thrombosis (hamsters))

Renal Amyloidosis Glomerular amyloidosis > proteinuria (also renal papillary necrosis if interstitial) > ↓ plasma albumin > ↓ plasma colloid osmotic pressure > edema (anasarca) (Note: In female hamsters, often assoc w/ left atrial thrombosis)

Enzootic Hematuria chronic ingestion of Bracken Fern > Quercetin (carcinogen > TCC)X-linked Hereditary Nephropathy of Samoyeds

X-linked mutation in exon 35 of COL4A5 gene (encodes alpha 5(IV) collagen chain suspected to lead to inadequate corsslinking of type 4 collagen in glomerular BM failure of transition from a1/a2 to a3/a4/a5 network of type 4 collagen progressive glomerulosclerosis, mulitlaminar splitting of lamina densa of BM with electron-dense particles between splits

Polycystic Renal Disease AD or AR mutations of PKD genes altered polycystin protein production altered cell-cell and cell-matrix interactions; altered tubular epithelial growth and differentiation cyst formation in kidneys, liver; occasionally pancreas (AD)

Congenital Cystinuria AR Nonsense mutation of Slc3a1 gene defective renal resorption of dibasic amino acids (lysine, arginine, ornitine, cysteine predisposed to urolithiasis

Pyelonephritis Cystitis + endotoxemia (from infecting gram-negative bacteria) diminished competency of vesiculoureteral valve and abnormal ureteral peristalsis reflux of bacteria-contaminated urine to renal pelvis and collecting ducts+/- urethral obstruction increased pressure within urinary bladder enhanced vesiculoureteral reflux

Renal Cyst formation Four mechanisms of renal cyst formation are considered plausible: 1.Obstruction of nephrons can cause increased luminal pressure and secondary dilation.2.Modifications in extracellular matrix and cell-matrix interactions result in weakened tubular basement membranes allowing saccular dilation of tubules.3.Focal tubular epithelial hyperplasia with production of new basement membranes, increased tubular secretion, and increased intratubular pressure causes development of enlarged, dilated tubules.4.Dedifferentiation of tubular epithelial cells results in loss of polarity of cells with abnormal cell arrangements in tubules, reduced tubular fluid absorption, increased intratubular pressure, and dilation of tubules.

Urolithiasis  Hydronephrosis  Gentamycin Toxicosis  Acetaminophen Toxicosis  Renal Hypertension  

Infectious Disease (Bacterial) E. coli Enteroinvasive E. coli - ingestion and intestinal colonization by ETEC à expression of E.coli attaching and effacing factor (EAE) and

secretion of shiga-like toxin 1or2 > necrosis of enterocytes > necrotizing and ulcerative enteritisEnteroadherent/Enteropathogenic Collibacillosis - attach to microvillus border of enterocytes and gall bladder epithelium (cups and pedestals, via intimin) - loss of microvillus structure - loss of glycocalyx digestive enzymes - maldigestive/malabsorptive diarrheaEnterotoxigenic Colibacillosis (Neonatal enteritis) - ETEC colonize small intestine via fimbria (F4, 6,18) > enterotoxin LT 1 activatation of adenylate cyclase causing increased cAMP AND enterotoxins ST 1&2 activate guanylate cyclase causing increased GMP > increased secretion of Cl, Na, HCO3, water into lumen (secretory diarrhea)Enterotoxemic Colibacillosis (Edema disease) - ingestion and intestinal colonization by F18ab positive enterotoxigenic E.coli > expression of E.coli attaching and effacing factor (EAE) and secretion of shiga-like toxin IIe variant (Verotoxin) > toxin binds to globotriaosylceramide receptors on endothelial cells > widespread vascular damage and edema (mesocolon, eyelid, etc)Enterohemorrhagic E. coli - attach to microvillus border of enterocytes and gall bladder epithelium (cups and pedestals, via intimin-HP90 receptor binding) - tyrosine phosphorylase activity - increases intracellular Ca - releases inositol phosphate - loss of microvillus structure; release of bacterial hemolysin - mucosal absorption - necrosis

Salmonella adhesion of bacteria to apical membranes of intestinal M cells, enterocytes, goblet cells - secretion of endotoxins, verotoxins, enterotoxins - upregulation of CXC cytokines (IL-8, GRO-a, GCP2), IL-1B, IL-1 R-a, IL-4 - neutrophil influx - phagocytosis by macrophages - transported to regional LNs, via portal circulation to liver; endotoxemia with endothelial damage and thrombosisPorcine Rectal Stricture - Salmonella typhimurium inf > thrombosis of cranial hemorrhoidal artery > ulcerative proctitis > segmental rectal scarring & stricture & megacolon (per Thomson's) OR: Salmonella typhimurium infection > damage & ischemia in areas supplied by pudendal & caudal mesenteric arteries > ulcerative proctitis > segmental rectal scarring & stricture & megacolon (per J&K)

Mycobacterium bovis (TB) - intracellular survival (mycoside glycolipids form a barrier to phagosomal-lysosomal fusion and digestion - cell wall glycolipids/waxes + peptidoglycan - adjuvant activity - recruitment/stimulation of macrophages - IL-12 --> IFN-g and IL-2 immune response (CD4+ lymphs) - delayed-type hypersensitivity response and granuloma formation - impaired bacterial replication and spread - latent infection - reactivated with immune suppression

Mycobacterium avium ssp. paratuberculosis

ingestion - penetration of GI mucosa - taken up by macrophages

Mycobacterium avium, M. genovense ingestion - granulomatous enteritis - hepatitis - other sitesMycobacterium leprae Lepromatous form - no CMI

Tuberculoid form - vigorous CMIIntermediate form - intermediate CMI

Clostridial Necrotizing Hepatitis Bacillary Hemoglobinuria (Red Water) - Dormant Clostridium haemolyticum spores in Kupffer cells > hepatic injury from Fasciola hepatica migration > ↓ oxygen tension > spore germination > Phospholipase C toxin prod > hepatocellular necrosis & IV hemolysis > icterus, hemoglobinemia, & hemoglobinuriaBlack Dz (Infectious Necrotic Hepatitis) - Dormant Clostridium novyi (usually Type B) spores in liver> hepatic injury from Fasciola hepatica migration > ↓ oxygen tension > spore germination > toxin prod > hepatocellular necrosis

Clostridium chauvoei myositis (bovine) - Blackleg

Ingestion of spores of Clostridium chauvoei > deposition in muscle > trauma or transient ischemia to muscle > anaerobic environment > growth of latent spores > secretion of cytolytic exotoxins (lecithinases, hemolysin, deoxyribonuclease, hyaluronidase) > necrosis of endothelium and myofibers

Clostridium septicum myositis (equine)

wound infection - innoculation of bacteria into tissues - bacterial proliferation and toxin production

Clostridium septicum abomasitis (Braxy)

ingestion of frozen foods containing spores - exotoxin evolution - exotoxemia

Clostridium perfringens (Type A - alpha toxin; type B - beta toxin)Clostridium difficile (Types A, B, C, D)

proliferation of bacteria - elaboration of alpha toxin - mucosal necrosis and enterotoxemia; prediposed to by antibiotic administration, dietary chages

Subacute Clostridium perfringens type A (CPA, CPB2, CPE toxins?)

exposure - intestinal epithelial necrosis + secretory component?; secretion of CPA and CPB2 - uncertain of involvement in pathogenesis (CPB2 is expressed in 90% of cases); some strains produce CPE, associated with similar lesions

Clostridium perfringens type C - beta toxin (CPB)

exposure - Clostridial attachment to apical villus intestinal epithelium - desquamation of epithelium - infiltration of basement membrane/lamina propria - necrosis (secretion of CPB toxin) - toxemia

Clostridium perfringens type D lambs on good-quality feed - proliferation of bacteria - elaboration of epsilon toxin - absorption of epsilon toxin into bloodstream -

(epsilon toxin) (Pulpy Kidney Disease)

endothelial injury and edema

Clostridial Enterotoxemia - Focal Symmetric Encephalomalacia

Lambs - Fed on lush pasture or high grain diet > Clostridium perfringens Type D intestinal overgrowth > epsilon toxin activated by trypsin > endothelial damage > ↑ vascular permeability & edema > focal brain hypoxia & necrosisNigropallidal encephalomalacia in horses - Centaurea solstitialis (Yellow star thistle) OR Centaurea repens (Russian knapweed) chronic ingestion (repin, a sesquiterpene lactone) > gluthatione depletion > increase of reactive oxygen species (ROS) > bilaterally symmetric necrosis of the globus pallidus and substantia nigra

Clostridium piliformis infection via gastrointestinal system - systemic infection of liver, heart; associated with stressC. difficile-associated Antibiotic-induced dysbacteriosis (Guinea Pigs)

per os or parenteral administration of narrow-spectrum antibiotic with antibacterial activity against Gram-positive bacteria (esp. with penicillin/bacitracin/ampicillin (excreted in bile) (normal gut flora are G+ Lactobacillus and streptococci)) disruption of gut microflora decrease in cultivable Gram-positive bacteria within 12 hr up to a 10,000,000-fold increase in Gram-negative bacteria (high incidence of bacteremia due to Escherichia coli has also been observed in treated animals) and enterotoxigenic C. difficile

C. difficile-associated Antibiotic-induced dysbacteriosis (hamsters)

narrow-spectrum antibiotic (vancomycin, lincomycin, clindamycin, ampicillin, erythromycin, cephalosporins, gentamicin, penicillin) loss of Gram-negative aerobic bacteria or other clostridia? overgrowth with C. difficile elaboration of toxin acute colitis, diarrhea, and death; may occur as an endogenous infection (organism has been isolated from the intestinal tract of normal hamsters)

Botulism Exotoxicosis zinc-binding metalloprotease - cleaves specific proteins on synaptic vesicles - prevents release of acetylcholine from vesicles at nerve terminals - flaccid paralysis

Tetanus Exotoxicosis wound - innoculation of bacteria into tissue - proliferation and death of bacteria - production of toxin Tetanospasmin - absorbed by local motor nerves zinc-binding metalloprotease - cleaves synaptobrevin on synaptic vesicles - inhibition of glycine, GABA release by inhibitory neurons ("Renshaw cells") - extensor spasm, hyperesthesia

Hepatic Fusobacteriosis/Actinomycosis

Damaged rumenal mucosa > bacterial invasion > spread to liver via portal vein > hepatic necrosis

Fusobacterium necrophorum Laryngitis

abrasion/trauma - bacterial colonization - bacterial toxin production - necrosis

Contagious Foot Rot epidermal maceration > invasion of F. necrophorum > induction of interdigital dermatitis > secondary infection with B. nodusus > necrosuppurative digital dermatitis +/- extension to underlying tissues with osteomyelitis, tenosynovitis, and arthritis

Erysipelothrix rhusiopathiae septicemia > dermal vasculitis, thrombosis, & necrosis > cutaneous infarctStrep equi ssp. equi (Lancefield group C streptococcus)

virulence factors: - hyaluronic acid capsule - mediates binding of bactera to host cells, resistance to phagocytosis - M protein and a second cell wall constituent - bind fibrinogen, prevent deposition of C3 - block opsonization - peptidoglycan - activates complement by alternate pathway - neutrophil chemotaxis - streptolysin, other cytotoxin? - necrosis of neutrophils

Equine Pleuritis Streptococcus equi ssp. Zooepidemicus, S. equi ssp. equi, Actinobacillus suis-like bacteria, other streptococci, Pasteurella spp., Bordetella bronchiseptica, and E. coli, Bacteroides, and Fusobacterium; Mycoplasma felis appears to result from aspiration (mixed infection, often unilateral); risk factors include: transportation with held elevated (aspiration of tracheal pool of bacteria); generat anesthesia; stress; viral infection

Grain overload sudden change to highly fermentable diet - growth of Gram-positive bacteria (Strep bovis, Lactobacillus spp.) - evolution of lactic acid – rumenal acidosis (pH<5.5) – systemic acidosis; increased evolution of dissociated fatty acids - ruminal atony - increased osmolality of rumen content - dehydration (osmotic effect)

Purpura Hemorhagica Streptococcus equi equi Ag/Ab complexes. Ag/ab complex vasculitis.Atrophic Rhinitis Bordetella bronchiseptica inf allows Pasteurella multocida inf > Type A & D toxin prod > degen of osteoblasts & chondroblasts >

turbinate bone resorption (osteopenia)Bordetella bronchiseptica intracellular pathogen with heat-sensitive gene expression: first wave - filamentous hemagglutinin, pertactin, fimbriae (adhesion);

second wave - genes regulating motility, iron scavenging, urease and phosphatase activityvirulence factors: adenylate cyclase toxin (RTX toxin) - pore former allows entry of adenlyate cyclase component - increased cAMP - impaired leukocyte phagocytosis, oxidative burst; lipooligosaccharide - endotoxin activity; peptidoglycan-derived tracheal cytotoxin - induces cells to produce NO - induces ciliostasis and apoptosis of ciliated epithelium

Lawsonia intracellaris receptor-ligand-mediated invasion of enterocytes bacteria-induced stimulation of intestinal crypt epithelial cells of small intestine (largely ileum) - necrosis of proliferating crypt cells with hemorrhage - attraction of macrophages; induces immune suppression - reduction in CD8+ T cells and B cells; infection of macrophages - secretion of TNF-a - vascular permeability and hemorrhage

Rhodococcus equi survives engulfment by macrophages (prevention of phaosome/lysosomal fusion - pyogranulomatous inflammatory response (cytokine secretion by infected macrophages?); clearance of infection requires: - CD4+ T-cells - produce IFN-g - activate macrophages to produce bacteriocidal products - CD8+ T-cells - induce lysis of infected macrophages - opsonization of bacteria - optimized macrophage killing

Burkholderia mallei organisms traverse pharyngeal mucosa, and perhaps intestinal mucosa - conveyed to lungs where lesions almost always occur -hematogenous spread is believed to result in nasal, cutaneous, and lymph node lesions

Burkholderia pseudomallei bacterim survives in macrophage phagolysosomes - elicits a granulomatous and suppurative responsevirulence factors: iron-scavenging malleobactin; secreted proteases (degrade host tissues); capsular polysaccharide; resistance to phagocyte-mediated killing; LPS/endotoxin-derived polysaccharide - serum resistance

Histophilus somni - predisposed to by impaired pulmonary defenses (viral infection, stress, temp fluctuations, noxious gases) - proteins that bind Fc Ab component - prevent complement activation - Lipooligosaccharide - proinflammatory - transferrin-binding protein - vasculitis may be mediated by endothelial apoptosis - facultative intracellular pathogen (monocytes; impairs phagocytic actions of macrophages, neutrophils, induces neutrophil apoptosis, macrophage degeneration)

Mannheimia haemolytica - predisposed to by impaired pulmonary defenses (viral infection, stress, temp fluctuations, noxious gases) - leukotoxin (CD18-mediated pore-former) - LPS - proinflammatory, procoagulant, complement activation - capsular polysaccharide (resistance to phagocytosis and complement-mediated killing) - transferrin-binding proteins A and B - O-sialoglycoprotease - neuraminidase - AgG1-specific protease - outer membrane proteins - fimbriae

Pasteurella multocida - predisposed to by impaired pulmonary defenses (viral infection, stress, temp fluctuations, noxious gases) - antiphagocytic capsule - neuraminidase activity

Mycoplasma bovis - induces apoptosis of lymphocytes - suppression of lymphocyte responses to mitogens - impaired neutrophil activation - high frequency variation in expression of surface lipoproteins - evasion of humoral response

Mycoplasma mycoides mycoides small colony type (Contagious Bovine Pleuropneumonia)

- galactan in mucus capsule induces necrosis, thrombosis, inflammation

Corynebacterium bovis Primarily occurs in athymic nude mice (immunocompetent mice may have subclinical infection) > hyperplastic dermatitisBrachyspira hyodysenteriae cytotoxic hemolysin is primary virulence factor; acts synergistically with anaerobic colonic microfloraStaphylococcus aureus (primates) cutaneous injury and innoculation - cellulitis - bacteremia - endocarditis/visceral showering - secondary immune complex

glomerulonephritisEdwardsiella ictaluri (Hole in the Head Disease)

multifocal cutaneous ulceration 2o to thrombosis; septicemic lesions in other organs;

Listeria Monocytogenes  Corynebacterium pseudotuberculosis

 

   

Infectious Disease (Viral)Cerebellar hypoplasia, viral In utero viral inf > inf & necrosis of cerebellar external germinal cells > defective Purkinje cell localization & maturation > cerebellar

hypoplasiaBovine- in utero infection of Bovine Pestivirus (BVD), Akabane virus; Cat- Feline panleukopenia virus (in utero); Sheep- Border disease (Pestivirus),Cache valley fever virus; Dog- Segmental hypoplasia - canine herpes virus, canine Parvo virus; Pig- Hog cholera virus (Pestivirus)Goat- Cache valley fever virusBirds- Fowl glioma- inducing virus (avian leucosis virus group A)

Hydranencephaly/Porencephaly, viral

Bluetongue or Border Disease Virus In utero viral inf around 40-75 days gestation > inf & necrosis of undiff cerebral subventricular cells > cerebral cavitation

RetrovirusesRetroviral pathogenicity Receptor-mediated entry into target cells viral genome undergoes reverse transcription (RNA DNA)

1) In quiescent cells, may remain in cytoplasm2) In actively dividing cells, may enter nucleus integrated into host genomea) proviral genome may remain untranscribed for months-yearsb) proviral genome may be transcribed, producing infectious virus that causes membrane blebbing and rupture (cell death)c) proviral genome may contain viral oncogenes (v-Onc) uncontrolled cell proliferation (acute-transforming viruses)d) proviral genome may insert near a host protooncogene insertional mutagenesis (viral promoters cause overexpression of cell protooncogene product)

Equine Lentivirus (EIA) Virus adsorbed on erythrocytes > IgM, IgG attachment to virus > complement activation > hemolysis; bone marrow hyperplasia and then atrophy; ag-ab membranous glomerulonephritis; virus within macrophage cytoplasm (ISH)

Ovine/caprine Lentivirus (Maedi/visna virus)

infection - viremia - infection of choroid plexus epithelium, fibroblasts, endothelial cells, monocytes - insufficient HI/CMI - latency (months-years) in monocytes - activation of latent provirus by maturation into macrophages - immunopathology due to persistent viral antigen; infection of alveolar macrophages - proinflammatory cytokines - recruitment and activation of leukocytes - fibrosis, smooth muscle hyperplasia

Caprine Arthritis/Encephalitis Virus (Caprine Lentivirus)

infection - viremia - insufficient HI/CMI - latency (months-years) in monocytes - activation of latent provirus by maturation into macrophages - immunopathology due to persistent viral antigen

Feline Immunodeficiency Virus (Retrovirus - Lentivirus)

infection/replication in CD4+Th cells, macrophages, astrocytes, microglia - chronic viremia - progressive impairment of CMI due to reduced CD4+ cells - opportunistic infection

Feline leukemia virus (feline gammaretrovirus-A/B)

infection - local lymphoid replication - transient viremia - viral replication in lymphoid tissues, marrow - persistent viremia - extensive infection of marrow, GI tract, salivary glands, bladder, respiratory tractimmne suppression may relate to p15E envelope protein

Enzootic Bovine Leukosis - Bovine Leukemia Virus

Enzootic Bovine Leukosis - infection of B-cells - expression of Tax and Rex regulatory gene proteins - B-cell lymphoma

Ovine pulmonary adenocarcinoma virus (Jaagsiekte sheep retrovirus) (betaretrovirus)

- prolonged latency (2 yrs); disease more likely in certain breeds; B204unknown mechanism of oncogenesis; envelop protein is sufficient to induce similar tumors in immunosufficient mice

Avian retrovirus (alpharetrovirus – Type C oncornavirus) - Lymphoid Leukosis

in B-cells, provirus integrates closely to host c-myc oncogene - viral replication triggers cell replication; provirus genome may contain c-onc proto-oncogene - generate oncoproteins - stimulate cell transformation (fast-transforming strains)

Avian retrovirus (alpharetrovirus – Type C oncornavirus) - Erythroblastosis/Myeloblastosis

provirus integrates closely to host c-erbB oncogene - viral replication triggers cell replication

ParvovirusesParvoviral enteritis Virus inf of crypt epith cells during S/G2 cell cycle phase > utilize host cell DNA polymerase to replicate > necrosisCanine parvovirus-2 oral infection - viremia - replication in thymus, tonsils, retropharyngeal and mesenteric LNs, spleen - infection of intestinal crypt

epithelium (6d)Feline panleukopenia virus (feline parvovirus)

replication in oropharyngeal lymphoid tissues - viremia - infection of lymph nodes, spleen, thymus, bone marrow, intestinal crypts (other rapidly-dividing cell types)

Aleutian Mink Disease Parvoviral inf of lymphocytes >viral release > immune complex deposition in vessels, glomeruli, & other tissues > plasmacytic vasculitis, GN, splenomegaly/hepatomegaly, & hypergammaglobulinemia

CoronavirusesCoronaviral/Rotaviral enteritis selective destruction of mature villus cells - villus atrophy - malabsorption - diarrheaBovine enteric coronavirus infection of intestinal epithelium (fascilitated by digestive enzymes - trypsin) - villus atrophy - malabsorptive diarrhea; lymphoid

infection (mesenteric LNs) - lymphoid depletion; rarely infects lungs

Endogenous mutant of Feline enteric coronavirus

infection of epithelium of upper respiratory tract/intestine, regional lymph nodes - spontaneous mutation of FeCV? - dissemination within phagocytes - immune response - antigen-antibody complex formation - immun complex deposition within blood vessels - complement activation - C3b production - neutrophil chemotaxis - granulomatous-pyogranulomatous vasculitis - Effusive form - lack of CMI, primarily humoral response > viremia > non-neutralizing antibodies deposited in vessel walls > fibrinonecrotic peritonitis & vasculitis (effusive form) - Noneffusive form - Coronaviral inf of møs > weak cell-mediated immune response > virus persists in møs > pyogranulomatous inflam (non-effusive form)

Infectious Bronchitis virus (coronavirus)

primary infection of respiratory mucosal epithelium; some nephrotropic strains

Bovine Respiratory Coronavirus virus replicates in upper respiratory tract, rarely lungsOrbivirusesBluetongue (orbivirus) Culicoides (midge, gnat) bites sheep > hematopoietic cell viral replication > viremia > widespread endothelial cell viral replication &

damage > hemorrhage, edema, thrombosis, & infarction - Hemorrhage at the Base of the Pulmonary Artery; Rumenal Pillar Hemorrhage & Necrosis

African Horse Sickness virus (Equine Orbivirus - Reovirus)

virus replicates in lymph nodes, spleen, thymus, pharyngeal mucosa - infection of capillary endothelium

PestivirusesPersistently Infected BVDV Type 1 Noncytopathic Bovine Viral Diarrhea virus (bovine pestivirus) - immunotolerant animals with persistent infection in utero

(<100d gestation) with noncytopathic infectionBVDV enteritis - Mucosal Disease In utero inf w/ noncytopathic BVD virus (less than 4 months)> develop immunotolerance & persistent inf > postnatal inf w/ cytopathic

strain > inf epith > mucosal dz w/ necrotizing stomatitis, esophagitis, enteritis, etc.Acute BVDV infection Type 1 Noncytopathic Bovine pestivirus infection - replication in epithelium/palatine tonsils - viremia - infection of lymphocytes and

monocytes - necrosis of epithelia/leukocytes, limited submucosal vasculitisAcute Lethal BVDV (Type 2 Bovine pestivirus)

virulent Type 2 BVDV strain

Thrombocytopenic BVDV Type 2 Bovine pestivirus infection - reduced circulating platelets and impaired function"Hairy Shakers" persistent congenital infection of lambs with Border disease virus (ovine pestivirus) - fetal malformations (CNS hypomyelinogenesis,

hydranencephaly/ porencephaly, skeletal immaturity, decreased secondary hair follicles)Feline Herpesvirus-1 (varicellovirus-alphaherpesvirus)

viral replication in nasal mucosa, tonsils, pharynx - cytolytic infections of mucosal epithelial cells and establishment of latency in the trigeminal ganglion, optic nerve, olfactory bulb, and cornea - reactivation of latent infection is often of unknown cause, but may be triggered by corticosteroid therapy, stresses associated with environmental changes, or parturition; virus replicates optimally at temperatures less than 37oC; thus, most infections are limited to the upper respiratory tract and conjunctiva; neonates - subnormal temperatures - viremia - infection of vascular endothelium, parenchymal organs

HerpesvirusesCanine Herpesvirus-1 (varicellovirus-alphaherpesvirus)

viral replication in nasal mucosa, tonsils, pharynx - subnormal temperatures - viremia - infection of vascular endothelium, parenchymal organs

Porcine herpesvirus-1 (varicellovirus-alphaherpesvirus)

virus replicates in mucus membranes of nasopharynx, tonsils - spread to regional LNs, CNS via CN axons - viremia - infection of multiple organs; transplacental infection; latency

Equine Herpesvirus-1 and –4 (varicellovirus-alphaherpesvirus)

viral replication in nasopharynx and associated lymphoid tissues - endothelial infection

Malignant Catarrhal FeverAfrica - Alcephaline herpesvirus-1 (Rhadinovirus-Gammaherpesvirus)Other - Ovine Herpesvirus-2 (Rhadinovirus-Gammaherpesvirus)

contact with infected host species (Wildebeest, sheep) - probably respiratory infection - cell-associated viremia - possible immune-mediated disease

bovine herpesvirus-1 (varicellovirus-alphaherpesvirus)

virus replicates in upper respiratory tract - spread via nasolacrimal ducts

Gallid herpesvirus-2 (alphaherpesvirus) - Marek's Disease

infection of nervous system, lymphocytes (primary) and other tissues

Herpesvirus simiae/Simian Herpesvirus B (Cercopithecine herpesvirus-1)

bite by infected monkey - local inflammation and vesicle formation, necrosis - invasion of CNS by peripheral nerves

Elephant Endotheliotropic Herpesviruses (EEHV 1-3, probosciviruses, betaherpesviruses)

Endotheliotropism ascites, widespread visceral edema, petechiae, and capillary damage, grossly visible renal medullary hemorrhage, a tropism for larger veins and arteries in various tissues, relatively high density of renal herpetic inclusions, and involvement of the retinal vessels - less selective organ tropism, and this may confer a higher degree of virulence for EEHV3

ParamyxovirusesCanine Distemper Virus (Morbillivirus - paramyxovirus) - infection prior to 6 months of age

infection depends on haemagglutinin (mediates viral attachment to host cell) and fusion glycoproteins (penetration of host cell, fusion of infected and uninfected cells); replication in bronchial LNS, tonsils - leukocyte-mediated viremia - inadequate CMI/HI - infection of mononuclear cells of lymphatic, alimentary, respiratory systems, nervous systems - infection of alimentary, respiratory, urogenital, endocrine systems, foot pads, glial cells, ependymal cells, neurons; destruction of ameloblasts

Canine Parainfluenzavirus-2 (Rubulovirus - Paramyxovirus)

impaired mucociliar clearance; increased bronchoconstrictive response to agonists such as histamine

Hendra Virus (Henipahvirus - Paramyxovirus)

fruit bat reservoir - vascular tropism in lungs - spread of virus by infected macrophages to vasculature of brain, liver, kidneys, liver, myocardium, spleen

Rinderpest Virus (Morbillivirus - Paramyxovirus)

respiratory infection - replication in tonsils and lymph nodes - leukocyte-mediated viremia - dissemination to spleen, bone marrow, lymphoid tissues, epithelium of respiratory and alimentary tracts

Bovine/Ovine Respiratory Syncytial Viruses (Bovine Pneumovirus - Paramyxovirus)

virus replicates in respiratory epithelium, causes local necrosis

bovine parainfluenza virus-3 (paramyxovirus - respirovirus)

infection + stress - replicates in macrophages and alveolar epithelium - impaired mucociliary function, damage to alveolar macrophages (impaired phagocytosis/oxidative killing, induce contact-mediated suppression of lymphocyte responses) - impaired antibacterial defenses

Avian Paramyxovirus type 1 (Avulovirus - Paramyxovirus) - velogenic Newcastle DV

viral replication in respiratory tract - primary viremia - multiplication in parenchymal organs - secondary viremia; Velogenic strains are highly pathogenic, mesogenic less pathogenic, lentigenic low pathogenicity; Viscerotropic strains produce respiratory disease, enteric disease, Neurotropic strains produce nervous and respiratory disease

RhabdovirusesRabies (Rhabdovirus-Lyssavirus) bite - virus infects in muscle at site of wound (via nicotinic ACh receptor?) and multiplies - infects sensory neurons - axonal transport

to CNS (protected from immune system) - multiplies in CNS - travels down peripheral nerves - infects salivary gland, cornea, tonsilOrthomyxovirusesEquine Influenza Virus (Orthomyxovirus type A subtype H3N8)

infection of upper and lower airway epithelium; Hemaggliutinin mediates virus interactions with cell receptors, with later cleavage mediating fusion of cell membrane and virus envelope (Ab protect against infection); Neuraminidase mediates virus release from infected cells (Ab prevent disease/contagion)

Swine influenza virus (Orthomyxovirus Type A)

infection of upper and lower airway epithelium; Hemaggliutinin mediates virus interactions with cell receptors, with later cleavage mediating fusion of cell membrane and virus envelope (Ab protect against infection); Neuraminidase mediates virus release from infected cells (Ab prevent disease/contagion)

Avian Influenza virus (Type A orthomyxovirus)

Hemaggliutinin mediates virus interactions with cell receptors, with later cleavage mediating fusion of cell membrane and virus envelope (Ab protect against infection); Neuraminidase mediates virus release from infected cells (Ab prevent disease/contagion)

AdenovirusesCanine adenovirus type I (Mastadenovirus)

replication in tonsils, Peyer's patches - localization and replication in liver and kidneyUveitis - Type 3 (immune complex) hypersensitivity to persistent viral antigen - complement activation - neutrophil attraction and injury

Equine adenovirus A (Equine Adenovirus-1; Mastadenovirus) Bronchopneumonia

small white foci, mainly in Arabian foals with congenital combined immunodeficiency

Bovine Adenovirus may predispose to bacterial pneumonia by injuring ciliate epithelium, impairing alveolar macrophagesTogavirusesEastern Equine Encephalitis; Western Equine Encephalitis; Venezuelan Equine Encephalitis (Togaviruses - Alphaviruses)

innoculation by an infected insect (mosquito) - primary viral replication in lymph nodes - primary and secondary viremia - infection of many tissues (including brain, via exposed nerve endings or neuromuscular junctions)

ArterivirusesEquine Arteritis Virus (Arterivirus) repiratory infection - replication in pulmonary macrophages - replication in bronchial LNs - viremia - infection of endothelial cells -

necrosisPorcine reproductive and respiratory syndrome

presumed mucosal portal of entry virus replication in local macrophages transient viremia dissemination of phagocytic cells to the lungs and other organs, such as the thymus, liver (Kupffer cells), spleen, all lymph nodes, and intestine known to induce apoptosis as a mechanism of cell destruction and persistent infection as a mechanism of dissemination

Picornaviruses

Foot and Mouth Disease Virus (Bovine Aphthovirus - Picornavirus)

viral replication in pharynx - viremia - infection of epithelium via dermal papilla; vesicle formation secondary to lysis fo infected cells and release of cytoplasm

Swine vesicular diseas virus (Enterovirus - picornavirus)

infection of epithelium - viremia - generalized infection of lymphoid tissues

Avian encephalomyelitis virus (hepatovirus - picornavirus)

ingestion - infection of duodenum - viremia - infection of visceral organs, brain

FlavivirusesOvine Flavivirus (Louping Ill) transmitted by Ixodes ricinus - biphasic fever - progressive nervous dysfunctionPoxvirusesLumpy Skin Disease Virus (Capripoxvirus)

spread by biting flies - percutaneous infection - systemic spread (endothelium, keratinocytes, fibrocytes, skeletal muscle, macrophages, pericytes, glandular epithelium) - thrombosis-infarction-

Sheeppox (Capripoxvirus) infection - viremia - dissemination of virus to skin, lymph nodes, spleen, kidney, lungs; vasculitis 2o to immune complex deposition?Goatpox (Capripoxvirus) infection - viremia - dissemination of virus to skin, lymph nodes, spleen, kidney, lungsOrf Virus (Parapoxvirus) infection of cutaneous abrasionsSwinepox virus (Suipoxivirus) Transmitted by sucking louse (Haematopinus suis) - skin traumaFowlpox viruses (avipoxvirus) entry via abrasions; carried by mosquitosMyxoma virus (leporipoxvirus) - Myxomatosis, Shopes Fibroma

transmitted by biting insects; replicates in epithelial cells, fibromas in SQ and dermis

AsfarvirusesPorcine Asfarvirus oronasal infection - viral replication in pharynx, tonsils, lymph nodes - viremia - infection of lymphoreticular system within marrow,

lymph nodes, lungs, kidneys, liverCircovirusesPorcine circovirus-2 initial infection - viremia - infection of multiple organsBeak and feather disease virus (circovirus)

infection of cells of immune system, feather follicular epithelium

Chicken anemia virus (Gyrovirus - Circovirus)

infection of day-old chicks - viremia - infection of T-cells in Thymic cortex and bursa, hematopoitic cells of bone marrow - aplastic anemia and immune suppression

BirnavirusesInfectious bursal disease virus (avibirnavirus serotype 1)

infection (oral, respiratory, conjunctival) - infection of lymphohistiocytic cells in liver, jejunum, duodenum, cecum - infection of B-cells in Bursa of Fabricius - Viremia - infection of thymus, Harderian gland, spleen - depletion of Bursa - impaired immune response

CalicivirusesRabbit hemorrhagic disease virus and European Brown Hare Syndrome Virus (Calicivirus - Lagovirus)

oronasal infection - infection of mononuclear phagocytes

PapillomavirusesEquine Sarcoid (BPV-1/2) transformation activity of the virus is due to the binding of the E5 to the platelet-derived growth factor receptor (PDGF -r) β β

downstream activation of PI3K–AKT–cyclin D3

Infectious (Fungal)Mycotic Rumenitis Aspergillus fumigatus, Candida albicans, Absidia corymbifera, Rhizomucor (Mucor) pusillus; Mortierella spp.

Grain overload > rumenal acidosis > mucosal damage > opportunistic fungal inf > vasculitis > ischemia & mucosal ulcerationGuttural Pouch Mycosis Aspergillus nidulans guttural pouch infection> erosion of int. carotid artery > hemorrhage Aspergillus fumigatus uncertain whether disease relates to exposure dose or impaired nasal defenses; immune suppression is only rarely reported;

Antibiotics?Blastomyces dermatitidis inhalation of mycelial forms - convert into yeast forms - proliferate in lungs - disseminated via blood and lymphatic vessels; Th1

immune responses associated with protection in mouse models - BAD-1 - surface protein - mediates adhesion to host cells, may modulate inflammatory response

- cell wall polysaccharide a-glucan - may protect against killing by macrophagesHistoplasma capsulatum yeast invades tissues, causes necrosis, replicates in macrophagesCryptococcus neoformans var neoformansCryptococcus neoformans var gatii

inhalation of basidiospores (yeast cells) from contaminated dust - nasal disease - infection may progress by local spread to brain, aspiration to lung, or hematogenous spread to brain, eyes, lymph nodes, skin and other organs; disease only occurs with immune suppression - thick capsule - glucuronoxylomannan, other mannose-rich polysaccharides - impairs phagocytosis, activates complement, and may suppress T cell responses - ability to synthesize melanin - may scavenge oxygen radicals produced by activated macrophages, and modulate the host immunoinflammatory response - secretion of eicosanoids and mannose protein that modulate immune and inflammatory responses - production of superoxide dismutase and laccase that augment resistance to oxidative killing

Candida albicans underlying debility/immunodeficiency; antibiotic therapy (destruction of normal oropharyngeal flora); elevated blood glucoseCoccidioides immitis Inhalation of airborne arthroconidia is usual route of infection; local inoculation occasionally causes a cutaneous lesion that does not

usually progress to systemic infectionMicrosporum canis and Trichophyton

infection of stratum corneum and hairs/follicles

            

Infectious (Ectoparasites)Sarcoptes scabei intrepidermal migration - excretion - hypersensitivityDemodex canis mites proliferate - follicular dilation and hyperkeratosis - follicular plugging - follicular rupture - furunculosis reaction (foreign body

reaction against keratin)Ctenocephalides felis (common)Ctenocephalides canis

infestation - feeding injects proteolytic enzymes and histamine-like substances - immediate and delayed-type hypersensitivity responses

               

Infectious (Nematodes)Strongylus vulgaris Ingestion of L3 larvae of Strongylus vulgaris > larvae enter wall of cecum and colon and molt to L4 larvae > penetrate arterioles >

migrate up the vessel along the intima > localize in cranial mesenteric artery and its branches along the aorta > arteritis, thrombosis + aneurysm > + emboli to small and large intestine > intestinal infarction and abdominal pain (colic).

Toxocara cati (usually large burdens)Toxascaris leonina

Toxocara - infection by ingestion (milk, environment), horizontal transmission - infective larvae penetrate intestine - liver (portal bloodstream) - lungs (caudal vena cava) - larval development in alveoli - coughed and swallowed - development of adults - ova passed in fecesToxascaris - ingestion of intermediate host - no hepatopulmonary migration

entrapped larval Toxocara cati larval migration in stomach wall - tissue reaction to antigens in larval feces, sheath, salivaStrongyloides stercoralis both free-living and parasitic forms; larvae enter host by skin penetration, transplacentally or (rarely) ingestion - migrate into

bloodstream - lung airways - coughed and swallowed - intestinal tractEucoleus aerophilus parasitizes the trachea and bronchi of wild canids, domestic dogs, and occasionally cats; eggs are laid in the airways, move with mucus

to the pharynx, are swallowed and passed in the feces - larvae undergo initial development in the egg, and then progress to the infective stage within earthworms, which are a required intermediate host - Eggs also hatch in about 40 days under suitable environmental conditions, but the resulting larvae are apparently not infective - After ingestion of the earthworm, the larvae reach the lungs in ~1 week and are mature in the trachea in about 25 days

Aelurostrongylus abstrusis adults (slender and up to 1 cm long) live in terminal bronchioles and alveolar ducts - eggs form nodular deposits in alveoli, where they embryonate and hatch to give first-stage larvae - larvae reach the airways and are passed in the feces - Snails and slugs are intermediate hosts, while birds, rodents, frogs, and lizards are paratenic (transport) hosts - life cycle can be completed if a cat eats either an intermediate host or a paratenic host - Infective larvae migrate to the lungs and reach maturity ~4-6 weeks after ingestion of the third-stage larvae

Oslerus rostratus viviparous parasite; death of parasite provokes intense suppuration, mineralization, fibrosisSpirocerca lupi stomach - aorta - esophagus - discharge ova into esophageal lumenOslerus osleri (upper) acquired from the dam through grooming or regurgitative feeding; thin-walled embryonated eggs are coughed up and swallowed and

many hatch before being passed as infective larvae in the feces à do not require an intermediate host à first-stage larvae of O. osleri are immediately infective, and pups are infected by ingestion of larvae in the saliva, tracheobronchial secretions, or feces of their dams à Larvae migrate from the gut through the blood to the lung à develop into fifth-stage larvae by 5 weeks after infection, and tracheal nodules are detectable at 10 weeks and well developed by 18 weeks

Crenosoma vulpis snails and slugs are intermediate hosts - Adult worms reside in bronchioles and small bronchi - After a prepatent period of 18-21 days, adults produce larvae that are passed in the feces for about 8 months

Angiostrongylus vasorum Adults inhabit pulmonary arteries and right ventricle of dogs and foxes; eggs pass via the blood to the lungs, where the larvae hatch, penetrate into alveoli, are coughed up and passed in the fecesà prepatent period is 38-57 days. Snails and slugs serve as intermediate hosts.

Filaroides hirthi (lower) adults live in alveoli and respiratory bronchioles àhas a direct life cycle, and infective first-stage larvae are passed in the feces; many infections are probably acquired from the dam

Andersonstrongylus milksi molluscan intermediate host has been proposed, but the life cycle is unknownParascaris equorum infection by ingestion (milk, environment), horizontal transmission - infective larvae penetrate intestine - liver (portal bloodstream) -

lungs (caudal vena cava) - larval development in alveoli - coughed and swallowed - development of adults - ova passed in fecesadministration of anthelmintics with large parasite burdens - death of large numbers of ascarids - impaction and obstruction

Strongyloides westerii both free-living and parasitic forms; larvae enter host by skin penetration, transplacentally or (rarely) ingestion - migrate into bloodstream - lung airways - coughed and swallowed - intestinal tract

Oxyuris equi parasites inhabit lumen of distal colon/rectum - lay eggs on perineumOstertagia ostertagia Teladorsagia circumcincta

infection - enter gastric glands - lymphonodular hyperplasia, eosinophilic inflammation - induce mucus cell hyperplasia and atrophy of Chief and parietal cells - maldigestion

Oesophagostomum radiatumOesophagostomum columbianum

third stage larvae are ingested, penetrate deeply into small intestinal wall, excyst, molt to fourth stage - mature in colon - either encyst in colonic wall and form mineralizing granulomas or mature into adults

Oesophagostomum dentatumBunostomum spp. infection of infective larvae by ingestion (milk, environment), horizontal transmission, dermal penetration - migration to intestine -

development of adults - ova passed in fecesTrichostrongylus spp. direct life cycle - thrid stage larvae are rendered infective by abomasal pH - larvae burrow into crypts but do not penetrate - crypt

hyperplasia and paradoxical crypt atrophy - malabsorptive and protein-loss enteropathyNematodirus spp. overwinter to become infective - fourth and fifth-stage larvae reside in deeper layers of mucosa - villus atrophy; rarely cause diseaseCooperia spp nematodes live between small intestinal villi - pressure necrosisDictyocaulus viviparus, D. filariae third-stage larvae ingested - penetrate wall of intestine - migrate via lymphatics to mesenteric lymph nodes - molt to fourth-stage

larvae - travel by way of lymph and blood to enter lungs about 7 days after infection - final molt to fifth-stage larvae in bronchioles - adults develop in larger airways - eggs are embryonated when laid, hatch rapidly - First-stage larvae are expelled from lung by coughing, are swallowed, and then passed in feces - development to infective third-stage larvae occurs on ground over the next 5-7 days

Hemonchus contortus (barberpole worm)

infection - enter gastric glands - emerge as adults - feed on blood through abomasal mucosa - severe anemia and hypoproteinemia

Muelleria capillaris - Multiple 1-20 mm diameter (usually 2-4 mm) subpleural nodules in dorsal regions of caudal lobesProtostrongylus rufescens - 2-4cm diameter angular firm, tan nodules distributed throughout lungsNeostrongylus linearis - 1-4mm red-violet or grey-pink nodules in caudal lungCystocaulus creatus - 5-20mm diameter dark firm nodules in dorsocaudal lung; brown-black hair-like worms

Adults in nodular lesions in alveoli and rarely in bronchioles, but are usually not visible at necropsy - lay eggs - rapidly hatch - first-stage larvae are coughed up, swallowed, and passed in feces - intermediate hosts are various slugs and snails - infective stage is reached after 2 molts in intermediate host - sheep and goats swallow the intermediate hosts - larvae migrate to lungs, presumably via lymphatics, and break out into alveoli - infections are acquired gradually, and large worm burdens are seldom observed in animals <6 months of age

Ascaris suum (Roundworm) infection by ingestion (milk, environment), horizontal transmission - infective larvae penetrate intestine - liver (portal bloodstream) - lungs (caudal vena cava) - larval development in alveoli - coughed and swallowed - development of adults - ova passed in feces

Strongyloides spp. both free-living and parasitic forms; larvae enter host by skin penetration, transplacentally or (rarely) ingestion - migrate into bloodstream - lung airways - coughed and swallowed - intestinal tract

Globocephalus spp. infection of infective larvae by ingestion (milk, environment), horizontal transmission, dermal penetration - migration to intestine - development of adults - ova passed in feces

Macracanthorhynchus hirudinaceus arthropod intermediate host; attach to wall of GI tractBalisascaris procyonis (aberrant migration)

ingestion of embryonated eggs the larvae are released in the intestine and undergo aggressive somatic and pulmonary migration severe damage, particularly in the central nervous system, is attributed to the rapid growth of the larvae, ability to migrate into the brain (resulting in extensive trauma in target areas), metabolic wastes and enzymes elaborated by the parasite (may evoke a vigorous inflammatory response) 

   

TrematodesAlaria spp. paratenic hosts - frogs, snales, miceNanophyetus salmincola snail and fish as intermediate hostsParagonimus kellicoti first intermediate hosts are small aquatic snails; second intermediate host is a freshwater crab or crayfish - crayfish is eaten by the

definitive host - metacercariae are liberated in the intestine and migrate across the peritoneal and pleural cavities to the lungs - passage through the pleura is marked by multiple small hemorrhages and foci of eosinophilic and fibrinous pleuritis that heal as small umbilicated scars

Fascioloides magna, Fasciola hepatica

aberrant parasite migration within liver

         

CestodesTaenia pisiformis/taeniaformisDipylidium caninum (flea tapeworm)Diphyllobothrium spp. Mesocestoides spp. Anaplocephala perfoliataParanoplocephala mamillanaMonezia sppTaenia saginata

attach to GI wall via anterior scolex - absorb nutrients via outer surface - compete with host for nutrients

Cysticercosis (Cysticercus fasciolaris, Taenia taeniaformis)

infected by contamination of food with cat feces eggs of this tapeworm are ingested migrate through the bowel and often encyst in the liver

Coenurus cerebralis CNS of the sheep is invaded by Coenurus cerebralis, the cystic larval stage, or metacestode, of the tapeworm Taenia multiceps. ingestion of the larval stage by the carnivore (occurs when carnivore ingests raw, infected sheep's brain or offal) - Taenia multiceps then lives in small intestine of carnivores - sheep get infected by consuming herbage contaminated with onchospores or Taenia eggs - embryos then pass via the blood to the CNS

Hymenolepsis nana (“dwarf tapeworm”).

Direct or indirect (via arthropod IH) life cycle with cercocystis in villi – possible zoonosis

      

Infectious (Microparasites)Cystoisospora spp.Eimeria bovis, zuernii, leukarti, arloingi, christenseni, Eimeria nina-

ingestion of sporulated oocyst (2 sporocysts containing 4 sporozoites) - sporozoites excyst - invade enterocytes - merogony (asexual reproduction - schizont containing many merozoites) - rupture of host cell and reinvasion - gametogony (sexual reproduction - female macrogametocyte fertilized by male microgametocyte) - oocyst ruptures from host cell, passed in feces, sporulates

kohl-yakimovaeIsospora suisGiardia lamblia infection - attach to enterocyte microvilli - membrane damage - decreased absorption of monosaccharides/disaccharides - bacterial

fermentation - osmotic diarrheaCryptosporidium parvum Protozoa displace microvilli - enclosed by surface cell membranes (not vacuolated - intracellular but extracytoplasmic) - Neorickettsia helminthoeca ingestion of salmon containing infected fluke (Nanophyetus salmincola) Entamoeba histolytica fecal-oral transmission; cell associations are mediated by adhesins; intracellular organismBovine Enteric Chlamydiosis (Chlamydophilia psittaci)

chlamydia are endocytosed - multiply in epithelial cell apices - liberated into lamina propria

Babesia bovis altered RBC glycocalyx - "stickier" RBCs - adhesion to capillary endotheliumEncephalitozoon cuniculi Dwarf rabbits may be more susceptible; obligate intracellular Gram-positive microsporidian; persist for up to 6 weeks at RT, mature

spore stage has coiled polar filament to inject sporoplasm; oral or respiratory infection spores pass via mononuclear cells into systemic circulation → high blood flow organs (liver, kidney, lung → brain ~ 1 month); development of sporoblasts within cytoplasmic vacuole → xenoma → spores shed in urine 

   

Infectious (Other)Ovine or bovine neurotropic prion? polymorphisms in PrP gene influence susceptibility; exposure to PrP-sc prion induces conformational change in normal PrP - PrP-sc

forms abnormal protein aggregates/polymers in brainKennel Cough Canine Adenovirus-2 (Mastadenovirus)'+/- canine parainfluenzavirus (Rubulavirus - Paramyxovirus) '+/-Bordetella bronchiseptica

'+/- Canine Adenovirus-2 (Mastadenovirus) '+/- Canine Herpesvirus-1 (varicellovirus-alphaherpesvirus) '+/- Canine Reovirus '+/- Mycoplasma spp.