JPC SYSTEMIC PATHOLOGY
Signalment: Rabbit (Oryctolagus cuniculus)
HISTOPATHOLOGIC DESCRIPTION: Liver: Diffusely within periportal areas and variably extending into the midzonal and centrilobular areas (panlobular), there is lytic necrosis characterized by loss of hepatic cord architecture and replacement with eosinophilic cellular and karyorrhectic debris, hemorrhage, fibrin, heterophils, and mineral, as well as coagulative necrosis characterized by retention of hepatic cord architecture and loss of differential staining. Diffusely remaining hepatocytes within midzonal regions are extending into centrilobular areas have undergone one or more of the following changes: cell swelling with pale eosinophilic vacuolated cytoplasm (lipid-type degeneration); have an eosinophilic lacy cytoplasm (glycogen-type degeneration); or are hypereosinophilic with pyknotic nuclei (necrotic). Within affected areas, sinusoids are congested or compressed and Kupffer cells are occasionally in aggregates (micronodules) and contain yellow to brown cytoplasm pigment (hemosiderin or bile). Multifocally, portal areas are expanded by few lymphocytes, plasma cells and occasional heterophils with ectatic lymphatic vessels (edema).
MORPHOLOGIC DIAGNOSES: Liver: Hepatocellular degeneration and necrosis, panlobular, diffuse, acute, severe, rabbit, Oryctolagus cuniculus.
ETIOLOGIC DIAGNOSIS: Caliciviral hepatitis
CAUSE: Calicivirus: Rabbit hemorrhagic disease virus (RHDV)
CONDITION: Rabbit hemorrhagic disease virus (RHDV)
- There are two pathogenic lagoviruses: European brown hare syndrome virus (EBHS) and rabbit hemorrhagic disease (RHD) virus
- Highly contagious caliciviruses: Non-enveloped, ssRNA, icosahedral virus
- European brown hare syndrome (EBHS) affects only hare species (wild & farmed): Lepus europaeus (European brown hare), Lepus timidus (mountain or northern hare) and Lepus timidus (varying hare)
- RHD only affects Oryctolagus species of rabbits; Sylvilagus spp. rabbits found in the Americas are not affected
- EBHSV and RHD virus are part of the family Caliciviridae, genus Lagovirus
- EBHS and RHD represent distinct, though closely related agents, causing similar clinical signs and pathological and histological changes, mortality rates, virion morphology and antigenicity; however, there is no cross-species infection and no cross-species protection
- Affects older animals: young rabbits and hares < 4 weeks of age do not develop clinical disease (reason is unclear)
- Recently a third lagovirus has emerged, RHDV2, which kills rabbits under 30days age, including those vaccinated for RHDV, has 20% (5-80%) mortality, affects rabbits and hares, and RHD ELISA does not detect it
- Reportable disease in U.S., depopulation is required for control
- Both viruses are spread by direct and indirect routes; EBHSV primarily through oral fecal routes, and RHDV through both oral-fecal and respiratory routes
- EBHS: No vector/reservoir host has been identified; RHDV: Blood feeding insects may act as a mechanical vector
- Target organ: EBHS: Liver; RHD: Liver, lungs, spleen
- RHD: Viral replication occurs in the hepatocytes, and virus causes apoptosis via VP10; young animals have virus in their hepatocytes, but it does not cause apoptosis
- RHDV binds host-cell histo-blood group antigens (HBGA) which are expressed on the surface of epithelial cells of the upper respiratory and digestive tracts; possible site of entry into host
- RHDV: Death is likely due to multiple organ failure, secondary to consumptive coagulopathy (DIC); DIC may result from systemic endothelial damage from viremia or as a consequence of massive hepatic necrosis, with activation of extrinsic coagulation factors and failure of clearance of activated procoagulant factors
TYPICAL CLINICAL FINDINGS:
- 3 different clinical courses:
- Peracute: No clinical signs; sudden death
- Acute: anorexia, apathy and congestion of the palpebral conjunctiva, and neurological symptoms (opisthotonus, excitement, paralysis and ataxia), with variable respiratory signs (tracheitis, dyspnea and cyanosis); death within 3 days of clinical signs
- Subacute: Similar, though milder clinical signs as acute form; most survive
- Mortality highest in fall when population most dense
TYPICAL GROSS FINDINGS:
- Pale, fatty liver with attenuated lobular pattern & hemorrhage
- Hemorrhage and congestion in multiple organs, especially the lungs, heart and kidneys
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin all elevated shortly before death
- Hepatic calcium content in affected hares is increased up to 20 times normal
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Necrosis of hepatocytes in periportal areas which may extend to midzonal or pan-lobular necrosis
- May see cytosegrosomes (acidophilic bodies) as spherical, refractile, eosinophilic globules (condensed cytoplasm) expelled by sublethally injured hepatocytes into sinusoids to be consumed by Kupffer cells
- Hepatocellular degeneration with lipid vacuolar change
- Lymphopenia (T and B-cell) in both liver and spleen
- Splenic congestion & necrosis;
- Pulmonary edema & hemorrhage
- +/- inflammatory cells (macrophages, heterophils) at portal areas
- Segmental necrotizing enteritis in small intestine
- 27-39 nm in diameter; has scalloped border with 32 cup-shaped surface indentations arranged in icosahedral pattern
ADDITIONAL DIAGNOSTIC TESTS:
- Immunohistochemistry: Demonstration of viral antigen in hepatocytes, mononuclear cells
- Electron microscopy: Detection of viral particles
For hepatic necrosis in hares:
- Toxoplasma gondii
- Tyzzer’s disease (Clostridium piliforme): Characteristic bacilli within the cytoplasm of hepatocytes along the periphery of the lesion
- Tularemia/rabbit fever (Francisella tularensis): Necrosis in liver, spleen, and bone marrow; suppurative acute lesions; granulomatous chronic lesions; many gram-negative bacteria
- Bubonic plague (Yersinia pestis): Rare in domestic species; necrosis of liver, spleen, cecum, occasionally reproductive tract and lymph nodes; large bacterial colonies
- Salmonella: Hepatic necrosis with paratyphoid nodules
- Listeriosis (Listeria monocytogenes): Hepatic necrosis; abortions in pregnant does
- Caliciviridae of veterinary importance: Four genera:
- Rabbit hemorrhagic disease virus
- European brown hare syndrome virus
- Feline calicivirus: Important cause of respiratory disease in cats; ulcerative stomatitis, mucopurulent conjunctivitis, and oculonasal discharge; virulent systemic strains associated with profound fever; anorexia; marked subcutaneous edema (esp. limbs and face); icterus; alopecia; crusting; ulceration of the nose, lips, pinnae, and feet; bronchointerstitial pneumonia; and pancreatic, hepatic, and splenic necrosis in addition to oculonasal discharge; adult cats at higher risk for severe disease and death
- San Miguel sea lion virus: Vesicular lesions on flippers; infects a variety of sea mammals; causes vesicular exanthema of swine when infected sea mammal carcasses are fed to pigs
- Vesicular exanthema of swine: Grossly indistinguishable from foot-and-mouth disease (Picornaviridae, Aphthovirus), swine vesicular disease (Picornaviridae, Enterovirus), and vesicular stomatitis (Rhabdoviridae, Vesiculovirus); eradicated from the U.S.; virus still present in marine mammals
- Norwalk virus: humans
- Causes gastroenteritis in pigs (genogroup III) and humans (genogroup I, II, IV, V)
- Avian hepatitis E virus
- Swine hepatitis E virus
- Hepatitis E virus (human, monkey, pig)
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