JPC SYSTEMIC PATHOLOGY
SIGNALMENT (AFIP #1431298): 6-month-old Appaloosa foal
HISTORY: The foal was vaccinated 2 weeks prior to death for tetanus, Eastern equine encephalitis and Western equine encephalitis. Clinical findings included blindness, incoordination, constipation, head pressing, icterus, AST=1800 (205-555 U/L), bilirubin=12 (0.1-1.9 mg/dl).
HISTOPATHOLOGIC DESCRIPTION: Liver: There is diffuse hepatic necrosis affecting the centrilobular and midzonal regions characterized by loss of hepatocytes, stromal collapse, distortion of the reticulin framework and replacement by eosinophilic cellular and karryohectic debris. Remaining adjacent periportal hepatocytes are often individualized, degenerate with swollen, pale, vacuolated cytoplasm; necrotic, with shrunken hyper eosinophilic cytoplasm and pyknotic nuclei; or occasionally contain large, distinct, clear intracytoplasmic vacuoles (vacuolar change, lipid type). Hepatic cords are disrupted and hepatocytes are individualized and separated by multifocal areas of hemorrhage, there are increased numbers of Kupffer cells which often contain phagocytosed erythrocytes and minimal amounts of globular brown pigment (hemosiderin or bile), and scattered lymphocytes and plasma cells. Portal areas are mildly expanded by clear space (edema) and contain mildly increased amounts of fibrous connective tissue, few lymphocytes, plasma cells, macrophages, and rare neutrophils.
MORPHOLOGIC DIAGNOSIS: Liver: Hepatocellular necrosis and hepatocyte loss, submassive, diffuse, severe, with stromal collapse, hemorrhage, and biliary ductular reaction, Appaloosa, equine.
ETIOLOGIC DIAGNOSIS: Unknown (flavivirus suspected)
CONDITION: Equine serum hepatitis
SYNONYMS: Theiler's disease, idiopathic acute hepatic disease (IAHD), post-vaccinal hepatitis
- Common cause of acute hepatic failure in horses
- Etiology not known; infectious etiology suspected because of sporadic occurrence in horses that have not received equine biological products; there are reports of in-contact non-treated horses developing the disease
- Incubation period of 42-60 days (sometimes as long as 90 days) after receiving injections of equine-origin biologics, including tetanus antitoxin, equine encephalomyelitis antiserum, pregnant mare serum gonadotropin, African horse sickness antiserum, anthrax antiserum, and plasma
- Cause of hepatocellular loss unknown; recent study identified Theiler’s disease-associated virus (TDAV) a Flaviviridae member that appears to be a plausible candidate viral cause of this disease
- Possible equine DNA virus (equine parvovirus) another potential causative agent (has fulfilled Koch’s postulates in n=2 experimental trial)
- Acute hepatic insufficiency secondary to loss of hepatocytes
- Hyperammonemia linked to hepatic encephalopathy
TYPICAL CLINICAL FINDINGS:
- Prolonged incubation period and a very rapid clinical course; acute hepatic failure with death occurring within 6 to 24 hours
- Mildly affected animals: Afebrile, depression, anorexia, excessive yawning, icterus, +/- type II photosensitization
- Hepatic encephalopathy: Restlessness, hyperexcitability, compulsive walking and head pressing, apparent blindness, ataxia, muscle tremors, seizures, and sudden death
- Clinical pathology: Leukocytosis (neutrophilia, lymphocytopenia), hypoglycemia, hyperbilirubinemia, hyperammonemia, increased serum bile acids, prolonged one-stage prothrombin time (OSPT), increased liver enzymes:
- Aspartate aminotransferase (AST): Hepatocellular leakage enzyme; not liver specific, found in liver, muscle and erythrocytes
- Sorbitol dehydrogenase (SDH): Hepatocellular leakage enzyme; liver specific
- Gamma-glutamyltransferase (GGT): Membrane bound induced enzyme; liver specific
TYPICAL GROSS FINDINGS:
- Liver: Shrunken and flaccid “dish-rag liver” (classic lesion); stained by bile pigments; mottled appearance; enhanced lobular pattern because of necrosis of hepatocytes in centrilobular areas with congestion
- Icterus, ascites, +/- splenic congestion and petechial hemorrhages
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Few surviving swollen and vacuolated periportal hepatocytes or sometimes complete depletion of parenchymal cells (lesion appears older than clinical symptoms suggest)
- Severe macrovesciular fatty change; may coalesce and form fatty cysts; dilated sinusoids and condensed reticulin framework
- Extensive bile pigment deposits in hepatocytes and Kupffer cells
- Diffuse mild fibroplasia primarily in portal areas
- No hemorrhage; acute necrosis typically not seen, instead hepatocyte loss is the main feature with collapsed or distortion of reticulin framework; prominent inflammation not a feature
- Equine hepatic necrosis:
- Pyrrolizidine alkaloid toxicity: Chronic; hepatocyte necrosis; megalocytosis; centrilobular fibrosis; bile duct proliferation and fibrosis
- Equine infectious anemia (equine lentivirus): Subacute; centrilobular fatty degeneration and hepatocellular loss; increased numbers of sinusoidal Kupffer cells; portal infiltration by lymphocytes and plasma cells very characteristic
- Acute toxic hepatitis: Usually centrilobular necrosis with minimal inflammation; biliary hyperplasia; fibrosis with chronicity; +/- photosensitization
- Aflatoxicosis: At low doses, resembles pyrrolizidine alkaloid toxicity; at high doses, periacinar hepatocytes disappear and are replaced by a mixture of inflammatory cells, fibroblasts, and primitive vascular channels
- Hepatitis B virus causes similar lesions in human beings
- “Serum sickness” – a Type III hypersensitivity approximately 10 days after administration of antiserum or certain medications, characterized by generalized vasculitis with erythema, edema and urticaria of the skin, neutropenia, joint swelling and proteinuria
- Chandriani S, Skewes-Cox P, et al. Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis. Proc Natl Acad Sci USA. 2013; 110(15):E1407-15.
- Brown DL, Van Wettere AJ, and Cullen JM. Hepatobiliary System and Exocrine Pancreas. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:456.
- Cullen JM, Stalker MJ. Liver and Biliary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Ltd; 2016:313-314.
- Divers TJ and Barton MH. Disorders of the Liver. In: Reed SM, Bayly WM, and Sellon DC, eds. Equine Internal Medicine. 4th ed. St. Louis, MO: Elsevier Ltd; 2018: 865-866.
- Divers TJ, Tennant BC, et al. New parvovirus associated with serum hepatitis in horses after inoculation of common biological product. Emerg Infect Dis. 2018; 24(2):303-310.