JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

September 2024

D-M06

 

SIGNALMENT (JPC #1431298): 6-month-old Appaloosa foal

 

HISTORY: Two weeks prior to death, this foal was vaccinated 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 karyorrhectic debris. Remaining periportal hepatocytes are often degenerate with swollen, pale, vacuolated cytoplasm; necrotic, with shrunken hypereosinophilic cytoplasm and a pyknotic nucleus; or occasionally contain large, distinct, clear intracytoplasmic vacuoles (vacuolar change, lipid type). Hepatic cords are disorganized and hepatocytes are discohesive and individualized causing widened, irregular sinusoids. There are increased numbers of Kupffer cells which often contain phagocytosed erythrocytes and/or globular brown pigment (hemosiderin or bile), and there are scattered lymphocytes and plasma cells. There is a mild increase in the number of biliary profiles (ductular reaction) which are often dysplastic. 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 loss, centrilobular and midzonal, diffuse, severe, with stromal collapse and mild 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, +/- equine parvovirus hepatitis (EqPV-H)

 

GENERAL DISCUSSION:

• Common cause of acute hepatic failure in horses
• Etiology not known; historically associated with injectable equine biologic products, however infectious etiology is more recently suspected because of sporadic occurrence in horses that have not received equine biological products and 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

 

PATHOGENESIS:

• Cause of hepatocellular loss unknown
• A novel hepatotropic equine parvovirus (EqPV-H) has been shown to be strongly associated with cases of Theiler’s disease and identified as another potential causative agent (Jager, Vet Pathol, 2024)
• Theiler’s disease-associated virus (TDAV), a Flaviviridae member, was previously identified as a possible viral cause of this disease
• 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 (hepatogenous) 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 is not a feature

 

DIFFERENTIAL DIAGNOSIS:

For 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 is 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

 

COMPARATIVE PATHOLOGY:

• 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

 

REFERENCES:

1. 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.
2. Divers TJ and Barton MH. Disorders of the Liver. In: Reed SM, Bayly WM, and Sellon DC, eds. Equine Internal Medicine. 4^th ed. St. Louis, MO: Elsevier Ltd; 2018: 865-866. 
3. Jager MC, Choi E, Tomlinson JE, Van de Walle G. Naturally acquired equine parvovirus-hepatitis is associated with a wide range of hepatic lesions in horses. Vet Pathol. 2024;61(3):442-452. 
4. Van Wettere AJ and Brown DL. Hepatobiliary System and Exocrine Pancreas. In: Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:527-528.

 

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