JPC SYSTEMIC PATHOLOGY
Signalment: (JPC #2019285): 9-month-old castrated Merino sheep
HISTORY: This sheep was dosed with a toxic preparation over a 25-day period. During the last 3 days the animal became increasingly weak and was anorectic.
HISTOPATHOLOGIC DESCRIPTION: Liver: Diffusely hepatic cord and sinusoidal architecture is disrupted by swollen, vacuolated, haphazardly arranged hepatocytes (degeneration) that are often separated by moderate to abundant fine, loose fibrous connective tissue. Some hepatocytes are large, with abundant granular eosinophilic cytoplasm and a large vesiculate nucleus, and occasional multinucleation. Others are individualized with a shrunken hypereosinophilic cytoplasm and a pyknotic or karyorrhectic nucleus (necrotic) or have intracytoplasmic round, variably sized discrete clear vacuoles (lipid-type degeneration). Mitotic figures average 1 per HPF and bizarre mitoses are common. Portal areas contain increased numbers of bile ducts (biliary hyperplasia) and are expanded by low numbers of lymphocytes. Occasionally bile ducts and bile canaliculi contain brown to bright yellow globular material (cholestasis). Multifocally, macrophages are distended with intracytoplasmic bright yellow to brown pigment (bile or hemosiderin). Multifocally lymphatics are ectatic (edema).
MORPHOLOGIC DIAGNOSIS: Liver: Hepatocellular degeneration and necrosis, chronic, diffuse, severe, with fibrosis, lipid-type degeneration, bizarre mitoses, multinucleated hepatocytes, biliary hyperplasia, and edema, merino, ovine.
ETIOLOGY: Phomopsin mycotoxin
ETIOLOGIC DIAGNOSIS: Phomopsin hepatopathy
- Phomopsin is a cyclic hexapeptide mycotoxin produced by the saprophytic fungus Diaporthe toxica, which grows on Lupinus spp. plants.
- Several wild lupin plant species are themselves toxic (via alkaloids), resulting in syndromes characterized by teratogenic effects and limb malformations, which are separate from the condition caused by the mycotoxicosis
- Intoxication is most common in animals grazing lupine stubble, which has the highest toxin concentrations; warmth and rain enhance fungal growth and Phomopsin toxin production
- Two toxic metabolites exist; phomopsin A is 2-5 times more toxic than phomopsin B
- Phomopsin is a potent microtubule inhibitor via blocking the polymerization of tubulin, the major component of microtubules
- Defective microtubule formation arrests mitosis in metaphase
- This entity is separate from the toxicosis induced by ingestion of Lupine spp. plants which have teratogenic and neurotoxic effects themselves
- Evidence exists that purified phomopsin A directly stimulates the onset of mitosis in hepatocytes, leading to increased numbers of mitotic figures
- Secondary photosensitization, particularly in sheep
TYPICAL CLINICAL FINDINGS:
- Anorexia, jaundice, photosensitization
- Stumbling gait, recumbency (from hepatic encephalopathy)
- Elevated GGT, AST, serum/liver copper and iron
TYPICAL GROSS FINDINGS:
- Icterus and ascites
- Swollen, firm, friable, pale yellow liver in acute cases
- Small fibrotic liver in chronic cases
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Hepatocyte degeneration and single cell necrosis
- Enlarged hepatocytes with pale granular cytoplasm and vesicular nuclei, or chromatin clumping
- Biliary hyperplasia, diffuse hepatic fibrosis, +/- nodular regeneration
- Numerous mitoses which are often abnormal
- Mitotic arrest at late metaphase
- Lipid type vacuolar change (dependent on the fat reserves of the animal)
- Pigment (lipofuscin, ferric iron, copper) accumulation within macrophages
- Hepatocytes may contain vesicular intranuclear pseudoinclusions
ADDITIONAL DIAGNOSTIC TESTS:
- History of exposure to lupines and clinical signs
- Gross evidence of hepatic necrosis:
- Hepatotoxins such as aflatoxin, pyrrolizidine alkaloids, copper, Lantana, Xanthium (cocklebur), microcystin (blue-green algal toxin), Amanita mushrooms
- Cattle: Phomopsin toxicity causes anorexia and ketosis in pregnant or lactating cows; chronically, fibrotic hepatitis with nodular regeneration (cirrhosis) occurs
- Rats: Phomopsin toxicity produces nodular cirrhosis and biliary hyperplasia; cholangiomas and cholangiocarcinomas/hepatocellular carcinomas are reported
- Brown DL, Van Wettere AJ, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. Elsevier Mosby; 2017:450.
- 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; 2016:334-335.