SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
October 2021
D-T12 (NP)

SIGNALMENT (JPC #2289065):  4-month-old Shorthorn calf

HISTORY:  Severe weight loss, anorexia, and photophobia.  Diet included grain, lucerne hay, and grazed reclaimed land.  Was in very poor body condition, icteric, and had crusty excoriations around the eyes and muzzle. Gross lesions included a mild accentuation of the lobular pattern of the liver and gallbladder distention.

HISTOPATHOLOGIC DESCRIPTION:  Liver: Hepatocytes are diffusely enlarged up to 100 um in diameter (megalocytosis) and compress adjacent sinusoids.  Hepatocytes often contain abundant pale, lacy, finely vacuolated cytoplasm (glycogen-type degeneration) or few discrete, clear vacuoles that peripheralize the nucleus (lipid-type degeneration). Hepatocytes have large, vesiculate nuclei up to 30 um in diameter with 1-3 prominent nucleoli, and hepatocytes are frequently multinucleated.  Rarely, there are randomly distributed foci of lytic necrosis characterized by individualized or lost hepatocytes with replacement by cellular and karyorrhectic debris admixed with few lymphocytes, macrophages, neutrophils, hemorrhage, fibrin, and edema. Periportal connective tissue is expanded by numerous variably mature small duct profiles (ductular reaction).

MORPHOLOGIC DIAGNOSIS:  Liver: Hepatocellular degeneration, diffuse, moderate, with megalocytosis, ductular reaction, and rare hepatocellular necrosis, Shorthorn, bovine.

ETIOLOGIC DIAGNOSIS:  Lantana hepatotoxicosis

CAUSE:  Lantadene A, B, or C, or icterogenin of the plant Lantana camara

GENERAL DISCUSSION:

• Lantana camara is an ornamental shrub that contains multiple toxic pentacyclic triterpenes, primarily Lantadene A and C and icterogenin, and Lantadene B in lesser amounts
• Lantadene A is the most toxic and is found in higher concentration in the plant
• Intoxication is most common in cattle, and rare in sheep, goats (highly susceptible to the toxin but rarely consume it), and horses
• Ingestion by ruminants causes chronic functional intrahepatic cholestasis

PATHOGENESIS:

• Mechanism of toxicity is unknown; Lantadene A may affect mitochondrial energetics, and can cause severe acute hepatic centrilobular necrosis at experimentally high doses
• The toxic plant may remain within the rumen, prolonging toxin exposure after no longer consuming the plant
• Hepatocellular cholestasis in general is due to a disturbance in at least one of the following steps of bile excretion:
  • Failure to take up bilirubin, bile acids, or other bile constituents; mediated by members of the organic anion-transporting polypeptide (OATP) family, and bile acids are taken up from plasma by Na+-taurocholate cotransporting polypeptide (NTCP)
  • Failure to conjugate bilirubin, bile acids, or other bile constituents; conjugation is by uridine diphosphate-glucoronyl transferase in hepatocellular endoplasmic reticulum
  • Failure to transport and excrete conjugated bilirubin, bile acids, or other bile constituents into bile canaliculi; bile salts transported into canaliculi by bile salt export pump (BSEP), water movement facilitated by aquaporin channels, bilirubin transported into canaliculi by multidrug-resistance-associated protein-2 (MRP-2)
  • Disruption of bile canalicular structural integrity; this appears to be the method of hepatocellular cholestasis in lantana toxicity, with plausible toxin targets including the contractile pericanalicular cytoskeleton or structural integrity-requiring cell adhesion molecules
  • Hepatogenous (secondary, or type III) photosensitization is associated with cholestasis > decreased excretion of phytoporphyrins (phylloerythrins) in bile > increased levels of phytoporphyrins in blood > dermatitis
• Renal acute tubular injury: unknown mechanism, including unknown role of hyperbilirubinemia
• Myocardial necrosis: unknown mechanism, possibly due to reduced myocardial perfusion from decreased circulating blood volume, may be the cause of early death in cattle

TYPICAL CLINICAL FINDINGS:

• Subacute to chronic cholestasis with severe icterus and photosensitization
  • Time course: Photosensitization is severe after 2 days, death may occur within 2 days in heavily intoxicated cattle, disease lasts 2 weeks in most fatal cases, jaundice is more severe in chronic cases
• Cholestasis can occur without significant hepatocellular damage and other signs of liver failure (fairly unique to this entity)
• Plasma bilirubin is predominantly conjugated, indicating that cholestasis is “post-hepatic”, i.e. due to disruption of canalicular transport of bile
• Polyuria due to acute tubular injury à severe dehydration

TYPICAL GROSS FINDINGS:

• Liver: enlarged, pale, bile pigment-stained (yellow, orange, or green-gray)
• Gallbladder: markedly distended with bile
• Large bowel: contains dark, dry feces
• Severe icterus
• Severe photosensitization
• Kidneys: slightly enlarged, wet, pale cortex with hyperemic medulla

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Hepatocellular enlargement with fine cytoplasmic vacuolation (more severe in periportal areas) +/- periportal hepatocellular apoptosis, coagulative necrosis, or dissociation
• Bile accumulation within canaliculi (more severe in centrilobular areas), hepatocytes, and Kupffer cells
• Kidney: Acute tubular injury of variable severity +/- tubular cast formation
• Skin: Ulceration and necrosis (type III [hepatogenous, secondary] photosensitization)

TYPICAL ULTRASTRUCTURAL FINDINGS:

• Characteristic collapse of bile canaliculi
• Increased volume of smooth endoplasmic reticulum

DIFFERENTIAL DIAGNOSIS:

• Pyrrolizidine alkaloids (D-T04; Senecio, Crotalaria, Heliotropium): Similar liver lesions but lacks prominent cholestasis and has marked megalocytosis, +/- pulmonary lesions
• Phomopsin (D-T06; Lupines): Phomopsis leptostromiformis (a parasitic fungus on lupines): Diffuse mild fibrosis, numerous mitotic figures (many abnormal), bile duct proliferation, photosensitization
• Copper (D-M17): Significant variation between species; hepatocellular necrosis, fibrosis, intravascular hemolysis, jaundice, hemoglobinuria, sudden death (sheep), and chronic active hepatitis (dogs)
• Sporidesmin (D-T13; Pithomyces chartarum): Facial eczema, toxic hepatitis, cirrhosis, photosensitization, pasture plants, esp. ryegrass, (sheep, cattle in Texas)
• Aflatoxin (D-T03; Aspergillus flavus): Hepatocellular megalocytosis

COMPARATIVE PATHOLOGY: 

• Sheep and goats are susceptible to Lantana hepatotoxicosis, but disease is uncommon because they are less likely than cattle to consume the plant

REFERENCES:

1. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:450.
2. 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; 2016:293-294, 338.
3. Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1063.
4. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier Ltd; 2016:36.

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