Toxic Hepatic Disease Chapter 286

Toxic Hepatic Disease

• Liver is the site of first-pass metabolism of many orally absorbed metabolites, some of which can generate toxic metabolites.
• Two types of hepatotoxicities:
  • Cytotoxic injury leading to hepatocellular pattern of liver enzyme elevation due to hepatocyte necrosis.
  • Cholestatic injury occurs when a compound inhibits transport pumps in sinusoidal or canalicular membranes, leading to interference with bile salt efflux and hepatocyte function.

Dose-Dependent Hepatotoxicity

• Mechanisms of dose-dependent hepatotoxicity:
  • Oxidative stress: acetaminophen, azathioprine, azole antifungals.
  • Mitochondrial dysfunction: tetracyclines, amiodarone.
  • P450 induction: phenytoin, phenobarbital.
  • Transporter dysfunction: endotoxin.
• Examples of dose-dependent hepatotoxicity:
  • Acetaminophen:
    • Safe in dogs as an anti-pyretic or pain reliever at 10-15 mg/kg PO q8 hr.
    • Doses > 150-250 mg/kg can lead to acute centrilobular necrosis in dogs.
    • In cats, hematologic toxicosis with methemoglobinemia and cyanosis occurs over liver toxicity.
  • Phenobarbital:
    • Toxicity occurs with cumulative dose and after years of treatment.
    • Bridging portal fibrosis, bile duct hyperplasia, nodular regeneration.
  • Azole antifungals:
    • Can lead to mild, clinically insignificant increases in ALT.
    • Toxicity may be associated with toxic metabolite N-deacetyl ketoconazole, which leads to glutathione depletion.
  • Azathioprine:
    • Increases in ALT and bilirubin in 20% of dogs.
    • Mechanism is due to generation of oxidative metabolites and depletion of glutathione.
  • Amiodarone:
    • Clinically significant heptotoxicosis in 45% of dogs at a median of 16 weeks.
    • Clinically significant increases in ALT and occasional hyperbilirubinemia.
  • Lomustine (CCNU):
    • Alkylating agent used for single-agent chemo in dogs with mast cell tumors, lymphoma, and histiocytic sarcoma.
    • 30% of dogs will have a substantial increase in ALT.
  • Tetracyclines:
    • 36-39% of dogs showed an increase in ALT or ALP into the abnormal range during treatment.
    • Toxicity may be due to inhibition of beta-oxidation of fatty acids in hepatic mitochondria.

Idiosyncratic Hepatotoxicity

• Examples of idiosyncratic hepatotoxicity:
  • Potentiated sulfonamides:
    • Hepatic necrosis is the common histologic lesion.
    • Clinical signs occur at a mean of 12 days after initiation of therapy.
  • Carprofen:
    • 1.4 cases per 10,000 dogs treated.
    • Acute hepatic failure 5 to 30 days after drug initiation with bridging hepatic fibrosis.
  • Methimazole:
    • 1-2% of hyperthyroid cats treated with methimazole develop hepatocellular or cholestatic liver enzyme pattern and visible jaundice.
  • Diazepam:
    • Idiosyncratic reaction in cats.
    • Dramatic increases in ALT with marked centrilobular hepatic necrosis.

Household and Environmental Toxins

• Examples of household and environmental toxins:
  • Alfatoxin:
    • Produced by Aspergillus species and can be found in moldy corn or soy.
    • Activated by cytochrome P450 enzymes to metabolites that lead to protein and DNA adducts and glutathione depletion.
  • Xylitol:
    • When ingested by dogs at dosages of 0.15 g/kg or higher, xylitol leads to acute intoxication characterized by insulin release and clinical signs of hypoglycemia within 30 to 60 minutes.
    • Acute hepatic necrosis can occur 6 to 72 hours after exposure.
  • Amanita:
    • Contain amatoxins, which inhibit RNA polymerases, leading to decreased mRNA generation, arrested protein synthesis, and necrosis of metabolically active cells.
    • Vomiting, bloody diarrhea, and abdominal pain occur within 6 to 24 hours of ingestion.
  • Blue-green algae:
    • Proliferate in warm, stagnant, nutrient-rich waters.
    • The cyanotoxins microcystin and nodularin inhibit serine/threonine protein phosphatases in the liver, with subsequent hyperphosphorylation and disruption of cytoskeletal proteins.
  • Cycad palms:
    • The toxic principle, cycasin, is bioactivated to methylazoxymethanol by gut bacteria, leading to gastrointestinal and hepatic toxicosis.
    • GI signs can develop within minutes to hours of ingestion, while biochemical signs of hyperbilirubinemia and increases in hepatocellular and cholestatic enzyme activities may not develop for 24 to 48 hours.