Toxic Hepatic Diseases

Question 1

By what two major mechanisms are hepatocytes damaged during toxicosis?

Answer 1

1. Hepatoxicosis
   
   • Either the parent compound or a metabolite causes direct hepatocellular damage
2. Cholestasis
   
   • Toxin directly inhibits/damages/downregulates transporter pumps leading to inhivited bile salt efflux and inhibited hepatocyte function

Question 2

Describe the differences between dose-dependent toxicosis and an idiosyncratic drug reaction

Answer 2

Dose Dependent

• Dose-dependent (intrinsic) toxicosis cause a failry predictable inrease in toxicicty with increasing dose across all individuals of a species
• High doses will be toxic to all individuals
• Toxicity is produced by the parent compound or a metabolite that is reliably produced by all individuals

Idiosyncratic Drug Reaction:

• Not possible to predict and do not occur in all individuals of one species
• Toxicity is not dose-dependent, but increased doses will increase the toxicity in susceptible individuals
• Usually produced by a reactive metabolite that is variably produced
• Toxic effect can be due to:
  
  • Oxidative damage
  • Mitochondrial damage
  • Trigger a humoral or T-cell mediated reponse.
• A drug hypersensitivity is an idiosyncrative reaction that involves the adaptive immune response.

Question 3

List 6 drugs that are known to cause a dose dependent hepatotoxicosis

Answer 3

1. Acetominophen
2. Azathioprine
3. Phenobarbital
4. Amiodarone
5. Lomustine
6. Azole anti-fungals

Question 4

List 4 described causes of idiosyncratic drug reactions in dogs and cats

Answer 4

1. Carprofen
2. Methimazole
3. Potentiated sulphonamides
4. Diazepam

Question 5

Describe the mechanism of toxicosis with acetaminophen.

Based on the mechanism of action, how is toxicosis best managed

Answer 5

• Small doses in cats can be toxic, with the formation of methaemoglobinaemia the predominating effect toxic effect
• In dogs, doses over 150 mg/kg may be toxic
• Acetaminophen is detoxified via glucuronidation - cats lack the enzyme that catalyses that reaction causing production of toxic metabolites.
• High doses cause centrilobular hepatic necrosis

As the drug /metabolites are primarily detoxified via glucuronidation, provision of glutathione is necessary in cases of intoxication.

NAC is a glutathione precursor that can be administered IV

sAME may also help restore depleted glutathione stores

Methaemaglobinaemia is managed supportively with oxygen. Methylene blue is used in humans with methaemaglobinaemia

Question 6

What is the mechanism of toxic injury to hepatocytes with phenobarbital excess

Answer 6

• Dependent on cumulative dose, often over years
• Bridging portal fibrosis, bile duct hyperplasia and nodular regeneration
• Phenobarbital induces cytochrome P450 enzymes
  
  • CYPs are involved in drug metabolism to assist clearance
  • CYPs also bioactivate numerous substances including clopidogrel
• CYP induction may increase the hepatotoxic effects of other drugs, dietary components or environmental toxins
• Increases in liver enzymes can be an indicator of early damage prior to functional loss

Question 7

What is the mechanism of hepatic toxicity with azole anti-fungal medications

Answer 7

• The hepatotoxicity of ketaconazole has been attributed to the an oxidative metabolite, N-deactyl ketoconazole.
• The product convalently bonds to liver proteins and leads to glutathione depletion
• Glutathione deficiency leads to increased risk of oxidative damage from any cause.

Question 8

What is the mechanism of hepatic toxicity of azathioprine?

Answer 8

• Azathioprine metabolism leads to the generation of oxidative metabolites by xanthine oxidase and subsequent depletion of anti-oxidants
• Liver enzymes typically increase at a median of 14 days (9-52)
• As the effects are in part caused by anti-oxidant depletion, treatment with NAC or sAME may help prevent or reverse the effects of toxicity