DRUG-INDUCED HEPATOTOXICITY

"Hepatotoxicity is the injury or liver damage caused by exposure to certain drugs, when taken in overdoses and sometimes when administered at therapeutic ranges, may injure the organ".

• Drug-induced hepatotoxicity is also referred to as the Drug-Induced Liver Injury (DILI).

Physiological functions of liver:

1. Formation and sensation of bile.
2. Nutrient and vitamin metabolism (amino acid, lipid).
3. Detoxification and inactivation of various substances (toxin drugs).
4. Synthesis of plasma proteins (Albumin, clotting factors).
5. Immune systems (Kupffer cells).

• Hepatotoxicity is most prevalent in older patients especially in those with pre-existing hepatic impairment.

The few examples of drugs that cause hepatotoxicity are listed below:

1. ACE Inhibitors:

• Hepatic injury occurs occasionally with ACE-Inhibitors.
• Captopril and Enalapril are implicated in most reported cases, but others also have similar hepatotoxic potential.
• Most cases show cholestatic injury, but mixed and hepatocellular damage are also reported.

2. Acetaminophen:

• Acetaminophen is a widely used drug found in many over the counter and prescription analgesics medicine.
• In adults, toxicity may occur by ingestion of >7.5-10 g over a period of 8hrs. or less.
• Acetaminophen is metabolized in the liver by conjugation to non-toxic glutathione. The conjugated product is eliminated in urine. But in acute overdoses, the livers normal glutathione reserves are depleted, and the excess acetaminophen is then metabolized to highly toxic metabolite N-Acetyl-p-benzoquinone (NABQI), causing hepatocellular death and liver cell necrosis.
• Alcohol consumption increase Acetaminophen toxicity.
• Hepatitis is reported in patients taking large Acetaminophen doses for therapeutic purposes.

3. Alcohol:

• Ethanol is oxidized in liver to Acetaldehyde that results in injury to cells and mitochondria with striking impairment of O2 utilization.
• Fatty infiltration of liver occurs in 70-100% of alcoholic.
• 30% alcoholics develop alcoholic hepatitis and 10% develop liver cirrhosis.
• Alcohol can also enhance the hepatotoxicity of other drugs.
• Malnutrition can potentiate alcoholic disease.

4. Antidepressants, Heterocyclics:

• The prevalence of hepatic injury is estimated to be 1%; with most cases presenting as cholestasis.
• The idiosyncratic reaction resembles the cholestasis associated with Phenothiazine.

5. Cephalosporins:

• Transient-minor increase in AST, ALT, and Alkaline phosphate occur frequently.
• Ceftriaxone use is associated with development of "gallbladder sludge" in up to 25% of patients.

6. Contraceptives, Oral:

• Data from two large, long-term cohort studies did not detect any association between oral contraceptives use and serious liver disease.
• One study detected an increase in the frequency of mild-liver diseases among users of older, high estrogen products.
• Frequency of gall-bladder disease was also increased by older oral contraceptives.

7. Gold-Salts:

• Cholestasis occur occasionally with normal doses of parenteral gold salts.
• Hypersensitivity is the suspected mechanism.
• Onset is commonly with first few weeks of therapy and recovery usually occur 3 months after drug discontinuation.
• Lipo-granulomas are frequently found in liver biopsy of parenteral gold-treated patients.
• Hepatic necrosis can result from overdose.

8. Histamine H2-Receptor Antagonists:

• Cimetidine and Ranitidine are associated with increased liver enzymes.
• Risk of acute liver injury (ALI) with cimetidine is about 1/5000 with most cases occurring during first 2 months of use.

9. NSAIDs:

• The incidence of clinically apparent hepatic injury from non-salicylates NSAIDs estimated to be 1/10000 patients.
• The incidence for Sulindac may be 5-10 times higher than for other non-salicylate NSAIDs. 50% reaction to Sulindac are cholestatic 25% hepatocellular.

10. Penicillin:

• Cloxacillin and Flucloxacillin are associated with cholestatic hepatitis.
• The effect is reversible but can persist for months after drug discontinuation.

11. Steroids, C-17-a-Alkyl:

• Canalicular cholestasis occurs with a minimal amount of hepatic inflammation.
• Prevalence appears to be dose related.
• Jaundice may or may not be preceded by clinical signs and usually follows 1-6 months therapy.
• Examples are: Methyltestosterone, Oxymetholone, Oxandrolone.

12. Vitamin A:

• Hepatomegaly, portal hypertension and mild increase in liver enzyme leads are common features of Vitamin A.
• Central vein sclerosis and perisinusoidal fibrosis which can progress to cirrhosis have also been reported in Vit-A toxicity. These affects are associated with doses >50000 IU/day.
• Hepatotoxicity is possible with acute doses >600000IU/day.