Martin Black

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Eximination of isoniazid metabolites revealed that rapid acetylators hydrolze much more isoniazid to isonic otinic hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazed is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.

A recently described method for assaying the specific hepatic enzyme responsible for the conjugation of bilirubin was applied to specimens of liver obtained at laparotomy or by percutaneous needle biopsy. Seventy-nine patients with parenchymatous liver disease, biliary obstruction or Gilbert's syndrome were studied, and the results obtained were compared with those from 11 patients without liver disease. A reduction in enzyme activity was observed in each of the 11 patients with Gilbert's syndrome, and in the four patients with Wilson's disease. Biliary obstruction appeared to cause an increase in the activity of the enzyme.

This review of acetaminophen hepatotoxicity begins with a history of the drug and consideration of the scope of its current use. The molecular basis for hepatotoxicity is discussed and this serves as a background for delineation of its clinical manifestations and treatment. Although massive overdose in attempted suicide remains the most common setting for hepatotoxicity from acetaminophen, its occurrence with ingestion of the drug in therapeutic quantities is being recognized increasingly. The particular susceptibility of the alcoholic individual to this complication is reviewed, and recommendations regarding more complete labelling of the drug are offered.