Abnormal serum transaminases following therapeutic doses of acetaminophen in the absence of known risk factors

Abstract

J.M., a healthy, 25-year-old male, volunteered for a study involving warfarin and acetaminophen. Acetaminophen 1 g four times a day was started for 21 days. Liver function tests taken at regular intervals for the first 12 days were unremarkable. On day 18, however, aspartate aminotransferase (AST) was 527 IU/liter and alanine aminotransferase (ALT) was 166 IU/liter. Acetaminophen was discontinued and serum transaminase levels returned to baseline levels two weeks later (AST = 26, ALT = 20). Analysis of J.M.'s urine samples over the first 18 days showed excretion patterns of glucuronide, sulfate, and glutathione derived cysteine and mercapturic acid conjugates were similar to the other subjects in the study. Acetaminophen causes hepatotoxicity in overdose or malnourished or alcoholic patients, none of which applied to our subject. Differences in metabolic activation and capacity for glutathione synthesis can predispose individuals given therapeutic doses of acetaminophen to adverse effects. Failure to detoxify a highly reactive metabolite, formed by P-450 metabolism, via glutathione conjugation is responsible for the development of acute hepatic necrosis. Accumulation of the toxic metabolite due to depleted glutathione stores may have occurred with prolonged high dosing in our subject and been responsible for his abnormal rise in liver enzymes.

Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase

“…28 However, several reported cases of severe, idiosyncratic liver injury caused by APAP were not associated with malnourishment, alcohol intake, or overdoses. 29,30 Furthermore, many other instances of DIH were found to be host dependent and could not be explained by metabolic variability. 2,3 In cases such as these, an immunologic idiosyncrasy has been proposed wherein certain susceptible patients mount an immunopathologic reaction against neoantigens generated by the binding of reactive drug metabolites to cellular proteins.…”

Acetaminophen metabolism after liver resection: A prospective case–control study

“…This has been observed in healthy individuals at doses of less than twice the recommended limit. (3) Acetaminophen is metabolized by the liver. Glucuronidation and sulphation produces non-toxic end-products.…”

Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury

“…Acetaminophen is a widely used nonprescription analgesic and antipyretic that causes severe cetrilobular hepatic necrosis and eventual liver failure, even in the absence of known risk factors such as pre-existing liver disease, overdose, malnourishment, or excess alcohol consumption. 9 Clearly, therapeutic strategies are required that prevent the hepatotoxicity following hepatic viral gene delivery and analgesic consumption.…”