Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure

Abstract

Background Despite extensive investigation, the cause of liver injury in 14% of acute liver failure patients remains unknown (indeterminate). In a pilot study, using a novel assay, highly specific acetaminophen-cysteine adducts were detected in 7 of 36 (19%) indeterminate patients. Methods To extend these observations, sera from 110 subjects enrolled in the Acute Liver Failure Study Group registry with indeterminate acute liver failure were analyzed using a similar but more efficient and sensitive adduct assay. As positive controls, an additional 199 patients with known or presumed acetaminophen-induced liver failure were assessed for the presence and quantity of adducts. Clinical, laboratory and outcome data were compared for the two groups. Results Based on previous data from known therapeutic exposures and acetaminophen overdoses, an adduct concentration of ≥1.0 nmol/mL serum indicated a definite acetaminophen overdose. Among the 110 indeterminate cases, 18% had assay values ≥1.0, with a median level of 9.2 nmol/mL; 94.5 % of the positive control (known APAP) cases had values ≥1.0 nmol/mL. Regardless of initial diagnosis, subjects with elevated adduct levels demonstrated the clinical profile and hyperacute biochemical injury pattern associated with acetaminophen overdose: predominance of female gender, very high aminotransferase levels and low bilirubin levels. Conclusions These data confirm and extend previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. N-acetylcysteine use was limited in this group, presumably because of the lack of a specific diagnosis of acetaminophen toxicity.

Confirming the Causative Role of Acetaminophen in Indeterminate Acute Liver Failure Using Acetaminophen-Cysteine Adducts

“…Prior studies estimate that up to 50 % of all cases of ALF in adults are secondary to acetaminophen toxicity [6]. Current acetaminophen treatment protocols require direct measurement of a patient's serum acetaminophen concentration, which is interpreted using the RumackMatthew nomogram.…”

“…Late entry to care (>15 h) after acetaminophen overdose in patients without ALF on presentation is also associated with an increased risk of later developing liver failure [9]. This delay means that serum acetaminophen concentrations may no longer be detectable at the time of presentation, and patients may be unable to provide an ingestion history due to altered mental status or unwilling to disclose a history of overdose [6].…”

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

“…Ten of the enrolled subjects in our experiment had measurable protein-derived APAP-CYS serum concentrations, although none demonstrated APAP-CYS protein adducts considered clinically alarming (>1 ng/mL) [2,7].…”

“…3-para-cysteinyl APAP has been demonstrated in human patients with fulminant hepatic failure thought to be related to APAP, as well as following acute overdose of APAP [2] and after ingestion of therapeutic doses of APAP in 4 g/day doses [4,6,7,8].…”

“…Several early studies explored the possibility of using APAP-CYS protein adducts to identify and confirm APAP as the etiology behind unexplained hepatic failure [7,8], but specificity and accuracy for this purpose are unproven.…”