A TYLENOL A DAY BRINGS THE PATIENT TO THE BAY: A CASE OF USUAL DOSING ACETAMINOPHEN TOXICITY

Abstract

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Acetaminophen (APAP) toxicity is responsible for nearly 50% of acute liver failure (ALF) in the United States (1). Most cases are not deliberate overdoses (2). Chronic administration of APAP is associated with additional toxic pathways, leading to organ dysfunction. Presented is a case of ALF due to therapeutic doses of APAP with toxicity from the metabolite 5-oxoproline (pyroglutamic acid). CASE PRESENTATION: An 80 year old man with hypertension, diabetes, and chronic lower back pain presented with nausea and vomiting found to have fulminant liver failure with AST 15,000 and ALT 4,037 along with an anion gap metabolic acidosis. APAP levels ranged between 29 and 34 (10-30 ug/ml). The patient took only two to three APAP tablets daily for chronic lower back pain for the past 2 years as confirmed by family. He denied taking any other medications or herbal supplements. Ethanol, salicylate and CPK levels were normal. IR-guided liver biopsy confirmed APAP toxicity as culprit for ALF. His liver failure progressed with encephalopathy requiring intubation and rapidly worsening renal failure. The diagnosis of 5-oxoproline intoxication was made and after a week of continuous N-acetylcysteine infusion, his ALF resolved. DISCUSSION: Over 10,000 hospitalizations in the United States are due to APAP toxicity, and what is most concerning is that more than 50% of these cases are unintentional and only in the setting of therapeutic use (2, 5). Typically, in acute APAP toxicity the hepatic injury is due to the accumulation of hepatoxic N-acetyl-para-benzoquinoeimine (NAPQI) via depletion of hepatic glutathione stores. In these cases N-acetylcysteine (NAC) increases and repletes glutathione storage by being a glutathione synthesis precursor. However, in chronic APAP use even when taken in recommended doses a different toxic metabolite can accumulate. This metabolite is known as 5-oxoproline is overproduced due to the activation of an ATP depleting cycle (Figure 1). The condition generally resolves with discontinuation of acetaminophen and general supportive measures. Although many reports suggest that administration of N-acetylcysteine may accelerate recovery, this has not been proven. Here NAC increases the negative feedback of γ-glutamylcysteine synthetase, resulting in reduced generation of pyroglutamic acid from γ-glutamylcysteine (7). Other factors lower the dose threshold for APAP toxicity, including alcohol use, malnutrition, use of CYP 450-inducers, and delayed gastric emptying (3). In our patient, malnutrition and ileus may have increased his risk for APAP toxicity, which were both diagnosed during the hospitalization. We present a case of APAP toxicity with likely contribution from the rarely described 5-oxoproline. CONCLUSIONS: ALF from APAP toxicity is not only associated with acute overdose, but also with usual administration. One of these processes is due to the accumulation of 5-oxoproline. Reference #1: Ostapowicz G, et al. “Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.” Annals of Internal Medicine 2002; 137:947-954. Reference #2: Ghanem CI. “Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity.” Pharmacological Research. 2016; 109:119–131. Reference #3: Bunchorntavakul C, Reddy KR. “Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and acute liver failure.” Clinical Liver Disease. 2018; 22:325-246. DISCLOSURES: no disclosure on file for Alfredo Astua; No relevant relationships by Dawn Maldonado, source=Web Response No relevant relationships by Michael Megally, source=Web Response