The Journal of Emergency Medicine, Vol. 23, No. 3, pp. 253Ð256, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/02 $Ðsee front matter PII S0736-4679(02)00526-7

Selected Topics: Toxicology

CHRONIC ACETAMINOPHEN TOXICITY: A CASE REPORT AND REVIEW OF THE LITERATURE

Joshua E. Lane, MD,* Martin G. Belson, MD,† D. Kaine Brown, BS,* and Allison Scheetz, MD*

*Department of Internal Medicine, Mercer University School of Medicine, Macon, Georgia and †Georgia Poison Center, Emory University School of Medicine, Atlanta, Georgia Reprint Address: Allison Scheetz, MD, Department of Internal Medicine, Mercer University School of Medicine, The Medical Center of Central Georgia, 777 Hemlock Street, Macon, GA 31208 e Abstract—Acetaminophen is one of the most frequently Hepatotoxicity resulting from chronic APAP thera- used medications in the United States. While usual dosing of peutic misadventures in adults has been previously re- acetaminophen is considered harmless, both acute and ported. The overwhelming majority of these cases occur chronic overdoses can be fatal. The majority of reported with chronic ethanol use or chronic use of P450-inducing cases of chronic acetaminophen toxicity in adults occur in medications (1-7). Additionally, an association between chronic alcohol abusers, patients taking P450-inducing chronic APAP use with short-term fasting and hepatotox- medications, or following massive dosing. We describe a case of toxic hepatitis free of the aforementioned risk fac- icity has been described (8,9). We present a patient who tors associated with chronic ingestion of moderately exces- developed significant hepatotoxicity from excessive chronic sive doses of acetaminophen. Our patient ingested approx- APAP use without the aforementioned risk factors. imately 5.0 to 6.5 g of acetaminophen daily for 6 to 8 weeks via multiple medications. The inclusion of acetaminophen in numerous medications combined with the frequency of CASE REPORT use of acetaminophen necessitates an increased concern for not only acute but also chronic acetaminophen toxicity. A 54-year-old woman was admitted to our ED with © 2002 Elsevier Science Inc. altered mental status, decreased appetite, and a question- able history of loss of consciousness. The patient was e Keywords—acetaminophen toxicity; poisoning; chronic; hepatotoxicity lethargic and poorly responsive to interview; however, she complained of lower abdominal pain, weakness, and INTRODUCTION drowsiness for 1 week’s duration. She denied headache, chest pain, shortness of breath, vomiting, or diarrhea. Acetaminophen (N-acetyl-p-aminophenol [APAP]) is Medical and surgical history was significant for hyper- one of the most frequently used medications in the cholesterolemia, depression, rheumatoid arthritis, gastric United States. Its analgesic and antipyretic properties and bypass, and cervical spine fusion. She took the following presumed safety in recommended doses reflects its wide medications as directed: carisoprodol, citalopram, fexo- use alone and in combination preparations. Acute APAP fenadine, celecoxib, estradiol, and gabapentin. She was toxicity is commonly diagnosed in an Emergency De- allergic to penicillin and non-steroidal anti-inflammatory partment (ED); however, chronic APAP toxicity is not so agents. The patient denied the use of alcohol (confirmed apparent. by family members) and did not smoke. She denied fasting

Selected Topics: Toxicology is coordinated by Kenneth Kulig, MD of Denver, Colorado

RECEIVED: 12 June 2001; FINAL SUBMISSION RECEIVED: 9 November 2001; ACCEPTED: 4 December 2001 253 254 J. E. Lane et al.

Table 1. Laboratory Data

Test Range Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8

Acetaminophen 0–20 ␮g/mL 66 30 4 — — ——— Ammonia 18–54 UM/L 77 131 105 107 70 45 51 57 AST 15–38 U/L 7816 6691 2836 1212 371 187 119 94 ALT 5.0–37 U/L 2918 3066 2508 1771 1344 993 761 563 PT 10.2–13.0 s 34.5 25.9 22.2 15.6 13.9 13.9 13.3 13 PTT 21–35s4743302826283231 INR Ͻ1 10.4 5.6 4 1.9 1.5 1.5 1.3 1.3 Total bilirubin 0.2–1.3 mg/dL 2.9 2.7 3.8 5.9 6.5 5.6 3.6 3.3 Conj. bilirubin 0–0.2 mg/dL 1.3 1.3 2.1 3 3.5 2.8 1.7 1.5 Alk. phosphatase 30–95 U/L 162 136 153 141 162 173 183 183 BUN 5–22 mg/dL 32 29 13 10 6 7 11 15 Creatinine 0.5–1.2 mg/dL 5.4 2.4 1 0.9 0.6 0.5 0.7 0.7 the month before admission. She denied a history of hepa- 444/566 ms). Cardiac enzymes were within normal lim- titis, blood transfusions, or illicit drug use. Family history its. Chest radiograph was normal. Blood and urine cul- was significant for colon cancer and uterine cancer. tures were obtained and showed no growth of bacteria or Physical examination revealed a well-developed and fungal elements. well-nourished lethargic woman in acute distress (Glas- Therapy for acetaminophen toxicity was implemented gow Coma Scale 13). Vital signs included the following: and included N-acetylcysteine (NAC) 140 mg/kg for one blood pressure 97/56 mm Hg; pulse 93 beats/min; respi- dose followed by 70 mg/kg orally for 17 additional doses rations 16 breaths/min; temperature 37.3¡C. She had every four hours. Oxygen and intravenous IV fluids scleral icterus with mild jaundice of the skin. Cardiac and (normal saline with 5% dextrose and bicarbonate) were pulmonary examinations were normal. Neurologic exam- started and subcutaneous (SC) vitamin K was given. She ination revealed cranial nerves II through XII to be intact was given lactulose 30 mL every 6 h. The patient was with normal deep tendon reflexes and Babinski sign. The transferred to the intensive care unit for continued treat- abdomen was tender to palpation in the lower quadrants ment and observation. Liver enzymes, serum electro- without rebound tenderness or guarding. Asterixis was lytes, and acetaminophen levels all corrected during the present with extension of the arms. hospital course (Table 1). Her mental status returned to Laboratory analysis on admission revealed hyponatre- normal and both her scleral icterus and cutaneous jaun- mia, acidosis, renal insufficiency, and hepatic damage: dice disappeared. She was discharged home on hospital Sodium 122 mEq/L; Potassium 4.7 mEq/L; Chloride 88 Day 8 and followed routinely as an outpatient. mEq/L; CO2 14 mEq/L; Glucose 142 mg/dL; BUN 32 Subsequent discussion with the patient revealed that mg/dL; Creatinine 5.4 mg/dL. Arterial blood gas showed for 6 to 8 weeks she had taken one acetaminophen 500 a metabolic acidosis: pH 7.33; pCO2 25 mm Hg; pO2 115 mg gelcap every 3 to 4 h around the clock, and Lortab 10 Ϫ mm Hg; bicarbonate 13 mmol/L; base excess 1 (an analgesic containing 500 mg acetaminophen) 4 to 5 mmol/L; oxygen saturation 98%; FiO2 21%. Lactic acid times a day. This approximates a daily dose of 5.0 to was elevated at 5.4 (normal 0.5-2.2 mEq/L). A complete 6.5 g of APAP (recommended maximal daily dose is 4 g blood count with differential was normal. Urinalysis for adults). Her last dose of APAP was taken approxi- showed large blood, protein 100, and trace ketones, and mately 10 h prior to arrival at our ED. She had taken both microscopic urinalysis revealed RBC 20-50; WBC 0-2; the Tylenol and Lortab for persistent leg, back, and neck hyaline casts, course granular crystals, and amorphous pain. crystals. Urine electrolytes were within normal limits. Serum salicylates and ethanol were undetected. An acetaminophen level was elevated at 66 ␮g/mL (normal 0-20 ␮g/mL). A comprehensive urine drug screen and DISCUSSION analysis for volatiles (methanol, ethanol, acetone, isopro- panol) were negative. Acetaminophen is the most commonly used analgesic- Hepatitis profile was negative, including hepatitis B antipyretic and is responsible for more hospitalizations surface antigen and antibody, hepatitis core antibody, after overdose than any other common medication (10). hepatitis A IgM antibody, and hepatitis C antibody. Thy- While acute APAP toxicity has been well described, roid profile (TSH, T4,T3 uptake) was normal. chronic APAP toxicity is less common (3,11,12). The Electrocardiogram revealed normal sinus rhythm with availability of APAP both alone and in combination left axis deviation and increased QT intervals (QT/QTc preparations sets the stage for unintentional overdose. Chronic Acetaminophen Toxicity 255

Susceptibility to the hepatotoxic effects of acetamin- isoniazid, rifampin, and anticonvulsants (e.g., phenobar- ophen is, therefore, dependent upon many factors, some bital, phenytoin) (6,7,17-20). Short-term fasting and mal- of which have interindividual variability (e.g., the dose nutrition also have been associated with increased risk of taken, genetically determined P-450 activity, GSH [re- hepatotoxicity in patients taking excessive chronic doses duced glutathione] availability, capacity for glucuronida- of APAP, as well as in patients with certain underlying tion and sulfation, and regeneration capacity) (10). Our diseases (8,9,21). patient consumed 5.0 to 6.5 g/day overa6to8week Outside of these “high risk” groups, the incidence of period and did not develop signs of toxicity until 1 week serious chronic APAP toxicity appears to be rare (10). It before her presentation to a medical facility. We know has been proposed that an asymptomatic patient without from animal experiments that exposure of hepatocytes to risk factors taking repeated doses of APAP in any 24 h APAP results in a time and dose-dependent depletion of period does not require laboratory evaluation unless the cellular GSH and that hepatic toxicity is evident only dose exceeds 7.5 g, and possibly as high as 10 to 12 g when hepatic GSH is Յ30% (14,15). A human study (22). demonstrated that the hepatic supply of reduced gluta- N-acetylcysteine has been traditionally utilized as a thione began to be depleted over the range of 0.5 to 3.0 g glutathione precursor to prevent the development of of acetaminophen (16). Despite these data, the ability to hepatoxicity following a significant overdose of APAP predict the dose taken and the length of time taking that (23). Recent evidence has shown the benefit of delayed dose required for the development of toxicity is very treatment with NAC in patients with acetaminophen re- difficult given the interindividual variability of acetamin- lated hepatic failure (24). ophen metabolism. Our case is unique in that no associated risk factor Acetaminophen toxicity manifests as hepatic necrosis known to increase the patient’s susceptibility to APAP characteristically appearing in zone 3 of the hepatic toxicity was found. Two medications that our patient was lobule. This appears to be secondary to an active elec- taking for 2 to 3 months, celecoxib and estradiol, have trophilic metabolite [N-acetyl-p-benzoquinoneimine been described in a few case reports to potentially cause (NAPQI)] that binds covalently to tissue macromole- an elevation of liver function tests from therapeutic use cules (1). Under normal circumstances, a therapeutic (25). Also, a third medication that she was taking, cari- dose of APAP results in the production of a small frac- soprodol, is metabolized to meprobamate, an anxiolytic tion (5%) of NAPQI after metabolism by cytochrome that has been shown to affect various hepatoenzymatic P450 enzymes (13). The majority of APAP is excreted as activities in rats, and theoretically could have altered her conjugates of glucuronide and sulfate. The small amount acetaminophen metabolism (26). We believe that our of NAPQI that is produced is rapidly detoxified in a patient’s hepatotoxicity was secondary to her excessive reaction with glutathione to form mercapturic acid or chronic APAP use; however, we cannot rule out hepa- cysteine conjugates and is excreted, resulting in no he- totoxicity from her other medications. NAC may have patic damage (1). Hepatic necrosis occurs only when the been beneficial in treating her hepatotoxicity. We pro- amount of NAPQI produced exceeds the binding capac- pose that there is a need for increased awareness of ity of the liver’s store of GSH. The excessive NAPQI APAP-containing medications. Healthcare providers combines covalently with hepatocyte membrane pro- should educate patients on the risk of acetaminophen teins. It is the binding to mitochondrial proteins that toxicity with use of these medications on a routine basis. appear to be the key lesions for necrosis (1). Most reported cases of APAP hepatotoxicity as a therapeutic misadventure involve the use of alcohol REFERENCES (1,13). Johnston and Pelletier reported 53 cases of acet- aminophen hepatotoxicity associated with alcohol use 1. Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liver Dis 1998;2:523-41. (13). Alcohol lowers hepatic glutathione levels, which 2. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen decreases the available amount of GSH for detoxification hepatotoxicity in alcoholics. 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