OVERVIEW

CASE REPOT

Case 1. Mild acute liver injury due to alprazolam.

[Modified from: Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. Am J Psychiatry 1986; 143: 388-9. PubMed Citation]

A 32 year old woman with a long history of panic attacks developed fatigue and abdominal pain 2 weeks after starting alprazolam (1 mg daily increasing to 8 mg daily), and she became jaundiced one week later. She had no history of liver disease and was known to have had normal serum liver tests before starting alprazolam. On examination, she was jaundiced but had no fever or rash. Laboratory results showed elevations in serum enzymes and bilirubin (Table). Tests for hepatitis A and B and for mononucleosis were negative. Alprazolam was stopped and diazepam (which she had received in the past) substituted. She improved rapidly and all tests were normal when she was seen one month after stopping alprazolam.

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Alprazolam	28981-97-7	C17-H13-Cl-N4

ANNOTATED BIBLIOGRAPHY

References updated: 24 January 2017

• Zimmerman HJ. Benzodiazepines. Psychotropic and anticonvulsant agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 491-3.

  (Expert review of benzodiazepines and liver injury published in 1999; mentions rare instances of cholestatic hepatitis have been reported due to alprazolam, chlordiazepoxide, diazepam, flurazepam, and triazolam, and hepatocellular injury with clorazepate and clotiazepam, but no reports of hepatic injury with lorazepam, oxazepam or temazepam).
• Larrey D, Ripault MP. Anxiolytic agents. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 455.

  (Review of sedative induced liver injury mentions that rare instances of acute liver injury [usually cholestatic] have been reported with alprazolam, bentazepam, clotiazepam, chlordiazepoxide, diazepam, flurazepam and triazolam; a hepatitis-like pattern has been reported with clonazepam and clorazepate).
• Mihic SJ, Harris RA. Hypnotics and sedatives. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 457-80.

  (Textbook of pharmacology and therapeutics).
• Roy-Byrne P, Vittone BJ, Uhde TW. Alprazolam-related hepatotoxicity. Lancet. 1983; 2: 786-7. [PubMed: 6137615]

  (Patient was found to have elevated ALT [96 U/L] 2 weeks after starting alprazolam, with prompt resolution upon stopping; rechallenge led to asymptomatic rise of ALT [28 to 70 U/L] within 9 days).
• Davion T, Capron-Chivrac D, Andrejak M, Capron JP. [Hepatitis due to antiepileptic agents] Gastroenterol Clin Biol 1985; 9: 117-26. [PubMed: 3920108]

  (Review of hepatotoxicity of anticonvulsants; among benzodiazepines, cases of cholestatic hepatitis have been linked to chlordiazepoxide and diazepam, but liver injury from this class of drugs is exceptionally rare).
• Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. Am J Psychiatry 1986; 143: 388-9. [PubMed: 2869702]

  (32 year old woman had onset of lethargy 2 weeks after starting alprazolam followed by jaundice [bilirubin 2.6 mg/dL, AST 156 U/L, Alk P 241 U/L], resolving within 4 weeks of switching to diazepam: Case 1).
• Noyes R, DuPont RL, Pecknold JC, Rifkin A, Rubin RT, Swinson RP, Ballenger JC, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 1988; 45: 423-8. [PubMed: 3358644]

  (Controlled trial of alprazolam vs placebo in 525 patients with panic disorder; side effects were sedation, ataxia, fatigue, slurred speech, amnesia and increased appetite; 2 patients on alprazolam developed liver disease, one with jaundice at 4 weeks resolving quickly on stopping and a second with abnormal laboratory values that returned to normal with lowering the dose; details not given).
• Lewis JH, Zimmerman HJ. Drug- and chemical-induced cholestasis. Clin Liver Dis 1999; 3: 433-64. [PubMed: 11291233]

  (Review of drug induced cholestatic syndromes, listing many causes including chlordiazepoxide and flurazepam; “Benzodiazepines may cause cholestatic injury, although this is rare”).
• Gil-Martin A, Saez-Royuela F, Arias L, Angulo ML, Nogal B. [Hepatic fibrosis after antidepressant treatment] Rev Esp Enferm Dig 2005; 97: 461-2. Spanish. [PubMed: 16048430]

  (Case report of patient developing fatigue, pruritus and jaundice after 1-2 months of therapy with sertraline, alprazolam and clorazepate, resolving with stopping sertraline, but with minor ALT elevations and biopsy showing mild bridging fibrosis 4 months later).
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]

  (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 20 were attributed to benzodiazepines including 5 for clorazepate, 5 alprazolam, 6 lorazepam and 4 diazepam, but compared to controls, the relative risk of injury was increased only for clorazepate [8.3 and frequency 3.4 per 100,000 person-year exposures]).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to a benzodiazepine).
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118: 281-90. [PubMed: 18341684]

  (Review of hepatotoxicity of all anticonvulsants focusing upon phenytoin, valproate, carbamazepine; “Furthermore, hepatoxicity has not been convincingly shown to be associated with the use of benzodiazepines”).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to a benzodiazepine).
• Drugs for insomnia. Treat Guidel Med Lett 2012; 10 (119): 57-60. [PubMed: 22777275]

  (Guidelines for therapy of insomnia mentions that benzodiazepines are controlled substances and, when used for sleep, may impair next day performance).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to alprazolam or any other benzodiazepine, despite the fact that more than 1 million prescriptions for alprazolam are filled yearly).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature on drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to a benzodiazepine).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to alprazolam or any other benzodiazepine).