OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Diazepam	439-14-5	C16-H13-Cl-N2-O

ANNOTATED BIBLIOGRAPHY

References updated: 25 January 2017

• Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 498-516.

  (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, prazepam, oxazepam and temazepam).
• Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007: pp 485-506.

  (Review of anticonvulsant induced liver injury published in 2007; the benzodiazepines are not discussed).
• McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 501-525.

  (Textbook of pharmacology and therapeutics).
• Cook GC, Sherlock S. Jaundice and its relation to therapeutic agents. Lancet 1965; 1: 175-9. PubMed Citation (11 cases of drug induced liver disease, all due to agents no longer in use; 2 patients were receiving diazepam, but other agents were more likely the cause).
• Cunningham ML. Acute hepatic necrosis following treatment with amitriptyline and diazepam. Brit J Psychiat 1965; 111: 1107-9. [PubMed: 5841222]

  (54 year old woman with dementia-depression placed on amitriptyline and diazepam developed progressive confusion 5 months later followed by jaundice, obtundation and death [bilirubin 5.2 mg/dL, ALT 200 U/L, Alk P 9.5 unknown units], autopsy showed small liver but no description of histology).
• Buchanan N, Cane RD. Liver function tests and the prolonged use of high-dose diazepam with special reference to tetanus. S Afr Med J 1978; 54: 768. [PubMed: 741305]

  (After noting jaundice in a few patients receiving high doses of diazepam for tetanus, the authors prospectively tested 4 patients finding no consistent rises in serum ALT, Alk P or bilirubin on therapy).
• Stacher G. Intrahepatic cholostasis following combined diazepam-barbiturate therapy in patients with tetanus]. Wien Klin Wochenschr. 1973; 85: 401-6. German. [PubMed: 4705881]
• Franks E, Jacobs WH. Cholestatic jaundice possibly due to benzodiazepine-type drugs. Mo Med 1975; 72: 605-6. (40 year old woman on multiple drugs including chlorpromazine developed jaundice [bilirubin 2.0 rising to 9.7 mg/dL, ALT 280 U/L, Alk P 546 U/L, 16% eosinophils], seemed to worsen on benzodiazepines including chlordiazepoxide, diazepam and flurazepam, resolving rapidly when they were stopped, but attribution to benzodiazepines difficult .

  ).
• Fors B, Nilsson F. [Hepatitis probably induced by diazepam medication] Lakartidningen 1968; 65: 4528-31. Swedish. [PubMed: 5745628]

  (24 and 34 year old women developed mild hepatitis with jaundice 1 and 4 months after starting diazepam [bilirubin 11 and 4.2 mg/dL, ALT 434 U/L Alk ~2 times ULN], rapid resolution with stopping).
• Fang MH, Ginsberg AL, Dobbins WO 3rd. Cholestatic jaundice associated with flurazepam hydrochloride. Ann Intern Med 1978; 89: 363-4. [PubMed: 28685]

  (70 year old man developed fatigue followed by pruritis 3 months after starting flurazepam [bilirubin 6.6 mg/dL, ALT 179 U/L, Alk P 232 U/L, no eosinophilia], improving only when drug withdrawn).
• Bonkovsky HL, Sinclair PR, Emery S, Sinclair JF. Seizure management in acute hepatic porphyria: risks of valproate and clonazepam. Neurology 1980; 30: 588-92. [PubMed: 6770287]

  (38 year old man with acute intermittent porphyria and seizures did not respond to clonazepam, and testing in chicken embryos showed that it increased hepatic prophyrins and ALA synthase activity).
• Reynolds R, Lloyd DA, Slinger RP. Cholestatic jaundice induced by flurazepam hydrochloride. Can Med Assoc J 1981; 124: 893-4. [PMC free article: PMC1705357] [PubMed: 7214289]

  (44 year old woman taking flurazepam intermittently for 6 months developed abdominal pain [bilirubin 8.2 mg/dL, AST 106 U/L, Alk P 209 U/L], resolving rapidly upon stopping, biopsy showed intrahepatic cholestasis).
• Tedesco FJ, Mills LR. Diazepam(Valium) hepatitis. Dig Dis Sci 1982; 27: 470-2. [PubMed: 7075434]

  (45 year old man developed elevations of ALT [130 U/L] while on isoniazid [for 1 day] and diazepam [3 days], which resolved upon stopping and recurred upon rechallenge with diazepam, but not isoniazid which was tolerated long term).
• Døssing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol 1982; 17: 205-11. [PubMed: 6982502]

  (Among 572 cases of hepatotoxicity reported to a Danish registry between 1968 and 1978, 97 were due to psychotropic agents, but only two attributed to benzodiazepines).
• Roy-Byrne P, Vittone BJ, Uhde TW. Alprazolam-related hepatotoxicity. Lancet 1983; 2: 786-7. [PubMed: 6137615]

  (30 year old woman was found to have elevated ALT [96 U/L] 2 weeks after starting alprazolam, which promptly resolved when drug was stopped; rechallenge led to asymptomatic ALT rise within 9 days [28 to 70 U/L]).
• 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 rare).
• Judd FK, Norman TR, Marriott PF, Burrows GD. A case of alprazolam-related hepatitis. Am J Psychiatry 1986; 143: 388-9. [PubMed: 2869702]

  (59 year old woman developed 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).
• Olsson R, Zettergren L. Anticonvulsant-induced liver damage. Am J Gastroenterol 1988; 83: 576-7. [PubMed: 3364416]

  (30 year old man developed fever, rash and jaundice 6 weeks after starting phenytoin; he was switched to carbamazepine and clonazepine, but redeveloped jaundice 3 months later; resolved with stopping, but recurred with restarting clonazepine alone [bilirubin 1.8 mg/dL, ALT 1380 U/L, Alk P 176 U/L] without rash, fever or eosinophilia, resolving in 6 weeks of stopping clonazepine).
• Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou J-P. Clotiazepam-induced acute hepatitis. J Hepatol 1989; 9: 256-9. [PubMed: 2572625]

  (65 year old woman developed jaundice 6 months after starting clotiazepam [bilirubin 5.1 mg/dL, ALT 1028 U/L, GGT 143 U/L] with no rash or fever, resolving on stopping clotiazepam and no recurrence after taking triazolam and temazepam).
• Nahata MC, Murray RD, Zingarelli J, Li BU, McClung HJ, Lininger B. Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures. J Pediatr Gastroenterol Nutr 1990; 10: 335-8. [PubMed: 2324894]

  (Safety of use of intravenous diazepam in children undergoing endoscopy; no mention of ALT abnormalities or liver injury).
• Suzuki A, Aso K, Ariyoshi C, Ishimaru M. Acute intermittent porphyria and epilepsy: safety of clonazepam. Epilepsia 1992; 33: 108-11. [PubMed: 1733741]

  (13 year old girl with acute intermittent porphyria worsened on valproate and on phenytoin therapy, but clonazepam led to control of seizures and no worsening of porphyria).
• Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf 1996; 15: 378-93. [PubMed: 8968693]

  (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, 1% on carbamazepine; “No child taking… benzodiazepines had raised liver enzyme levels,”).
• 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.”).
• Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs. Hepatology 1999; 29: 1347-51. [PubMed: 10216114]

  (Review of hepatotoxicity of phenothiazines, butyrophenones, tricyclics, MAO inhibitors, acetylcholesterase inhibitors, and psychotropic drugs of abuse; “benzodiazepines…have a very low hepatotoxic potential, with only case reports in the literature, usually with a cholestatic pattern”).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants done in the US between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 10 were attributed to phenytoin, 10 to valproate and 1 to carbamazepine, but none to benzodiazepines or other anticonvulsants).
• Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]

  (36 years of reporting to Swedish registry identified 103 cases of acute liver failure due to drugs, of which 1 was attributed to phenytoin, 1 to valproate and 1 to carbamazepine, but none to benzodiazepines or other anticonvulsants).
• 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 Citation (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, relative risk of injury was increased only for clorazepate [8.3: estimated frequency 3.4 per 100,000 person-year exposures]).
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. [PubMed: 18341684]

  (Review of hepatotoxicity of all anticonvulsants focusing upon phenytoin, valproate, carbamazepine; “Furthermore, hepatotoxicity has not been convincingly shown to be associated with the use of benzodiazepines”).
• 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 between 2004 and 2008, none were attributed to benzodiazepines).
• Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]

  (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, benzodiazepines were not among the top 40 agents implicated).
• 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).
• 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 a benzodiazepine).
• Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. [PubMed: 23348233]

  (Concise review of indications and side effects of anticonvulsants; no mention of hepatotoxicity of benzodiazepines).
• 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: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 40 [4.5%] were attributed to anticonvulsants, but none to benzodiazepine anticonvulsants).