Hepatotoxicity, Liver Diseases Side Effect
Hepatotoxicity is a liver dysfunction or liver damage due to drugs, toxins, dietary supplements, phytotherapeutics , and other substances. Untreated drug-induced liver injury can progress to liver failure.
Drug-induced liver disease is usually indistinguishable from liver injury of other causes. In most cases hepatic symptoms caused by a medication subside after cessation of the causative agent.
Most symptoms of drug-induced liver damage are similar to the symptoms of acute hepatitis and cholestasis. Drug-induced liver injury is characterized by significant elevations in the serum alanine aminotransferase (ALT), which usually precede elevations in total bilirubin levels and alkaline phosphatase levels. Most injuries occur within 1 year of initiating the offending agent.
Antibiotics are the most common cause of liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, and lipid-lowering medications37.
| Drug | Incidence |
|---|---|
| Acetaminophen (paracetamol, Tylenol®)36 | Metabolites of acetaminophen are generated by CYP450s and damage hepatocytes. The induction of these enzymes may enhance acetaminophen toxicity. Blood levels are directly related to the risk of hepatotoxicity. High doses >10–15 g lead to liver injury ranging from elevated aminotransferases to acute liver failure. |
| Adriamycin | |
| Advicor | |
| Alka-Seltzer Plus | |
| Alkeran | Rare |
| Allopurinol | reports of granulomatous hepatitis 23 |
| Amiodarone (Cordarone®)33 | abnormal liver biochemical tests in 15% to 80% of patients, seriouse liver disease, rare cases of acute liver failure amiodarone-induced liver disease may proceed despite discontinuation of amiodarone 34 |
| Amoxicillin-Clavulanate | hepatotoxicity is mainly related to the clavulanic acid component, incidence is 1.7 |
| cases per 10 000 patients, risk factors are male gender, age over 55 years, prolonged use 29 | |
| Amodiaquine (Camoquin®, Flavoquine®)5 | |
| Amnesteem | |
| Anabolic Steroids | produce reversible cholestasis 26 |
| Anadrol-50 | |
| Asacol | Rare |
| Acarbose (Precose®, Prandase®) | rare |
| Aspirin | hepatotoxicity occurs when blood salicylate concentrations exceed 25 mg/100 mL |
| Azasan | |
| Bosentan (Tracleer®)39 | |
| Busulfex | |
| Campath | |
| Carbamazepine (Tegretol®) | may cause granulomatous hepatitis 22 |
| Carbatrol | |
| Captopril (Capoten®)12 | |
| Casodex | |
| CellCept | 3% to 20% |
| Chlorpromazine (Thorazine®) | cholestatic hepatitis28, asymptomatic liver biochemical test abnormalities in 20% to 50% of patients, and rare cases of fulminant hepatic necrosis |
| Combivir | |
| Cosmegen | |
| Cyclosporine (Neoral®) | 1% to 7%, inhibits transport of bile acid and commonly causes mild increases in serum bilirubin concentrations |
| Dantrolene (Dantrium®) | 1% case-fatality rate of about 28% 20 |
| Depacon | |
| Dextropropoxyphene32 | reports of cholestasis with bile duct injury |
| Diclofenac (Voltaren®, Cataflam®) | elevated serum aminotransferase levels occur in up to 15% of patients, reports of chronic hepatitis 24, the risk of diclofenac-induced hepatitis is increased in women and with aging |
| Diltiazem (Cardizem®, Dilacor XR ®, Tiazac®) | |
| Disulfiram (Antabuse)10 | |
| Duloxetine (Cymbalta®)41 | |
| Enalapril (Vasotec®)12 | |
| Erythromycin2 | |
| Estratest | |
| Excedrin | |
| Flucloxacillin1 | |
| Fluconazole (Diflucan®) | causes mild transient elevation of transaminase levels, fluconazole is less hepatotoxic than ketoconazole and terbinafine15 |
| Furosemide | |
| Gemzar | Rare |
| Gengraf | 1% to 7% |
| Gleevec | 6% to 12% |
| HIVID | |
| Ibuprofen (Motrin®)18 | |
| Intron A | Rare |
| Isoniazid (Laniazid®, Nydrazid®, Rimifon®, Tubizid®)13 | hepatitis develops in 21 per 1000 paients, about 5-10% of cases are fatal |
| Isotretinoin (Accutane®) | |
| Itraconazole (Sporanox®) | Rare |
| Ketoconazole (Nizoral®)14 | 5% to 17% symptomatic hepatitis occurs in 7-20 of 100 000 exposed patients, onset of toxicity within 6 to 12 weeks |
| Lamotrigine (Lamictal®)35 | 1%, hepatotoxicity of lamotrigine represents immuno-allergic reaction called anticonvulsant hypersensitivity syndrome |
| Lansoprazole (Prevacid®) | |
| Levofloxacin (Levaquin®) | rare 30, 31 |
| Leukeran | |
| Leukine | 13% |
| Mebaral | < 1% |
| Methyldopa (Aldomet®)8 | may cause immunoallergic drug hepatitis |
| Minocycline | causes several types of liver damage, acute hepatitis, chronic hepatitis with autoimmune features 25 |
| Mirtazapine (Remeron®)18 | |
| Moxifloxacin (Avelox®) | rare 30, 31 |
| Mylotarg | |
| Niacin (Nicotinic Acid) | |
| Nicomide® | |
| Nitrofurantoin (Furadantin®, Macrodantin®, Macrobid®)6 | risk of liver toxicity increases with age particularly after 64, nitrofurantoin has been associated with acute hepatitis, occasionally with features of cholestasis, hepatic granulomas, acute liver failure, and cirrhosis 7 |
| Norvir | < 2% |
| Oral Contraceptive Steroids 27 | cholestasis develops in 2.5 per 10 000 women exposed |
| Omeprazole (Prilosec®)36 | |
| Pentasa | |
| Periostat | |
| Pentobarbital (Nembutal®) | |
| Phenytoin (Dilantin®, Phenytek®)9 | causes serious idiosyncratic reaction that occurs in less than 1 per 10 000 persons |
| Pioglitazone (Actos®) | does not share the hepatotoxic profile of troglitazone 16 |
| Prevpac® | |
| Purinethol® | Frequent |
| Pyrazinamide38 | |
| Rapamune® | |
| Reyataz® | < 3% |
| Rifater® | |
| Riluzole (Rilutek®)21 | |
| Risperdal | Rare |
| Robitussin® | |
| Roferon-A | Rare |
| Sandimmune | 1% to 7% |
| Singlet® | |
| Soriatane | |
| Sudafed® | |
| Tacrolimus (Prograf®) | 3% to 15% |
| Terbinafine (Lamisil®)3 | rare cases of liver failure have been reported |
| TheraFlu® | |
| Thiabendazole (Mintezol®) | |
| Tikosyn | > 2% |
| Trasylol | 0.5% |
| Trazodone19 | |
| Trimethoprim-Sulfamethoxazole | hepatotoxicity mostly attributed to the sulfonamide component, sulfa-hepatotoxicity is associated with a systemic hypersensitivity trimethoprim has been associated with some cases of cholestatic hepatitis that occurs in 1.4 cases per 100,000 exposed patients |
| Valproic Acid (Sodium Valproate, Depakene®, Depakote®)4 | occurs generally in children younger than 3 years of age |
| Viramune | |
| Venlafaxine (Effexor®)17 | |
| Verapamil (Covera-HS®)11 | |
| Xeloda | < 5% |
| Zerit |
Advertisement
Discontinuation of the offending medication generally results in normalization of liver enzyme levels and functon.
Risk factors for developing hepatotoxicity:
- Drug dose
- Half-life of the drug. Long-acting medications are more likely to cause injury than short-acting medications.
- Female sex
- Old age. Elderly are at increased risk of liver disease, while liver toxicity is rare in children.
- Use of concomitant medications.
- Genetic polymorphism, familial cases
- Chronic alcohol use
- Underlying diseases, e.g. preexisting liver disease, obesity, diabetes, renal failure, active or chronic hepatitis
- Nutritional deficiency
References
- 1. Andrews E, Daly AK. Flucloxacillin-induced liver injury. Toxicology. 2008 Dec 30;254(3):158-63. PubMed
- 2. Tolman KG, Sannella JJ, Freston JW. Chemical structure of erythromycin and hepatotoxicity. Ann Intern Med. 1974 Jul;81(1):58-60.
- 3. Ajit C, Suvannasankha A, Zaeri N, Munoz SJ. Terbinafine-associated hepatotoxicity. Am J Med Sci. 2003 May;325(5):292-5. PubMed
- 4. Chang TK, Abbott FS. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity. Drug Metab Rev. 2006;38(4):627-39. PubMed
- 5. Shimizu S, Atsumi R, Itokawa K, Iwasaki M, Aoki T, Ono C, Izumi T, Sudo K, Okazaki O. Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch Toxicol. 2009 Jul;83(7):701-7. PubMed
- 6. Sakaan SA, Twilla JD, Usery JB, Winton JC, Self T. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J. 2014 Feb;107(2):107-13. PubMed
- 7. Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: A clinicopathological study of 52 reported cases. Hepatology 1988; 8:599-606. PubMed
- 8. Rodman JS, Deutsch DJ, Gutman SI. Methyldopa Hepatitis. A report of six cases and review of the literature. Am J Med. 1976 Jun;60(7):941-8.
- 9. Smythe MA, Umstead GS. Phenytoin hepatotoxicity: a review of the literature. DICP. 1989 Jan;23(1):13-8. PubMed
- 10. Berlin RG. Disulfiram hepatotoxicity: a consideration of its mechanism and clinical spectrum. Alcohol Alcohol. 1989;24(3):241-6. PubMed
- 11. Hare D, Horowitz J. Verapamil hepatotoxicity: A hypersensitivity reaction. Am Heart J 1986; 11:610-11.
- 12. Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated with angiotensin-converting enzyme inhibitors. Ann Pharmacother. 1993 Feb;27(2):228-31. PubMed
- 13. Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection. Chest. 2005 Jul;128(1):116-23. PubMed
- 14. Yan JY, Nie XL, Tao QM, Zhan SY, Zhang YD. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci. 2013 Jul;26(7):605-10. PubMed
- 15. Rodriguez RJ, Acosta D Jr. Comparison of ketoconazole- and fluconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology. 1995 Feb 6;96(2):83-92. PubMed
- 16. Scheen AJ. Hepatotoxicity with thiazolidinediones: is it a class effect? Drug Saf. 2001;24(12):873-88. PubMed
- 17. Christensen RC, Garces LK. Hepatotoxic effects with high-dose venlafaxine. Psychiatry (Edgmont). 2006 Jul;3(7):10-1. PubMed
- 18. Hui CK, Yuen MF, Wong WM, Lam SK, Lai CL. Mirtazapine-induced hepatotoxicity. J Clin Gastroenterol. 2002 Sep;35(3):270-1. PubMed
- 19. Beck P, Bridges R, Demetrick D, et al. Chronic active hepatitis with trazodone therapy. Ann Intern Med 1993; 118:791-3.
- 20. Wilkinson S, Portmann B, Williams R. Hepatitis from dantrolene sodium. Gut 1979; 20:33- 6.
- 21. Roch-Torreilles I, Camu W, Hillaire-Buys D. Therapie. 2000 Mar-Apr;55(2):303-12.
- 22. Swinburn BA, Croxson MS, Miller MV, Crawford KB. Carbamazepine induced granulomatous hepatitis. N Z Med J. 1986 Mar 12;99(797):167.
- 23. Swank LA, Chejfec G, Nemchausky BA. Allopurinol-induced granulomatous hepatitis with cholangitis and a sarcoid-like reaction. Arch Intern Med. 1978 Jun;138(6):997-8. PubMed
- 24. Scully LJ, Clarke D, Barr RJ. Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci. 1993 Apr;38(4):744-51. PubMed
- 25. Teitelbaum JE, Perez-Atayde AR, Cohen M, Bousvaros A, Jonas MM. Minocycline-related autoimmune hepatitis: case series and literature review. Arch Pediatr Adolesc Med. 1998 Nov;152(11):1132-6. PubMed
- 26. Gurakar A, Caraceni P, Fagiuoli S, Van Thiel DH. Androgenic/anabolic steroid-induced intrahepatic cholestasis: a review with four additional case reports. J Okla State Med Assoc. 1994 Sep;87(9):399-404.
- 27. Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis. 1987;7:8–23
- 28. Ishak KG, Irey NS. Hepatic injury associated with the phenothiazines. Clinicopathologic and follow-up study of 36 patients. Arch Pathol. 1972 Apr;93(4):283-304.
- 29. Thomson JA, Fairley CK, Ugoni AM, et al. Risk factors for the development of amoxycillin-clavulanic acid associated jaundice. Med J Aust. 1995 Jun 19;162(12):638-40. PubMed
- 30. Alshammari TM, Larrat EP, Morrill HJ, Caffrey AR, Quilliam BJ, LaPlante KL. Risk of hepatotoxicity associated with fluoroquinolones: a national case-control safety study. Am J Health Syst Pharm. 2014 Jan 1;71(1):37-43. PubMed
- 31. Paterson JM, Mamdani MM, Manno M, Juurlink DN; Canadian Drug Safety and Effectiveness Research Network. Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study. CMAJ. 2012 Oct 2;184(14):1565-70. PubMed
- 32. Rosenberg WM, Ryley NG, Trowell JM, et al. Dextropropoxyphene induced hepatotoxicity: a report of nine cases. J Hepatol. 1993 Nov;19(3):470-4.
- 33. Babatin M, Lee SS, Pollak PT. Amiodarone hepatotoxicity. Curr Vasc Pharmacol. 2008 Jul;6(3):228-36. PubMed
- 34. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology. 1989 May;9(5):679-85. PubMed
- 35. Fayad M, Choueiri R, Mikati M. Potential hepatotoxicity of lamotrigine. Pediatr Neurol. 2000 Jan;22(1):49-52. PubMed
- 36. James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos. 2003 Dec;31(12):1499-506. PubMed
- 37. Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Semin Liver Dis. 2002;22(2):169-83 PubMed
- 38. Shih TY, Pai CY, Yang P, Chang WL, Wang NC, Hu OY. A novel mechanism underlies the hepatotoxicity of pyrazinamide. Antimicrob Agents Chemother. 2013 Apr;57(4):1685-90. PubMed
- 39. Seyfarth HJ, Favreau N, Tennert C, et al. Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension. Ann Hepatol. 2014 Nov-Dec;13(6):803-9. PubMed
- 40. Castell JV, Larrauri A, Gómez-Lechón MJ. A study of the relative hepatotoxicity in vitro of the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen and butibufen. Xenobiotica. 1988 Jun;18(6):737-45.
- 41. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther. 2010 Nov;32(9):1174-83.
Published: August 16, 2016
Last updated: December 14, 2017
- Drug-induced liver injury is one of the most common reasons for withdrawal of an approved medicine.
Advertisement
