Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Drug-induced liver injury

Section Editor
Keith D Lindor, MD
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Drug-induced liver injury can develop following the use of many drugs, both prescription and over-the-counter, through a variety of mechanisms [1-3]. A high index of suspicion is often necessary to expeditiously establish the diagnosis.

This topic will review the epidemiology, clinical manifestations, diagnosis, and management of drug-induced liver injury. The metabolism of drugs by the liver, the mechanisms by which drugs might injure the liver, and the use of medications in patients with liver disease are discussed separately. (See "Drugs and the liver: Metabolism and mechanisms of injury" and "Overview of the management of chronic hepatitis C virus infection", section on 'Dose adjustments of medications' and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Medication adjustments'.)


Drug-induced liver injury (DILI) has an estimated annual incidence between 10 and 15 per 10,000 to 100,000 persons exposed to prescription medications [4-11]. DILI accounts for approximately 10 percent of all cases of acute hepatitis [12], and it is the most common cause of acute liver failure in the United States [13,14]. DILI is also the most frequently cited reason for withdrawal of medications from the marketplace [13,15]. DILI may not be detected prior to drug approval, because most new drugs are tested in fewer than 3000 people prior to drug approval. As a result, cases of DILI with an incidence of 1 in 10,000 may be missed. It has been suggested that for every 10 cases of alanine aminotransferase elevation (>10 times the upper limit of normal) in a clinical trial, there will be one case of more severe liver injury that develops once the drug is widely available [16,17].

Several risk factors have been associated with the development of DILI [18]. In general, adults are at higher risk for DILI than children (with the notable exception of DILI from valproic acid, which is more common in children). Women may be more susceptible to DILI than men, which may in part be due to their generally smaller size [9]. Alcohol abuse and malnutrition predispose to DILI in some cases, as is seen with acetaminophen toxicity. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis", section on 'Clinical factors influencing toxicity'.)


Over 1000 medications and herbal products have been implicated in the development of drug-induced liver injury (DILI), and the list continues to grow (table 1) [19,20]. The National Institutes of Health maintains a searchable database of drugs, herbal medications, and dietary supplements that have been associated with DILI. Herbal products associated with DILI are discussed separately. (See "Hepatotoxicity due to herbal medications and dietary supplements".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 10, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349:474.
  2. Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther 2007; 25:1135.
  3. Yuan L, Kaplowitz N. Mechanisms of drug-induced liver injury. Clin Liver Dis 2013; 17:507.
  4. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002; 36:451.
  5. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007; 11:477.
  6. Friis H, Andreasen PB. Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992; 232:133.
  7. Holt M, Ju C. Drug-induced liver injury. Handb Exp Pharmacol 2010; :3.
  8. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002; 22:145.
  9. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135:1924.
  10. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis 2009; 29:337.
  11. Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144:1419.
  12. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis 2000; 4:73.
  13. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947.
  14. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364.
  15. Xu JJ, Diaz D, O'Brien PJ. Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chem Biol Interact 2004; 150:115.
  16. Maddur H, Chalasani N. Idiosyncratic drug-induced liver injury: a clinical update. Curr Gastroenterol Rep 2011; 13:65.
  17. Lewis JH. 'Hy's law,' the 'Rezulin Rule,' and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective. Pharmacoepidemiol Drug Saf 2006; 15:221.
  18. Davern TJ. Drug-induced liver disease. Clin Liver Dis 2012; 16:231.
  19. Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly 2010; 140:w13080.
  20. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37:3.
  21. Galan MV, Potts JA, Silverman AL, Gordon SC. The burden of acute nonfulminant drug-induced hepatitis in a United States tertiary referral center [corrected]. J Clin Gastroenterol 2005; 39:64.
  22. Goldberg DS, Forde KA, Carbonari DM, et al. Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system. Gastroenterology 2015; 148:1353.
  23. Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129:512.
  24. Batt AM, Ferrari L. Manifestations of chemically induced liver damage. Clin Chem 1995; 41:1882.
  25. Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11:272.
  26. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995; 19:1409.
  27. De Valle MB, Av Klinteberg V, Alem N, et al. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006; 24:1187.
  28. 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; 22:169.
  29. Björnsson E. Drug-induced liver injury: Hy's rule revisited. Clin Pharmacol Ther 2006; 79:521.
  30. de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004; 58:71.
  31. Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004; 10:1018.
  32. Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17:191.
  33. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006; 43:618.
  34. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354:731.
  35. Reuben A. Hy's law. Hepatology 2004; 39:574.
  36. Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010; 138:2246.
  37. Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005; 42:481.
  38. Barritt AS 4th, Lee J, Hayashi PH. Detective work in drug-induced liver injury: sometimes it is all about interviewing the right witness. Clin Gastroenterol Hepatol 2010; 8:635.
  39. USFDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation http://www.fda.gov/cder/guidance/7507dft.htm (Accessed on August 21, 2008).
  40. Navaro, V. Hepatic adverse event nomenclature document http://www.fda.gov/cder/livertox/presentations2005/Vic_Navaro.ppt (Accessed on August 21, 2008).
  41. Lucena MI, Camargo R, Andrade RJ, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33:123.
  42. Danan G, Benichou C. Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46:1323.
  43. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology 2001; 33:308.
  44. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26:664.
  45. Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology 2010; 51:2117.
  46. Zhang X, Ouyang J, Thung SN. Histopathologic manifestations of drug-induced hepatotoxicity. Clin Liver Dis 2013; 17:547.
  47. Kleiner DE. Drug-induced Liver Injury: The Hepatic Pathologist's Approach. Gastroenterol Clin North Am 2017; 46:273.
  48. Björnsson E, Kalaitzakis E, Av Klinteberg V, et al. Long-term follow-up of patients with mild to moderate drug-induced liver injury. Aliment Pharmacol Ther 2007; 26:79.
  49. Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62:481.
  50. O'Connor N, Dargan PI, Jones AL. Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM 2003; 96:787.
  51. Andrade RJ, Lucena MI, Kaplowitz N, et al. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006; 44:1581.
  52. Hou FQ, Zeng Z, Wang GQ. Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes. Cell Biochem Biophys 2012; 64:77.
  53. Efe C. Drug induced autoimmune hepatitis and TNF-α blocking agents: is there a real relationship? Autoimmun Rev 2013; 12:337.
  54. Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56:958.
  55. Suzuki A, Brunt EM, Kleiner DE, et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 2011; 54:931.
  56. Kleiner DE. The pathology of drug-induced liver injury. Semin Liver Dis 2009; 29:364.
  57. Zimmerman HJ. Chapter 16: Drug-induced liver disease. In: Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver, 1st ed, Appleton-Century-Crofts, New York 1978. p.353.
  58. Speeg KV, Bay MK. Prevention and treatment of drug-induced liver disease. Gastroenterol Clin North Am 1995; 24:1047.
  59. Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000; 118:422.
  60. Zimmerman HJ, Lewis JH. Chemical- and toxin-induced hepatotoxicity. Gastroenterol Clin North Am 1995; 24:1027.
  61. Larrey D. Drug-induced liver diseases. J Hepatol 2000; 32:77.
  62. Studniarz M, Czubkowski P, Cielecka-Kuszyk J, et al. Amoxicillin/clavulanic acid-induced cholestatic liver injury after pediatric liver transplantation. Ann Transplant 2012; 17:128.
  63. Stadlmann S, Portmann S, Tschopp S, Terracciano LM. Venlafaxine-induced cholestatic hepatitis: case report and review of literature. Am J Surg Pathol 2012; 36:1724.
  64. Avelar-Escobar G, Méndez-Navarro J, Ortiz-Olvera NX, et al. Hepatotoxicity associated with dietary energy supplements: use and abuse by young athletes. Ann Hepatol 2012; 11:564.
  65. Palta R, Thobani S, Donovan JA, et al. Prolonged cholestasis associated with benazepril therapy. Am J Gastroenterol 2009; 104:245.
  66. Moradpour D, Altorfer J, Flury R, et al. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 1994; 20:1437.
  67. Degott C, Feldmann G, Larrey D, et al. Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia. Hepatology 1992; 15:244.
  68. Macías FM, Campos FR, Salguero TP, et al. Ductopenic hepatitis related to Enalapril. J Hepatol 2003; 39:1091.
  69. Cullen JM. Mechanistic classification of liver injury. Toxicol Pathol 2005; 33:6.
  70. Agozzino F, Picca M, Pelosi G. Acute hepatitis complicating intravenous amiodarone treatment. Ital Heart J 2002; 3:686.
  71. Lee WM. Acute liver failure. N Engl J Med 1993; 329:1862.
  72. Rigas B. The evolving spectrum of amiodarone hepatotoxicity. Hepatology 1989; 10:116.
  73. Gehenot M, Horsmans Y, Rahier J, Geubel AP. Subfulminant hepatitis requiring liver transplantation after benzarone administration. J Hepatol 1994; 20:842.
  74. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology 1989; 9:679.
  75. Rätz Bravo AE, Drewe J, Schlienger RG, et al. Hepatotoxicity during rapid intravenous loading with amiodarone: Description of three cases and review of the literature. Crit Care Med 2005; 33:128.
  76. Kumar S, DeLeve LD, Kamath PS, Tefferi A. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 2003; 78:589.
  77. Poucell S, Ireton J, Valencia-Mayoral P, et al. Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies. Gastroenterology 1984; 86:926.
  78. Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes. Hepatology 1990; 11:81.
  79. Lewis JH, Mullick F, Ishak KG, et al. Histopathologic analysis of suspected amiodarone hepatotoxicity. Hum Pathol 1990; 21:59.
  80. Farrell GC. Drugs and steatohepatitis. Semin Liver Dis 2002; 22:185.
  81. Polson J, Lee WM, American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41:1179.
  82. Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001; 56:1405.
  83. Giannattasio A, D'Ambrosi M, Volpicelli M, Iorio R. Steroid therapy for a case of severe drug-induced cholestasis. Ann Pharmacother 2006; 40:1196.
  84. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333:1118.
  85. O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439.
  86. Björnsson E, Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatol 2009; 50:511.
  87. Mindikoglu AL, Magder LS, Regev A. Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the United Network for Organ Sharing database. Liver Transpl 2009; 15:719.
  88. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015; 148:1340.
  89. Huang YL, Hong HS, Wang ZW, Kuo TT. Fatal sodium valproate-induced hypersensitivity syndrome with lichenoid dermatitis and fulminant hepatitis. J Am Acad Dermatol 2003; 49:316.
  90. Newman M, Auerbach R, Feiner H, et al. The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment. Improvement in liver abnormalities after cessation of treatment. Arch Dermatol 1989; 125:1218.
  91. Lee WM, Denton WT. Chronic hepatitis and indolent cirrhosis due to methyldopa: the bottom of the iceberg? J S C Med Assoc 1989; 85:75.
  92. Beyeler C, Reichen J, Thomann SR, et al. Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. Br J Rheumatol 1997; 36:338.
  93. Graham DJ, Green L, Senior JR, Nourjah P. Troglitazone-induced liver failure: a case study. Am J Med 2003; 114:299.