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What is drug-induced hepatitis?
Drug-induced hepatitis involves inflammation of the liver, caused by medication. Drug-induced hepatitis is similar to acute viral hepatitis but parenchymal destruction tends to be more extensive. Certain drugs can cause damage to the liver in a variety of ways:
- Acute hepatocellular damage:
- Dose-unrelated - eg, antituberculous drugs, halothane, anticonvulsants.
- Dose-related - eg, alcohol, paracetamol poisoning, amiodarone, methotrexate.
- Both dose-unrelated and dose-related liver cell damage - eg, azathioprine.
- Autoimmune hepatitis: drugs implicated in drug-induced autoimmune hepatitis include antimicrobials, such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents.
- Cirrhosis - eg, alcohol, methotrexate.
- Hepatic tumours - eg, anabolic steroids, combined oral contraceptives.
- Intrahepatic cholestasis: either dose-unrelated (eg, carbimazole, erythromycin, phenothiazines) or dose-related (eg, anabolic steroids, azathioprine, oestrogens).
- Gallstones - eg, clofibrate, oestrogens.
Drug-induced liver injury can occur in overdose or at therapeutic dosing, either because of direct, intrinsic drug hepatotoxicity or as a result of idiosyncratic (unpredictable) hepatotoxicity. About 10% of cases are idiosyncratic.
How common is drug-induced hepatitis? (Epidemiology)
- Drug-induced liver injury is the most common cause of acute liver failure in the western world. However idiosyncratic drug-induced liver injury is an uncommon adverse event when taking prescription or non-prescription medications.
- It is difficult to assess the true incidence because of different diagnostic criteria and under-reporting. However, recent population-based studies estimate the incidence to vary between 13.9-19.1 cases per 100,000 people per year.
- Approximately 15% of patients with autoimmune hepatitis have drug-induced liver disease.
- The development of drug-induced liver disease is dependent on the drug as well as individual patient factors, including genetic predisposition, age, gender, pre-existing liver disease and comorbidities.
Drug-induced hepatitis symptoms
There is no specific or diagnostic clinical presentation, laboratory test or histological pattern to aid in the diagnosis of drug-induced liver disease. Clinical features vary with the pattern and severity of injury, which vary with the particular drug and the individual patient.
- Often detected by routine drug monitoring - eg, disease-modifying antirheumatic drugs.
- Symptoms and signs are similar to other causes of liver damage. Thus, identifying drug-induced hepatitis relies on the history of exposure more than any particular finding on examination or investigation.
- Clinical evidence of sensitivity to a medication may occur on the first day of its use or not until several months later, depending on the medication.
- Usually, the onset is abrupt, with chills, fever, rash, pruritus, arthralgia, headache, abdominal pain, anorexia, nausea and vomiting.
- Later, overt evidence of liver damage, such as jaundice, dark urine and an enlarged and tender liver, may develop.
- Two general pathogenic mechanisms are recognised:
- Predictable or direct: usually promptly follows an exposure to a new medication. The mechanism appears to be due to direct toxicity or a toxic metabolite - eg, paracetamol.
- Unpredictable or idiosyncratic: may be related to immune hypersensitivity; rash, fever and eosinophilia are typically present. These reactions follow exposure by a few weeks - eg, Augmentin®.
- Late-onset idiosyncratic reactions are difficult to recognise. They follow exposure by many months and usually do not display features of hypersensitivity - eg, isoniazid.
- Other causes of abnormal liver function tests.
- Other causes of hepatitis, including:
- Viral hepatitis.
- Other viral infections - eg, glandular fever, cytomegalovirus, HIV infection.
- Autoimmune hepatitis.
- Wilson's disease, haemochromatosis.
- Toxins - eg, alcoholic liver disease.
- Poisoning - eg, paracetamol poisoning, and mushroom and toadstool poisoning.
- Other causes of liver failure and coagulation disorders.
Medication-induced liver injury typically presents in one of three clinical patterns:
- Hepatitis: elevated AST/ALT - eg, paracetamol poisoning, thiazolidinediones, statins.
- Cholestasis: elevated alkaline phosphatase - eg, chlorpromazine, erythromycin, oestrogens.
- Mixed picture with damage to both biliary canaliculi and hepatocytes: variable elevations in aminotransferases and alkaline phosphatase - eg, Augmentin®.
- Investigations may also need to include an assessment for other causes of hepatitis and may include hepatitis viral serology, antinuclear antibodies, copper and iron levels, abdominal ultrasound, CT/MRI scan and liver biopsy.
See also the article on Abnormal Liver Function Tests.
- There is no specific treatment for drug-induced hepatitis other than discontinuing the medication that is causing the problem.
- People with acute hepatitis should avoid physical exertion, alcohol, paracetamol and any other hepatotoxic substances.
- Unfortunately, other than the use of N-acetylcysteine for paracetamol hepatotoxicity, there are no specific antidotes for drug-induced liver disease.
- Supportive care for acute liver failure and even liver transplantation may be required.
Liver failure is a possible but uncommon complication of drug-induced hepatitis. The risk of acute liver failure is dependent on the degree of abnormality of liver enzyme levels and the presence of pre-existing liver disease. The risk is higher in women.[10, 11]
- Usually symptoms subside when the causative drug has been discontinued and drug-related hepatitis subsides within days or weeks after the offending drug is stopped.
- Reactions may be severe and even fatal.
- Patients with jaundice have approximately 10% risk of liver-related mortality and/or need for liver transplantation.
Prevention of drug-induced hepatitis
- Careful prescribing and, when recommended, monitoring of all medication in line with established guidelines.
- Always consider drugs as a cause of any patient presenting with hepatitis in order to provide early effective management.
Further reading and references
Kleiner DE; Drug-induced Liver Injury: The Hepatic Pathologist's Approach. Gastroenterol Clin North Am. 2017 Jun46(2):273-296. doi: 10.1016/j.gtc.2017.01.004.
British National Formulary (BNF); NICE Evidence Services (UK access only)
Tan CK, Ho D, Wang LM, et al; Drug-induced autoimmune hepatitis: A minireview. World J Gastroenterol. 2022 Jun 2828(24):2654-2666. doi: 10.3748/wjg.v28.i24.2654.
Kumachev A, Wu PE; Drug-induced liver injury. CMAJ. 2021 Mar 1193(9):E310. doi: 10.1503/cmaj.202026.
Leise MD, Poterucha JJ, Talwalkar JA; Drug-induced liver injury. Mayo Clin Proc. 2014 Jan89(1):95-106. doi: 10.1016/j.mayocp.2013.09.016.
Katarey D, Verma S; Drug-induced liver injury. Clin Med (Lond). 2016 Dec16(Suppl 6):s104-s109. doi: 10.7861/clinmedicine.16-6-s104.
Yeong TT, Lim KH, Goubet S, et al; Natural history and outcomes in drug-induced autoimmune hepatitis. Hepatol Res. 2015 May 5. doi: 10.1111/hepr.12532.
Fisher K, Vuppalanchi R, Saxena R; Drug-Induced Liver Injury. Arch Pathol Lab Med. 2015 Jul139(7):876-87. doi: 10.5858/arpa.2014-0214-RA.
Teschke R, Danan G; Drug induced liver injury with analysis of alternative causes as confounding variables. Br J Clin Pharmacol. 2018 Jul84(7):1467-1477. doi: 10.1111/bcp.13593. Epub 2018 May 14.
Weiler S, Merz M, Kullak-Ublick GA; Drug-induced liver injury: the dawn of biomarkers? F1000Prime Rep. 2015 Mar 37:34. doi: 10.12703/P7-34. eCollection 2015.
Bjornsson ES; Clinical management of patients with drug-induced liver injury (DILI). United European Gastroenterol J. 2021 Sep9(7):781-786. doi: 10.1002/ueg2.12113. Epub 2021 Jun 28.
Lo Re V 3rd, Haynes K, Forde KA, et al; Risk of Acute Liver Failure in Patients with Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model. Clin Gastroenterol Hepatol. 2015 Jun 26. pii: S1542-3565(15)00844-7. doi: 10.1016/j.cgh.2015.06.020.
Robles-Diaz M, Lucena MI, Kaplowitz N, et al; Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014 Jul147(1):109-118.e5. doi: 10.1053/j.gastro.2014.03.050. Epub 2014 Apr 1.