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: either dose-unrelated, e.g. antituberculous drugs, halothane, anticonvulsants; dose-related, e.g. alcohol, paracetamol poisoning, amiodarone, methotrexate; or both dose-unrelated and dose-related liver cell damage, e.g. azathioprine.
• Chronic active hepatitis, e.g. isoniazid, nitrofurantoin.
• Cirrhosis, e.g. alcohol, methotrexate.
• Hepatic tumours, e.g. anabolic steroids, combined oral contraceptives.
• Intrahepatic cholestasis: either dose-unrelated (e.g. carbimazole, erythromycin, phenothiazines) or dose-related (e.g. anabolic steroids, azathioprine, oestrogens).
• Gallstones, e.g. clofibrate, oestrogens

Epidemiology

• A very large number of drugs have been implicated as a potential cause of drug-induced hepatitis but with variable risk of both frequency and severity.
• Estimates vary widely but 25-50% of all cases of hepatitis and even hepatic failure may be due to adverse drug effects.
• Risk factors for drug-induced liver injury include:¹
  • Race, e.g. Afro-Caribbean and Hispanics may be more susceptible to isoniazid toxicity.
  • Increasing age: elderly patients are at increased risk of hepatic injury.
  • Gender: hepatic drug reactions are more common in females.
  • Alcoholics are more susceptible to drug toxicity.
  • Chronic liver disease: patients with pre-existing liver disease may be more susceptible to drug toxicity but this varies between individual patients and drugs prescribed, and will be dependent on specific enzyme levels and specific drugs.
  • Genetic factors: genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions.
  • Patients with AIDS, and those who are malnourished or fasting may be susceptible to drug reactions. Long-acting drugs may cause more injury than shorter-acting drugs.

Presentation

• Often detected by routine drug monitoring, e.g. 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, e.g. 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, e.g. augmentin.
• Late-onset idiosyncratic reactions are difficult to recognise. They follow exposure by many months and usually do not display features of hypersensitivity, e.g. isoniazid.

Differential diagnosis

• Other causes of abnormal liver function tests.
• Other causes of hepatitis, including:
  • Viral hepatitis.
  • Other viral infections, e.g. glandular fever, cytomegalovirus, HIV infection.
  • Autoimmune hepatitis.
  • Wilson's disease, haemochromatosis.
  • Toxins, e.g. alcoholic liver disease.
  • Poisoning, e.g. paracetamol poisoning, and mushroom and toadstool poisoning
  • Other causes of liver failure and coagulation disorders.

Investigations

Medication-induced liver injury typically presents in one of three clinical patterns:

• Hepatitis: elevated AST/ALT - e.g. paracetamol poisoning, thiazolidinediones, statins.
• Cholestasis: elevated alkaline phosphatase - e.g. chlorpromazine, erythromycin, oestrogens.
• Mixed picture with damage to both biliary canaliculi and hepatocytes: variable elevations in aminotransferases and alkaline phosphatase - e.g. 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.

Management

• 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.

Complications

Liver failure is a possible but uncommon complication of drug-induced hepatitis.

Prognosis

• 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.

Prevention

• 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.

Document references

1. Metha N et al; Drug-Induced Hepatotoxicity, eMedicine, Apr 2010

Internet and further reading

• British National Formulary; 60th Edition (September 2010) British Medical Association and Royal Pharmaceutical Society of Great Britain, London.

Acknowledgements