Drug-induced hepatitis

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.¹

• 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.² About 10% of cases are idiosyncratic.³

How common is drug-induced hepatitis? (Epidemiology)⁴

• 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.⁵

• 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.⁶

• 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.

Differential diagnosis⁷

• 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.

Investigations

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.

Drug-induced hepatitis treatment and management^{8 9}

• 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. 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}

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.

• Patients with jaundice have approximately 10% risk of liver-related mortality and/or need for liver transplantation.⁹

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.