Risk of drug-induced liver injury from tumor necrosis factor antagonists

Clin Gastroenterol Hepatol. 2015 Mar;13(3):602-8. doi: 10.1016/j.cgh.2014.07.062. Epub 2014 Aug 15.


Background & aims: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.

Methods: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n = 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n = 22).

Results: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n = 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P = .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.

Conclusions: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.

Keywords: ANA; Autoimmune Hepatitis; Liver Disease; TNF-α; Toxicity.

MeSH terms

  • Adult
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / adverse effects*
  • Chemical and Drug Induced Liver Injury / epidemiology*
  • Female
  • Hospitals, University
  • Humans
  • Iceland / epidemiology
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / adverse effects*
  • Infliximab
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects
  • Middle Aged
  • Prevalence
  • Prospective Studies
  • Risk Assessment
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Immunologic Factors
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Methotrexate