Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment.

BACKGROUND & AIMS: Infliximab has been associated with drug-induced liver injury (DILI), particularly drug-induced autoimmune hepatitis (DIAIH). DIAIH is commonly treated with corticosteroids, but there is limited data on the efficacy of corticosteroids in infliximab-induced DILI. METHODS: Patients were included for assessment if they had been treated with infliximab between 2009-2020 in Iceland and had developed elevated liver tests. Other specific etiologies of liver enzyme elevations were excluded. Patients treated with corticosteroids were compared to patients not receiving corticosteroids. RESULTS: A total of 36 patients with infliximab-induced DILI were identified: median age was 46 years (IQR 32-54) and 28 (78%) were female. Type of liver injury was predominantly hepatocellular (64%). Median peak liver enzymes were: alanine aminotransferase (ALT) 393 (328-695) U/L, aspartate aminotransferase 283 (158-564) U/L, alkaline phosphatase 116 (83-205) U/L, and bilirubin (10-20) 13 µmol/L. A total of 25 (69%) were positive for anti-nuclear antibody and/or had elevated IgG. Corticosteroids were initiated in 17 (47%). Median time from onset of liver injury to peak ALT value was longer in patients treated with corticosteroids, 22 (12-59) vs. 0 (0-3) days (p = 0.001). Time from peak ALT to normalization of liver enzymes was 45 days in the corticosteroid group vs. 77 days in others (p = 0.062). Corticosteroids were tapered in all patients, with no cases of relapse during the follow-up period of 1,245 (820-2,698) days. Overall 75% received another biologic, mostly adalimumab, without evidence of liver injury. CONCLUSION: Approximately half of patients with infliximab-induced liver injury had slow improvement in ALT despite cessation of therapy and were treated with corticosteroids. Treatment response was good with prompt resolution of liver test abnormalities. Relapse of liver injury was not observed after tapering of corticosteroids despite prolonged follow-up and no patients developed DILI due to a second biologic. LAY SUMMARY: A rare side effect of infliximab, a biologic medicine used to treat multiple inflammatory diseases, is liver injury and liver inflammation. Steroid treatment has been used in some patients with liver injury caused by infliximab, but there have been few studies supporting this treatment. In this study of 36 patients with infliximab-induced liver injury, approximately half of patients were treated with steroids and the results suggest that patients receiving steroids recover more quickly.

A prospective study on the causes of notably raised alanine aminotransferase (ALT).

OBJECTIVE: High levels of alanine aminotransferase (ALT) can be a marker of severe liver disease with variable aetiologies and prognosis. Very few prospective studies have been undertaken on the aetiology and prognosis of patients with high ALT levels. No population-based prospective study has systematically evaluated drug-induced liver injury (DILI) among these patients. The objective was to determine the aetiology and prognosis of patients with high ALT. MATERIALS AND METHODS: In a catchment area of 160,000 inhabitants, a population-based prospective study identified all adult patients with serum level of ALT >500 U/L during a 12-month period. All underwent thorough diagnostic work-up and follow-up. In suspected DILI, causality was assessed with Roussel Uclaf Causality Assessment Method. RESULTS: A total of 155 patients were identified with ALT >500 U/L, 12 children and one with ALT of non-liver-related origin, leaving 142 patients for the analysis: 73 (51%) males, median age 52 (IQR 36-68, range 19-89 years). The most common causes were choledocholithiasis 48/142 (34%), ischaemic hepatitis 26 (18%), viral hepatitis 16 (11%) and DILI 15 (11%), hepatobiliary malignancy (n = 6), surgery/interventions (n = 8) and other aetiologies (n = 23). No specific aetiology was found in 6% of cases. In the total study cohort 99 (70%) required hospitalisation, 78 (55%) had jaundice and 22 (16%) died, liver-related death in 10%, 35% in IH and 7% in DILI. CONCLUSIONS: The most common cause of notably high ALT was choledocholithiasis. Ischaemic hepatitis was a common aetiology with approximately 35% liver-related mortality. Viral hepatitis and DILI were important aetiologies among these patients.

Review of human risk factors for idiosyncratic drug-induced liver injury: latest advances and future goals.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is a common cause of acute liver injury and can lead to death from acute liver failure or require liver transplantation. Although the total burden of liver injury is high, the frequency of DILI caused by specific agents is often low. As the liver injury is by per definition idiosyncratic, the prediction of which patients will develop liver injury from specific drugs is currently a very difficult challenge. AREAS COVERED: The current paper highlights the most important studies on prediction of DILI published in 2019-2023, including studies on genetic, metabolomic, and demographic risk factors, concomitant medication, and the role of comorbid liver diseases. Risk stratification using demographic, metabolomic, and multigenetic risk factors is discussed. EXPERT OPINION: Great advances have been made in identifying genetic risk factors for DILI. Combining these risk factors with demographic information and other biomarkers into multigenetic risk models might become highly useful in risk stratifying patients exposed to DILI. However, a more detailed mapping of genetic risk factors is needed. Results of these studies need to be validated in the selected ethnic groups before applicability and cost-effectiveness can be determined.