Azathioprine and 6-Mercaptopurine-induced Liver Injury: Clinical Features and Outcomes

J Clin Gastroenterol. 2017 Jan;51(1):63-69. doi: 10.1097/MCG.0000000000000568.

Abstract

Objective: The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.

Background: Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist.

Methods: Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed.

Results: Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset.

Conclusions: Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alanine Transaminase / blood
  • Alkaline Phosphatase / blood
  • Azathioprine / administration & dosage
  • Azathioprine / adverse effects*
  • Bilirubin / blood
  • Chemical and Drug Induced Liver Injury / blood*
  • Chemical and Drug Induced Liver Injury / etiology
  • Child
  • Cholestasis / chemically induced*
  • Databases, Factual
  • Female
  • Humans
  • Inflammatory Bowel Diseases / drug therapy
  • Male
  • Mercaptopurine / administration & dosage
  • Mercaptopurine / adverse effects*
  • Middle Aged
  • Prospective Studies
  • Time Factors
  • Young Adult

Substances

  • Mercaptopurine
  • Alanine Transaminase
  • Alkaline Phosphatase
  • Azathioprine
  • Bilirubin