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

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.

Figure 1

Selection and bases for exclusion of cases from the DILIN cohort.

Figure 2

Latency to onset of laboratory abnormalities in months from start of therapy (left) and from the time of the last dose escalation (right) for 12 cases of azathioprine (blue circles) and 10 cases of 6-mercaptopurine hepatotoxicity (red circles). Calculation of latency from first starting the thiopurines yielded a wide range of latencies whereas calculation from the time of the last dose increase yielded latencies that were largely within 3 months.

Figure 3

Use of the initial ALT and alkaline phosphatase levels and four quadrants to characterize the pattern of liver injury as suggested by Zimmerman (29). The plotting of 12 cases of azathioprine (blue circles) and 10 cases of 6-mercaptopurine liver injury (red circles) for both icteric (closed circles) and anicteric cases (open circles) shows a similar pattern for the two drugs but a different pattern for anicteric cases which were typically hepatocellular compared to the icteric cases which were typically cholestatic but with modest alkaline phosphatase elevations which is typical of canalicular as opposed to hepatocanalicular cholestasis.

Figure 4

Liver biopsy histology from [Case #20 described in Supplementary material] shows cholestatic hepatitis with nodular regenerative hyperplasia due to 6-mercaptopurine liver injury. a. Portal inflammation consists mainly of foamy macrophages with scattered neutrophils (H&E, 400x). b: Bile stasis (arrowheads) is evident in zone 3 (H&E, 600x). c: A reticulin stain shows small nodular areas of hepatocyte plate expansion bounded by narrowed, atrophic hepatocyte plates (200x).