Systematic Review and Meta-Analysis of Thiopurine Metabolite Levels and Biochemical Remission in Autoimmune Hepatitis

Abstract

Objectives and study: The utility of measuring thiopurine metabolites (TM) to individualize therapy in autoimmune hepatitis (AIH) has not been defined, and the evidence regarding its use in clinical practice is heterogeneous. This systematic review and meta-analysis aimed to compare the mean concentration of TM between patients in biochemical remission and those not in remission. Methods: A systematic literature search was conducted using PubMed, Scopus, the Cochrane Library, and Google Scholar for keywords related to TM and AIH. Two reviewers independently searched and selected studies comparing the levels of 6-methyl mercaptopurine (6-MMP) and 6-thioguanine nucleotide (6-TGN) and their ratio in cases of AIH in remission and otherwise. Meta-analysis was performed by calculating the weighted mean difference using the inverse variance heterogeneity model. Results: A total of 1066 records were identified through systematic search, of which 7 (n = 3 pediatric, n = 4 adults) were considered for inclusion and 442 TM measurements (n = 128 in children) were analyzed. Mean 6-TGN levels were significantly higher among patients in remission than in those who were not, with a pooled weighted mean difference (WMD) of 15.67 [95% confidence interval (CI), 6.68–24.66] pmol/8 × 10⁸ red blood cells (RBC). The difference was higher in the pediatric age group [WMD 56.11, 95% CI: 13.60–98.62] than in adults [WMD 13.77, 95% CI: 4.58–22.97]. There was no significant difference in the 6-MMP levels (WMD -431.7, 95% CI:-1237.4–373.9 pmol/8 × 10⁸ RBC, I² = 82%, n = 3 studies) or 6-MMP/6-TGN ratio among the patients who were in biochemical remission and those who were not (WMD -0.97, 95% CI: -5.77–3.84, I² = 82%, n = 3 studies]. Conclusions: This meta-analysis suggests a link between 6-TGN levels and biochemical remission in AIH. Further high-quality studies are required to determine the therapeutic cut-off of 6-TGN.