Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis

Background Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease. Aim To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism. Methods We describe the clinical efficacy and tolerability of allopurinolthiopurine combination therapy with allopurinol 100mg and low-dose thiopurine (2533% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n=3), nonresponse (n=3) or loss of response (n=2) to conventional thiopurine treatment. Results All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62U/L at start to 35U/L at 1month (P=0.03). This clinical benefit was sustained in seven patients. Allopurinolthiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200pmol/8x108 red blood cells (RBC) at 3months (P=0.04). Median 6-MMP levels decreased in all patients from 6090 to 175pmol/8x108 RBC (P=0.01). Conclusion Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.