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

Abstract

SUMMARY BackgroundTen 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.

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

“…In the series of 8 adult patients on combination therapy, all patients had documented decrease in 6MMP levels (from pretreatment median value of 6090 pmol/8 Â 10 8 RBC to 175 pmol/8 Â 10 8 RBC at 3 months; P = 0.01) and increase in 6TG levels (from pretreatment median value of 100 pmol/8 Â 10 8 RBC to 200 pmol/8 Â 10 8 RBC at 3 months; P = 0.04) after combination therapy in comparison to baseline value. 20 The median 6MMP:6TG ratio decreased significantly from a pre-treatment value of 55.7 (18-122) to 1.3 (0-2; P = 0.01) after combination therapy in these 8 cases. 20 This signifies the importance of monitoring serum metabolite levels in these patients to guide therapy.…”

“…20 The median 6MMP:6TG ratio decreased significantly from a pre-treatment value of 55.7 (18-122) to 1.3 (0-2; P = 0.01) after combination therapy in these 8 cases. 20 This signifies the importance of monitoring serum metabolite levels in these patients to guide therapy.…”

“…15). 20 In adult and pediatric patients with IBD, use of allopurinol, along with lower dose of thiopurines (AZA or 6MP), has been shown to be of benefit in nonresponders and patients with hepatotoxicity by achieving higher 6TG and lower 6MMP levels. [21][22][23] The exact mechanism of action of allopurinol is still not clear.…”

“…Majority were type 1 AIH, however details of type were not available in the largest case series. 20 Five (5/13, 38.5%) patients had overlap syndrome (4 with AIH-PSC [3 children, 1 adult] and one adult with AIH-PBC). Patient details including indication for use of combination therapy is shown in Table 1.…”

“…The adverse reaction reported were reversible neuropathy and myelosuppression manifesting as uncomplicated mild pancytopenia in one case each. 20 The patient with neuropathy was a known case of multiple sclerosis who presented with myalgia and numbness, after 4 months of combination therapy. She was shifted back to her previous therapy with 6MP and subsequently neuropathy improved.…”