Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands.
Aliment Pharmacol Ther. 2013 Mar;37(6):640-6. doi: 10.1111/apt.12223. Epub 2013 Jan 24.
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.
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.
We describe the clinical efficacy and tolerability of allopurinol-thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25-33% 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.
All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol-thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 10(8) red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 × 10(8) RBC (P = 0.01).
Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.
10%的自身免疫性肝炎（AIH）患者对硫嘌呤治疗无反应或不耐受。代谢异常导致（肝）毒性硫嘌呤代谢物（6-MMPs）优先生成，而不是代谢活性 6-硫鸟嘌呤核苷酸（6-TGNs），这可能解释了这种不良结局。在炎症性肠病中，小剂量硫嘌呤治疗联合别嘌醇可有效逆转这种异常代谢。
描述因代谢异常导致对常规硫嘌呤剂量不耐受或无反应的 AIH 患者，加用别嘌醇降低硫嘌呤剂量治疗的效果。
我们描述了 8 例因硫嘌呤代谢异常而转换为硫嘌呤联合别嘌醇（别嘌醇 100mg 和低剂量硫嘌呤[原剂量的 25-33%]）治疗的 AIH 患者的临床疗效和耐受性。这些患者转换治疗的原因分别是剂量限制不耐受（n=3）、无反应（n=3）或应答丧失（n=2）。
所有 8 例患者的生化指标均有改善，丙氨酸氨基转移酶（ALT）中位数从治疗开始时的 62U/L 降低至 1 个月时的 35U/L（P=0.03）。7 例患者的这种临床获益得以维持。硫嘌呤联合别嘌醇治疗在 5 例中的 4 例中有效避免了硫嘌呤的副作用。3 个月时，6-硫鸟嘌呤核苷酸中位数从 100pmol/8×10(8)红细胞（RBC）增加到 200pmol/8×10(8)RBC（P=0.04）。所有患者的 6-MMP 中位数从 6090pmol/8×10(8)RBC 降低至 175pmol/8×10(8)RBC（P=0.01）。
在因硫嘌呤代谢不良而不耐受和/或无反应的自身免疫性肝炎患者中，别嘌醇安全有效地优化了硫嘌呤治疗。
