Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai 201508, China.
Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
World J Gastroenterol. 2019 Feb 21;25(7):859-869. doi: 10.3748/wjg.v25.i7.859.
Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China.
To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA.
Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in , were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.
Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.
The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.
如果未被诊断出或未接受原发性胆汁酸替代治疗，原发性胆汁酸合成紊乱可能会危及生命。迄今为止，有关Δ4-3-氧固醇 5β-还原酶（AKR1D1）缺乏症患者的管理和随访的报告很少。我们假设对口服胆汁酸替代疗法用鹅脱氧胆酸（CDCA）治疗此类胆汁酸合成障碍患者的反应进行回顾性分析，将增加我们对疾病进展的了解，并评估该治疗方案作为替代美国食品和药物管理局（FDA）批准药物胆酸的一种选择，而胆酸目前在中国无法获得。
评估 AKR1D1 缺乏症患者对口服胆汁酸治疗，特别是 CDCA 的治疗反应。
通过快速原子轰击电离质谱分析尿液和基因测序突变，确认 12 例 AKR1D1 缺乏症患者，并用不同剂量的 CDCA 或熊去氧胆酸（UDCA）进行治疗。通过监测 0.5-6.4 年的时间，评估治疗的临床和生化反应。根据血清生化参数（尤其是肝功能检查）的变化以及通过质谱测量抑制非典型肝毒性 3-氧代-Δ4-胆汁酸的尿液水平，调整剂量以优化治疗剂量。
在接受胆汁酸治疗的 12 例患者中，除 1 例接受肝移植的患者外，体格检查、血清生化参数和超声检查结果均得到改善。尿液胆汁酸分析证实，在接受 CDCA 治疗的患者中，非典型肝毒性 3-氧代-Δ4-胆汁酸显著减少，同时临床和生化改善。UDCA 不能下调内源性胆汁酸合成，因为不能抑制非典型 3-氧代-Δ4-胆汁酸的排泄。根据最大抑制非典型胆汁酸和改善血清生化参数，每位患者所需的 CDCA 最佳临床和生化反应剂量从 5.5-10mg/kg/天不等，需要仔细滴定剂量以避免 CDCA 的副作用。
初级胆汁酸 CDCA 治疗 AKR1D1 缺乏症有效，但治疗剂量需要个体化优化。不建议长期使用 UDCA。
