Björnsson Einar S, Gu Jiezhun, Kleiner David E, Chalasani Naga, Hayashi Paul H, Hoofnagle Jay H
*Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institutes of Health, Bethesda, MD †The Faculty of Medicine, University of Iceland ‡National University Hospital of Iceland, Reykjavik, Iceland §Duke Clinical Research Institute, Durham, NC ∥Laboratory of Pathology, National Cancer Institute, National Institutes of Health ¶Indiana University School of Medicine, Indianapolis, IN #University of North Carolina, Chapel Hill, NC.
J Clin Gastroenterol. 2017 Jan;51(1):63-69. doi: 10.1097/MCG.0000000000000568.
The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.
Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist.
Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed.
Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset.
Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.
本研究的目的是明确硫唑嘌呤所致肝损伤的临床、生化和组织学特征。
硫唑嘌呤（Aza）和6-巯基嘌呤（6-MP）可导致肝损伤，但尚无大型系列研究。
分析药物性肝损伤网络前瞻性研究中硫唑嘌呤肝毒性患者的临床和实验室数据以及6个月的转归情况。
共确定22例患者，其中12例由Aza引起，10例由6-MP引起，中位年龄55岁；大多数为女性（68%）。55%的患者因炎症性肠病使用硫唑嘌呤，硫唑嘌呤的中位剂量为每日150（范围25至300）mg。发病的中位潜伏期为75（范围3至2584）天。59%的患者在剂量增加后首次出现损伤，剂量增加后的中位潜伏期为44（范围3至254）天。发病时，丙氨酸氨基转移酶中位水平为210 U/L，碱性磷酸酶为151 U/L，胆红素为7.4 mg/dL（峰值为13.4 mg/dL）。Aza和6-MP病例之间无重大差异，但无黄疸病例通常有非特异性症状且酶升高呈肝细胞型，而黄疸病例则为胆汁淤积性肝炎，酶升高程度较轻，呈混合模式。1例已有肝硬化的患者需要肝移植；其他所有患者临床症状均缓解。1例患者在发病2年后碱性磷酸酶仍中度升高。
近四分之三的硫唑嘌呤所致肝损伤患者表现为自限性胆汁淤积性肝炎，通常在开始用药或增加剂量后3个月内出现。除已有肝硬化的患者外，预后良好。
