URSODIOL-METHOTREXATE FOR PRIMARY BILIARY CIRRHOSIS

这项随机双盲临床试验的主要目的是 原发性胆汁性肝硬化患者的治疗 (PBC)与熊去氧胆酸（熊去氧胆酸-UDCA）联合甲氨蝶呤（MTX） 比单用UDCA治疗更有效。 PBC是一种慢性 胆汁淤积性肝病，主要发生于女性，其中小叶间 并且隔胆管经历炎症和破坏。 一旦 开始时，疾病持续存在并以不同的速度进展。 既不 启动机制和持续机制都很好理解。 电流 发病机制的概念包括（1）胆管破坏， 维持并可能由自身免疫机制启动;（2） 疏水胆汁酸在血清和肝脏中积累， 功能性和细胞毒性肝损伤;（3）细胞因子和淋巴因子 在炎症部位释放可能导致细胞损伤， 纤维化 大量证据表明，UDCA在喂食时 口服可改善肝功能检查、瘙痒和肝脏 组织学，特别是血清胆红素低于3的患者 mg%。 现在确定是否出现并发症还为时过早。 肝脏疾病，需要移植或生存受到影响。 UDCA，a 相对无毒的胆汁酸，当口服给药时， 胆汁酸池的组成有利于其富集UDCA 并且似乎可以防止内源性胆汁的细胞毒性作用 由于胆管破坏而积聚的酸。 MTX正在 在一个小的实验中， PBC患者的数量。 其作用机制 未知，但认为与抗炎-免疫抑制相关 MTX的作用 目前的提案将探讨MTX是否能改善 UDCA治疗PBC的疗效。 PBC患者血清 胆红素低于3 mg%，已接受UDCA至少6 个月，并且满足一系列入选和排除标准的人将 根据肝脏组织学分期分为2组 （路德维希分类），即早期（I期或II期）与晚期（ III或IV）。 然后将他们随机接受甲氨蝶呤或 或其安慰剂作为第二种药物，同时继续接受UDCA。 的 通过比较两个治疗组的相对值， 它们对症状、实验室检查结果、 肝病并发症，肝脏组织学变化，需要 移植和生存。 每种治疗方案的安全性 也将被确定。

The major thrust of this randomized, double-blinded clinical trial Is to determine whether treatment of patients with Primary Biliary Cirrhosis (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective than treatment with UDCA alone. PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well understood. Current concepts of pathogenesis include (1) destruction of bile ducts is maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A considerable body of evidence indicates that UDCA when fed orally leads to improvement in liver tests, in pruritus and in liver histology, particularly in patients whose serum bilirubin is less than 3 mg%. It is too early to determine if development of complications of liver disease, need for transplantation or survival is affected. UDCA, a relatively non-toxic bile acid, when administered orally, alters the composition of the bile acid pool in favor of its enrichment with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that accumulate as a result of bile duct destruction. MTX is being shown to improve liver tests, symptoms and liver histology in a small number of precirrhotic patients with PBC. The mechanism of action is unknown but felt to be related to antiinflammatory-immunosuppressive effects of MTX. The current proposal will explore whether MTX improves the therapeutic effects of UDCA in PBC. Patients with PBC whose serum bilirubin is less than 3 mg%, who have been on UDCA for at least 6 months, and who satisfy a series of inclusion and exclusion criteria will be stratified into 2 groups on the basis of liver histologic stage (Ludwig classification), i.e. early (Stages I or II) versus late (Stages III or IV). They will then be randomized to receive either methotrexate or its placebo as a second drug while continuing to receive UDCA. The relative value of the two treatment arms will be assessed by comparing their effects on symptoms, results of laboratory tests, development of complications of liver disease, histologic changes in liver, need for transplantation, and on survival. Safety of each therapeutic regimen will also be determined.