URSODIOL-METHOTREXATE FOR PRIMARY BILIARY CIRRHOSIS

这项随机、双盲临床试验的主要目的是 确定是否治疗原发性胆汁性肝硬变 (PBC)与熊去氧胆酸(熊去氧胆酸-UDCA)加甲氨蝶呤(MTX) 比单独使用UDCA治疗更有效。PBC是一种慢性疾病 胆汁淤积性肝病，主要发生在女性，其中小叶间 间隔胆管会受到炎症和破坏。一次 开始时，这种疾病会持续存在，并以不同的速度发展。都不是 启动或持久的机制是很好理解的。当前 发病机制的概念包括(1)胆管的破坏是 维持并可能由自身免疫机制启动；(2) 在血清和肝脏中积聚的疏水性胆汁酸会导致 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会导致细胞损伤和 纤维化症。大量证据表明，当喂食UDCA时 口服可改善肝脏检查、瘙痒和肝脏症状 组织学，特别是血清胆红素低于3的患者 Mg%。现在确定是否发生并发症还为时尚早。 肝脏疾病，需要移植或存活受到影响。UDCA，a 相对无毒的胆汁酸，当口服时，改变 有利于UDCA浓缩的胆酸池的组成 对内源性胆汁的细胞毒性作用有保护作用 由于胆管破坏而积聚的酸。甲氨蝶呤正在被 对小鼠的肝脏检查、症状和肝组织学有改善作用 有PBC的肝硬变前患者的数量。其作用机制是 未知，但认为与抗炎免疫抑制有关 甲氨蝶呤的影响。目前的提案将探索MTX是否会改善 UDCA治疗PBC的疗效观察PBC患者的血清 胆红素低于3mg%，服用UDCA至少6年 几个月，满足一系列纳入和排除标准的人将 按肝组织学分期分为2组 (路德维希分类)，即早期(阶段I或阶段II)和晚期(阶段 III或IV)。然后，他们将被随机接受甲氨蝶呤 或其安慰剂作为第二种药物，同时继续接受UDCA。这个 两个治疗机构的相对价值将通过比较进行评估 他们对症状的影响，实验室测试的结果，发展 肝脏疾病的并发症，肝脏的组织学变化，需要 移植和生存方面的问题。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.