TREATMENT OF METABOLIC PRURITIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。瘙痒是胆汁淤积性肝病的一个标志性特征，估计在20%-50%的黄疸患者和70%-80%的原发性胆汁性肝硬化（PBC）患者中发生。瘙痒症严重影响生活质量，并可能导致慢性睡眠剥夺。目前使用的治疗方法往往无效和/或耐受性差。只有少数人在对照试验中得到了检验。美国肝病研究协会发布的实践指南指出，胆汁淤积性瘙痒的一线治疗方法是胆汁酸结合树脂，如胆酸胺。胆汁酸结合树脂对高达85%的患者部分有效，但由于制备方法难吃，依从性往往较差。此外，这些树脂极易与几乎所有其他药物结合并阻止其吸收，严重限制了患者的医疗管理。第二种治疗方法是利福平，在几项小型试验中显示出适度的效果。利福平的主要问题是它会导致血清胆红素水平升高。血清胆红素是PBC患者生存的唯一最重要的预测指标，因此利福平治疗削弱了医生跟踪患者病程的能力。此外，也有利福平引起肝炎的报道，这可能对肝功能已经受限的患者造成严重问题。三线疗法都被认为是实验性的，因为它们要么没有得到证实的疗效和/或严重限制副作用。它们包括：阿片受体阻滞剂，这是令人不快的，因为它们会导致PBC患者出现阿片样戒断综合征；苯巴比妥和异丙酚，有很强的镇静作用；抗组胺药不是很有效，而且还会加重干燥综合征的口干症，80%的PBC患者和许多丙型肝炎（HCV）患者都存在这种症状；s-腺苷蛋氨酸（SAMe，一种膳食补充剂），光疗；抗惊厥药，昂丹司琼，血浆置换。顽固性胆汁淤积性瘙痒被认为是肝移植的有效指征，在没有明显的肝细胞衰竭的情况下，这是一种有效但激烈和昂贵的措施。在极少数情况下，患者选择自杀是为了避免难以控制的瘙痒带来的持续痛苦。该项目的长期目标是改善引起瘙痒的全身性疾病患者的健康和生活质量。本项目的假设是基于我们之前观察到的一些PBC患者在服用舍曲林后瘙痒得到缓解，舍曲林治疗可以改善胆汁淤积性瘙痒的症状。本研究旨在作为可行性和剂量寻找试点试验，以确定舍曲林作为治疗胆汁淤积性瘙痒的耐受性和有效剂量。预计该试点试验之后将进行更大规模的双盲、随机、安慰剂对照试验，以明确评估舍曲林治疗瘙痒的疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pruritus is a hallmark feature of cholestatic liver diseases and is estimated to occur in 20%-50% of patients with jaundice and 70%-80% of patients with primary biliary cirrhosis (PBC). Pruritus significantly affects quality of life and can lead to chronic sleep deprivation. Currently used therapies are often ineffective and/or poorly tolerated. Only a few have been examined in the setting of controlled trials. Practice guidelines issued by the American Association for the Study of Liver Diseases state that the first line of therapy for cholestatic pruritus is bile acid binding resins such as cholestyramine. Bile acid binding resins can be partially effective in up to 85% of patients, but compliance tends to be poor because the preparation is unpalatable. In addition, these resins avidly bind to and prevent absorption of almost all other medications, severely restricting the medical management of the patients. The second line of therapy is rifampicin, which has been shown to be modestly effective in several small trials. The major problem with rifampicin is that it leads to increases in serum bilirubin levels. Serum bilirubin is the single most important predictor of survival in patients with PBC, and thus rifampicin therapy impairs the physician's ability to follow the patient's course. In addition, there have been reports of rifampicin-induced hepatitis, which could pose a serious problem in patients with already limited liver function. The third line therapies are all considered experimental because they either have unproved efficacy and/or severely limiting side effects. They include: opioid receptor blockers, which are unpleasant because they result in an opioid withdrawal-like syndrome in PBC patients; phenobarbitol and propofol, which are heavily sedating; anti-histamines, which are not very effective and also worsen the xerostomia of sicca syndrome that is present in 80% of patients with PBC and many patients with hepatitis C (HCV); s-adenosylmethionine (SAMe, a dietary supplement), phototherapy; anti-convulsants, ondansetron, and plasmapheresis. Intractable cholestatic pruritus is considered a valid indication for liver transplantation in the absence of overt hepatocellular failure, an effective but drastic and costly measure. In rare cases, patients have opted for suicide in order to avoid the constant distress of unmanageable pruritus. The broad, long-term objective of this project is to improve the health and quality of life of patients with systemic diseases that cause pruritus. The hypothesis of this project, which is based on our previous observation that some patients with PBC have experienced resolution of their pruritus when given sertraline, is that sertraline therapy will improve the symptom of cholestatic pruritus. This particular study is intended to serve as a feasibility and dose-finding pilot trial to determine the tolerability and effective dose of sertraline as a treatment for cholestatic pruritus. It is anticipated that this pilot trial will be followed by a larger, double-blind, randomized, placebo-controlled trial to definitively evaluate the efficacy sertraline therapy for pruritus.