贝特类药物治疗原发性胆汁性胆管炎的研究现状

目前被美国食品药品监督管理局批准用于治疗原发性胆汁性胆管炎(PBC)的药物包括熊去氧胆酸和奥贝胆酸。对熊去氧胆酸应答不佳、不能耐受奥贝胆酸瘙痒副作用的患者亟需新的治疗药物。近年来大量基础实验和临床研究认为贝特类药物对PBC疗效显著。就贝特类药物治疗原发性胆汁性胆管炎的机制进展及临床应用作一综述。     

原发性胆汁性胆管炎的药物治疗新靶点

原发性胆汁性胆管炎以进展性胆汁淤积,肝内中小胆管非化脓性炎症为表现,最终发展成肝硬化、肝癌,严重威胁患者生命。研究发现熊去氧胆酸可有效治疗原发性胆汁性胆管炎。对熊去氧胆酸反应较差的患者接受移植或死亡的比例逐年增加,亟需新治疗方案。新药物作用于疾病进展的关键进程,如"上游"免疫反应,"中游"胆道损伤和"下游"纤维化进程。针对不同通路的多药物联合治疗是未来的发展趋势。总结了目前原发性胆汁性胆管炎的潜在治疗方案,评估了治疗实施所面临的挑战。     

胆汁淤积性肝病的治疗靶点及药物应用前景

胆汁淤积性肝病是由胆管的破坏、胆汁酸的积聚和炎症过程的持续导致胆管细胞及肝细胞的损伤而引起。若不及时治疗,胆汁淤积会导致肝纤维化、肝硬化甚至出现终末期肝病。原发性胆汁性胆管炎(PBC)和原发性硬化性胆管炎(PSC)是成人中最常见的2种胆汁淤积性肝病,其病因目前尚不明确。虽然熊去氧胆酸(UDCA)可以较好地改善PBC患者的预后,延长患者肝移植的存活率,但存在部分患者对UDCA治疗无应答的现象。此外,目前尚无有效药物治疗PSC。随着近年来胆汁酸调节分子机制的研究进展及免疫途径的理解加深,涌现了越来越多新的药物。介绍了近年来PBC及PSC新兴治疗靶点及相关药物方面的研究进展。     

贝特类药物在原发性胆汁性胆管炎中的应用及作用机制

原发性胆汁性胆管炎(PBC)是一种自身免疫介导的慢性胆汁淤积性肝病。熊去氧胆酸(UDCA)是唯一经美国食品药品监督管理局批准的治疗PBC安全有效的药物。对UDCA应答不佳的患者应如何处理,目前尚无统一的方案。贝特类降脂药是一类人工合成的过氧化物酶体增殖物激活受体的配体,目前研究认为其具有抗胆汁淤积、抗炎及抗纤维化的作用。综述了贝特类药物在PBC治疗中的应用及可能存在的机制。     

间充质干细胞在原发性胆汁性胆管炎中的研究

原发性胆汁性胆管炎是一种慢性自身免疫性胆汁淤积性肝病。近年来研究发现,鉴于间充质干细胞具有免疫调节、抗纤维化和肝细胞分化的特性,正在成为治疗肝脏疾病的新方式,并且越来越多的证据表明间充质干细胞对原发性胆汁性胆管炎的治疗有积极作用。本文从原发性胆汁性胆管炎的发病机制以及间充质干细胞治疗原发性胆汁性胆管炎的作用机制、研究进展等方面展开叙述。间充质干细胞治疗原发性胆汁性胆管炎的前景十分广阔,值得进一步研究。     

法尼醇X受体在原发性胆汁性胆管炎治疗中的作用

原发性胆汁性胆管炎(PBC)是一种常见的胆汁淤积性肝病。熊去氧胆酸(UDCA)是目前惟一被批准并能有效治疗PBC的药物,但高达40%的PBC患者对UDCA应答不佳。法尼醇X受体(FXR)具有抑制胆汁酸合成、调控胆汁酸转运和抗肝纤维化的作用。本文就FXR在PBC治疗中的作用作一综述。     

熊去氧胆酸对肝细胞凋亡作用的分子机制

熊去氧胆酸是人胆汁的生理成分,占正常人总胆汁酸的1％～3％。它是一亲水性强,去垢性差,几乎无毒性的胆汁酸,具有利胆、细胞保护和拮抗疏水性胆汁酸的细胞毒性等作用,已广泛在临床上用于治疗原发性硬化性胆管炎、原发性胆汁性肝硬变和妊娠肝内胆汁淤积症等。近年来发现UDCA具有抗肝细胞凋亡作用,并对其作用机制有了一定了解。     

肝脏碱性磷酸酶:胆汁淤积和胆道损伤的标志物

血清ALP不仅可以作为胆汁淤积症的评判指标,也可以作为评估原发性胆汁性肝硬化(又名原发性胆汁性胆管炎)(PBC)和原发性硬化性胆管炎(PSC)及一些胆汁淤积性肝病病情严重程度的替代指标。介绍了健康人群及胆汁淤积性肝病患者其肝脏ALP的作用机制。在炎症引起的胆汁淤积情况下,酸性环境以及毛细胆管的重定位导致肝脏ALP活性缺失,脂多糖积聚增多,从而引起炎症的恶化及迁延不愈。在PBC和PSC的治疗中,促进肝细胞极性的恢复、促进毛细胆管胆汁酸的排出以及调节胆汁酸碱度的药物均能起到较好的抗炎作用。口服肠道ALP治疗胆汁淤积性疾病值得在实验室和临床中进一步验证。     

原发性胆汁性胆管炎肝移植术后预后研究现状与挑战

原发性胆汁性胆管炎(PBC)是一种病因尚不明确的慢性胆汁淤积性肝病。熊去氧胆酸、奥贝胆酸等药物治疗不佳的患者最终发展为肝硬化,甚至肝衰竭。目前,肝移植是治疗PBC的唯一有效手段。主要阐述了PBC患者进行肝移植的概况、肝移植术后生存期、并发症、PBC复发以及肝移植治疗前景及挑战,为PBC移植术后的临床转归及治疗提供参考。     

利妥昔单抗抑制PBC患者免疫反应,但对改善其乏力无效

原发性胆汁性胆管炎(Primary biliary cholangitis),原名为原发性胆汁性肝硬化,是一种以肝内胆汁淤积为主要特征的自身免疫性肝病,可缓慢进展为肝纤维化、肝硬化甚至肝衰竭。目前PBC的一线治疗药物是熊去氧胆酸(UDCA)[1]。30%~40%对熊去氧胆酸不敏感的患者可选用二线治疗药物奥贝胆酸,一种法尼醇X受体(FXR)激动剂,或非特异性过氧化物酶体增殖相关受体(PPAR)激动剂苯扎贝特。此外,生物制剂如利妥昔单抗也逐渐应用于PBC的治疗[3]。     

Finding the cure for primary biliary cholangitis – Still waiting

The introduction of ursodeoxycholic acid (UDCA)may well have contributed to some of the improvements in morbidity and mortality of primary biliary cholangitis (PBC). Yet nearly 40% of PBC patients are unresponsive to UDCA. Further the data on UDCA is confounded by the changes in the goepidemiology and particularly the earlier diagnosis of PBC. In this regard we welcome the addition of obeticholic acid (OCA) as an alternative therapeutic option forthe treatment of PBC in those patients refractory to UDCA. However, OCA is intellectually disappointing.There is no data on OCA that reflects dynamic and critical endpoints, for example death or liver transplantation; only surrogate endpoints have been used in the clinical trials. A nested study with liver histology wouldbeanideal surrogate marker,including intensive use of immunohistochemistry to define cellular infiltrates and cytokine/chemokine activity. More importantly, the clinical characteristics of PBCmay vary among patients and progression is not always predictable. We need to identify more appropriate and specific biomarkers that predict the clinical course, and we need to know which therapies are applicable at different stages, since treatmentfor PBC should be individualized. We need to know more about the etiology of PBC,and we want a cure for PBC.     

原发性胆汁性胆管炎治疗现状

原发性胆汁性胆管炎(PBC)是一种发生在肝内小胆管的慢性、进行性、非化脓性炎症。熊去氧胆酸是目前唯一的一线治疗药物,对奥贝胆酸、贝特类和免疫抑制剂等二线药物的疗效研究已经取得新进展,而非药物治疗措施的效果和安全性还在进一步探索中。对于PBC患者,不同的肝外表现也有不同的治疗方案。本文就PBC的治疗现状进行了综述,为临床治疗和研究提供思路。     

Emerging novel treatments for autoimmune liver diseases

The etiology of autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), still remains largely unknown and no therapeutic agents that are able to “cure” these diseases have been developed. Although corticosteroids for AIH and ursodeoxycholic acid for PBC have been shown to significantly improve liver transplantation (LT)‐free survival and are recommended as first‐line drugs, treatment strategies for patients who show incomplete response to these drugs have not yet been fully established. No drug is significantly associated with long LT‐free survival in PSC patients. Nevertheless, with progress in genetics, immunology, and cellular biology, several new compounds or antibodies are expected to have an effect on autoimmune liver diseases and several drugs are under consideration for clinical use. Although most clinical trials have been carried out in the USA or Europe, some are, or will be, undertaken in Japan in the future. In this review, the current standard‐of‐care of autoimmune liver diseases will be summarized, together with emerging novel treatments relevant to clinical practice in Japan.     

熊去氧胆酸治疗老年原发性胆汁性肝硬化的临床研究

目的探讨老年原发性胆汁肝硬化（PBC）的临床特征、诊断和治疗效果。方法将66例诊断为PBC的病人分为老年组40例,中年组26例,比较两组的临床表现、生化免疫指标（碱性磷酸酶：ALP、谷氨酰转肽酶：GGT、抗线粒体抗体：AMA）。两组病例均给予口服熊去氧胆酸（UDCA：优思弗）治疗,服药8W后比较疗效。结果90％病人因体检发现ALP、GGT升高就诊,治疗前两组患者的ALP、GGT升高程度差异无统计学意义（P〉0．05）。非特异性皮肤瘙痒是老年PBC患者的主要表现,中年组患者中88．5％无症状,明显高于老年组的37．5％;口服优思弗8W后,两组ALP、GGT均较治疗前明显程度降低（P〈0．05）。老年组中3例肝硬化患者服用优思弗后,其症状、体征及ALP、GGT均无改善,2例死亡。服药后两组患者乏力、皮肤瘙痒症状均无改善,影像学也无变化。结论：（1）PBC早期缺乏特异症状;（2）AMA对PBC诊断有重要意义,ALP、GGT的升高早于黄疸、肝肿大出现。（3）应重视体检中无法解释的ALP、GGT异常升高。（4）UDCA对早期原发性胆汁肝硬化疗效满意。（5）老龄可能是影响PBC患者预后的因素之一。     

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality.     

原发性胆汁性胆管炎的熊去氧胆酸生化应答预测及中西医结合治疗

原发性胆汁性胆管炎(PBC)是免疫介导的慢性进展性的肝内胆汁淤积性疾病,熊去氧胆酸(UDCA)的治疗可明显改善PBC患者的预后,但仍存在一定的UDCA应答不佳的人群,是目前导致疾病进展的主要危险因素。多个基于生化应答的评估模型及评分系统已应用于临床用于筛选应答不佳者。中西医结合治疗PBC在临床上显示了很好的前景,在改善PBC患者症状、肝脏生化及纤维化指标,提高生化应答率等方面有一定优势,但在临床研究设计、疗效判定等方面尚需要进一步完善。     

原发性胆汗性肝硬化的药物治疗研究进展

原发性胆汁性肝硬化（PBC）是一种自身免疫性疾病,熊去氧胆酸（UDCA）是唯一经随机对照临床试验证实治疗PBC安全有效的一线治疗药物,对于UDCA反应不佳者亟需其他有效的药物治疗。回顾了UDCA的疗效,重点叙述了对UDCA反应不佳者的备选治疗和辅助治疗的分类和最新研究进展,评估了药物的疗效和治疗前景,但布地奈德、依那西普等免疫抑制剂和其他类药物的疗效有待更多长期临床试验来验证。一些新兴的PBC分子疗法正处于积极的临床研究中。目前,对UDCA反应欠佳者的药物治疗方法尚不确定,尽管研究表明部分药物可以改善肝功能和肝脏生化指标,尚无确切的证据证明可改善长期预后。     

Geoepidemiology and changing mortality in primary biliary cholangitis

Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.     

Pharmacotherapy of cholestatic liver diseases

New insights into the molecular mechanisms of bile formation and cholestasis have provided new concepts for pharmacotherapy of cholestatic liver diseases. The major aim in all forms of cholestasis is the reduction of hepatocellular retention of bile acids and other potentially toxic constituents of bile. Reduction of hepatocellular retention may be achieved by drugs that stimulate hepatocellular secretion via the canalicular route into the bile or via the alternative route across the basolateral membrane into the blood, and by drugs that stimulate the hepatocellular metabolism of hydrophobic bile acids to hydrophilic, less toxic metabolites. In cholestatic liver diseases that start with an injury of the biliary epithelium (e.g., primary biliary cirrhosis; PBC), protection of the cholangiocytes against the toxic effects of hydrophobic bile acids is most important. When hepatocellular retention of bile acids has occurred, the inhibition of bile acid-induced apoptosis becomes another target of therapy. Ursodeoxycholic acid protects the biliary epithelium by reducing the toxicity of bile, stimulates hepatobiliary secretion by upregulating transporters and inhibits apoptosis. It is the mainstay of therapy in PBC but of benefit also in a number of other cholestatic liver diseases. New drugs such as 6-ethyl-chenodeoxycholic acid and 24-nor-ursodeoxycholic acid are being evaluated for the treatment of cholestatic liver diseases.