对熊去氧胆酸应答不佳或不耐受的原发性胆汁性胆管炎患者应用奥贝胆酸和贝特类药物治疗的研究进展

熊去氧胆酸治疗原发性胆汁性胆管炎会发生应答不佳或不耐受,更换为奥贝胆酸或贝特类单药或联合治疗后,部分治疗方案也会出现应答不佳或不耐受。近年奥贝胆酸和贝特类药物临床研究逐步解决这些问题,奥贝胆酸/贝特类药物与熊去氧胆酸的联合治疗对非晚期肝硬化原发性胆汁性胆管炎患者是有效和安全的。     

原发性胆汁性胆管炎的治疗进展

原发性胆汁性胆管炎(PBC)是一种自身免疫性疾病,常见于中年女性。疾病进展可导致肝硬化、肝衰竭。熊去氧胆酸和奥贝胆酸为美国食品药品管理局唯一批准的一、二线用药,但是约有40%的患者对熊去氧胆酸应答不敏感,多种二线用药如贝特类药物、免疫抑制剂的研究正在开展,而肝移植是终末期PBC治疗的唯一手段。本文就PBC近年来的治疗研究进展及相关机制进行综述,旨在为临床实践提供参考。     

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]。     

原发性胆汁性胆管炎的药物治疗进展

原发性胆汁性胆管炎是一种病因及发病机制尚不明确的胆汁淤积性肝病。熊去氧胆酸和奥贝胆酸是美国食品药品监督管理局批准使用的治疗药物,两者均有减轻肝内胆汁淤积的作用,但仍有部分患者对其治疗无生化应答,亟需探索新的治疗药物或方法。贝特类药物、免疫抑制剂及中医药对原发性胆汁性胆管炎患者有一定疗效,但临床安全性及作用机制尚需进一步研究。     

IgM反应是熊去氧胆酸和苯扎贝特治疗原发性胆汁性胆管炎的预后生物标志物

【据《J Gastroenterol Hepatol》2019年11月报道】题:IgM反应是熊去氧胆酸和苯扎贝特治疗原发性胆汁性胆管炎的预后生物标志物(作者Takano K等)原发性胆汁性胆管炎(PBC)患者对熊去氧胆酸(UDCA)不敏感,有可能发展为肝硬化和肝衰竭。苯扎贝特可作为这些患者的二线药物选择。该研究旨在评价UDCA联合苯扎贝特治疗UDCA难治性PBC的远期疗效,并探讨影响预后的因素。     

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。     

对熊去氧胆酸应答不佳的原发性胆汁性胆管炎治疗策略

原发性胆汁性胆管炎(PBC)的治疗近年来主要应用熊去氧胆酸,而增长的患者人数、应答不佳和治疗不耐受的出现对治疗方案提出了挑战,新药奥贝胆酸的获批为PBC患者带来了希望,联合使用贝特类药物也具有前景,更多的试验正在进行之中。新型药物如单克隆抗体、成纤维细胞生长因子19、钠依赖性胆汁酸转运蛋白抑制剂等虽然疗效数据有限,但为PBC治疗提供了新的方向。通过个性化随访以及分层治疗,PBC患者的管理将进入新的阶段。     

难治性原发性胆汁性胆管炎的治疗新进展

原发性胆汁性胆管炎(PBC)是一种以小胆管损伤为特点的自身免疫性肝病。熊去氧胆酸(UDCA)是治疗本病的主要药物,但约40%的PBC患者对UDCA生化应答欠佳,预后较差。总结了难治性PBC患者的治疗新选择。2017年,奥贝胆酸已被欧洲肝病学会推荐作为UDCA应答不佳PBC的二线治疗药物。贝特类药物或布地奈德联合UDCA治疗难治性PBC的相关研究也取得了一定进展,但其疗效与安全性仍需大样本随机双盲对照试验进一步验证。单克隆抗体、改变胆汁酸生成或重吸收药物等尚处于实验阶段。目前,肝移植仍然是延长终末期PBC患者生存期的唯一治疗方法。     

原发性胆汁性胆管炎的研究进展

原发性胆汁性胆管炎是一种慢性肝内胆汁淤积性疾病,文献报道其发病率和患病率不断提高。通过检查血清抗线粒体抗体M2亚型等特异性抗体或肝组织病理学检查可确定诊断。熊去氧胆酸是治疗本病的主要药物,但对熊去氧胆酸生化学应答欠佳者疾病进展快,目前尚无统一有效的治疗手段。加用布地奈德、非诺贝特、苯扎贝特或奥贝胆酸可能对部分患者有效,但仍需进一步临床研究验证。     

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。     

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.     

Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population

Introduction and objectivesLittle is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population.Material and methodsThe Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC.Results562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates.Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.     

Pentoxifylline,but not ursodeoxycholic acid or tauroursodeoxycholic acid inhibits the proliferative effect of sera samples from primary biliary cirrhosis patients

Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by progressive hepatic fibrosis. Fibroproliferation is one of two major events occurring in hepatic fibrosis. In this study we evaluated PBC patients sera samples (n = 27) and our results demonstrate that the sera of PBC patients has fibroproliferative activity. Our results further demonstrate that this effect is partially mediated by platelet derived growth factor (PDGF). We then tested the effect of potential antifibrotic drugs in vitro for their ability to inhibit patient sera-stimulated proliferation. The two drugs tested were pentoxifylline and ursodeoxycholic acid (UDCA). Both pentoxifylline and UDCA have been reported to inhibit PDGF stimulated proliferation of fibroblasts. Pentoxifylline has been reported to block experimental liver fibrosis and inhibit fibroproliferation in this experimental model. UDCA has been used in clinical trials in patients with PBC. Our results indicate that pentoxifylline when added in vitro, reduced the fibroproliferative activity of PBC patient sera. UDCA and taurour-sodeoxycholic acid (TUDCA) did not reduce fibroproliferative activity of PBC patient sera. This group of PBC patients were then started on UDCA and preliminary results following 1 year of UDCA treatment indicate that there is no decrease but rather an increase in the fibroproliferative activity of PBC patient sera. These results suggest that PBC patient sera samples stimulate proliferation of fibroblasts and that this effect is due at least in part to PDGF. The results also indicate that pentoxifylline reduces the fibroproliferative activity of PBC patient sera while UDCA and TUDCA did not reduce fibroproliferation. Results obtained from PBC patients following 1 year of UDCA treatment together with results obtained from an experimental model of hepatic fibrosis following successful treatment with pentoxifylline suggest that this test may prove to be predictive of a beneficial response to potential antifibrotic drugs.     

The UDCA dosage deficit: a fate shared with CDCA

Ursodeoxycholic acid (UDCA) is used both as the treatment of choice in many cholestatic syndromes and as complementary therapy in many liver diseases. However, few dose-finding studies exist, and none has evaluated the efficacy and long-term safety of UDCA therapy in primary biliary cirrhosis (PBC). There is an open debate about UDCA's impact on the natural history of PBC, and no universal evidence of benefits on the major endpoint exists. This is perhaps due to a UDCA dosage deficit. Most clinical trials on PBC therapy have used conservative dosages of UDCA similar to those of chenodeoxycholic acid (CDCA) used for dissolution of gallstones. It may be necessary to re-evaluate the dosage of UDCA that provides the most effective treatment.     

The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis

Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.     

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。     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化（PBC）是一种慢性肝内胆汁淤积性疾病。熊去氧胆酸（UDCA）是惟一经随机对照临床试验证实的治疗PBC安全有效的药物。经UDCA治疗1年后有较好生化应答的患者,其长期预后较好。目前,对UDCA应答欠佳患者的治疗方法尚不确定。肝移植是治疗终末期PBC患者惟一有效的方法     

Obeticholic acid for the treatment of primary biliary cirrhosis

Introduction: There is significant unmet need in Primary Biliary Cholangitis (PBC) in patients under-responsive to the only approved therapy Ursodeoxycholic Acid (UDCA) who are at increased risk of progressing to end-stage liver disease. Obeticholic Acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second line therapy in PBC and has recently been licenced by the FDA.

Areas covered: The pharmacology and biology of OCA as an FXR agonist and its clinical benefits. A systematic review was undertaken of published literature, meeting abstracts and trial registries using the search terms FXR, FGF-19 (& FGF-15), Obeticholic Acid and INT-747.

Expert commentary: OCA reduces exposure to toxic hydrophobic bile acids through reduction in bile acid synthesis (by direct and indirect (via enterocyte-released FGF19) actions on Cyp7A1-mediated bile acid synthesis) and bile acid excretion by hepatocytes. It significantly improves liver biochemical parameters strongly associated with risk of disease progression in UDCA under-responsive patients and the key side-effect of pruritus can be reduced by optimised dosing. OCA will be the first stratified therapy introduced in PBC, however confirmatory trial and real life data are needed to confirm that suggestive biochemical improvements are matched by improvement in key clinical outcomes.     

Hepatoprotective bile acid 'ursodeoxycholic acid (UDCA)' Property and difference as bile acids.

Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is a 7beta-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug 'Yutan' a powder preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation, crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only drug approved by the U.S. Food and Drug Administration (FDA). In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of UDCA is evidently involved. We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in liver disease.     

Effects of chenodeoxycholic and ursodeoxycholic acids on interferon-γ production by peripheral blood mononuclear cells from patients with primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) administration can obtain marked improvement of primary biliary cirrhosis (PBC). Recently, UDCA has been demonstrated to have a direct effect on immunological reactions in patients with PBC in that the aberrant expression of major histocompatibility complex (MHC) class I molecules was markedly reduced after UDCA treatment. To understand the immunological effect of UDCA, we analyzed interferon (IFN)-γ production in peripheral blood mononuclear cells (PBMCs) from 29 patients with PBC treated with UDCA (group 1), 19 patients with PBC who were not treated with UDCA (group 2), 11 healthy subjects (group 3), and 12 patients with chronic viral hepatitis (group 4). IFN-γ production was investigated because the excess production of this cytokine is associated with the aberrant expression of MHC molecules. Whereas IFN-γ production in the patients in group 2 was significantly increased, the level of production in group 1 was similar to that in the control groups (groups 3 and 4). There was significant improvement in IFN-γ production in 6 patients with PBC after UDCA treatment. The effect of UDCA and chenodeoxycholic acid (CDCA) on IFN-γ production in PBMCs from 12 normal subjects was also analyzed. IFN-γ was produced dose-dependently according to concentrations of CDCA ranging from 0.1 to 10 μM, but the increase in production was markedly suppressed by the addition of UDCA. We conclude that low doses of CDCA enhance IFN-γ production and may therefore lead to the aberrant hepatic expression of MHC molecules, and that the increase in IFN-γ production is suppressed by UDCA.