Chazouillères Olivier
AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, Paris, France.
Dig Dis. 2016;34(4):340-6. doi: 10.1159/000444544. Epub 2016 May 11.
There is a great need for risk stratification in patients with chronic cholestatic diseases in order to allow for more personalized care and adapted management as well as for well-designed therapeutic trials. Novel tools for monitoring primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patients have been recently proposed. In addition, major insight has been gained into bile acid (BA) physiology during the last decade including the role of BAs as metabolic modulators and the gut-liver axis. As a consequence, alongside drugs targeting immune response or fibrotic processes, a number of novel anti-cholestatic agents have undergone pre-clinical and clinical evaluation and have shown promising results although none has been approved yet.
Biochemical non-response to ursodeoxycholic acid (UDCA) (mainly defined by bilirubin and alkaline phosphatase levels at 1 year) is a strong prognostic factor in PBC whereas present biochemical surrogates are far from robust in PSC. By contrast, liver stiffness measurement by vibration-controlled transient elastography (VCTE) is a very promising tool in both PBC and PSC. Novel therapeutic approaches include (i) agonists of nuclear receptors, especially farnesoid X receptor (FXR), pregnane X receptor (PXR), glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor α (PPARα) that are transcriptional modifiers of bile formation; (ii) agonists of TGR5, a BA membrane receptor expressed in various tissues; (iii) inhibitors of the ileal apical sodium BA transporter; (iv) derivatives of the FXR-induced fibroblast growth factor 19 from the ileum that suppresses hepatic BA synthesis and (v) norUDCA, a side chain shortened UDCA derivative with specific physicochemical and therapeutic properties. The most advanced clinical evaluation (PBC patients) relates to agonists for PPARα, FXR and GR/PXR most often in combination with UDCA, namely fibrates, obeticholic acid (OCA) and budesonide, respectively. Existing results look promising even though some side effects are worrisome such as pruritus in OCA-treated patients. Results of large well-designed studies are eagerly awaited.
Major advances in the management of cholestatic liver diseases are in progress and promising times for these patients seem likely in the near future.
慢性胆汁淤积性疾病患者非常需要进行风险分层，以便实现更个性化的护理和适应性管理，并开展精心设计的治疗试验。最近已提出用于监测原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）患者的新工具。此外，在过去十年中，人们对胆汁酸（BA）生理学有了重大认识，包括胆汁酸作为代谢调节剂和肠-肝轴的作用。因此，除了针对免疫反应或纤维化过程的药物外，一些新型抗胆汁淤积药物已进行临床前和临床评估，并显示出有前景的结果，尽管尚未有药物获批。
对熊去氧胆酸（UDCA）生化无反应（主要由1年时的胆红素和碱性磷酸酶水平定义）是PBC的一个强有力的预后因素，而目前的生化替代指标在PSC中远不够可靠。相比之下，通过振动控制瞬时弹性成像（VCTE）测量肝脏硬度在PBC和PSC中都是非常有前景的工具。新型治疗方法包括：（i）核受体激动剂，特别是法尼醇X受体（FXR）、孕烷X受体（PXR）、糖皮质激素受体（GR）和过氧化物酶体增殖物激活受体α（PPARα），它们是胆汁形成的转录调节因子；（ii）TGR5激动剂，TGR5是一种在各种组织中表达的BA膜受体；（iii）回肠顶端钠胆汁酸转运体抑制剂；（iv）来自回肠的FXR诱导的成纤维细胞生长因子19的衍生物，其可抑制肝脏BA合成；以及（v）norUDCA，一种具有特定物理化学和治疗特性的侧链缩短的UDCA衍生物。最先进的临床评估（针对PBC患者）涉及PPARα、FXR和GR/PXR激动剂，最常与UDCA联合使用，分别为贝特类药物、奥贝胆酸（OCA）和布地奈德。现有结果看起来很有前景，尽管一些副作用令人担忧，如OCA治疗患者出现瘙痒。人们急切期待大型精心设计研究的结果。
胆汁淤积性肝病的管理正在取得重大进展，这些患者在不久的将来似乎有望迎来充满希望的时期。
