Ali Ahmad H, Lindor Keith D
a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.
b College of Health Solutions , Arizona State University , Phoenix , AZ , USA.
Expert Opin Pharmacother. 2016 Sep;17(13):1809-15. doi: 10.1080/14656566.2016.1218471. Epub 2016 Aug 9.
Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.
This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.
If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.
原发性胆汁性胆管炎（PBC）是一种肝脏自身免疫性疾病，其特征为肝内胆管的破坏和炎症。该疾病主要影响女性。通常通过碱性磷酸酶（ALP）活性异常发现此病，若存在抗线粒体抗体（AMA）则可确诊。PBC的病因尚不清楚。吸烟、免疫失调、指甲油、尿路感染和社会经济地位低下都曾被认为与之有关，但均未得到证实。全基因组关联研究（GWAS）已揭示某些人类白细胞抗原（HLA）等位基因与PBC之间存在强关联。PBC可进展为肝硬化和终末期肝病。高达3.5%的PBC患者会发展为肝细胞癌（HCC）。熊去氧胆酸（UDCA）是唯一被批准用于治疗PBC的药物。在PBC中使用UDCA可延缓组织学进展并延长无移植生存期。40%的PBC患者对UDCA反应不佳，这些患者发生严重并发症的风险很高。因此，迫切需要针对这种疑难疾病的更有效疗法。多种其他药物已被或正在作为UDCA无反应的PBC患者的治疗选择进行研究。六乙基鹅去氧胆酸（6-ECDCA）是一种强效法尼醇X受体（FXR）激动剂，在胆汁淤积的啮齿动物模型中显示出抗胆汁淤积活性。奥贝胆酸（OCA，6-ECDCA或INT-747）是首个FXR激动剂，已在对UDCA反应不佳的PBC患者中进行了研究，并显示出有前景的结果。特别是，初步临床试验表明，在对UDCA反应不佳的PBC患者中使用OCA（联合UDCA）可显著降低血清碱性磷酸酶（ALP，PBC中的一个重要预后标志物）。最近，一项OCA单药治疗PBC的随机临床试验结果报告，与安慰剂相比，治疗组的ALP显著降低。
本综述涵盖了OCA在PBC中的临床前和临床研究。此外，本综述还将讨论目前正在PBC患者中研究的其他替代疗法。使用PubMed数据库进行了文献检索。
如果获得美国食品药品监督管理局（FDA）批准，OCA可能会成为对UDCA反应不佳的PBC患者的一种重要的替代附加疗法。
