编者按：第68届美国肝病研究学会年会期间，美国加利福利亚大学Davis医学中心Christopher L. Bowlus教授在“胆汁淤积性肝病和自身免疫性肝病”专题中介绍了原发性胆汁性胆管炎（PBC）的最新管理进展。

 

《国际肝病》前方记者在会上采访了Bowlus教授，请他介绍自身免疫性肝病的国际进展，包括原发性胆汁性胆管炎、原发性硬化性胆管炎和自身免疫性肝炎。

 

一、原发性胆汁性胆管炎的治疗进展

 

原发性胆汁性胆管炎（PBC）的治疗药物为熊去氧胆酸（UDCA），美国和欧洲最近批准了奥贝胆酸。当PBC患者对UDCA应答不完全或者不能耐受UDCA时，为应用奥贝胆酸治疗的指征。已经表明，应用奥贝胆酸的主要益处包括肝脏生化改善，表明患者在临床转归方面，可以获得长期益处，但是，临床转归的获益有待临床试验证实。

 

应用奥贝胆酸治疗时，最常见的不良事件为瘙痒，在之前存在瘙痒基础的患者中，瘙痒可能相当常见。然而，在应用目前推荐的剂量（5 mg/d，滴定至10 mg/d）时，瘙痒比较轻微，患者的耐受性相对良好。最近，在PBC患者应用奥贝胆酸方面，FDA发布警告，主要是关注失代偿期肝病（Child B级或C级肝硬化）患者在应用奥贝胆酸时，可能导致严重肝损伤或死亡风险，对这些患者的推荐剂量为每周5mg，如果能够耐受，缓慢增加剂量。失代偿期肝病患者应用奥贝胆酸时，必须给予谨慎考虑。

 

目前，正在对其他几种药物进行临床试验，包括其他法尼酯X受体（FR）激动剂。在最近的国际肝病会议上，已经发布一些研究，PBC患者应用苯扎贝特很有前景，正在对其他过氧化物酶体增殖物激活受体（PPAR）激动剂进行研究。

 

二、原发性硬化性胆管炎（PSC）的治疗进展

 

对原发性硬化性胆管炎（PSC）尚无确认的有效治疗。在新的治疗研发方面存在难题，一部分是由于在临床试验中，尚无确认的生物标志物用于反映PSC的疾病进展。当然，在临床实践中，我们监测肝脏生化和门脉高压的指标，并且对相对常于PSC患者的胆管癌进行监测。

 

在新的生物标志物用于临床试验方面，已经做了一些研究工作，其中，血清标志物最有前景，包括增强肝纤维化（ELF）检测。检测肝脏硬度值的影像学方法包括振动控制瞬时弹性成像（FibroScan）和MR弹性成像，也表明与患者的转归有关。通过肝活检的肝脏组织学是反映患者转归的另一良好指标。将来，需要进一步研究，对上述标志物用于反映PSC转归的性能进行验证。

 

最近，有一些研究应用去甲熊脱氧胆酸（norUDCA）以及奥贝胆酸治疗PSC，可以使患者的生化得到改善，还有其他一些治疗处于临床试验，我们期待这些试验的研究结果。

 

三、自身免疫性肝炎的治疗进展

 

在自身免疫性肝炎（AIH）治疗方面，应用目前的强的松和硫唑嘌呤方案，可以取得满意的疗效，但是，仍然需要研究新的治疗，用于对上述药物应答不佳的患者。目前，正在进行几项研究，但是，近年来，该病治疗领域的研究进展很少。

 

Dr Bowlus: Treatments for primary biliary cholangitis (PBC) are currently ursodeoxycholic acid, and recently approved in the United States and Europe, obeticholic acid. Obeticholic acid is indicated in PBC when there is an incomplete response to urso, or in patients who are unable to tolerate urso. The main benefit of obeticholic acid that has been demonstrated has been the improvement in liver biochemistry with treatment. These improvements suggest that there are long-term benefits in terms of clinical outcomes, but that remains to be demonstrated in a clinical trial. In terms of the consideration for use of obeticholic acid, the most common adverse event associated with it has been itching or pruritis. That can be relatively common in patients who have pre-existing underlying pruritis. However, at the dose that is currently recommended (5mg daily with titration to 10mg), pruritis or itching tends to be relatively well tolerated and minimal. There was a recent warning issued by the FDA in terms of use of obeticholic acid in patients with PBC where most of the concerns were associated with patients with decompensated liver disease (Child's B or C cirrhosis). For those patients, the recommended dose is 5mg weekly, then to increase slowly if tolerated. The problems have been in patients who were dosed at 5mg daily. I think strong consideration should be given to any use of obeticholic acid in those patients who have decompensated cirrhosis.

 

Dr Bowlus: Primary sclerosing cholangitis (PSC) remains a disease without any proven therapies. Part of the problem in developing new treatments for PSC has to do with the lack of validated biomarkers for disease progression that could be used in clinical trial development. In clinical practice, of course, we monitor liver tests and markers of portal hypertension, liver biochemistries, as well as surveillance for cholangiosarcoma, which is relatively common in these patients. There has been some work developing new biomarkers for this condition to be used in clinical trials. Some of the most promising ones involve serum markers, including the enhanced liver fibrosis (ELF) test. Imaging modalities to measure liver stiffness including vibration controlled transient elastography (FibroScan) and MR elastography have also been shown to be associated with outcomes. Then liver histology via biopsy is another good indicator of outcomes. Any number of these need to be validated further and likely will be in the future.

 

Dr Bowlus: For new therapies for the autoimmune diseases (typically considered to be PBC, PSC, autoimmune hepatitis and rarely IgG4-related sclerosing cholangitis), the biggest advances have obviously been made with PBC where we have obeticholic acid. There are several other drugs in clinical trials right now, including other farnesoid X receptor (FR) agonists. There have also been some recently published studies at the International Liver Congress on the use of bezafibrate in PBC, which is very promising. Other PPAR agonists are being studied as well. In PSC, there have been some recent studies with norursodeoxycholic acid, as well as obeticholic acid showing biochemical improvements. Those are promising as well. There are other therapies in clinical trials for that disease, and we look forward to some results from those studies. In terms of autoimmune hepatitis, we are doing well with our current regimen of prednisone and azathioprine, but there is still a need for new therapies in that group of patients who don’t have a good response to those drugs. There are a couple of studies in development right now, but much less has been done in that disease area.