第24届亚太地区肝脏研究协会年会（APASL 2014）于2014年3月12～15日在澳大利亚布里斯班召开。3月14日，澳大利亚国立大学医学院Geoff Farrell教授介绍了有关非酒精性脂肪性肝炎（NASH）治疗的最新进展。
Geoff Farrell教授
当APASL日报记者问道，NASH患者应该接受降脂治疗吗？他的回答是肯定的。首先，非酒精性脂肪性肝病患者的首要死亡原因是心血管疾病，其次是癌症。大量资料显示，降血脂治疗可降低不良心血管事件的风险。尽管这可能并不会改善肝脏疾病，但是也有很强的证据显示这并不会加重肝脏疾病。因此，Farrell教授鼓励医生为患者处方他汀类药物，而不要顾及损害肝脏。
其次，是脂毒性问题。一些脂类，特别是胆固醇，可进入活化JNK激酶的途径。研究显示，JNK抑制剂能刺激HMGB1释放，后者通过与TLR-4的相互作用，发挥促炎活性。
此外，在临床上，减少胆固醇非常重要，通过降脂治疗，例如依折麦布和阿托伐他汀可预防NAFLD患者发生肝纤维化。另外一种靶向治疗为法尼酯X受体（FXR）激动剂，如obeticholic acid（一种鹅脱氧胆酸衍生物）。FXR参与了NASH时的胆固醇稳态调节障碍，尽管机制不明，但研究显示，这些激动剂具有抗炎活性并刺激胆汁流出。
为什么降脂与肝损伤减轻没有明显的联系？Farrell教授认为是胰岛素的作用。我们的患者都存在营养过剩和超重，他们一般为糖尿病前期、有糖尿病或有糖尿病家族史。血脂异常时常存在高胰岛素血症和胰岛素抵抗，驱动了心血管疾病的发生。在肝内，同样会发生胆固醇累积，只不过速度很慢。当加强运动的方式失败后，靶向胆固醇的方法可使很多患者受益。
然而，Farrell教授也说，针对胆固醇的治疗最好还是放在第二选择。体育锻炼能增加肌肉细胞对胰岛素的敏感性，能阻止胆固醇进入肝脏，促进脂肪组织内的脂肪分解。即使体重轻微超标的人群，规律的体育活动也能减少大部分非酒精性脂肪性肝病和心血管疾病风险。要达到减肥的目的，医患双方都要付出很大努力，而且还有很多外在因素发挥作用。
原文阅读》》》Lipid-Lowering in NASH
Dr. Geoff Farrell, Professor of Hepatic Medicine, Australian National University Medical School, Canberra. His clinical interests are in NASH, the natural history and management of chronic hepatitis B and C, and drug-induced liver disease. On Friday, March 14, he will give a JGHF Distinguished Lecture about NASH treatment. He shared some highlights of his lecture topic with our APASL Daily reporter.
When asked the question that is the basis of his talk, “Should We Lower Lipids in NASH?”, Dr. Geoff Farrell left nothing to ambiguity: “the simple answer is a resounding, unequivocal yes.”
There are several reasons for this statement. First, the leading cause of death for those with NAFLD is cardiovascular disease, the next is cancer. Much data already exists that validates the use of lipid-lowering therapy to reduce the risk of poor cardiovascular outcomes. While this does not imply an improvement in the liver disease, Dr. Farrell makes it clear that “there is certainly strong evidence that it does not worsen the liver disease.” He encourages doctors to prescribe statins without fear of harming the liver.
The second issue is that of lipotoxicity. Some lipids, cholesterol in particular, will enter a pathway that activates c-Jun N-terminal kinase (JNK). JNK inhibitors have been found to stimulate the release of HMGB1, which, in turn promotes a pro-inflammatory pathway through interactions with Toll-like receptor 4.
Clinically, lowering cholesterol may be critical. “Using lipid-lowering therapy,” states Dr. Farrell “such as ezetimibe and atorvastatin (i.e. a statin plus ezetimibe) will certainly prevent fibrosis in NAFLD in experimental models.” Another targeted therapy may be a farnesoid X receptor (FXR) agonist in a drug called obeticholic acid. FXR can contribute to the dysregulation of cholesterol homeostasis in NASH. While the exact mechanism is unknown, these agonists have been observed to be anti-inflammatory and stimulate bile flow.
Another interesting aspect to the story is why there is not an obvious correlation between lower-lipids and reducing liver injury. Dr. Farrell explains that it all comes down to insulin. “We start off with patients who are over nourished and overweight,” says Dr. Farrell, “who typically have pre-diabetes, diabetes, or a family history of diabetes.”
It is hyperinsulinaemia and insulin esistance in blood lipid abnormalities that in turn drive cardiovascular disease. The same build-up of cholesterol can occur in the liver, but is much slower. Targeting cholesterol when exercise fails may be beneficial in many patients.
However, cholesterol is, at best, a secondary option. Exercise increases insulin sensitivity in the muscle cells through an insulin-dependent GLUT4 pathway. It will also prevent cholesterol from being driven into the liver and continued lipolysis in adipose tissue. Even in those who are slightly overweight, regular physical activity will alleviate most risks of NAFLD and cardiovascular disease. However, it takes strong dedication on the part of the both the doctor, the patient, and many other outside factors to attain weight-loss goals.
