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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
世界华人消化杂志. 2016-09-28; 24(27): 3860-3869
在线出版日期: 2016-09-28. doi: 10.11569/wcjd.v24.i27.3860
非酒精性脂肪性肝病研究进展
张莉, 张福奎
张莉, 张福奎, 首都医科大学石景山教学医院 北京市石景山医院消化内科 北京市 100043
张莉, 副主任医师, 主要从事肝脏疾病的诊治与消化内镜下治疗方向的研究.
作者贡献分布: 本文由张莉与张福奎共同完成.
通讯作者: 张莉, 副主任医师, 100043, 北京市石景山区石景山路24号, 首都医科大学石景山教学医院; 北京市石景山医院消化内科. wwwhhh9688@163.com
电话: 010-88429999
收稿日期: 2016-04-29
修回日期: 2016-05-21
接受日期: 2016-05-31
在线出版日期: 2016-09-28

非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)已经成为全世界最常见的肝脏疾病, 与肝硬化和肝细胞肝癌的发病率及死亡率增加有关, 然而, 其对健康的主要影响为导致2型糖尿病(type 2 diabetes, T2D)、心血管疾病和恶性肿瘤的发病率及死亡率增加. 本文对NAFLD的流行病学、风险因素、疾病进展及合并心血管疾病和/或T2D的风险评估以及治疗的最新研究进展进行综述.

关键词: 非酒精性脂肪性肝病; 风险因素; 流行病学; 评估; 管理

核心提要: 非酒精性脂肪性肝病的风险因素为代谢综合征及其组分, 对疾病进展进行准确评估以及对心血管疾病和2型糖尿病风险进行分层管理非常重要, 治疗措施主要包括生活方式干预、药物治疗和减肥手术.


引文著录: 张莉, 张福奎. 非酒精性脂肪性肝病研究进展. 世界华人消化杂志 2016; 24(27): 3860-3869
Advances in research of nonalcoholic fatty liver disease
Li Zhang, Fu-Kui Zhang
Li Zhang, Fu-Kui Zhang, Shijingshan Teaching Hospital of Capital Medical University; Department of Gastroenterology, Beijing Shijingshan Hospital, Beijing 100043, China
Correspondence to: Li Zhang, Associate Chief Physician, Shijingshan Teaching Hospital of Capital Medical University; Department of Gastroenterology, Beijing Shijingshan Hospital Affiliated to Capital Medical University, 24 Shijingshan Road, Shijiingshan District, Beijing 100043, China. wwwhhh9688@163.com
Received: April 29, 2016
Revised: May 21, 2016
Accepted: May 31, 2016
Published online: September 28, 2016

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide. It is related with increased morbidity and mortality of cirrhosis and hepatocellular carcinoma (HCC); however, its main health implications are increased risks of developing type 2 diabetes (T2D), cardiovascular diseases and malignancies. This paper reviews the advances in research of NAFLD in terms of epidemiology, risk factors, assessment of disease progression and risks for combined cardiovascular diseases and/or T2D as well as management.

Key Words: Nonalcoholic fatty liver disease; Risk factor; Epidemiology; Assessment; Management

Citation: Zhang L, Zhang FK. Advances in research of nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2016; 24(27): 3860-3869
0 引言

随着肥胖和代谢综合征(metabolic syndrome, MS)的流行, 非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)已成为发达国家和地区最常见的慢性肝病, 全球和我国大陆的NAFLD患病率分别约为25%和20%[1,2]. 根据临床和组织学表现, NAFLD可分为非酒精性单纯性脂肪肝和非酒精性脂肪性肝炎, 后者可进展为肝硬化甚至肝细胞肝癌(hepatocellular carcinoma, HCC), 然而, NAFLD对健康的主要影响为导致2型糖尿病(type 2 diabetes, T2D)、心血管疾病和恶性肿瘤的发病率及死亡率增加. 本文对NAFLD的流行病学、风险因素、疾病进展及合并心血管疾病和/或T2D的风险评估以及治疗的最新研究进展进行综述.

1 流行病学

世界范围内, NAFLD已经成为最常见的慢性肝病, 多数患者存在肥胖(特别是中心性肥胖)以及与肥胖相关的T2D、动脉粥样硬化、高血压、高脂血症等疾病, 即存在MS及其组分.

总共纳入86项研究, 包括22个国家8515431例患者的一项荟萃分析结果表明, NAFLD的总体患病率为25.24%, 与NAFLD有关的代谢合并征包括肥胖、T2D、高脂血症、高血压和MS. NASH患者中, 肝纤维化进展比例为40.76%, HCC发生率为0.44/(1000人•年), 肝脏特异性死亡率和总死亡率分别为15.44/(1000人•年)和25.56/(1000人•年)[1].

我国大陆人群的NAFLD患病率约为20%[2]. 香港两项研究[3,4]也表明NAFLD呈高度流行, 其中一项研究[3]对2493例志愿者进行综合问卷调查、血液化验、腹部超声和瞬时弹性成像检查, NAFLD的患病率高达42%. 另外一项研究[4]应用质子-磁共振波谱分析, 对来自社区的565例参与者进行肝内甘油三酯含量的检测, 随访中位数时间47 mo后, 有78例参与者(13.8%)新发脂肪肝, 其中16例为中到重度脂肪变. 该组人群在3-5年的NAFLD发生率为13.5%, 每年的NAFLD发生率为3.4%, 基线时患有MS是罹患脂肪肝的最强预测因素.

2 风险因素

目前常用的体质量指数(body mass index, BMI)并不能对身体脂肪和肌肉以及内脏和皮下脂肪进行区别, 肌肉质量较低但身体脂肪较高者仍有可能为BMI正常. 这些正常体质量的肥胖患者具有下列特征: 身体脂肪含量较高, 肌肉质量较低, 存在内脏肥胖, 甘油三酯水平升高, 高密度脂蛋白胆固醇(high-density lipoprotein-C, HDL-C)水平降低, 对胰岛素的敏感性降低, 同样具有发生T2D、高血压和心血管疾病的高风险. 研究[5,6]表明, 非肥胖人群中的NAFLD患病率为20%左右, BMI较高、糖化血红蛋白(glycosylated hemoglobin, HbA1c)水平较高、胰岛素抵抗(insulin resistance, IR)、高铁蛋白血症以及PNPLA3 G等位基因为非肥胖个体患有NAFLD的独立风险因素.

与外周肥胖者相比, 内脏肥胖个体更易罹患NAFLD, 内脏脂肪量与NAFLD呈显著相关性[7]. 韩国一项横断面研究[8]表明, 肌肉减少症可独立于肥胖和MS, 显著增加NAFLD和进展期纤维化的发生风险.

高脂肪高热量膳食结构是NAFLD的风险因素, 然而, 一项研究[9]对接受常规健康检查的615例僧人进行回顾性分析表明, 这一长期素食人群与匹配对照人群的NAFLD患病率差异并无显著性(29.90% vs 25.05%, P = 0.055), 因此, 长期素食对脂肪肝可能并无保护作用.

经常饮用含糖饮料是NAFLD的显著风险因素. 一项研究[10]对2634例参与者进行分析表明, 经常饮用含糖饮料与通过计算机断层扫描(computed tomography, CT)测量肝脏衰减诊断脂肪性肝病的风险增加有关. 不饮用含糖饮料、饮用1份/mo-<1份/wk、1份/wk-<1份/d和≥1份/d的参与者患有脂肪性肝病的比值比(odds ratio, OR)分别为1、1.16, 95%可信区间(confidence interval, CI): 0.88-1.54、1.32(95%CI: 0.93-1.86)和1.61(95%CI: 1.04-2.49)(趋势检验, P = 0.04), 饮用含糖饮料与丙氨酸氨基转移酶(alanine transaminase, ALT)水平也呈正相关(趋势检验, P = 0.007). 一项系统评价和荟萃分析[11]也证实, 饮用含糖汽水与NAFLD存在显著相关性: 饮用含糖汽水者患有NAFLD的合并相对危险度(relative risk, RR)为1.53(95%CI: 1.34-1.75, I2 = 0), 限于具有校正分析的研究时, 饮用含糖汽水者患有NAFLD的合并RR为1.55(95%CI: 1.36-1.78, I2 = 0).

法国一项研究[12]表明, 缺乏体力活动可不依赖于脂肪量, 使正常体质量女性的血浆ALT、天冬氨酸氨基转移酶(aspartate transaminase, AST)和细胞角蛋白18等NAFLD指标升高(均P<0.05), 经常锻炼则可以限制这些指标的升高. 韩国一项研究[13]也表明, 久坐和缺乏体力活动与NAFLD的患病率正相关, 与静坐时间为<5 h/d者相比, 静坐时间为5-9 h/d和≥10 h/d者的NAFLD患病率比分别为1.04(95%CI: 1.02-1.07)和1.09(95%CI: 1.06-1.11)(趋势检验, P<0.001), 在BMI<23 kg/m2的参与者中, 仍然观察到这些关联.

除了饮食和体力活动之外, NAFLD还可能与生活方式的其他方面有关. 意大利一项研究[14]表明, 除了BMI较高和久坐的生活方式之外, 穿衣服较实际尺寸大、缺乏睡眠和每日进餐次数较少, 均与年轻人患有NAFLD的风险增加有关. 日本一项研究[15]表明, 每日睡眠时间为≤4 h、5-6 h、7-8 h和≥9 h成人女性的NAFLD患病率分别为19.3%、13.5%、11%和8%(P = 0.003). 芬兰一项研究[16]表明, 成人经常看电视(≥3 h/d)与γ-谷氨酰转肽酶(gamma-glutamyl transpeptidase, GGT)水平和脂肪肝指数较高有关(均P<0.02), 使脂肪肝的风险增加2.3倍(95%CI: 1.2-4.5).

血清尿酸(uric acid, UA)水平升高或可作为NAFLD的风险因素. 一项研究[17]表明, 82608例成人参与者的血清UA和ALT水平升高之间呈显著正相关, 具有量效关系, 对潜在混杂因素进行控制后, UA和ALT水平升高之间仍然保持相关性(最高四分位数和最低四分位数相比的风险比: 2.10, 95%CI: 1.93-2.29). 一项荟萃分析[18]证实, 血清UA水平升高是MS和NAFLD的风险因素, 血清UA水平每升高1 mg/dL, 导致NAFLD的风险增加21%.

我国一项研究[19]表明, 中老年人群的全血黏度(whole blood viscosity, WBV)增加与IR及NAFLD有关, 与WBV水平为最低四分位数的成人相比, 最高四分位数者的NAFLD患病率显著较高(校正的HR: 1.77, 95%CI: 1.48-2.13).

NAFLD的诊断必须除外过量饮酒, 适量饮酒的定义一般为: 男性和女性饮用酒精分别<20 g/d(140 g/wk)和10 g/d(70 g/wk). 日本两项研究[20,21]表明, 少量饮酒可以保护机体不易罹患脂肪肝, 尤其是对男性的保护作用更为明显.

3 疾病评估

许多研究关注于如何应用无创性生物指标、影像学检测以及多个因素建立的评分系统, 对NAFLD患者的NASH和纤维化进行评估.

血清ALT、AST和GGT等肝酶水平是最常用的NAFLD替代指标. 我国一项研究[22]表明, 肥胖成人的血清ALT水平与IHTG含量独立相关, 可作为NAFLD程度的预测指标. 美国一项研究[23]也表明, NAFLD患者的脂肪组织IR程度和IHTG含量是血浆转氨酶水平升高的主要决定因素, ALT升高者的脂肪变程度更重(P<0.0001).

日本一项研究[24]表明, TG/HDL-C升高是发生NAFLD的风险因素, 男性和女性的校正OR分别为1.55(95%CI: 1.35-1.77, P<0.0001)和2.72(95%CI: 1.88-3.95, P<0.0001).

以往通常认为NAFL患者病情进展缓慢, 然而, 近期两项研究[25,26]表明, 相当比例的NAFLD患者数年内即可发生肝纤维化进展. 一项研究[25]纳入35例NAFLD患者, 6.4年±0.8年后再次肝活检, 13例患者发生NAFLD活动度评分恶化, 18例患者发生肝纤维化进展, 其中2例已经进展至肝硬化, 无1例患者发生肝纤维化逆转, 血清AST和GGT水平升高是与NAFLD活动度评分恶化相关的风险因素. 另外一项研究[26]纳入接受连续肝活检的108例NAFLD患者, 中位数间隔6.6(范围: 1.3-22.6年)后, 45例(42%)患者发生了肝纤维化进展, 基线时诊断为NAFL/NASH者发生肝纤维化进展的比例并无显著性差异(37% vs 43%, P = 0.65), 患有糖尿病为NAFLD发生纤维化进展的风险因素(P = 0.005).

许多研究应用多个因素建立评分系统, 对NAFLD的疾病进展进行评估. 一项研究[27]应用AST水平、BMI、血小板计数、T2D和高血压等常规变量以及铁蛋白水平, 建立的评分系统用于预测NAFLD患者NASH风险的受试者工作特征曲线下面积(area under the receiver operating characteristic curve, AUROC)为0.81(95%CI: 0.76-0.86). 一项研究[28]表明, NAFLD患者存在进展期肝纤维化(纤维化2期和3期)的风险因素包括: 年龄、血小板计数、红细胞计数/分布宽度比值以及血清内脂素和组织多肽特异性抗原水平, 基于这些变量建立的评分系统对检出进展期肝纤维化具有较高的灵敏度和特异性. 另外一项研究[29]应用Ⅳ型胶原7S、血小板计数、AST及ALT等指标建立的评分系统, 可准确预测NASH患者的肝纤维化分期, 用于预测进展期纤维化(分期≥3)的AUROC为0.909(95%CI: 0.847-0.970, P<0.001), 优于其他几种纤维化评分系统.

尽管AST/ALT比值升高通常用作NAFLD患者进展期纤维化的替代指标, 美国一项研究[30]表明, 患者年龄对AST/ALT比值用于预测进展期纤维化的能力具有影响, 随着年龄增加, ALT水平逐渐降低, 而AST水平保持稳定, 导致AST/ALT比值升高, 有相当高比例的无进展期纤维化老年患者为AST/ALT比值≥1.

一项研究[31]表明, NAFLD患者的血清穿透素-2(pentraxin-2, PTX-2)水平显著降低, 进展期肝纤维化患者进一步降低, 血清PTX-2水平用于诊断NAFLD以及伴进展期纤维化的AUROC分别为0.84(95%CI: 0.71-0.97)和0.77(95%CI: 0.65-0.90). 另外一项研究[32]表明, NAFLD患者较对照组的血浆穿孔素-3(pentraxin-3, PTX-3)和肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)水平显著升高, NASH亚组较非NASH亚组的PTX-3和TNF-α水平显著升高, 血浆PTX-3水平与NAFLD活动度评分、纤维化分期和脂肪变分级显著相关.

美国一项研究[33]表明, 二维-磁共振弹性成像(2 dimension-magnetic resonance elastography, 2D-MRE)可作为无创手段, 用于准确预测NAFLD患者的进展期肝纤维化(AUROC: 0.924, P<0.0001). 采用>3.63 kPa的阈值, 2D-MRE用于预测NAFLD患者存在进展期肝纤维化的敏感度和特异度分别为0.86(95%CI: 0.65-0.97)和0.91(95%CI: 0.83-0.96), 阳性预测值和阴性预测值分别为0.68(95%CI: 0.48-0.84)和0.97(95%CI: 0.91-0.99).

4 心血管疾病和糖尿病风险评估

心血管疾病和NAFLD具有共同的风险因素, 包括不健康的生活方式、IR、中心性肥胖以及T2D、血脂异常和高血压等, 应该对NAFLD患者进行心血管疾病的风险分层和管理.

一项研究[34]表明, NAFLD患者的肝脏脂肪含量与MS的风险独立相关, 肝脏脂肪含量高于中位数的NAFLD患者更可能患有腹部肥胖, HDL-C水平更低, TG和空腹血糖水平更高, 患有MS的风险更高.

此外, 肝脂肪变与之前非致死性心肌梗塞、卒中、短暂性缺血发作、心力衰竭或外周动脉疾病等临床心血管疾病的预后存在相关倾向, 并且与冠状动脉钙化和腹部动脉钙化显著相关[35]. 一项荟萃分析[36]表明, 成人和儿童NAFLD患者的颈动脉内膜中层厚度增加, 并且成人NAFLD患者的颈动脉斑块患病率增加. 另外一项研究[37]也表明NAFLD和高风险的冠状动脉斑块存在相关性, NAFLD患者更常见正性重构、CT衰减<30 HU、餐巾环征、点状钙化等高风险冠状动脉斑块的特征(59.3% vs 19.0%, P<0.001), NAFLD与是高风险冠状动脉斑块的独立风险因素(OR = 2.13, 95%CI: 1.18-3.85).

意大利一项研究[38]表明, 跨膜蛋白6超家族成员2(transmembrane 6 superfamily member 2, TM6SF2)E167K变体携带者更容易患有NASH(OR = 1.84, 95%CI: 1.23-2.79)和进展期肝纤维化(OR = 2.08, 95%CI: 1.20-3.55), 然而, 血脂水平更低(P<0.05), 颈动脉斑块(OR = 0.49, 95%CI: 0.25-0.94)或心血管事件的发生风险更低(HR = 0.61, 95%CI: 0.39-0.95). 研究者认为, TM6SF2 E167K变体携带者分泌极低密度脂蛋白的能力降低, 对肝脏有害, 但是, 体内的循环脂质较低, 从而可降低动脉粥样硬化的发生风险.

一项研究[39]提示NAFLD可能与亚临床心肌损伤存在关联: 在无饮酒增加的情况下, 较高的ALT、AST和GGT等肝酶水平与高灵敏度心肌肌钙蛋白T浓度可检出(>3 ng/L)以及升高(≥14 ng/L)呈显著独立相关.

一项研究[40]纳入4629例参与者, 平均随访12.8年表明, 非超重无NAFLD组、超重无NAFLD组、非超重NAFLD组和超重NAFLD组的T2D发生率分别为3.2%、8.0%、14.4%和26.4%, NAFLD患者罹患T2D的校正HR显著高于无NAFLD者. 另外一项长期随访研究[41]表明, NAFLD的改善与T2D的发生率降低有关. 美国一项研究[42]表明, 即使转氨酶水平正常, 超重或肥胖T2D患者的NAFLD患病率仍然高达50%, NAFLD患者中的NASH患病率高达56%, 其中, NAFLD患病率随着BMI的增加而增加(趋势检验, P = 0.001), 血浆HbA1c水平较高与NAFLD患病率较高和肝脏TG沉积程度较重有关(P = 0.01).

5 治疗

NAFLD的治疗措施主要包括生活方式干预、药物治疗和减肥手术, 然而, 目前尚无药物得到美国食品和药物管理局的批准.

通过低热量饮食或者联合增加运动, 使超重或肥胖NAFLD患者的体质量减轻, 可以有效改善肝脏脂肪变性. 一项研究[43]表明, 如果NASH患者的BMI减少≥5%, MRI检测的肝脏脂肪可由(18.3%±7.6%)显著减少至(13.6%±13.6%)(相对减少25.5%, P = 0.03), 肝脏体积缩小5.3%, 相比之下, 没有达到该体质量减轻目标者的肝脏脂肪以及肝脏体积则显著增加. 另外一项研究[44]表明, 体质量减轻≥10%患者的肝纤维化消退(纤维化评分改善≥1期)率显著较高.

日本一项研究[45]表明, 作为生活方式管理的一部分, 中度至剧烈强度的体力活动≥250 min/wk, 和<150 min/wk相比, 可使男性肥胖NAFLD患者的腹部内脏脂肪组织显著减少, 脂质过氧化显著减轻, 铁蛋白水平显著降低. 英国一项随机对照试验[46]表明, 改良的高强度间歇训练, 可使NAFLD患者的肝脏和全身脂肪量显著减少, ALT、AST水平显著降低, 并且有益于心脏功能. 美国一项前瞻性研究[47]表明, 6 mo时体质量减轻≥5%, 可使NAFLD患者的生活质量显著改善(P<0.0001), 无糖尿病、无进展期肝纤维化的NASH患者最有可能通过体质量减轻获得生活质量改善.

一项研究[48]表明, 可以预测经生活方式干预后NASH消退的独立因素包括: 年龄、体质量减轻、T2D、干预结束时ALT水平正常和NAFLD活动度评分, 应用这些因素建立的无创性评分模型, 可以准确预测NASH的消退.

越来越多的研究表明, 调节肠道微生物或可用于治疗肥胖相关性疾病. 一项小型随机试验[49]应用益生菌胶囊治疗8 wk后, NAFLD患者的IR程度减轻, 胰岛素、TNF-α以及IL-6水平均显著降低. 另外一项随机临床试验[50]发现, NAFLD患者每日食用300 g益生菌酸奶, 治疗8 wk时, 血清ALT、AST、总胆固醇以及LDL-C等水平有所降低. 因此, 补充益生菌可作为NAFLD的辅助性治疗.

NAFLD患者常见血脂异常, 数项研究观察了降脂药物对NASH的疗效. 一项小样本初步研究[51]对肝活检证实为NASH的血脂异常患者应用瑞舒伐他汀(10 mg/d)治疗1年, 肝活检和超声检查均有改善. 美国一项随机双盲对照试验[52]纳入50例经活检证实的NASH患者, 随机分组至口服依折麦布(10 mg/d)或安慰剂, 治疗24 wk结束时, 治疗组患者应用磁共振成像检测的质子密度脂肪部分(magnetic resonance imaging-PDFF, MRI-PDFF)显著减少(15.0%-11.6%, P<0.016), 然而, 和安慰剂组相比, 平均MRI-PDFF减少差异未达到显著性(-1.3%, P = 0.4), 组织学应答率、血清ALT和AST水平或者由MRE所检测的肝脏弹性值变化均无显著性差异. 二十碳五烯酸乙酯(eicosapentaenoic acid ethyl ester, EPA-E)是一种合成的多不饱和脂肪酸, 用于治疗高TG血症. 北美一项多中心前瞻性随机双盲安慰剂对照2b期试验[53]结果表明, EPA-E对NASH患者的肝脏组织学特征以及肝酶水平均无显著疗效. 另外一项小型研究[54]纳入无肝硬化的NASH患者, 应用N-3多不饱和脂肪酸(3000 mg/d)治疗1年, 可使患者的肝脏脂肪含量显著减少, 然而, 对纤维化和NAFLD活动度积分并无显著疗效.

一项研究[55]对60例NAFLD患者应用安慰剂或不同剂量的脂肪酸-胆汁酸偶合物aramchol治疗3 mo, 安全耐受性良好, 患者的肝脏脂肪含量呈剂量依赖性显著减少.

一项系统评价和荟萃分析[56]纳入19项RCT和14项非随机研究, 对应用抗糖尿病药物治疗T2D患者NAFLD的效果进行比较, 结果表明, 应用噻唑烷二酮类或胰高血糖素样肽-1受体激动剂治疗, 可使NAFLD患者的肝脏脂肪含量减少. 英国一项研究[57]纳入14例经肝活检证实为NASH、BMI≥25 kg/m2的成人患者, 在研究之前至少3 mo, 合并T2D者得到饮食控制或应用稳定剂量的二甲双胍±格列齐特, HbA1c<9.0%. 患者随机接受利拉鲁肽(1次/d, 皮下注射1.8 mg)或安慰剂治疗. 12 wk时, 利拉鲁肽使BMI、HbA1c、LDL-C、ALT、血清瘦素、脂联素水平等显著下降, 肝脏和脂肪组织的胰岛素敏感性增加. 英国4家中心进行的随机双盲安慰剂对照2期试验[58]结果证实, 应用利拉鲁肽治疗(1.8 mg/d)48 wk, 可以使NASH消退, 患者的耐受性良好. 用于治疗T2D的GLP-1 RA和二肽基肽酶-4抑制剂统称为基于肠促胰素的治疗药物, 具有调节代谢和抗炎活性. 一项系统评价和荟萃分析纳入4项研究, 总共包括136例合并T2D的NAFLD患者, 应用基于肠促胰素的治疗后, 患者血清ALT水平显著降低(平均降低14.1 IU/L, 95%CI: 8.3-19.8, P<0.0001), 具有影像学和组织学数据的2项研究[59]表明, 基于肠促胰素的治疗可使脂肪变、炎症和纤维化显著减轻.

通过抑制肾素-血管紧张素系统(renin-angiotensin system, RAS)减轻炎症坏死和纤维化, 可望成为NAFLD的有效治疗. 一项横断面研究[60]对活检证实为NAFLD的290例高血压患者的数据资料进行分析, 应用RAS阻滞剂治疗患者和未应用RAS阻滞剂者相比, 肝细胞气球样变更轻(1.02 vs 1.31, P = 0.001), 肝纤维化分期更低(1.63 vs 2.16, P = 0.002), 应用RAS阻滞剂与进展期纤维化呈显著负相关(OR = 0.37, 95%CI: 0.21-0.65, P = 0.001).

Elafibranor是一种过氧化物酶体增殖物激活受体-α(peroxisome proliferator-activated receptor-α, PPARA)和PPAR-激动剂, 可改善胰岛素敏感性、葡萄糖稳态和脂代谢, 并且可减轻炎症. 一项随机双盲安慰剂对照试验[61]结果表明, 应用Elafibranor(120 mg/d)治疗52 wk, NASH消退且无纤维化加重的患者比例显著较高, 发生NASH消退患者的肝纤维化分期显著减轻, 肝酶、血脂、血糖及全身炎症指标均得到改善. Elafibranor的耐受性良好, 患者可发生轻微、可逆的血清肌酐值升高, 无体质量增加或心血管事件发生.

一项2b期随机临床试验[62]表明, 奥贝胆酸治疗可使NASH患者包括肝纤维化的肝脏组织学获益, 但是, 奥贝胆酸具有引起瘙痒以及对血脂具有负面影响等不良反应.

一项为期6 mo的前瞻性随机对照试验[63]结果表明, 对NAFLD患者通过静脉放血减少铁蛋白, 并未改善肝脏酶学指标、肝脏脂肪或IR程度.

在接受减肥手术的患者中, NAFLD十分常见. 一项研究[64]应用患者年龄、血糖、BMI、血小板计数、白蛋白以及AST/ALT比值等指标所组成的评分系统进行评估, NAFLD患者接受Roux-en-Y胃旁路术后12 mo时, NAFLD肝纤维化评分显著降低, 进展期肝纤维化的消退率达到55%, 肝纤维化的消退与女性性别、术后体质量减轻、术后BMI、术后血小板计数以及糖尿病的消退显著相关.

6 结论

目前, NAFLD已经成为全世界范围内最常见的肝脏疾病, 需要对NAFLD患者进行准确的疾病评估, 检出其中的NASH和肝纤维化患者, 并且加强对患者心血管疾病和T2D的风险分层和管理, 治疗措施主要包括生活方式干预、药物治疗和减肥手术, 然而, 目前尚无治疗药物得到FDA批准.

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背景资料

非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)现已成为全球范围内最常见的慢性肝病, 其风险因素为高脂肪高热量膳食结构和久坐少动的生活方式所致的代谢综合征(metabolic syndrome, MS)及其组分, 与肝硬化和肝细胞肝癌(hepatocellular carcinoma, HCC)的发病率及死亡率增加有关, 更重要的是, NAFLD使2型糖尿病(type 2 diabetes, T2D)、心血管疾病和恶性肿瘤的发病率及死亡率增加.

同行评议者

汪安江, 副主任医师, 南昌大学第一附属医院消化科

研发前沿

对NAFLD患者中的非酒精性脂肪性肝炎和纤维化进行准确评估以及对患者合并心血管疾病和/或T2D的风险进行分层和管理非常重要, 治疗措施主要包括生活方式干预、药物治疗和减肥手术.

创新盘点

应用多种无创性生物指标或影像学检测技术以及多种因素建立的评分系统, 有助于准确评估NAFLD患者的疾病进展, 亟需加强对患者合并心血管疾病和/或T2D风险的管理, 目前, 对NAFLD的治疗措施仍然是以生活方式干预为主, 临床试验表明一些治疗药物具有应用前景.

应用要点

对NAFLD患者的NASH和纤维化进行准确评估, 重视对合并心血管疾病和/或T2D的风险分层和管理, 目前的主要治疗措施仍然为低热量饮食或者联合增加运动的生活方式干预.

同行评价

本文对NAFLD进行了较为全面和充分的阐释, 有一定的价值.

手稿来源: 邀请约稿

学科分类: 胃肠病学和肝病学

手稿来源地: 北京市

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编辑:于明茜 电编:胡珊

1.  Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.  [PubMed]  [DOI]
2.  Li Z, Xue J, Chen P, Chen L, Yan S, Liu L. Prevalence of nonalcoholic fatty liver disease in mainland of China: a meta-analysis of published studies. J Gastroenterol Hepatol. 2014;29:42-51.  [PubMed]  [DOI]
3.  Fung J, Lee CK, Chan M, Seto WK, Lai CL, Yuen MF. High prevalence of non-alcoholic fatty liver disease in the Chinese - results from the Hong Kong liver health census. Liver Int. 2015;35:542-549.  [PubMed]  [DOI]
4.  Wong VW, Wong GL, Yeung DK, Lau TK, Chan CK, Chim AM, Abrigo JM, Chan RS, Woo J, Tse YK. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol. 2015;62:182-189.  [PubMed]  [DOI]
5.  Feng RN, Du SS, Wang C, Li YC, Liu LY, Guo FC, Sun CH. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol. 2014;20:17932-17940.  [PubMed]  [DOI]
6.  Wei JL, Leung JC, Loong TC, Wong GL, Yeung DK, Chan RS, Chan HL, Chim AM, Woo J, Chu WC. Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy. Am J Gastroenterol. 2015;110:1306-1314; quiz 1315.  [PubMed]  [DOI]
7.  Ha Y, Seo N, Shim JH, Kim SY, Park JA, Han S, Kim KW, Yu E, Kim KM, Lim YS. Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: A case-control study. J Gastroenterol Hepatol. 2015;30:1666-1672.  [PubMed]  [DOI]
8.  Lee YH, Jung KS, Kim SU, Yoon HJ, Yun YJ, Lee BW, Kang ES, Han KH, Lee HC, Cha BS. Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008-2011). J Hepatol. 2015;63:486-493.  [PubMed]  [DOI]
9.  Choi SH, Oh DJ, Kwon KH, Lee JK, Koh MS, Lee JH, Kang HW. A vegetarian diet does not protect against nonalcoholic fatty liver disease (NAFLD): A cross-sectional study between Buddhist priests and the general population. Turk J Gastroenterol. 2015;26:336-343.  [PubMed]  [DOI]
10.  Ma J, Fox CS, Jacques PF, Speliotes EK, Hoffmann U, Smith CE, Saltzman E, McKeown NM. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. J Hepatol. 2015;63:462-469.  [PubMed]  [DOI]
11.  Wijarnpreecha K, Thongprayoon C, Edmonds PJ, Cheungpasitporn W. Associations of sugar- and artificially sweetened soda with nonalcoholic fatty liver disease: a systematic review and meta-analysis. QJM. 2016;109:461-466.  [PubMed]  [DOI]
12.  Rudwill F, Bergouignan A, Gastebois C, Gauquelin-Koch G, Lefai E, Blanc S, Simon C. Effect of enforced physical inactivity induced by 60-day of bed rest on hepatic markers of NAFLD in healthy normal-weight women. Liver Int. 2015;35:1700-1706.  [PubMed]  [DOI]
13.  Ryu S, Chang Y, Jung HS, Yun KE, Kwon MJ, Choi Y, Kim CW, Cho J, Suh BS, Cho YK. Relationship of sitting time and physical activity with non-alcoholic fatty liver disease. J Hepatol. 2015;63:1229-1237.  [PubMed]  [DOI]
14.  Trovato FM, Martines GF, Brischetto D, Catalano D, Musumeci G, Trovato GM. Fatty liver disease and lifestyle in youngsters: diet, food intake frequency, exercise, sleep shortage and fashion. Liver Int. 2016;36:427-433.  [PubMed]  [DOI]
15.  Miyake T, Kumagi T, Hirooka M, Furukawa S, Kawasaki K, Koizumi M, Todo Y, Yamamoto S, Nunoi H, Tokumoto Y. Significance of exercise in nonalcoholic fatty liver disease in men: a community-based large cross-sectional study. J Gastroenterol. 2015;50:230-237.  [PubMed]  [DOI]
16.  Helajärvi H, Pahkala K, Heinonen OJ, Juonala M, Oikonen M, Tammelin T, Hutri-Kähönen N, Kähönen M, Lehtimäki T, Mikkilä V. Television viewing and fatty liver in early midlife. The Cardiovascular Risk in Young Finns Study. Ann Med. 2015;47:519-526.  [PubMed]  [DOI]
17.  Zelber-Sagi S, Ben-Assuli O, Rabinowich L, Goldstein A, Magid A, Shalev V, Shibolet O, Chodick G. The association between the serum levels of uric acid and alanine aminotransferase in a population-based cohort. Liver Int. 2015;35:2408-2415.  [PubMed]  [DOI]
18.  Yuan H, Yu C, Li X, Sun L, Zhu X, Zhao C, Zhang Z, Yang Z. Serum Uric Acid Levels and Risk of Metabolic Syndrome: A Dose-Response Meta-Analysis of Prospective Studies. J Clin Endocrinol Metab. 2015;100:4198-4207.  [PubMed]  [DOI]
19.  Zhao HY, Li J, Xu M, Wang TG, Sun WW, Chen Y, Bi YF, Wang WQ, Ning G. Elevated whole blood viscosity is associated with insulin resistance and non-alcoholic fatty liver. Clin Endocrinol (Oxf). 2015;83:806-811.  [PubMed]  [DOI]
20.  Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, Ando M, Yamamoto K. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol. 2015;62:921-927.  [PubMed]  [DOI]
21.  Sogabe M, Okahisa T, Taniguchi T, Tomonari T, Tanaka T, Tanaka H, Nakasono M, Takayama T. Light alcohol consumption plays a protective role against non-alcoholic fatty liver disease in Japanese men with metabolic syndrome. Liver Int. 2015;35:1707-1714.  [PubMed]  [DOI]
22.  Chen Z, Han CK, Pan LL, Zhang HJ, Ma ZM, Huang ZF, Chen S, Zhuang XJ, Li ZB, Li XY. Serum alanine aminotransferase independently correlates with intrahepatic triglyceride contents in obese subjects. Dig Dis Sci. 2014;59:2470-2476.  [PubMed]  [DOI]
23.  Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology. 2015;61:153-160.  [PubMed]  [DOI]
24.  Fukuda Y, Hashimoto Y, Hamaguchi M, Fukuda T, Nakamura N, Ohbora A, Kato T, Kojima T, Fukui M. Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study. Liver Int. 2016;36:713-720.  [PubMed]  [DOI]
25.  Chan WK, Ida NH, Cheah PL, Goh KL. Progression of liver disease in non-alcoholic fatty liver disease: a prospective clinicopathological follow-up study. J Dig Dis. 2014;15:545-552.  [PubMed]  [DOI]
26.  McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62:1148-1155.  [PubMed]  [DOI]
27.  Goh GB, Issa D, Lopez R, Dasarathy S, Dasarathy J, Sargent R, Hawkins C, Pai RK, Yerian L, Khiyami A. The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016;31:995-1000.  [PubMed]  [DOI]
28.  Chwist A, Hartleb M, Lekstan A, Kukla M, Gutkowski K, Kajor M. A composite model including visfatin, tissue polypeptide-specific antigen, hyaluronic acid, and hematological variables for the diagnosis of moderate-to-severe fibrosis in nonalcoholic fatty liver disease: a preliminary study. Pol Arch Med Wewn. 2014;124:704-712.  [PubMed]  [DOI]
29.  Kawamura Y, Ikeda K, Arase Y, Sorin Y, Fukushima T, Kunimoto H, Hosaka T, Kobayashi M, Saitoh S, Sezaki H. New discriminant score to predict the fibrotic stage of non-alcoholic steatohepatitis in Japan. Hepatol Int. 2015;9:269-277.  [PubMed]  [DOI]
30.  Goh GB, Pagadala MR, Dasarathy J, Unalp-Arida A, Pai RK, Yerian L, Khiyami A, Sourianarayanane A, Sargent R, Hawkins C. Age impacts ability of aspartate-alanine aminotransferase ratio to predict advanced fibrosis in nonalcoholic Fatty liver disease. Dig Dis Sci. 2015;60:1825-1831.  [PubMed]  [DOI]
31.  Verna EC, Patel J, Bettencourt R, Nguyen P, Hernandez C, Valasek MA, Kisselva T, Brenner DA, Loomba R. Novel association between serum pentraxin-2 levels and advanced fibrosis in well-characterised patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2015;42:582-590.  [PubMed]  [DOI]
32.  Boga S, Koksal AR, Alkim H, Yilmaz Ozguven MB, Bayram M, Ergun M, Sisman G, Tekin Neijmann S, Alkim C. Plasma Pentraxin 3 Differentiates Nonalcoholic Steatohepatitis (NASH) from Non-NASH. Metab Syndr Relat Disord. 2015;13:393-399.  [PubMed]  [DOI]
33.  Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, Valasek M, Lin G, Brenner D, Gamst A. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology. 2014;60:1920-1928.  [PubMed]  [DOI]
34.  Arulanandan A, Ang B, Bettencourt R, Hooker J, Behling C, Lin GY, Valasek MA, Ix JH, Schnabl B, Sirlin CB. Association Between Quantity of Liver Fat and Cardiovascular Risk in Patients With Nonalcoholic Fatty Liver Disease Independent of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2015;13:1513-1520.e1.  [PubMed]  [DOI]
35.  Mellinger JL, Pencina KM, Massaro JM, Hoffmann U, Seshadri S, Fox CS, O'Donnell CJ, Speliotes EK. Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study. J Hepatol. 2015;63:470-476.  [PubMed]  [DOI]
36.  Madan SA, John F, Pyrsopoulos N, Pitchumoni CS. Nonalcoholic fatty liver disease and carotid artery atherosclerosis in children and adults: a meta-analysis. Eur J Gastroenterol Hepatol. 2015;27:1237-1248.  [PubMed]  [DOI]
37.  Puchner SB, Lu MT, Mayrhofer T, Liu T, Pursnani A, Ghoshhajra BB, Truong QA, Wiviott SD, Fleg JL, Hoffmann U. High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial. Radiology. 2015;274:693-701.  [PubMed]  [DOI]
38.  Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61:506-514.  [PubMed]  [DOI]
39.  Lazo M, Rubin J, Clark JM, Coresh J, Schneider AL, Ndumele C, Hoogeveen RC, Ballantyne CM, Selvin E. The association of liver enzymes with biomarkers of subclinical myocardial damage and structural heart disease. J Hepatol. 2015;62:841-847.  [PubMed]  [DOI]
40.  Fukuda T, Hamaguchi M, Kojima T, Hashimoto Y, Ohbora A, Kato T, Nakamura N, Fukui M. The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals. Liver Int. 2016;36:275-283.  [PubMed]  [DOI]
41.  Yamazaki H, Tsuboya T, Tsuji K, Dohke M, Maguchi H. Independent Association Between Improvement of Nonalcoholic Fatty Liver Disease and Reduced Incidence of Type 2 Diabetes. Diabetes Care. 2015;38:1673-1679.  [PubMed]  [DOI]
42.  Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015;100:2231-2238.  [PubMed]  [DOI]
43.  Patel NS, Doycheva I, Peterson MR, Hooker J, Kisselva T, Schnabl B, Seki E, Sirlin CB, Loomba R. Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2015;13:561-568.e1.  [PubMed]  [DOI]
44.  Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS, Toor A. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2015;60:1024-1030.  [PubMed]  [DOI]
45.  Oh S, Shida T, Yamagishi K, Tanaka K, So R, Tsujimoto T, Shoda J. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology. 2015;61:1205-1215.  [PubMed]  [DOI]
46.  Hallsworth K, Thoma C, Hollingsworth KG, Cassidy S, Anstee QM, Day CP, Trenell MI. Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial. Clin Sci (Lond). 2015;129:1097-1105.  [PubMed]  [DOI]
47.  Tapper EB, Lai M. Weight loss results in significant improvements in quality of life for patients with nonalcoholic fatty liver disease: A prospective cohort study. Hepatology. 2016;63:1184-1189.  [PubMed]  [DOI]
48.  Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Villa-Jimenez O, Friedman SL, Diago M. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology. 2016;63:1875-1887.  [PubMed]  [DOI]
49.  Sepideh A, Karim P, Hossein A, Leila R, Hamdollah M, Mohammad E G, Mojtaba S, Mohammad S, Ghader G, Seyed Moayed A. Effects of Multistrain Probiotic Supplementation on Glycemic and Inflammatory Indices in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial. J Am Coll Nutr. 2015; Oct 2. [Epub ahead of print].  [PubMed]  [DOI]
50.  Nabavi S, Rafraf M, Somi MH, Homayouni-Rad A, Asghari-Jafarabadi M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J Dairy Sci. 2014;97:7386-7393.  [PubMed]  [DOI]
51.  Kargiotis K, Katsiki N, Athyros VG, Giouleme O, Patsiaoura K, Katsiki E, Mikhailidis DP, Karagiannis A. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol. 2014;12:505-511.  [PubMed]  [DOI]
52.  Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, Soaft L, Hooker J, Kono Y, Bhatt A. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015;61:1239-1250.  [PubMed]  [DOI]
53.  Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147:377-384.e1.  [PubMed]  [DOI]
54.  Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, Shah NL, Al-Osaimi AM, Pramoonjago P, Jayakumar S. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol. 2015;62:190-197.  [PubMed]  [DOI]
55.  Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085-2091.e1.  [PubMed]  [DOI]
56.  Tang W, Xu Q, Hong T, Tong G, Feng W, Shen S, Bi Y, Zhu D. Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. Diabetes Metab Res Rev. 2016;32:200-216.  [PubMed]  [DOI]
57.  Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, Nasiri M, Yu J, Gough SC, Newsome PN. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399-408.  [PubMed]  [DOI]
58.  Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, Abouda G, Aldersley MA. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679-690.  [PubMed]  [DOI]
59.  Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31:23-31.  [PubMed]  [DOI]
60.  Goh GB, Pagadala MR, Dasarathy J, Unalp-Arida A, Sargent R, Hawkins C, Sourianarayanane A, Khiyami A, Yerian L, Pai R. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int. 2015;35:979-985.  [PubMed]  [DOI]
61.  Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and-δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150:1147-1159.e5.  [PubMed]  [DOI]
62.  Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956-965.  [PubMed]  [DOI]
63.  Adams LA, Crawford DH, Stuart K, House MJ, St Pierre TG, Webb M, Ching HL, Kava J, Bynevelt M, MacQuillan GC. The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial. Hepatology. 2015;61:1555-1564.  [PubMed]  [DOI]
64.  Cazzo E, Jimenez LS, Pareja JC, Chaim EA. Effect of Roux-en-Y gastric bypass on nonalcoholic fatty liver disease evaluated through NAFLD fibrosis score: a prospective study. Obes Surg. 2015;25:982-985.  [PubMed]  [DOI]