修回日期: 2012-11-12
接受日期: 2012-11-15
在线出版日期: 2013-01-18
大非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)患病率高, 西方国家15%-30%, 我国约15%. 单纯性脂肪肝(nonalcoholic simple fatty liver, NAFL)病情稳定, 脂肪性肝炎(nonalcoholic steatohepatitis, NASH)是病情恶化的拐点, 可发展为肝硬化, 甚至肝癌. 候选基因研究显示, 肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、瘦素、脂联素等基因单核苷酸多态性(single nucleotide polymorphisms, SNP)与其发病易感性相关. 近年全基因组扫描发现, 染色体22上调节磷脂酶基因的SNP(adiponutrin或PNPLA3)更为重要. 表观遗传学研究发现miR-122表达下调参与NAFLD发病机制. 病理组织学是诊断的金标准, 但实施困难, 影像学检查(特别B超)是临床诊断的主要方法, 但无法鉴别NASH和NAFL. 基础治疗包括纠正不良生活方式、控制饮食、运动、减肥等, 是治疗成功的基石. 药物是辅助手段, 包括减肥药、胰岛素增敏剂、调脂药、保肝抗炎药物等, 尚没有循证医学验证的特效药物.
引文著录: 李瑜元. 非酒精性脂肪性肝病的研究进展. 世界华人消化杂志 2013; 21(2): 109-115
Revised: November 12, 2012
Accepted: November 15, 2012
Published online: January 18, 2013
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a prevalence of 15%-30% in Western continues and about 15% in China. Nonalcoholic simple fatty liver (SFL) usually has a benign prognosis, whereas nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and even hepatocellular carcinoma. Genetic studies show that a number of single nucleotide polymorphisms (SNPs) in the genes of tumor necrosis factor-α (TNF-α), leptin, and adiponectin are associated with susceptibility to NAFLD. Recently, genome-wide association studies (GWASs) reveal a more important relevant SNP (adiponutrin or PNPLA3), which is located on chromosome 22 and regulates phospholipase. Epigenetic studies demonstrate that down-expression of miR-122 is involved in the pathogenesis of NAFLD. Histology remains the gold standard for the diagnosis of NAFLD. In clinical practice, the diagnosis is usually made by imaging techniques (e.g. ultrasonography), as liver biopsy is usually difficult. However, imaging techniques cannot differentiate NASH from NAFL. Modification of lifestyle factors such as diet, exercise, and weight control is important for treatment and should be encouraged in all patients. Pharmacotherapy with weight reduction agents, insulin sensitizers, statins, or hepatoprotectors is helpful clinically, although their efficacy has not been well proved by evidence-based medicine.
- Citation: Li YY. Recent progress in research of nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2013; 21(2): 109-115
- URL: https://www.wjgnet.com/1009-3079/full/v21/i2/109.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i2.109
非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)患病率不断上升, 引起关注. 近年基础和临床研究均取得可喜成果, 各国也先后更新指南, 规范临床诊疗工作. NAFLD俗称脂肪肝, 是指以肝实质细胞脂肪变性为病理特征, 而无过量饮酒史, 又排除其他肝病的临床综合征, 其病理类型包括单纯性非酒精性脂肪肝(nonalcoholic simple fatty liver, NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)及NASH相关肝硬化, 后者可发展为肝癌. NAFL病情稳定, 而NASH是发生肝硬化的必经阶段, 也是病情恶化的拐点和防治的重点. 近年NAFLD患病率逐年增加, 呈低龄化发病趋势, 已成为全球重要的公共健康问题. 在发达国家, NAFLD已成为慢性肝病及血清氨基酸转移酶(下称转氨酶)升高的首要原因, 在我国仅次于病毒性肝炎排第2位. 随着基础和临床研究新资料的涌现, 美国、英国和欧洲肝病学会均修订了诊疗指南[1-3], 2010年我国也对旧指南进行更新[4]. 本文结合近年研究进展和指南内容作述评.
NAFLD在全球广泛分布, 患病率因目标人群和诊断方法的不同有很大差异, 其确切患病率仍未完全清楚. 病理组织学是诊断的金标准, 因肝活检难于普及, 用于流行病学调查存在困难. 在意外死亡, 病死尸解和捐肝者的报告中, NAFLD患病率在20%左右, 其中NASH约5%[5,6]. B超诊断是人群调查的常用方法, 设计严格、纳入大样本普通人群的B超调查显示[5,6], 欧美等西方发达国家成人患病率多在15%-30%之间, 而我国上海和广州两组调查均约15%[7,8]. 在发达国家, 因病毒性肝炎少见, 用血清转氨酶升高作为指标的人群调查(如美国NHANES研究)显示的患病率较低(5%-10%), 这是仅部分NAFLD患者转氨酶升高所导致. 文献也有用CT或磁共振(magnetic resonance imaging, MRI)调查的报告, 样本均较少, 获得的患病率较B超稍高. 以体检人群为对象的报告很多, 差异很大, 因其代表性差, 结果难以比较. NAFLD人群患病率随年龄增长而增加, 中老年后达高峰, 然后下降[5-10]. 我们在广东的调查显示, 男性患病率高峰期(50岁)早于女性(60岁), 在50岁前男性高于女性, 50岁(女性绝经期)后女性高于男性, 接受雌激素替代治疗的女性NAFLD发病率显著下降, 提示雌激素是机体免受NAFLD的保护因素[8]. 发病率调查需前瞻性队列研究, 资料有限. 日本Hamagchi等[11]采用B超随访3 147例健康人414 d, 年发病率10%. 意大利Bedogni等[12]用B超随访144例健康人8.5年, 年发病率为1.9%. 日本Suzuki等[13]以血清转氨酶作标志物随访健康体检者, 年发病率为3.1%. 我们用B超随访广东省507例健康人4年, 年发病率为9.1%[14]. NAFLD发病危险因素包括: 高脂肪高热量的膳食结构、多坐少动的生活方式, 胰岛素抵抗(insulin resistance, IR)、代谢综合征(metabolic syndrome, MetS)及其组分病(肥胖、高血压、血脂紊乱和2型糖尿病)等. 患MetS人群的NAFLD危险率是正常人的4-11倍, NASH比NAFL更常合并MetS[11,15,16].
NAFLD的自然病程尚未完全清楚, 一般认为NAFL是一个良性、可逆性疾病, 进展很慢, 肝硬化发生率很低, 随访10-20年仅0.6%-3.0%发展为肝硬化, 而NASH患者则高达15%-25%. 在NAFLD漫长的进程中, NASH是发生肝硬化的必经阶段, 也是病情恶化的拐点[1-4]. NAFLD患者常合并MetS[11,15-17], 死亡原因也多为心脑血管疾病, 而非肝病. 因此如仅仅关注NAFLD向肝硬化和肝癌发展, 则低估了NAFLD的危害性. Dam-Larsen等[18]随访109例NAFL患者中位数16.7年, 仅2例进展为NASH, 其中一例进展为肝硬化. Matteoni等[19]观察49例NAFL患者18年, 仅2例(4%)进展为肝硬化. Teli等[20]随访40例NAFL患者中位数11年, 没有发现NASH及肝纤维化病例. Adams等[17]随访血清转氨酶升高, 排除其他相关疾病, 诊断为NAFLD的109例11年, 无1例发展为肝硬化. 我们用B超随访广东省人群117例NAFLD共4年, 病情不变者51例(43.6%), 加重26例(22.2%), 改善40例(34.2%), 其中死于心脑血管疾病者10例(2.2%), 显著高于对照组的0.2%(P = 0.005), 无死于肝相关性疾病的病例[14].
近年全球儿童和青少年肥胖率快速增高, NAFLD患病率也随之明显上升, 引起极大关注. 美国一项研究显示, 2-4岁儿童NAFLD患病率为0.7%, 而15-19岁年龄组达17.3%[21]. 儿童患NAFLD预后较成人差[22]. 肝穿活检研究显示, 儿童NAFLD中NASH比率较高(可达68%)[21]. 国内相关资料较少, 2000年教育部、卫生部等五部委的全国学生调查结果, 城市7-12岁学生肥胖率为12%, 肥胖儿童脂肪肝检出率达18%, 因此估计我国儿童脂肪肝的发病率在2%-4%[23]. 我们在广东的人群调查显示, 7-18岁患病率为5.7%, 远低于西方国家水平[8].
NAFLD是复杂基因关联性疾病, 以往研究挑选与发病机制相关的基因(候选基因研究), 由于MetS基因研究较为深入, NAFLD常与MetS并存, 发病机制均与IR相关, 故理论上凡是和MetS及IR相关的基因都可能与NAFLD有关. 这些基因包括(1)与肥胖和IR有关的基因: 脂联素、胰岛素受体、过氧化物酶体增殖物激活受体-γ(peroxisome proliferators-activated receptor-gamma, PPAR-γ)等; (2)影响脂肪酸代谢的基因: 肝脂肪酶、瘦素、脂联素、微粒体甘油三酯转运蛋白、PPAR-α、细胞色素酶2E1和4A(CPY2E1, CYP4A)等; (3)影响相关细胞因子的基因: 肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)等; (4)影响NAFLD肝纤维化严重程度的基因: 瘦素、脂联素、转化生长因子β1等. 这些基因的SNPs均可能影响NAFLD的发病易感性, 其中TNF-α、PPAR-γ、瘦素、脂联素等基因文献报告较多, 由于研究对象和方法不同, 各组报告的结果并不完全一致[24,25]. 我们对其中7个候选基因共9个位点SNPs的研究显示, 有些因子和发病易感性正相关(即增加易感性): 如TNF-α-238、脂联素-45、瘦素-2548、PPAR-161、PEMT-175; 有些因子负相关(即降低易感性): 如脂联素-276、肝脂肪酶-514; 有些因子不相关: 如TNF-α-380、PGC-1α-48[26].
2008年Romeo等[27]首先应用全基因扫描(genome-wide association studies, GWAS)研究NAFLD, 他用磁共振波谱(1H-MRS)检查2 111例美国各族人群, 比较NAFLD和对照组发现9229个差异SNPs, 其中在染色体22上1个和磷脂酶代谢相关基因的SNP, 即adiponutrin(亦称PNPLA3, SNP编码rs738409, 本文译为脂酶素)与肝脂肪含量密切相关, 在易患NAFLD的白种人显著高于黑人. 这结果随后被多个以肝活检为依据的GWAS所证实[28-34]. 最近有Meta分析纳入16个高质量的临床研究共2937例, 结果显示, 携带脂酶素变异型纯合子(GG)者和野生型纯合子(CC)者比较, 肝脂肪含量升高73%, 肝炎症-坏死评分升高3.24倍, 肝纤维化危险性升高3.20倍, 血清谷丙转氨酶升高28%, NASH危险性升高3.49倍, 然而患重症肝病的危险性并不显著增加[35]. 然而, 并不是所有的研究均能重复这结果, 有一组GWAS纳入236例肝活检确诊的NAFLD患者, 并未检出脂酶素的显著影响, 却发现另一和胆固醇代谢相关的SNP(FDFT1, 编码rs2645424)和NAFLD组织学评分相关[36]. GWAS给基因研究带来希望, 但其结果还需进一步验证, 因其发现的基因前无记载, 缺乏传统病理生理学知识的支持.
表观遗传学(epigenetics)主要包括: 短链非编码RNA(如微小RNA亦称microRNAs、miRNAs、miRs)、DNA甲基化作用、组蛋白修饰作用、染色质重塑、遗传印记和泛化作用等, 在基因组DNA序列不发生变化的条件下, 令基因表达(蛋白)发生改变, 导致表型变化, 其在肿瘤、心血管病、精神病等领域已有较多报告, 而在NAFLD则刚起步[37,38]. 2008年Cheung等[39]首先报告15例活检证实的NASH和15例正常人对比结果, 有46个差异表达miRs, 其中23个上调(如miR-34a和miR-146b), 23个下调(如miR-122). 其结果很快被多个临床研究证实, 并进一步发现, miR-122是肝脏含量最多的miRs(占全部的70%), 在NASH患者表达下调63%, 并促进脂肪细胞分化[40]. 在肝脂肪变的大鼠模型, 用反义引物抑制miR-122表达, 可显著降低血胆固醇水平, 肝脏脂肪酸含量及多种脂肪酸合成酶的mRNA和蛋白表达, 并伴随脂肪肝组织学改善[41,42]. 除miR-122外, 尚有文献报告其他miRs和NAFLD发病相关: miR-34a和miR-146b在NASH患者表达上调(99%和80%)[39], miR-335表达随着肝脂肪、甘油三酯、胆固醇含量以及脂肪分化水平而升高[43], miR-181d表达上调伴随肝脏甘油三酯、胆固醇含量减少[44], miR-10b通过PPAR-α通道调节肝脂肪水平[45].
基因启动子区域CpG岛DNA甲基化可妨碍转录因子与启动子结合, 导致该基因转录下降甚至沉默, 在肝细胞癌已发现多种基因高甲基化[46], 然而在NAFLD领域的研究甚少. 最近一组纳入63例肝活检确诊NAFLD患者和11例正常人的对照研究显示, NAFLD组PPAR-γ共激因子1α(PPARGC1A)和线粒体转录因子A(mitochondrial transcription factor A, TFAM)的DNA甲基化显著增高, 但甲基化水平与组织学的严重性却不相关[47]. 在脂肪肝大鼠模型发现表观遗传学的异常, 包括基因组重复序列胞嘧啶甲基化丢失、转录物复制水平增高、组蛋白修饰异常和DNA甲基转移酶表达异常等[48].
NAFLD的诊断前需除(1)酒精性肝病, 即患者无饮酒史或饮酒折合乙醇量<140 g/wk(女性<70 g/wk); (2)病毒性肝炎、药物性肝病、自身免疫性肝病等可导致肝脂肪变性的特定疾病. 病理组织学是NAFLD诊断的金标准, 特征为肝细胞脂肪变和气球样变、小叶内炎症细胞浸润、窦周纤维化[1-4]. 推荐用美国立卫生研究院临床研究网病理工作组指南评估NAFLD严重性, 即按肝细胞脂肪变、小叶内炎症和肝细胞气球样变的程度计算NAFLD活动度积分(NAS), 肝细胞脂肪变>5%可诊断NAFLD, NAS>4分则可诊断NASH[49]. 腹部B超检查无创、价廉, 是诊断脂肪肝的首选方法, 表现如下: (1)肝脏近场回声弥漫性增强(所谓明亮肝), 回声强于肾脏; (2)肝内管道结构显示不清; (3)肝脏远场回声逐渐衰减. 具备上述3项中2项者可诊断. B超诊断特异性高(可达97%), 敏感性较低(64%), 对轻症者(肝脂肪化<30%)会漏诊, 而对肝脂肪化>30%患者, 敏感性接近100%. 换句话说B超诊断脂肪肝结果可信, 而阴性者不能除外轻症脂肪肝. CT和MRI诊断肝脂肪变的准确性稍强于B超, CT诊断依据为肝脏密度普遍降低, 其中肝/脾CT值降低<1.0但≥0.7为轻度, <0.7但≥0.5为中度, <0.5为重度脂肪肝, MRI的原理和准确性和CT接近[1-4,50]. 新技术如氙CT(xenon CT)、氢质子MRI(1HMRI)、氢质子MR波谱分析(1H-MRS)等可半定量肝内脂肪含量, 但这些检查花费大, 目前只用于科研, 其中1HMRI技术较成熟, 有较高准确性. 瞬时弹性超声(fibroscan)和瞬时弹性图(transient elastography)通过检测肝脏弹性评估肝纤维化, 但对肝脏脂肪变、炎症等的判断无帮助. NASH是病情转变的拐点, 也是治疗的重点, 但目前所有影像学检查的共同缺点是不能检测肝脏的炎症和坏死, 故无法鉴别NAFL和NASH. 尽管血转氨酶水平升高、伴有MetS相关组分病和IR抵抗等均提示NASH的可能性, 但没有任何一项无创技术真正反映组织学改变[1-4,50,51]. 在临床工作中实施肝活检困难, 为此中国指南为NAFLD制定了工作定义: (1)影像学表现符合弥漫性脂肪肝的诊断标准, 且无饮酒史, 除外病毒性肝炎、药物性肝病、全胃肠外营养、肝豆状核变性、自身免疫性肝病等可导致脂肪肝的特定疾病; (2)有MetS相关组分病的患者出现不明原因的血清转氨酶增高持续半年以上. 减肥和改善IR后, 异常酶谱和影像学脂肪肝改善甚至恢复正常者, 符合其中1项可临床诊断NAFLD[4]. 目前NASH并无工作定义, 对疑诊者建议肝活检确诊.
NAFLD治疗的目标是延缓或阻止肝病进展、延缓或阻止MetS及其组分病(特别动脉硬化)的并发症发生, 提高患者生活质量和延长寿命. 主要方法包括基础治疗和药物治疗, 极少数患者需肝移植. 临床上需根据患者具体病情制定个体化诊疗方案, 大多数患者处于NAFL阶段, 病情稳定, 基础治疗为主, 而NASH患者易向肝硬化进展, 还需配合药物治疗. 治疗前评估代谢危险因素, 特别是MetS及其组分病, 常需一并处理[1-4].
基础治疗是治疗成功的基石, 适用于所有NAFLD患者. 方法是通过健康宣教, 纠正不良生活方式和行为, 如控制饮食、增加有氧运动、减肥等. 临床医师通常只笼统地和患者讲道理, 未和患者深入沟通, 制定具体的治疗方式和目标, 患者不会重视或无所适从, 效果当然不满意. NAFLD患者需如同糖尿病患者一样在医师指导下调节生活, 针对患者饮食、运动、体质量、腰围以及与生活质量等不同个体情况, 设置患者理解和接受的控制饮食方案(总热卡数和食谱等)、制定合理的运动量(包括运动方式和时间等), 必要时请营养师和理疗师会诊, 共同确定方案. 治疗开始后长期随诊, 加强管理, 对方案及时调整, 才能保证疗效, 这要求医师付出大量精力和时间[1-4,52].
药物治疗是重要的辅助手段, 鉴于NAFLD通常和MetS及其相关组分病并存, 许多研究显示, NAFLD也是MetS的组分病之一, 故治疗NAFLD需同时兼顾防治代谢紊乱, 改善IR. 药物包括减肥药: 西布曲明、奥利司他等; 胰岛素增敏剂: 二甲双胍、噻唑烷二酮类药物(吡格列酮、罗格列酮等); 调脂药: 他汀类、贝特类等和保肝抗炎药物, 但至今尚没有任何一种得到循证医学证明的特效药物[1-4,51]. 近年发表的多个Meta分析, 纳入以肝穿刺结果为依据的临床随机对照研究, 显示减肥可显著改善NASH组织学的各项指标, 疗效与体质量下降正相关, 体质量下降3%-5%以上就可减轻肝脂肪变, 但只有体质量下降高达10%才能改善肝脏炎症和坏死程度, 临床有过半数患者无法达减肥目标[2,53]. 噻唑烷二酮类药物可显著改善NASH的肝细胞脂肪变、小叶内炎症和肝细胞气球样变, 而对肝纤维化的疗效仅刚达到显著性, 尚需更多研究证实[54,55]. 二甲双胍对NASH的疗效并不显著[56]. 他汀类药物对肝组织学的改善作用未被证实[53,57]. 保肝抗炎药物中的抗氧化剂Vit E在国外报告较多, 结果不一, 尚没有足够资料支持或否定其疗效[58]. 其他护肝新药如己酮可可碱、L-卡尼汀等资料不足, 仅有几个小样本的临床随机对照研究认为有效[53]. 其他保肝抗炎药物(护肝药)包括多不饱和脂肪酸(易善复)、水飞蓟素(宾)、甘草酸制剂、双环醇、熊去氧胆酸、S-腺苷蛋氨酸和还原型谷胱甘肽等和中药材等, 许多在国外未上市, 或虽然上市但说明书的适应证不含NAFLD, 其作用机制涉及到抗氧化、甲基化、膜修复、抗炎、改善血脂、解毒等多方面, 在国内使用很广泛. 临床研究显示, 护肝药可改善肝脏影像学和血生化(肝功能)指标, 但因欠缺组织学验证的临床随机对照研究, 其地位至今仍有争论. 中国指南推荐, 在保证基础治疗的前提下, 下列情况使用护肝药: (1)肝组织学确诊的NASH; (2)临床、实验室以及影像学资料提示有肝损伤或进展性肝纤维化者, 例如合并血清转氨酶增高、MetS、2型糖尿病的NAFLD患者; (3)伴其他药物诱发的肝损伤, 或基础治疗中出现血清转氨酶增高者; (4)合并嗜肝病毒现症感染或其他肝病者, 推荐疗程6-12 mo以上[4]. 综上所述, 噻唑烷二酮类是目前循证医学证据最多的药物, 美国指南推荐可在医师指导下治疗NASH[1], 因药品说明书的适应证并不包括NAFLD, 我国指南只建议用于有IR的NAFLD患者[4]. 对二甲双胍和调脂药, 所有指南均只推荐用于有IR或血脂紊乱的NAFLD患者[1-4]. 他汀类药物可引起部分患者转氨酶增高, 多为一过性, 如患者无症状, 转氨酶增高在1-3正常上限范围内无需处理, 如>3正常上限则需减量或停药, 如总胆红素增加及凝血酶原时间延长, 提示显著肝功能损伤需立即停药[57]. 对接受药物治疗的患者需加强随诊, 主管医师至少每月随访1次, 每半年复查体质量、腰围、血压、肝功能、血脂和血糖和上腹部超声检查, 评估疗效和调整方案[1-4,51,53].
NAFLD患病率逐年增高, 引起关注. NAFL病情稳定, NASH是发生肝硬化的必经阶段, 也是肝病恶化的拐点和防治的重点. NAFLD常和MetS并存, 死亡原因也多为心脑血管疾病, 因此需兼顾处理两病. 病理组织学是诊断的金标准, B超是临床诊断的常用方法, 但无法鉴别NASH和NAFL. 控制饮食和增加运动等基础疗法是治疗成功的基石. 药物包括减肥药、胰岛素增敏剂、调脂药、保肝抗炎药物等, 尚没有循证医学证实的特效药物. 近年基因和表观遗传学研究为靶向诊治带来希望.
非酒精性脂肪性肝病(NAFLD)俗称脂肪肝, 是指以肝实质细胞脂肪变性为病理特征, 而无过量饮酒史, 又排除其他肝病的临床综合征, 其病理类型包括单纯性非酒精性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及NASH相关肝硬化, 后者可发展为肝癌.
张明辉, 副主任医师, 河北医科大学第一医院肝病中心(传染病)
NAFLD是复杂基因关联性疾病, 以往研究挑选与发病机制相关的基因(候选基因研究), 由于代谢综合征(MetS)基因研究较为深入, NAFLD常与MetS并存, 发病机制均与胰岛素抵抗(IR)相关, 故理论上凡是和MetS及IR相关的基因都可能与NAFLD有关.
Cheung首先报告15例活检证实的NASH和15例正常人对比结果, 有46个差异表达miRs, 其中23个上调(如miR-34a和miR-146b), 23个下调(如miR-122). 其结果很快被多个临床研究证实, 并进一步发现, miR-122是肝脏含量最多的miRs(占全部的70%), 在NASH患者中表达下调63%, 并促进脂肪细胞分化.
本文综述NAFLD基础和临床研究的相关文献, 报道不同观点以及创新成果, 并结合国内外指南, 对本领域的热点问题进行总结和提炼, 为读者提供有价值的信息, 促进NAFLD临床和科研两方面的知识普及和提高.
近年NAFLD发病率迅速升高, 受到极大关注. 本文综述NAFLD基础和临床研究文献, 报道不同观点以及创新成果, 并结合国内外指南, 对本领域的热点问题进行总结和提炼, 为读者提供有价值的信息, 促进NAFLD临床和科研两方面知识的普及和提高.
编辑: 翟欢欢 电编: 闫晋利
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