修回日期: 2014-06-17
接受日期: 2014-06-19
在线出版日期: 2014-08-18
非酒精性脂肪肝病(nonalcoholic fatty liver disease)是指除酒精和其他明确因素所致, 以肝实质细胞脂肪变性和肝小叶内炎症为特征的临床病理综合征, 是遗传-环境-代谢应激相关性疾病, 包括单纯性脂肪肝(nonalcoholic simple fatty liver)及由其演变的非酒精性脂肪性肝炎(nonalcoholic steatohepatitis)和肝硬化.
核心提示: 非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)早期病情稳定, 尽早干预后期较好. 非酒精性脂肪性肝炎(nonalcoholic steatohepatitis)是病情转化的拐点和防治的重点, 容易发展成肝硬化, 因此早期诊断成为该病预后的关键因素. 虽然病理活检是诊断NAFLD的"金标准", 但目前临床上最常用的仍是影像学检查, 如: 超声、计算机断层扫描、核磁共振成像. 近年来瞬时弹性波扫描(Fibroscan)成为评估NAFLD肝纤维化程度的重要手段. Fibroscan根据声波传导速率与组织硬度相关的原理对肝脏的纤维化程度进行瞬时弹性测定, 适用于初次活检后随访患者, 可靠价廉, 且重复性好.
引文著录: 王素琴, 黄缘. 非酒精性脂肪肝病的研究进展. 世界华人消化杂志 2014; 22(23): 3410-3415
Revised: June 17, 2014
Accepted: June 19, 2014
Published online: August 18, 2014
Nonalcoholic fatty liver disease (NAFLD) refers to a clinicopathologic syndrome characterized by a spectrum of histological abnormalities such as hepatocyte fatty degeneration and liver inflammation, not including those caused by alcohol and other specific factors. NAFLD is a heredity, environmental, metabolic disease, and its spectrum ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis and liver cirrhosis.
- Citation: Wang SQ, Huang Y. Advances in research of nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2014; 22(23): 3410-3415
- URL: https://www.wjgnet.com/1009-3079/full/v22/i23/3410.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i23.3410
在欧美、日本等国家非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)是慢性肝病的首因, 在我国仅次于病毒性肝炎, 居第2位. NAFLD的发病率呈上升趋势, 在发达国家发病率为20%-30%, 非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)发病率为10%-20%, 肝硬化发病率为2%-3%. 我国NAFLD的患病率因性别、年龄以及地区不同有较大差异. 国内男女发病比例约为2:1, 但55岁以后发病率女性多于男性, 可能与激素水平改变有关. 其中41-50岁占47.92%, 但脂肪肝的发生率有显著年轻化趋势, 可能是青春期、男性、低出生体质量儿出生后快速生长等原因造成的, 目前我国肥胖儿约占59.6%. 非洲平均发病年龄略低于欧洲[1-7].
该病的病因及发病机制复杂, 目前有几个假说. Day提出的"二次打击"学说仍占主导地位,"二次打击"学说中胰岛素抵抗(insulin resistance, IR)、氧化应激和脂质过氧化仍是当前公认的关键因素[8-10].
一次打击主要为IR, 临床研究发现几乎所有患者都有肝脏及周围组织IR, 其严重程度与NAFLD病情进展正相关. IR不仅可以加强周围组织脂肪的分解, 也可形成高胰岛素血症, 从而形成肝细胞的第一次打击. 异常的肝细胞表面胰岛素受体减少且受体缺陷, 使肝细胞对胰岛素的敏感性降低, 加重IR. NAFLD患者出现IR, 而IR的产生又加重了NAFLD的发生, 形成了IR与NAFLD之间的不良循环[11-13].
二次打击有多种因素导致的损伤, 包括氧化应激、脂质过氧化、瘦素抵抗、自由基大量产生等. 氧化应激与随之产生的脂质过氧化是使机体受到"二次打击"、促进 NAFLD发展的重要因素[14].
1.2.1 氧化应激: 若细胞内抗氧化系统不能及时清除活性氧基团(reactive oxygen species, ROS), 大量ROS可改变细胞膜的通透性及流动性、引起蛋白及核酸的损伤, 使细胞功能失调产生氧化应激反应. 氧化应激可激活库普弗细胞, 激活的库普弗细胞又能诱导解耦联蛋白2(uncoupling protein 2, UCP2)的表达. 当UCP2高表达时, 脂肪酸氧化与三磷酸腺苷(ATP)形成解耦联, 形成甘油三酯(triglyceride, TG)时能量供应不足, 肝脏中TG的蓄积相应减少. 但随着氧化反应的持续进行, 可能会导致ATP 耗竭, 造成氧化应激, 生成大量过氧化物, 从而导致肝细胞的损伤死亡. 死亡的肝细胞刺激机体自身免疫系统, 促使纤维化的发生, 又导致NAFLD的加重. 在NAFLD中, UCP2表达有着双面性, 高表达使细胞损伤加剧, 低表达又使机体处于持续性的氧化应激状态. 所以, UCP2在NAFLD作用机制的研究将为NAFLD新的治疗方法提供可能[10,15].
1.2.2 脂质过氧化: ROS生成增加, 他与多价不饱和脂肪酸结合, 形成脂质过氧化物, 即丙二醛(malondialdehyde, MDA)和β-羟化壬烯(β- hydroxy nonene, β-HNE). MDA可使蛋白质发生交联形成酒精性透明小体, 诱发自身免疫反应; β-HNE趋化中性粒细胞, 导致炎性细胞浸润. MDA与β-HNE毒性强, 通过损伤线粒体DNA及蛋白质、改变谷胱甘肽代谢来影响呼吸链中的电子传递, 促进ROS及过氧化脂的增多. 脂质过氧化物既可以增加内源性ROS毒性, 亦抑制抗氧化剂活性, 提高对外源性过氧化物损害的敏感性. 同时细胞内的ATP及抗氧化物减少, 使ROS不能及时灭活, 使ROS、脂质过氧化物大量积聚, 抗氧化能力下降的恶性循环, 最终导致 NAFLD、肝纤维化甚至肝硬化发生[16].
近来也有学者提出"四次打击"的学说, 即在二次打击的基础上, 机体对受损的肝细胞进行修复, 发生肝纤维化(第三步), 肝脏微循环障碍, 组织细胞缺血坏死, 肝小叶重建, 最终导致肝硬化, 即"四次打击". 但无论是二次打击还是四次打击, 都认为IR是NAFLD发生、进展的中心环节.
目前认为肝细胞有5%以上被脂肪浸润或组织学上每单位面积有三分之一以上肝细胞脂肪变就诊断为脂肪肝[17]. 临床采用B超、计算机断层扫描(computed tomography, CT)、肝细胞活检及3.0T磁共振氢波谱成像技术等多种方法进行诊断. B超为首选诊断方法, 其诊断特异性高(可达97%), 敏感性较低(64%), CT诊断依据是肝组织密度普遍降低[18-20], 新技术疝CT、氢离子MRI、氢质子波谱分析等可半定量肝内脂肪含量, 瞬时弹性超声和瞬时弹性图可通过检测肝脏弹性评估肝纤维化[21], 但对肝脂肪变、炎症等的判断帮助不大. 目前认为影像学的共同缺点是不能评估肝脏的炎症和坏死情况, 故无法鉴别NAFL和NASH. 肝活检为确诊金标准, 典型病理改变为大泡性或以大泡为主并伴有小泡[22-25].
包括运动疗法、饮食疗法和行为疗法. NAFLD的初期, 通过一般治疗就可得到较好控制, 科学的运动加上合理饮食, 常无需药物治疗, 即可逆转脂肪肝. 有研究报道, 合理的饮食与科学的减重有助于肝功能的恢复. 然而过快的体质量下降会诱发潜在的肝脏疾病, 引起肝炎甚至肝硬化[26,27].
3.2.1 噻唑烷二酮类药物(thiazolidinediones, TZDs): 主要通过结合与活化过氧化物酶增殖物激活受体γ(peroxisome proliferator-activated receptor γ, PPARγ)起作用, 主要有两种药物: 罗格列酮和吡格列酮. 据国内报道, 罗格列酮治疗NAFLD是安全有效的, 尚缺少组织学依据, 国际上仍质疑长期使用罗格列酮的安全性. 2010年美国食品和药物管理局(Food and Drug Administration, FDA)已因罗格列酮心血管的不良反应限制其使用. 口服吡格列酮组患者的丙氨酸氨基转移酶(alanine transaminase, ALT)、γ-谷氨酰转肽酶(gamma glutamyl transpeptidase, GGT)明显下降, 肝脏组织炎症、IR均有明显改善, 但充血性心脏疾病、骨质疏松、增加体质量等不良反应也令人担忧[26].
3.2.2 二甲双胍: 通过减轻肝脏的IR, 来减少肝细胞葡萄糖的输出, 降低血糖, 控制肝脏的糖异生. 二甲双胍可降低血清ALT、天冬氨酸转氨酶、胰岛素和c-肽水平, 改善IR, 但对改善肝纤维化效果不明显. 二甲双胍对脂肪性肝炎患者确实有一定的治疗作用[28-30].
3.3.1 熊去氧胆酸(ursodeoxycholic acid, UDCA): UDCA具有抗氧化、抗凋亡、具有稳定细胞膜、保护线粒体、调节免疫的作用, 通过抑制细胞凋亡来控制由脂肪变性向脂肪炎症转变. 研究证实该药可使脂肪肝患者改善肝功能酶学异常以及肝细胞脂肪变程度. 近来发现胆汁酸是糖脂代谢途径的信号分子之一, 为UDCA治疗NAFLD提供了可靠依据, 至于确切疗效, 尚待临床验证[31,32].
3.3.2 还原型谷胱甘肽: 含有活性的-SH基团, 具有抑制脂质过氧化、减少活性氧、稳定生物膜及抗凋亡的作用, 能维持细胞完整性及正常代谢, 肝受损时可减少自由基产生, 起保护作用. 补充还原型谷胱甘肽及其前体能有效降低NAFLD患者的转氨酶水平[33].
研究表明高脂血症是NAFLD的重要危险因素之一, 降脂药辛伐他汀的机制主要是竞争性抑制肝内合成的胆固醇的限速酶活性, 使肝内胆固醇合成减少, 降低血浆总胆固醇活度. 随着对他汀类药物研究深入, 辛伐他汀的抗氧化、抗炎、抑制细胞增殖、改善内皮功能、减少血栓形成等非降脂作用日益受到重视. 已有报道辛伐他汀能降低NAFLD患者的血脂水平, 减轻肝脏脂质沉积, 在NAFLD肝纤维化发展中也有一定保护作用[34].
肥胖是NAFLD的重要发病因素, 奥利司他是一种特异性胃肠道脂肪酶抑制剂, 1999年FDA批准其作为一种减肥处方药, 配合低卡路里饮食可减少食物中30%的脂肪吸收. 但在2010年FDA又发出警告, 奥利司他也会发生罕见的严重肝损害[35].
微生态制剂有减轻体质量、抗炎、改善脂质代谢紊乱及降血脂的作用, 治疗效果可能与局部微生态的改变、肠道炎症、上皮细胞的屏障功能、氧化应激等机制有关, 因此调整肠道微生态平衡成为NAFLD防治的新靶点. 目前使用的微生态制剂包括微生态调节剂(益生菌、益生元和合生元)和抗生素(多黏菌素B和新霉素). 但微生态制剂治疗NAFLD确切的疗效尚需探讨[36-42].
3.7.1 减肥手术: 适合于改变生活方式及药物治疗不理想但同时合并肥胖相关疾病的患者. 外科减肥术式包括限制摄入和吸收两大类, 分别以胃囊袋术(adjustable gastric banding, AGB)和Roux-en-Y胃旁路术(Roux-en-Y gastric bypass, RYGB)为代表. 国外研究表明, 采用AGB和RYGB术式配合, 手术前后病理对比, 均提示患者坏死活动性炎症、肝脂肪变性、肝纤维化有改善. 但术后可出现倾倒综合征、维生素缺乏等并发症, 手术治疗还存在争议[43].
3.7.2 肝移植术: 当NASH发展至终末期, 肝移植是可以延长生命的唯一选择, 但NAFLD在肝脏移植后还会复发, 且从NAFLD很快进展为NASH. 这种移植后的复发表明, 肝移植不能治愈潜在的代谢紊乱, 故术前应全面评估代谢危险因素及其合并症, 术后仍需加强代谢综合征的治疗, 对一些高危患者进行移植前应慎重评估[44-50].
NAFLD早期病情稳定, 应尽早进行干预. NASH是病情转化的拐点和防治的重点, 容易发展成肝硬化, 因此早期诊断成为该病预后的关键因素. 虽然病理活检是诊断NAFLD的"金标准", 但目前临床上最常用的仍是影像学检查, 如: 超声、CT、核磁共振成像. 近年来瞬时弹性波扫描(Fibroscan)成为评估NAFLD肝纤维化程度的重要手段. Fibroscan根据声波传导速率与组织硬度相关的原理对肝脏的纤维化程度进行瞬时弹性测定, 适用于初次活检后随访患者, 可靠价廉, 且重复性好, 在欧洲已广泛应用, 使越来越多的人对NAFLD有了更多认识.
随着肥胖及相关代谢综合征全球化的趋势, 脂肪肝已成为发达国家和我国发达地区慢性肝病的重要病因, 成为我国仅次于病毒性肝炎的第二大肝病, 是隐蔽性肝硬化的常见原因, 严重威胁人类的健康.
庄林, 主任医师, 昆明市第三人民医院肝病科.
脂肪肝属早期为可逆性疾病, 预防与治疗本病的关键在于早诊断, 金标准为病理组织活检, 为有创性检查不作为常规, 新技术疝CT、氢离子MRI、氢质子波谱分析等可半定量肝内脂肪含量, 瞬时弹性超声图可通过检测肝弹性评估肝纤维化程度.
非酒精性脂肪肝病(non alcoholic fatty liver disease, NAFLD)的发病率呈上升趋势, 在我国 NAFLD 的患病率因性别、年龄以及地区不同有较大差异. 发病机制复杂, 二次打击学说占主导地位, 近来也有学者提出"四次打击"的学说, 即在二次打击的基础上, 机体对受损的肝细胞进行修复, 发生肝纤维化(第三步), 肝脏微循环障碍, 组织细胞缺血坏死, 肝小叶重建, 最终导致肝硬化, 即"四次打击".
NAFLD在我国趋向于低龄化, 尤其是肥胖儿童, 妊娠期急性脂肪肝也不少见, 且预后较差, 要提高警惕.
早期脂肪肝是可逆的, 应尽早对其进行干预, 尤其是早期的饮食、生活方式的控制可以取得很好的效果, 药物治疗也是多方面的, 需根据发病机制进行减肥、降糖、降脂、抗纤维化等综合治疗, 必要时给予手术治疗, 取得最佳治疗效果.
早期脂肪肝是可逆的, 应尽早对其进行干预, 尤其是早期的饮食、生活方式的控制可以取得很好的效果, 药物治疗也是多方面的, 需根据发病机制进行减肥、降糖、降脂、抗纤维化等综合治疗, 必要时给予手术治疗, 取得最佳治疗效果.
编辑 田滢 电编 都珍珍
| 1. | Pascale A, Pais R, Ratziu V. An overview of nonalcoholic steatohepatitis: past, present and future directions. J Gastrointestin Liver Dis. 2010;19:415-423. [PubMed] |
| 2. | Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2013;28 Suppl 1:11-17. [PubMed] [DOI] |
| 3. | Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679-689. [PubMed] [DOI] |
| 4. | Lin YC, Chang PF, Hu FC, Yang WS, Chang MH, Ni YH. A common variant in the PNPLA3 gene is a risk factor for non-alcoholic fatty liver disease in obese Taiwanese children. J Pediatr. 2011;158:740-744. [PubMed] [DOI] |
| 5. | Lin YC, Chang PF, Chang MH, Ni YH. Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am J Clin Nutr. 2014;99:869-874. [PubMed] [DOI] |
| 6. | Lin YC, Chang PF, Chang MH, Ni YH. A common variant in the peroxisome proliferator-activated receptor-γ coactivator-1α gene is associated with nonalcoholic fatty liver disease in obese children. Am J Clin Nutr. 2013;97:326-331. [PubMed] [DOI] |
| 7. | Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58:1538-1544. [PubMed] [DOI] |
| 8. | Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med. 2009;9:299-314. [PubMed] [DOI] |
| 9. | Day CP. Non-alcoholic fatty liver disease: a massive problem. Clin Med. 2011;11:176-178. [PubMed] [DOI] |
| 10. | Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010;16:1941-1951. [PubMed] [DOI] |
| 11. | Orlik B, Handzlik G, Olszanecka-Glinianowicz M. [The role of adipokines and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease]. Postepy Hig Med Dosw (Online). 2010;64:212-219. [PubMed] [DOI] |
| 12. | Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:575-94, ix. [PubMed] [DOI] |
| 13. | Gariani K, Philippe J, Jornayvaz FR. Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside. Diabetes Metab. 2013;39:16-26. [PubMed] [DOI] |
| 14. | Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis. Hepatology. 2008;48:670-678. [PubMed] [DOI] |
| 15. | Asrih M, Jornayvaz FR. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J Endocrinol. 2013;218:R25-R36. [PubMed] [DOI] |
| 16. | Kasapoglu B, Turkay C, Yalcin KS, Carlioglu A, Sozen M, Koktener A. Low vitamin D levels are associated with increased risk for fatty liver disease among non-obese adults. Clin Med. 2013;13:576-579. [PubMed] [DOI] |
| 17. | Ogawa Y, Imajo K, Yoneda M, Nakajima A. [Pathophysiology of NAsh/NAFLD associated with high levels of serum triglycerides]. Nihon Rinsho. 2013;71:1623-1629. [PubMed] |
| 18. | Lidofsky SD. Nonalcoholic fatty liver disease: diagnosis and relation to metabolic syndrome and approach to treatment. Curr Diab Rep. 2008;8:25-30. [PubMed] [DOI] |
| 20. | Basaranoglu M, Kayacetin S, Yilmaz N, Kayacetin E, Tarcin O, Sonsuz A. Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:2223-2226. [PubMed] [DOI] |
| 21. | Xia MF, Yan HM, He WY, Li XM, Li CL, Yao XZ, Li RK, Zeng MS, Gao X. Standardized ultrasound hepatic/renal ratio and hepatic attenuation rate to quantify liver fat content: an improvement method. Obesity (Silver Spring). 2012;20:444-452. [PubMed] [DOI] |
| 23. | Novakovic T, Mekic M, Smilic L, Smilic T, Inić-Kostic B, Jovicevic L, Mirkovic Z, Milinic S. Anthropometric and biochemical characteristics of patients with nonalcoholic fatty liver diagnosed by non-invasive diagnostic methods. Med Arh. 2014;68:22-26. [PubMed] [DOI] |
| 24. | Paul S, Sepehr GJ, Allison HV. Abnormal liver function tests in the third trimester: a diagnostic dilemma. Acute fatty liver of pregnancy. Gastroenterology. 2014;146:910, 1136. [PubMed] [DOI] |
| 25. | Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013;58:1007-1019. [PubMed] [DOI] |
| 26. | Expert Committee on the Diagnosis and Management of Fatty Liver Disease, Chinese Medical Association. [Recommendation for standardization of diagnosis and treatment of fatty liver disease]. Zhonghua Ganzangbing Zazhi. 2013;21:652-655. [PubMed] |
| 27. | Centis E, Moscatiello S, Bugianesi E, Bellentani S, Fracanzani AL, Calugi S, Petta S, Dalle Grave R, Marchesini G. Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease. J Hepatol. 2013;58:771-777. [PubMed] [DOI] |
| 28. | Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-1685. [PubMed] [DOI] |
| 29. | Shyangdan D, Clar C, Ghouri N, Henderson R, Gurung T, Preiss D, Sattar N, Fraser A, Waugh N. Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Health Technol Assess. 2011;15:1-110. [PubMed] [DOI] |
| 30. | Targher G, Bellis A, Fornengo P, Ciaravella F, Pichiri I, Cavallo Perin P, Trimarco B, Marchesini G. Prevention and treatment of nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42:331-340. [PubMed] [DOI] |
| 31. | Linden MA, Fletcher JA, Morris EM, Meers GM, Kearney ML, Crissey JM, Laughlin MH, Booth FW, Sowers JR, Ibdah JA. Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am J Physiol Endocrinol Metab. 2014;306:E300-E310. [PubMed] [DOI] |
| 32. | Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rössle M, Cordes HJ, Zeuzem S, Hein J, Berg T. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472-479. [PubMed] [DOI] |
| 33. | Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, Sogni P, Maynard M, Larrey D, Serfaty L. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54:1011-1019. [PubMed] [DOI] |
| 35. | Tokunaga A, Miura A, Okauchi Y, Segawa K, Fukuhara A, Okita K, Takahashi M, Funahashi T, Miyagawa J, Shimomura I. The -1535 promoter variant of the visfatin gene is associated with serum triglyceride and HDL-cholesterol levels in Japanese subjects. Endocr J. 2008;55:205-212. [PubMed] |
| 36. | Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes (Lond). 2010;34:190-194. [PubMed] [DOI] |
| 37. | Ryder E, Mijac V, Fernández E, Palazzi N, Morales MC, Connell L, Parra A, Romero M, Fernández N. [Hepatic steatosis, visceral fat and metabolic alterations in apparently healthy overweight/obese individuals]. Invest Clin. 2014;55:3-14. [PubMed] |
| 38. | Iacono A, Raso GM, Canani RB, Calignano A, Meli R. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem. 2011;22:699-711. [PubMed] [DOI] |
| 39. | Mykhal'chyshyn HP, Bodnar PM, Kobyliak NM. [Effect of probiotics on proinflammatory cytokines level in patients with type 2 diabetes and nonalcoholic fatty liver disease]. Lik Sprava. 2013;56-62. [PubMed] |
| 40. | Delzenne NM, Cani PD. Gut microbiota and the pathogenesis of insulin resistance. Curr Diab Rep. 2011;11:154-159. [PubMed] [DOI] |
| 41. | Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:691-701. [PubMed] [DOI] |
| 42. | Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS One. 2013;8:e63388. [PubMed] [DOI] |
| 44. | Reddy SK, Zhan M, Alexander HR, El-Kamary SS. Nonalcoholic fatty liver disease is associated with benign gastrointestinal disorders. World J Gastroenterol. 2013;19:8301-8311. [PubMed] [DOI] |
| 45. | Newsome PN, Allison ME, Andrews PA, Auzinger G, Day CP, Ferguson JW, Henriksen PA, Hubscher SG, Manley H, McKiernan PJ. Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. Gut. 2012;61:484-500. [PubMed] [DOI] |
| 46. | Shiota G, Uto H, Ono M, Tokushige K, Sumida Y, Hyogo H. [Progress in treatment and study of NAFLD. Discussion]. Nihon Shokakibyo Gakkai Zasshi. 2014;111:42-60. [PubMed] |
| 47. | Yoneda M. [Update of the management and prognosis of nonalcoholic fatty liver disease]. Nihon Shokakibyo Gakkai Zasshi. 2014;111:35-41. [PubMed] |
| 48. | Kemmer N, Neff GW, Franco E, Osman-Mohammed H, Leone J, Parkinson E, Cece E, Alsina A. Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation. Transplantation. 2013;96:860-862. [PubMed] [DOI] |
| 49. | Charlton M. Evolving aspects of liver transplantation for nonalcoholic steatohepatitis. Curr Opin Organ Transplant. 2013;18:251-258. [PubMed] [DOI] |