Background

Non-alcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (non-alcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly arising from the worldwide obesity and diabetes epidemics.

Scope of review

This review summarizes knowledge on the pathogenesis underlying NAFLD, focussing on studies in humans, addressing hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, oxidative stress, but also highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials.

Major Conclusions.

Recent studies provide evidence that certain conditions seem to predispose for excessive risk of NAFLD and its accelerated progression, such as the severe insulin resistance diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants. Recent clinical trials were frequentely unsuccessful to halt or prevert NAFLD progression, which may be resulting in part from including unselected cohorts in later stages of NAFLD. It is proposed to screen for people with the highest genetic or acquired risk of disease progression, e. g. the SIRD subgroup and to develop treatment concepts, specifically targetting the earliest pathophysiolgical alterations, i. e. adipocyte dysfunction and insulin resistance.

中文翻译：

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非酒精性脂肪肝（NAFLD）从人类发病机制到治疗理念

背景

非酒精性脂肪肝病 (NAFLD) 包括肝脏改变，伴有脂质积累增加（脂肪变性），不伴有或伴有炎症（非酒精性脂肪性肝炎，NASH）和/或纤维化，但没有其他肝病原因。NAFLD 正在成为一项新兴的健康挑战，主要源于全球肥胖和糖尿病的流行。

审查范围

这篇综述总结了 NAFLD 发病机制的知识，重点关注人类研究，解决高热量营养问题，包括饱和脂肪和果糖的影响，以及脂肪组织功能障碍，导致肝脂毒性、线粒体功能异常、氧化应激，但也强调肠道菌群失调。这些机制是在当前针对代谢途径的治疗和相关临床试验结果的背景下讨论的。

主要结论。

最近的研究提供的证据表明，某些条件似乎容易导致 NAFLD 风险过高及其加速进展，例如严重胰岛素抵抗糖尿病 (SIRD) 亚组（簇）以及越来越多的基因变异的存在。最近的临床试验经常未能成功阻止或预防 NAFLD 进展，部分原因可能是由于纳入了 NAFLD 后期未经选择的队列。建议筛查具有最高遗传或获得性疾病进展风险的人群，例如SIRD亚组，并制定治疗概念，特别针对最早的病理生理学改变，即脂肪细胞功能障碍和胰岛素抵抗。