Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β-Catenin, Hedgehog, HIPPO/Yap/TAZ and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient-specific activation of these pathways may explain the variability in clinical presentation, and the zone-specific response observed in clinical trials.

中文翻译：

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NASH 分区——理解病理生理学和临床结果的关键范例

非酒精性脂肪性肝病 (NAFLD) 的存在范围从简单的脂肪变性到组织学定义的肝细胞损伤和定义脂肪性肝炎 (NASH) 的炎症变化，并增加纤维化的风险。尽管尚未系统研究 NASH 的区域差异，但与中心周围疾病相比，门静脉周围受累与更差的代谢结果和更多的肝纤维化相关。这些数据表明，肝脏疾病分区可能影响临床表现的多样性。同样，几项随机临床试验表明，基于疾病分区的不同反应，对门静脉周围（半胱胺）或中心周围疾病（奥贝胆酸、吡格列酮）具有优先影响。耐人寻味的是，已知影响区域发育和维持的形态发生途径——WNT/β-Catenin、Hedgehog、HIPPO/Yap/TAZ 和 Notch——与 NASH 发病机制有关，潜在 NASH 疗法下游的核激素受体显示区域偏好。在这篇综述中，我们总结了这些数据，并提出这些途径的患者特异性激活可以解释临床表现的变异性，以及临床试验中观察到的区域特异性反应。