Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, 150 South Huntington Avenue, Room 6A-46, Boston, MA, 02130, USA.
Dig Dis Sci. 2018 Mar;63(3):563-576. doi: 10.1007/s10620-017-4903-5. Epub 2018 Jan 22.
Nonalcoholic fatty liver disease (NAFLD) advanced to cirrhosis is often complicated by clinically significant portal hypertension, which is primarily caused by increased intrahepatic vascular resistance. Liver fibrosis has been identified as a critical determinant of this process. However, there is evidence that portal venous pressure may begin to rise in the earliest stages of NAFLD when fibrosis is far less advanced or absent. The biological and clinical significance of these early changes in sinusoidal homeostasis remains unclear. Experimental and human observations indicate that sinusoidal space restriction due to hepatocellular lipid accumulation and ballooning may impair sinusoidal flow and generate shear stress, increasingly disrupting sinusoidal microcirculation. Sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells are key partners of hepatocytes affected by NAFLD in promoting endothelial dysfunction through enhanced contractility, capillarization, adhesion and entrapment of blood cells, extracellular matrix deposition, and neovascularization. These biomechanical and rheological changes are aggravated by a dysfunctional gut-liver axis and splanchnic vasoregulation, culminating in fibrosis and clinically significant portal hypertension. We may speculate that increased portal venous pressure is an essential element of the pathogenesis across the entire spectrum of NAFLD. Improved methods of noninvasive portal venous pressure monitoring will hopefully give new insights into the pathobiology of NAFLD and help efforts to identify patients at increased risk for adverse outcomes. In addition, novel drug candidates targeting reversible components of aberrant sinusoidal circulation may prevent progression in NAFLD.
非酒精性脂肪性肝病（NAFLD）进展为肝硬化时，常伴有临床显著的门静脉高压，这主要是由肝内血管阻力增加引起的。肝纤维化已被确定为这一过程的关键决定因素。然而，有证据表明，当纤维化程度较低或不存在时，门静脉压力可能在 NAFLD 的最早阶段开始升高。窦状隙稳态这些早期变化的生物学和临床意义仍不清楚。实验和人体观察表明，由于肝细胞脂质堆积和气球样变导致的窦状隙空间受限，可能会损害窦状隙血流并产生剪切力，从而越来越破坏窦状隙微循环。窦状内皮细胞、肝星状细胞和枯否细胞是受 NAFLD 影响的肝细胞的关键伙伴，通过增强收缩性、毛细血管化、血细胞黏附与捕获、细胞外基质沉积和新生血管形成，促进内皮功能障碍。这些生物力学和流变学变化因肠道-肝脏轴功能障碍和内脏血管调节而加重，最终导致纤维化和临床显著的门静脉高压。我们可以推测，门静脉压力升高是整个 NAFLD 发病机制的一个重要因素。改进的非侵入性门静脉压力监测方法有望深入了解 NAFLD 的病理生物学，并有助于识别发生不良结局风险增加的患者。此外，针对异常窦状循环可逆成分的新型药物候选物可能会阻止 NAFLD 的进展。
