The potential role of vascular alterations and subsequent impaired liver blood flow and hepatic hypoxia in the pathophysiology of non-alcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from steatosis to steatohepatitis (NASH) and fibrosis, but the underlying pathophysiological mechanisms remain largely unknown. As there is currently no approved pharmacological therapy and the prevalence of NAFLD keeps increasing, understanding of its pathophysiology is crucial. We hypothesise that vascular alterations in early NAFLD play a role in the progression of the disease by inducing an increased intrahepatic vascular resistance and consequently relative hypoxia in the liver. Evidence of the detrimental effects of hypoxia in NAFLD has already been observed in liver surgery, where the outcomes of steatotic livers after ischaemia-reperfusion are worse than in healthy livers, and in obstructive sleep apnoea, which is an independent risk factor of NAFLD. Moreover, early histological damage in NAFLD is situated in the pericentral zone, which is also the first zone to be affected by a decreased oxygen tension because of the unique hepatic vacsular anatomy that causes the pericentral oxygen tension to be the lowest. Angiogenesis is also a characteristic of NAFLD, driven by hypoxia-induced mechanisms, as demonstrated in both animal models and in humans with NAFLD. Relative hypoxia is most probably induced by impaired blood flow to the liver, caused by increased intrahepatic vascular resistance. An increased intrahepatic vascular resistance early in the development of disease has been convincingly demonstrated in several animal models of NAFLD, whereas an increased portal pressure, a consequence of increased intrahepatic vascular resistance, has been proven in patients with NAFLD. Animal studies demonstrated a decreased intrahepatic effect of vasodilators and an increased reactivity to vasoconstrictors that results in an increased intrahepatic vascular resistance, thus the presence of a functional component. Pharmacological products that target vasoregulation can hence improve the intrahepatic vascular resistance and this might prevent or reverse progression of NAFLD, representing an important therapeutic option to study. Some of the drugs currently under evaluation in clinical trials for NASH have interesting properties related to the hepatic vasculature. Some other interesting drugs have been tested in animal models but further study in patients with NAFLD is warranted.In summary, in this paper we summarise the evidence that leads to the hypothesis that an increased intrahepatic vascular resistance and subsequent parenchymal hypoxia in early NAFLD is an important pathophysiological driving mechanism for the progression of the disease.