Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges

Abstract

Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.

Keywords: Non-alcoholic fatty liver disease, Portal hypertension, Mechanotransduction, Endothelial dysfunction, Hepatic venous pressure gradient

Core Tip: Portal hypertension (PH) occurs in patients with cirrhosis, but in non-alcoholic fatty liver disease (NAFLD) it is sometimes observed in non-cirrhotic stages due to perisinusoidal fibrosis and damage to liver microcirculation. The severity of PH tends to be underestimated by hepatic venous pressure gradient (HVPG) measurement in NAFLD, potentially due to the presence of pre-sinusoidal component, and some patients decompensate at HVPG < 10 mmHg. Liver elastography needs further validation in obese patients as it might overestimate the severity of PH. While candidate drugs for PH are currently in development, lifestyle changes and modulation of metabolic derangements remain the mainstay of treatment.