Nonalcoholic fatty liver disease and portal hypertension

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.

Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging

“…Supraphysiological pressure in the portal venous system, called portal hypertension (PH), is a detrimental complication in liver cirrhosis ( 65 ). The pathophysiology of PH is complex, involving hepatic (increased intrahepatic resistance to portal venous blood flow due to tissue remodeling) and/or extrahepatic (splanchnic arterial vasodilation) factors ( 65 , 66 ). Despite the fact that PH has mostly been discussed in the context of cirrhosis, elevated portal venous pressure has also been detected in experimental or human NAFLD, when fibrosis was less advanced and cirrhosis was absent ( 66 , 67 ).…”

Idiopathic Non-Cirrhotic Portal Hypertension and Porto-Sinusoidal Vascular Disease: Review of Current Data

“…There is growing evidence that PH can occur in alcoholic fatty liver disease and NAFLD even in the absence of significant fibrosis/cirrhosis and that it correlates with the degree of steatosis [95][96][97][98][99][100][101]. Although the exact etiopathogenesis remains unclear, multiple hypotheses have been proposed.…”

SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial–mesenchymal transition

“…Liver fibrosis is a major risk factor to cause progressive liver diseases including cirrhosis, liver failure, and hepatocellular carcinoma, which are global health problem leading to severe morbidity and mortality (D. Y. Zhang & Friedman, 2012). Hepatic fibrosis, resulting from a dysregulated wound healing response to liver injury, is characterized by excessive deposition of extracellular matrix (ECM; Friedman, 2003; Ryou et al, 2020). It is widely acknowledged the contribution of activated hepatic stellate cells (HSCs) to the pathogenesis of liver fibrosis.…”