The genetics of portal hypertension: Recent developments and the road ahead

Abstract

Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome‐wide association studies or whole‐exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non‐cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

Genetics of liver disease in adults

“…Insights into porto-sinusoidal vascular diseases (PSVDs), a clinically heterogeneous group of disorders that coalesce into a common phenotype of noncirrhotic portal hypertension, have been further elucidated by the recent discovery of several monogenic diseases underlying their pathogenesis. 115 These include rare biallelic variants in DGUOK , GIMAP5 , and TRMT5 , as well as heterozygous variants in KCNN3 , FOPV (C4ORF54) , and FCHSD1 . 82 , 83 , 116 – 119 GIMAP5 , KCNN3 , and FOPV have been suggested to contribute to maintaining the integrity of the liver vasculature, while DGUOK and TRMT5 play a role in mitochondrial DNA maintenance.…”

Transjugular Intrahepatic Portosystemic Shunt in Nonmalignant Noncirrhotic Portal Vein Thrombosis and Portosinusoidal Vascular Disorder

“…This underscores the need for targeted research to develop specific guidelines and treatment thresholds for PSVD patients. The lack of data specific to this population is secondary to both the rare nature of the disorder, which causes difficulties for single-center studies, and the relatively recent individuation of the disease with continuously evolving definitions and diagnostic criteria [ 56 , 57 ].…”