Genetic Landscape of PSVD: Hepatology, Feb.26

Porto-sinusoidal vascular disorder (PSVD) is a rare, non-cirrhotic vascular liver disease characterised by portal venule and sinusoidal abnormalities leading to portal hypertension. Despite its clinical significance, the underlying pathophysiology has remained poorly understood. In this comprehensive review, Ciriaci et al. systematically evaluate genetic mutations associated with PSVD, offering critical insights into its mechanistic basis.

The authors identify 34 genes and one chromosomal abnormality previously linked to PSVD and report an additional mutation in TBL1XR1 (Pierpont syndrome). Genetic associations fall into two broad categories:

Syndromic PSVD – occurring in multisystem disorders (e.g., telomere biology disorders, immune deficiencies, cystic fibrosis, Williams-Beuren syndrome, Turner syndrome).

Isolated PSVD – involving mutations such as KCNN3, DGUOK, GIMAP5, FCHSD1, TRMT5, and HRG.

Most cases present clinically with complications of portal hypertension rather than early liver dysfunction. Importantly, gene expression analyses reveal predominant involvement of immune cells, suggesting that immune-mediated vascular remodelling may play a central role in disease development. Pathway analyses further support two mechanistic subtypes: one driven by morphogenetic vascular abnormalities, and another secondary to immune dysregulation.

Clinically, the review recommends next-generation sequencing panels for patients with early-onset PSVD, syndromic features, or a family history.

This work redefines PSVD as a genetically heterogeneous disorder and highlights immune pathways as promising targets for future research and therapeutic development.