Transjugular Intrahepatic Portosystemic Shunt Promotes Hepatocellular Carcinoma Growth in Metabolic Dysfunction Associated Liver Disease

Abstract

Introduction: Transjugular intrahepatic portosystemic shunt (TIPS) is validated procedure to alleviate portal hypertension. However, its impact on hepatocellular carcinoma (HCC) remains poorly understood and its potential role in modulating tumor growth is debated. Methods: We performed bulk RNA sequencing of HCC samples from 34 patients with (n=17) and without (n=17) TIPS to identify transcriptional changes associated with shunting. Murine models of diethylnitrosamine (DEN)-induced HCC with surgically induced portosystemic shunt (PSS) were established under either normal diet (ND) or high-fat diet (HFD) to assess molecular and phenotypic effects of PSS in different metabolic contexts. Clinical validation was conducted using the Scientific Registry of Transplant Recipients (SRTR), comparing propensity score-matched MASH-related cirrhosis patients (n=913) with and without TIPS. Results: HCC nodules sequencing showed that TIPS is associated with a positive enrichment of immune-related pathways, without significant changes in immune cell composition. Five differentially expressed genes were upregulated, including coding genes FABP4, GCK, and FOSB which are correlated with improved survival in an independent dataset. ND mice with shunt did not show any difference in growth or carcinogenesis compared to controls. In contrast, HFD mice with shunts showed larger and faster growing HCCs (1.14 vs 0.22 mm3/week, p<0.001) with transcriptomic enrichment of metabolic and proliferative programs. In MASH patients from the SRTR, TIPS was also associated with larger and faster growing HCC (0.20 vs -0.47 cm3/month, p=0.004) consistent with preclinical data. Conclusion: TIPS leads to diverging effects on HCC depending on the underlying metabolic context: immunostimulatory in non-MASLD and tumor-promoting in MASLD. These results warrant further validation but suggest that the use of TIPS in MASLD-related HCC patients should be monitored carefully.