Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives

Simple Summary Portal hypertension (PH) and hepatocellular carcinoma (HCC) are major complications of liver cirrhosis with a detrimental impact on patient outcomes that share common mechanisms. The incidence of PH in patients with advanced HCC is increasing due to the significant improvement of survival outcomes due to systemic therapies, so the management of the complications associated with clinically significant portal hypertension (such as variceal bleeding and ascites) becomes crucial. Moreover, the administration of systemic treatment presents challenges due to the drug-related bleeding risks. This review aims to elucidate the common pathophysiology of PH and HCC, with a specific focus on the influence of systemic therapies on PH. Moreover, we summarize the available evidence regarding PH management in HCC patients. Finally, we discuss potential new strategies for addressing the coexistence of CSPH and HCC.Abstract The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.