Impact of Hepatocellular Carcinoma on the risk of liver decompensation: a comparative analysis of patients with and without HCC: Role of HCC in liver decompensation

Background & aims: Hepatocellular Carcinoma (HCC) is a leading cause of death and the large majority of HCC occurs in the setting of cirrhosis. Nevertheless, its impact on the development of decompensation in these patients has not been investigated, yet. Our aim was to investigate the role of HCC in the development of decompensating events in patients with cirrhosis. Methods: Clinical data of outpatients with cirrhosis from two Italian tertiary centers (Padua and Milan) were collected and followed prospectively from January 2000 to December 2021, until the end of the study, death or liver transplantation. Demographic, clinical, and laboratory data were collected. The primary outcome was the development of decompensating events after the diagnosis of HCC. HCC and effective etiological treatment were considered as a time-varying covariate for the statistical analysis. Results: Overall, 1,176 cirrhotics of any etiology were enrolled (Padua 876, Milan 300), and 358 (30.4%) developed HCC. In the study cohort (Padua cohort), patients who developed HCC on compensated cirrhosis had a higher risk of developing the first decompensation event (hazard ratio [HR] = 4.05; p < 0.001), primarily occurring as ascites (HR = 4.79; p < 0.001), hepatic encephalopathy (HR = 3.68; p <0.001), and gastro-intestinal bleeding (HR = 2.98; p = 0.004). All these findings were confirmed in the extended cohort (Milan cohort). HCC remained an independent predictor of first decompensation even considering the study period in two eras (2000-2013 and 2014-2021) (HR 3.64, 95% CI 2.10-6.31, 2000- 2013; HR 4.95, 95% CI 1.62-15.1, 2014-2021). Conclusions: The occurrence of HCC is associated with a high risk of first decompensation. Further prospective studies are needed to confirm these results. Impact and implications: Hepatocellular carcinoma (HCC) frequently arises in patients with cirrhosis and is associated with poor clinical outcomes, particularly in the presence of decompensating events. While cirrhosis progresses from a compensated to a decompensated stage characterized by severe complications, the contribution of HCC to this transition remains inadequately understood and under-investigated. This multicentre study demonstrates that the occurrence of HCC in compensated cirrhotics significantly increases the risk of first decompensation. These results highlight the importance for hepatologists and researchers to include HCC in algorithms aiming to stratify the risk of decompensation in HCV cirrhotics, thereby enhancing patient management strategies.