Hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD).

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) with increased alcohol consumption (MetALD) is an important, yet understudied cause of liver disease. This study aimed to examine hepatocellular carcinoma (HCC) rates in patients with MetALD and compare them with MASLD, alcohol-associated liver disease (ALD), and controls. Methods: We conducted a retrospective cohort study of veterans with MetALD, MASLD, ALD, or no SLD. We used Poisson regression to estimate incidence rates within stratifications of patient characteristics, and a multivariable time-updated Fine and Gray model with death as a competing risk to examine HCC risks. Results: We included 666,428 participants (392,286 MASLD, 104,065 MetALD, 40,230 ALD, and 129,847 controls) between 1 January 2011 and 31 December 2022, with a follow-up until 31 May 2023. All participants underwent abdominal imaging or transient elastography, confirming the presence (among SLD) or absence (among controls) of steatosis, along with identification of harmful alcohol use and ascertainment of cardiometabolic risk factors. In patients without cirrhosis, the adjusted HCC rates per 100,000 person-years were lowest for MASLD, higher for MetALD, and highest for ALD. The cumulative incidence of HCC at 5 years was highest with ALD, followed by MASLD and MetALD, with rates similar in the latter two groups. At 10 years, the cumulative incidence of HCC per 100,000 individuals was the highest with ALD (1,176.65), followed by MetALD (814.16), and MASLD (762.86). Conclusions: The risk of HCC associated with MetALD is higher than MASLD, significantly lower than ALD, and likely driven by alcohol. Although HCC rates in non-cirrhotic patients with MetALD are not high enough to justify surveillance, this study identifies a relatively higher risk group compared to MASLD, which warrants counselling on alcohol cessation. Impact and implications: Limited data exist on the risk of hepatocellular carcinoma (HCC) in patients with MetALD (metabolic dysfunction-associated steatotic liver disease [MASLD] with increased alcohol consumption) and how it compares with other steatotic liver diseases. In this retrospective study of 666,428 patients from the Veterans Analysis of Liver Disease cohort, we observed that the risk of HCC per 100,000 person-years in patients without cirrhosis with MetALD was 80.24 (95% CI 73.23-87.94), which was intermediate between MASLD (71.64, 95% CI 68.14-75.32) and ALD (104.83, 91.59-119.98). The cumulative incidence of HCC per 100,000 persons at 5 years was the highest with ALD (663.79, 581.77-754.83), followed by MASLD (450.71, 428.46-473.89), MetALD (449.89, 407.56-495.74), and controls (76.03, 61.47-93.46). The limitations of the study include its retrospective design and a study population enriched with male veterans with a higher prevalence of metabolic syndrome.