Background Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). Aim To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. Methods This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. Results We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6–8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). Conclusions Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Improved understanding of the molecular mechanisms responsible for the progression from a “non-pathogenic” steatotic state to Non-Alcoholic Steatohepatitis is an important clinical requirement. The cell death-inducing DFF45 like effector (CIDE) family members (A, B and FSP27) regulate hepatic lipid homeostasis by controlling lipid droplet growth and/or VLDL production. However, CIDE proteins, particularly FSP27, have a dual role in that they also regulate cell death. We here report that the hepatic expression of CIDEA and FSP27 (α/β) was similarly upregulated in a dietary mouse model of obesity-mediated hepatic steatosis. In contrast, CIDEA expression decreased, but FSP27-β expression strongly increased in a dietary mouse model of steatohepatitis. The inverse expression pattern of CIDEA and FSP27β was amplified with the increasing severity of the liver inflammation and injury. In obese patients, the hepatic CIDEC2 (human homologue of mouse FSP27β) expression strongly correlated with the NAFLD activity score and liver injury. The hepatic expression of CIDEA tended to increase with obesity, but decreased with NAFLD severity. In hepatic cell lines, the downregulation of FSP27β resulted in the fractionation of lipid droplets, whereas its overexpression decreased the expression of the anti-apoptotic BCL2 marker. This, in turn, sensitized cells to apoptosis in response to TNF α and saturated fatty acid. Considered together, our animal, human and in vitro studies indicate that differential expression of FSP27β/CIDEC2 and CIDEA is related to NAFLD progression and liver injury.

Despite its growing incidence, hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) in non-cirrhotic livers remains poorly characterized. We compared the characteristics, management, survival, and trends of MASLD-related HCC in patients with or without underlying cirrhosis in a large multicenter cohort. A total of 354 cases of MASLD-related HCC presented at the liver tumor meetings of four French university hospitals between 2007 and 2018 were included in the study. Data were extracted from the meetings’ databases and from the French Birth and Death Registry. Of HCC cases, 35% occurred in the absence of cirrhosis. HCC was diagnosed through screening in 60% of patients with cirrhosis, and incidentally in 72% of patients without it. Patients without cirrhosis were older, had a greater tumor burden, but also better liver function than patients with cirrhosis. Patients without cirrhosis showed better overall survival than those with cirrhosis (p = 0.043). However, cirrhosis was not independently associated with overall survival, the independent predictors were age, liver function, tumor burden and BCLC classification. Patients without cirrhosis underwent surgery more frequently than patients with cirrhosis (41% vs. 11%, p <0.001), even in cases where the largest tumors were ≥5 cm (42% vs. 14%, p = 0.002) or there were four or more lesions (19% vs. 2%, p = 0.024). Among the patients (with/without cirrhosis) who underwent surgery, survival was not significantly different. The cirrhosis/no cirrhosis ratio remained stable over the study period. In MASLD-related HCC, patients without cirrhosis account for 35% of cases and have poor prognostic factors (higher age and larger tumors) but also better liver function, resulting in more aggressive management of advanced tumors and better survival compared to patients with cirrhosis. The incidence of hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is projected to increase by 47% to 130% by year 2030 with one-third of cases occurring in non-cirrhotic livers, making them inaccessible to screening and therefore more likely to be diagnosed at an advanced stage. Our study shows that survival in patients with MASLD-related HCC depends on age, tumor burden and underlying liver function and the preserved liver function of these non-cirrhotic patients allows them to be managed surgically. A better understanding of the pathophysiological processes driving HCC occurrence in patients with non-cirrhotic MASLD will help guide the screening and early management of these patients.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the general population and is the fastest growing cause of hepatocellular carcinoma (HCC). Current guidelines recommend HCC surveillance in patients with cirrhosis when annual HCC incidence exceeds 1% without specifying the role of non-invasive tests in patient selection. Objective To define non-invasive test thresholds to select patients with MASLD for HCC surveillance. Design A multicentre longitudinal study of adults with MASLD from 16 tertiary centres in the USA, Europe and Asia between February 2004 and January 2023. Primary outcome was incident HCC. Results 12 950 patients had Fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM) (mean age 51.7 years; 41.1% male). At a median follow-up of 47.7 (IQR 23.3–72.3) months, 109 (0.8%) developed HCC. FIB-4 was below the low cut-off (<1.3 if aged <65 years and <2.0 if aged ≥65 years), between the low cut-off and <2.67, 2.67 to <3.25, and ≥3.25 in 66.3%, 23.9%, 3.4% and 6.4% of patients; the corresponding annual HCC incidence was 0.07%, 0.17%, 0.77% and 1.18%. As a stand-alone test, the annual HCC incidence exceeded 0.2% for LSM ≥10 kPa and 1% for LSM ≥20 kPa. If LSM was performed as a second step only among patients with FIB-4 above the low cut-off, the annual HCC incidence exceeded 0.2% for LSM ≥10 kPa and 1% for LSM ≥15 kPa. Conclusion HCC surveillance should be offered to patients with MASLD with FIB-4 ≥3.25 or LSM ≥20 kPa. When a two-step approach is adopted, LSM ≥15 kPa in patients with increased FIB-4 predicts a high HCC risk.