Impact of first and further decompensation in patients with compensated ACLD due to MASLD

Background & Aims: First and further decompensation events mark key transitions in the natural history of cirrhosis and significantly influence mortality risk. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We conducted an international, multicenter (17 centers), retrospective study involving 6,061 consecutive patients with cACLD due to MASLD, diagnosed either clinically (liver stiffness measurement >10 kPa) or histologically (F3–F4 fibrosis). Decompensation events were defined according to the Baveno VII criteria. Cumulative incidence functions and cause-specific Cox models (with baseline and time-dependent variables) were used to analyze competing risks. A multistate model was developed to better describe the clinical trajectory of cACLD due to MASLD. Results: The 5-year cumulative incidence of first decompensation was 3.5% (95% CI 3.0–4.1), which was associated with an 18.9-fold increase (95% CI 10.8–32.9) in the cause-specific hazard of LR-D. Among patients who experienced a first decompensation, the 5-year cumulative incidence of further decompensation was 43.9% (95% CI 37.2–50.2), further increasing the hazard of LR-D by 1.52-fold (95% CI 1.02–2.34). Ascites, followed by variceal bleeding, were the most common decompensation events. Hepatocellular carcinoma independently increased the cause-specific hazard of LR-D by 2.95-fold (95% CI 2.02–4.31) in the overall cohort and by 1.43-fold (95% CI 1.03–2.00) in patients who had experienced a first decompensation. Conclusions: First and subsequent decompensation events are major inflection points in the clinical progression of cACLD due to MASLD, increasing the cause-specific hazard of LR-D by 18.9- and an additional 1.52-fold, respectively. Hepatocellular carcinoma is an independent predictor of LR-D and further exacerbates mortality risk when present alongside decompensation. Impact and implications: In this large international multicenter cohort of 6,061 patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD), we examined the clinical impact of first and further decompensation events. At 5 years, the cumulative incidences of first and further decompensation were 3.5% and 43.9%, respectively, each significantly increasing the cause-specific hazard of liver-related death (18.9-fold and 1.52-fold). Ascites, more so than variceal bleeding, was the predominant and most impactful event. Both acute and non-acute decompensation similarly contributed to liver-related mortality. Additionally, hepatocellular carcinoma independently increased the hazard of liver-related death, even post-decompensation. Notably, extrahepatic deaths also represented a considerable burden, reflecting the high metabolic risk of MASLD. These findings highlight key prognostic inflection points in MASLD-related cACLD.