Abstract

Background: Studies on incident liver and cardiovascular outcomes in lean (body mass index: BMI <25 kg/m², or <23 kg/m² for Asians) vs. non-lean individuals with metabolic dysfunction-associated steatohepatitis (MASH) have reported mixed results. We aimed to compare incident clinical outcomes and mortality between lean and non-lean individuals with compensated MASH cirrhosis in a large national cohort.

Methods: This was a retrospective cohort study of patients with newly diagnosed compensated MASH cirrhosis from 1/2008-5/2021 in the Veterans Health Administration. Average BMI in the 12 months prior to cirrhosis diagnosis was used to classify lean vs. non-lean MASH, and alternate etiologies of liver disease were excluded using validated algorithms. Our primary outcome was incident hepatic decompensation. Secondary outcomes were incident major adverse cardiovascular events (MACE- a composite of myocardial infarction, cardiac arrest, stroke, heart failure, atrial fibrillation) and all-cause mortality. Multivariable Cox proportional hazard models were constructed to assess the effects of lean status on clinical outcomes and survival. Fine and Gray competing risk regression was used where applicable.

Results: We included 15,974 MASH patients in our analytic sample: 1,731 lean and 14,243 non-lean patients. Included patients were mostly male (95%), median age was 68 years, and 67% were non-Hispanic white. At baseline, prevalence of diabetes was lower in lean vs. non-lean individuals (44.8% vs. 72.9%, p<0.001). Lean individuals also had fewer cardiometabolic risk factors at baseline. In multivariable models (Figure 1), with adjustments for age, sex, race, smoking status, diabetes, MELD-Na, and alcohol use per AUDIT-C, lean status was associated with a 92% increased risk of all-cause mortality (aHR=1.92; 95% CI: 1.77–2.08). Paradoxically, lean status was associated with a 39% decreased risk of incident hepatic decompensation (aSHR=0.67; 95% CI: 0.58–0.77). There was no significant association between lean status and major adverse cardiovascular events (aSHR=0.84, [95% CI: 0.70–1.01], P=0.07).

Conclusion: In patients with compensated MASH cirrhosis, lean status was associated with increased all-cause mortality and decreased risk of hepatic decompensation. Despite low prevalence of diabetes and better cardiometabolic profile, lean individuals were at equally high risk of MACE. Future studies should evaluate other drivers (e.g., extrahepatic cancer, renal disease, and genetics) of mortality in lean MASH patients.