Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts

Background Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at increased risk of both hepatic and extrahepatic adverse outcomes. However, the evidence regarding lean MASLD and its prognosis remains controversial. Objective To comprehensively investigate the long-term prognosis of lean patients with MASLD versus non-lean MASLD in Western and Asian populations. Design This prospective multicohort study included 153 192 patients with MASLD from UK Biobank (UKB), 29 700 from Kailuan cohort and 3329 from China Kadoorie Biobank (CKB). Lean MASLD was defined as body mass index (BMI)<23 kg/m² in Kailuan and CKB and <25 kg/m² in UKB. Primary endpoints were liver-related events (LREs), all-cause mortality, liver-related mortality (LRM), cardiovascular disease (CVD) mortality, CVD, hepatocellular carcinoma (HCC) and extrahepatic cancer. Results Overall, 181 191 non-lean and 5030 lean patients with MASLD were included. During a median of 14.2-year follow-up (median 14.1, 14.8 and 13.4 years in UKB, Kailuan and CKB), 2501 incident LREs, 22 482 all-cause deaths, 28 722 incident CVD cases, 326 HCC and 25 258 extrahepatic cancer cases were identified, with 375 LRM and 4511 CVD deaths. Pooled analysis of three cohorts showed lean MASLD had higher risks of LREs (HR=2.14; 95% CI 1.27 to 3.62), all-cause mortality (HR=1.26; 95% CI 1.14 to 1.39), LRM (HR=2.31; 95% CI 1.54 to 3.46) and CVD mortality (HR=1.22; 95% CI 1.05 to 1.41). By contrast, lean MASLD exhibited comparable HCC risk (HR=1.76; 95% CI 0.84 to 3.71) and extrahepatic cancer risk (HR=1.14; 95% CI 0.88 to 1.48), but reduced CVD risk (HR=0.89; 95% CI 0.83 to 0.95) versus non-lean MASLD. Conclusion Lean patients with MASLD have worse liver outcomes and greater risk of all-cause mortality, but similar risk of HCC and extrahepatic cancer, and lower CVD risk.