Histologic Features and Clinical Outcomes of Lean Metabolic Dysfunction–Associated Steatotic Liver Disease

Importance Although metabolic dysfunction–associated steatotic liver disease (MASLD) is traditionally associated with obesity, it is increasingly recognized in individuals with normal weight (ie, lean MASLD). Objective To characterize the clinical, histologic, and prognostic features of lean MASLD, and evaluate the performance of noninvasive tests for advanced fibrosis. Design, Setting, and Participants Multinational, retrospective observational study of adults with biopsy-confirmed MASLD from 41 countries from the Global MASLD project. Exposures Lean vs overweight/obese MASLD, defined by body mass index (BMI) and waist circumference. Main Outcomes and Measures Primary outcomes were all-cause mortality and clinical events (hepatocellular carcinoma, hepatic decompensation, liver transplant, death), intermediate outcomes included histologic fibrosis severity, and tests included the Fibrosis-4 (FIB-4) score and liver stiffness measurement (LSM) by transient elastography. Results Among 18 326 patients (mean [SD] age, 50.9 [13.1] years; 8714 [47.6%] male), 6.7% were lean by BMI. Among 12 202 patients with waist circumference available, 6.0% were lean by waist circumference (κ = 0.41). Lean MASLD was most prevalent in Asia (11.3% by BMI, 11.7% by waist circumference). Compared with overweight/obese MASLD, lean MASLD had lower prevalence of type 2 diabetes (38.2% vs 48.3%; difference, −10.2% [95% CI, −13.0% to −7.4%]), advanced fibrosis (29.3% vs 37.2%; difference, −7.8% [95% CI, −10.5% to −5.2%]), and Non-Alcoholic Fatty Liver Disease Activity Scores (mean [SD], 3.96 [1.81] vs 4.41 [1.68]; difference, −0.44 [95% CI, −0.56 to −0.33]). The FIB-4 demonstrated lower accuracy for predicting advanced fibrosis (F3-F4) in lean vs overweight/obese MASLD (area under the curve, 0.76 [95% CI, 0.73-0.79] vs 0.79 [95% CI, 0.78-0.80]; difference, −0.03 [95% CI, −0.06 to 0.00]), while LSM had higher accuracy (area under the curve, 0.87 [95% CI, 0.84-0.90] vs 0.83 [95% CI, 0.82-0.84]; difference, 0.04 [95% CI, 0.01-0.07]). Unadjusted rates per 100 person-years in lean vs overweight/obese MASLD were 1.08 vs 0.91 for all-cause mortality and 1.51 vs 1.43 for clinical events, respectively; lean status was not independently associated with all-cause mortality (adjusted hazard ratio [aHR], 0.90 [95% CI, 0.69-1.16]) or clinical events (aHR, 0.94 [95% CI, 0.76-1.17]). Advanced fibrosis (F3-F4) was associated with all-cause mortality (1.46 vs 0.77 per 100 person-years; aHR, 2.10 [95% CI, 1.71-2.57]) and clinical events (3.21 vs 0.89 per 100 person-years; aHR, 3.41 [95% CI, 2.90-4.03]). Conclusions and Relevance Lean MASLD represents a distinct phenotype with milder histologic disease but similar clinical outcomes compared with overweight/obese MASLD. Fibrosis severity, rather than body composition, was associated with prognosis and LSM was reliable in lean individuals.