Background and Aims: There is conflicting data on the risk of fibrosis and liver-related outcomes in patients with lean MASLD and the role of genetic testing in this population. We aimed to evaluate the risk of advanced fibrosis and genetic predictors of fibrosis in prospectively recruited matched patients with lean, overweight and obese MASLD.

Method: This cross-sectional study included adults who underwent a standardized clinical research visit with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) and genotyping for effect alleles associated with MASLD. MASLD was defined per AASLD guidance, and patients with a body mass index of < 25 kg/m², or < 23 kg/m² in Asians were considered lean MASLD and matched 1:1:1 based on age, sex and race/ethnicity to overweight and obese MASLD patients. The primary outcome was the prevalence of advanced fibrosis using MRE ≥ 3.63 kPa as the reference. The effect of a simple polygenic risk score (PRS) using established effect alleles in PNPLA3 and HSD17B13 was evaluated.

Results: 81 patients (30% male, 47% Hispanic ethnicity) with MASLD were included and evenly split between lean, overweight and obese participants. The mean (±SD) age was 58 (±12) years and 43% of participants had Type 2 diabetes mellitus. Waist circumference was more often normal in lean participants (77%) than overweight (26%) and obese participants (4%), P<0.001. The prevalence of advanced fibrosis was similar in the lean, overweight and obese groups at 22%, 15% and 26% respectively, P=0.70. Mean (±SD) MRE values in the lean, overweight and obese groups were 3.14 (±1.78) kPa, 2.87 (±1.82) kPa and 3.05 (±2.23) kPa respectively, P=0.87. Median (IQR) VCTE values in the lean, overweight and obese groups 5.3 (7.2) kPa, 5.4 (3.0) kPa and 6.8 (4.9) kPa, P=0.59, respectively. Higher PRS was associated with significantly higher liver stiffness on MRE (0.67 kPa, P=0.006) and VCTE (3.5 kPa, P=0.077). A simple dichotomized PRS was high in 43% of non-lean individuals and 55% of lean individuals P=0.27. Mean MRE values were higher in those with high PRS vs low PRS (P=0.048) but not significantly different between lean and non-lean participants (Figure). The effect of PRS on MRE was similar in lean (0.62 kPa) and non-lean participants (0.69 kPa), (P=0.875).

Conclusion: In a well-characterized matched cohort of lean, overweight and obese MASLD patients there was a similar risk of advanced fibrosis. Polygenic risk amplified the risk of fibrosis similarly in lean and non-lean participants. Polygenic risk may also assist in stratifying patients with lean MASLD.

Mean Liver Stiffness on Magnetic Resonance Elastography in Lean and Non-Lean MASLD Participants Stratified by Polygenic Risk

Egbert Madamba

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