An Invisible Early Steatosis Phenotype Defined for a Large Population-Based Cohort

Background: The current definition of metabolic dysfunction-associated steatotic liver disease (MASLD) requires a classical assessment of steatosis via liver biopsy, with steatosis grades of S0–S3 (5–100% fat) potentially underestimating low-grade steatosis. We propose a new, more sensitive classification based on magnetic resonance imaging proton-density fat-fraction (MRI-PDFF), splitting the standard S0 and S1 grades into three classes: new-S0, very early S1 (S1A), and a second early (S1B) grade. We aim to determine whether these early steatosis phenotypes differed clinically or biologically from the new-S0 grade using large population cohort datasets. Methods: We assess the prevalence of the new PDFF grades in 29,252 healthy UK-Biobank participants and six previously published databases (n = 149,498) using SteatoTest or a proxy. We performed a multimodal steatosis assessment with longitudinal PDFF and liver biopsy data (n = 286). Models were used to adjust for phenotypes and overall mortality based on age, gender and cardiometabolic factors. Results: In the UK-Biobank, the new-S0, S1A, and S1B prevalences were 54%, 26%, and 17%, respectively. Between S1A vs S0, the most discriminating characteristics were triglycerides, odds ratio=2.40 (95% CI: 2.07–2,77; P < 0.00001), and BMI=1.30 (1.27–1.33; P < 0.00001), similar to those between S1A vs S1B, plus systolic-blood-pressure (SBP) and HbA1c. Adjustment on age, sex, SBP, BMI, HbA1c, triglycerides, and HDL-cholesterol) revealed a significant 15-year lower survival in the high-risk (97.2%; 95%CI = 96.9–97.7) vs the low-risk group (99.4%; 95%CI = 99.2–99.6; P < 0.00001). Conclusion: The early trajectory of liver steatosis is invisible and undetected in 26% of the middle-aged population. This early steatosis phenotype differs clinically and biologically from the new-S0 in large population cohorts.