Editorial: Comparable Hepatic Fibrosis Risk Demands Equal Vigilance in Lean and Non‐Lean Patients With Metabolic Dysfunction‐Associated Steatotic Liver Disease—Authors' Reply

We appreciate Yokoyama S. and Ito T. for highlighting our recently published manuscript entitled “Inherited Genetic Risk of Liver Fibrosis in Lean vs. Non-Lean Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)” [1, 2]. In this original research study, we prospectively recruited over 300 participants with MASLD and revealed that lean (BMI < 25 kg/m2) and non-lean (BMI ≥ 25 kg/m2) patients with MASLD have comparable prevalence of significant fibrosis and advanced fibrosis and share a similar effect from genetic risk on liver fibrosis. We agree with Yokoyama S. and Ito T. that lean and non-lean MASLD demands equal vigilance in screening and risk stratification for liver fibrosis to improve long-term outcomes. Genetic testing in lean MASLD can be leveraged to enhance risk stratification. In our manuscript, we made a genetic risk score (GRS) comprising PNPLA3, TM6SF2 and the protective HSD17B13 genotype. We not only showed that individuals with high GRS have a higher prevalence of liver fibrosis compared to low GRS, but we showed that amongst those with high GRS, the prevalence of significant fibrosis was similar between lean and non-lean MASLD (31.3% vs. 37.1%, p = 0.645). Our work adds to the growing literature demonstrating the potential utility of incorporating genetic testing into the assessment of individuals with lean MASLD to identify individuals who may benefit from more frequent follow-up care and targeted intervention [3-5]. Although lean MASLD patients have a normal BMI (BMI < 25 kg/m2), they can still experience many of the same metabolic co-morbidities as non-lean MASLD, such as insulin resistance, hypertension, and dyslipidemia, which increase the risk of liver fibrosis [6]. In addition to the presence of these metabolic co-morbidities, lean MASLD patients may also have increased visceral adiposity. Thus, other tools beyond BMI can be used to assess for increased visceral adiposity. In our manuscript, we show that using anthropometric measurements like waist-to-hip ratio (WHR), the prevalence of abnormal WHR in lean and non-lean MASLD were similar. This finding indicates that many “lean” MASLD patients based on BMI show signs of increased adiposity, further supporting the growing literature that BMI alone should not be used as the main criterion to assess adiposity [7]. However, a subset of lean patients with steatotic liver disease without increased adiposity may harbour rare monogenic drivers of disease [8, 9]. Future research with larger cohorts of lean MASLD patients are needed to elucidate the drivers of disease within this subpopulation of patients with MASLD. Additionally, given that alcohol use and metabolic co-morbidities have a synergistic effect on risk of liver fibrosis [10], future research is needed to better understand how this affects the aetiology and disease trajectory of lean MASLD. Lastly, future studies are needed to identify, which current and emerging pharmacotherapies primarily used in the non-lean MASLD population are most effective for managing lean MASLD. Kaleb Tesfai: conceptualization, writing – original draft, writing – review and editing. Luis Antonio Díaz: conceptualization, writing – review and editing, writing – original draft. Veeral Ajmera: conceptualization, writing – review and editing, writing – original draft. The authors' declarations of personal and financial interests are unchanged from those in the original article: Tesfai et al. Inherited Genetic Risk of Liver Fibrosis in Lean vs. Non-Lean Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Aliment Pharmacol Ther. 2025; in press. This article is linked to Tesfai et al. papers. To view these articles, https://doi.org/10.1111/apt.70433 and https://doi.org/10.1111/apt.70451. The data that support the findings of this study are available from the corresponding author upon reasonable request.