Letter on ‘Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction‐Associated Steatotic Liver Disease ( <scp>MASLD</scp> )’; Authors’ reply

We appreciate Chang and Zhou for their insight into risk stratification in lean MASLD [1]. In our original research study, we prospectively recruited over 300 participants with MASLD and demonstrated that lean (BMI < 25 kg/m2) and non-lean (BMI ≥ 25 kg/m2) MASLD patients have a comparable prevalence of significant and advanced fibrosis and share a similar effect of inherited risk on liver fibrosis [2]. First, we agree that a subset of patients with lean MASLD may be affected by monogenic drivers of disease. In a prospectively recruited cohort of lean and non-lean biopsy-proven MASLD patients, Zheng and colleagues reported two of six (33%) lean MASLD patients without visceral adiposity harboured monogenic disorders [3]. Specifically, patient 1 had hereditary fructose intolerance due to a homozygous mutation in aldolase B, and patient 2 had familial hypobetalipoproteinaemia resulting from a heterozygous mutation in apolipoprotein B. Based on previous research and our current study, we propose that lean MASLD may encompass at least two biologically distinct subtypes. Type 1 lean MASLD embodies patients with cardiometabolic comorbidities and a similar contribution from polygenic risk driven by common variants, whereas Type 2 lean MASLD includes those with low visceral adiposity and is enriched for rare monogenic drivers of disease [4]. While our study demonstrated that elevated polygenic risk based on common MASLD- and fibrosis-associated variants is associated with increased liver fibrosis risk in lean MASLD, future studies are needed to comprehensively assess the contribution of monogenic variants in lean MASLD cohorts. Secondly, we agree that adipokine profiling can provide additional mechanistic insight into lean MASLD. Given that metabolic imbalance drives adipokine dysregulation and a substantial proportion of lean MASLD patients have insulin resistance, hypertension and dyslipidaemia, adipokine profiling may be beneficial to differentiate between lean MASLD subtypes [5]. Third, we appreciate the insight that γ-glutamyl transferase (GGT) influences fibrosis risk and completed additional analyses considering this variable. The median [IQR] GGT was similar between lean and non-lean MASLD, 33 (23–52) vs. 38 (24–67) U/L, p = 0.395, with lean MASLD having a trend towards lower GGT, an effect seen in previous studies [6, 7]. Given that GGT might reflect undisclosed alcohol intake, future incorporation of quantitative alcohol biomarkers, such as phosphatidylethanol, may also help to exclude hepatic steatosis driven by alcohol use [8]. In conclusion, we agree with Chang and Zhou that lean MASLD represents a biologically heterogeneous condition requiring refined phenotypic and mechanistic classification. Our findings support the concept that a substantial proportion of lean MASLD patients share cardiometabolic dysfunction and polygenic risk profiles similar to those observed in non-lean MASLD, underscoring the importance of fibrosis risk assessment regardless of BMI. Moreover, pharmacotherapies like semaglutide have shown to treat MASH-related significant and advanced fibrosis in the non-lean population [9]. Future research is needed to evaluate the efficacy of MASH therapies in patients with lean MASH. Integrating deep genetic sequencing, adipokine profiling and longitudinal phenotyping will be critical to distinguish polygenic lean MASLD from monogenic mimics and to guide precision-based therapeutic strategies. Kaleb Tesfai: conceptualization, writing – original draft, writing – review and editing. Luis Antonio Díaz: conceptualization, writing – review and editing. Veeral Ajmera: conceptualization, writing – review and editing. V.A. is supported by SDDRC P30 DK120515. V.A. is a consultant for Madrigal Pharmaceuticals. This article is linked to Tesfai et al papers. To view these articles, visit https://doi.org/10.1111/apt.70433 and https://doi.org/10.1111/apt.70555. The data that support the findings of this study are available from the corresponding author upon reasonable request.