Letter on “Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction‐Associated Steatotic Liver Disease ( <scp>MASLD</scp> )”

We read with great interest the study by Tesfai et al. [1], which provides important insights into genetic fibrosis risk in lean versus non-lean metabolic dysfunction–associated steatotic liver disease (MASLD). Demonstrating that the cumulative burden of common variants (PNPLA3, TM6SF2 and HSD17B13) confers a comparable fibrosis risk across BMI strata substantially advances our understanding. This aligns with broader epidemiological data highlighting global genetic variations [2]. Furthermore, while genetics are pivotal, acknowledging the intersection with environmental factors, such as social determinants of health, remains essential for a holistic view of disease susceptibility [3]. Building on these findings, we would like to offer several complementary considerations that may further refine risk stratification in lean MASLD. First, lean MASLD cohorts may include a subset of patients with monogenic disorders of adipose tissue, particularly lipodystrophy syndromes. Current international guidelines recognise these conditions as distinct entities characterised by severe ectopic fat deposition, insulin resistance, and progressive liver disease despite a lean or near-normal BMI [4]. This perspective is strongly reinforced by the authors' data: notably, 82.5% of ‘lean’ participants exhibited an abnormal Waist-to-Hip Ratio. This specific phenotype, central adiposity with a lean periphery, is consistent with adipose tissue dysfunction and may help distinguish monogenic adipose failure from polygenic lean MASLD. While the current low-coverage sequencing was optimised for common variants, this striking phenotypic signal warrants targeted assessment of lipodystrophy-associated genes (e.g., LMNA, PPARG) in future high-depth sequencing or clinical screening efforts to distinguish these monogenic mimics. Second, adipokine profiling offers mechanistic resolution. Leptin levels in conventional MASLD typically rise due to resistance [5]. In stark contrast, lipodystrophy is characterised by disproportionately low leptin due to adipose tissue failure. Identifying discordant leptin levels could thus serve as a non-invasive tool to unmask monogenic mimics. Furthermore, longitudinal data confirm that hypoadiponectinemia is a potent, early predictor of steatotic liver disease, warranting its inclusion in risk models [6]. Third, regarding biochemistry, the study focused on aminotransferases and alkaline phosphatase. However, γ-glutamyl transferase (GGT) may be a more sensitive indicator of metabolic stress, oxidative injury, and hepatic lipotoxicity, particularly in lean metabolic phenotypes. Prior analyses in lean populations highlight GGT as an independent marker of cardiometabolic and fibrotic risk, even when aminotransferase levels remain within the normal range [7]. Inclusion of GGT may therefore further enhance biochemical risk stratification in lean MASLD. Finally, precise phenotypic stratification has profound clinical implications. Metabolic dysfunction drives adverse outcomes, including hepatocellular carcinoma, necessitating rigorous risk assessment even in complex comorbidities [8]. Moreover, as we enter the era of targeted pharmacotherapy with agents such as the thyroid hormone receptor-β agonist resmetirom [9] and GLP-1 receptor agonists like semaglutide [10], distinguishing polygenic lean MASLD from monogenic mimics becomes mandatory to ensure appropriate patient selection and therapeutic efficacy. In summary, integrating consideration of adipose-related monogenic disorders, adipokine profiling, and GGT assessment may further refine genetic and metabolic risk stratification and support the authors' conclusion that lean MASLD represents a biologically distinct and heterogeneous entity. Di Chang: writing – original draft. Yimeng Zhou: conceptualization, writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. 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.70577. The authors have nothing to report.