Lean MASH: A High‐Risk Subtype With Significant Cardiometabolic Burden

We read with great interest the paper published in the journal by Ghani et al., which demonstrated that lean individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) face a dramatically higher risk of all-cause mortality compared to their non-lean counterparts [1]. This important revelation challenges long-held beliefs and necessitates a re-evaluation of risk stratification in MASLD that extends beyond body mass index (BMI). Steatotic liver disease (SLD), particularly MASLD, exhibits a substantial heterogeneity, as exemplified among non-obese subjects [2], which represents a considerable proportion of the MASLD population, though it is still largely unexplored. Notably, MASLD is a multisystemic disease that increases the risk of cardiovascular disease, chronic kidney disease, diabetes, and various extrahepatic cancers, with metabolic dysfunction representing the core pathogenesis basis linking these conditions [2]. Acknowledging the interconnected link between metabolic disorders and aiming to promote a holistic management approach for them, the American Heart Association (AHA) introduced the Cardiovascular-Kidney-Metabolic (CKM) syndrome term in 2023, as a progressive risk continuum, starting with Stage 0, where individuals have no risk factors, up to Stage 4 which encompasses overt clinical cardiovascular manifestations, including heart failure, coronary artery disease, stroke, or atrial fibrillation, along with metabolic and renal dysfunction [3]. Thus, building on the work of Ghani et al. [1], we sought to investigate the CKM risk among lean MASLD (L-MAFLD) patients for determining the risk of systemic metabolic dysfunction in this population. To this end, we utilized the NHANES database (2017–2020), comparing CKM risk among 111 individuals with L-MASLD and 1206 lean controls without MASLD aged 20–79, with available relevant variables for this analysis. Results revealed a markedly elevated risk of ASCVD among L-MASLD individuals compared to their lean counterparts (38.8% vs. 20.6%, p < 0.001). Additionally, the prevalence of coronary heart disease (11.7% vs. 3.1%, p < 0.001) and recent heart attacks (9.9% vs. 2.6%, p < 0.001) was significantly higher among L-MASLD individuals. Moreover, stratification by CKM stage highlights a stepwise increase in CKM prevalence among L-MASLD patients relative to lean controls, with risk markedly rising in Stage 3 (31.5% vs. 17.4%) and Stage 4 (16.2% vs. 8.2%), p < 0.001, for both comparisons (Table 1). In conclusion, we demonstrated that L-MASLD subjects have an elevated cardiometabolic risk compared to their lean counterparts without MASLD, further emphasizing the importance of consideration of metabolic dysfunction in the pathogenesis of the disease [4, 5]. This evidence insists on the urgent need for increased awareness of lean MASLD in clinical practice and research initiatives. The data that support the findings of this study are available in NHANES at https://www.cdc.gov/nchs/nhanes. These data were derived from the following resources available in the public domain: NHANES 2017–2020, https://www.cdc.gov/nchs/nhanes.