Lean Masld: Metabolic Heterogeneity and Implications for Disease Progression

One of the most widespread liver diseases in the world is metabolic dysfunction-associated steatotic liver disease (MASLD), known until recently as non-alcoholic fatty liver disease (NAFLD). Its prevalence is estimated at 25% in the global population. MASLD is defined as a clinical condition characterized by excessive fat accumulation in the liver in the presence of at least one cardiometabolic risk factor. Although obesity plays a significant role in the pathomechanism of MASLD, it is estimated that approximately 10-20% of MASLD cases occur in individuals with a BMI <25 kg/m² (<23 kg/m² in the Asian population). As studies show, individuals with lean MASLD have a higher risk of liver fibrosis and overall mortality. The aim of this study is a critical review of the current literature regarding the Lean MASLD phenotype, with particular emphasis on its metabolic heterogeneity. The work analyzes unique pathophysiological mechanisms, such as genetic predispositions and adipose tissue distribution disorders, and evaluates their impact on the risk of progression to advanced fibrosis and hepatocellular carcinoma. This work constitutes a literature review, focusing on clinical and cohort studies as well as review papers concerning the pathogenesis, diagnostics, and clinical course of liver steatosis in individuals with a normal BMI. The literature analysis indicates a significant role of genetic variants, mainly the PNPLA3 polymorphism (I148M), which predisposes lean individuals to disease progression independently of metabolic factors. It has been shown that despite a normal BMI, these patients are often characterized by visceral adipose tissue dysfunction and an altered gut microbiota profile. Metabolic heterogeneity is manifested by the existence of a subgroup of patients with a "metabolically healthy" profile, in whom cardiovascular risk may be lower, but the risk of progression of liver lesions remains significant. The following work emphasizes that Lean MASLD is not a milder form of liver steatosis, and its diagnostics require going beyond the standard BMI measurement. It is necessary to implement personalized monitoring strategies, taking into account the genetic profile and metabolic assessment, to prevent long-term complications in this specific group of patients.