Clinical characterization and proteomic profiling of lean nonalcoholic fatty liver disease

Obesity has been historically associated with nonalcoholic fatty liver disease (NAFLD), but it can also occur in lean individuals. However, limited data is available on this special group. To investigate the clinical and proteomic characteristics of lean subjects with NAFLD, and to identify potential clinical variables and plasma proteins for diagnosing NAFLD in lean individuals, we collected clinical data from a large cohort of 2,236 subjects.

Diagnosis of NAFLD relied on detecting pronounced hepatic steatosis through abdominal ultrasonography. Participants were categorized into four groups based on body mass index: overweight NAFLD, overweight control, lean NAFLD, and lean control. Plasma proteomic profiling was performed on samples from 20 subjects in each group. The lean NAFLD group was compared to both lean healthy and obese NAFLD groups across all data.

The results indicated that the lean NAFLD group exhibited intermediate metabolic profiles, falling between those of the lean healthy and overweight NAFLD groups. Proteomic profiling of plasma in lean subjects with or without NAFLD revealed 45 statistically significant changes in proteins, of which 37 showed high diagnostic value (AUC > 0.7) for lean NAFLD. These potential biomarkers primarily involved lipid metabolism, the immune and complement systems, and platelet degranulation. Furthermore, AFM, GSN, CFH, HGFAC, MMP2, and MMP9 have been previously associated with NAFLD or NAFLD-related factors such as liver damage, insulin resistance, metabolic syndromes, and extracellular homeostasis. Overall, lean individuals with NAFLD exhibit distinct clinical profiles compared to overweight individuals with NAFLD. Despite having worse metabolic profiles than their healthy counterparts, lean NAFLD patients generally experience milder systemic metabolic disturbances compared to obese NAFLD patients. Additionally, the plasma proteomic profile is significantly altered in lean NAFLD, highlighting the potential of differentially expressed proteins as valuable biomarkers or therapeutic targets for diagnosing and treating NAFLD in this population.