Liver fat accumulation more than fibrosis causes early liver dynamic dysfunction in patients with non-alcoholic fatty liver disease

•Excessive fat accumulation increases liver stiffness in the absence of fibrosis•The efficiency of portal extraction decreases with liver stiffness and steatosis•Steatosis impairs the efficiency of portal extraction but not microsomal function•Combined use of Fibroscan and 13C-MBT can reveal early dysfunction in steatosis In Non-Alcoholic Fatty Liver Disease (NAFLD), events driving early hepatic dysfunction with respect to specific metabolic pathways are still poorly known. We enrolled 84 subjects with obesity and/or type 2 diabetes (T2D). FibroScan® served to assess NAFLD by controlled attenuation parameter (CAP), and fibrosis by liver stiffness (LS). Patients with LS above 7 kPa were excluded. APRI and FIB-4 were used as additional serum biomarkers of fibrosis. The stable-isotope dynamic breath test was used to assess the hepatic efficiency of portal extraction (as DOB15) and microsomal metabolization (as cPDR30) of orally-administered (13C)-methacetin. NAFLD occurred in 45%, 65.9%, and 91.3% of normal weight, overweight, and obese subjects, respectively. Biomarkers of liver fibrosis were comparable across subgroups, and LS was higher in obese, than in normal weight subjects. DOB15 was 23.2 ± 1.5‰ in normal weight subjects, tended to decrease in overweight (19.9 ± 1.0‰) and decreased significantly in obese subjects (16.9 ± 1.3, P = 0.008 vs. normal weight). Subjects with NAFLD had lower DOB15 (18.7 ± 0.9 vs. 22.1 ± 1.2, P = 0.03) but higher LS (4.7 ± 0.1 vs. 4.0 ± 0.2 kPa, P = 0.0003) than subjects without NAFLD, irrespective of fibrosis. DOB15 (but not cPDR30) decreased with increasing degree of NAFLD (R = −0.26; P = 0.01) and LS (R = −0.23, P = 0.03). Patients with T2D showed increased rate of NAFLD than those without T2D but similar LS, DOB15 and cPDR30. Overweight, obesity and liver fat accumulation manifest with deranged portal extraction efficiency of methacetin into the steatotic hepatocyte. This functional alteration occurs early, and irrespective of significant fibrosis and presence of T2D.