INTRODUCTION: Hepatic fibrosis reduces the serum level of lipoprotein (a) (Lp(a)) and may affect its accuracy in cardiovascular disease prediction of metabolic-associated fatty liver disease (MAFLD). We aimed to estimate the association between Lp(a) levels and the risk of carotid atherosclerosis in MAFLD patients with advanced fibrosis. METHODS: This was a cross-sectional study enrolling 4,348 consecutive individuals (1,346 patients with MAFLD and 3,002 non-MAFLD patients) who were admitted to the First Affiliated Hospital, Sun Yat-sen University, and underwent abdominal and carotid ultrasonography from 2015 to 2021. Lp(a) levels, liver biochemical markers, metabolic indices, and anthropometric parameters were measured. Liver fat content and fibrosis severity were assessed by MRI-PDFF, using the NAFLD fibrosis score (NFS) and liver stiffness measurement (LSM) of two-dimensional shear wave elastography, respectively. RESULTS: There was an L-shaped relationship between Lp(a) levels and LSMs in patients with MAFLD, and Lp(a) levels had a different relationship with liver fat content in MAFLD patients with F1-2 versus those with F3-4. Non-MAFLD patients had higher levels of Lp(a) than MAFLD patients with or without advanced fibrosis (both P < 0.05). Lp(a) levels and degree of liver fibrosis were both positively correlated with carotid atherosclerosis in patients with MAFLD. Lp(a) levels performed well on carotid atherosclerosis risk prediction for non-MAFLD patients with an area under the curve (AUC) of 0.819, which was significantly better than the carotid atherosclerosis risk prediction for MAFLD patients with NFS ≤ −1.836 (AUC: 0.781), NFS > −1.836 (AUC: 0.692), and LSM ≥ 9.0 kPa (AUC: 0.635) (all P < 0.05). DISCUSSION: Advanced liver fibrosis significantly reduces the predictive value of Lp(a) levels for the risk of carotid atherosclerosis in patients with MAFLD.

Background: Abnormal phospholipid metabolism is linked to metabolic dysfunction–associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether genetic variants of phospholipid metabolism modify these relationships. Methods: This case-control study consecutively recruited 600 patients who underwent MRI-based proton density fat fraction examination (240 participants with serum metabonomics analysis, 128 biopsy-proven cases) as 3 groups: healthy control, nonobese MASLD, and obese MASLD, (n = 200 cases each). Ten variants of phospholipid metabolism-related genes [phospholipase A2 Group VII rs1805018, rs76863441, rs1421378, and rs1051931; phospholipase A2 receptor 1 (PLA2R1) rs35771982, rs3828323, and rs3749117; paraoxonase-1 rs662 and rs854560; and ceramide synthase 4 (CERS4) rs17160348)] were genotyped using SNaPshot. Results: The T-allele of CERS4 rs17160348 was associated with a higher risk of both obese and nonobese MASLD (OR: 1.95, 95% CI: 1.20–3.15; OR: 1.76, 95% CI: 1.08–2.86, respectively). PLA2R1 rs35771982-allele is a risk factor for nonobese MASLD (OR: 1.66, 95% CI: 1.11–1.24), moderate-to-severe steatosis (OR: 3.24, 95% CI: 1.96–6.22), and steatohepatitis (OR: 2.61, 95% CI: 1.15–3.87), while the paraoxonase-1 rs854560 T-allele (OR: 0.50, 95% CI: 0.26–0.97) and PLA2R1 rs3749117 C-allele (OR: 1.70, 95% CI: 1.14–2.52) are closely related to obese MASLD. After adjusting for sphingomyelin level, the effect of the PLA2R1 rs35771982CC allele on MASLD was attenuated. Furthermore, similar effects on the association between the CERS4 rs17160348 C allele and MASLD were observed for phosphatidylcholine, phosphatidic acid, sphingomyelin, and phosphatidylinositol. Conclusions: The mutations in PLA2R1 rs35771982 and CERS4 rs17160348 presented detrimental impact on the risk of occurrence and disease severity in nonobese MASLD through altered phospholipid metabolism.

Whether the associations between serum vitamin D (VitD) and metabolic-associated fatty liver disease (MAFLD) vary with chronic hepatitis B (CHB) infection has not been well established. This study aims to investigate the relationships between serum VitD and metabolism, liver fat content (LFC) and fibrosis among MAFLD patients with and without CHB. Consecutive subjects (healthy controls: 360, CHB: 684, MAFLD: 521, CHB with MAFLD: 206) were prospectively enrolled between January 2015 and December 2021. Anthropometric, laboratory, imaging, and histological evaluations were conducted, with LFC measured via magnetic resonance imaging-based proton density fat fraction (MRI-PDFF). Serum VitD levels were lower in MAFLD patients than in healthy controls and patients with CHB alone or overlapping with MAFLD (24.4 ± 8.1 vs. 29.0 ± 9.5 vs. 27.4 ± 9.6 vs. 26.8 ± 8.4 ng/mL respectively; p < 0.001 in one-way ANOVA test). After adjusting for confounding factors, including season, hypersensitive C-reactive protein, insulin resistance, liver stiffness measurements, sun exposure, exercise and dietary intake, multivariate linear regression analysis revealed that VitD remained significantly negatively correlated with LFC in MAFLD patients (β = −0.38, p < 0.001), but not in CHB with MAFLD patients. Moreover, quantile regression models also demonstrated that lower VitD tertiles were inversely associated with the risk of insulin resistance and moderate–severe steatosis in the MAFLD group (p for trend <0.05) but not in the MAFLD with CHB group. VitD deficiency was associated with the severity of metabolic abnormalities and steatosis independent of lifestyle factors in MAFLD-alone subjects but not in MAFLD with CHB subjects.

The redefinition of metabolic-associated fatty liver disease (MAFLD) from nonalcoholic fatty liver disease (NAFLD) has caused a revolution in clinical practice, and the characteristics of patients with steatosis but not MAFLD remain unclear. The aims were to compare the diagnosis rate of MAFLD in NAFLD using different steatosis methods and explore the features of non-MAFLD–NAFLD and MAFLD–non-NAFLD.

Background/Objectives: Weight loss is the primary therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the proportion and factors influencing therapeutic changes in the liver condition contrary to weight loss remain unclear. Methods: This observational cohort study spanned between January 2015 and January 2024, with a 48-week lifestyle modification until January 2025. The liver fat content (LFC) determined using MRI-PDFF and liver stiffness measurement (LSM) via 2D-SWE were assessed at baseline and 48 weeks. The weight loss target (WLT) was determined as a reduction of ≥3% in body weight for lean/normal-weight patients and ≥5% for patients who were overweight/obese. Results: Overall, 397 patients with MASLD (30.5% achieving WLT) were included. For participants with WLT, 24.8% presented MRI-PDFF non-response, which was associated with moderate–vigorous physical activity (MVPA) ≥ 150 min/week, indicating a lower likelihood of non-response. Alanine aminotransferase (ALT) non-response occurred in 29.6% of patients and was linked to changes in LFC (ΔLFC, calculated as the baseline minus week 48). LSM non-response was observed in 48.2%, with high free fatty acid (FFA) levels identified as a risk factor. Among individuals without WLT, 29.0% demonstrated an MRI-PDFF response that correlated with greater reductions in low-density lipoprotein cholesterol; 39.4% exhibited an ALT response, which was associated with more significant reductions in LFC. The LSM response was 37.8%, also correlating with a reduction in LFC. Conclusions: Our results identified that MVPA, baseline steatosis degree, FFA, and their responses served as significant markers for treatment response contrary to weight loss in MASLD.