Association of serum 25-hydroxyvitamin D with cardiovascular and all-cause mortality in patients with chronic kidney disease: NHANES 2007‒2018 results.

BACKGROUND: Vitamin D insufficiency is a prevalent issue in patients suffering from CKD. The purpose of this study was to determine whether serum 25(OH)D levels are associated with all-cause and cardiovascular mortality in patients with CKD. METHODS: To examine the associations between 25(OH)D levels and cardiovascular mortality, this retrospective cohort study used the National Health and Nutrition Examination Survey (NHANES) and the National Death Index (NDI) 2007‒2018 database. A total of 2,668 eligible subjects were included in this study, with follow-up conducted until December 31, 2019. The associations were assessed using Cox proportional hazards regression, restricted cubic splines, Kaplan-Meier survival curves, and competing risks survival analysis. Furthermore, subgroup and sensitivity analyses were performed. RESULTS: During a median follow-up of 72 months in a weighted population of 11,715,452 eligible participants, there were 665 deaths from any cause, including 196 cardiovascular-related deaths. After adjusting for covariates, lower levels of 25(OH)D were significantly associated with increased risks for both all-cause mortality (HR= 0.85, 95 % CI 0.77∼0.94) and cardiovascular mortality (SHR= 0.80, 95 % CI 0.67∼0.94). Consistent results were also observed when analyzing 25(OH)D as a categorical variable (quartile). Compared to group Q1, both group Q3 (HR = 0.71, 95 % CI 0.54‒0.93) and group Q4 (HR = 0.72, 95 % CI 0.55‒0.94) exhibited a significantly reduced mortality risk. Weighted restricted cubic splines revealed an inverse J-shaped linear association between levels of 25(OH) D and all-cause mortality ((PNonliner > 0.05). Subgroup analysis and sensitivity analysis yielded similar findings. CONCLUSIONS: All-cause mortality and cardiovascular disease-related mortality were significantly increased by lower 25(OH)D levels, both as continuous and categorical variables. 25(OH)D has an inverse J-shaped linear association with all-cause and cardiovascular mortality.

Inflammation activity affects liver stiffness measurement by magnetic resonance elastography in MASLD.

BACKGROUND: Magnetic resonance elastography (MRE) is recognized as the most precise imaging technology for assessing liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the clinical factors and pathological characteristics that may impact LSM in MASLD patients. METHODS: This cross-sectional study recruited 124 patients who concurrently performed MRE, MRI-PDFF, and biopsy-proven MASLD. Linear regression models, Spearman's correlation, and subgroup analysis were employed to identify the variables affecting LSM. RESULTS: The AUROC (95 % CI) of MRE for diagnosing fibrosis stage ≥ 1, 2, 3, and 4 was 0.80 (0.70-0.90), 0.76 (0.66-0.85), 0.92 (0.86-0.99), and 0.99 (0.99-1.00), with corresponding cutoffs of 2.56, 2.88, 3.35, and 4.76 kPa, respectively. Multivariate analyses revealed that AST was the only independent clinical variable significantly correlated with LSM. Furthermore, LSM exhibited a notable association with the grade of lobular inflammation and hepatocellular ballooning. Subgroup analysis showed that when AST ≥ 2 ULN or inflammation grade ≥ 2, LSM of patients with early fibrosis stages showed a slight but significant increase. CONCLUSION: MRE demonstrates significant diagnostic accuracy in predicting liver fibrosis stages for MASLD patients, especially for advanced liver fibrosis and cirrhosis. However, elevated AST and the severity of liver inflammation may impact its accuracy in staging early liver fibrosis.

Performance of MAST, FAST, and MEFIB in predicting metabolic dysfunction-associated steatohepatitis.

BACKGROUND AND AIM: To identify individuals with metabolic dysfunction-associated steatohepatitis (MASH) or "at-risk" MASH among patients with metabolic dysfunction-associated steatotic liver disease (MASLD), three noninvasive models are available with satisfactory efficiency, which include magnetic resonance imaging [MRI]- AST (MAST), FibroScan-AST (FAST score), and magnetic resonance elastography [MRE] plus FIB-4 (MEFIB). We aimed to evaluate the most accurate approach for diagnosing MASH or "at-risk" MASH. METHODS: We included 108 biopsy-proven MASLD patients who underwent simultaneous assessment of MRE, MRI proton density fat fraction (MRI-PDFF), and FibroScan scans. Compared with the histological diagnosis, we analyzed the AUC of each model and assessed the accuracy. RESULTS: Our study cohort consisted of 64.8% of MASH and 25.9% of "at-risk" MASH. When analyzing the performance of each model for the diagnostic accuracy of MASH, we found that the AUC [95% CI] of MAST was comparable to FAST (0.803 [0.719-0.886] vs 0.799 [0.707-0.891], P = 0.930) and better than MEFIB (0.671 [0.571-0.772], P = 0.005). Similar findings were observed in the "at-risk" MASH patients. The AUCs [95% CI] for MAST, FAST, and MEFIB were 0.810 [0.719-0.900], 0.782 [0.689-0.874], and 0.729 [0.619-0.838], respectively. The models of MAST and FAST had comparable AUCs (P = 0.347), which were statistically significantly higher than that of MEFIB (P = 0.041). Additionally, the cutoffs for diagnosis of MASH were lower than "at-risk" MASH. CONCLUSION: MAST and FAST performed better than MEFIB in diagnosing "at-risk" MASH and MASH using lower cutoff values. Our findings provided evidence for selecting the most accurate noninvasive model to identify patients with MASH or at-risk MASH.

SAMM50-rs2073082, -rs738491 and -rs3761472 Interactions Enhancement of Susceptibility to Non-Alcoholic Fatty Liver Disease.

BACKGROUND AND AIM: Several studies have identified that three SAMM50 polymorphisms (rs2073082, rs738491, rs3761472) are associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). However, the clinical significance of the SAMM50 SNP in relation to NAFLD remains largely unknown. Therefore, we conducted a clinical study and SNP-SNP interaction analysis to further elucidate the effect of the SAMM50 SNP on the progression of NAFLD in the elderly. METHODS: A total of 1053 patients over the age of 65 years were recruited. Liver fat and fibrosis were detected by abdominal ultrasound or FibroScan, respectively. Genomic DNA was extracted and then genotyped by Fluidigm 96.96 Dynamic Array. Multivariable logistic regression was used to evaluate the association between NAFLD and SNP. SNP-SNP interactions were analyzed using generalized multivariate dimensionality reduction (GMDR). RESULTS: The risk of NAFLD was substantially higher in people who carried SAMM50-rs2073082 G and -rs738491 T alleles (OR, 1.962; 95% CI, 1.448-2.659; p < 0.001; OR, 1.532; 95% CI, 1.246-1.884; p = 0.021, respectively) compared to noncarriers. Carriers of the rs738491 T and rs3761472 G alleles in the cohort showed a significant increase in liver stiffness measurements (LSM). The combination of the three SNPs showed the highest predictive power for NAFLD. The rs2073082 G allele, rs738491 T allele and rs3761472 G carriers had a two-fold higher risk of NAFLD compared to noncarriers. CONCLUSIONS: Our research has demonstrated a strong correlation between the genetic polymorphism of SAMM50 and NAFLD in the elderly, which will contribute to a better understanding of the impact of age and genetics on this condition. Additionally, this study provides a potential predictive model for the early clinical warning of NAFLD.

PNPLA3-I148M Variant Promotes the Progression of Liver Fibrosis by Inducing Mitochondrial Dysfunction.

Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is strongly associated with non-alcoholic steatohepatitis and advanced fibrosis; however, the underlying mechanisms remain largely unknown. In this study, we investigated the effect of PNPLA3-I148M on the activation of hepatic stellate cell line LX-2 and the progression of liver fibrosis. Immunofluorescence staining and enzyme-linked immunosorbent assay were used to detect lipid accumulation. The expression levels of fibrosis, cholesterol metabolism, and mitochondria-related markers were measured via real-time PCR or western blotting. Electron microscopy was applied to analyze the ultrastructure of the mitochondria. Mitochondrial respiration was measured by a Seahorse XFe96 analyzer. PNPLA3-I148M significantly promoted intracellular free cholesterol aggregation in LX-2 cells by decreasing cholesterol efflux protein (ABCG1) expression; it subsequently induced mitochondrial dysfunction characterized by attenuated ATP production and mitochondrial membrane potential, elevated ROS levels, caused mitochondrial structural damage, altered the oxygen consumption rate, and decreased the expression of mitochondrial-function-related proteins. Our results demonstrated for the first time that PNPLA3-I148M causes mitochondrial dysfunction of LX-2 cells through the accumulation of free cholesterol, thereby promoting the activation of LX-2 cells and the development of liver fibrosis.