Impact of nomenclature as metabolic associated steatotic liver disease on steatotic liver disease prevalence and screening: a prospective population survey in Asians.

BACKGROUND AND AIM: The introduction of the latest nomenclature, metabolic associated steatotic liver disease (MASLD), proposed by the multi-society without Asian society consensus statement, aims to redefine the diagnostic criteria for metabolic associated fatty liver disease (MAFLD). However, its effect on the epidemiology in Asia remains unclear. METHOD: We conducted a population-based cross-sectional survey on fatty liver disease using multistage stratified random sampling of participants from Guangzhou, a representative area in China (ChiCTR2000033376). Demographic, socioeconomic, lifestyle, and laboratory data were collected. Hepatic steatosis and the severity of fibrosis were assessed using FibroScan. RESULTS: A total of 7388 individuals were recruited, the proportion of which meeting the definitions for nonalcoholic fatty liver disease (NAFLD), MAFLD, and MASLD were 2359 (31.9%), 2666 (36.1%), and 2240 (30.3%), respectively. One hundred and twenty (1.6%) patients had cryptogenic SLD, and 537 (7.3%) patients were diagnosed with MetALD. MASLD did not significantly differ from NAFLD and MAFLD, except that MAFLD patients had a lower proportion of males, hypertension, and diabetes and were less likely to consume tea (P < 0.05). Both cryptogenic SLD and MASLD non-MAFLD patients exhibited milder hepatic steatosis and a lower frequency of liver injury than NAFLD, MAFLD, or MASLD patients (all P < 0.05). An increased HOMA-IR (adjusted OR: 1.33, 95% CI: 1.10-2.03) was associated with higher risk of moderate-to-severe steatosis for MASLD non-MAFLD patients, while consuming more cups of tea (P for trend = 0.015) showed inverse associations. CONCLUSION: Irrespective of terminology used is that fatty liver disease is highly prevalent in the Han Chinese population. Differences in insulin resistance and lifestyle risk factors are associated with redefinition disparities.

Association between metabolic dysfunction-associated steatotic liver disease and pulmonary function: a population-based and two-sample mendelian randomization study.

BACKGROUND: Hepatic steatosis and its related complications are risk factors for multiple respiratory diseases; however, the causal relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and pulmonary function remains controversial. We aimed to identify it using a national cohort and Mendelian randomization (MR). METHODS: We enrolled 30,442 participants from the 2007 to 2012 National Health and Nutrition Examination Survey. Demographics, pulmonary function indices (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC]), and variables used to calculate the liver fat score (LFS) were collected. A two-sample MR analysis employing the summary data of genome-wide association studies on MASLD and FEV1/FVC, chronic obstructive pulmonary disease (COPD), and asthma from the Finngen Biobank and Medical Research Council Integrative Epidemiology Unit was performed. RESULTS: A total of 3,462 participants, 1,335 of whom had MASLD (LFS > -0.640), were finally included in the study. The FEV1 (3,204.7 vs. 3,262.5 ml, P = 0.061), FVC (4,089.1 vs. 4,143.8 ml, P = 0.146), FEV1/FVC ratio (78.5% vs. 78.8%, P = 0.233), and FEV1/predicted FEV1 ratio (146.5% vs. 141.7%, P = 0.366) were not significantly different between people with MASLD and those without. Additionally, the MR analysis suggested no causal correlation between MASLD and FEV1/FVC (P = 0.817), MASLD and COPD (P = 0.407), and MASLD and asthma (P = 0.808). Reverse MR studies showed no causal relationships yet (all P > 0.05). CONCLUSION: Our study provides convincing evidence that there is no causal association between MASLD and pulmonary function.

Metabolomics to identify fingerprints of carotid atherosclerosis in nonobese metabolic dysfunction-associated fatty liver disease.

BACKGROUND/AIMS: Nonobese metabolic dysfunction-associated fatty liver disease (MAFLD) is paradoxically associated with improved metabolic and pathological features at diagnosis but similar cardiovascular diseases (CVD) prognosis to obese MAFLD. We aimed to utilize the metabolomics to identify the potential metabolite profiles accounting for this phenomenon. METHODS: This prospective multicenter cross-sectional study was conducted in China enrolling derivation and validation cohorts. Liquid chromatography coupled with mass spectrometry and gas chromatography-mass spectrometry were applied to perform a metabolomics measurement. RESULTS: The study involved 120 MAFLD patients and 60 non-MAFLD controls in the derivation cohort. Controls were divided into two groups according to the presence of carotid atherosclerosis (CAS). The MAFLD group was further divided into nonobese MAFLD with/without CAS groups and obese MAFLD with/without CAS groups. Fifty-six metabolites were statistically significant for discriminating the six groups. Among the top 10 metabolites related to CAS in nonobese MAFLD, only phosphatidylethanolamine (PE 20:2/16:0), phosphatidylglycerol (PG 18:0/20:4) and de novo lipogenesis (16:0/18:2n-6) achieved significant areas under the ROC curve (AUCs, 0.67, p = 0.03; 0.79, p = 0.02; 0.63, p = 0.03, respectively). The combination of these three metabolites and liver stiffness achieved a significantly higher AUC (0.92, p < 0.01). In obese MAFLD patients, cystine was found to be significant with an AUC of 0.69 (p = 0.015), followed by sphingomyelin (SM 16:1/18:1) (0.71, p = 0.004) and de novo lipogenesis (16:0/18:2n-6) (0.73, p = 0.004). The combination of these three metabolites, liver fat content and age attained a significantly higher AUC of 0.91 (p < 0.001). The AUCs of these metabolites remained highly significant in the independent validation cohorts involving 200 MAFLD patients and 90 controls. CONCLUSIONS: Diagnostic models combining different metabolites according to BMI categories could raise the accuracy of identifying subclinical CAS. Trial registration The study protocol was approved by the local ethics committee and all the participants have provided written informed consent (Approval number: [2014] No. 112, registered at the Chinese Clinical Trial Registry, ChiCTR-ChiCTR2000034197).

Interactions between Helicobacter pylori infection and host metabolic homeostasis: A comprehensive review.

The microbiota actively and extensively participates in the regulation of human metabolism, playing a crucial role in the development of metabolic diseases. Helicobacter pylori (H. pylori), when colonizing gastric epithelial cells, not only induces local tissue inflammation or malignant transformation but also leads to systemic and partial changes in host metabolism. These shifts can be mediated through direct contact, toxic components, or indirect immune responses. Consequently, they influence various molecular metabolic events that impact nutritional status and iron absorption in the host. Unraveling the intricate and diverse molecular interaction links between H. pylori and human metabolism modulation is essential for understanding pathogenesis mechanisms and developing targeted treatments for related diseases. However, significant challenges persist in comprehensively understanding the complex association networks among H. pylori itself, the infected host's status, the host microbiome, and the immune response. Previous metabolomics research has indicated that H. pylori infection and eradication may selectively shape the metabolite and microbial profiles of gastric lesions. Yet, it remains largely unknown how these diverse metabolic pathways, including isovaleric acid, cholesterol, fatty acids, and phospholipids, specifically modulate gastric carcinogenesis or affect the host's serum metabolism, consequently leading to the development of metabolic-associated diseases. The direct contribution of H. pylori to metabolisms still lacks conclusive evidence. In this review, we summarize recent advances in clinical evidence highlighting associations between chronic H. pylori infection and metabolic diseases, as well as its potential molecular regulatory patterns.

Impact of skeletal muscle mass evaluating methods on severity of metabolic associated fatty liver disease in non-elderly adults.

The study aimed to explore the relationships of skeletal muscle mass with disease severity in metabolic-associated fatty liver disease (MAFLD) patients with different methods. Consecutive subjects undergoing bioelectrical impedance analysis were included. The steatosis grade and liver fibrosis were evaluated by MRI-derived proton density fat fraction and two-dimensional shear wave elastography. The appendicular skeletal muscle mass (ASM) was adjusted by height2 (ASM/H2), weight (ASM/W) and BMI (ASM/BMI). Overall, 2223 subjects (50·5 %, MAFLD; 46·9 %, male) were included, with the mean age 37·4 ± 10·6 years. In multivariate logistic regression analysis, the subjects with the lowest quartile (Q1) of ASM/W or ASM/BMI had higher risk ratios for MAFLD (OR (95 % CI) in male: 2·57 (1·35, 4·89), 2·11(1·22, 3·64); in female: 4·85 (2·33, 10·01), 4·81 (2·52, 9·16), all P < 0·05, all for Q1 v. Q4). The MAFLD patients with lower quartiles of ASM/W had the higher risk OR for insulin resistance (IR), both in male and female (2·14 (1·16, 3·97), 4·26 (1·29, 14·02) for Q4 v. Q1, both P < 0·05). While the significant OR were not observed when ASM/H2 and ASM/BMI were used. There were significant dose-dependent associations between decreased ASM/W as well as ASM/BMI and moderate-severe steatosis (2·85(1·54, 5·29), 1·90(1·09, 3·31), both P < 0·05) in male MAFLD patients. In conclusion, ASM/W is superior to ASM/H2 and ASM/BMI in predicting the degree of MAFLD. A lower ASM/W is associated with IR and moderate-severe steatosis in non-elderly male MAFLD.

Comparisons of Insulin Resistance- and Steatosis-Based Scores in Monitoring Metabolic Associated Fatty Liver Disease Treatment Response.

BACKGROUND: Quantitative measurements of liver fat contents (LFCs) by magnetic resonance imaging derived-proton density fat fraction (MRI-PDFF) are accurate but limited by availability, convenience, and expense in the surveillance of metabolic associated fatty liver (MAFLD). Insulin resistance (IR) and steatosis-associated serum indices are useful in screening for MAFLD, but their value in monitoring MAFLD with or without chronic hepatitis B virus (CHB) infection remains unclear and we aimed to evaluate these scores in predicting changes in LFC. METHODS: We conducted a prospective study between January 2015 and December 2021 with 620 consecutive participants with MAFLD (212 participants with CHB) who received a 24-week lifestyle intervention. The homeostasis model assessment of IR (HOMA-IR), HOMA2 index, glucose-insulin ratio, quantitative insulin sensitivity check index, fasting insulin resistance index, fatty liver index (FLI), hepatic steatosis index (HSI), liver fat score (LFS), visceral adiposity index, and triglycerides * glucose were calculated. RESULTS: When using endpoints such as LFS improvements of ≥5% or 10% or escalations of ≥5%, LFS had the highest area under the curve (AUC) values at all endpoints for MAFLD alone (0.756, 95% CI: 0.707-0.805; 0.761, 95% CI: 0.705-0.818; 0.807, 95% CI: 0.713-0.901, all p < 0.05, respectively). With CHB, the FLI (AUC = 0.750) and HIS (AUC = 0.770) exhibited the highest AUCs between the former two outcomes, respectively, but no score could predict LFC escalation of ≥5%. CONCLUSION: Among IR and steatosis scores, changes in LFC through lifestyle interventions can be captured with LFS possessing moderate precision but not in those with CHB.

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease.

BACKGROUND: The normalization of liver biochemical parameters usually reflects the histological response to treatment for nonalcoholic fatty liver disease (NAFLD). Researchers have not clearly determined whether different liver enzymes exhibit various metabolic changes during the follow-up period in patients with NAFLD. METHODS: We performed a retrospective analysis of patients with NAFLD who were receiving therapy from January 2011 to December 2019. Metabolism indexes, including glucose levels, lipid profiles, uric acid levels and liver biochemical parameters, were measured. Magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and liver ultrasound were used to evaluate steatosis. All patients received recommendations for lifestyle modifications and guideline-recommended pharmacological treatments with indications for drug therapy for metabolic abnormalities. RESULTS: Overall, 1048 patients with NAFLD were included and received lifestyle modification recommendations and pharmaceutical interventions, including 637 (60.7%) patients with abnormal GGT levels and 767 (73.2%) patients with abnormal ALT levels. Patients with concurrent ALT and GGT abnormalities presented higher levels of metabolism indexes and higher liver fat content than those in patients with single or no abnormalities. After 12 months of follow-up, the cumulative normalization rate of GGT was considerably lower than that of ALT (38% vs. 62%, P < 0.001). Greater weight loss resulted in higher cumulative normalization rates of GGT and ALT. Weight loss (OR = 1.21, 95% CI 1.11-1.32, P < 0.001), ALT normalization (OR = 2.75, 95% CI 1.41-5.36, P = 0.01) and lower TG and HOMA-IR values (OR = 2.03, 95% CI 1.11-3.71, P = 0.02; OR = 2.04, 95% CI 1.07-3.89, P = 0.03) were independent protective factors for GGT normalization. Elevated baseline GGT (OR = 0.99, 95% CI 0.98-0.99, P = 0.01) was a risk factor. CONCLUSIONS: For NAFLD patients with concurrently increased ALT and GGT levels, a lower normalization rate of GGT was observed, rather than ALT. Good control of weight and insulin resistance was a reliable predictor of GGT normalization.

Compositional alterations of gut microbiota in nonalcoholic fatty liver disease patients: a systematic review and Meta-analysis.

BACKGROUND: Although imbalanced intestinal flora contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), conflicting results have been obtained for patient-derived microbiome composition analyses. A meta-analysis was performed to summarize the characteristics of intestinal microbiota at the species level in NAFLD patients. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, a completed search (last update: December 30, 2020) of databases was performed to identify eligible case-control studies detecting gut microbiota in NAFLD patients. The meta-analysis results are presented as the standard mean difference (SMD) and 95% confidence interval (CI). Bias controls were evaluated with the Newcastle-Ottawa Scale (NOS), funnel plot analysis, and Egger's and Begg's tests. RESULTS: Fifteen studies (NOS score range: 6-8) that detected the gut microbiota in the stools of 1265 individuals (577 NAFLD patients and 688 controls) were included. It was found that Escherichia, Prevotella and Streptococcus (SMD = 1.55 [95% CI: 0.57, 2.54], 1.89 [95% CI: 0.02, 3.76] and 1.33 [95% CI: 0.62, 2.05], respectively) exhibited increased abundance while Coprococcus, Faecalibacterium and Ruminococcus (SMD = - 1.75 [95% CI: - 3.13, - 0.37], - 9.84 [95% CI: - 13.21, - 6.47] and - 1.84 [95% CI, - 2.41, - 1.27], respectively) exhibited decreased abundance in the NAFLD patients compared with healthy controls. No differences in the abundance of Bacteroides, Bifidobacterium, Blautia, Clostridium, Dorea, Lactobacillus, Parabacteroides or Roseburia were confirmed between the NAFLD patients and healthy controls. CONCLUSIONS: This meta-analysis revealed that changes in the abundance of Escherichia, Prevotella, Streptococcus, Coprococcus, Faecalibacterium and Ruminococcus were the universal intestinal bacterial signature of NAFLD.

Keratin 8 Mutations Were Associated With Susceptibility to Chronic Hepatitis B and Related Progression.

BACKGROUND: Keratin 8 and 18 (K8/K18) are the exclusively expressed keratins intermediate filaments pair in hepatocytes that protect against liver injuries and viral infection. We aimed to explore the genetic link between keratin variants and chronic hepatitis B virus (CHB) infection in a large cohort from a high-epidemic area. METHODS: Genomic deoxyribonucleic acid was isolated from patients, and Sanger sequencing was applied to analyze variations in exon regions of K8/18. Biochemical and functional analysis of novel mutations was also performed. RESULTS: The 713 participants comprised 173 healthy controls and 540 patients, which covered chronic hepatitis (n = 174), decompensated cirrhosis (n = 192), and primary liver carcinoma (n = 174). The frequency of mutations in K8/18 was significantly higher among patients than among controls (8.15% vs 0.58%, P < .001). Significant differences were found between the chronic hepatitis subgroup and controls in multiple comparisons (6.32% vs 0.58%, P = .006). All 21 missense mutations (3.89%) were detected in the keratin 8 (K8), including 4 novel conserved missense variants (R469C, R469H, A447V, and K483T). Multivariate logistic regression analysis demonstrated a higher risk of acute-on-chronic liver failure (ACLF) and missense variants (odds ratio = 4.38, P = .035). Transfection of these variants caused keratin network disruption in vivo. CONCLUSIONS: Novel K8 cytoskeleton-disrupting variants predispose toward ACLF in CHB.

Early Predictors of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease: Non-obese Versus Obese Patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is regarded as a risk factor of cardiovascular disease (CVD). However, the association between non-obese NAFLD and CVD has not been well established. AIM: We aimed to compare the CVD risk between non-obese and obese NAFLD patients, and explored the factors associated with subclinical atherosclerosis. METHOD: Consecutive NAFLD patients estimated by magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) were recruited. Liver fat content (LFC) and liver stiffness were measured with MRI-PDFF and shear wave elastography, respectively. CVD risk was estimated by atherosclerosis index (AI), carotid intima-media thickness, carotid plaque, and Framingham risk score (FRS). RESULTS: This study included 543 NAFLD patients. The presence of carotid intima-media thickening and carotid plaque, FRS, and AI were comparable between non-obese and obese patients. Age increased per 10 years (OR 9.68; P < 0.001) and liver fibrosis (liver stiffness > 6.1 kPa, OR 4.42; P = 0.004) were significant factors associated with carotid intima-media thickening in non-obese patients, while age increased per 10 years (OR 2.02; P < 0.001), liver fibrosis (OR 2.18; P = 0.039), and LFC > 10% (OR 2.29; P = 0.021) were independent predictors in obese patients. Only elevated triglyceride was significantly associated with carotid plaque in non-obese patients (OR 2.42; P = 0.033), while age increased per 10 years (OR 1.77; P = 0.002) and LFC > 10% (OR 2.83; P = 0.019) were significant predictors in obese patients. CONCLUSIONS: Liver stiffness and age were strongly predictive of subclinical atherosclerosis in all NAFLD, while LFC was an additional predictor in obese NAFLD patients. Our findings highlight that early CVD screening strategy should be established for NAFLD patients according to different BMIs.

Prevalence of Insulin Resistance in Subjects with Nonalcoholic Fatty Liver Disease and Its Predictors in a Chinese Population.

OBJECTIVE: Insulin resistance (IR) is a key factor involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the prevalence of IR in NAFLD patients and its risk factors have been rarely reported, especially in China. This prospective study was undertaken to clarify these issues in the Chinese population. METHODS: A total of 600 NAFLD patients and 300 age- and sex-matched healthy controls were recruited between January 1, 2011, and December 31, 2013. Demographic information and clinical characteristics were collected, and the presence of IR was evaluated using the homeostasis model. Uni- and multivariate analyses were conducted, and receiver operating characteristic (ROC) curves were generated to identify IR predictors. RESULTS: NAFLD patients had a much higher prevalence of IR than healthy controls (37.8 vs. 2.3 %, P < 0.001). The rates of elevated alanine transferase (ALT) and aspartate transferase (AST) levels were much higher in NAFLD patients with IR than those without (53.7 vs. 41.6 % and 28.6 vs. 18.2 %, respectively, P < 0.001). Uni- and multivariate analyses revealed that female sex, general obesity, abdominal obesity, and hypertension were independent predictors for IR. The area under the ROC curve for fasting plasma insulin (FPI) detecting IR was 0.93 (P < 0.001), and the optimal cutoff was 11.3 µU/ml (sensitivity = 0.86, specificity = 0.92). CONCLUSION: Chinese NAFLD patients are susceptible to IR. Female sex, general and abdominal obesity, and hypertension were independent predictors for IR in NAFLD patients. FPI is an optimal predictor for IR.

Optimized strategy among diet, exercise, and pharmacological interventions for nonalcoholic fatty liver disease: A network meta-analysis of randomized controlled trials.

BACKGROUND: Emerging treatment methods, including exercise, diet, and drugs, for nonalcoholic fatty liver disease have been proposed. However, the differences in their efficacy have not been determined. We aimed to compare the effects of these treatments excluding surgery via a systematic review and network meta-analysis of randomized controlled trials. DATA SOURCE: The data sources included PubMed, Embase, Web of Science and Cochrane up to February 1st, 2023. The endpoints consisted of body mass index (BMI), serum markers of metabolism and liver injury markers, liver fat content, and stiffness. RESULTS: A total of 174 studies with 10,183 patients were included in this meta-analysis. In terms of improving BMI, Pan-agonist of peroxisome proliferator-activated receptors (PPAR) is the best treatment with the highest SUCRA (surface under the cumulative ranking) of 84.8% (mean = -3.40, 95% CI -5.55, -1.24) by the comparative effectiveness ranking. GLP-1 (glucagon-like peptide-1) has the best effect in improving the liver fat content based on the MRI-PDFF, steatosis score (SUCRA 99.7%, mean = -2.19, 95% CI -2.90, -1.48) and ballooning score (SUCRA 61.2%, mean = -0.82, 95% CI -4.46, 2.83). CONCLUSIONS: Pan-agonist of PPAR was the most efficacious regimen in lowering BMIs, whereas GLP-1R agonists achieved the highest efficacy of steatosis improvement in this network meta-analysis.

Phospholipid metabolism-related genotypes of PLA2R1 and CERS4 contribute to nonobese MASLD.

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.

Specific metabolic impairments indicate loss of sustained liver improvements in metabolic dysfunction-associated steatotic liver disease treatment.

Background: High liver fat content (LFC) induces increased risks of both hepatic and extrahepatic progression in metabolic dysfunction-associated steatotic liver disease (MASLD), while maintaining a significant decline in magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) (≥30% decline relative to baseline) without worsening fibrosis results in improved histological severity and prognosis. However, the factors associated with the loss of sustained responses to treatment remain unclear, and we aim to identify them. Methods: Consecutive treatment-naïve MASLD patients between January 2015 and February 2022, with follow-up until April 2023, were included in this prospective cohort study. LFC quantified by MRI-PDFF and liver stiffness measurements (LSM) determined by two-dimensional shear wave elastography (2D-SWE) were evaluated at weeks 0, 24 and 48. MRI-PDFF response was defined as a ≥30% relative decline in PDFF values, and LSM response was defined as a ≥1 stage decline from baseline. Results: A total of 602 MASLD patients were enrolled. Of the 303 patients with a 24-week MRI-PDFF response and complete follow-up of 48 weeks, the rate of loss of MRI-PDFF response was 29.4%, and multivariable logistic regression analyses showed that 24-week insulin resistance (IR), still regular exercise and caloric restriction after 24 weeks, and the relative decline in LFC were risk factors for loss of MRI-PDFF response. Loss of LSM response at 48 weeks occurred in 15.9% of patients, and multivariable analysis confirmed 24-week serum total bile acid (TBA) levels and the relative decline in TBA from baseline as independent predictors. No significant association was found at 48 weeks between loss of MRI-PDFF response and loss of LSM response. Conclusions: MASLD patients with IR and high TBA levels are at higher risks of subsequent diminished sustained improvements of steatosis and fibrosis, respectively.

Quantitative assessment of brown adipose tissue whitening in a high-fat-diet murine model using synthetic magnetic resonance imaging.

Purpose: This study aimed to quantitatively evaluate the whitening process of brown adipose tissue (BAT) in mice using synthetic magnetic resonance imaging (SyMRI) and analyzed the correlation between SyMRI quantitative measurements of BAT and serum lipid profiles. Methods: Fifteen C57BL/6 mice were divided into three groups and fed different diets as follows: normal chow diet for 12 weeks, NCD group; high-fat diet (HFD) for 12 weeks, HFD-12w group; and HFD for 36 weeks, HFD-36w group. Mice were scanned using 3.0 T SyMRI. T1 and T2 values of BAT and interscapular BAT (iBAT) volume were measured. After sacrifice, the body weight of mice, lipid profiles, BAT morphology, and uncoupling protein 1 (UCP1) levels were determined. Statistical analysis was performed using one-way analysis of variance or Kruskal-Wallis test followed by Bonferroni correction for pairwise comparisons. Bonferroni-adjusted significance level was set at P < 0.017 (alpha: 0.05/3 = 0.017). Results: T2 values of BAT in the HFD-12w group were significantly higher than those in the NCD group (P < 0.001), and those in the HFD-36w group were significantly higher than those in the other two groups (both P < 0.001). The iBAT volume in the HFD-36w group was significantly higher than that in the HFD-12w (P = 0.013) and NCD groups (P = 0.005). T2 values of BAT and iBAT volume were significantly correlated with serum lipid profiles and mouse body weight. Conclusions: SyMRI can noninvasively evaluate the whitening process of BAT using T2 values and iBAT volume, thereby facilitating the visualization of the whitening process.

Alterations in Circulating Bile Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis.

Background: Previous studies have suggested that bile acids (BAs) may participate in the development and/or progression of metabolic dysfunction-associated steatotic liver disease (MASLD). The present study aimed to define whether specific BA molecular species are selectively associated with MASLD development, disease severity, or geographic region. Methods: We comprehensively identified all eligible studies reporting circulating BAs in both MASLD patients and healthy controls through 30 July 2023. The pooled results were expressed as the standard mean difference (SMD) and 95% confidence interval (CI). Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Results: Nineteen studies with 154,807 individuals were included. Meta-analysis results showed that total BA levels in MASLD patients were higher than those in healthy controls (SMD = 1.03, 95% CI: 0.63-1.42). When total BAs were divided into unconjugated and conjugated BAs or primary and secondary BAs, the pooled results were consistent with the overall estimates except for secondary BAs. Furthermore, we examined each individual BA and found that 9 of the 15 BAs were increased in MASLD patients, especially ursodeoxycholic acids (UDCA), taurococholic acid (TCA), chenodeoxycholic acids (CDCA), taurochenodeoxycholic acids (TCDCA), and glycocholic acids (GCA). Subgroup analysis revealed that different geographic regions or disease severities led to diverse BA profiles. Notably, TCA, taurodeoxycholic acid (TDCA), taurolithocholic acids (TLCA), and glycolithocholic acids (GLCA) showed a potential ability to differentiate metabolic dysfunction-associated steatohepatitis (MASH) (all p < 0.05). Conclusions: An altered profile of circulating BAs was shown in MASLD patients, providing potential targets for the diagnosis and treatment of MASLD.

Treatment of obesity and metabolic-associated fatty liver disease with a diet or orlistat: A randomized controlled trial.

BACKGROUND: Losing weight by lifestyle interventions is the first-line treatment for metabolic-associated fatty liver disease (MAFLD) but is limited by low compliance. OBJECTIVES: This study aimed to compare the effects of orlistat or an experimental high-protein/lower-carbohydrate diet with a control diet in Asian patients with obesity and MAFLD. METHODS: A total of 118 Asian patients with obesity and MAFLD confirmed with MRI-based proton density fat fraction with Dixon sequence were enrolled and allocated to the control group, the orlistat group, or the experimental diet group for 24 wk. The primary endpoint was the relative change in liver fat content (LFC) assessed by MRI-based proton density fat fraction. RESULTS: A total of 118 subjects with obesity and MAFLD were randomly assigned to the control group (n = 39), the orlistat group (n = 40), or the experimental diet group (n = 39). All 3 groups demonstrated improvement in liver steatosis at wk 24. The absolute decrease in LFC in the orlistat group was 9.1% and 5.4% in the experimental diet group, both significantly higher than that in the control group (P < 0.05). The relative reduction in LFC was 30.2% in the experimental diet group, which was significantly higher than the 12.2% observed in the control group (P = 0.01). CONCLUSIONS: Orlistat and the experimental diet group reduced liver steatosis compared to the control group. This trial was registered at Chinese Clinical Trial Registry (ChiCTR-1900027172). http://www.chictr.org.cn.

Restoring skeletal muscle mass as an independent determinant of liver fat deposition improvement in MAFLD.

AIMS: Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are scarce. We aimed to explore the impact of changes in relative skeletal muscle mass on the MAFLD treatment response. METHODS: MAFLD patients undergoing magnetic resonance imaging-based proton density fat fraction for liver fat content (LFC) assessments and bioelectrical impedance analysis before and after treatment (orlistat, meal replacement, lifestyle modifications) were enrolled. Appendicular muscle mass (ASM) was adjusted by weight (ASM/W). RESULTS: Overall, 256 participants were recruited and divided into two groups: with an ASM/W increase (n=166) and without an ASM/W increase (n=90). There was a great reduction in LFC in the group with an ASM/W increase (16.9% versus 8.2%, P < 0.001). However, the change in LFC in the group without an ASM/W increase showed no significant difference (12.5% versus 15.0%, P > 0.05). △ASM/W Follow-up-Baseline [odds ratio (OR)=1.48, 95% confidence interval (CI) 1.05-2.07, P = 0.024] and △total fat mass (OR=1.45, 95% CI 1.12-1.87, P = 0.004) were independent predictors for steatosis improvement (relative reduction of LFC ≥ 30%). The subgroup analysis showed that, despite without weight loss, decrease in HOMA-IR (OR=6.21, 95% CI 1.28-30.13, P=0.023), △total fat mass Baseline -Follow-up (OR=3.48, 95% CI 1.95-6.21, P <0.001 and △ASM/W Follow-up-Baseline (OR=2.13, 95% CI 1.12-4.05, P=0.022) independently predicted steatosis improvement. CONCLUSIONS: ASM/W increase and loss of total fat mass benefit the resolution of liver steatosis, independent of weight loss for MAFLD.

An Optimized Strategy Based on Conventional Ultrasound for Diagnosing Metabolic Dysfunction-Associated Steatotic Liver Disease.

The inherent drawbacks of the conventional B-mode ultrasound for metabolic dysfunction-associated steatotic liver disease (MASLD) are poorly understood. We aimed to investigate the impact factors and optimize the screening performance of ultrasound in MASLD. In a prospective pilot cohort recruited from July 2020 to January 2022, subjects who had undergone magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), ultrasound, and laboratory test-based assessments were included in the deprivation cohort. A validation cohort including 426 patients with liver histologic assessments from five medical centers in South China was also recruited. A total of 1489 Chinese subjects were enrolled in the deprivation cohort, and ultrasound misdiagnosed 62.2% of the non-MASLD patients and failed to detect 6.1% of the MASLD patients. The number of metabolic dysfunction components and the alanine aminotransferase (ALT) level were associated with a missed diagnosis by ultrasound (OR = 0.67, 95% CI 0.55-0.82 p < 0.001; OR = 0.50, 95% CI 0.31-0.79, p = 0.003, respectively). Compared with ultrasound alone, the new strategy based on ultrasound, in combination with measurements of the number of metabolic dysfunction components and ALT and uric acid levels, significantly improved the AUROC both in the research cohort and the validation cohort (0.66 vs. 0.84, 0.83 vs. 0.92, respectively). The number of metabolic dysfunction components and ALT and uric acid levels improved the screening efficacy of ultrasound for MASLD.

Prevalence and Significance of Antinuclear Antibodies in Biopsy-Proven Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Aim: Associations between antinuclear antibodies (ANAs) and disease severity in nonalcoholic fatty liver disease (NAFLD) remain unclear. This study aimed to provide reliable estimates of ANA prevalence in subjects with biopsy-proven NAFLD and to investigate whether its associations with liver disease severity were established. Methods: Observational studies measuring ANA in NAFLD patients were derived from the PubMed, Embase, and Web of Science databases from inception to March 30, 2022. The effect size was presented as the pooled risk difference, unstandardized mean differences (MDs), and odds ratio (OR) with a 95% confidence interval (CI). Results: Thirteen articles involving 2331 patients were finally included. Among the subjects with biopsy-proven NAFLD, the overall prevalence of ANA positivity was high as 23% (95% CI: 19%-28%), but there were no statistically significant differences between ANA-positive and ANA-negative NAFLD patients in the levels of liver enzymes and blood lipids, grades of hepatocellular ballooning, lobular and portal inflammation, or risks of moderate-severe steatosis and significant fibrosis. However, the subgroup analysis showed that different geographic regions led to diverse results. ANA positivity was associated with a significantly elevated risk of significant fibrosis in the Eastern population (OR = 2.30, 95% CI: 1.30-4.06) but not in the Western population (OR = 1.00, 95% CI: 0.54-1.83). Conclusions: Serum ANA was present in approximately one-quarter of subjects with biopsy-proven NAFLD, but it conferred a greater risk of significant fibrosis only in Eastern but not Western populations.