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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

Age patterns of nonalcoholic fatty liver disease incidence: heterogeneous associations with metabolic changes.

BACKGROUND: As the nonalcoholic fatty liver disease (NAFLD) epidemic matures, understanding how metabolic changes in NAFLD development vary over the age distribution is important to guide precise prevention. We aimed to clarify metabolic trends in age-specific NAFLD incidence. METHODS: We conducted a 4-year longitudinal retrospective cohort study enrolling 10,240 consecutive healthy individuals who received annual physical examination during 2012-2019. Baseline and dynamic changes in metabolism and hepatic steatosis determined with ultrasound were collected and analyzed stratified by age into the following groups: 20-34, 35-49, 50-64, and over 65 years. RESULTS: Overall, 1701 incident NAFLD participants (16.6%) were identified. Adjusted Cox regression analysis showed that the baseline and increased body mass index were the main risk factors for NAFLD in people ≤ 65 years old. Baseline high-density lipoprotein (HR = 0.56; 95% CI 0.39-0.78) was a protective factor for newly onset NAFLD in the 50-to-64-year-old group, while baseline SBP (HR = 1.03; 95% CI 1.01-1.05), baseline uric acid (HR = 1.04; 95% CI 1.01-1.07), triglyceride increase (HR = 4.76; 95% CI 3.69-6.14), fasting blood glucose increase (HR = 1.32; 95% CI 1.06-1.65) were independently associated with incident NAFLD in over-65-year-old group. CONCLUSIONS: NAFLD incidence attributable to potentially metabolic risk factors varied substantially across age groups in a cohort of Chinese people. The adoption of age targeted metabolic prevention strategies might reduce the burden of NAFLD.

Discrepancies between Nonalcoholic and Metabolic-associated Fatty Liver Disease by Multiple Steatosis Assessment.

Background and Aims: 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. Methods: A cross-sectional study enrolling consecutive individuals was conducted at three medical centers in southern China from January 2015 to September 2020. Steatosis was evaluated by liver biopsy or magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), ultrasound, controlled attenuation parameter (CAP), and fatty liver index (FLI). Fibrosis was assessed by the NAFLD fibrosis score, transient elastography, or shear wave elastography. Results: The study enrolled 14,985 Chinese adults. The agreement of MAFLD and NAFLD diagnoses were 83% for FLI, 95% for ultrasound, 94% for both CAP and MRI-PDFF, and 95% for liver biopsy. The body mass index, blood pressure and lipid levels among non-MAFLD-NAFLD patients were similar metabolic parameters (p>0.05 for all), but not the alanine aminotransferase and the proportion of patients with insulin resistance, which were significantly higher in non-MAFLD-NAFLD with significant fibrosis. Conclusions: The new MAFLD definition ruled out 5-17% of NAFLD cases. NAFLD and MAFLD-NAFLD involved more severe metabolic abnormalities than MAFLD and MAFLD-non-NAFLD. Non-MAFLD-NAFLD patients with significant fibrosis had more severe liver injury and increased glycemic dysregulation within the normal range. Attention should be paid to its progression.

Metabolic benefits of changing sedentary lifestyles in nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

This study seeks to evaluate the effects of a reversal of sedentary lifestyles on the improvement of metabolic profiles in patients with NAFLD. The PubMed, Cochrane Library, Web of Science, and CNKI databases were searched up to May 15, 2021. Ten randomized controlled trials on changes in the sedentary lifestyle of patients with NAFLD were included in the analysis. Data from self-controlled case arms of randomized controlled trials investigating sedentary lifestyle alterations were extracted, and the effect size was reported as the MD and 95% CI. A total of 455 participants in 10 studies met the selection criteria. The results showed that changing a sedentary lifestyle can significantly improve ALT [MD = 4.35 (U/L), 95% CI: 0.53, 8.17], CHOL [MD = 0.31 (mmol/L), 95% CI: 0.19, 0.43], TG [MD = 0.22 (mmol/L), 95% CI: 0.10~0.34], LDL-C [MD = 0.30 (mmol/L), 95% CI: 0.02, 0.57], fasting blood glucose [MD = 0.17 (mmol/L), 95% CI: 0.03, 0.31], insulin [MD = 3.23 (pmol/L), 95% CI: 1.37~5.08], and HOMA-IR levels (MD = 0.39, 95% CI: 0.15, 0.63). Changing sedentary lifestyle can also significantly improve body mass index (BMI) [MD = 1.12 (kg/m2), 95% CI: 0.66, 0.58], body fat (%) [MD = 0.34 (%), 95% CI: 0.13, 0.55] and VO2peak levels [MD = -4.00 (mL/kg/min), 95% CI: -5.93, -2.06]. No differences in AST or GGT were noted before or after lifestyle changes. Altering a sedentary lifestyle to a lifestyle with regular exercise can slightly improve the levels of liver enzymes, blood lipids, blood glucose, insulin resistance, and body mass index in NAFLD patients.

The Additive Values of the Classification of Higher Serum Uric Acid Levels as a Diagnostic Criteria for Metabolic-Associated Fatty Liver Disease.

Serum uric acid (SUA) is regarded as an independent risk factor for nonalcoholic fatty liver disease (NAFLD). However, the role of SUA in the new diagnosis flowchart of metabolic-associated fatty liver disease (MAFLD) remains unclear. A cross-sectional study enrolled consecutive individuals with ultrasonography and magnetic resonance imaging−based proton density fat fraction (MRI-PDFF) measurements in the First Affiliated Hospital of Sun Yat-sen University from January 2015 to December 2021. All patients were divided into four groups according to their baseline SUA levels and sex. Of the 3537 ultrasound-diagnosed and 1017 MRI-PDFF-diagnosed MAFLD patients included, the prevalence of severe steatosis determined with ultrasound or MRI-PDFF increased across the serum SUA quartiles. The SUA cutoffs were identified as ≥478 µmol/L and ≥423.5 µmol/L for severe steatosis in male and female MAFLD, respectively. Furthermore, using these cutoff values, patients with higher SUA levels in the NAFLD−non-MAFLD group had higher liver fat contents than those without (16.0% vs. 9.7%, p < 0.001). The lean/normal-weight NAFLD−non-MAFLD patients with higher SUA levels are still at high risk of severe steatosis. This study supports the rationale for SUA being established as another risk factor for metabolic dysfunctions in lean/normal-weight MAFLD.

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.

Novel metabolic classification for extrahepatic complication of metabolic associated fatty liver disease: A data-driven cluster analysis with international validation.

BACKGROUND: Traditional classification systems of metabolic-associated fatty liver disease (MAFLD) do not account for the high rate of extrahepatic complications. To create a new classification of MAFLD using metabolic parameters to identify risks of complications more accurately. METHODS: The retrospective study included MAFLD patients from the First Affiliated Hospital of Sun Yat-sen University for model development, and the model was validated respectively using Chinese cohort and UK Biobank database. Cluster analysis with k-means cluster was built using age, body mass index (BMI), glycosylated hemoglobin (HbA1c), total cholesterol/high density lipoprotein cholesterol (HDL-C) ratio, triglyceride, and lipoprotein(a) [Lp(a)] levels. Cox regression models were used to compare the risk of type 2 diabetes (T2DM), chronic heart disease (CHD), stroke and mortality between the clusters. RESULTS: 1038 MAFLD patients from cross-sectional population were recruited for the model derivation, with 10,451 cases (33.4 % of MAFLD) from Chinese cohort and 304,141 cases (34.9 % of MAFLD, 1010 cases with magnetic resonance imaging proton density fat fraction measurement [MRI-PDFF]) from the international cohort validated. Five replicable clusters of MAFLD patients were identified: Cluster 1(mild obesity and dyslipidemia-related), Cluster 2 (age related), Cluster 3 (severe insulin resistance-related), Cluster 4[high Lp(a)-related], and Cluster 5 (severe mixed hyperlipidemia-related). Patients in different clusters exhibited differences in the development of T2DM, CHD, stroke and all-causes mortality. Patients in Cluster 3 had significantly worst survival outcomes and higher risks of T2DM and CVD than those in other clusters. CONCLUSION: The novel classification offers improved discrimination of new-onset MAFLD patients with different metabolic complications.

The Ability of Lipoprotein (a) Level to Predict Early Carotid Atherosclerosis Is Impaired in Patients With Advanced Liver Fibrosis Related to Metabolic-Associated Fatty Liver Disease.

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.