Association between biological aging and the risk of mortality in individuals with non-alcoholic fatty liver disease: A prospective cohort study.

BACKGROUND: The biological process of aging plays an important role in nonalcoholic fatty liver disease (NAFLD) development. However, epidemiological evidence about the association of biological aging with mortality risk among people with NAFLD is limited. METHODS: A total of 2199 participants with NAFLD from the National Health and Nutrition Examination Surveys (NHANES) III were included. The outcomes were all-cause and cause-specific (cardiovascular disease [CVD], cancer, and diabetes) mortality. We computed three BA measures, the Klemera-Doubal method (KDM) age, Phenotypic age, and homeostatic dysregulation (HD), by using 18 age-associated clinical biomarkers, and assessed their associations with mortality risk using Cox proportional hazards (CPH) models. RESULTS: After a median follow-up of 16 years, a total of 1077 deaths occurred. People with NAFLD who died during follow-up period exhibited higher baseline biological age (BA) and biological age accelerations (BAAs). The multivariate-adjusted CPH suggested that a one-standard deviation (SD) increase in KDM age acceleration, Phenotypic age acceleration, or HD was associated with a 3 %, 7 %, or 39 % elevated risk of all-cause mortality, respectively. The results of age-varying HRs showed that the associations of KDM age accelerations (AAs) and Phenotypic AAs with all-cause mortality appeared to be stronger in people with NAFLD younger than 45 years. CONCLUSIONS: Biological aging was positively associated with both all-cause and cause-specific mortality among people with NAFLD, particularly among younger individuals.

Machine learning-based plasma metabolomic profiles for predicting long-term complications of cirrhosis.

BACKGROUND AND AIMS: The liver cirrhosis complications occur after long asymptomatic stages of progressive fibrosis and are generally diagnosed late. We aimed to develop a plasma metabolomic-based score tool to predict these events. APPROACH AND RESULTS: We enrolled 64,005 UK biobank participants with metabolomic profile. Participants were randomly divided into the training (n=43,734) and validation cohorts (n=20,271). Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with hepatocellular carcinoma. Interpretable machine learning framework was applied to learn the metabolomic states extracted from 168 circulating metabolites in the training cohort. An integrated nomogram was developed and compared to conventional and genetic risk scores. We created three groups: low-risk, middle-risk, and high-risk through selected cut-offs of the nomogram. The predictive performance was validated through area under time-dependent receiver operating characteristic curve (time-dependent AUC), calibration curves, and decision curve analysis. The metabolomic state model could accurately predict 10-year risk of liver cirrhosis complications in the training cohort (time-dependent AUC 0.84 [95% CI 0.82-0.86]), and outperform the fibrosis-4 index (time-dependent AUC difference 0.06 [0.03-0.10]) and polygenic risk score (0.25 [0.21-0.29]). The nomogram, integrating metabolomic state, aspartate aminotransferase, platelet count, waist/hip ratio, and smoking status, showed a time-dependent AUC of 0.930 at 3 years, 0.889 at 5 years, and 0.861 at 10 years in the validation cohort, respectively. The hazard ratio in the high-risk group was 43.58 (95% CI 27.08-70.12) compared with the low-risk group. CONCLUSIONS: We developed a metabolomic state-integrated nomogram, which enables risk stratification and personalized administration of liver-related events.

Circulating Lipoproteins Mediate the Association Between Cardiovascular Risk Factors and Cognitive Decline: A Community-Based Cohort Study.

Cardiovascular health metrics are now widely recognized as modifiable risk factors for cognitive decline and dementia. Metabolic perturbations might play roles in the linkage of cardiovascular diseases and dementia. Circulating metabolites profiling by metabolomics may improve understanding of the potential mechanism by which cardiovascular risk factors contribute to cognitive decline. In a prospective community-based cohort in China (n = 725), 312 serum metabolic phenotypes were quantified, and cardiovascular health score was calculated including smoking, exercise, sleep, diet, body mass index, blood pressure, and blood glucose. Cognitive function assessments were conducted in baseline and follow-up visits to identify longitudinal cognitive decline. A better cardiovascular health was significantly associated with lower risk of concentration decline and orientation decline (hazard ratio (HR): 0.84-0.90; p < 0.05). Apolipoprotein-A1, high-density lipoprotein (HDL) cholesterol, cholesterol ester, and phospholipid concentrations were significantly associated with a lower risk of longitudinal memory and orientation decline (p < 0.05 and adjusted-p < 0.20). Mediation analysis suggested that the negative association between health status and the risk of orientation decline was partly mediated by cholesterol ester and total lipids in HDL-2 and -3 (proportion of mediation: 7.68-8.21%, both p < 0.05). Cardiovascular risk factors were associated with greater risks of cognitive decline, which were found to be mediated by circulating lipoproteins, particularly the medium-size HDL components. These findings underscore the potential of utilizing lipoproteins as targets for early stage dementia screening and intervention. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00120-2.

Prevalence of nonalcoholic fatty liver disease and liver cirrhosis in Chinese adults with type 2 diabetes mellitus.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and liver cirrhosis are significant clinical concerns, especially among individuals with type 2 diabetes mellitus (T2DM). However, in China, there is a paucity of reliable evidence detailing the characteristics of NAFLD and liver cirrhosis in T2DM. Furthermore, the relationship between blood glucose levels and NAFLD prevalence remains unclear. METHODS: Data from the Shanghai Suburban Adult Cohort and Biobank were analyzed, including 6621 participants with T2DM. NAFLD was diagnosed by ultrasonography and liver cirrhosis was performed according to the health information systems. Logistic regression and restricted cubic spline analysis were used to explore the potential risk factors for NAFLD and liver cirrhosis. RESULTS: The prevalence of NAFLD was 59.36%, and liver cirrhosis was 1.43% among T2DM patients. In these patients, factors like age, being female, marital status, and obesity significantly increased the risk of NAFLD. Specifically, obesity had a strong positive association with NAFLD (odds ratio [OR] = 4.70, 95% confidence interval [CI]: 4.13-5.34). The higher glycated hemoglobin (HbA1c) quartile was associated with a heightened NAFLD risk compared to the lowest quartile (all p < .001). The HbA1c-NAFLD relationship displayed a linear that mimicked an inverted L-shaped pattern. A significant positive association existed between HbA1c levels and NAFLD for HbA1c <8.00% (OR = 1.59, 95% CI: 1.44-1.75), but this was not observed for HbA1c >8.00% (OR = 1.03, 95% CI: 0.92-1.15). CONCLUSION: Systematic screening for NAFLD is essential in T2DM patients, especially with poor glucose control and obesity in female.

Low thyroid function is associated with metabolic dysfunction-associated steatotic liver disease.

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is recently introduced to better highlight the pathogenic significance of cardiometabolic dysfunction, as compared with non-alcoholic fatty liver disease. This study aimed to investigate the association between low thyroid function and MASLD in the new context. Methods: We recruited 2901 participants for our retrospective cohort study from 2016 to 2021. Participants were divided into strict-normal thyroid function and low thyroid function groups (low-normal thyroid function, subclinical hypothyroidism) based on initial thyroid stimulating hormone (TSH) levels, respectively. Cox regression models were used to estimate the hazard ratios (HRs) and 95% CI. Results: During a median follow-up of 15.6 months, 165 (8.9%) strict-normal thyroid function subjects and 141 (13.4%) low thyroid function subjects developed MASLD; this result was statistically relevant (P < 0.05). Univariate regression analysis showed that low thyroid function and subclinical hypothyroidism were statistically significantly associated with MASLD (low thyroid function: HR1.53; 95% CI 1.22-1.92; subclinical hypothyroidism: HR1.95; 95% CI 1.47-2.60). Conclusions: MASLD is associated with low thyroid function and the relationship between MASLD and low thyroid function is independent.

Prognostic factors for competing risk in patients with AIDS-related Kaposi's sarcoma: A SEER population-based study.

OBJECTIVES: Despite the improved survival of patients with AIDS and Kaposi's sarcoma (KS), competing events are a non-negligible issue affecting the survival of such patients. In this study, we explored the prognostic factors of KS-specific and non-KS-specific mortality in patients with AIDS-related KS (AIDS-KS), accounting for competing risk. METHODS: We identified 17 103 patients with AIDS-KS aged 18-65 years between 1980 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) 18 registry database. Prognostic factors for KS-specific and non-KS-specific mortality were determined by the Fine and Grey proportional subdistribution hazard model. We built competing risk nomograms and assessed their predictive performance based on the identified prognostic factors. RESULTS: In total, 12 943 (75.68%) patients died, 1965 (15.50%) of whom died from competing events. The KS-specific mortality rate was 14 835 per 100 000 person-years, and the non-KS specific mortality rate was 2719 per 100 000 person-years. Specifically, age >44 years was associated with an 11% decrease in the subdistribution hazard of KS-specific mortality compared with age <43 years but a 50% increase in the subdistribution hazard of non-KS-specific mortality. Being male was associated with a 26% increase in the subdistribution hazard of KS-specific mortality compared with being female but a 32% decrease in the subdistribution hazard of non-KS-specific mortality. Notably, being in the antiretroviral therapy (ART) era consistently showed a decrease in the subdistribution hazard of both KS-specific and non-KS-specific mortality than being in the pre-ART era. CONCLUSIONS: Competing events commonly occurred among patients with AIDS-KS, which deserves further attention to improve the prognosis of these patients.

Global epidemiology of early-onset liver cancer attributable to specific aetiologies and risk factors from 2010 to 2019.

Background: Considering its emergence as a public health concern worldwide, with potential spatial-temporal heterogeneities, we aimed to determine the global burden of early-onset liver cancer attributable to aetiologies and concomitant risk factors. Methods: We used data from the Global Burden of Diseases Study 2019 to determine age-standardised disability-adjusted life-year (DALY) rates for early-onset liver cancer by aetiologies and the population DALYs attributable to concomitant risk factors between 2010 and 2019. We also calculated estimated annual percentage changes (EAPCs) to measure temporal trends. Results: There were 2.9 million DALYs related to early-onset liver cancer globally in 2019. East Asia contributed over half of DALYs, which increased annually by 1.23% (95% confidence interval (CI) = 0.71, 1.76) between 2010 and 2019. Non-alcoholic steatohepatitis was the only growing aetiology. The proportion of DALYs attributed to metabolic risks increased by 22.50% (95% CI = 14.33, 38.13), while behavioral risks remained stable. Obesity surpassed smoking as the most prevalent nondeterministic aetiological risk factor from 2010 to 2019, while the population DALY attributable to hepatitis B combined with obesity increased by 29.93% (95% CI = 8.49, 60.77) in the same period, making it the principal joint contributor. Conclusions: Early-onset liver cancer poses considerable disability and continues to increase in many regions, especially in East Asia. Metabolic risk factors, particularly when hepatitis B and obesity coexist, are the fastest-growing contributors to this type of cancer. More targeted interventions are imperative to curb the growing burden of early-onset liver cancer due to metabolic risks.

Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: a systematic literature review and meta-analysis of 3740 studies and 231 million people.

OBJECTIVE: China concentrates a large part of the global burden of HBV infection, playing a pivotal role in achieving the WHO 2030 global hepatitis elimination target. METHODS: We searched for studies reporting HBV surface antigen (HBsAg) seroprevalence in five databases until January 2023. Eligible data were pooled using a generalised linear mixed model with random effects to obtain summary HBsAg seroprevalence. Linear regression was used to estimate annual percentage change (APC) and HBsAg prevalence in 2021. RESULTS: 3740 studies, including 231 million subjects, were meta-analysed. HBsAg seroprevalence for the general population decreased from 9.6% (95% CI 8.4 to 10.9%) in 1973-1984 to 3.0% (95% CI 2.1 to 3.9%) in 2021 (APC=-3.77; p<0.0001). Decreases were more pronounced in children <5 years (APC=-7.72; p<0.0001) and 5-18 years (-7.58; p<0.0001), than in people aged 19-59 years (-2.44; p<0.0001), whereas HBsAg seroprevalence increased in persons ≥60 years (2.84; p=0.0007). Significant decreases were observed in all six major Chinese regions, in both men (APC=-3.90; p<0.0001) and women (-1.82; p<0.0001) and in high-risk populations. An estimated 43.3 million (95% uncertainty interval 30.7-55.9) persons remained infected with HBV in China in 2021 (3.0%), with notable heterogeneity by region (<1.5% in North China to>6% in Taiwan and Hong Kong) and age (0.3%, 1.0%, 4.7% and 5.6% for <5 years, 5-18 years, 19-59 years and ≥60 years, respectively). CONCLUSIONS: China has experienced remarkable decreases in HBV infection over the last four decades, but variations in HBsAg prevalence persist in subpopulations. Ongoing prevention of HBV transmission is needed to meet HBV elimination targets by 2030. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021284217).

Associations of healthy lifestyle and three latent socioeconomic status patterns with physical multimorbidity among middle-aged and older adults in China.

BACKGROUND: Multimorbidity is an emerging global public health concern. However, complex associations of healthy lifestyle and socioeconomic status (SES) with multimorbidity have not been identified. METHODS: This population-based prospective cohort study used data from four waves of the China Health and Retirement Longitudinal Study (CHARLS) to explore these relationships. Physical multimorbidity was measured using 12 non-communicable diseases. Latent class analysis (LCA) was conducted to determine the optimal SES patterns based on annual per-capita household expenditure, occupation, education level, and health insurance. The healthy lifestyle score (0-5) was constructed comprising information on smoking, drinking, physical activity, sleep, and body shape. RESULTS: Of 17,708 participants in the CHARLS, 7776 were eligible for inclusion in our analysis (13.3% with high SES, 26.1% with medium SES, and 60.6% with low SES). Compared with high SES participants, those with low SES had higher risks of incident physical multimorbidity (OR 1.22, 95% CI 1.05, 1.42), which was competitively mediated by lifestyle (mediation proportion, -10.17%, 95% CI -19.12%, -1.23%). Significant interactions were observed between lifestyle factors and SES in patients with incident diabetes. Participants with low SES and no or one healthy lifestyle factor had a higher risk of incident physical multimorbidity than those with high SES and four to five healthy lifestyle factors (OR 2.19, 95% CI 1.57, 3.04). CONCLUSION: Healthy lifestyles competitively mediate a fractional proportion of socioeconomic inequity in incident physical multimorbidity. Furthermore, healthy lifestyles were associated with lower multimorbidity risk in the SES subgroups, supporting the important role of lifestyle in reducing physical multimorbidity burden.

Candidate biomarkers and persistent transcriptional responses after low and high dose ionizing radiation at high dose rate.

PURPOSE: Development of an integrated time and dose model to explore the dynamics of gene expression alterations and identify biomarkers for biodosimetry following low- and high-dose irradiations at high dose rate. MATERIAL AND METHODS: We utilized multiple transcriptome datasets (GSE8917, GSE43151, and GSE23515) from Gene Expression Omnibus (GEO) for identifying candidate biological dosimeters. A linear mixed-effects model with random intercept was used to explore the dose-time dynamics of transcriptional responses and to functionally characterize the time- and dose-dependent changes in gene expression. RESULTS: We identified genes that are correlated with dose and time and discovered two clusters of genes that are either positively or negatively correlated with both dose and time based on the parameters of the model. Genes in these two clusters may have persistent transcriptional alterations. Twelve potential transcriptional markers for dosimetry-ARHGEF3, BAX, BBC3, CCDC109B, DCP1B, DDB2, F11R, GADD45A, GSS, PLK3, TNFRSF10B, and XPC were identified. Of these genes, BAX, GSS, and TNFRSF10B are positively associated with both dose and time course, have a persistent transcriptional response, and might be better biological dosimeters. CONCLUSIONS: With the proposed approach, we may identify candidate biomarkers that change monotonically in relation to dose, have a persistent transcriptional response, and are reliable over a wide dose range.

Global Burden, Risk Factor Analysis, and Prediction Study of Ischemic Stroke, 1990-2030.

BACKGROUND AND OBJECTIVES: Ischemic stroke (IS), 1 of the 2 main subtypes of stroke, occurs because of brain ischemia caused by thrombosis of a cerebral blood vessel. IS is one of the most important neurovascular causes of death and disability. It is affected by many risk factors, such as smoking and a high body mass index (BMI), which are also critical in the preventive control of other cardiovascular and cerebrovascular diseases. However, there are still few systematic analyses of the current and predicted disease burden and the attributable risk factors of IS. METHODS: Based on the Global Burden of Disease 2019 database, we used age-standardized mortality rate and disability-adjusted life year to systematically present the geographical distribution and trends of IS disease burden worldwide from 1990 to 2019 by calculating the estimated annual percentage change and to analyze and predict the death number of IS accounted by 7 major risk factors for 2020-2030. RESULTS: Between 1990 and 2019, the global number of IS deaths increased from 2.04 million to 3.29 million and is expected to increase further to 4.90 million by 2030. The downward trend was more pronounced in women, young people, and high sociodemographic index (SDI) regions. At the same time, a study of attributable risk factors of IS found that 2 behavioral factors, smoking and diet in high sodium, and 5 metabolic factors, including high systolic blood pressure, high low-density lipoprotein cholesterol, kidney dysfunction, high fasting plasma glucose, and a high BMI, are major contributors to the increased disease burden of IS now and in the future. DISCUSSION: Our study provides the first comprehensive summary for the past 30 years and the prediction of the global burden of IS and its attributable risk factors until 2030, providing detailed statistics for decision-making on the prevention and control of IS globally. An inadequate control of the 7 risk factors would lead to an increased disease burden of IS in young people, especially in low SDI regions. Our study identifies high-risk populations and helps public health professionals develop targeted preventive strategies to reduce the global disease burden of IS.

IGF2BP1 regulates the cargo of extracellular vesicles and promotes neuroblastoma metastasis.

Neuroblastoma is a highly metastatic cancer, and thus is one of the leading causes of cancer-related mortalities in pediatric patients. More than 50% of NB cases exhibit 17q21-ter partial chromosomal gain, which is independently associated with poor survival, suggesting the clinical importance of genes at this locus in NB. IGF2BP1 is one such proto-oncogene located at 17q locus, and was found to be upregulated in patients with metastatic NBs. Here, utilizing multiple immunocompetent mouse models, along with our newly developed highly metastatic NB cell line, we demonstrate the role of IGF2BP1 in promoting NB metastasis. Importantly, we show the significance of small extracellular vesicles (EVs) in NB progression, and determine the pro-metastatic function of IGF2BP1 by regulating the NB-EV-protein cargo. Through unbiased proteomic analysis of EVs, we discovered two novel targets (SEMA3A and SHMT2) of IGF2BP1, and reveal the mechanism of IGF2BP1 in NB metastasis. We demonstrate that IGF2BP1 directly binds and governs the expression of SEMA3A/SHMT2 in NB cells, thereby modulating their protein levels in NB-EVs. IGF2BP1-affected levels of SEMA3A and SHMT2 in the EVs, regulate the formation of pro-metastatic microenvironment at potential metastatic organs. Finally, higher levels of SEMA3A/SHMT2 proteins in the EVs derived from NB-PDX models indicate the clinical significance of the two proteins and IGF2BP1-SEMA3A/SHMT2 axis in NB metastasis.

Investigating the Effect of Metabolic Phenotypes on Health Events in Alcoholic and Nonalcoholic Fatty Liver Disease.

Background and Aims: Metabolic dysfunction and obesity commonly coexist with both alcoholic and nonalcoholic fatty liver disease (AFLD and NAFLD). The association of AFLD and NAFLD with incident diseases in individuals with different metabolic phenotypes are unclear. Methods: UK Biobank study participants were screened for the presence of fatty liver at baseline. Body mass index and metabolic dysfunction were used to define metabolic phenotypes. Cox regression model was performed to examine the associations of AFLD and NAFLD with incident significant liver diseases (SLDs), cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and cancers, respectively. Results: A total of 43,974 AFLD and 103,248 NAFLD cases were identified. Both AFLD and NAFLD were associated with an increased risk of diseases of interest. The effects were amplified by obesity and metabolic abnormalities and modified by metabolic phenotypes. Compared to individuals free of fatty liver and with phenotype of metabolically healthy-normal weight, AFLD [hazard ratio (HR) 3.27; 95% CI: 1.95-5.47)] and NAFLD (HR 2.25; 95% CI: 1.28-3.94) cases with phenotype of metabolically obese-normal weight had the greatest risk of SLDs. For CVDs, CKDs, and cancer, the greatest risks were detected in AFLD and NAFLD cases with phenotype of metabolically obese-overweight/obesity. In this subpopulation, AFLD and NAFLD conferred a 2.75-fold (95% CI: 2.32-3.25) and 4.02-fold 95% CI: (3.64-4.43) increased risk of CVDs, 4.37-fold 95% CI: (3.38-5.64) and 6.55-fold 95% CI: (5.73-7.48) increased risk of CKDs, and 1.19-fold 95% CI: (1.08-1.27) and 1.21-fold 95% CI: (1.14-1.28) increased risk of cancers, respectively. Conclusions: Metabolic phenotypes modified the association of AFLD and NAFLD with intrahepatic and extrahepatic diseases.

Characteristics and long-term mortality of patients with non-MAFLD hepatic steatosis.

BACKGROUND & AIMS: A cluster of hepatic steatosis without metabolic abnormalities has been excluded by the MAFLD definition, referred to as non-MAFLD steatosis. We aimed to characterize the non-MAFLD steatosis. METHODS: We included 16,308 individuals from the UK Biobank who had magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) to describe the clinical and genetic features of non-MAFLD steatosis in a cross-sectional design, and 14,797 individuals of the NHANES III who underwent abdominal ultrasonography at baseline to assess the long-term mortality of non-MAFLD steatosis in a prospective cohort design. RESULTS: Of 16,308 individuals in the UK Biobank, 2747 fatty liver disease (FLD) cases (2604 MAFLD and 143 non-MAFLD) and 3007 healthy controls (without metabolic dysfunctions) were identified. The mean PDFF (10.65 vs. 9.00) and the proportion of advanced fibrosis (fibrosis-4 index > 2.67, 1.27% vs. 1.40%) were comparable between MAFLD and non-MAFLD steatosis. Non-MAFLD steatosis has the highest minor allele frequency of PNPLA3 rs738409, TM6SF2 rs58542926, and GCKR rs1260326 in contrast to the other two groups. The genetic risk score calculated by PNPLA3, TM6SF2, and GCKR has a certain predictive ability for non-MAFLD steatosis (AUROC = 0.69). NHANES III population showed that compared to healthy individuals, the adjusted hazard ratio of non-MAFLD steatosis increased by 1.52 (95% confidence interval: 1.21-1.91) and 1.78 (95% confidence interval: 1.03-3.07) for all-cause and heart disease-related mortality, respectively. CONCLUSIONS: Non-MAFLD steatosis has comparable degrees of hepatic steatosis and fibrosis to MAFLD and increases the risk of mortality. Genetic predisposition highly contributes to the risk of non-MAFLD steatosis.

Identification of novel genes for triple-negative breast cancer with semiparametric gene-based analysis.

Triple-negative breast cancer (TNBC) is generally considered an aggressive breast cancer subtype associated with poor prognostic outcomes. Up to now, the molecular and cellular mechanisms underlying TNBC pathology have not been fully understood. In this manuscript, we propose a novel semiparametric model with kernel for gene-based analysis with a breast cancer GWAS data. The software of SPMGBA (semiparametric method for gene-based analysis) in MATLAB is available at GitHub (https://github.com/zliu3/SPMGBA). Genetic signatures associated with breast cancer are discovered. We further validate the prognostic power of the identified genes with a large cohort of expression data from the European Genome-Phenome Archive, and discover that SEL1L is associated with the overall survival of TNBC with the p-value of .0002. We conclude that gene SEL1L is down-regulated in TNBC and the expression of SEL1L is positively associated with patient survival.

Low thyroid function is associated with an increased risk of advanced fibrosis in patients with metabolic dysfunction-associated fatty liver disease.

AIMS: Observational studies showed that low thyroid function may perturb liver function. We aimed to evaluate the association of low thyroid function with both metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced hepatic fibrosis. METHODS: Participants who underwent abdominal ultrasonography and thyroid function test in a Chinese hospital from 2015 to 2021were enrolled. Fibrosis-4 index (FIB-4) > 2.67 and/or non-alcoholic fatty liver disease fibrosis score (NFS) > 0.676 were used to define advanced fibrosis. Descriptive analyses were performed to characterize the epidemiology of MAFLD according to levels of thyroid-stimulating hormone (TSH). The logistic regression model was applied to estimate the association of low thyroid function with MAFLD and advanced fibrosis. RESULTS: A total of 19,946 participants (52.78% males, mean age: 47.31 years, 27.55% MAFLD) were included, among which 14,789 were strict-normal thyroid function, 4,328 were low-normal thyroid function, 829 were subclinical hypothyroidism. TSH levels were significantly higher in MAFLD patients with a FIB-4 > 2.67 and /or NFS > 0.676 than their counterparts. The logistic regression model adjusted for age and sex showed that low-normal thyroid function increased the risk of MAFLD (odds ratio [OR] = 1.09; 95% confidence interval [CI] 1.01-1.18). Multivariable regression model adjusted for age, sex, body mass index, type 2 diabetes, and hypertension showed low-normal thyroid function increased the risk of advanced fibrosis in patients with MAFLD (FIB-4 > 2.67: OR = 1.41, 95% CI 1.02-1.93; NFS > 0.676: OR = 1.72, 95% CI 1.08-2.72). CONCLUSION: Elevated TSH concentrations are associated with advanced hepatic fibrosis, even in the euthyroid state.

Positive hepatitis B core antibody is associated with advanced fibrosis and mortality in nonalcoholic fatty liver disease.

OBJECTIVE: Concomitant hepatitis B virus infection and nonalcoholic fatty liver disease (NAFLD) are relatively common, while little is known about the impact of anti-hepatitis B core antibody (anti-HBc) on NAFLD individuals. We aimed to investigate the association of positive anti-HBc with advanced fibrosis and mortality in NAFLD. METHODS: We analyzed data from 3268 NAFLD participants who underwent abdominal ultrasonography during the Third National Health and Nutrition Examination Survey (NHANES III). The fibrosis 4 index (FIB-4) score >2.67, NAFLD fibrosis score >0.676, or aspartate aminotransferase to platelet ratio index >1.5 were defined as advanced fibrosis. All-cause and cause-specific mortality were obtained from the NHANES III-linked follow-up file through 31 December 2015. RESULTS: A total of 242 (7.4%) patients had positive anti-HBc. Patients with positive anti-HBc had a higher percentage of advanced fibrosis than those with negative anti-HBc (12.2% vs. 5.8%). Positive anti-HBc was significantly associated with advanced fibrosis [adjusted odds ratio = 1.69, 95% confidence interval (CI), 1.05-2.72]. During a median follow-up of 22 years, the cumulative all-cause and cancer-related mortalities were higher in participants with positive anti-HBc than in their counterparts (log-rank test P < 0.001). When demographic and metabolic risk factors were considered, NAFLD cases with positive anti-HBc had a significantly higher cancer-related mortality (adjusted hazard ratio = 1.54, 95% CI, 1.05-2.25). CONCLUSION: Our findings suggested that NAFLD cases with positive anti-HBc had higher risks for liver fibrosis and long-term mortality, justifying the medical importance of testing anti-HBc in NAFLD patients.

The association between thyroid hormones and MAFLD is mediated by obesity and metabolic disorders and varies among MAFLD subtypes.

BACKGROUND: Thyroid hormone (TH) disorders increased the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM: To assess whether the association between TH and MAFLD is mediated via metabolic dysfunctions and varies among MAFLD subtypes (diabetes-MAFLD, overweight/obesity-MAFLD, metabolic disorders-MAFLD). METHODS: A total of 18,427 participants (661 diabetes-MAFLD, 3,600 overweight/obesity-MAFLD, 691 metabolic disorder-MAFLD cases, 13,475 non-MAFLD controls) from a Chinese hospital were enrolled. Hepatic ultrasound measurements and thyroid function were assessed. RESULTS: Overweight/obesity mediated the associations of MAFLD with triiodothyronine (T3), free triiodothyronine (FT3), free thyroxine (FT4), and the mediator accounted for 46.43%, 39.69%, and 42.68%, respectively. Metabolic disorder mediated the association of MAFLD with T3, FT3, FT4, thyroid stimulating hormone (TSH), and the mediator accounted for 36.57%, 23.19%, 34,65%, and 60.92%, respectively. Diabetes did not complementary mediate any association between TH and MAFLD. Elevated T3, FT3, TSH and decreased FT4 increased the risk of overweight/obesity-MAFLD, and the odds ratios were 1.59, 1.72, 1.18, and 0.60, respectively (Q4 vs.Q1, false discovery rate (FDR)<0.05). Elevated T3, FT3, and decreased FT4 increased the risk of metabolic disorder-MAFLD, and the odds ratios were 1.45, 1.33, and 0.52, respectively (Q4 vs.Q1, FDR<0.05). No significant association between TH and diabetes-MAFLD was detected. CONCLUSION: The association between TH and MAFLD is mediated by overweight/obesity and metabolic disorders and varies among MAFLD subtypes.

Global Burden of Nonalcoholic Fatty Liver Disease, 1990 to 2019: Findings From the Global Burden of Disease Study 2019.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases worldwide. We provided a comprehensive description regarding the disease burden of NAFLD in 204 countries and territories. MATERIALS AND METHODS: We reported the deaths and disability-adjusted life years (DALYs) related to NAFLD in the Global Burden of Disease database by sex, age, specific causes, and regions. Estimated annual percentage change was applied to describe the changing trends. RESULTS: Globally, the NAFLD-related deaths and DALYs in 2019 were 0.17 million [95% uncertainty interval (UI): 0.13 to 0.21] and 4.42 million (95% UI: 3.35 to 5.67), increased by 80.2% and 62.9% compared with 1990, respectively. The overall age-standardized rate of mortality and DALYs (ASMR and ASDR) showed a downward trend from 1990 to 2019, the estimated annual percentage change were -0.67 (95% confidence interval: -0.76, -0.57) and -0.82 (95% confidence interval: -0.93, -0.7), respectively. NAFLD-related deaths due to cirrhosis and liver cancer increased by 76.7% and 95.1% between 1990 and 2019. The ASMR and ASDR were the highest in the middle and low sociodemographical index regions in 2019, respectively. Of the 21 Global Burden of Disease regions, Eastern Europe, Central Asia, High-income North America, and Australasia experienced an increase in both ASMR and ASDR. CONCLUSIONS: NAFLD imposes heavy disease burden on humankind worldwide, especially in countries with low-to-middle sociodemographical index level. More potent measures are urgently needed in regions with rising age-standardized rate to forestall the increase of NAFLD disease burden.