Objective To analyze the changing trends of the burden of non-alcoholic fatty liver disease(NAFLD)in China from 1990 to 2021 and provide a basis for formulating prevention and treatment strategies.Methods The standardized incidence rate,prevalence,mortality,and disability-adjusted life year(DALY)rate of NAFLD in China from 1990 to 2021 were extracted from the Global Burden of Disease Study 2021.The average annual percentage change of rate data was calculated by Joinpoint 4.2 and the age,period,and birth cohort effects of the prevalence and DALY rate were analyzed by the age-period-cohort model.Results Compared to 1990,the incidence rate and prevalence of NAFLD have been on the rise,while the mortality and DALY rate have been declining.The age effect curves of prevalence and DALY rate showed an upward trend followed by a downward trend for both males and females.With the period from 1992 to 1996 as the reference group,the period effect curve of prevalence showed a downward trend followed by an upward trend,being the lowest in the period from 2002 to 2006(RR=0.93).The period effect curve of DALY rate showed a downward trend from 1992 to 2011 and then tended to flatten out.With the period from 1972 to 1981 as the reference group,the birth cohort effect curve of prevalence showed a steady upward trend in the general population and both male and female populations.The birth cohort effect curve of DALY rate showed an overall upward trend followed by a downward trend,with the peak occurring in the birth cohort group between 1922 and 1931.The DALY rate of NAFLD caused by smoking and high fasting blood glucose has shown a downward trend since 2014,and fasting blood glucose gradually became the dominant factor as age increased.Conclusions From 1990 to 2021,NAFLD in China has shown a rising prevalence but a significantly declining DALY rate.This suggests that current prevention and control strategies are effective,and further efforts should be made to raise residents' health awareness in controlling the occurrence and development of NAFLD.
Humans ; Non-alcoholic Fatty Liver Disease/epidemiology* ; China/epidemiology* ; Prevalence ; Female ; Male ; Incidence ; Disability-Adjusted Life Years ; Middle Aged ; Adult

OBJECTIVES: To systematically evaluate the prevalence and risk factors of non-alcoholic fatty liver disease (NAFLD) in overweight and obese children and adolescents in China. METHODS: Databases including China National Knowledge Infrastructure, Wanfang Data, VIP Database, China Biomedical Literature Database, PubMed, Embase, Web of Science, and Cochrane Library were searched, from database inception to October 2024. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies according to inclusion and exclusion criteria. A Meta analysis was conducted using Stata 16.0 software. RESULTS: A total of 42 studies involving 16 481 overweight and obese children and adolescents were included. The Meta analysis results showed that the prevalence of NAFLD among overweight and obese children in China was 43% (95%CI: 37%-48%). Factors associated with NAFLD included being male (OR=1.61, 95%CI: 1.17-2.04), increased weight (MD=10.33, 95%CI: 9.08-11.57), increased waist circumference (MD=5.49, 95%CI: 3.36-7.62), longer duration of obesity (MD=0.31, 95%CI: 0.02-0.61), higher body mass index (MD=3.11, 95%CI: 2.07-4.16), elevated fasting blood glucose levels (MD=0.17, 95%CI: 0.06-0.29), higher triglyceride levels (MD=0.32, 95%CI: 0.17-0.47), elevated total cholesterol levels (MD=0.15, 95%CI: 0.10-0.21), higher low-density lipoprotein cholesterol levels (MD=0.14, 95%CI: 0.04-0.23), increased alanine aminotransferase levels (MD=24.39, 95%CI: 18.57-30.20), increased aspartate aminotransferase levels (MD=12.49, 95%CI: 9.67-15.32), elevated serum insulin levels (MD=4.47, 95%CI: 2.57-6.36), higher homeostasis model assessment-insulin resistance (MD=0.45, 95%CI: 0.30-0.59), and elevated uric acid levels (MD=55.91, 95%CI: 35.49-76.32) (P<0.05). CONCLUSIONS The prevalence of NAFLD among overweight and obese children and adolescents in China is high. Male gender, increased weight, increased waist circumference, prolonged obesity duration, higher body mass index, dyslipidemia, and elevated levels of fasting blood glucose, liver enzymes, serum insulin, homeostasis model assessment-insulin resistance, and uric acid are potential risk factors for NAFLD in this population.
Humans ; Non-alcoholic Fatty Liver Disease/etiology* ; Risk Factors ; Adolescent ; Child ; Overweight/complications* ; Prevalence ; China/epidemiology* ; Obesity/complications* ; Male ; Female

Inflammaging is a process of cellular dysfunction associated with chronic inflammation, which plays a significant role in the onset and progression of liver diseases. Research on its mechanisms has become a hotspot. In viral hepatitis, inflammaging primarily involve oxidative stress, cell apoptosis and necrosis, as well as gut microbiota dysbiosis. In non-alcoholic fatty liver disease, inflammaging is more complex, involving insulin resistance, fat deposition, lipid metabolism disorders, gut microbiota dysbiosis, and abnormalities in NAD⁺ metabolism. In liver tumors, inflammaging is characterized by weakening of tumor suppressive mechanisms, remodeling of the liver microenvironment, metabolic reprogramming, and enhanced immune evasion. Therapeutic strategies targeting inflammaging have been developing recently, and antioxidant therapy, metabolic disorder improvement, and immunotherapy are emerging as important interventions for liver diseases. This review focuses on the mechanisms of inflammaging in liver diseases, aiming to provide novel insights for the prevention and treatment of liver diseases.
Humans ; Liver Diseases/pathology* ; Inflammation ; Oxidative Stress ; Non-alcoholic Fatty Liver Disease ; Liver Neoplasms ; Gastrointestinal Microbiome

OBJECTIVES

Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, especially in patients with type 2 diabetes mellitus (T2DM). Significant prevalence of liver fibrosis has been observed in Indian diabetic patients with fatty liver. Early detection of liver fibrosis in persons with diabetes prevents serious problems. This study compares noninvasive liver fibrosis scores and vibration-controlled transient elastography (VCTE) utilising FIBROSCAN™ to assess fibrosis prevalence in patients with T2DM and NAFLD.

This cross-sectional, observational study enrolled 351 patients with T2DM and NAFLD from September to October 2023 from eight West Bengal diabetes facilities. Liver stiffness measurement (LSM) via VCTE was used to detect fibrosis. Non-invasive tests (NITs), including fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), fibrotic NASH-index (FNI), and AST to platelet ratio index (APRI) were also calculated. To evaluate NIT diagnostic performance, AUROC curve calculations were used.

Among patients with T2DM, 26.5% had fibrosis and 3.13% of individuals had advanced fibrosis (≥F3), whereas 11.97% had substantial fibrosis (≥F2). Fibrotic NASH-index could detect fibrosis best with area under the curve (AUROC) >0.70, whereas FIB-4 and NFS were better (AUROC >0.8) to identify advanced fibrosis, and APRI struggle to diagnose severe fibrosis.

In patients with T2DM with NAFLD, VCTE detects fibrosis. FNI is best tool for detection of fibrosis, whereas FNI and NFS are better for distinguishing advanced fibrosis in such patients. To increase fibrosis identification in this population, multiple diagnostic approaches are needed.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), now known as Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), is linked to cardiovascular disease. This renaming emphasizes the role of metabolic problems. Coronary artery calcification (CAC) reflects early coronary artery disease, but data on the MAFLD-CAC link is limited. OBJECTIVE: To demonstrate the association between metabolic dysfunction-associated fatty liver disease (MAFLD) based on its criteria and coronary artery calcification, as measured by CT CAC score. METHODS: This single-center retrospective study involved adult Filipino patients who underwent CT CAC scoring between January 2021 and January 2023. Clinical and laboratory data were obtained via review of electronic records. RESULTS: This study involved 147 patients with an average age of 62 years, primarily females (57.14%), and mostly falling into the Obese-Class I category (31.29%). The most common comorbidities were hypertension (95.24%), dyslipidemia (62.59%), and diabetes mellitus (38.1%). In terms of CAC scores using the CT Agatston method, majority (30.61%) had low calcium buildup (Stage 2 with scores between 1-99). Approximately 26.53% had higher liver fat content with liver HU below 40, while 73.47% had lower liver fat content with HU equal to or greater than 40. Furthermore, 25.17% of patients with fatty livers and other risk factors were diagnosed with MAFLD, while 74.83% were not. The p-value indicated a significant difference in proportions, suggesting a lower proportion of MAFLD among those who had undergone CT CAC scoring. However, the Pearson Chi-Square statistic (4.051) and the p-value (0.256) indicated no statistically significant association between MAFLD and CT CAC. CONCLUSION The study found a notably lower proportion of MAFLD diagnoses in patients who underwent CT CAC scoring. Additionally, there was no statistically significant link between MAFLD and CT CAC.
Cardiovascular Diseases ; Coronary Artery Disease ; Fatty Liver, Alcoholic

BACKGROUND

Non-Alcoholic Fatty Liver Disease (NAFLD) is common in Type 2 Diabetes Mellitus (T2DM). The FIB-4 index is one of the most-studied non-invasive biomarkers that combines age and laboratory parameters (platelet count, alanine-and aspartate- aminotransferase) to evaluate underlying hepatic fibrosis. This study aims to determine the diagnostic value of Fibrosis-4 (FIB-4) index scoring in screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus, which is a high-risk population in development of advance fibrosis.

A single center, analytical cross-sectional study was conducted among adult T2DM patients with and without NAFLD seen at the Out-Patient Department (OPD) and those with NAFLD enrolled under the Liver Disease Databank of the Liver Disease and Transplant Center in collaboration with Research and Biotechnology Division at St. Luke’s Medical Center, Quezon City. Medical history was obtained by reviewing charts of eligible patients using data collection form. Liver ultrasound was used as the reference standard in the diagnosis of NAFLD. The FIB-4 index was calculated with this formula: age (years) x AST (U/L)/(platelets (10^9/L) x ALT (U/L)^1/2.

A total of 305 adult patients with type 2 diabetes mellitus were included in the study. The prevalence of non-alcoholic fatty liver disease based on ultrasound among diabetic patients is 76.07%. The median age (p = 0.0204), AST (p < 0.00001), ALT (p < 0.00001) were significantly higher in patients with NAFLD than those without. Platelet count (p = 0.0002) was significantly lower in patients with NAFLD than those without. The proportion of patients with low platelet count, high AST and high ALT were significantly higher in patients with NALFD than those without. In this study, the FIB-4 index cutoff score for screening of NAFLD is ≥0.76, which has an accuracy of 66.23%, sensitivity of 75%, specificity of 38.3%, PPV of 79.46% and NPV of 32.56% in detecting fatty liver.

A FIB-4 index value of ≥0.76 has an acceptable sensitivity for screening NAFLD even in the absence of fibrosis among patients with T2DM. However, due to its low specificity, additional tests to establish NAFLD diagnosis may be required.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is prevalent in patients with Type 2 Diabetes Mellitus (T2DM) and is associated with chronic kidney disease (CKD). The aim of this cross-sectional study was to determine the association of Fibrosis-4 (FIB-4) index with CKD among T2DM patients with concomitant NAFLD.

A single center, analytical cross-sectional study was conducted among 216 T2DM patients with concomitant NAFLD. Clinical data were obtained via retrospective review of medical charts. The outcome of interest was CKD which was based on self-report obtained from medical charts or estimated Glomerular Filtration Rate (eGFR) < 60mL/min result nearest to the date of liver ultrasound. FIB-4 index of patient on admission was calculated using an online calculator and subjects were grouped into low, moderate and high risk of developing severe fibrosis depending on their FIB-4 index. In order to determine the association between FIB-4 index and CKD, logistic regression analysis was performed.

Higher FIB-4 index was found to be significantly associated with CKD. Patients with FIB-4 index of 1.45-3.25 (moderate risk) and > 3.25 (high risk) have about 3 times higher odds of CKD. However, after controlling for the significant confounders, only those who belong to high-risk group was found to be associated with CKD.

This study has demonstrated that FIB4 index > 3.25, an index of liver fibrosis, is significantly associated with development of CKD in T2DM patients with concomitant NAFLD.

BACKGROUND: Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population. METHODS: This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes. RESULTS: Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group. CONCLUSION The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
Humans ; Gastrointestinal Microbiome ; Male ; Female ; Membrane Proteins/metabolism* ; Lipase/genetics* ; Middle Aged ; Liver Cirrhosis/epidemiology* ; Cohort Studies ; Genotype ; Adult ; Non-alcoholic Fatty Liver Disease/microbiology* ; Polymorphism, Single Nucleotide ; Acyltransferases ; Phospholipases A2, Calcium-Independent

BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation