Dysfunction-associated Fatty Liver Disease Research Articles

Expression of TWEAK/Fn14 axis in the context of metabolic dysfunction associated-fatty liver disease: an approach in liver regeneration

Background: One of the pathways involved in liver regeneration processes is TWEAK/Fn14 (tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14), which has been proposed to act directly and selectively on hepatic progenitor cells; however, its role in the regeneration of steatotic liver metabolic dysfunction associated fatty liver disease has not been fully elucidated. Objective: To evaluate the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals as biochemical cues for possible liver regeneration in MAFLD. Materials and methods: A prospective study was carried out where the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals were observed as biochemical indications of a possible liver regeneration in a condition of tissue damage caused by excessive lipid accumulation. The expression of TWEAK, Fn14 and heat shock proteins in hepatic steatosis of non-alcoholic origin was assessed using immunohistochemistry and western blotting. Results: The histological classification of the tissues under study corresponded to microvesicular steatosis. We report a high level of expression of heat shock proteins in the cytoplasm. The expression of TWEAK and Fn14 in liver tissue affected by lipid accumulation was localized in the cytoplasm of hepatocytes, showing a higher intensity of reactivity for Fn14 compared to its ligand TWEAK. Conclusion: The expression of TWEAK/Fn14 axis was positive suggesting reactivity of the signaling pathway in metabolic dysfunction associated fatty liver disease.

Association between dietary carbohydrate to fiber ratio and metabolic dysfunction associated fatty liver disease in adults: evidence from the NHANES 2017–2020

This study aimed to explore the association of carbohydrate to fiber ratio (CFR) with metabolic dysfunction-associated fatty liver disease (MAFLD) in adults. In this study, data from the 2 cycles (2017–2018 and 2019–2020) of the NHANES were used. Univariate and multivariate weighted logistic regression analyses were applied to evaluate the association between CFR and MAFLD. Odds ratios (ORs) and 95% confidence levels (CIs) were estimated. Subgroup analysis was further performed in terms of gender, age and comorbidity (diabetes, hypertension). A total of 3180 individuals were included, with 1408 (44.28%) in the non-MAFLD group and 1772 (55.72%) in the MAFLD group. After adjusting different variables, a dietary fiber intake of 11.15–18.40 g was associated with significantly lower odds of MAFLD compared with a fiber intake < 11.15 g (OR = 0.71, 95% CI 0.54–0.93). In contrast to a dietary CFR < 12.58, a CFR > 19.91 was associated with significantly higher odds of MAFLD (OR = 1.57, 95% CI 1.09–2.27). Compared with females with a dietary CFR < 12.58, those with a CFR > 19.91 had significantly increased odds of MAFLD (OR = 1.87, 95% CI 1.29–2.73). Among individuals aged < 65 years, a dietary CFR > 19.91 was associated with higher odds of MAFLD than a dietary CFR < 12.58 (OR = 1.52, 95% CI 1.02–2.25). For participants without diabetes (OR = 1.79, 95% CI 1.26–2.54) or hypertension (OR = 1.93, 95% CI 1.02–3.65), a dietary CFR > 19.91 was associated with elevated odds of MAFLD than a CFR < 12.58. In summary, a higher CFR was associated with significantly greater odds of MAFLD, indicating the negative association between carbohydrate quality and MAFLD. The research would be conducive to metabolic dysfunction-associated fatty liver disease treatment.

Association between blood heavy metal exposure levels and risk of metabolic dysfunction associated fatty liver disease in adults: 2015-2020 NHANES large cross-sectional study.

The relationships between heavy metals and fatty liver, especially the threshold values, have not been fully elucidated. The objective of this research was to further investigate the correlation between blood heavy metal exposures and the risk of Metabolic dysfunction Associated Fatty Liver Disease (MAFLD) in adults. Laboratory data on blood metal exposure levels were obtained from National Health and Nutrition Examination Survey (NHANES) data for the period 2015 to 2020 for a cross-sectional study in adults. Associations between blood levels of common heavy metals and the risk of MAFLD in adults were analyzed using multifactorial logistic regression and ranked for heavy metal importance using a random forest model. Finally, thresholds for important heavy metals were calculated using piecewise linear regression model. In a multifactorial logistic regression model, we found that elevated levels of selenium (Se) and manganese (Mn) blood exposure were strongly associated with the risk of MAFLD in adults. The random forest model importance ranking also found that Se and Mn blood exposure levels were in the top two positions of importance for the risk of disease in adults. The restricted cubic spline suggested a non-linear relationship between Se and Mn blood exposure and adult risk of disease. The OR (95% CI) for MAFLD prevalence was 3.936 (2.631-5.887) for every 1 unit increase in Log Mn until serum Mn levels rose to the turning point (Log Mn = 1.10, Mn = 12.61 μg/L). This correlation was not significant (p > 0.05) after serum Mn levels rose to the turning point. A similar phenomenon was observed for serum Se levels, with a turning point of (Log Se = 2.30, Se = 199.55 μg/L). Blood heavy metals, especially Se and Mn, are significantly associated with MAFLD in adults. They have a non-linear relationship with a clear threshold.

Elevated small dense low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio is associated with an increased risk of metabolic dysfunction associated fatty liver disease in Chinese patients with type 2 diabetes mellitus.

It is demonstrated that elevated small dense low-density lipoprotein cholesterol (sdLDL-C), and reduced high-density lipoprotein cholesterol (HDL-C) is associated with Metabolic dysfunction-associated fatty liver disease (MAFLD). This study aims to explore the relationship between sdLDL-C to HDL-C ratio (SHR) and MAFLD in Chinese patients with type 2 diabetes mellitus (T2DM). A cross-sectional study was performed among 1904 patients with T2DM. Weighted multivariable logistic regression analysis was conducted to explore the relationship between the SHR and the risk of MAFLD. In addition, this study used a two-part linear regression model to identify threshold effects. Subgroup analysis, interaction tests and receiver operating characteristic (ROC) curve analysis were also carried out. The overall MAFLD prevalence reached 48.1%. Multiple logistic regression analysis showed that SHR was positively correlated with the risk of MAFLD (OR = 2.37, 95% CI = 1.80-3.12). Subgroup analysis stratified by age, gender, hypertension and BMI showed that there was a consistent positive correlation. A non-linear relationship and saturation effect between SHR and MAFLD risk were identified, with an inverted L shaped curve and an inflection point at 1.02. The area under the curve (AUC) for SHR in the ROC analysis was significantly greater than sdLDL-C and HDL-C, with a sensitivity of 71.2% and a specificity of 62.1%. Elevated levels of SHR is independently associated with an increased risk of MAFLD in patients with T2DM. SHR may be taken as practical indicators to assess the risk of MAFLD in T2DM patients.

Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus

PurposeThis study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database.MethodsWe analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors.ResultsAfter propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, − 3.8 [95% CI − 4.7 to − 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors.ConclusionsOur analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

Therapeutics for Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

Metabolic dysfunction associated fatty liver disease (MAFLD) has been recently recognized as a new global chronic liver disease entity with non-alcoholic fatty liver disease (NAFLD) associated with overweight/obesity or type 2 diabetes mellitus (T2DM) and evidence of metabolic dysregulation. Due to the rising rates of obesity and diabetes, MAFLD is considered a rapidly emerging chronic liver disease globally. Nearly 25–30% of the global population poses health issues due to MAFLD with a substantial economic burden to societies. Disease progression depends on the persistence of risk factors and etiological agents, from simple steatosis, hepatitis, fibrosis, to cirrhosis, and if untreated, leads to hepatocellular carcinoma. In this review article we summarize various risk and etiological factors, diagnostic techniques, and therapeutic evaluation of pharmacological agents developed for MAFLD. Effective pharmaceutical agents for the treatment of MAFLD (and NAFLD) are lacking, and research is ongoing to search for effective medications in this direction. Currently, pioglitazone is advised for MAFLD patients, whereas Vitamin E is advised for non-diabetic MAFLD patients with ≥F2 non-cirrhosis. Current approaches to disease management emphasize diet control, lifestyle changes, and weight loss. In this review, we summarized the pharmacological agents currently being developed and their current status to treat patients with MAFLD.

Metabolic Dysfunction-Associated Fatty Liver Disease in Taiwanese Patients with Inflammatory Bowel Disease: A Study in Patients with Clinical Remission.

The prevalence of inflammatory bowel disease (IBD) has increased worldwide. The prevalence of metabolic dysfunction associated fatty liver disease (MAFLD) has also risen. However, there is limited research on the connection between MAFLD and IBD in the Asian population. This study aims to analyze the prevalence and clinical significance of MAFLD in Taiwanese IBD patients with clinical remission. We retrospectively analyzed IBD patients who received transient elastography for liver fibrosis and controlled attenuation parameter evaluation for liver steatosis. This study enrolled 120 patients with IBD, including 45 Crohn's disease (CD) and 75 ulcerative colitis (UC). MAFLD prevalence in IBD was 29.2%. Patients with MAFLD had a shorter disease duration (2.8 years vs. 5.3 years, p = 0.017), higher alanine aminotransferase levels (24 U/L vs. 17 U/L, p = 0.003), a lower estimated glomerular filtration rate (91.37 mL/min/1.73 m2 vs. 103.92 mL/min/1.73 m2, p = 0.004), and higher γ-glutamyl transferase (γ-GT) (24 mg/dL vs. 13 mg/dL, p < 0.001). The prevalence of significant fibrosis in IBD with MAFLD was 17.1%. Significant fibrosis was found in older age (58.5 years vs. 40 years, p = 0.004) and the high type 2 diabetes mellitus proportion (50.0% vs. 10.3%, p = 0.049). A trend of longer disease duration was found in significant fibrosis (4.9 years vs. 1.6 years, p = 0.051). The prevalence of MALFD in IBD was 29.2%. and 17.1% of them had significant fibrosis. In addition to the intestinal manifestation, the study findings remind clinicians that they should be aware of the possibility of hepatic complications for IBD patients.

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n= 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and exvivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Correlation of the pediatric metabolic index with NAFLD or MAFLD diagnosis, and serum adipokine levels in children

IntroductionNon-alcoholic fatty liver disease (NAFLD) is characterized by ectopic fat deposition in the liver. However, a recent classification of this condition, which also integrates the presence of coexisting metabolic disorders, termed Metabolic dysfunction Associated Fatty Liver Disease (MAFLD), has been proposed.NAFLD is increasingly common in early childhood, partly due to the increase in metabolic disease in this age. Thus, studying hepatic steatosis in the metabolic context has become important in this population as well. However, NAFLD, and thus MAFLD, diagnosis in children is challenging by the lack of non-invasive diagnostic tools comparable to the gold standard of hepatic biopsy. Recent studies have reported that the Pediatric Metabolic Index (PMI) could be a marker of insulin resistance and abnormal liver enzymes, but its association with NAFLD, MAFLD, or altered adipokines in these conditions has not been reported. The aim of this study is to evaluate the correlation between PMI with the diagnosis of NAFLD or MAFLD, together with serum levels of leptin and adiponectin, in school-age children. MethodsA cross sectional study was carried out in two hundred and twenty-three children without medical history of hypothyroidism, genetic, or chronic diseases. Anthropometry, liver ultrasound, and serum levels of lipids, leptin, and adiponectin were evaluated. The children were classified as having NAFLD or non-NAFLD, and a subgroup of MAFLD in the NAFLD group was analyzed. The PMI was calculated by the established formulas for age and gender. ResultsPMI correlated positively with the presence and severity of NAFLD (r = 0.62, p<0.001 and r = 0.79, p<0.001 respectively) and with the presence of MAFLD (r = 0.62; p<0.001). Also, this index correlated positively with serum leptin levels (r = 0.66; p<0.001) and negatively with serum adiponectin levels (r= -0.65; p<0.001). PMI showed to be a good predictor for diagnosing NAFLD in school-age children when performing a ROC curve analysis (AUROC=0.986, p< 0.0001). ConclusionPMI could be a useful tool for the early diagnosis of NAFLD or MAFLD in children. However, future studies are necessary to establish validated cut-off points for each population.

Cardiovascular Disease Risk and Statin Use Among Adults with Metabolic Dysfunction Associated Fatty Liver Disease

BackgroundA leading cause of mortality in fatty liver disease is cardiovascular disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is new terminology that classifies fatty liver due to metabolic dysfunction attributable to obesity and associated complications. We evaluated atherosclerotic cardiovascular disease (ASCVD) risk and statin use in adults with MAFLD. MethodsThis was a retrospective study of the 2011-2018 National Health and Nutrition Examination Survey. Adults with MAFLD were identified using established criteria: presence of hepatic steatosis (US Fatty Liver Index>30) plus ≥1 of the following: 1) body mass index >25 kg/m2 in non-Asians or >23 kg/m2 in Asians, 2) diabetes mellitus, and 3) ≥2 metabolic risk factors. Cardiovascular disease risk was estimated using the validated 10-year ASCVD risk score. Statin use was assessed in intermediate and high 10-year ASCVD risk groups. ResultsPrevalence of MAFLD was 34.8% (95% confidence interval [CI], 33.9%-35.8%), comprising 54.4% males, 27.9% aged 65 years and older, and 38.2% non-Hispanic white. Among adults with MAFLD, 23.3% and 23.0% had intermediate and high 10-year ASCVD risk, respectively. Compared with females, males were more likely to have high 10-year ASCVD risk (28.7% vs 16.1%, adjusted odds ratio 5.24, 95% CI, 3.87-7.10, P < .01). In intermediate and high ASCVD risk groups, overall statin use was 48.3% (95% CI, 46.1-51.3). ConclusionsOver 46% of adults with MAFLD had intermediate or high 10-year ASCVD risk. Statin use was underutilized at 48.3% in those meeting statin criteria. These findings are alarming given the high cardiovascular disease risk and low statin use in this cohort.

Chinese Visceral Adipose Index Shows Superior Diagnostic Performance in Predicting the Risk of Metabolic Dysfunction Associated Fatty Liver Disease in Early Postmenopausal Chinese Women.

Previous studies have reported the diagnostic values of multiple obesity indicators for predicting the risk of non-alcoholic fatty liver disease. However, the diagnostic values of obesity indicators for predicting the risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in early postmenopausal women is still unknown. Therefore, this study investigated the predictive values of common obesity indices for estimating the risk of MAFLD in early postmenopausal Chinese women. This study enrolled 2514 early postmenopausal women, aged between 45 and 55 years, who underwent abdominal ultrasonography examination at the Health examination center of the Huadong Sanatorium between June 2021 and December 2021. The values for six obesity indices, namely, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body adiposity index (BAI), and Chinese visceral adiposity index (CVAI) were extracted from the medical records. Our data showed that all the six obesity indices were significantly associated with the risk of MAFLD (P < 0.05) in the obese subjects and five obesity indices except for BAI were significantly associated with the risk of MAFLD (P < 0.05) in the lean subjects. The six obesity indices showed a linear relationship with the risk of MAFLD (all P-values > 0.05). The ORs for the obesity indices with the exception of BAI showed proportional increase with the risk of MAFLD in the lean subjects. CVAI was the strongest predictor of the risk of MAFLD in both lean (AUC=0.868) and overweight/obese subjects (AUC=0.704) among the early postmenopausal women. This study demonstrated that all the obesity indices were associated with an increased risk of MAFLD in the obese subjects and five obesity indices except for BAI were associated with an increased risk of MAFLD in the lean subjects among the early postmenopausal women. CVAI showed the strongest predictive performance in estimating the risk of MAFLD among early menopausal women.

Metabolic dysfunction associated fatty liver disease: The new nomenclature and its impact.

In 2020, an international expert panel proposed a new definition of fatty liver: Metabolic dysfunction-associated fatty liver disease (MAFLD). The MAFLD added the criteria for defining metabolic dysfunctions, which are high-risk factors for liver-related and cardiovascular events. Contrary to the non-alcoholic fatty liver disease (NAFLD) definition, it allows the coexistence of MAFLD and significant alcohol use in the same patient. To review the existing data that evaluate the clinical profile and long-term outcome difference between the patients identified as MAFLD and NAFLD. Databases MEDLINE via PubMed and EMBASE were searched and relevant publications up to June 28, 2022 were assessed. Studies were included if they involved human participants diagnosed with MAFLD. A total of 2324 records were reviewed, of which 1575 duplicate citations were removed. Of the 2324 records screened, 207 articles were excluded, and 542 articles were assessed for their eligibility, for which 511 were excluded. The remaining 31 articles were selected for review. MAFLD diagnostic criteria were able to identify more individuals with fatty liver. Studies have shown that patients included using the MAFLD criteria were associated with higher risks of hepatic fibrosis when compared to NAFLD. All-cause mortality, cardiovascular disease-related, and cancer-related mortality were shown to be higher in MAFLD patients. MAFLD patients also had higher baseline metabolic derangement, and risks of developing obesity, diabetes, and cardiovascular events. Of the 3 subtypes, diabetes mellitus has the strongest association with negative outcomes, followed by metabolic dysfunction and elevated body mass index. Within the subtypes of MAFLD, patients with more metabolic conditions at the time of diagnosis had worse hepatic and liver injury compared to those with a single metabolic condition. MAFLD is a new definition of fatty liver disease that is gaining increasing acceptance. It is based on empirical clinical practice on positive inclusion of metabolic risk factors and recent evidence suggests that it helps to identify patients with higher risk for liver-related as well as cardiovascular events.

Metabolic dysfunction associated fatty liver disease identifies subjects with cardiovascular risk better than non-alcoholic fatty liver disease.

Cardiovascular disease (CVD) is the main cause of mortality in subjects with non-alcoholic fatty liver disease (NAFLD). We investigated the association between CVD risk and metabolic dysfunction-associated fatty liver disease (MAFLD) or NAFLD and the influence of significant liver fibrosis on the CVD risk. Subjects who underwent a comprehensive medical check-up were recruited (2014-2019). Significant liver fibrosis was defined using NAFLD fibrosis score, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, or FibroScan-aspartate aminotransferase score. High probability of atherosclerotic CVD (ASCVD) was defined as ASCVD risk score > 10%. Of the study population (n=78 762), 27 047 (34.3%) and 24 036 (30.5%) subjects had MAFLD and NAFLD respectively. A total of 1084 (4.0%) or 921 (3.8%) subjects had previous CVD history in MAFLD or NAFLD subgroup respectively. The previous CVD history and high probability of ASCVD were significantly higher in MAFLD or NAFLD subgroup with significant liver fibrosis than in the other groups (all p < .001). In multivariable analysis, MAFLD was independently associated with previous CVD history after adjusting for confounders (adjusted odds ratio [aOR]=1.10, p=.038), whereas NAFLD was not (all p > .05). MAFLD (aOR=1.40) or NAFLD (aOR=1.22) was independently associated with high probability of ASCVD after full adjustment respectively (all p < .001). Significant liver fibrosis was independently associated with previous CVD history and high probability of ASCVD after adjustment in MAFLD or NAFLD subgroup respectively (all p < .05). MAFLD might better identify subjects with CVD risk than NAFLD. Fibrosis assessment might be helpful for detailed prognostication in subjects with MAFLD.

Blood pressure stratification for predicting liver fibrosis risk in metabolic dysfunction associated fatty liver disease

Introduction and ObjectivesThe optimal blood pressure (BP) range for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) is currently unknown. This study aimed to explore the relationship between stratified BP levels and MAFLD progression. Patients and MethodsThe data of adults who underwent yearly health check-ups were screened to establish both a cross-sectional and a 6-year longitudinal cohort of individuals with MAFLD. BP was classified into the following categories optimal, normal, high-normal, and hypertension. Liver fibrosis was diagnosed with fibrosis-4 (FIB-4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and aspartate aminotransferase-to-platelet ratio index (APRI). ResultsA total of 10,232 individuals were included in the cross-sectional cohort. In the MAFLD population, individuals with liver fibrosis had significantly higher BP levels and hypertension prevalence (P < 0.001) than those without. Furthermore, liver fibrosis score was significantly associated with BP levels (P < 0.001). In the 6-year longitudinal cohort of 3661 individuals with MAFLD without liver fibrosis, the incidence rates of liver fibrosis increased with increasing BP levels as follows optimal=11.20%, normal=13.90%, high-normal=19.50%, hypertension=26.20% (log-rank 22.205; P < 0.001). Cox regression analysis showed that both baseline high-normal BP (hazard ratio [HR], 1.820; P=0.019) and hypertension (HR, 2.656; P < 0.001) were predictive of liver fibrosis. ConclusionsBP stratification may be useful in predicting the progression of MAFLD. Individuals having MAFLD with concurrent hypertension or high-normal BP are at a higher risk of liver fibrosis. These findings may provide a criteria for early intervention of MAFLD to prevent liver fibrosis.

Residential greenness associated with decreased risk of metabolic- dysfunction-associated fatty liver disease: Evidence from a large population-based epidemiological study

BackgroundNumerous studies have shown that residential greenness positively correlates with enhanced health. Metabolic dysfunction-associated fatty liver disease (MAFLD) affects about a quarter of the population while lacking specific treatments. Given that the association between green space and MAFLD is still unknown, we explored the association between residential greenness and MAFLD as well as the potential mechanisms based on the baseline survey of the China Multi-Ethnic Cohort (CMEC). MethodsResidential greenness was expressed as normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI). MAFLD was assessed through hepatic steatosis, the presence of overweight/obesity, type 2 diabetes mellitus, and evidence of metabolic dysregulation. We used logistic regression to examine the association between NDVI/EVI and the prevalence of MAFLD. Moreover, we utilized causal mediation analyses to explore the role of physical activity and ambient particulate matters (PM1, PM2.5, and PM10) on the association between residential greenness and MAFLD. ResultsWe included 72,368 participants from the CMEC and found that residential greenness was negatively associated with the prevalence of MAFLD. For an interquartile range (IQR) increase in NDVI500 m and EVI500 m, the odds ratio (OR) of MAFLD were 0.78 (95 %CI: 0.75, 0.81) and 0.81 (95 %CI: 0.78, 0.84), respectively. Greater association between residential greenness and MAFLD was observed among males. Air pollutants and physical activity could mediate a partial effect (8.5–22.9 %) of residential greenness on MAFLD. ConclusionHigher residential greenness was associated with decreased risk of MAFLD. Moreover, the association was greater among males. The protective effects of residential greenness may be achieved by mitigating the hazardous effects of air pollutants and encouraging physical activity.

The crosstalk between insulin resistance and nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease: a culprit or a consequence?

Nonalcoholic fatty liver disease (NAFLD), which has recently undergone a change in its definition and acronym to “metabolic dysfunction associated fatty liver disease (MAFLD),” is clinically significant as an increasingly prevalent independent risk factor for cardiovascular diseases. Insulin resistance is considered to be a key mechanism in the development and progression of NAFLD/MAFLD, and fatty liver disease itself may exacerbate insulin resistance. In this review, we describe the mechanisms underlying the interaction between insulin resistance and fatty liver, and we summarize the therapeutic attempts based on those mechanisms.

Targeting the Gut Microbiome to Treat Metabolic Dysfunction-Associated Fatty Liver Disease: Ready for Prime Time?

Numerous studies show a modification of the gut microbiota in patients with obesity or diabetes. Animal studies have also shown a causal role of gut microbiota in liver metabolic disorders including steatosis whereas the human situation is less clear. Patients with metabolic dysfunction associated fatty liver disease (MAFLD) also have a modification in their gut microbiota composition but the changes are not fully characterized. The absence of consensus on a precise signature is probably due to disease heterogeneity, possible concomitant medications and different selection or evaluation criteria. The most consistent changes were increased relative abundance of Proteobacteria, Enterobacteriaceae and Escherichia species and decreased abundance of Coprococcus and Eubacterium. Possible mechanisms linking the microbiota and MAFLD are increased intestinal permeability with translocation of microbial products into the portal circulation, but also changes in the bile acids and production of microbial metabolites such as ethanol, short chain fatty acids and amino acid derivatives able to modulate liver metabolism and inflammation. Several interventional studies exist that attempt to modulate liver disease by administering antibiotics, probiotics, prebiotics, synbiotics, postbiotics or fecal transplantation. In conclusion, there are both gaps and hopes concerning the interest of gut microbiome evaluation for diagnosis purposes of MAFLD and for new therapeutic developments that are often tested on small size cohorts.

Extracellular vesicles in metabolic dysfunction associated fatty liver disease: mechanisms, diagnostic and therapeutic implications

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing rapidly worldwide due to the obesity epidemic. Advanced stages of the MAFLD, such as non-alcoholic steatohepatitis (NASH) with advanced fibrosis or cirrhosis are affecting global health. Extracellular vesicles (EVs) are released by all cell types and are important in cell-to-cell communication and maintaining homeostasis, but they also play a role in the pathogenesis of various diseases. EVs contain biological information such as lipids, proteins, messenger RNAs (mRNAs), small RNAs, and DNA, and they act on (distant) target cells. The cargo of EVs is dependent on the type and the state of the releasing cell. EVs have been proposed as biomarkers, prognostic, and even therapeutic agents, also in the context of liver diseases. This review aims to give an overview of the current knowledge on EVs in MAFLD, including the role and interaction of EVs with different cell types in the liver. Several aspects of EVs, including their origin, characteristics, cargo, and functions are reviewed. Moreover, the potential of EVs as targets for the treatment of MAFLD is discussed.

Impact of Metabolic Dysfunction Associated Fatty Liver Disease on the Prognosis of Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma Based on Propensity Score Matching Analysis.

PurposeBoth metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatitis B virus (HBV) are risk factors for hepatocellular carcinoma (HCC). Although concurrent MAFLD is common in patients with HBV-related HCC, whether MAFLD increases the risk of poor prognosis in patients with HBV-related HCC remains unclear. This study aimed to investigate the impact of MAFLD on prognosis in patients with HBV-related HCC.Patients and MethodsIn this retrospective cohort study, 549 patients with HBV-related HCC were enrolled from January 2010 to April 2020 in Guangdong Provincial Hospital of Chinese Medicine, including 169 patients with MAFLD (MAFLD group) and 380 patients without MAFLD (Non-MAFLD group). Propensity score matching (PSM) analysis was performed to balance the baseline characteristics. Kaplan–Meier survival curves were performed to compare the prognosis between the two matched groups. A multivariate Cox proportional hazards model was used to determine the risk factors for poor prognosis.ResultsThe median follow-up time for all patients was 20 (interquartile range 8–40) months. We found concurrent MAFLD was associated with a significantly decreased PFS rate before and after PSM analysis. The 1-year, 2-year, and 3-year PFS rates for the MAFLD and Non-MAFLD groups after PSM were 61.3% and 70.8%, 43.9% and 54.5%, 31.1% and 41.8%, respectively. Cox multivariable analysis showed that concurrent MAFLD was an independent risk factor for poor prognosis (death or progression) (HR = 1.49, P = 0.001). More interestingly, the risk of poor prognosis was significantly higher in the MAFLD subtype with metabolic components ≥2 compared to those with metabolic components <2 (HR = 1.97, P < 0.001).ConclusionConcurrent MAFLD was associated with a higher risk of poor prognosis in patients with HBV-related HCC, especially MAFLD with metabolic components ≥2.

Fibrotic Burden Determines Cardiovascular Risk among Subjects with Metabolic Dysfunction-Associated Fatty Liver Disease.

Background/AimsMetabolic dysfunction associated fatty liver disease (MAFLD) has recently been introduced to compensate for the conventional concept of nonalcoholic fatty liver disease (NAFLD). We explored whether fibrotic burden determines the risk of atherosclerotic cardiovascular disease (ASCVD) among subjects with MAFLD.MethodsWe recruited 9,444 participants from the Korea National Health and Nutrition Examination Survey (2008 to 2011). Liver fibrosis was identified using the fibrosis-4 (FIB-4) index and NAFLD fibrosis score. The 10-year ASCVD risk score (>10%) was used to determine a high probability ASCVD risk. For sensitivity analysis, propensity score matching was assessed to subjects with aged 40 to 75 years free from ASCVD.ResultsThe prevalence of MAFLD was 38.0% (n=3,592). The ASCVD risk scores stratified in quartile were positively correlated to MAFLD and FIB-4 defined-significant liver fibrosis (p for trend <0.001). Individuals with both MAFLD and FIB-4 defined-significant liver fibrosis had a greater chance of high probability ASCVD risk (odds ratio [OR]=2.40; p<0.001) than those without MAFLD. The impact of MAFLD on high probability ASCVD risk was greater than that of significant liver fibrosis (OR=4.72 for MAFLD vs OR=1.88 for FIB-4 defined-significant liver fibrosis; all p<0.001). Among participants with MAFLD, low muscle mass enhanced the risk of significant liver fibrosis (OR=1.56 to 2.43; p<0.001). When NAFLD fibrosis score was applied to define significant liver fibrosis, similar findings were observed.ConclusionsIndividuals with MAFLD had a substantial ASCVD risk compared to those without MAFLD. Accompanying significant liver fibrosis further enhanced the risk of ASCVD among subjects with MAFLD.