Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.

Non-alcoholic fatty liver disease (NAFLD) affects more than a quarter of the global population and has become the world's number one chronic liver disease, seriously jeopardizing public life and health. Despite the new terminology of metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed, the mechanisms underlying the heterogeneity across BMI stratification in non-alcoholic fatty liver disease (NAFLD) remain unclear. The aim of this study was to reveal the differences in metabolic and fibrotic characteristics between lean (BMI < 23 kg/m2) and non-lean NAFLD in an Asian population.

The current study collected NAFLD patients from the physical examination population. Patients were divided into two groups by BMI to compare their clinical parameters, including lean (BMI < 23 kg/m2) and non-lean (BMI ≥ 23 kg/m2) and fibrosis subgroups (with a threshold of LSM = 8 kPa) and analyzed for risk factors by logistic regression models.

Of the 11,577 NAFLD patients who participated in the study, there were 916 lean and 10,661 non-lean. The non-lean group was younger than the lean group (median age 50 vs. 52 years, P < 0.001) and had a significantly higher prevalence of hypertension (28.0% vs. 18.3%), diabetes mellitus (10.1% vs. 6.1%), and liver fibrosis (9.1% vs. 5.1%) (all P < 0.001). Analysis of metabolic indexes showed that TyG, TyG-BMI, TG/HDL-C and APRI were higher in the non-lean group (all P < 0.001). Gender stratification revealed that ALT was significantly higher in the male non-lean group, while HDL-C was lower in the female non-lean group (1.35 vs. 1.47 mmol/L). Multiple regression suggested that the risk of fibrosis was independently associated with CAP values and fasting glucose, BMI, direct bilirubin, globulin, and age in the non-lean group, whereas the risk was mainly driven by GGT and ALP in the lean group.

Non-lean NAFLD patients showed more significant metabolic disturbances and risk of liver fibrosis. Although metabolic indicators (TyG, FIB-4) have limited predictive value for liver fibrosis, they are strongly associated with metabolic risk in MASLD.

Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease are common conditions associated with high mortality and morbidity, yet opportunities for integrated prevention are underinvestigated. We explored the association between impairment in the liver (defined by increased iron-corrected T1 (cT1) time) and/or heart (reduced left ventricular ejection fraction ≤ 50) and risk of experiencing cardiovascular- or liver-related events or all-cause mortality among 28,841 UK Biobank participants who underwent magnetic resonance imaging. Using Cox proportional hazard models, adjusted for age, sex, body mass index, type 2 diabetes and dyslipidaemia, we observed that cardiac impairment was associated with increased incidence of cardiovascular events (hazard ratio (HR) 2.3 (1.9-2.7)) and hospitalization (HR 2.1 (1.8-2.4)). Liver impairment was associated with incident cardiovascular hospitalization (cT1 ≥ 800 ms, HR 1.3 (1.1-1.5)), liver events (cT1 ≥ 875 ms, HR 9.2 (3.2-26) and hospitalization (cT1 ≥ 875 ms, HR 5.5 (3.2-9.3). Associations between cT1 and liver events were maintained in participants with metabolic dysfunction-associated steatotic liver disease (N = 6,223). Reduced left ventricular ejection fraction (≤50) combined with elevated cT1 (≥800 ms) were associated with earlier cardiovascular events (time to event 0.8 versus 2.4 years; P < 0.05). Cardiac and liver impairment are independently, or in combination, associated with cardiovascular or liver events, suggesting a dual role for magnetic resonance imaging in integrated prevention pathways.

Global metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is estimated at 30% and projected to reach 55.7% by 2040. In the Veterans Affairs (VA) healthcare system, an estimated 1.8 million veterans have metabolic dysfunction-associated steatohepatitis (MASH).

Adult patients at risk for MASLD in a VA healthcare system underwent Fibrosis-4 (FIB-4) and Enhanced Liver Fibrosis (ELF®) testing. Referral rates and cost savings were compared among 6 noninvasive testing (NIT) strategies using these 2 tests independently or sequentially at various cutoffs.

Enrolled patients (N = 254) had a mean age of 65.3 ± 9.3 years and mean body mass index (BMI) of 31.7 ± 6, 87.4% male: 78.3% were non-Hispanic/Latino, and 96.5% had type 2 diabetes mellitus (T2DM). Among the 6 evaluated strategies, using FIB-4 followed by ELF at a 9.8 cutoff yielded the highest proportion of patients retained in primary care without need of referral to hepatology clinic (165/227; 72.7%), and was associated with the lowest costs ($407.62). Compared to the FIB-4 only strategy, FIB-4/ELF with a 9.8 cutoff strategy resulted in 26% fewer referrals and 8.47% lower costs. In the subgroup of patients with BMI >32, there were 25.17% fewer referrals and costs were 8.31% lower.

Our study suggests that sequential use of ELF with a 9.8 cutoff following indeterminate FIB-4 tests results in lower referral rates and lower care costs in a veteran population at risk of MASLD. Adding ELF as a sequential test after indeterminate FIB-4 might help reduce the number of referrals and overall cost of care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent, multifactorial systemic metabolic disorder, now recognized as the most common chronic liver disease globally. Female susceptibility to MASLD varies across menstrual states, influenced by genetic factors, age, menopausal status, and physical activity. Postmenopausal women, experiencing a significant reduction in estrogen, are particularly vulnerable to metabolic imbalances, increasing their risk of MASLD, disease progression, liver fibrosis, insulin resistance, and adverse cardiovascular events compared to premenopausal women and age-matched men. This review systematically synthesizes current research on extrahepatic abnormalities associated with MASLD in postmenopausal women. This review identifies key extrahepatic markers associated with MASLD in postmenopausal women, highlighting gaps in current research and proposing targeted screening and management strategies. (Graphical Abstract).

The impact of moderate drinking on the risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) remains controversial worldwide. Notably, China, with the fastest-growing incidence of NAFLD and the highest number of alcohol-attributable deaths globally, has relatively few studies addressing this issue. This study aimed to explore the association between alcohol consumption and liver fibrosis in Chinese men with metabolic dysfunction-associated steatotic liver disease (MASLD).

We recruited 4,683 male employees diagnosed with MASLD from southwest China, including 4,287 with pure MASLD and 396 with metabolic and alcohol-related liver disease (MetALD) who consumed increased alcohol (30-60 g/d). Advanced fibrosis was defined as a fibrosis-4 index (FIB-4) ≥ 2.67, and FIB-4 ≥ 1.30 indicated an intermediate/high probability of hepatic fibrosis. Logistic regression models were used to assess the association between alcohol consumption and hepatic fibrosis, and analyze the modification effect of body mass index (BMI) and waist-to-hip ratio (WHR) on the association. Propensity score matching method was used to test the robustness of the regression results.

Compared with non-drinkers, both moderate (OR = 3.02, 95% CI: 1.16-10.31) and increased alcohol consumption (OR = 4.64, 95% CI: 1.60-16.82) were significantly associated with an increased risk of advanced fibrosis in males with MASLD. Additionally, moderate (OR = 1.33, 95% CI: 1.07-1.66) and increased drinking (OR = 1.74, 95% CI: 1.28-2.34) were associated with intermediate/high probability of hepatic fibrosis, with similar results from logistic regression analysis in propensity score-matched cases. Trend analysis revealed the risk of hepatic fibrosis increased with increasing alcohol intake (FIB-4 ≥ 1.30, p for trend < 0.001; FIB-4 ≥ 2.67, p for trend = 0.007). Further subgroup analysis showed that the association between moderate drinking and intermediate/high probability of hepatic fibrosis was predominantly observed in males with BMI ≥ 23 kg/m2 (OR = 1.35, 95% CI: 1.08-1.69) and those with WHR ≥ 0.9 (OR = 1.40, 95% CI: 1.11-1.78).

In China, moderate alcohol intake may heighten the risk of hepatic fibrosis in males with MASLD who are overweight/obese or have abdominal obesity. Moreover, males with MetALD may have a higher risk of fibrosis compared to those with pure MASLD.

The relationship between sodium intake and the incidence and mortality of non-alcoholic fatty liver disease (NAFLD) is underexplored in nutritional epidemiology, highlighting the need for further research.

This longitudinal cohort study analyzed data from 13,853 Participants aged 20 and older from the National Health and Nutrition Examination Survey (NHANES) (2003-2018), including 4,465 participants with NAFLD. We collected comprehensive data on mortality, dietary sodium intake, and relevant covariates. Logistic regression assessed the relationship between sodium consumption and NAFLD incidence, while Cox regression and smooth curve fitting explored sodium intake's link to all-cause mortality among Participants with NAFLD.

After adjusting for confounders, logistic regression revealed a positive association between higher sodium intake and NAFLD incidence (OR = 1.16, 95% CI = 1.11, 1.21). Adjusted odds ratios for the second (Q2), third (Q3), and fourth (Q4) quartiles of sodium intake were 0.91, 1.23, and 1.52, respectively. Smooth curve fitting and threshold analysis revealed a non-linear association between sodium intake and NAFLD risk, with an inflection point at 2.49 g/d, above which NAFLD risk significantly increased. In Cox regression, sodium intake was inversely correlated with all-cause mortality in Participants with NAFLD (HR = 0.87, 95% CI = 0.80, 0.96), with adjusted hazard ratios for Q2, Q3, and Q4 being 0.79, 0.66, and 0.63, respectively. A nonlinear model indicated a threshold effect, revealing a correlation between dietary sodium intake and mortality risk (p = 0.001). We identified a threshold intake of 3.5 grams per day (equivalent to 8.9 grams of sodium chloride): below this, each unit increase in sodium intake was associated with a 16% reduction in mortality risk (HR = 0.84, 95% CI = 0.80, 0.90). For intakes above this threshold, no significant relationship with mortality risk was observed (HR = 0.99, 95% CI = 0.90, 1.08).

This study suggests that higher sodium intake in individuals with NAFLD is associated with increased disease incidence but decreased all-cause mortality. The dose-response relationship between sodium intake and mortality risk exhibited a nonlinear pattern, with a critical inflection point around 3.5 grams per day.

The Hepatic Steatosis Index (HSI) serves as a non-invasive indicator for assessing liver fat accumulation. Its potential association with hypertension has garnered increasing attention, as metabolic dysfunctions, including hepatic steatosis, may contribute to elevated blood pressure via mechanisms such as insulin resistance and chronic inflammation.

Utilizing data from the NHANES database (2011-2018), the HSI was calculated on the basis of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and BMI.The association between HSI and hypertension was assessed by univariate analysis, weighted multivariate Logistic regression, and restricted cubic spline (RCS) models. Subgroup analyses were performed to increase the reliability of the data.

This cross-sectional study analysed data from 17,501 adults (NHANES 2011-2018) to assess the association between HSI and hypertension. Of these, 9,890 (56.51%) were diagnosed with hypertension.In the unadjusted model, HSI demonstrated a statistically significant correlation with hypertension, showing an odds ratio (OR) of 1.05 (95% confidence interval: 1.04-1.06).After adjustment for potential confounders, a higher prevalence of hypertension was observed in participants in the upper HSI quartiles (Q3 and Q4), with corresponding ORs of 2.29 (95% CI: 2.29-2.63) and 4.03 (95% CI: 3.42-4.74), respectively. RCS analysis revealed a U-shaped non-linear relationship between HSI and hypertension (P < 0.001), indicating that while hypertension risk primarily escalated with increasing HSI, a modest risk elevation was also detected at lower HSI levels. This suggests that both excessive liver fat accumulation (indicated by a high HSI) and underlying metabolic disorders (such as malnutrition or sarcopenia) may contribute to hypertension risk in individuals with unexpectedly low HSI. Subgroup analyses identified significant interactions in relation to education, cancer, and diabetes mellitus (p for interaction < 0.05), whereas no significant interactions were observed in other stratifications.

This study found a U-shaped relationship between the hepatic steatosis index (HSI) and the risk of hypertension. Although the HSI shows potential as a practical screening tool in primary care, further longitudinal studies are needed to establish causality and explore the complex bidirectional pathways involved.

Not applicable.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases characterized by hepatic steatosis, the presence of at least one cardiometabolic risk factor, and no other apparent cause. Metabolic syndrome (MetS) is a cluster of clinical conditions associated with increased risk of cardiovascular disease, type 2 diabetes, and overall morbidity and mortality. This narrative review summarizes the changes in the management of people with MetS and NAFLD/MASLD from screening to therapeutic strategies that have occurred in the last decades. Specifically, we underline the clinical importance of considering the different impacts of simple steatosis and advanced fibrosis and provide an up-to-date overview on non-invasive diagnostic tests (i.e., imaging and serum biomarkers), which now offer acceptable accuracy and are globally more accessible. Early detection of MetS and MASLD is a top priority as it allows for timely interventions, primarily through lifestyle modification. The liver and cardiovascular benefits of a global and multidimensional approach are not negligible. Therefore, a holistic approach to both conditions, MetS and related chronic liver disease, should be applied to improve overall health and longevity.

The escalating global prevalence of diabetes underscores the urgency of addressing its treatment and associated complications. Paeoniflorin, a monoterpenoid glycoside compound, has garnered substantial attention in recent years owing to its potential therapeutic efficacy in diabetes management. Thus, this study aims to systematically overview the pharmacological effects, pharmacokinetics and toxicity of paeoniflorin in diabetes. Plenty of evidences have verified that paeoniflorin improves diabetes and its complication through reducing blood sugar, enhancing insulin sensitivity, regulating gut microbiota and autophagy, restoration of mitochondrial function, regulation of lipid metabolism, anti-inflammation, anti-oxidative stress, inhibition of apoptosis, immune regulation and so on. Paeoniflorin possess the characteristics of rapid absorption, wide distribution, rapid metabolism and renal excretion. Meanwhile, toxicity studies have suggested that paeoniflorin has low acute toxicity, minimal subacute and chronic toxicity, and no genotoxic or mutational toxic effects. In conclusion, this paper systematically elucidates the potential therapeutic application and safety profile of paeoniflorin in diabetes management.

Transient elastography (TE) has become a prominent technique for the detection of fibrosis, owing to its non-invasive nature, rapid execution, safety, and ease of repetition. This study aims to conduct a bibliometric analysis of the historical development and trends in the application of TE for the assessment of liver fibrosis.

In the Web of Science (Core Collection database), we selected the Science Citation Index Expanded database to search for relevant literature from 1 January 1983 to 20 November 2023. We performed a search using the following topic words: transient elastography, liver fibrosis. After screening according to the title, abstract and keyword and removing the repetition, the literature included in the study was finally determined, and full records were downloaded. Bibliometric analysis was performed using VOSviewer and CiteSpace.

Through the bibliometric visualization analysis of 577 articles, it was found that since TE was first reported for the measurement of liver fibrosis in 2003, the number of publications in this field has generally shown an upward trend, and the distribution of publications has shown a bimodal distribution, with peaks in 2010 and 2019. France and China have shown a high contribution in this field with a high number of publications. In terms of contributions from individual research centers, Yonsei University stands out prominently. Throughout the history of research in this field, early studies focused on chronic viral hepatitis, by comparing TE and Fibrosis-4, aspartate aminotransferase to platelet ratio index, FibroTest, liver biopsy and other liver fibrosis detection indicators to verify its diagnostic efficacy. Subsequently, the focus of research gradually shifted to non-alcoholic fatty liver disease and other liver diseases, and the scope of research extended to the establishment of prediction models and efficacy evaluation through TE.

The application scope of TE is gradually expanding, and its safety, simplicity, rapidity, high accuracy, quantitative results, repeatability and good tolerance make it popular in clinical practice. Nowadays, the application of TE is not limited to the diagnosis of liver fibrosis, but has been extended to the establishment of prognostic models and efficacy evaluation of various liver diseases. To explore the deeper value of TE through new research methods such as machine learning models, radiate the advantages of TE to more liver diseases, and combine TE with a variety of non-invasive detection indicators to improve its application value, may be the future development and application prospect of TE in the field of liver fibrosis.

Patients with type 2 diabetes are at high risk of developing steatotic liver disease (SLD). Weight loss has proven effective in treating metabolic dysfunction-associated steatotic liver disease (MASLD) in obese patients with type 2 diabetes, with sodium-glucose cotransporter 2 (SGLT2) inhibitors showing promising results. However, lean MASLD is more prevalent in Japan, necessitating alternative approaches to body weight reduction.

We used the J-STEP/LT dataset including up to 3-year treatment data to analyze the effects of the SGLT2 inhibitor tofogliflozin on liver function and treatment safety and conducted a subgroup analysis based on body mass index (BMI; kg/m2, <20, 20-<23, 23-<25, 25-<30, and ≥30).

This study included 4,208 participants. Tofogliflozin significantly reduced alanine aminotransferase (ALT) levels in participants with baseline ALT levels >30 U/L across all BMI groups, with median changes of -12, -16, -13, -15, and -15 U/L, respectively (P = 0.9291 for trends). However, median changes in body weight with tofogliflozin were -2.00, -2.75, -2.00, -3.00, and -3.80 kg, respectively (P < 0.0001 for trends), with no significant weight loss observed in the BMI <20 group. ALT levels were also significantly decreased in participants who did not lose weight. Safety assessments according to BMI and age categories revealed no clear differences in the frequency of adverse events.

Tofogliflozin reduced ALT levels without substantial body weight reduction among lean participants. These findings suggest that SGLT2 inhibitors may be a viable treatment option for non-obese patients with type 2 diabetes and SLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern that necessitates early screening and timely intervention to improve prognosis. The current diagnostic protocols for MASLD involve complex procedures in specialised medical centres. This study aimed to explore the feasibility of utilising machine learning models to accurately screen for MASLD in large populations based on a combination of essential demographic and clinical characteristics.

A total of 10,007 outpatients who underwent transient elastography at the First Affiliated Hospital of Gannan Medical University were enrolled to form a derivation cohort. Using eight demographic and clinical characteristics (age, educational level, height, weight, waist and hip circumference, and history of hypertension and diabetes), we built predictive models for MASLD (classified as none or mild: controlled attenuation parameter (CAP) ≤ 269 dB/m; moderate: 269-296 dB/m; severe: CAP > 296 dB/m) employing 10 machine learning algorithms: logistic regression (LR), multilayer perceptron (MLP), extreme gradient boosting (XGBoost), bootstrap aggregating, decision tree, K-nearest neighbours, light gradient boosting machine, naive Bayes, random forest, and support vector machine. These models were externally validated using the National Health and Nutrition Examination Survey (NHANES) 2017-2023 datasets.

In the hospital outpatient cohort, machine learning algorithms demonstrated robust predictive capabilities. Notably, LR achieved the highest accuracy (ACC) of 0.711 in the test cohort and 0.728 in the validation cohort, coupled with robust areas under the receiver operating characteristic curve (AUC) values of 0.798 and 0.806, respectively. Similarly, MLP and XGBoost showed promising results, with MLP achieving an ACC of 0.735 in the test cohort, and XGBoost registering an AUC of 0.798. External validation using the NHANES datasets yielded consistent AUC results, with LR (0.831), MLP (0.823), and XGBoost (0.784) performing robustly.

This study demonstrated that machine learning models constructed using a combination of essential demographic and clinical characteristics can accurately screen for MASLD in the general population. This approach significantly enhances the feasibility, accessibility, and compliance of MASLD screening and provides an effective tool for large-scale health assessments and early intervention strategies.

Metabolic-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is prevalent worldwide and is highly associated with cardiovascular disease (CVD). Lean MASLD is defined by hepatic steatosis and cardiometabolic risk factors in individuals with a body mass index below 25 in Western populations or below 23 in Asian populations. Paradoxically, some studies indicate that lean MASLD is associated with an elevated risk of cardiovascular (CV) disease and CV mortality compared with nonlean MASLD. Lean MASLD patients exhibit distinctive metabolic, genetic, and microbiome profiles contributing to increased visceral adiposity, sarcopenia, hepatic fibrosis, systemic inflammation, and endothelial dysfunction. This review examines the epidemiology, pathophysiology, and CV outcomes associated with lean MASLD, addressing discrepancies in the literature. Furthermore, it highlights current clinical guidelines, emphasizes lifestyle modifications, and discusses emerging pharmacotherapies as potential treatment options.

To examine the mortality risk associated with metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD type, lean/non-lean MASLD and different cardiometabolic risk factors (CMRFs) in patients with inflammatory bowel disease (IBD) based on a long-term prospective cohort.

Prevalent IBD patients at baseline who were free of alcoholic liver disease, cancer and hepatitis B/C virus seropositive were included (N=4622). MASLD, MASLD type [pure MASLD, MASLD with increased alcohol intake (MetALD)], lean/non-lean MASLD and CMRFs at baseline were defined according to the latest criteria proposed by AASLD and EASL. Primary outcome was all-cause mortality. Cox proportional hazard model was used to examine the association.

Overall, 1,763 (38.1%) were diagnosed with MASLD. During a median of 13.3-year follow-up, 451 all-cause deaths were identified. Compared with IBD-only patients, those with MASLD had a 58% excess risk of mortality (HR=1.58, 95%CI:1.07-2.32). Furthermore, as number of CMRFs increased in MASLD patients, mortality risk was significantly increased (Ptrend=0.005), with a 85% and 83% higher risk in MASLD with 3 CMRFs (HR=1.85, 95%CI:1.20-2.85) and ≥4 CMRFs (HR=1.83, 95%CI:1.16-2.89) versus IBD-only patients. Specifically, similar elevated mortality risk was observed in either pure MASLD (HR= 1.62, 95%CI:1.09-2.43) or MetALD (HR=2.03, 95%CI:1.24-3.32). Moreover, the excess mortality risk was both indicated in lean (HR=3.14, 95%CI:1.57-6.29) and non-lean MASLD (HR=1.67, 95%CI:1.12-2.48).

MASLD, either pure MASLD or MetALD, as well as lean/non-lean MASLD, is associated with increased mortality risk in IBD patients, with greater risk as number of cardiometabolic risk factors increased and evidently higher risk in lean MASLD patients.

To compare outcomes of MASLD in obese and nonobese populations.

MASLD is emerging as one of the leading causes of liver failure and liver-related morbidity and mortality, with an increasing prevalence in the nonobese or lean population. The purpose of this study is to compare hepatic and oncological outcomes between MASLD patients with lean BMI and nonlean BMI.

The National Inpatient Sample (NIS) was queried from 2016 to 2020 for adult hospitalizations with MASLD. Exclusion criteria included concurrent diagnoses of viral hepatitis, alcoholic hepatitis, primary biliary cholangitis, hereditary hemochromatosis, autoimmune hepatitis, or Wilson disease. Outcomes of MASLD and its complications were compared between the lean and nonlean subgroups.

Patients with lean BMI had higher mortality rates (odds ratio: 2.10, P<0.001). The lean cohort also had higher odds of cirrhosis, portal hypertension, SBP, and ascites. The lean subgroup had higher odds of gastrointestinal malignancies including esophageal cancer, gastric cancer, pancreatic cancer, and colorectal cancer.

Hospitalized lean MASLD patients had higher odds of mortality, ​​hepatic morbidities, and gastrointestinal malignancies. These results challenge the use of BMI as a predictor of morbidity and mortality for MASLD patients. Future studies should focus on therapeutic options for MASLD and compare their efficacies between lean and nonlean populations.

The human microbiota, a complex ecosystem of microorganisms, plays a pivotal role in regulating host immunity and metabolism. This review investigates the interplay between microbiota and inflammatory markers, emphasizing their impact on metabolic and autoimmune disorders. Key inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), lipopolysaccharides (LPS), zonulin (ZO-1), and netrin-1 (Ntn1), are discussed in the context of intestinal barrier integrity and chronic inflammation. Dysbiosis, characterized by alterations in microbial composition and function, directly modulates the levels and activity of these biomarkers, exacerbating inflammatory responses and compromising epithelial barriers. The disruption of microbiota is further correlated with increased intestinal permeability and chronic inflammation, serving as a precursor to conditions like type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease. Additionally, this review examines therapeutic strategies, including probiotics and prebiotics, designed to restore microbial balance, mitigate inflammation, and enhance metabolic homeostasis. Emerging evidence positions microbiota-targeted interventions as critical components in the advancement of precision medicine, offering promising avenues for diagnosing and treating inflammatory and metabolic disorders.

Cornus officinalis (CO) has been widely used as Chinese herbal medicine and has a good clinical efficacy in liver disease. In particular, it has a significant therapeutic effect on metabolic liver disease. However, systematic pharmacological studies on its hepatoprotective effect on non-alcoholic fatty liver disease (NAFLD) are lacking.

We investigated the impact of Cornus officinalis extract (COE) on two mouse models of NAFLD, screened the potential mechanisms of action by using metabolomics assays, and explored the protective effects on hepatocyte proliferation by regulating glutamate metabolism and tricarboxylic acid (TCA) cycle.

The main components of COE were identified by high performance liquid chromatograph (HPLC). Male C57BL/6J mice were subjected to construct carbon tetrachloride (CCl4) or methionine choline deficient (MCD) induced NAFLD mice. Liver function and lipid biochemical indicators were detected using commercial assay kits. Masson staining, Western blot, and immunohistochemistry analyses were used for assessing hepatic injury and fibrosis. LC-MS non-targeted analysis was performed using the 1290 Ultra-High Performance Liquid Chromatograph System and the 6540 Q-TOF Mass Spectrometry. Palmitic acid (PA) induced L-02 cell model was established. The mediators in glutamate metabolism and TCA cycle were assessed by assay kits.

In vivo experiments validated that COE significantly improved liver function in NAFLD mice, reduced lipid accumulation, and alleviated pathological damage and liver fibrosis. The non-targeted metabolomics analysis combined with Ingenuity Pathway Analysis (IPA) located glutamate metabolism and the downstream TCA cycle as potential mechanisms of COE, which was further confirmed in NAFLD model mice and PA-induced L-02 cells. Finally, we confirmed that COE could promote mitochondrial energy supply by remodeling the homeostasis of the TCA cycle, thereby enhancing hepatocyte proliferation.

This study demonstrated that COE could significantly improve CCl4 or MCD-induced NAFLD by promoting hepatocyte proliferation. These results highlighted the potential of COE as leads for the development of innovative treatments for NAFLD.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Although appendicular skeletal muscle mass (ASM) has been linked to the severity of hepatic steatosis, investigations of its correlation among younger age groups are lacking. We aimed to elucidate the role of ASM in determining the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in younger patients.

Retrospective data were collected from patients younger than 35 years who visited the Armed Forces Goyang Hospital between June 2022 and February 2024. Steatosis presence was determined by a controlled attenuation parameter score ≥ 250 dB/m, and significant fibrosis was identified with liver stiffness measurement > 8.0 kPa. ASM was measured using multifrequency bioelectrical impedance analysis (InBody 620).

Of 910 participants, 630 were diagnosed with MASLD. Patients with MASLD had lower ASM/fat mass (ASM/F) (1.02 vs. 1.91; p < 0.001), ASM/body mass index (BMI) (0.91 vs. 1.04/m2; p < 0.001), and ASM/body weight (ASM/W) (29.5% vs. 33.8%; p < 0.001) than non-MASLD patients. Additionally, ASM/F, ASM/BMI, and ASM/W significantly decreased with worsening steatosis severity and were notably lower in patients with significant fibrosis. Among 107 patients with MASLD who underwent two examinations with a median interval of 6.0 months, those with increased ASM/F showed a higher proportion of steatosis regression and a lower proportion of steatosis worsening than those with decreased ASM/F (steatosis regression, 43.1% vs. 22.9%; worsening, 11.1% vs. 28.6%; p = 0.031). All three ASM indices were significant factors in steatosis regression during the study period.

ASM is associated with the severity of steatosis and significant fibrosis in MASLD in young adults < 35 years.

Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2025;97:270-280.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25%. Studies on incident liver and cardiovascular outcomes in lean (Body mass index: BMI < 25 kg/m2, or < 23 kg/m2 for Asians) vs. non-lean individuals with MASLD have reported mixed results. We aimed to compare incident clinical outcomes and mortality between lean and non-lean individuals with compensated MASLD cirrhosis in a large national cohort.

This was a retrospective cohort study of patients with newly diagnosed compensated MASLD cirrhosis in the Veterans Health Administration between 01/2008 and 05/2021. The primary outcome was incident hepatic decompensation, and secondary outcomes were incident major adverse cardiovascular events (MACE) and all-cause mortality. Multivariable Cox proportional hazard models were used to assess association. Fine and Gray competing risk regression was used where applicable.

The study included 15155 patients with MASLD cirrhosis: 1,597 lean and 13558 non-lean patients. Included patients were mostly male (95%), median age was 67 years, and 72.8% were non-Hispanic white. At baseline, the prevalence of diabetes was lower in lean vs. non-lean individuals (46.7 vs. 73.9%, p < 0.001). In multivariable models, lean status was associated with a 64% increased risk of all-cause mortality (aHR = 1.64) but decreased risk of hepatic decompensation (aSHR = 0.67). Lean individuals experienced significantly higher rates of cardiovascular-related mortality (aHR = 1.40).

Lean MASLD patients with compensated cirrhosis had a higher mortality risk but a lower risk of hepatic decompensation than non-lean patients. Despite having a better baseline cardiometabolic profile and similar rates of MACE, lean individuals with MASLD cirrhosis have a higher risk of cardiovascular mortality.

The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future.

Metabolism-related fatty liver disease (MAFLD) is associated with abnormal fat accumulation in the liver. The exact mechanism underlying the occurrence and development of MAFLD remains to be elucidated. Here, we discovered that the expression of sucrose non-fermenting-related kinase (SNRK) is elevated in the liver of the MAFLD population. Mice deficient in SNRK exhibited damage to fatty acid oxidation and persistent accumulation of lipids in the liver. Pharmacological inhibition of the mTOR pathway in SNRK-deficient mice restored autophagy and improved lipid accumulation. In terms of mechanism, we observed that SNRK binds to the raptor component of mTOR complex 1, promoting fatty acid oxidation in the liver by activating autophagy. Overexpression of SNRK in high-fat diet-induced obese mice restored autophagy and ameliorated lipid accumulation. Notably, we also demonstrated that overexpression of SNRK significantly enhanced fatty acid oxidation in the mouse liver. We further confirmed that SNRK is essential for the liver to regulate autophagy and fatty acid oxidation. These findings underscore the importance of the potential of SNRK in the treatment of MAFLD.

There is a new awareness of the widespread nature of metabolic dysfunction-associated steatotic liver disease (MASLD) and its connection to cardiovascular disease (CVD). This has catalyzed collaboration between cardiologists, hepatologists, endocrinologists, and the wider multidisciplinary team to address the need for earlier identification of those with MASLD who are at increased risk for CVD. The overlap in the pathophysiologic processes and parallel prevalence of CVD, metabolic syndrome, and MASLD highlight the multisystem consequences of poor cardiovascular-liver-metabolic health. Metabolic dysfunction and associated insulin resistance, together with the predilection for ectopic fat deposition in the liver and surrounding tissues, are associated with elevated risk of endothelial dysfunction, systemic inflammatory response, and ectopic fat deposition in the epicardium. This complex pathophysiology can accelerate atherogenic dyslipidemia, atherogenesis, diastolic dysfunction, valvular calcification, and cardiac arrhythmias. Despite the mounting evidence of mechanistic pathways underpinning MASLD and CVD, current recommendations have not clearly focused upon MASLD as a risk factor or target for intervention in CVD. We have brought together a diverse range of international experts committed to promoting cardiovascular-liver-metabolic health and related outcomes across the globe. The overarching goal of this document is to offer a construct for clinicians in the cardiovascular field with regards to (1) diagnosis and screening of MASLD through the use of noninvasive serum and imaging tests; (2) screening for CVD in all individuals with MASLD regardless of established atherosclerotic risk factors; and (3) the approach to management of MASLD with respect to prevention of CVD through lifestyle, as well as pharmacologic and surgical strategies. To achieve this, the modified Delphi method was applied and a series of evidence-based quality standard recommendations have been identified.

The incidence of NAFLD is increasing. Preclinical evidences indicate that modulation of the gut microbiome could be a promising target in nonalcoholic fatty liver disease.

A systematic review and network meta-analysis was conducted to compare the effect of probiotics, synbiotics, prebiotics, fecal microbiota transplant, and antibiotics on the liver-enzyme, metabolic effects and liver-specific in patients with NAFLD. The randomized controlled trails (RCTs), limited to English language were searched from database such as Pubmed, Embase, Web of science and Cochrane Library from inception to November 2024. Review Manager 5.3 was used to to draw a Cochrane bias risk. Inconsistency test and publication-bias were assessed by Stata 14.0. Random effect model was used to assemble direct and indirect evidences. The effects of the intervention were presented as mean differences with 95% confidence interval.

A total of 1921 patients from 37 RCTs were eventually included in our study. 23 RCTs evaluated probiotics, 10 RCTs evaluated synbiotics, 4 RCTs evaluated prebiotics, 3 RCTs evaluated FMT and one RCT evaluated antibiotics. Probiotics and synbiotics were associated with a significantly reduction in alanine aminotransferase [ALT, (MD: -5.09; 95%CI: -9.79, -0.39), (MD: -7.38, 95CI%: -11.94, -2.82)] and liver stiffness measurement by elastograph [LSM, (MD: -0.37;95%CI: -0.49, -0.25), (MD: -1.00;95%CI: -1.59, -0.41)]. In addition to, synbiotics was superior to probiotics in reducing LSM. Synbiotics was associated with a significant reduction of Controlled Attenuation Parameter [CAP, (MD: -39.34; 95%CI: -74.73, -3.95)]. Both probiotics and synbiotics were associated with a significant reduction of aspartate transaminase [AST, (MD: -7.81; 95%CI: -15.49, -0.12), (MD: -13.32; 95%CI: -23, -3.64)]. Probiotics and Allogenic FMT was associated with a significant reduction of Homeostatic Model Assessment for Insulin Resistance [HOMA-IR, (MD: -0.7, 95%CI: -1.26, -0.15), (MD: -1.8, 95%CI: -3.53, - 0.07)]. Probiotics was associated with a significant reduction of body mass index [BMI, MD: -1.84, 95%CI: -3.35, -0.33].

The supplement of synbiotics and probiotics maybe a promising way to improve liver-enzyme, LSM, and steatosis in patients with NAFLD. More randomized controlled trials are needed to determine the efficacy of FMT and antibiotics on NAFLD. And the incidence of adverse events of MTTs should be further explored.

https://www.crd.york.ac.uk/prospero/, CRD42023450093.

Despite causing significant morbidity and mortality, nonalcoholic fatty liver disease (NAFLD) is underdiagnosed. Clinical indices developed to identify hepatic steatosis are often used by providers but their potential for use at the population level remains unexplored. We assessed clinical phenotypes for their ability to identify potential patients with NAFLD and nonalcoholic steatohepatitis (NASH) in the electronic health record.

We conducted a single-center retrospective cohort study of adult patients from January 1, 2016, to December 31, 2022. We developed 4 phenotypes: clinical NAFLD (C-NAFLD), clinical NASH (C-NASH), NAFLD with diagnosis (D-NAFLD) and NASH with diagnosis (D-NASH) and compared characteristics across them to identify differences between patients with and without International Classification of Diseases diagnoses.

Each of the (C) phenotypes identified a cohort of patients who had clinical evidence suggestive of disease without a documented diagnosis. Black patients were overrepresented in the (C) relative to (D) groups (C-NAFLD 24.3% vs D-NAFLD 21.2%; C-NASH 28.5% vs D-NASH 14.0%). Patients with D-NASH were more likely to be prescribed medications that may be effective in treating NAFLD-NASH spectrum disease, ie, glucagon-like peptide 1 receptor agonists (C-NASH 5.0% vs D-NASH 16.7%, P < .001). Fewer patients with D-NASH had cardiovascular (C-NASH 58.0% vs D-NASH 46.3%, P < .001) and heart failure (C-NASH 33.9% vs D-NASH 24.8%, P < .001) hospitalizations than those with C-NASH.

Noninvasive clinical indices may improve identification of patients with or at risk for NAFLD-NASH at the population level. Systematic differences between populations with and without International Classification of Diseases diagnoses of NAFLD-spectrum disease suggest disparities in the application of screening and diagnostic procedures.

This study aimed to examine the association between the triglyceride-glucose (TyG) index and liver fibrosis (LF) in U.S. adults with Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD).

Using data from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES) database, we conducted a population-based cross-sectional study with 1,324 participants. MAFLD was defined as a controlled attenuation parameter (CAP) score ≥ 248 dB/m accompanied by metabolic dysfunction. A median liver stiffness measurement ≥ 8.2 kPa was used to identify significant fibrosis (≥ F2). Multivariable logistic regression was employed to assess the impact of the TyG index on LF outcomes. A restricted cubic spline (RCS) model was used to explore nonlinear effects, and receiver operating characteristic (ROC) curves were applied to evaluate the effectiveness in predicting.

Among the participants, 716 were men and 608 were women, aged 20 to 80 years, representing various racial groups. Significant fibrosis was observed in 137 out of 1,324 participants. After adjusting for confounding factors, a higher TyG index was significantly associated with an increased incidence of MAFLD-related LF (OR = 2.18, 95% CI, 1.14-4.18; p < 0.05). Elevated TyG levels showed a positive correlation with significant fibrosis, with an odds ratio (OR) exceeding 1 when the TyG index was above 8.054. Subgroup analyses stratified by sex, age, and body mass index (BMI) revealed differences after adjusting for confounders. The association was stronger in women (OR = 2.53, 95% CI, 1.16-5.53) than in men (OR = 1.95, 95% CI, 0.81-4.72). A significant correlation was also found between TyG levels and obesity status (overweight: OR = 4.80, 95% CI, 1.27-18.2; obese: OR = 2.26, 95% CI, 1.20-5.53). In MAFLD patients aged 40-59, TyG was strongly associated with LF (OR = 2.85, 95% CI, 1.16-6.79). Furthermore, the area under the ROC curve (AUC) for the TyG index in predicting significant fibrosis in MAFLD patients was 0.73 (95% CI, 0.68-0.78), indicating moderate predictive ability.

In the general U.S. population, elevated TyG index levels were positively associated with an increased risk of LF in MAFLD patients.

The current definition of lean is based on body mass index (BMI). However, BMI is an imperfect surrogate for adiposity and provides no information on central obesity (CO). Hence, we explored the differences in clinical profile and liver disease severity in lean patients with nonalcoholic fatty liver disease (NAFLD) with and without CO.

One hundred seventy lean patients with NAFLD (BMI <23 kg/m2) were divided into two groups depending upon the presence or absence of CO (waist circumference ≥80 cm in females and ≥90 cm in males). Noninvasive assessment of steatosis was done by ultrasound and controlled attenuation parameter (CAP), while fibrosis was assessed with FIB-4 and liver stiffness measurement (LSM). FibroScan-AST (FAST) score was used for non-invasive prediction of NASH with significant fibrosis.

Of 170 patients with lean NAFLD, 96 (56.5%) had CO. Female gender (40.6% vs. 17.6%, P = 0.001), hypertriglyceridemia (58.3% vs. 39.2%, P = 0.01) and metabolic syndrome (23.9% vs. 4.1%, P < 0.001) were more common in the CO group. There was a poor correlation between BMI and waist circumference (r = 0.24, 95% CI: 0.09-0.38). Grade 2-3 steatosis on ultrasound was significantly more common in CO patients (30% vs. 12.3%, P = 0.007). CAP [312.5 (289.8-341) dB/m vs. 275 (248-305.1) dB/m, P = 0.002], FAST score [0.42 (0.15-0.66) vs. 0.26 (0.11-0.39), P = 0.04], FIB-4 and LSM were higher in those with CO. Advanced fibrosis was more prevalent among CO patients using FIB-4 (19.8% vs 8.1%, P = 0.03) and LSM (9.5% vs. 0, P = 0.04). CO was independently associated with advanced fibrosis after adjusting for BMI and metabolic risk factors (aOR: 3.11 (1.10-8.96), P = 0.03). Among these 170 patients, 142 fulfilled metabolic dysfunction associated steatotic liver disease (MASLD) criteria. CO was also an independent risk factor for advanced fibrosis in MASLD (3.32 (1.23-8.5), P = 0.02).

Lean patients with NAFLD or MASLD and CO have more severe liver disease compared to those without CO.

Histopathologic evaluation of liver biopsy has played a longstanding role in the diagnosis and management of liver disease. However, the utility of liver biopsy has been questioned by some, given the improved imaging modalities, increased availability of noninvasive serologic tests, and development of artificial intelligence over the past several years. In this review, we discuss the current and future role of liver biopsy in both non-neoplastic and neoplastic liver diseases in the era of improved noninvasive laboratory, radiologic, and digital technologies.

Emerging research indicates that individuals with non-alcoholic fatty liver disease (NAFLD) who carry excess weight have similar or even higher survival rates than their normal-weight counterparts. This puzzling "obesity paradox" may be attributed to underlying biases. To explore this phenomenon, we examined data extracted from the third National Health and Nutrition Examination Survey (NHANES) III, which spanned from 1988-1994.

We specifically targeted participants diagnosed with NAFLD through ultrasound due to fatty liver presence and employed multivariate Cox regression to assess mortality risk associated with body mass index (BMI) and the waist-to-height ratio (WHtR).

Over a median follow-up period of 20.3 [19.9-20.7] years, 1832 participants passed away. The study revealed an intriguing "obesity-survival paradox", in which individuals classified as overweight (HR 0.926, 95% CI 0.925-0.927) or obese (HR 0.982, 95% CI 0.981-0.984) presented reduced mortality risks compared with those categorized as normal weight. However, this paradox vanished upon adjustments for smoking and exclusion of the initial 5-year follow-up period (HR 1.046, 95% CI 1.044-1.047 for overweight; HR 1.122, 95% CI 1.120-1.124 for obesity class I). Notably, the paradox was less pronounced with the WHtR, which was significantly different only in quartile 2 (HR 0.907, 95% CI 0.906-0.909) than in quartile 1, and was resolved after appropriate adjustments. In particular, when BMI and WHtR were considered together, higher levels of adiposity indicated a greater risk of mortality with WHtR, whereas BMI did not demonstrate the same trend (p <0.05).

The "obesity paradox" in NAFLD patients can be explained by smoking and reverse causation. WHtR was a better predictor of mortality than BMI.

To examine the relationship between changes in alanine aminotransferase (ALT) and those in body composition and metabolic factors in participants receiving medical health checkups (4350 men [mean age 52.5 years] and 5398 women [mean age 50.5 years]) METHODS: We divided the participants into four types based on their ALT value at baseline and 1 year: A, ALT ≤30 (baseline) and ≤30 (1 year); B, ALT ≥31 (baseline) and ≤30 (1 year); C, ALT ≤30 (baseline) and ≥31 (1 year); and D, ALT ≥31 (baseline) and ≥31 (1 year). The change in each body composition-related parameter (waist circumference, fat mass, fat-free mass, fat mass to fat-free mass ratio, etc.) after 1-year was defined as Δ.

The mean changes in waist circumference (cm) in the four types (A, B, C, and D) were -0.33, -1.54, 0.66, and -0.29 (overall p < 0.0001) in men, and -0.19, -0.90, 0.30, and 0.090 (overall p < 0.0001) in women. The mean changes in fat mass (kg) in the four types were -0.027, -0.86, 0.62, and 0.092 (overall p < 0.0001) in men, and 0.0067, -0.48, 0.39, and 0.063 (overall p < 0.0001) in women. The mean changes in fat-free mass (kg) in the four types were -0.028, -0.55, 0.42, and -0.034 (overall p < 0.0001) in men, and -0.0091, -0.34, 0.12, and -0.045 (overall p = 0.0012) in women. The mean changes in fat mass to fat-free mass ratio in the four types were -0.00042, -0.0120, 0.00837, and 0.00171 (overall p < 0.0001) in men, and -0.00013, -0.00817, 0.00730, and 0.00628 (overall p < 0.0001) in women.

A decrease in ALT to ≤30 IU/L may be associated with improved body composition balance, but caution should be exercised for the decrease in muscle mass.

A multicenter study in patients with type 2 diabetes mellitus (T2DM) was performed to assess the differences of liver steatosis and fibrosis between lean and nonlean individuals.

Patients with T2DM from 16 centers were recruited and underwent transient elastography examination for diagnosis of liver steatosis and fibrosis. Clinical information, such as diabetes status, serum lipids profiles, and inflammatory markers, were collected. Potential risk factors of liver steatosis and fibrosis in lean (body mass index [BMI] < 23 kg/m2) and nonlean (BMI ≥ 23 kg/m2) groups were analyzed.

A total of 1762 patients were included. The prevalence of liver steatosis and fibrosis in the lean group was 44.7% and 23.4%, respectively. The prevalence of hypertension and cardiovascular disease was higher in lean patients when compared with nonlean group. Lean patients with liver steatosis or fibrosis were older, had longer diabetes duration, lower levels of homeostatic model assessment for insulin resistance and serum lipids. The BMI, visceral fat area, and triglyceride were among the most significant correlators of liver steatosis for both nonlean and lean patients. However, lipid profiles were different between the two groups. Besides, insulin resistance, BMI, and lipid levels were not observed to be associated with fibrosis in the lean group.

In lean patients with T2DM, liver steatosis and fibrosis were less associated with insulin resistance. Risk factors of liver steatosis were different between lean and nonlean patients, indicating the necessity of risk stratification and tailored management strategies.