Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.

Physical activity (PA), sedentary behavior (SB), metabolic syndrome (MetS), and non-alcoholic fatty liver disease (NAFLD) have been linked in previous studies. Nevertheless, it is unclear whether MetS has a mediating influence on the relationships among physical activity, sedentary behavior, and non-alcoholic fatty liver disease. This study aims to assess the connections between physical activity, sedentary behavior, and non-alcoholic fatty liver disease and to explore the extent to which metabolic syndrome acts as a mediator in this association.

A total of 3351 adults from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018 were included in our study. Physical activity and sedentary behavior were categorized as work activity (WA), recreational activity (RA), walking/bicycling (for commuting) and sedentary behavior to investigate the association with metabolic syndrome and non-alcoholic fatty liver disease. Besides, mediation analysis was utilized to determine the extent to which metabolic syndrome mediates the relationships among inadequate physical activity, prolonged sedentary behavior, and non-alcoholic fatty liver disease.

Regression analysis revealed that a reduced risk of developing NAFLD was associated with sufficient recreational activity (OR = 0.61, 95% CI: 0.44-0.83, P = 0.004), while an increased risk of MetS was observed in sedentary behavior group (OR = 1.28, 95% CI: 1.00-1.64, P < 0.05). In addition, strong associations were detected between MetS and NAFLD. Mediation analysis indicated that metabolic syndrome accounts for 17.9% of the influence that recreational activity has on the risk of NAFLD. Subgroup analysis indicated sex differences in these associations. Specifically, recreational activity may not significantly influence the risk of developing NAFLD in females, and the mediating role of MetS was no longer significant in both sex-specific subgroups.

In the general adult population, metabolic syndrome may account for nearly 18% of the association between insufficient recreational activity and non-alcoholic fatty liver disease.

In recent years, we have witnessed a sharp growth of metabolic dysfunction associated steatotic liver disease (MASLD). How to achieve early prevention of MASLD is imminent. We aimed to determine the dietary pattern and other factors influencing MASLD, to explore whether it mediated by serum uric acid (SUA) or not.

A total of 4,038 adults attending the Health Management Center of the Second Affiliated Hospital of Dalian Medical University between October 2018 and May 2019 were surveyed using a questionnaire and underwent physical measurements. Structural equation model (SEM) was used to verify the risk factors and determine the path affecting MASLD.

A total of 3,589 participants were studied. The standardized prevalence of MASLD was 47.8%. Three dietary patterns were identified using factor analysis. The SEM showed that SUA was positively associated with MASLD (standardization coefficient 0.285). In rank order, sex, SUA, dyslipidemia, age, a high-protein diet, and a fast-food diet were risk factors for MASLD. Sex, dyslipidemia, and a fast-food diet had positive and indirect effects on NAFLD through SUA, while age and a high-protein diet had negative and indirect effects on MAFLD through SUA.

SUA may be an important mediator of the risk of MASLD. People with abnormal SUA, especially men, should limit their intake of fried and cured foods and desserts; have their blood lipid profiles monitored carefully; appropriately increase their consumption of high-quality protein sources, such as eggs, milk, and beans; and be aware of their MASLD risk.

Liver-kidney-metabolic health (LKMH) depends on complex interactions between metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease (CKD), sex, and reproductive status. This study evaluates in a holistic manner how LKMH, sex, and menopause influence coronary artery calcification (CAC) burden.

Patients without previous cardiovascular disease were prospectively recruited. Liver fat was assessed via ultrasonography and categorized as mild or moderate-to-severe. CKD was classified using estimated glomerular filtration rate (eGFR). CAC burden was quantified as 0, 1-299, ≥ 300, single-vessel, or multivessel with coronary computed tomography. Stepwise backward multinomial logistic regression was applied for analysis.

A total of 446 patients (59.2% female, average age 52.9 years) were included. Moderate-to-severe MASLD was independently associated with an increased risk of CAC 1-299 [OR 2.30 (1.21-4.36)], CAC ≥ 300 [OR 4.93 (1.46-16.59)], and single-vessel CAC [OR 2.03 (1.03-4.00)]. Mild MASLD [OR 2.47 (1.20-4.21)], moderate-to-severe MASLD [OR 3.74 (1.76-7.93)], and CKD stage 2 [OR 2.27 (1.26-4.08)] were independently associated with increased multivessel CAC risk. Liver fat content showed a dose-response association with CAC burden. Subgroup analysis revealed that MASLD and CKD increased CAC risk in male but not female patients, with menopause significantly modifying LKMH's effect.

LKMH's impact on CAC burden is significantly influenced by liver fat content, eGFR, sex, and menopause, suggesting that MASLD, CKD, sex, and reproductive status should be integrated into CAC risk prediction models.

Males suffer more often from profibrotic changes in liver than females. The underlying mechanism for this sex difference in the prevalence and manifestation of Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) is not yet completely known. We studied male and female mice that were induced to develop MASLD by consuming a "fast food" diet (FFD) and assessed metabolic phenotype as well as liver histology and compared them with mice fed with a matched control diet (CD). Our aim was to check for sex-specific differences in MASLD development in a mouse model of diet-induced profibrotic changes in the liver. Our results demonstrate a clear difference in body weight, fat distribution and changes in liver tissue for male and female mice fed with FFD. We found that female mice stored lipids mainly in subcutaneous and visceral adipose tissue while males increased ectopic lipid accumulation in the liver which resulted in hepatomegaly and increased transforming growth factor β 1 (Tgfb1) and collagen I (Col1a1) expression concomitant to fibrosis development. This was absent in female mice. Analysis of estrogen receptor -α (Esr1) and -β (Esr2) expression revealed an upregulation of Esr2 in livers of male FFD-fed mice whereas in female liver tissue a higher expression in Esr1 could be observed. This study supports Esr1 and Esr2 as potential targets to reverse negative effects of diet-induced profibrotic changes in the liver.

The exact mechanisms of non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), remain unclear. However, oxidative stress is recognized as a factor across all stages of NAFLD. The Pro-oxidant Antioxidant Balance (PAB) method is an important clinical tool that provides an assessment of the balance between oxidants and antioxidant. We aimed to explore oxidative stress in NAFLD using the PAB method.

Individuals with NAFLD were recruited in 2021. Eligible participants underwent detailed assessments, including liver elastography for fibrosis evaluation. Blood samples (5 mL) were collected to measure serum PAB levels. The METAVIR score, derived from FibroScan measurements of liver stiffness, categorized fibrosis severity from F0 (no fibrosis) to F4 (advanced fibrosis or cirrhosis).

The study included 102 participants, with a mean age of 50.12 ± 10.03 years. Significant correlations were observed between FibroScan scores and variables such as age, body mass index (BMI), history of chronic diseases, and family history of NAFLD. PAB levels were notably higher in patients with advanced fibrosis (F2 and F3 groups: 86.32 ± 25.53) compared to those in early stages (F0 and F1 groups: 45.36 ± 21.29). Moreover, FibroScan scores showed a significant positive association with PAB values (odds ratio [OR]: 1.07; 95% confidence interval (CI): 1.04, 1.10), even after adjusting for confounding variables (OR: 1.13; 95% CI: 1.07, 1.18).

Elevated PAB levels were strongly associated with advanced stages of liver fibrosis in NAFLD patients, reflecting increased oxidative stress with disease progression. These results highlight the potential of PAB as a marker for monitoring oxidative stress and disease severity in NAFLD. Nevertheless, further large-scale studies are warranted.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising due to rapid lifestyle changes. Although females may be less prone to MASLD than males, specific studies on MASLD in females should still be conducted. Previous research has shown that sex hormone levels are strongly linked to MASLD in females. By reviewing a large number of experimental and clinical studies, we summarized the pathophysiological mechanisms of estrogen, androgen, sex hormone-binding globulin, follicle-stimulating hormone, and prolactin involved in the development of MASLD. We also analyzed the role of these hormones in female MASLD patients with polycystic ovarian syndrome or menopause, and explored the potential of targeting sex hormones for the treatment of MASLD. We hope this will provide a reference for further exploration of mechanisms and treatments for female MASLD from the perspective of sex hormones.

The goal of this study was to determine the role of histone deacetylase 9 (HDAC9) in the development of diet-induced metabolic dysfunction-associated steatohepatitis (MASH) and white adipose tissue (WAT) dysfunctions.

We fed male and female mice with global Hdac9 knockout (KO) and their wild-type (WT) littermates an obesogenic high-fat/high-sucrose/high-cholesterol (35%/34%/2%, w/w) diet for 20 weeks.

Hdac9 deletion markedly inhibited body weight gain and liver steatosis with lower liver weight and triglyceride content than WT in male mice but not females. Consistently, hepatic expression of genes crucial for de novo lipogenesis was markedly suppressed only in male, but not female, Hdac9 KO mice. However, Hdac9 deletion had a minimal effect on hepatic inflammation and fibrosis. In WAT, Hdac9 KO showed less adipocyte hypertrophy, inflammation, and fibrosis in male mice compared with WT. In addition, indirect calorimetry demonstrated that male Hdac9 KO mice had significantly higher metabolic rates, respiratory exchange ratios, and energy expenditure without altering physical activities than WT, which was not observed in female mice.

Our findings indicate that global deletion of Hdac9 prevented the development of obesity, hepatic steatosis, and WAT inflammation and fibrosis in male mice with diet-induced obesity and MASH, suggesting that a sex-dependent role of HDAC9 may exist in the pathways mentioned above.

Many studies have shown a link between physical activity (PA) and nonalcoholic fatty liver disease (NAFLD). However, more research is needed to investigate the relationship between different types of PA and NAFLD. This study aimed to explore the potential link between different types of PA, hepatic steatosis, and liver fibrosis.

A cross-sectional study was conducted using the data set from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. A multiple linear regression model was used to examine the linear relationship between different types of PA, the controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). In addition, smoothing curve fitting and threshold effect analysis were used to depict their nonlinear relationship.

This study involved 5933 adults. Multiple linear regression analysis revealed a significantly negative correlation between leisure-time PA and CAP, while the relationship between occupation-related PA, transportation-related PA, and CAP was not significant. Subgroup analysis further revealed that leisure-time PA was significantly negatively correlated with CAP in women and younger age groups (under 60 y old), while the relationship was not significant in men and older age groups. In addition, there was a significant negative correlation between leisure-time PA and liver fibrosis in men.

Leisure-time PA can prevent hepatic steatosis, and women and young people benefit more. Occupation-related PA is not associated with hepatic steatosis and cannot replace leisure-time PA. In men, increasing leisure-time PA is more effective in preventing liver fibrosis.

Over 30% of people worldwide suffer from metabolic dysfunction-associated steatotic liver disease (MASLD), a significant global health issue. Identifying and preventing high-risk individuals for MASLD early is crucial. The purpose of our study is to investigate the factors related to the development of MASLD and develop a risk prediction model for its occurrence.

The study included 5107 subjects, divided into training and validation groups in a 7:3 ratio using a random number table method. Collinearity diagnosis and Cox regression were used to identify factors associated with MASLD incidence, and a risk prediction model was created. The model's accuracy, reliability, and clinical applicability were assessed.

Our study indicated that male, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), serum uric acid to creatinine ratio (SUA/Cr) and white blood cell (WBC) were associated with MASLD incidence. The elements were determined to be crucial for creating a risk prediction model. The model showed strong discriminative potential with a C-index of 0.783 and the time-dependent AUCs of 0.781, 0.789, 0.814 and 0.796 for 1-4 years in the training group, and a C-index of 0.788 and the time-dependent AUCs of 0.798, 0.782, 0.787 and 0.825 for 1-4 years in validation. Calibration curves confirmed the model's accuracy, and decision curve analysis (DCA) validated its clinical utility.

The model may provide clinical physicians with a reliable method for identifying high-risk populations for MASLD and serve as a guide for developing prediction models for other diseases.

To assess the effects of testosterone (T)-based gender affirming hormone therapy (GAHT) on liver blood tests (LBTs) in assigned female at birth adults, using a meta-analytic approach.

Prospective and retrospective studies were selected that reported the prevalence of biochemical liver damage (BLD) and LBTs changes during T therapy. Data collected included pre-and-during therapy alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamyl-transferase (GGT), and alkaline phosphatase (ALP) mean concentration values.

The prevalence of BLD in 14 studies on 1698 subjects was 1% (95% CI 0.00-3.00; I2 = 14.1%; p = 0.82). In 17 studies on 2758 subjects, GAHT was associated with a statistically (but not clinically) significant increase in AST, GGT and ALP at 12 months and ALT at 3-7 (MD: 1.19 IU/l; 95% CI 0.31, 2.08; I2: 0%), at 12 (MD: 2.31 IU/l; 95% CI 1.41, 3.21; I2: 29%), but with no more significant increase at 24 months (MD: 1.71 IU/l; 95% CI -0.02, 3.44; I2: 0%).

Analysis of aggregate estimates confirms a low risk of BLD and abnormalities in LBTs, transient in most cases, during T-based GAHT, thus suggesting a limited need for careful liver monitoring in AFAB people.

This retrospective study aimed to investigate the role of an additional high mechanical index (MI) setting scan during the post-vascular phase (PVP) in detecting deep-seated hepatocellular carcinoma (HCC) lesions.

A total of 805 confirmed HCCs, which underwent Sonazoid-based contrast-enhanced ultrasound (CEUS) between January 2014 and October 2021, were included. Low MI scan was initially employed for lesion detection during the PVP, followed by high MI scan. Propensity score matching (PSM) was utilized to address confounding variables.

Of the 805 study lesions, 668 were detected as perfusion defects at the initial low MI setting, while 137 remained undetected. Among these 137 undetected lesions, 77 were identified at the subsequent high MI setting, whereas 60 remained undetected. Lesions that were larger (18.69 ± 11.27 mm vs. 16.55 ± 7.42 mm, p = 0.006), more superficial (6.06 ± 2.41 cm vs. 7.40 ± 2.74 cm, p < 0.001), and hypoechoic (482/668 vs. 62/137, p < 0.001) were detectable at the initial low MI setting. Male patients benefited more from the additional high MI scan (63/97 vs. 14/40, p < 0.001). Lesions identified with additional high MI were larger (18.30 ± 8.76 mm vs. 14.30 ± 4.34 mm, p < 0.001) and deeper than undetected ones (8.48 ± 2.48 cm vs. 6.02 ± 2.43 cm, p < 0.001). After PSM, depth was shown to be an independent predictor in multivariate analysis (odds ratio: 1.557, 95% confidence interval: 1.249-1.941). The depth cutoff was 7.75 cm, with a sensitivity of 0.681, specificity of 0.851, and area under the curve of 0.774.

The additional high MI setting scan during the PVP of Sonazoid-based CEUS leads to enhanced detection of deep-seated HCCs.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as the most common chronic liver disease, is soon to be the leading indication for liver transplantation; however, the diagnosis may remain occult for decades. There is a need for biomarkers that identify patients at risk for MASLD and patients at risk for disease progression to optimize patient management and outcomes. Lymph node adiposity (LNA) is a novel marker of adiposity identified within axillary lymph nodes on screening mammography. Recent studies have demonstrated a correlation between LNA and cardiometabolic disease and cardiovascular disease risk. This study aimed to investigate the association between MASLD and LNA to evaluate the potential of mammographic LNA to serve as an imaging biomarker of MASLD. Methods: We identified women with pathology-proven MASLD who had a liver biopsy and a screening mammogram within 12 months of the liver biopsy. This resulted in a sample size of 161 women for final analysis that met the inclusion criteria. We evaluated lymph node adiposity through multiple measurements of the largest axillary lymph node visualized on mammography and correlated LNA with MASLD histology. Statistical analysis using univariable and multivariable logistic regression and odds ratios was performed using R version 4.1.0 (2021), the R Foundation for Statistical Computing Platform. Results: We found a significant association between MASLD and mammographic LNA, defined as lymph node (LN) length > 16 mm (p = 0.0004) that remained significant after adjusting for clinical factors, including body mass index (BMI). We additionally found a significant association between LNA and metabolic dysfunction-associated steatohepatitis (MASH), identified via liver biopsy (p = 0.0048). Conclusions: Mammographic lymph node adiposity may serve as a helpful imaging biomarker of MASLD in women who have an elevated risk for the development of MASH.

This study aimed to investigate the association between Metabolic-dysfunction-associated steatotic liver disease(MASLD)and C-reactive protein/lymphocyte ratio (CLR).

MASLD was defined as a Controlled Attenuation Parameter (CAP ≥ 274dB/m) and CLR = C-reactive protein/lymphocyte. A multifactor linear regression model was used to test the relationship between MASLD and CLR. Smoothed curves and threshold effects analyses were fitted to describe nonlinear relationships. Subgroup analyses and interaction tests were then performed according to gender, prevalence of diabetes, ethnicity, and smoking status.

A total of 1846 participants from the NHANES database were included in this study. In the unadjusted model and model 1 (adjusted for age, sex, and race), CLR was positively associated with MASLD pathogenicity. Unadjusted model (OR = 1.04, 95% CI: 1.02-1.07, P = 0.0017), model 1 (OR = 1.04, 95% CI: 1.01-1.07, P = 0.0056). The results of the fitted smoothed curves showed that CLR and the risk of developing MASLD were nonlinear. Interaction tests and subgroup analyses confirmed that there were no significant interactions between CLR and MASLD causation with gender, race, prevalence of diabetes mellitus, and smoking status(P interaction>0.05).

This study shows that CLR is positively associated with the risk of developing MASLD Targeting CLR levels may be a new approach to treating MASLD.

As people with human immunodeficiency virus experience longer life expectancy, other causes of morbidity and mortality are being increasingly identified. The incidence of non-alcoholic fatty liver disease has recently been on the rise in Indonesia. People with human immunodeficiency virus on antiretroviral therapy are also at an increased risk of having non-alcoholic fatty liver disease. The study aimed to define the prevalence and factors associated with non-alcoholic fatty liver disease in people with human immunodeficiency virus on stable antiretroviral therapy.

A cross-sectional study of people with human immunodeficiency virus, on antiretroviral therapy, age younger than 18 years old, and without hepatitis co-infection was conducted at the human immunodeficiency virus Integrated Clinic Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Non-alcoholic fatty liver disease was diagnosed using transient elastography with associated controlled attenuation parameter examination (diagnostic cutoff: 238 db/m). A logistic regression test with Poisson regression was used to evaluate factors associated with non-alcoholic fatty liver disease.

One hundred and five people with human immunodeficiency virus were included, with a median age of 39 years and 65.7% were men. The prevalence of non-alcoholic fatty liver disease was 52.4%. Factors related to non-alcoholic fatty liver disease were hypertension (aPR: 1.49, 95% CI: 1.03-2.14, p = 0.033) and triglyceride levels (aPR: 1.001, 95% CI: 1.000-1.002, p = 0.024). No human immunodeficiency virus-specific variables were associated with non-alcoholic fatty liver disease.

More than half of Indonesian people with human immunodeficiency virus on antiretroviral therapy in this study were found to have non-alcoholic fatty liver disease. Hypertension and increased triglyceride levels were related to non-alcoholic fatty liver disease. Screening for non-alcoholic fatty liver disease should be implemented as a means of early intervention and to prevent complications.

Prevalence estimates are crucial for enhancing preparedness to prevent and manage chronic diseases. This is the first study to estimate the prevalence of hepatic steatosis and advanced fibrosis in Canada, leveraging a nationally representative survey and multiple validated non-invasive tests (NITs).

The Canadian Health Measures Survey (CHMS) is Canada's largest direct health measures survey, which collects data on sociodemographic, clinical factors, and blood chemistry. We determined steatosis using two NITs: the Hepatic Steatosis Index (HSI) and the NAFLD Ridge Score (NRS). The FIB-4 Index and NAFLD fibrosis score (NFS) were used to assess the risk of advanced fibrosis among adults with steatosis. Survey weights were incorporated to account for oversampling, survey nonresponse, and post-stratification.

Between 2009 and 2019, 1365 children (55 % males, median age 13 (IQR: 10-15) and 4664 adults (51 % males, median age 45 (IQR: 34-62), 57 % reporting weekly alcohol consumption) were included in our study. The weighted steatosis prevalence ranged from 9 to 11 % among children to 38-48 % among adults based on the NRS and HSI, respectively. Between 86-87 % of adults with type 2 diabetes and 65-72 % with hypertension had evidence of steatosis. Overall, 1.2-2.4 % of adults with steatosis were at risk of advanced liver fibrosis.

We estimate between 1 in 3 and 1 in 2 adults have hepatic steatosis, and 195,000-406,200 are at high risk of advanced liver fibrosis in Canada. No routine screening guidelines for liver fibrosis exist in Canada, and most patients are unaware of their condition. Prevalence studies are essential for raising awareness and advocating for the inclusion of steatotic liver disease on national public health agendas.

Metabolic dysfunction-associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post-LT setting of patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings.

This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1-year after LT.

In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16-46) and 26.0 (IQR: 16.8-41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0-5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post-LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8-80.4, p = .010) and post-LT dyslipidaemia (OR: 7.9, 95% CI: 1.3-47.1, p = .024) with LSM (OR: 1.7, 95% CI: 1.1-2.8, p = .030) was independently associated with MASLD.

Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.

The impact of dietary niacin on metabolic dysfunction-associated steatotic liver disease (MASLD) is elusive. This sub-study aimed to investigate the relationship between dietary niacin intake and the presence of MASLD in participants from two Catalonian cohorts.

A total of 222 subjects with MASLD were age- and sex-matched to 222 non-MASLD subjects. Dietary nutrients were analyzed using a validated food frequency questionnaire (FFQ). Dietary niacin and other nutrients were adjusted for total energy intake. MASLD was defined by a Fatty Liver Index (FLI) of >60 and by having at least one component of metabolic syndrome. The association between niacin intake (distributed into tertiles) and the presence of MASLD was assessed using multivariate logistic regression. Potential non-linear relationships were also analyzed through restricted cubic spline regression (RCS).

Our data revealed that subjects with MASLD had worse metabolic profiles. The dietary intake of niacin did not differ between subjects with and without MASLD. Even after adjusting for different confounding variables, i.e., sociodemographic variables, smoking status, physical activity, and cardiometabolic comorbidities, no significant associations were observed between higher intakes of niacin (tertiles 2 and 3) and the presence of MASLD: odds ratio (95% confidence) second tertile: 0.99 (0.89-1.09); third tertile: 0.98 (0.89-1.10). However, RCS analysis uncovered a significant non-linear dose-response association between dietary niacin intake and odds of MASLD. Specifically, such analysis revealed that MASLD risk was decreased in subjects with niacin intake values of <35 mg/day.

Our data showed that dietary niacin intake was associated with lower odds of MASLD in a Mediterranean population; however, our logistic regression analysis failed to reveal significant associations between the intake of niacin and the risk of MASLD. Further research is warranted to establish a causal relationship between dietary niacin interventions and MASLD.

Glucose metabolism status (GMS) is linked to non-alcoholic fatty liver disease (NAFLD). Higher levels of advanced glycation end products (AGEs) are observed in people with type 2 diabetes mellitus (T2DM) and NAFLD. We examined the association between GMS, non-invasive tests and AGEs, with liver steatosis and fibrosis.

Data from The Maastricht Study, a population-based cohort, were analysed. Participants with alcohol overconsumption or missing data were excluded. GMS was determined via an oral glucose tolerance test. AGEs, measured by skin autofluorescence (SAF), were assessed using an AGE Reader. Associations of GMS and SAF with the fibrosis-4 score (FIB-4), Forns index (FI) and fatty liver index (FLI) were investigated using multivariable linear regression, adjusted for sociodemographic, lifestyle and clinical variables.

1955 participants (56.6%) were analysed: 598 (30.6%) had T2DM, 264 (13.5%) had pre-diabetes and 1069 (54.7%) had normal glucose metabolism. Pre-diabetes was significantly associated with FLI (standardised regression coefficient (Stβ) 0.396, 95% CI 0.323 to 0.471) and FI (Stβ 0.145, 95% CI 0.059 to 0.232) but not FIB-4. T2DM was significantly associated with FLI (Stβ 0.623, 95% CI 0.552 to 0.694) and FI (Stβ 0.307, 95% CI 0.226 to 0.388) but not FIB-4. SAF was significantly associated with FLI (Stβ 0.083, 95% CI 0.036 to 0.129), FI (Stβ 0.106, 95% CI 0.069 to 0.143) and FIB-4 (Stβ 0.087, 95% CI 0.037 to 0.137).

The study showed that adverse GMS and higher glycaemia are positively associated with steatosis. FI, but not FIB-4, was related to adverse GMS concerning fibrosis. This study is the first to demonstrate that SAF is positively associated with steatosis and fibrosis.

The Weight-Adjusted Waist Index (WWI) is a novel indicator of obesity that accurately reflects body composition. However, the association between WWI and depression in patients with non-alcoholic fatty liver disease (NAFLD) remains unclear. This study aims to explore this relationship through a nationally representative cross-sectional analysis.

This study included adult participants diagnosed with NAFLD from NHANES 2017-2020. WWI was calculated as the waist circumference (cm) divided by the square root of body weight (kg). NAFLD diagnosis relied on vibration-controlled transient elastography (VCTE) with a controlled attenuation parameter (CAP) exceeding 248 dB/m to indicate hepatic steatosis. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9), with scores ≥ 10 indicating the presence of major depression.

After adjusting for all covariates, a significant positive association was found between WWI and depression in NAFLD (OR = 1.725, 95% CI: 1.442-2.063, p < 0.00001), with a dose-response relationship indicated by restricted cubic spline analysis. The association was stronger in men and lean/normal weight NAFLD patients. Adjusting further for BMI did not alter these findings (OR = 1.643, 95% CI: 1.357-1.989, p < 0.00001). BMI's association with depression was negated after adjusting for WWI.

WWI had a positive association with depression in NAFLD, independent of BMI. This association was more pronounced in men and lean/normal weight NAFLD. These findings suggest that WWI may be a novel indicator of depression in NAFLD and potentially valuable in depression prevention.

To explore any correlation between serum urate (SU) level or insulin resistance (IR) and metabolic dysfunction associated steatotic liver disease (MASLD) in patients with metabolic syndrome (MS).

Data from all MASLD patients, diagnosed by liver biopsy, were enrolled and divided into MASLD alone group and MASLD with MS group. They were subdivided into hyperuricemia group and normal SU group to find correlation between SU/IR and MASLD in patients with MS and independent risk factors for MASLD.

Data from 539 MASLD patients were analyzed. Body mass index (BMI) (p = 0.000), waist circumference (WC) (p = 0.004), and low-density lipoprotein (LDL) (p = 0.000) were dramatically higher in MASLD with MS group than those with MASLD alone; MASLD with MS patients had significantly more family history of diabetes (p = 0.000) and hypertension (p = 0.000) than patients with MASLD alone. Height (p = 0.000), weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.001), and LDL (p = 0.007) were dramatically higher in hyperuricemia patients than those with normal SU. SU was inversely associated with age (p = 0.000) and high-density lipoprotein (HDL) (p = 0.003), and positively correlated with weight (p = 0.000), BMI (p = 0.000) and WC (p = 0.000), TG (p = 0.000), and LDL (p = 0.000). Logistic Regression analysis showed that age (p = 0.031), TG (p = 0.002), LDL (p = 0.010), HbA1c (p = 0.026), and family history of hypertension (p = 0.000) may be independent risk factors for MASLD in patient with MS.

Insulin resistance (IR) in MASLD patients with MS, but not higher SU levels, has closer correlation with the occurrence of MASLD in patients with family history of hypertension and diabetes having higher BMI, LDL, HbA1c.

The relationship between dietary antioxidants and fatty liver disease remains a topic of debate. This study aimed to examine the association between the Composite Dietary Antioxidant Index (CDAI) and nonalcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD).

The study analyzed data from the 2003-2018 cycles of the National Health and Nutrition Examination Survey. The study included 16,321 individuals aged 20-85 years. Food and nutrient intake data were based on the 24-h recall method. Multivariate logistic regression models were employed to examine the relationship between CDAI and NAFLD/MAFLD.

In the fully adjusted multivariate logistic regression model, CDAI demonstrated a significant negative correlation with NAFLD and MAFLD. Mediation analysis showed that inflammatory factors partially mediated the relationship between CDAI and NAFLD/MAFLD prevalence. The combination of high CDAI levels with effective physical activity was associated with a greater reduction in NAFLD/MAFLD prevalence than high CDAI levels alone.

Our study highlighted a negative association between CDAI and NAFLD/MAFLD, mediated by inflammatory factors. Additionally, participants with characteristics of active physical activity and high levels of CDAI were more strongly correlated with the reduced prevalence of NAFLD/MAFLD. Further research in clinical cohorts should be conducted to comprehensively investigate the impact of CDAI on NAFLD/MAFLD prevalence.

Background/Objectives: Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) increases the risk of Type-2 Diabetes (T2DM). The Mediterranean diet (MD) has shown advantages in the management of MAFLD and preventing co-morbidities; however, its relationship with T2DM development in MAFLD has been less investigated. We aimed to evaluate the association of MD adherence with the risk of incident T2DM in the Spanish adult population with MAFLD and according to their weight gain at 7.5 years follow-up. Methods: A cohort of 714 participants (without weight increment: 377; with weight increment: 337) from the Di@bet.es cohort study with MAFLD and without T2DM at baseline were investigated. Anthropometric, sociodemographic, clinical data, and a survey on habits were recorded. OGTT and fasting blood biochemistry determinations were made. Baseline adherence to MD was estimated by the adapted 14-point MEDAS questionnaire and categorized as high and low adherence. Results: In total, 98 people developed T2DM at follow-up. The high adherence to MD was inversely associated with the development of T2DM in both the overall population (0.52 [0.31-0.87]) and subjects without weight gain at follow-up (0.35 [0.16-0.78]). Conclusions: Our results suggest the protective effect of high adherence to MD regarding the risk of T2DM in subjects with MAFLD, with this health benefit being more evident in men with the absence of weight gain. These results support the recommendations for MD use in these patients.

We have previously shown that body mass index attenuates a positive association of platelet count (PLT) and inverse of mean platelet volume (MPV) with lung cancer risk in men. It is unclear whether fat mass, lean mass, or liver function tests (LFTs) show similar attenuations. Using bioelectrical impedance measurements (UK Biobank cohort) and multivariable Cox proportional hazards models, we examined the associations of allometric fat-mass index (AFI, fat mass adjusted for height), allometric lean-mass index (ALI, fat-free mass adjusted for height and fat mass), and LFTs with lung cancer risk and their multiplicative and additive interactions with platelet parameters. Based on 1573 lung cancer cases in men and 1473 in women with body composition measurements (1541 in men; 1428 in women with biomarker measurements), AFI in women, ALI in both sexes, alanine aminotransferase (ALT) and total bilirubin in men were inversely associated, while gamma-glutamyl transferase in men and alkaline phosphatase in both sexes were positively associated with lung cancer risk. Only AFI and ALT interacted inversely with PLT and positively with MPV in men. The attenuation of the associations of platelet parameters with lung cancer risk by high-AFI and high-ALT in men suggests that adiposity-related factors hinder lung-cancer-related platelet associations.

Menopause, characterized by a sudden decline in estrogen levels, has significant effects on women's health, especially when it occurs early. This study aimed to investigate the associations between menopausal age and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) using a large cohort and a long-term follow-up.

Menopausal age was categorized into four groups (G1-4 [<40, 40-44, 45-49, and ≥50 years, respectively]). Cox proportional hazards regression analysis was used to assess the risk of developing MAFLD during the follow-up period according to the menopausal age categories.

A total of 1,888 participants were included in the final analysis and followed for a median period of 12.3 years. The unadjusted hazard ratios (95 % CIs) for the incidence of new-onset MAFLD were 1.11 (0.93-1.32), 1.15 (0.90-1.47), and 1.52 (1.12-2.07) in G3, G2, and G1, respectively, compared with that in G4. After adjusting for confounders, the hazard ratio (95 % CIs) for the incidence of new-onset MAFLD was 1.40 (1.00-1.95) in G1 compared with that in G4.

The risk of developing MAFLD was higher in women with premature menopause (<40 years) than in those with menopause aged ≥50 years.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. The increasingly sedentary lifestyle in recent years may have accelerated the development of NAFLD, independent of the level of physical activity.

The purpose of this cross-sectional study was to determine the association between leisure-time physical activity (LTPA) and time spent sitting (TSS) and the likelihood of developing NAFLD in a sample of men and women aged 18-64 years, from southern Italy.

The study is based on two cohort studies, a randomized clinical trial and an observational cost-benefit study.

A total of 1269 participants (51.5% women) drawn from 3992 eligible subjects were enrolled in this study.

Leisure-time physical activity (LTPA) and time spent sitting (TSS) were assessed using the Italian long form of the International Physical Activity Questionnaire (IPAQ-LF), designed for administration to adults aged 18 to 65 years.

The association of exposures with the probability of belonging to a certain NAFLD degree of severity.

The probability of having mild, moderate, and severe NAFLD tends to decrease with increasing LTPA and decreasing TSS levels. We selected a combination of participants aged 50 years and older stratified by gender. Men had a statistically significant difference in the probability of developing moderate NAFLD if they spent 70 h per week sitting and had low LTPA, while among women there was a statistically significant difference in the probability of developing mild or moderate NAFLD if they had moderate LPTA and spent 35-70 h/week sitting.

The study thus showed that the amount of LTPA and the amount of TSS are associated with development and progression of NAFLD, but this relationship is not a linear one-especially in women aged ≥ 50 years old.

Previous studies have demonstrated a significant association between serum vitamin A concentration and non-alcoholic fatty liver disease (NAFLD) development. However, the long-term prognostic implications of serum vitamin A in patients with NAFLD remain underexplored. This study aims to investigate whether there exists a correlation between serum vitamin A concentrations and overall mortality among subjects diagnosed with NAFLD.

To investigate the association between serum vitamin A concentrations and NAFLD outcomes, we conducted prospective cohort studies using data from the 1999-2006 and 2017-2018 National Health and Nutrition Examination Survey (NHANES). We utilized a multivariate Cox regression model to explore the relationship between serum vitamin A levels and all-cause mortality. Survival curves related to serum vitamin A were constructed using the Kaplan-Meier method. Additionally, the restricted cubic splines (RCS) method was applied to examine potential nonlinear relationships between serum vitamin A concentrations and all-cause mortality of NAFLD.

Over a median follow-up period of 10.3 years, a total of 1,399 all-cause deaths were recorded. The weighted average concentration of serum vitamin A was 61.48 ± 0.37 μg/dL. After adjusting for potential confounders, a significant U-shaped relationship was identified between serum vitamin A concentrations and the risk of all-cause mortality in NAFLD patients. This relationship was particularly pronounced in men and elderly individuals aged 60 to 85.

Our study reveals a significant non-linear relationship between serum vitamin A concentrations and the risk of all-cause mortality in patients with NAFLD. These findings underscore the importance of monitoring and maintaining optimal serum vitamin A levels to potentially improve survival outcomes in NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD) prevalence and severity may be higher in people with human immunodeficiency virus (HIV) than the general population, and vary with sex and age. We explored NAFLD characteristics by gender.

Adult transgender women (TW), cisgender women (CW), and cisgender men (CM) with HIV on antiretroviral therapy and without other known causes of liver disease underwent screening for NAFLD (2017-2020). Circulating factors associated with NAFLD were measured. Hepatic steatosis and fibrosis were assessed using transient elastography by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Analysis of variance/Wilcoxon testing compared normally/non-normally distributed variables, respectively. Logistic regression evaluated factors associated with CAP and LSM.

Participants (n=194) had median age 48 years and body mass index 28.3 kg/m2; 42% were CM, 37% TW, and 21% CW; 95% were non-white; and 16% had diabetes, 40% dyslipidemia, and 49% hypertension. NAFLD prevalence was 59% using CAP ≥248 dB/m (≥S1 steatosis), 48% using CAP ≥260 dB/m (≥S2 steatosis), and 32% using CAP ≥285 dB/m (≥S3 steatosis). Compared to CM and CW, TW had the highest median CAP scores, were more likely to have ≥S2 steatosis, and had the highest insulin resistance, interleukin-6, and fetuin-A values. TW off versus on gender-affirming hormone therapy (GAHT) had slightly higher median CAP scores.

TW on GAHT had less hepatic steatosis than TW not on GAHT, although overall NAFLD severity was greater than expected for TW compared to CM and CW. The effects of estrogen supplementation and androgen deprivation on liver health in TW require further study.

Previously published studies have shown that women with type 2 diabetes have a higher risk of atherosclerotic cardiovascular disease than men with type 2 diabetes. The exact reason for this is not yet known. The association between metabolic dysfunction-associated steatotic liver disease and type 2 diabetes appears to be bidirectional, meaning that the onset of one may increase the risk of the onset and progression of the other. Dyslipidemia is common in both diseases. Our aim was therefore to investigate whether there is a sex difference in the pathogenesis and management of dyslipidemia in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction. While the majority of published studies to date have found no difference between men and women in statin treatment, some studies have shown reduced effectiveness in women compared to men. Statin treatment is under-prescribed for both type 2 diabetics and patients with dysfunction-associated steatotic liver disease. No sex differences were found for ezetimibe treatment. However, to the best of our knowledge, no such study was found for fibrate treatment. Conflicting results on the efficacy of newer cholesterol-lowering PCSK9 inhibitors have been reported in women and men. Results from two real-world studies suggest that up-titration of statin dose improves the efficacy of PCSK9 inhibitors in women. Bempedoic acid treatment has been shown to be effective and safe in patients with type 2 diabetes and more effective in lipid lowering in women compared to men, based on phase 3 results published to date. Further research is needed to clarify whether the sex difference in dyslipidemia management shown in some studies plays a role in the risk of ASCVD in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction.

Nonalcoholic fatty liver disease (NAFLD) is a global health challenge, with a rising rate in line with other metabolic diseases. We aimed to assess the global prevalence of NAFLD in adult and pediatric populations.

PubMed, Scopus and Web of Science databases were systematically searched up to May 2023. Heterogeneity was assessed using Cochran's Q test and I2 statistics, and random-effects model was used for meta-analysis. Analyses were performed using STATA version 18.

A total of 479 studies with 78,001,755 participants from 38 countries were finally included. The global prevalence of NAFLD was estimated to be 30.2% (95% CI: 28.7-31.7%). Regionally, the prevalence of NAFLD was as follows: Asia 30.9% (95% CI: 29.2-32.6%), Australia 16.1% (95% CI: 9.0-24.8%), Europe 30.2% (95% CI: 25.6-35.0%), North America 29% (95% CI: 25.8-32.3%), and South America 34% (95% CI: 16.9-53.5%). Countries with a higher human development index (HDI) had significantly lower prevalence of NAFLD (coefficient = -0.523, p = 0.005). Globally, the prevalence of NAFLD in men and women was 36.6% (95% CI: 34.7-38.4%) and 25.5% (95% CI: 23.9-27.1%), respectively. The prevalence of NAFLD in adults, adults with obesity, children, and children with obesity was 30.2% (95% CI: 28.8-31.7%), 57.5% (95% CI: 43.6-70.9%), 14.3% (95% CI: 10.3-18.8%), and 38.0% (95% CI: 31.5-44.7%), respectively.

The prevalence of NAFLD is remarkably high, particularly in countries with lower HDI. This substantial prevalence in both adults and children underscores the need for disease management protocols to reduce the burden.

While sex-based differences in various health scenarios have been thoroughly acknowledged in the literature, we lack sufficient tools and methods that allow for an in-depth analysis of sex as a variable in biomedical research. To fill this knowledge gap, we created MetaFun as an easy-to-use web-based tool to meta-analyze multiple transcriptomic datasets with a sex-based perspective to gain major statistical power and biological soundness.

MetaFun is a complete suite that allows the analysis of transcriptomics data and the exploration of the results at all levels, performing single-dataset exploratory analysis, differential gene expression, gene set functional enrichment, and finally, combining results in a functional meta-analysis. Which biological processes, molecular functions or cellular components are altered in a common pattern in different transcriptomic studies when comparing male and female patients? This and other biological questions of interest can be answered with the use of MetaFun. This tool is available at https://bioinfo.cipf.es/metafun while additional help can be found at https://gitlab.com/ubb-cipf/metafunweb/-/wikis/Summary .

Overall, Metafun is the first open-access web-based tool to identify consensus biological functions across multiple transcriptomic datasets, helping to elucidate sex differences in numerous diseases. Its use will facilitate the generation of novel biological knowledge that can be used in the research and application of Personalized Medicine considering the sex of patients.

Sirtuins 1 (SIRT1) and Forkhead box protein O1 (FOXO1) expression have been associated with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Exercise and/or docosahexaenoic acid (DHA) supplementation have shown beneficial effects on MASLD. The current study aims to assess the relationships between Sirt1, Foxo1 mRNA levels and several MASLD biomarkers, as well as the effects of DHA-rich n-3 PUFA supplementation and/or exercise in the steatotic liver of aged obese female mice, and in peripheral blood mononuclear cells (PBMCs) of postmenopausal women with overweight/obesity. In the liver of 18-month-old mice, Sirt1 levels positively correlated with the expression of genes related to fatty acid oxidation, and negatively correlated with lipogenic and proinflammatory genes. Exercise (long-term treadmill training), especially when combined with DHA, upregulated hepatic Sirt1 mRNA levels. Liver Foxo1 mRNA levels positively associated with hepatic triglycerides (TG) content and the expression of lipogenic and pro-inflammatory genes, while negatively correlated with the lipolytic gene Hsl. In PBMCs of postmenopausal women with overweight/obesity, FOXO1 mRNA expression negatively correlated with the hepatic steatosis index (HSI) and the Zhejiang University index (ZJU). After 16-weeks of DHA-rich PUFA supplementation and/or progressive resistance training (RT), most groups exhibited reduced MASLD biomarkers and risk indexes accompanying with body fat mass reduction, but no significant changes were found between the intervention groups. However, in PBMCs n-3 supplementation upregulated FOXO1 expression, and the RT groups exhibited higher SIRT1 expression. In summary, SIRT1 and FOXO1 could be involved in the beneficial mechanisms of exercise and n-3 PUFA supplementation related to MASLD manifestation.