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Purpose: The causal relationship between life course adiposity with metabolic dysfunction-associated steatotic liver disease (MASLD) is ambiguous. We aimed to investigate whether there is an independent genetic causal relationship between body size at various life course and MASLD. Methods: We performed univariable and multivariable Mendelian randomization (MR) to estimate the causal effect of body size at different life stages on MASLD (i.e., defined by the clinical comprehensive diagnosis from the electronic health record [HER] codes [ICD9/ICD10] or diagnostic phrases), including birthweight, childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), body fat percentage (BFP). Results: In univariate analyses, higher genetically predicted lower birthweight (ORIVW = 0.61, 95%CI, 0.52 to 0.74), Childhood BMI (ORIVW = 1.37, 95%CI, 1.12 to 1.64), and adult BMI (ORIVW = 1.41, 95%CI, 1.27 to 1.57) was significantly associated with subsequent risk of MASLD after Bonferroni correction. The MVMR analysis demonstrated compelling proof that birthweight and adult BMI had a direct causal relationship with MASLD. However, after adjusting for birthweight and adult BMI, the direct causal relationship between childhood BMI and MASLD disappeared. Conclusion: For the first time, this MR elucidated new evidence for the effect of life course adiposity on MASLD risk, providing lower birthweight and duration of obesity are independent risk factors for MASLD. Our findings indicated that weight management during distinct time periods plays a significant role in the prevention and treatment of MASLD. [ABSTRACT FROM AUTHOR]

Background: The preservation of the Lingguizhugan (LGZG) decoction and patient compliance issue often limit the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, herein, an LGZG oral solution was developed for alleviating MASLD. Additionally, the potential mechanisms underlying LGZG-mediated MASLD mitigation were explored. Methods: A MASLDmousemodel was constructed using oleic and palmitic acid-induced LO2 cells and a high-fat diet. The apoptosis, lipid deposition, and mouse liver function were analyzed to assess the therapeutic effects of the LGZG oral solution on MASLD. Serum untargeted metabolomics, gut microbiota, bile acid (BA) metabolism, immunohistochemistry, and Western blotting analyses were performed to investigate the potentialmechanismof action of LGZG oral solution on MASLD. Results: The LGZG oral solution ameliorated lipid deposition, oxidative stress, inflammation, and pathological damage. Serumuntargetedmetabolomics results revealed the LGZG-mediated regulation of the primary BA biosynthetic pathway. The 16S ribosomal RNA sequencing of the fecal microbiota showed that LGZG oral solution increased the relative abundance of the BA metabolism-associated Bacteroides, Akkermansia, and decreased that of Lactobacillus. Additionally, the BA metabolism analysis results revealed a decrease in the total taurine-α/β-muricholic acid levels, whereas those of deoxycholic acid were increased, which activated specific receptors in the liver and ileum, including farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5). Activation of FXR resulted in an increase in short heterodimer partner and subsequent inhibition of cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, and activation of FXR also results in the upregulation of fibroblast growth factor 15/19 expression, and consequently inhibition of cholesterol 7α-hydroxylase, which correlated with hepatic BA synthesis and lipogenesis, ultimately attenuating lipid deposition and bile acid stasis, thereby improving MASLD. Conclusion: Altogether, the findings of this study suggest that modulating microbiota--BA--FXR/TGR5 signaling pathway may be a potential mechanism of action of LGZG oral solution for the treatment of MASLD. [ABSTRACT FROM AUTHOR]

Dietary fatty acids (FA) affect metabolic risk factors. The aim of this study was to explore if changes in dietary fat intake during energy restriction were associated with plasma FA composition. The study also investigated if these changes were associated with changes in liver fat, liver stiffness and plasma lipids among persons with non-alcoholic fatty liver disease. Dietary and plasma FA were investigated in patients with non-alcoholic fatty liver disease (n 48) previously enrolled in a 12-week-long open-label randomised controlled trial comparing two energy-restricted diets: a low-carbohydrate high-fat diet and intermittent fasting diet (5:2), to a control group. Self-reported 3 d food diaries were used for FA intake, and plasma FA composition was analysed using GC. Liver fat content and stiffness were measured by MRI and transient elastography. Changes in intake of total FA (r 0·41; P = 0·005), SFA (r 0·38; P = 0·011) and MUFA (r 0·42; P = 0·004) were associated with changes in liver stiffness. Changes in plasma SFA (r 0·32; P = 0·032) and C16 : 1 n -7 (r 0·33; P = 0·028) were positively associated with changes in liver fat, while total n -6 PUFA (r −0·33; P = 0·028) and C20 : 4 n -6 (r −0·42; P = 0·005) were inversely associated. Changes in dietary SFA, MUFA, cholesterol and C20:4 were positively associated with plasma total cholesterol and LDL-cholesterol. Modifying the composition of dietary fats during dietary interventions causes changes in the plasma FA profile in patients with non-alcoholic fatty liver disease. These changes are associated with changes in liver fat, stiffness, plasma cholesterol and TAG. Replacing SFA with PUFA may improve metabolic parameters in non-alcoholic fatty liver disease patients during weight loss treatment. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p < 0.00001] at 36–52 weeks as well as at 12–16 weeks [SMD − 30.92 (95% CI − 36.44 to − 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36–52 weeks [SMD − 36.05 (95% CI − 40.67 to − 31.43), p < 0.00001] and 12–16 weeks [SMD − 36.89 (95% CI − 40.73 to − 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD. [ABSTRACT FROM AUTHOR]

Given the global high prevalence of MASLD and its poor CVD prognosis, it is essential to perform risk stratification for MASLD patients. The specific impact of High Sensitivity Troponins (hs-cTn) on mortality in MASLD patients remains unexplored. The NHANES databases from 1999 to 2004, which include data on high-sensitivity cardiac troponin (hs-cTn) levels and comorbidities, were linked with the most recent mortality dataset. Myocardial injury was determined using the 99th upper reference limits (URL) for hs-cTn. Our study included 3460 MASLD patients. The mean follow-up duration was 192 months, during which 1074 (23%) MASLD participants died from all-cause mortality, and 363 (7.3%) died from CVD mortality. Our findings indicate that MASLD patients with elevated levels of hs-cTnT (> 99th URL) exhibit increased risks of all-cause mortality [adjusted hazard ratio (aHR) = 1.93] and CVD mortality (aHR = 2.4). Similar results were observed for hs-cTnI, where the aHRs for all-cause mortality and CVD mortality were 2.03 and 2.97, respectively. Furthermore, we identified a nonlinear dose-response relationship between hs-cTn levels and the risk of mortality (P for nonlinearity < 0.001). Our findings suggest that hs-cTn can predict mortality risk in MASLD, aiding clinicians in risk-stratifying this population. Therefore, we recommend considering hs-cTn detection in individuals with MASLD to effectively assess their future mortality risk. [ABSTRACT FROM AUTHOR]

Background: Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems. Main body of the manuscript: In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis. Conclusion: Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions. [ABSTRACT FROM AUTHOR]

About one-third of the global population suffers from metabolic dysfunctionassociated steatotic liver disease (MASLD), but specific treatments for MASLD have long been lacking, primarily due to the unclear etiology of the disease. In addition to lifestyle modifications and weight loss surgery, pharmacotherapy is the most common treatment among MASLD patients, and these drugs typically target the pathogenic factors of MASLD. However, bioavailability, efficacy, and side effects all limit the maximum therapeutic potential of the drugs. With the development of nanomedicine, recent years have seen attempts to combine MASLD pharmacotherapy with nanomaterials, such as liposomes, polymer nanoparticles, micelles, and cocrystals, which effectively improves the water solubility and targeting of the drugs, thereby enhancing therapeutic efficacy and reducing toxic side effects, offering new perspectives and futures for the treatment of MASLD. [ABSTRACT FROM AUTHOR]

Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients. [ABSTRACT FROM AUTHOR]

Background: Existing studies have presented limited and disparate findings on the nexus between immune cells, plasma metabolites, and metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to investigate the causal relationship between immune cells and MASLD. Additionally, we aimed to identify and quantify the potential mediating role of metabolites. Methods: A Mendelian randomization (MR) analysis was conducted using two samples of pooled data from genome-wide association studies on MASLD that included 2568 patients and 409,613 control individuals. Additionally, a mediated MR study was employed to quantify the metabolite-mediated immune cell effects on MASLD. Results: In this study, eight immunophenotypes were linked to the risk of MASLD, and thirty-five metabolites/metabolite ratios were linked to the occurrence of MASLD. Furthermore, a total of six combinations of immunophenotypic and metabolic factors demonstrated effects on the occurrence of MASLD, although the mediating effects of metabolites were not significant. Conclusion: Our study demonstrated that certain immunophenotypes and metabolite/metabolite ratios have independent causal relationships with MASLD. Furthermore, we identified specific metabolites/metabolite ratios that are associated with an increased risk of MASLD. However, their mediating role in the causal association between immunophenotypes and MASLD was not significant. It is important to consider immune and metabolic disorders among patients with MASLD in clinical practice. [ABSTRACT FROM AUTHOR]

Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether patients with metabolic dysfunctionassociated steatotic liver disease (MASLD) are allowed variable low levels of alcohol. This study aimed to evaluate the effect of mild-moderate alcohol consumption on the biochemical and histological characteristics of patients with MASLD. Methods: Alcohol consumption was assessed in 713 patients with steatotic liver disease (SLD) who underwent liver biopsy. Non-drinking, mild-moderate drinking, and excessive drinking were defined as 0 g/day, 1-<20 g/day, and >20 g/day for women and 0 g/day, 1-<30 g/day, and >30 g/day for men, respectively. Liver biopsies were scored according to the NASH CRN system. Results: A total of 713 participants (median age 39.0 years and 77.1% male) with biopsy-proven SLD were enrolled, including 239 nondrinkers, 269 mildmoderate drinkers and 205 excessive drinkers. Excessive drinking was associated with increased risks for lobular inflammation and liver fibrosis compared to nondrinkers and mild-moderate drinkers. Compared with nondrinkers, mild-moderate drinkers had significantly lower odds for steatosis (OR = 0.60, 95% CI = 0.38-0.93, p = 0.025), hepatocellular ballooning (OR = 0.52, 95% CI = 0.29-0.91, p = 0.020) and fibrosis (OR = 0.50, 95% CI = 0.31-0.81, p = 0.005). However, in non-excessive drinkers with type 2 diabetes mellitus (T2DM), there was no association between mild-moderate alcohol consumption and liver fibrosis (OR = 0.562, 95% CI = 0.207-1.530, p = 0.257). Conclusions: Mild-moderate alcohol consumption might be protective against liver fibrosis in MASLD patients, which is modified by the presence of T2DM. However, further longitudinal studies are needed to determine the effect of ongoing alcohol consumption on disease severity. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunctionassociated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

Sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Oxidative stress and inflammation are involved in the progression of MASLD. Thus, we aimed to evaluate liver redox homeostasis and inflammation in male and female rats fed a high-fat diet (HFD). Male and female Wistar rats were divided into the following groups: standard chow diet (SCD) or HFD during 12 weeks. HFD groups of both sexes had higher hepatocyte injury, with no differences between the sexes. Portal space liver inflammation was higher in females-HFD compared to females-SCD, whereas no differences were observed in males. Lobular inflammation and overall liver inflammation were higher in HFD groups, regardless of sex. TNF-α, IL-6, and IL-1β levels were higher in males-HFD compared to males-SCD, but no differences were observed in females. Catalase activity was higher in males compared to females, with no differences between the SCD and HFD groups of both sexes. Glutathione peroxidase activity was higher in females compared to males, with no differences between the SCD and HFD groups in both sexes. Lipid peroxidation was higher in female-SCD when compared to male-SCD, and in both male- and female-HFD compared to SCD groups. Furthermore, both cytoplasmic and nuclear NRF2 staining were lower in the HFD group compared to the SCD group in males. However, female-HFD exhibited reduced nuclear NRF2 staining compared to the female-SCD group. In conclusion, our study demonstrated that while both male and female rats developed metabolic dysfunction-associated steatohepatitis after 12 weeks of HFD, the alterations in inflammatory cytokines and redox balance were sexually dimorphic. [ABSTRACT FROM AUTHOR]

Extrahepatic malignancies are the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Of these cancers, pancreatic cancer is one of the most lethal; however, the link between NAFLD and pancreatic cancer remains unclear. Recently, various research results have been reported on the association between NAFLD and pancreatic cancer, and the results of compiling this information revealed the following. First, the prevalence of pancreatic cancer in patients with NAFLD is at 0.26%. Second, the currently evident pathogenesis includes intrapancreatic risk factors, such as: (1) non‐alcoholic fatty pancreas disease, and (2) intraductal papillary mucinous neoplasm; and extrapancreatic risk factors, such as: (1) insulin resistance and adipocytokines, (2) proinflammatory cytokines, and (3) dysbiosis. Finally, metformin and sodium–glucose cotransporter 2 inhibitors may reduce the risk of pancreatic cancer in diabetes patients with NAFLD. In this review, we summarize the recent evidence on the epidemiology and mechanisms for NAFLD‐related pancreatic cancer. We further discuss the impact of anti‐diabetic medication on pancreatic cancer. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate the prevalence of anxiety and depression traits in Italian patients with metabolic dysfunction-associated steatotic liver disease (MASLD), and the possible relation with the severity of liver disease. Methods: Demographic, anthropometric, clinical and laboratory parameters were collected in patients referred to a metabolic unit for a comprehensive evaluation of possible liver disease. Hepatic steatosis and fibrosis were evaluated by surrogate biomarkers. Imaging (controlled attenuation parameter-CAP and vibration-controlled transient elastography-VCTE). Beck depression inventory (BDI) and state-trait anxiety inventory-Y (STAI-Y) were used to define depressive/anxiety states; calorie intake and lifestyle were self-assessed by questionnaires. Results: The whole sample comprised 286 patients (61.9% females; mean age 52.0 years; BMI, 34.6 kg/m2); 223 fulfilled MASLD criteria. BDI and trait anxiety scores were lower in the MASLD cohort, and the prevalence of both moderate/severe depression and severe trait anxiety was reduced compared with non-MASLD cases, despite VCTE-diagnosed fibrosis F3–F4 present in over 15% of cases. However, after correction for demographic and anthropometric confounders, MASLD was not associated with a lower risk of moderate/severe depression or severe anxiety trait (odds ratio, 0.34; 95% confidence interval, 0.12–1.01 and 0.79, 0.27–2.34). Additional adjustment for the severity of fibrosis did not change the results. No differences in state anxiety were observed. Conclusion: The risk of anxiety and depression in MASLD is not different from that generated by diabetes and obesity per se. MASLD patients do not perceive liver disease as a specific source of psychological distress, possibly as a consequence of the unawareness of progressive liver disease. [ABSTRACT FROM AUTHOR]

Aim: To date, there are limited clinical studies and real‐world evidence investigating whether sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) are associated with improved hepatic steatosis. This study aimed to evaluate the effectiveness of SGLT2i compared with that of dipeptidyl peptidase‐4 inhibitors (DPP4i) in improving the fatty liver index (FLI) in patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: This retrospective cohort study included new users of SGLT2i or DPP4i with T2DM and MASLD from a large claims database (JMDC Claims Database). The primary outcome was the incidence of improvement of the FLI. Cox proportional hazard models, weighted using propensity scores for predicting the initiation of treatment, were fitted to estimate hazard ratios with 95% confidence intervals (CIs). Time‐course changes in the FLI values were also assessed. Results: This study included 9127 SGLT2i and 12 286 DPP4i initiators. SGLT2i showed a higher incidence of improvement in the FLI (≥30%, ≥40% and ≥50% reduction from baseline FLI) compared with DPP4i, and the weighted hazard ratios were 1.27 (95% CI 1.18‐1.38), 1.24 (95% CI 1.13‐1.37) and 1.19 (95% CI 1.05‐1.33), respectively. SGLT2i indicated a greater decreased in FLI values compared with DPP4i at up to 3 years of the follow‐up period. Conclusion: SGLT2is use appeared to be associated with a greater improvement of the FLI than DPP4i use in patients with T2DM and MASLD. In the absence of direct head‐to‐head comparisons from clinical studies, our study, using real‐world data, may support physicians' decision‐making in clinical practice. [ABSTRACT FROM AUTHOR]

Sodium glucose cotransporter inhibitor (SGLTi) drugs have been widely used in clinical practice. In addition to their benefits in hyperglycemia, heart failure (HF), and kidney disease, their effects on obesity, metabolic dysfunction‐associated steatotic liver disease (MASLD, formerly named nonalcoholic fatty liver disease [NAFLD]), polycystic ovarian syndrome (PCOS), abnormal lipid metabolism, hyperuricemia, obstructive sleep apnea syndrome (OSAS), anemia, and syndrome of inappropriate antidiuresis (SIAD, formerly named syndrome of inappropriate antidiuretic hormone [SIADH]) have been explored. In this review, we searched the data of clinical randomized controlled trials (RCTs) and meta‐analyses of SGLTis in patients with diabetes from the PubMed library between January 1, 2020, and February 1, 2024. According to our review, certain SGLTis exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can provide additional medication options for patients with different disease scenarios. However, studies of SGLTis in these diseases are relatively rare, with shortcomings such as small sample sizes and short intervention periods. Therefore, further large‐scale, long‐term, well‐designed studies are needed to clarify the findings. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with type 2 diabetes and a developing several cancers including esophageal cancer (EC). However, the association between MASLD and EC in diabetic patients has not been investigated. Therefore, we aimed to investigate the relation between MASLD and developing EC in diabetic patients. This was a population-based retrospective cohort study of data from the Korean National Health Insurance Service (NHIS). A total of 1,904,468 subjects diagnosed with diabetes who underwent NHIS-provided health checkups from 2009 to 2012 were included. We constructed a Cox proportional hazard model for the association of fatty liver index (FLI) and the risk of EC stratified by potential confounders. Over a mean follow-up duration of 6.9 years, the incidence of EC was higher in the high (≥60) FLI group compared to the low (<30) FLI group (14.4 vs. 13.7 event per 100,000 person-years). The risk of EC correlated with the degree of FLI, particularly in older (P =  0.002), female (P =  0.033), non-smoking (P =  0.002), and non-drinking patients (P =  0.025). Among obese patients, the risk of EC was not associated with FLI; however, the risk of EC was higher in the high FLI group in non-obese patients. Lean MASLD patients had the highest risk of EC (adjusted hazard ratio 1.78; 95% confidence interval, 1.5–2.13). MASLD was associated with an increased risk of EC in diabetic patients, and lean MASLD has the highest risk. Further studies are required to determine the causal relationship between MASLD and EC. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common paediatric liver disease. Latinos have high MASLD risk due to 50% prevalence of GG genotype of PNPLA3. Our primary aim was to evaluate associations between dietary carbohydrates/sugars and liver stiffness in Latino adolescents with obesity. Our secondary aim was to examine effect modification by (a) PNPLA3 genotype or (b) liver disease severity. Data were obtained from 114 Latino adolescents with obesity involved in two prior studies. No associations were seen between dietary carbohydrates/sugars and liver stiffness in the group as a whole. In subjects with GG genotype of PNPLA3, total sugar, fructose, sucrose, and glucose were associated with liver stiffness. Positive relationships between carbohydrate, total sugar, and sucrose and liver stiffness were stronger in those with MASLD and fibrosis compared to those with healthy livers and MASLD without fibrosis. [ABSTRACT FROM AUTHOR]

The World Federation for Ultrasound in Medicine and Biology (WFUMB) endorsed the development of this document on multiparametric ultrasound. Part 1 is an update to the WFUMB Liver Elastography Guidelines Update released in 2018 and provides new evidence on the role of ultrasound elastography in chronic liver disease. The recommendations in this update were made and graded using the Oxford classification, including level of evidence (LoE), grade of recommendation (GoR) and proportion of agreement (Oxford Centre for Evidence-Based Medicine [OCEBM] 2009). The guidelines are clinically oriented, and the role of shear wave elastography in both fibrosis staging and prognostication in different etiologies of liver disease is discussed, highlighting advantages and limitations. A comprehensive section is devoted to the assessment of portal hypertension, with specific recommendations for the interpretation of liver and spleen stiffness measurements in this setting. [ABSTRACT FROM AUTHOR]

Background: Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. Objective: To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. Method: In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Results: Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. Conclusion: These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. Trial registration: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043). [ABSTRACT FROM AUTHOR]

The recent renaming of 'non-alcoholic fatty liver disease' (NAFLD) to 'metabolic dysfunction-associated steatotic liver disease' (MASLD) emphasizes metabolic dysfunction in steatotic liver disease and advocates for tailored, comprehensive treatment strategies, driving forward the development of personalized care and innovative therapeutic approaches. [ABSTRACT FROM AUTHOR]

Steatotic liver escalates the risk of diverse cancers ranging from primary liver cancer to extrahepatic cancers and liver metastasis. Dysregulated hepatic lipid metabolism triggers hepatocyte damage and oxidative stress, resulting in steatotic liver-associated hepatocellular carcinoma. Extracellular vesicles, operating both locally and remotely, play a pivotal role in extrahepatic cancer development and liver metastasis in the context of steatotic liver. Steatotic liver remodels the tumor microenvironment, promoting tumor expansion through the involvement of M2 macrophages, and concurrently suppressing antitumor immunity. Recognizing steatotic liver as a cancer risk underscores the need for early detection, tailored management, and strategic interventions to improve patient outcomes. Steatotic liver, characterized by the accumulation of fat in the liver, poses significant health risks including metabolic dysfunction-associated steatotic liver disease (MASLD) and an elevated risk of primary liver cancer. Emerging evidence indicates a robust association between steatotic liver and increased susceptibility to extrahepatic primary cancers and their metastases. The deposition of fat induces dynamic changes in hepatic microenvironments, thereby fostering inflammation and immune responses that enhance liver metastasis from extrahepatic primary cancers. This review explores the impact of steatotic liver on hepatic carcinogenesis and metastasis from extrahepatic cancers, with a specific focus on hepatocyte-derived factors and the immune microenvironment. By emphasizing novel conclusions, this article underscores the timely relevance of understanding these intricate connections. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most widespread global chronic liver disease, affecting over 30% of adults. MASLD has effects beyond adverse liver outcomes, affecting cardiovascular disease, chronic kidney disease, and various extrahepatic cancers. The economic burden of MASLD is substantial, exceeding $100 billion in the USA alone, with liver transplantation being a significant contributor to healthcare costs. Regional variations in MASLD prevalence occur with the highest rates in Latin America and the Middle East, highlighting the need for culturally tailored interventions and a comprehensive global effort. Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease globally, affecting more than a third of the world's adult population. This comprehensive narrative review summarizes the global incidence and prevalence rates of MASLD and its related adverse hepatic and extrahepatic outcomes. We also discuss the substantial economic burden of MASLD on healthcare systems, thus further highlighting the urgent need for global efforts to tackle this common and burdensome liver condition. We emphasize the clinical relevance of early interventions and a holistic approach that includes public health strategies to reduce the global impact of MASLD. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs in subjects with obesity and metabolic syndrome. MASLD may progress from simple steatosis (i.e., hepatic steatosis) to steatohepatitis, characterized by inflammatory changes and liver cell damage, substantially increasing mortality. Lifestyle measures associated with weight loss and/or appropriate diet help reduce liver fat accumulation, thereby potentially limiting progression to steatohepatitis. As for diet, both total energy and macronutrient composition significantly influence the liver’s fat content. For example, the type of dietary fatty acids can affect the metabolism of lipids and hence their tissue accumulation, with saturated fatty acids having a greater ability to promote fat storage in the liver than polyunsaturated ones. In particular, polyunsaturated fatty acids of n -3 series (omega-3), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been intensively studied for their antisteatotic effects, both in preclinical animal models of obesity and hepatic steatosis and in overweight/obese patients. Their effects may depend not only on the dose and duration of administration of omega-3, or DHA/EPA ratio, but also on the lipid class used for their supplementation. This review summarizes the available evidence from recent comparative studies using omega-3 supplementation via different lipid classes. Albeit the evidence is mainly limited to preclinical studies, it suggests that phospholipids and possibly wax esters could provide greater efficacy against MASLD compared to traditional chemical forms of omega-3 supplementation (i.e., triacylglycerols, ethyl esters). This cannot be attributed solely to improved EPA and/or DHA bioavailability, but other mechanisms may be involved. [ABSTRACT FROM AUTHOR]

Metabolomics and lipidomics have emerged as tools in understanding the connections of metabolic syndrome (MetS) with cardiovascular diseases (CVD), type 1 and type 2 diabetes (T1D, T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review highlights the applications of these omics approaches in large-scale cohort studies, emphasizing their role in biomarker discovery and disease prediction. Integrating metabolomics and lipidomics has significantly advanced our understanding of MetS pathology by identifying unique metabolic signatures associated with disease progression. However, challenges such as standardizing analytical workflows, data interpretation, and biomarker validation remain critical for translating research findings into clinical practice. Future research should focus on optimizing these methodologies to enhance their clinical utility and address the global burden of MetS-related diseases. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3–4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

This study aimed to describe sonographic features of rectus femoris muscle (RFM) in patients with metabolic dysfunction-associated fatty liver disease (MASLD) and their correlation with body composition parameters and muscle strength. A total of 67 patients with MASLD underwent dual-energy X-ray absorptiometry (DEXA), bioimpedance analysis (BIA), muscle strength measurement (grip strength [GS] and chair stand test [CST]), and ultrasound (US) investigation of the RFM in the dominant thigh using a 4 to 18 MHz linear probe. MASLD patients exhibited increased RFM echogenicity, possibly due to fatty infiltration. We confirmed that the greater the subcutaneous fat thickness, the smaller was the muscle mass (p < 0.001), and the lower was the muscle strength (p < 0.001 for GS and p = 0.002 for CST). On the contrary, the greater the anteroposterior diameter (APD) of RFM, the higher was the muscle mass (p < 0.001), and the greater was the muscle strength (p < 0.001 for GS and p = 0.007 for CST). In addition, APD of the RFM and stiffness of RFM exhibited direct correlation with bone mineral density values of the lumbar spine (p = 0.005 for both GS and CST). We concluded that US investigation of the RFM in the dominant thigh can be helpful in identifying MASLD patients at a high risk of musculoskeletal disorders given repeated point-of-care clinical evaluations. [ABSTRACT FROM AUTHOR]

Background: Despite its high prevalence and impact on health, metabolic dysfunction-associated steatotic liver disease (MASLD) is inadequately addressed in European primary care (PC), with a large proportion of cases going undiagnosed or diagnosed too late. A multi-country European research consortium led a project to design and evaluate a patient-centered, integrated model for MASLD screening, diagnosis, and linkage to specialty care for European PC settings. Based on the lessons from this project, the latest research evidence, and existing guidelines for the management of MASLD, we sought to develop a set of practice recommendations for screening, referral, and management of MASLD in PC. Methods: The Rand/UCLA modified Delphi panel method, with two rounds, was used to reach consensus on practice recommendations. The international panel consisted of experts from six countries, representing family medicine, gastroenterology, hepatology, cardiology, and public health. Initially, fifteen statements were drafted based on a synthesis of evidence from the literature and earlier findings from our consortium. Prior to the consensus meeting, the statements were rated by the experts in the first round. Then, in a hybrid meeting, the experts discussed findings from round one, adjusted the statements, and reassessed the updated recommendations in a second round. Results: In round one, there was already a high level of consensus on 10 out of 15 statements. After round 2, there were fourteen statements with a high degree of agreement (>90%). One statement was not endorsed. The approved recommendations addressed the following practice areas: risk screening and diagnosis, management of MASLD–lifestyle interventions, pharmacological treatment of MASLD/MASH, pharmacological treatment for co-morbidity, integrated care, surgical management, and other referrals to specialists. Conclusions: The final set of 14 recommendations focuses on increasing comprehensive care for MASLD in PC. The recommendations provide practical evidence-based guidance tailored to PC practitioners. We expect that these recommendations will contribute to the ongoing discussion on systematic approaches to tackling MASLD and supporting European PC providers by integrating the latest evidence into practice. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (DM) are the most prevalent metabolic disorders globally. The numbers affected in both disorders are also rapidly increasing with alarming trends in children and young adults. Areas covered: Insulin resistance (IR) and the subsequent metabolic dysregulation are the fundamental pathogenesis pathways of the prevalent metabolic disorders. The interaction and impacts are bidirectional between MASLD and DM in terms of disease mechanisms, disease course, risks, and prognosis. There's a pressing issue for highlighting the links between MASLD and DM for both care specialists and primary care providers. The review collected the scientific evidence addressing the mutual interactions between the two disorders. The strategies for surveillance, risk stratification, and management are discussed in a practical manner. It also provides individualized viewpoints of patient care in hepatology and diabetology. Expert opinion: Both MASLD and DM shared similar disease mechanisms, and affected the disease development and progression in a bidirectional manner. The high prevalence and the cross-link between the two disorders raise clinical issues from awareness, screening, risk stratification, optimal referral, to appropriate management for primary care providers. [ABSTRACT FROM AUTHOR]

Background and Objectives: The trends in metabolic dysfunction-associated steatotic liver disease (MASLD) and related metabolic dysfunctions in Japan are unknown. Thus, we aimed to clarify these trends before the novel coronavirus disease 2019 pandemic in Japan. Materials and Methods: We included Japanese individuals aged 25–79 years who underwent health examinations at our center. We analyzed anthropometry, lifestyle-related disease, and nutritional intake in relation to MASLD trends from 2010–2019. Results: The prevalence of MASLD increased in all ages and body mass index (BMI) classes, reaching 30.3% in males and 16.1% in females, with MASLD accounting for 75% of steatotic liver cases and more than half of all type 2 diabetes mellitus (T2DM) and high waist circumference (HWC) cases. The increase in the prevalence of MASLD was thought to be largely attributable to an increase in that of the incidence of steatotic liver itself, and there was no increase in the prevalence of other factors, such as overweight, T2DM, hypertension, and dyslipidemia. The prevalence of glucose metabolic disorders (GMDs) and hypertension decreased. National nutritional data showed an increase in energy intake, total fat, saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids, which correlated with a decrease in GMDs. Salt intake also decreased, which correlated with hypertension. The MASLD group had a higher prevalence of all related metabolic factors than the non-MASLD group, especially HWC, T2DM, and hyperlipidemia. Conclusions: The prevalence of MASLD increased with that of steatotic liver, regardless of age or BMI. A relationship between increased dietary fat, increased steatotic liver, and decreased GMDs was suggested. [ABSTRACT FROM AUTHOR]

Context The presence of metabolic dysfunction–associated steatotic liver disease (MASLD) in patients with diabetes mellitus (DM) is associated with a high risk of cardiovascular disease, but is often underdiagnosed. Objective To develop machine learning (ML) models for risk assessment of MASLD occurrence in patients with DM. Methods Feature selection determined the discriminative parameters, utilized to classify DM patients as those with and without MASLD. The performance of the multiple logistic regression model was quantified by sensitivity, specificity, and percentage of correctly classified patients, and receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) assessed the model's net benefit for alternative treatments. Results We studied 2000 patients with DM (mean age 58.85 ± 17.37 years; 48% women). Eight parameters: age, body mass index, type of DM, alanine aminotransferase, aspartate aminotransferase, platelet count, hyperuricaemia, and treatment with metformin were identified as discriminative. The experiments for 1735 patients show that 744/991 (75.08%) and 586/744 (78.76%) patients with/without MASLD were correctly identified (sensitivity/specificity: 0.75/0.79). The area under ROC (AUC) was 0.84 (95% CI, 0.82-0.86), while DCA showed a higher clinical utility of the model, ranging from 30% to 84% threshold probability. Results for 265 test patients confirm the model's generalizability (sensitivity/specificity: 0.80/0.74; AUC: 0.81 [95% CI, 0.76-0.87]), whereas unsupervised clustering identified high-risk patients. Conclusion A ML approach demonstrated high performance in identifying MASLD in patients with DM. This approach may facilitate better risk stratification and cardiovascular risk prevention strategies for high-risk patients with DM at risk of MASLD. [ABSTRACT FROM AUTHOR]

Background: The relationship between Helicobacter pylori (H. pylori) infection and metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increased clinical attention. However, most of those current studies involve cross-sectional studies and meta-analyses, and experimental mechanistic exploration still needs to be improved. This study aimed to investigate the mechanisms by which H. pylori impacts MASLD. Methods: We established two H. pylori-infected (Cag A positive and Cag A negative) mouse models with 16 weeks of chow diet (CD) or high-fat diet (HFD) feeding. Body weight, liver triglyceride, blood glucose, serum biochemical parameters, inflammatory factors, and insulin resistance were measured, and histological analysis of liver tissues was performed. Mouse livers were subjected to transcriptome RNA sequencing analysis. Results: Although H. pylori infection could not significantly affect serum inflammatory factor levels and serum biochemical parameters in mice, serum insulin and homeostatic model assessment for insulin resistance levels increased in CD mode. In contrast, H. pylori Cag A + infection significantly aggravated hepatic pathological steatosis induced by HFD and elevated serum inflammatory factors and lipid metabolism parameters. Hepatic transcriptomic analysis in the CD groups revealed 767 differentially expressed genes (DEGs) in the H. pylori Cag A + infected group and 1473 DEGs in the H. pylori Cag A- infected group, and the "nonalcoholic fatty liver disease" pathway was significantly enriched in KEGG analysis. There were 578 DEGs in H. pylori Cag A + infection combined with the HFD feeding group and 820 DEGs in the H. pylori Cag A- infected group. DEGs in the HFD groups were significantly enriched in "fatty acid degradation" and "PPAR pathway." Exploring the effect of different Cag A statuses on mouse liver revealed that fatty acid binding protein 5 was differentially expressed in Cag A- H. pylori. DEG enrichment pathways were concentrated in the "PPAR pathway" and "fatty acid degradation." Conclusions: Clinicians are expected to comprehend the impact of H. pylori on MASLD and better understand and manage MASLD. H. pylori infection may exacerbate the development of MASLD by regulating hepatic lipid metabolism, and the H. pylori virulence factor Cag A plays a vital role in this regulation. [ABSTRACT FROM AUTHOR]

Background and aims: In recent years, the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and colorectal cancer (CRC) or colorectal adenoma (CRA) has gained widespread attention. Previous meta-analyses on this subject either incorporated numerous cross-sectional studies, which were susceptible to bias, or concentrated solely on a restricted number of cohort studies. Moreover, with the release of a substantial number of high-quality cohort studies on this subject in the past two years, the findings continue to be debated and contradictory. Therefore, we conducted an updated systematic review and meta-analysis of cohort studies to quantitatively evaluate the magnitude of the association between them. Methods: Comprehensive searches of PubMed, Web of Science, and Embase were conducted without language restrictions from the time of their creation up to December, 2023. The pooled hazard ratios (HRs) with 95% confidence interval (CIs) were calculated by the generic inverse variance based on the random-effects model. Moreover, subgroup and sensitivity analyses were performed. Results: A total of 15 cohort studies were analyzed in this meta-analysis, which included 9,958,412 participants. The meta-analysis of 13 cohort studies showed that MASLD was linked to a higher risk of CRC (HR=1.25, 95% CI: 1.15-1.36, P < 0.00001). Additionally, further subgroup analysis indicated that the combined HR remained consistent regardless of the study location, nomenclature of fatty liver disease (FLD), confirmation methods for FLD, sample size, follow-up time, and study quality. Furthermore, the meta-analysis of four cohort studies demonstrated that MASLD was correlated with an increased risk of CRA (HR=1.38, 95% CI: 1.17-1.64, P = 0.0002). The sensitivity analysis results further validated the robustness of the aboved findings. Conclusion: The results of our meta-analysis indicated that MASLD was associated with an increased risk of incident CRC/CRA. In the future, it is necessary to conduct more prospective cohort studies to thoroughly assess potential confounding factors, particularly in individuals from Europe and North America. Furthermore, related mechanism studies should be conducted to enhance our understanding of the link between MASLD and CRC/CRA. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease, impacts 30% of the global population. This educational pilot focused on the role primary care providers may play in the delivery of guidelines-based metabolic dysfunction-associated steatohepatitis (MASH) care. Objective: Accelerate the application of guidelines-based MASH care pathways to clinical workflows. Methods: A panel of six hepatologists was convened in 2021 to develop the care pathway and the subsequent pilot occurred between 2022 – 2023. The pilot was conducted across three U.S. health systems: Boston Medical Center (Boston), Methodist Health System (Dallas), and Weill Cornell Medicine (New York). Clinicians were educated on the care pathway and completed baseline/follow-up assessments. 19 primary care clinicians participated in the educational pilot baseline assessment, nine primary care clinicians completed the two-month assessment, and 15 primary care clinicians completed the four-month assessment. The primary endpoint was to assess clinician-reported adherence to and satisfaction with the care pathway. The pilot was deemed exempt by the Western Consensus Group Institutional Review Board. Results: At baseline, 38.10% (n = 8) of respondents felt they had received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and 42.86% (n = 9) had not referred any patients suspected of metabolic dysfunction-associated liver disease to hepatology within a month. At four months post-intervention, 79% (n = 15) of respondents agreed or strongly agreed they received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and there was a 25.7% increase in self-reported adherence to the institution's referral guidelines. Barriers to care pathway adherence included burden of manually calculating fibrosis-4 scores and difficulty ordering non-invasive diagnostics. Conclusions: With therapeutics anticipated to enter the market this year, health systems leadership must consider opportunities to streamline the identification, referral, and management of patients with metabolic dysfunction-associated steatohepatitis. Electronic integration of metabolic dysfunction-associated steatohepatitis care pathways may address implementation challenges. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) significantly impacts renal and hepatic function, necessitating comprehensive understanding and management strategies. Renal involvement, namely diabetic kidney disease (DKD), presents a global challenge, with increasing prevalence paralleling DM rates. Lifestyle modifications and pharmacotherapy targeting hypertension and glycemic control have pivotal roles in DKD management. Concurrently, hepatic involvement in DM, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD), presents a bidirectional relationship. DM exacerbates MASLD progression, while MASLD predisposes to DM development and worsens glycemic control. Screening for MASLD in DM patients is of high importance, utilizing non-invasive methods like ultrasound and fibrosis scores. Lifestyle modifications, such as weight loss and a Mediterranean diet, mitigate MASLD progression. Promising pharmacotherapies, like SGLT2 inhibitors and GLP-1 agonists, demonstrate efficacy in both DM and MASLD management. Special populations, such as diabetic individuals undergoing hemodialysis or kidney transplant recipients, demand special care due to unique clinical features. Similarly, DM exacerbates complications in MASLD patients, elevating the risks of hepatic decompensation and hepatocellular carcinoma. Recognizing the interconnectedness of DM, renal, and hepatic diseases underscores the need for multidisciplinary approaches for optimal patient outcomes. The present review aims to present the main characteristics and crucial points not to be overlooked regarding the renal and hepatic involvement in DM patients focusing on the inter-relationships between the renal and the hepatic involvements. [ABSTRACT FROM AUTHOR]

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction‐associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH‐associated hepatocellular carcinoma (MASH‐HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA‐16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD‐HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH‐HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH‐fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver. [ABSTRACT FROM AUTHOR]

While many studies have explored dietary substitutes and mobile apps separately, a combined approach to metabolic dysfunction-associated steatotic liver disease (MASLD) has not been investigated. This study evaluated short-term mobile interventions coupled with partial meal replacement in patients with MASLD. Sixty adults with MASLD and a body mass index ≥25 kg/m2 from a health examination center were randomized into an intervention group using a mobile app with partial meal replacements or a control group receiving standard educational materials. Liver enzyme levels, lipid profiles, and anthropometric measurements were assessed at baseline and after 4 weeks. Twenty-five participants in the intervention group and 24 in the control group completed the trial. Significant reductions were observed in the intervention group for alanine aminotransferase (−28.32 versus [vs.] −10.67, p = 0.006) and gamma-glutamyl transferase (−27.76 vs. 2.79, p = 0.014). No significant changes in aspartate aminotransferase, body weight, or waist circumference were noted in the intervention group. Four weeks of mobile lifestyle intervention incorporating partial meal replacements improved liver enzyme profiles in patients with MASLD. This strategy demonstrated the potential for mitigating elevated liver enzyme levels without altering body weight or waist circumference. Comprehensive and longer-term research is needed to substantiate and elaborate these preliminary outcomes. [ABSTRACT FROM AUTHOR]

Background: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. Methods: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan–Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. Results: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54–3.90) for severe liver disease (SLD), and 2.81 (2.60–3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. Conclusions: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management. [ABSTRACT FROM AUTHOR]

Affecting approximately 25% of the global population, steatotic liver disease (SLD) poses a significant health concern. SLD ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis and fibrosis with a risk of severe liver complications such as cirrhosis and hepatocellular carcinoma. SLD is associated with obesity, atherogenic dyslipidaemia, and insulin resistance, increasing cardiovascular risks. As such, identifying SLD is vital for cardiovascular disease (CVD) prevention and treatment. Bile acids (BAs) have critical roles in lipid digestion and are signalling molecules regulating glucose and lipid metabolism and influencing gut microbiota balance. BAs have been identified as critical mediators in cardiovascular health, influencing vascular tone, cholesterol homeostasis, and inflammatory responses. The cardio-protective or harmful effects of BAs depend on their concentration and composition in circulation. The effects of certain BAs occur through the activation of a group of receptors, which reduce atherosclerosis and modulate cardiac functions. Thus, manipulating BA receptors could offer new avenues for treating not only liver diseases but also CVDs linked to metabolic dysfunctions. In conclusion, this review discusses the intricate interplay between BAs, metabolic pathways, and hepatic and extrahepatic diseases. We also highlight the necessity for further research to improve our understanding of how modifying BA characteristics affects or ameliorates disease. [ABSTRACT FROM AUTHOR]

Background: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited. Methods: We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD. Results: The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11–2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, p = 0.011). Conclusions: The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12. [ABSTRACT FROM AUTHOR]

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi‐stakeholder, multi‐specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non‐invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting. [ABSTRACT FROM AUTHOR]

Background: Recent observational studies examining the association between Helicobacter pylori infection and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) have reported conflicting results. We performed a metaanalysis to quantify the magnitude of the association between H. pylori infection and the risk of MASLD. Methods: We systematically searched three large electronic databases to identify eligible observational studies (published up to 30 November 2023) in which liver biopsy, imaging methods or blood-based biomarkers/scores were used for diagnosing MASLD. Data from selected studies were extracted, and meta-analysis was performed using common and random-effects modelling. Statistical heterogeneity among published studies, subgroup analyses, meta-regression analyses and publication bias were assessed. Results: A total of 28 observational studies (24 cross-sectional and 4 longitudinal studies) were identified, including 231291 middle-aged individuals of predominantly Asian ethnicity (~95%). Meta-analysis of cross-sectional studies showed that H. pylori infection was significantly associated with a small increase in the risk of prevalent MASLD (n = 24 studies; random-effects odds ratio 1.11, 95% CI 1.05-1.18; I² = 63%). Meta-analysis of data from longitudinal studies showed that H. pylori infection was significantly associated with an increased risk of developing incident MASLD over a mean 5-year follow-up (n=4 studies; random-effects odds ratio 1.20, 95%CI 1.081.33; I² = 44%). Sensitivity analyses did not modify these results. The funnel plot did not reveal any significant publication bias. Conclusions: H. pylori infection is associated with a mildly increased risk of prevalent and incident MASLD. Further well-designed prospective and mechanistic studies are required to better decipher the complex link between H. pylori infection and the risk of MASLD. [ABSTRACT FROM AUTHOR]

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Coffee consumption is globally widespread and has become a lifestyle habit. This study investigated coffee consumption and liver-related survival in a large cohort of 455,870 individuals with UK biobank, categorized into without steatosis, metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD and increased alcohol intake (MetALD). Inverse probability of treatment weighting (IPTW) adjusted for confounding variables was used, followed by Kaplan-Meier analysis. Moderate coffee consumption (1-2 cups per day) was associated with lower all-cause mortality across the entire cohort, without the steatosis, MASLD (p < 0.0001), and MetALD cohorts (p = 0.0047 for pre-IPTW, p = 0.027 for post-IPTW). Before IPTW adjustment, consuming one or more cups of coffee per day appeared to significantly reduce liver-related mortality in the overall (p = 0.015) and MASLD cohorts (p = 0.011). However, post-IPTW application, no significant differences in liver-related mortality were observed between the coffee intake groups (p = 0.778, 0.319, 0.564, 0.238 for each group). While increased coffee consumption initially seemed to reduce liver-related mortality, after IPTW adjustment, only all-cause mortality significantly decreased (p < 0.0001 and p = 0.027). These findings suggest that previous studies might have overestimated the favorable effect of coffee intake on chronic liver disease due to confounding factors. [ABSTRACT FROM AUTHOR]

Globally, metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), is one of the most common liver disorders and is strongly associated with copper deficiency. To explore the potential effects and mechanisms of Lactiplantibacillus plantarum LPJZ-658, copper deficiency combined with a high-sugar diet-induced MASLD mouse model was utilized in this study. We fed 40-week-old (middle-aged) male C57BL/6 mice a copper-deficient and high-sugar diet for 16 weeks (CuDS), with supplementary LPJZ-658 for the last 6 weeks (CuDS + LPJZ-658). In this study, we measured body weight, liver weight, and serum biochemical markers. Lipid accumulation, histology, lipidomics, and sphingolipid metabolism-related enzyme expression were investigated to analyze liver function. Untargeted metabolomics was used to analyze the serum and the composition and abundance of intestinal flora. In addition, the correlation between differential liver lipid profiles, serum metabolites, and gut flora at the genus level was measured. The results show that LPJZ-658 significantly improves abnormal liver function and hepatic steatosis. The lipidomics analyses and metabolic pathway analysis identified sphingolipid, retinol, and glycerophospholipid metabolism as the most relevant metabolic pathways that characterized liver lipid dysregulation in the CuDS group. Consistently, RT-qPCR analyses revealed that the enzymes catalyzing sphingolipid metabolism that were significantly upregulated in the CuDS group were downregulated by the LPJZ-658 treatment. In addition, the serum metabolomics results indicated that the linoleic acid, taurine and hypotaurine, and ascorbate and aldarate metabolism pathways were associated with CuDS-induced MASLD. Notably, we found that treatment with LPJZ-658 partially reversed the changes in the differential serum metabolites. Finally, LPJZ-658 effectively regulated intestinal flora abnormalities and was significantly correlated with differential hepatic lipid species and serum metabolites. In conclusion, we elucidated the function and potential mechanisms of LPJZ-658 in alleviating copper deficiency combined with sugar-induced middle-aged MASLD and hope this will provide possible treatment strategies for improving MASLD. [ABSTRACT FROM AUTHOR]

Background/Aim: To examine the relationship between the body surface area (BSA) and body composition in patients with metabolic dysfunction-associated steatotic liver disease (MASLD, 2,141 men and 986 women). Materials and Methods: BSA and body composition parameters were examined. Results: The median body mass index (BMI) was 25.0 kg/m² for both men and women (p=0.7754). The median body surface area (BSA) was 1.854 m² for men and 1.618 m² for women (p<0.0001). In men, the median fat mass was 17.7 kg, whereas in women, it was 22.1 kg (p<0.0001). Additionally, the median fat-free mass was 55.4 kg in men and 39.3 kg in women (p<0.0001).). In male cases, BSA significantly correlated with fat mass (r=0.82, p<0.0001) and fat-free mass (r=0.95, p<0.0001). In female cases, BSA significantly correlated with fat mass (r=0.87, p<0.0001) and fat-free mass (r=0.94, p<0.0001). Conclusion: BSA could be a useful marker for the estimation of body composition in patients with MASLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). The introduction of this new terminology has sparked a debate about the interchangeability of these terms. The pathogenesis of NAFLD/MASLD is thought to be multifactorial, involving both genetic and environmental factors. Among these factors, alterations in gut microbiota and gut dysbiosis have recently garnered significant attention. In this context, this review will further discuss the gut–liver axis, which refers to the bidirectional interaction between the human gut microbiota and the liver. Additionally, the therapeutic potential of probiotics, particularly next-generation probiotics and genetically engineered bacteria, will be explored. Moreover, the role of prebiotics, synbiotics, postbiotics, and phages as well as fecal microbiota transplantation will be analyzed. Particularly for lean patients with NAFLD/MASLD, who have limited treatment options, approaches that modify the diversity and composition of the gut microbiota may hold promise. However, due to ongoing safety concerns with approaches that modulate gut microbiota, further large-scale studies are necessary to better assess their efficacy and safety in treating NAFLD/MASLD. [ABSTRACT FROM AUTHOR]

Purpose: There is a strong association between metabolic dysfunction–associated steatotic liver disease (MASLD) and obesity which are both important risk factors for cardiovascular diseases (CVDs). The current study aimed to assess the association of MBS with different CVDs in patients with MASLD. Materials and Methods: The National Inpatient Sample (NIS) database from 2016 to 2020 were analyzed by using ICD-10 codes. A propensity score matching in a 1:1 ratio was done to match the MBS and non-MBS groups. Results: After weighted analysis, 1,124,155 and 68,215 patients were included in non-MBS and MBS groups, respectively. MBS was associated with significantly lower risk of hospitalization for coronary artery disease (OR 0.633 (0.569–0.703), p value < 0.001), acute myocardial infarction (OR 0.606 (0.523–0.701), p value < 0.001), percutaneous coronary intervention (OR 0.578 (0.489–0.682), p value < 0.001), and thrombolysis (OR 0.765 (0.589–0.993), p value = 0.044) compared to the non-MBS group in patients with MASLD. Furthermore, MBS was associated with 52% reduced risk of hospitalization for hemorrhagic stroke in patients with MASLD (OR 0.481, 95% CI 0.337–0.686, p value < 0.001). However, ischemic stroke was not significant between the two groups (OR 1.108 (0.905–1.356), p value = 0.322). In addition, MBS was associated with 63% and 60% reduced risk of hospitalization for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) in patients with MASLD (OR 0.373, 95% CI 0.300–0.465 and OR 0.405, 95% CI 0.325–0.504, p value < 0.001 for both), respectively. Conclusion: The current study showed that MBS is significantly associated with a reduced risk of hospitalization for CVD in patients with MASLD. [ABSTRACT FROM AUTHOR]

Context Metabolic dysfunction–associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development. Objective To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors. Methods This was a case–control study in patients with obesity undergoing bariatric surgery at a university hospital between January 2020 and December 2021. Participants were distributed in 3 groups: no MASLD (n = 26), steatotic liver disease (n = 33), and metabolic dysfunction–associated steatohepatitis (n = 32). Hepatic and serum FA levels were determined by gas chromatography-mass spectrometry. Nutritional status was evaluated using validated food frequency questionnaires. The hepatic expression of genes involved in FA metabolism was analyzed by reverse transcription quantitative polymerase chain reaction. Results The hepatic, but not serum, FA profiles were significantly altered in patients with MASLD compared with those without MASLD. No differences were observed in FA intake between the groups. Levels of C16:0, C18:1, and the C18:1/C18:0 ratio were higher, while C18:0 levels and C18:0/C16:0 ratio were lower in patients with MASLD, being significantly different between the 3 groups. Hepatic FA levels and ratios correlated with histopathological diagnosis and other MASLD-related parameters. The expression of genes involved in the FA metabolism was upregulated in patients with MASLD. Conclusion Alterations in hepatic FA levels in MASLD patients were due to enhancement of de novo lipogenesis in the liver. [ABSTRACT FROM AUTHOR]