The natural course of metabolic dysfunction-associated steatotic liver disease (MASLD) in the population with metabolically healthy obesity (MHO) has not been adequately explored. In the present narrative review, we summarize the evidence regarding the association between MHO and MASLD prevalence, incidence and progression.

Cross-sectional, population-based, cohort studies have shown an increased prevalence of hepatic steatosis and fibrosis in subjects with MHO compared with metabolically healthy non-obese individuals (MHNO). In large-scale longitudinal cohort studies among metabolically healthy subjects, increasing body mass index (BMI) has been found to be independently associated with an increased incidence of MASLD and progressive hepatic fibrosis over a mean follow-up period of 2.2-7.7 years. With regard to advanced MASLD, the prevalence of steatohepatitis and clinically significant liver fibrosis is lower in MHO compared with subjects with metabolically unhealthy obesity (MUO). The presence of MASLD has been proposed as a strong risk factor for metabolic health deterioration in MHO. Furthermore, subjects with MHO and MASLD display an elevated 10-year cardiovascular risk and a three-fold increased risk of incident diabetes compared with MHO without MASLD. MASLD may also predict the failure to convert from MUO to MHO after a weight loss intervention.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a prevalent liver condition in children and teenagers with obesity. Unfortunately, there is no standardized treatment.

To examine the connection between apolipoprotein B (apoB), apolipoprotein A1 (apoA1), and the apoB/apoA1 ratio with the occurrence of MASLD in this population.

A retrospective study was made on children and adolescents with obesity in a children's hospital between the period 2020 and 2022. Anthropometric data, ultrasound results, and blood biochemistry were analysed to assess the connection between apoB, apoA1, and the presence of MASLD.

Of the 916 participants included, 313 were diagnosed with MASLD. The level of serum apoB reflected a substantial dose-response correlation with the odds of having MASLD. When apoB levels exceeded the 50th percentile, the risk increased significantly, and at the 95th percentile, the odds were 4.83 times higher than at the 50th percentile (95% CI: 2.02-11.56). The ratio of apoB/apoA1 at the 95th percentile was connected to a 2.41-fold higher prevalence compared to the 50th percentile (95% CI: 1.33-4.37). No significant correlation was found between the levels of apoA1 and MASLD prevalence.

Elevated levels of apoB and the apoB/apoA1 ratio have been strongly connected to increased MASLD prevalence in children and adolescents with obesity; hence, signifying their potential usefulness as biomarkers for early detection and intervention.

Objective: Our study aims to develop a personalized nomogram model for predicting the risk of nonalcoholic fatty liver disease (NAFLD) in hypertension (HTN) patients and further validate its effectiveness. Methods: A total of 1250 hypertensive (HTN) patients from Guangxi, China, were divided into a training group (875 patients, 70%) and a validation set (375 patients, 30%). LASSO regression, in combination with univariate and multivariate logistic regression analyses, was used to identify predictive factors associated with nonalcoholic fatty liver disease (NAFLD) in HTN patients within the training set. Subsequently, the performance of an NAFLD nomogram prediction model was evaluated in the separate validation group, including assessments of differentiation ability, calibration performance, and clinical applicability. This was carried out using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The risk-prediction model for the HTN patients concomitant with NAFLD included oral antidiabetic drugs (OADs) (OR = 2.553, 95% CI: 1.368-4.763), antihypertensives (AHs) (OR = 7.303, 95% CI: 4.168-12.794), body mass index (BMI) (OR = 1.145, 95% CI: 1.084-1.209), blood urea nitrogen (BUN) (OR = 0.924, 95% CI: 0.860-0.992), triglycerides (TGs) (OR = 1.474, 95% CI: 1.201-1.809), aspartate aminotransferase (AST) (OR = 1.061, 95% CI: 1.018-1.105), and AST/ALT ratio (AAR) (OR = 0.249, 95% CI: 0.121-0.514) as significant predictors. The AUC of the NAFLD risk-prediction model in the training set and the validation set were 0.816 (95% CI: 0.785-0.847) and 0.794 (95% CI: 0.746-0.842), respectively. The Hosmer-Lemeshow test showed that the model has a good goodness-of-fit (p-values were 0.612 and 0.221). DCA suggested the net benefit of using a nomogram to predict the risk of HTN patients concomitant with NAFLD is higher. These results suggested that the model showed moderate predictive ability and good calibration. Conclusions: BMI, OADs, AHs, BUN, TGs, AST, and AAR were independent influencing factors of HTN combined with NAFLD, and the risk prediction model constructed based on this could help to identify the high-risk group of HTN combined with NAFLD at an early stage and guide the development of interventions. Larger cohorts with multiethnic populations are essential to verify our findings.

Our aim was to examine the effects of combined prebiotic fiber supplementation and weight loss counseling on liver fat, body composition, subjective appetite, serum metabolomics, and intestinal microbiota in adults with MASLD.

In a double blind, placebo-controlled trial, adult participants aged 18-70 years old with MASLD were randomized to receive prebiotic (oligofructose-enriched inulin, 16 g/day; n = 22) or isocaloric placebo (maltodextrin; n = 20) for 24 weeks alongside weight loss counseling from a registered dietitian. Primary outcomes were change in intrahepatic fat % (IHF%) and hepatic injury from baseline to 24 weeks. Secondary outcomes included body composition, subjective appetite, serum lipids and cytokines, fecal microbiota, and serum metabolomics.

At baseline, participants had IHF of 14.4 ± 8.4%. The change in IHF from baseline to 24 weeks did not differ between prebiotic and placebo. Prebiotic participants had a greater decrease (p = 0.029) in percent trunk fat compared to placebo. Compared to placebo, prebiotic significantly decreased desire to eat and hunger ratings over the course of the intervention. Fecal microbiota analysis showed a significant increase in Bifidobacterium abundance with prebiotic. A pathway analysis based on untargeted serum metabolomics revealed a downregulation of taurine and hypotaurine metabolism in the placebo group which was conserved in the prebiotic group.

Adding prebiotic fiber supplementation to weight loss counseling for adults with MASLD enhanced reductions in trunk fat and had a beneficial effect on subjective appetite compared to placebo. Improvements in fecal microbial profile and taurine metabolism revealed specific beneficial effects of prebiotics in the management of MASLD.

Clinicaltrials.gov/study/NCT02568605.

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

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

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

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

Non-alcoholic fatty liver disease (NAFLD) has frequently been associated with obesity, type 2 diabetes (T2D), and dyslipidemia, all of which are shared by increased insulin resistance. It has become the most common liver disorder in Korea as well as in developed countries and is therefore associated with an increased health burden of morbidity and mortality. It has an association with T2D, and T2D increases the risk of cirrhosis and related complications. NAFLD encompasses a disease continuum from simple steatosis to non-alcoholic steatohepatitis which is characterized by faster fibrosis progression. Although its liver-related complication is estimated to be, at most, 10%, it will be a leading cause of cirrhosis and hepatocellular carcinoma soon in Korea. Although the main causes of death in people with NAFLD are cardiovascular disease and extra-hepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and can be assessed with combinations of non-invasive tests in the community. A number of components of metabolic syndrome involved could be another important prognostic information of NAFLD assessed easily in the routine care of the community. There is a few approved therapies for NAFLD, although several drugs, including antioxidants, attract practitioners' attention. Because of the modest effect of the present therapeutics, let alone complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is a viable option for many patients with NAFLD in the Korean community. Comprehensive approach taking healthy lifestyle and weight reduction into account remain a mainstay to the prevention and treatment of NAFLD.

We aimed to compare the association of metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD-Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non-SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD-Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all-cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD-Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD-Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all-cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.

The connections between sarcopenia and various chronic conditions, including type 2 diabetes (T2DM), metabolic syndrome (MetS), and liver disease have been highlighted recently. There is also a high occurrence of sarcopenia in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, who are often disregarded. Both experimental and clinical findings suggest a complex, bidirectional relationship between MASLD and sarcopenia. While vitamin D, testosterone, and specific drug therapies show promise in mitigating sarcopenia, consensus on effective treatments is lacking. Recent focus on lifestyle interventions emphasizes dietary therapy and exercise for sarcopenic obesity in MASLD. Challenges arise as weight loss, a primary MASLD treatment, may lead to muscle mass reduction. The therapeutic approach to sarcopenia in morbidly obese MASLD patients also includes bariatric surgery (BS). BS induces weight loss and stabilizes metabolic imbalances, but its impact on sarcopenia is nuanced, underscoring the need for further research. Our aim is to provide a comprehensive review of the interplay between sarcopenia and MASLD and offer insight into the most recent therapeutic challenges and discoveries, as sarcopenia is often overlooked or unrecognized and poses significant challenges for managing these patients.

Insulin resistance is a primary feature of type 2 diabetes. This study compared the effects of curcumin and its nanoformulation on insulin resistance, fasting blood sugar, liver function, GLUT4, lipid profile, and oxidative stress in the liver and pancreas in a diabetic model.

Thirty male Wistar rats were divided into five groups: a control group, a diabetic group, a diabetic group treated with metformin (40 mg/kg), a diabetic group treated with curcumin (100 mg/kg), and a diabetic group treated with curcumin NPs (100 mg/kg). Diabetes was induced by injecting dexamethasone daily for 14 days. Treatment with curcumin and curcumin NPs was administered by gavage for 14 days. Body weight and fasting blood sugar levels were measured on days 1, 14, and 28.

The metformin, curcumin, and curcumin NPs groups showed significantly greater body weight gain than the untreated diabetic group (P < 0.001). In diabetic rats treated with curcumin and curcumin NPs, insulin resistance decreased by approximately 40 %, while fasting blood sugar levels dropped by 35-40 % (P < 0.001). The levels of liver enzymes (AST, ALT), cholesterol, triglycerides, LDL, and the oxidative stress marker MDA in liver and pancreatic tissues were reduced by 30-50 %. Additionally, beneficial markers such as albumin, HDL, antioxidants (GSH, SOD), and GLUT4 levels were increased by 25-45 % (P < 0.001). Nano-curcumin consistently showed greater improvements than curcumin, especially in reducing oxidative stress and supporting liver and pancreatic health.

This study demonstrates that curcumin NPs has a superior effect on reducing oxidative stress and improving metabolic parameters in diabetes compared to curcumin. by enhancing the bioavailability and stability of curcumin, the nanoformulation showed stronger therapeutic potential for managing high blood sugar, cholesterol issues, and liver health, positioning curcumin NPs as a promising alternative to conventional treatments for diabetes and its complications.

Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation.

Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom.

Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.

Since the role of the liver in metabolic dysfunction, including type 2 diabetes mellitus, was demonstrated, studies on non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) have shown associations between fatty liver disease and other metabolic diseases. Unlike the exclusionary diagnostic criteria of NAFLD, MAFLD diagnosis is based on the presence of metabolic dysregulation in fatty liver disease. Renaming NAFLD as MAFLD also introduced simpler diagnostic criteria. In 2023, a new nomenclature, steatotic liver disease (SLD), was proposed. Similar to MAFLD, SLD diagnosis is based on the presence of hepatic steatosis with at least one cardiometabolic dysfunction. SLD is categorized into metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related/-associated liver disease, alcoholrelated liver disease, specific etiology SLD, and cryptogenic SLD. The term MASLD has been adopted by a number of leading national and international societies due to its concise diagnostic criteria, exclusion of other concomitant liver diseases, and lack of stigmatizing terms. This article reviews the diagnostic criteria, clinical relevance, and differences among NAFLD, MAFLD, and MASLD from a diabetologist's perspective and provides a rationale for adopting SLD/MASLD in the Fatty Liver Research Group of the Korean Diabetes Association.

Liver transplantation offers a new lease of life to patients with end-stage liver disease and hepatocellular carcinoma. However, the implantation of an exogenous allograft and the accompanying immunosuppression bring their own challenges. Moreover, the persistence of risk factors for the initial liver insult place the new graft at a higher risk of damage. With the increasing number of liver transplants along with the improvement in survival posttransplant, the recurrence of primary disease in liver grafts has become more common. Pre-2015, the most common disease to recur after transplant was hepatitis C. However, directly acting antivirals have nearly eliminated this problem. The greatest challenge of disease recurrence we now face are those of nonalcoholic steatohepatitis, alcohol-related liver disease, and primary sclerosing cholangitis. We focus on the epidemiology and pathophysiology of the recurrence of primary disease after transplant. We also discuss means of early identification, risk stratification, prevention, and management of recurrent primary disease after liver transplantation.

Background  Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) frequently coexist due to overlapping risk factors such as metabolic syndrome and obesity. T2DM exacerbates the progression of NAFLD, increasing the risk of cirrhosis and hepatocellular carcinoma. Thus, early detection of liver fibrosis is crucial to prevent severe liver disease. A 2D shear wave elastography (2D SWE) has emerged as a reliable non-invasive method for assessing liver stiffness, potentially reducing the need for liver biopsies and facilitating prompt treatment interventions. Methods This cross-sectional study, conducted over 18 months, included 100 T2DM and NAFLD patients from the Medicine and Diabetes Outpatient Department at SRM Medical College Hospital and Research Centre, Chengalpattu, India. Participants underwent gray-scale ultrasound to classify fatty liver (Grades I, II, and III) and 2D SWE to evaluate liver stiffness. Additional data on fasting and postprandial blood glucose, glycosylated hemoglobin (HbA1c), lipid profiles, liver function tests, and body mass index (BMI) were collected. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 21 (Released 2012; IBM Corp., Armonk, New York, United States). Results The mean age of participants was 47.9 years, with 61% being male. Fatty liver Grades I, II, and III were present in 47%, 41%, and 12% of patients, respectively. SWE results showed that 30% had stiffness values <5 kPa, 53% had values between 5.1-9 kPa, 16% had values between 9.1-13 kPa, and 1% had values >13 kPa. Liver size increased significantly with fatty liver grade (p=0.029). HbA1c levels and blood glucose levels were significantly correlated with fatty liver grades (p<0.0001). Triglyceride levels were higher with increasing fatty liver grades (p<0.0001). A significant correlation was found between gamma-glutamyl transferase (GGT) levels and SWE values (p=0.04). In the lipid profile, significant correlations were noted between SWE values and triglycerides (p=0.005), cholesterol (p=0.026), and very-low-density lipoprotein (VLDL) (p=0.131). Higher levels of HbA1c, fasting blood sugar, and postprandial blood sugar were also significantly correlated with SWE values (p<0.0001). Increasing grades of hepatic steatosis significantly correlated with SWE values (p<0.0001). BMI positively correlated with SWE values (r=0.321, p=0.001). Conclusion This study highlights the prevalence of advanced liver stiffness in patients with T2DM and NAFLD, which correlates significantly with higher grades of fatty liver, elevated HbA1c, blood sugar levels, and abnormal lipid profiles. SWE is a valuable tool for assessing liver stiffness and guiding the management of NAFLD in patients with T2DM.

Nonalcoholic fatty liver disease (NAFLD), recently proposed to be renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), is a major global public health concern, affecting approximately 25-30% of the adult population and possibly leading to cirrhosis, hepatocellular carcinoma, and liver transplantation. The liver is involved in the actions of sex steroids via their hepatic metabolism and production of the sex hormone-binding globulin (SHBG). Liver disease, including NAFLD, is associated with reproductive dysfunction in men and women, and the prevalence of NAFLD in patients with hypogonadism is considerable. A wide spectrum of possible pathophysiological mechanisms linking NAFLD and male/female hypogonadism has been investigated. As therapies targeting NAFLD may impact hypogonadism in men and women, and vice versa, treatments of the latter may affect NAFLD, and an insight into their pathophysiological pathways is imperative. This paper aims to elucidate the complex association between NAFLD and hypogonadism in men and women and discuss the therapeutic options and their impact on both conditions.

Nonalcoholic fatty liver disease (NAFLD) is a disease process that is gaining increasing recognition. The global prevalence of NAFLD is increasing in parallel with growing rates of risk factors for NAFLD such as hypertension, obesity, diabetes, and metabolic syndrome. NAFLD has been referred to as a risk factor for cardiovascular disease (CVD). As CVD is the leading cause of morbidity and mortality worldwide, there are constant efforts to describe and alleviate its risk factors. Although there is conflicting data supporting NAFLD as a causative or associative factor for CVD, NAFLD has been shown to be associated with structural, electrical, and atherosclerotic disease processes of the heart. Shared risk factors and pathophysiologic mechanisms between NAFLD and CVD warrant further explication. Pathologic mechanisms such as endothelial dysfunction, oxidative stress, insulin resistance, genetic underpinnings, and gut microbiota dysregulation have been described in both CVD and NAFLD. The mainstay of treatment for NAFLD is lifestyle intervention including physical exercise and hypocaloric intake in addition to bariatric surgery. Investigations into various therapeutic targets to alleviate hepatic steatosis and fibrosis by way of maintaining the balance between lipid synthesis and breakdown. A major obstacle preventing the success of many pharmacologic approaches has been the effects of these medications on CVD risk. The future of pharmacologic treatment of NAFLD is promising as effective medications with limited CVD harm are being investigated.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

The liver has excellent regeneration potential and attains complete functional recovery from partial hepatectomy. The regenerative mechanisms malfunction in chronic liver diseases (CLDs), which fuels disease progression. CLDs account for 2 million deaths per year worldwide. Pathophysiological studies with clinical correlation have shown evidence of deviation of normal regenerative mechanisms and its contribution to fueling fibrosis and disease progression. However, we lack realistic in vitro models that can allow experimental manipulation for mechanistic understanding of liver regeneration in CLDs and testing of candidate drugs. In this review, we aim to provide the framework for building appropriate organotypic models for dissecting regenerative responses in CLDs, with the focus on non-alcoholic steatohepatitis (NASH). By drawing parallels with development and hepatectomy, we explain the selection of critical components such as cells, signaling, and, substrate-driven biophysical cues to build an appropriate CLD model. We highlight the organoid-based organotypic models available for NASH disease modeling, including organ-on-a-chip and 3D bioprinted models. With the focus on bioprinting as a fabrication method, we prescribe building in vitro CLD models and testing schemes for exploring the regenerative responses in the bioprinted model.

Myosteatosis is highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and could reciprocally impact liver function. Decreasing muscle fat could be indirectly hepatoprotective in MASLD. We conducted a review to identify interventions reducing myosteatosis and their impact on liver function. Non-pharmacological interventions included diet (caloric restriction or lipid enrichment), bariatric surgery and physical activity. Caloric restriction in humans achieving a mean weight loss of 3% only reduces muscle fat. Lipid-enriched diet increases liver fat in human with no impact on muscle fat, except sphingomyelin-enriched diet which reduces both lipid contents exclusively in pre-clinical studies. Bariatric surgery, hybrid training (resistance exercise and electric stimulation) or whole-body vibration in human decrease both liver and muscle fat. Physical activity impacts both phenotypes by reducing local and systemic inflammation, enhancing insulin sensitivity and modulating the expression of key mediators of the muscle-liver-adipose tissue axis. The combination of diet and physical activity acts synergistically in liver, muscle and white adipose tissue, and further decrease muscle and liver fat. Several pharmacological interventions (patchouli alcohol, KBP-089, 2,4-dinitrophenol methyl ether, adipoRon and atglistatin) and food supplementation (vitamin D or resveratrol) improve liver and muscle phenotypes in pre-clinical studies by increasing fatty acid oxidation and anti-inflammatory properties. These interventions are effective in reducing myosteatosis in MASLD while addressing the liver disease itself. This review supports that disturbances in inter-organ crosstalk are key pathophysiological mechanisms involved in MASLD and myosteatosis pathogenesis. Focusing on the skeletal muscle might offer new therapeutic strategies to treat MASLD by modulating the interactions between liver and muscles.

Steatotic liver disease (SLD) is characterized by hepatic fat accumulation, potentially causing major consequences such as liver decompensation. Currently, we lack medications for the treatment of SLD. Therapeutic recommendations for patients include a hypocaloric diet, weight loss, and physical activity. In particular, the Mediterranean diet is frequently recommended. However, this diet might exacerbate intestinal problems in a subset of patients with coexisting small intestinal bacterial overgrowth (SIBO). Previous studies have reported that SIBO is more predominant in patients with fatty liver than in healthy individuals. Both our research and the findings of others have highlighted a challenge related to nutritional therapy in patients with fatty liver who also suffer from SIBO inasmuch as SIBO induces several phenomena (like bloating or abdominal pain) that can adversely affect patients' quality of life and might be exacerbated by the Mediterranean diet. This may lower their adherence to the intervention. As a solution, we suggest introducing additional diagnostics (e.g., breath test) in patients with SLD who complain of SIBO-like symptoms. The next step is to modify their diets temporarily starting with several weeks of "elimination and sanitation." This would involve restricting products rich in fermentable sugars and polyols, while simultaneously treating the bacterial overgrowth. In summary, while the hypocaloric Mediterranean diet is beneficial for patients with fatty liver, those with coexisting SIBO may experience exacerbated symptoms. It is vital to consider additional diagnostics and dietary modifications for this subset of patients to address both liver and intestinal health concurrently.

There is limited research on the relationship between Life's Essential 8 (LE8) score and metabolic dysfunction-associated steatotic liver disease (MASLD). Our aim is to investigate the relationship between overall lifestyle assessed by LE-8 score and MASLD in a nationally representative sample. We employed the LE8 score to comprehensively evaluate cardiovascular health, the assessment of MASLD primarily utilized the Fatty Liver Index. The weighted logistic regression models, restrictive cubic splines (RCS), subgroup analyses and the weighted quantile sum (WQS) regression were used to evaluate the relationship between the cardiovascular health and MASLD. Logistic regression models revealed that higher LE8 scores were associated with lower odds of having MASLD. The RCS revealed a significant nonlinear dose-response relationship between LE8 scores and MASLD. The WQS regression model indicated that blood glucose contributed the most to the risk of MASLD. The subgroup analysis indicates that there are significant differences in this association across age, educational level, and poverty income ratio. Our study suggests that an inverse correlation between LE8 and the risk of MASLD. Our findings underscore the utility of the LE8 algorithm in MASLD risk assessment and provide support for MASLD prevention through the promotion of healthy lifestyles.

Nonalcoholic fatty liver disease (NAFLD), also known as metabolic associated fatty liver disease (MAFLD), is a common liver condition characterized by excessive fat accumulation in the liver which is not caused by alcohol. The main causes of NAFLD are obesity and insulin resistance. Dachaihu decoction (DCHD), a classic formula in traditional Chinese medicine, has been proved to treat NAFLD by targeting different aspects of pathogenesis and is being progressively used in the treatment of NAFLD. DCHD is commonly applied in a modified form to treat the NAFLD. In light of this, it is imperative to conduct a systematic review and meta-analysis to assess the effectiveness and safety of DCHD in the management of NAFLD. There is a need for a systematic review and meta-analysis to assess the effectiveness and safety of modified DCHD in treating NAFLD.

The objective of this meta-analysis was to systematically assess the clinical effectiveness and safety of DCHD in treating NAFLD.

This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Including seven databases, both Chinese and English databases were searched for relevant studies. The quality of included studies was carefully assessed using the bias risk assessment tool in the Cochrane Handbook. Eligible articles were the source of extracted data which was meta-analyzed by using Review Manager 5.4 and Stata 17.0.

A total of 10 studies containing 825 patients were included. Compared with conventional treatments, combined treatment could clearly improve the liver function of NAFLD patients, which could reduce the levels of ALT (MD = -7.69 U/L, 95% CI: -11.88 to -3.51, p < 0.001), AST (MD = -9.58 U/L, 95% CI: -12.84 to -6.33, p < 0.01), and it also had a certain impact on regulating lipid metabolism, which could reduce the levels of TC (MD = -0.85 mmol/L, 95% CI: -1.22 to 0.48, p < 0.01), TG (MD = -0.45 mmol/L, 95% CI: -0.64 to 0.21, p < 0.01). Adverse event showed that DCHD was relatively safe. Due to the inclusion of less than 10 trials in each group, it was not possible to conduct a thorough analysis of publication bias.

According to the meta-analysis, in the treatment of the NAFLD, it is clear that the combination of DCHD was advantages over conventional treatment alone in improving liver function, regulating lipid metabolism. Additionally, DCHD demonstrates a relatively safe profile. Nevertheless, due to limitations in the quality and quantity of the studies incorporated, the effectiveness and safety of DCHD remain inconclusive. Consequently, further high-quality research is imperative to furnish more substantial evidence supporting the widespread clinical application of DCHD.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023397353, CRD42023397353.

Plant-based diets (PBDs) are gaining attention as a sustainable and health-conscious alternative for managing various chronic conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD). In the absence of pharmacological treatments, exploring the potential of lifestyle modifications to improve biochemical and pathological outcomes becomes crucial. The adoption of PBDs has demonstrated beneficial effects such as weight control, increased metabolic health and improved coexisting diseases. Nonetheless, challenges persist, including adherence difficulties, ensuring nutritional adequacy, and addressing potential deficiencies. The aim of this review is to provide a comprehensive overview of the impact of PBDs on MASLD, emphasizing the need for tailored dietary interventions with professional support to optimize their effectiveness in preventing and treating metabolic diseases.

The terms non-alcoholic fatty liver disease and non-alcoholic steatohepatitis have some limitations as they use exclusionary confounder terms and the use of potentially stigmatising language. Recently, a study with content experts and patients has been set to change this nomenclature. The term chosen to replace non-alcoholic fatty liver disease was metabolic dysfunction-associated steatotic liver disease (MASLD), which avoids stigmatising and helps improve awareness and patient identification. MASLD is the most common cause of chronic liver disease with an increasing prevalence, accounting for 25% of the global population. It is considered the hepatic manifestation of the metabolic syndrome with lifestyle playing a fundamental role in its physiopathology. Diet change and physical activity are the cornerstones of treatment, encompassing weight loss and healthier behaviours and a holistic approach. In Europe, there is no approved drug for MASLD to date and there is a substantial unmet medical need for effective treatments for patients with MASLD. This review not only provides an update on advances in evidence for nutrition and physical activity interventions but also explores the different therapeutic options that are being investigated and whose development focuses on the restitution of metabolic derangements and halting inflammatory and fibrogenic pathways.

Nonalcoholic fatty liver disease (NAFLD) is a globally increasing health epidemic. Lifestyle intervention is recommended as the main therapy for NAFLD. However, the optimal approach is still unclear. This study aimed to evaluate the effects of a comprehensive approach of intensive lifestyle intervention (ILI) concerning enhanced control of calorie-restricted diet (CRD), exercise, and personalized nutrition counseling on liver steatosis and extrahepatic metabolic status in Chinese overweight and obese patients with NAFLD.

This study was a multicenter randomized controlled trial (RCT) conducted across seven hospitals in China. It involved 226 participants with a body mass index (BMI) above 25. These participants were randomly assigned to two groups: the ILI group, which followed a low carbohydrate, high protein CRD combined with exercise and intensive counseling from a dietitian, and a control group, which adhered to a balanced CRD along with exercise and standard counseling. The main measure of the study was the change in the fat attenuation parameter (FAP) from the start of the study to week 12, analyzed within the per-protocol set. Secondary measures included changes in BMI, liver stiffness measurement (LSM), and the improvement of various metabolic indexes. Additionally, predetermined subgroup analyses of the FAP were conducted based on variables like gender, age, BMI, ethnicity, hyperlipidemia, and hypertension.

A total of 167 participants completed the whole study. Compared to the control group, ILI participants achieved a significant reduction in FAP (LS mean difference, 16.07 [95% CI: 8.90-23.25] dB/m) and BMI (LS mean difference, 1.46 [95% CI: 1.09-1.82] kg/m2) but not in LSM improvement (LS mean difference, 0.20 [95% CI: -0.19-0.59] kPa). The ILI also substantially improved other secondary outcomes (including ALT, AST, GGT, body fat mass, muscle mass and skeletal muscle mass, triglyceride, fasting blood glucose, fasting insulin, HbA1c, HOMA-IR, HOMA-β, blood pressure, and homocysteine). Further subgroup analyses showed that ILI, rather than control intervention, led to more significant FAP reduction, especially in patients with concurrent hypertension (p < 0.001).

In this RCT, a 12-week intensive lifestyle intervention program led to significant improvements in liver steatosis and other metabolic indicators in overweight and obese Chinese patients suffering from nonalcoholic fatty liver disease. Further research is required to confirm the long-term advantages and practicality of this approach.

This clinical trial was registered on ClinicalTrials.gov (registration number: NCT03972631) in June 2019.

This multi-center retrospective study examined the effect of weight loss on the prevention of progression to cirrhosis in a sample exclusively composed of patients with obesity and MASH-related F3 liver fibrosis. Adult patients with obesity and biopsy-confirmed MASH-related F3 liver fibrosis (n = 101) from two liver transplant centers in the US were included in the study. A higher proportion of patients who did not progress to cirrhosis achieved >5% weight loss at follow-up (59% vs. 30%, p = 0.045). In multivariable analysis, patients with >5% weight loss at follow-up had a lower hazard of developing cirrhosis compared to patients with no weight loss or weight gain (HR: 0.29, 95%, CI: 0.08-0.96); whereas, diabetes (HR: 3.24, 95%, CI: 1.21-8.67) and higher LDL levels (HR: 1.02, 95%, CI: 1.01-1.04) were associated with higher hazards of progression to cirrhosis. Weight loss >5% has the potential to prevent disease progression to cirrhosis in patients with obesity and MASH-related F3 liver fibrosis. The realization of this benefit requires weight loss maintenance longer than one year. Larger prospective studies are needed to determine how weight loss impacts other patient-centered outcomes such as mortality, hepatic decompensation, and hepatocellular carcinoma in patients with obesity and MASH-related F3 liver fibrosis.

The effect of nonalcoholic fatty liver disease (NAFLD) on major adverse cardiovascular events (MACEs) can be influenced by the degree of coronary artery stenosis. However, the association between the severity of NAFLD and MACEs in patients who underwent coronary computed tomography angiography (CCTA) is unclear.

A total of 341 NAFLD patients who underwent CCTA were enrolled. The severity of NAFLD was divided into mild NAFLD and moderate-severe NAFLD by abdominal CT results. The degree of coronary artery stenosis was evaluated by using Coronary Artery Disease Reporting and Data System (CAD-RADS) category. Cox regression analysis and Kaplan-Meier analysis were used to assess poor prognosis.

During the follow-up period, 45 of 341 NAFLD patients (13.20%) who underwent CCTA occurred MACEs. The severity of NAFLD (hazard ratio [HR] = 2.95[1.54-5.66]; p = 0.001) and CAD-RADS categories 3-5 (HR = 16.31[6.34-41.92]; p < 0.001) were independent risk factors for MACEs. The Kaplan-Meier analysis showed that moderate to severe NAFLD patients had a worsen prognosis than mild NAFLD patients (log-rank p < 0.001). Moreover, the combined receiver operating characteristic curve of the severity of NAFLD and CAD-RADS category showed a good predicting performance for the risk of MACEs, with an area under the curve of 0.849 (95% CI = 0.786-0.911).

The severity of NAFLD was independent risk factor for MACEs in patients with obstructive CAD, having CAD-RADS 3-5 categories on CCTA.

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1-3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid commonly used for treating cholestatic liver disease. However, its efficacy on non-alcoholic steatohepatitis (NASH) was controversial. This study aimed to investigate the impact of a high dosage of UDCA on a mouse model of NASH. Forty 6-week-old mice were fed a high-fat high-cholesterol (HFHC) diet for 12 weeks to establish a mouse model of NASH, and then divided into four groups: two groups transitioned to a normal diet, and the other two groups maintained the HFHC diet. Each group was administered a daily dosage of 300 mg/kg of UDCA or saline for a period of 8 weeks. The 16 s ribosomal RNA genes extracted from mice fecal pellets were sequenced using next-generation sequencing techniques. Serum bile acid profiles were quantified using liquid chromatography electrospray ionization tandem mass spectrometry method. The results showed that UDCA treatment ameliorated liver inflammation, without affecting liver fibrosis. UDCA treatment reduced the relative abundance of the genera Bacteroides, Parabacteroides, and Intestinimonas, whereas increased the relative abundance of the genera norank_f_Muribaculaceae and Parasutterella in the HFHC-maintaining groups. The serum levels of total bile acids and total primary bile acids increased, whereas those of endogenous primary bile acids decreased after UDCA treatment. Correlation analysis showed that primary bile acids were negatively correlated with the genera norank_f_Christensenellaceae and unclassified_f_Ruminococcaceae. In conclusion, a high dosage of UDCA can alleviate liver inflammation, probably by modifying the composition of gut microbiota and serum bile acid profiles in NASH mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.

This study aimed to clarify the efficacy and safety of 48-week pemafibrate treatment in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) complicated by dyslipidemia.

A total of 110 patients diagnosed with MASLD complicated by dyslipidemia received pemafibrate at a dose of 0.1 mg twice daily for 48 weeks.

The participants were 54 males and 37 females, with a median age of 63 (52-71) years. Besides improvement in lipid profile, significant reductions from baseline to 48 weeks of treatment were found in liver-related enzymes, such as aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyl transpeptidase, and alkaline phosphatase (P < 0.001 for all). A significant decrease in the homeostasis model assessment-insulin resistance (HOMA-IR) was observed in patients with insulin resistance (HOMA-IR ≥ 2.5) (4.34 at baseline to 3.89 at Week 48, P < 0.05). Moreover, changes in ALT were weakly correlated with those in HOMA-IR (r = 0.34; p < 0.05). Regarding noninvasive liver fibrosis tests, platelets, Wisteria floribunda agglutinin-positive Mac-2-binding protein, type IV collagen 7s, and the non-alcoholic fatty liver disease fibrosis score significantly decreased from baseline to Week 48. Most adverse events were Grades 1-2, and no drug-related Grade 3 or higher adverse events were observed.

This study demonstrated that 48-week pemafibrate administration improved liver-related enzymes and surrogate marker of liver fibrosis in patients with MASLD. The improvement of insulin resistance by pemafibrate may contribute to the favorable effect on MASLD complicated by dyslipidemia.

Obesity and liver cirrhosis represent significant health challenges, often leading to various complications.

This prospective study aimed to investigate the impact of a four-year bariatric intervention, focusing on adherence to the Mediterranean Diet, on anthropometric, hematologic, and biochemical parameters in obese patients with compensated liver cirrhosis. Additionally, the study evaluated the concurrent contribution of weight loss to these health indicators.

The study involved 62 patients with compensated liver cirrhosis (mean age 65.87 ± 6 years) and 44 healthy controls (mean age 59.11 ± 8 years), all with a BMI > 30 kg/m2. Both groups underwent a weight loss intervention based on the Mediterranean diet, with a four-year follow-up. Anthropometric, biochemical and hematologic parameters were evaluated at several time points during the study and their statistical significance was assessed.

Anthropometric parameters, including weight, BMI, waist and hip circumference, percentage of fat mass, and handgrip strength, exhibited significant improvements (p < 0.05), particularly within the first year of the intervention. Liver function tests and lipid profiles of the patients also showed significant enhancements (p < 0.05). Hematological and biochemical indices, such as hematocrit and ferritin, experienced discreet improvements in the patient cohort (p < 0.05).

This study highlights the potential of a structured bariatric intervention rooted in the Mediterranean diet to positively influence the health of obese patients with compensated liver cirrhosis. The observed improvements in anthropometric, biochemical, and hematologic parameters, particularly within the first year of the intervention, suggest the importance of dietary modifications in managing the health of this patient population.

Weight loss is the mainstay of management for patients with metabolic dysfunction-associated steatotic liver disease. We studied the impact of referral to MOVE!, a nationally-implemented behavioral weight loss program, on weight in MASLD patients.

This retrospective cohort study included 102,294 MASLD patients from 125 Veterans Health Administration centers from 2008-2022.

Most patients lost no significant weight or gained weight. Increased engagement with MOVE! was associated with greater hazard of significant weight loss compared to no engagement.

A minority of patients experienced significant weight loss through 5 years using lifestyle interventions alone.

Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.