Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and its prevalence has risen sharply. However, whether nutrition, dietary strategies, exercise, lifestyle and environment have preventive value for NAFLD remains unclear.

Through searching 4 databases (PubMed, Web of Science, Embase and the Cochrane Library) from inception to January 2025, we selected studies about nutrition, dietary strategies, exercise, lifestyle and environment in the prevention of NAFLD and conducted a narrative review on this topic.

Reasonable nutrient intake encompassing macronutrients and micronutrients have an independent protective relationship with NAFLD. Besides, proper dietary strategies including mediterranean diet, intermittent fasting diet, ketogenic diet, and dietary approaches to stop hypertension diet have their inhibitory effects on the developmental process of NAFLD. Moreover, right exercises including walking, jogging, bicycling, and swimming are recommended for the prevention of NAFLD because they could effectively reduce weight, which is an important risk factor for NAFLD, and improve liver function. In addition, embracing a healthy lifestyle including reducing sedentary behavior, not smoking, sleeping well and brushing teeth regularly is integral since it not only could reduce the risk of NAFLD but also significantly contribute to overall prevention and control. Finally, the environment, including the social and natural environments, plays a potential role in NAFLD prevention.

Nutrition, dietary strategies, exercise, lifestyle and environment play an important role in the prevention of NAFLD. Moreover, this review offers comprehensive prevention recommendations for people at high risk of NAFLD.

Noninvasive assessment of liver fat content is crucial due to the high global prevalence of nonalcoholic fatty liver disease. Algorithms based on ultrasound (US) attenuation coefficient (AC) for estimating liver fat content are commercially available, but a lack of consensus exists regarding the best estimation protocol. The aim of our study was to evaluate the influence of the size of the region of interest (ROI) on the US AC.A prospective study was conducted. An abdominal US was done for 86 outpatients. A sampling box was positioned within the liver parenchyma, approximately 2 cm beneath the liver capsule with a ROI, measuring about 2 × 4 cm and then 4 × 5 cm, precisely placed at the center of this sampling box. Five readings of the AC were captured, and the average of these measurements was employed to assess the severity of hepatic steatosisA statistically significant difference between AC with 2 different ROI sizes was shown (P < 0.001) with AC values with 2 × 4 cm ROI were higher than those obtained with 4 × 5 cm ROI (AC mean 0.668 VS 0.653). However, the agreement between AC values obtained with 2 different ROI sizes was excellent (correlation coefficient 0.941)An ROI size dependence is observed in the measurement of AC in the liver. A standardized acquisition protocol with a fixed size of the ROI needs to be developed to minimize differences in AC measurements and to assess changes in serial measurements reliably.

Considering recent revisions in the nomenclature for fatty liver disease, alongside limited data on sex-specific differences in its cardiovascular/mortality outcomes, this study aims to investigate the prevalence and impact of metabolic-associated fatty liver disease (MAFLD) on cardiovascular disease (CVD) and mortality in men and women over a 12-year follow-up period.

In this large population-based cohort study, 7101 individuals aged ≥ 30 were enrolled. The prevalence of MAFLD was investigated in both genders. After excluding individuals with a history of previous CVD, 6331 participants were followed up for CVD and mortality over 12 years. Steatosis was defined as fatty liver index (FLI) ≥ 60. Multivariate-adjusted hazard ratios (HRs) were calculated for CVD and mortality.

The prevalence of MAFLD was 43.2%, higher in men (46.5%) than women (40.6%). Men with MAFLD (47.7 ± 12.1) were younger than women (52.2 ± 11.1). In the 12-year follow-up of 6331 individuals, multivariable-adjusted CVD HRs for MAFLD were 1.36 (1.10-1.67) in men and 1.48 (1.16-1.88) in women. Adjusted mortality HRs were 1.17 (0.86-1.59) and 1.38 (1.00-1.91) in men and women, respectively. Among patients with MAFLD, a subgroup with diabetes faced the highest hazard for CVD and mortality.

This study found that MAFLD is more common in men at a younger age. Despite the higher prevalence in men, women with MAFLD face a greater risk of cardiovascular events and mortality. Findings highlight the importance of gender-specific considerations in primary prevention programmes for MAFLD-related cardiovascular disease and mortality.

Although steatotic liver onset after natural menopause has been reported, evidence on the clinical course and treatment options for steatotic liver after surgical menopause is scarce. A 34-year-old woman with a history of severe obesity presented to our department with liver dysfunction following total hysterectomy and bilateral oophorectomy. Her serum estradiol level was notably low at 22 pg/mL, and a liver biopsy revealed significant fatty degeneration, lobular inflammation, hepatocyte ballooning, and stage F1 fibrosis. These findings supported a diagnosis of steatotic liver disease following surgical menopause. Subsequent initiation of hormone replacement therapy (HRT) with estrogen led to rapid improvements in liver function and steatotic liver symptoms. Steatotic liver disease should be considered in cases of liver impairment in postoperative menopausal patients, for which HRT represents a promising treatment option.

To comprehensively evaluate the therapeutic efficacy of pioglitazone and SGLT2 inhibitors (SGLT2i) in patients with MASLD and Type 2 Diabetes(T2DM).

Electronic databases, including Web of Science, PubMed, the Cochrane Library, China National Knowledge Internet (CNKI), Wan-Fang Digital Database, and China Science and Technology Journal Database (VIP) were searched from inception to December 2024. Two reviewers independently assessed study eligibility, performed continuous data extraction， and independently evaluated bias risks. Liver ultrasonography, computed tomography (CT), and biochemical indices were utilized to determine the impact of treatment in both groups. Improvement in liver biomarkers and fibrosis as primary outcome indicators; Improvement in body composition, metabolic parameters, glucose parameters, and incidence of adverse effects as a secondary outcome indicator. For continuous variables, mean and standard deviation (SD) were extracted. RevMan 5.4 software was used to systematically analyze the literature, including heterogeneity testing, odds ratios (OR) calculation, and 95 % confidence intervals (CI) for each influencing factor.

Nine randomly controlled trials with 755 Asian participants were included. Our research showed that SGLT2i was more effective than pioglitazone in improving fibrosis-4 score (SMD 0.41 [95%CI 0.18,0.64] p = 0.005), visceral fat area (SMD 0.34 [95%CI 0.14,0.54] p = 0.0007), BMI (SMD 0.29 [95%CI 0.03,0.56] p = 0.03), and low-density lipoprotein levels (SMD 0.21 [95%CI 0.04,0.38] p = 0.01). In contrast, no statistically significant differences were observed in other outcomes.

Our study demonstrated that in patients with MASLD and T2DM, SGLT2i was more effective overall in improving liver fibrosis, blood lipids, liver fat, and body composition in the short term. These findings establish a theoretical basis for safe and rational drug use in clinical practice. Additionally, they may contribute to new insights into the pathogenesis of MASLD and type 2 diabetes and drug discovery and development efforts.

Several scientific associations recommend a sequential combination of non-invasive tests (NITs) to identify high-risk MASLD patients but their cost-effectiveness is unknown.

A cost-utility model was developed to assess the incremental cost-effectiveness ratio (ICER) of recommended screening strategies for patients with clinically suspected MASLD, specifically those with type 2 diabetes (T2D) and obesity with multiple cardiometabolic risk factors which will be initiated in primary care. Six screening strategies were assessed, using either vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test as a second-line test following an initial Fibrosis-4 (FIB-4) assessment as the first line NIT. The model included treatment effects of resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) patients with F2 or F3 fibrosis.

All screening strategies for high-risk MASLD in US incurred additional costs compared to no screening, ranging from $13 587 to $14 730 per patient with T2D and $14 274 to $15 661 per patient with obesity. However, screening reduced long-term costs, ranging from $22 150 to $22 279 per patient with T2D and $13 704 to $13 705 per patient with obesity, compared to $24 221 and $14 956 for no screening, respectively. ICERs ranged from $26 913 to $27 884 per QALY for T2D patients and $23 265 to $24  992 per QALY for patients with obesity. While ICERs were influenced by VCTE availability, they remained cost-effective when using ELF as the second-line test. Our findings remain robust across a range of key parameters.

Screening for high-risk MASLD is cost-effective according to recent guidelines. Implementing these screening strategies in primary care should be considered.

Two main stages are differentiated in patients with advanced chronic liver disease (ACLD), one compensated (cACLD) with an excellent prognosis, and the other decompensated (dACLD), defined by the appearance of complications (ascites, variceal bleeding and hepatic encephalopathy) and associated with high mortality. Preventing the progression to dACLD might dramatically improve prognosis and reduce the burden of care associated with ACLD. Portal hypertension is a major driver of the transition from cACLD to dACLD, and a portal pressure of ≥10 mmHg defines clinically significant portal hypertension (CSPH) as the threshold from which decompensating events may occur. In recent years, innovative studies have provided evidence supporting new strategies to prevent decompensation in cACLD. These studies have yielded major advances, including the development of noninvasive tests (NITs) to identify patients with CSPH with reasonable confidence, the demonstration that aetiological therapies can prevent disease progression and even achieve regression of cirrhosis, and the finding that non-selective β-blockers can effectively prevent decompensation in patients with cACLD and CSPH, mainly by reducing the risk of ascites, the most frequent decompensating event. Here, we review the evidence supporting new strategies to manage cACLD to prevent decompensation and the caveats for their implementation, from patient selection using NITs to ancillary therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters.

Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools.

Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH.

Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.

To assess the performance and the reproducibility of ultrasound-guided attenuation parameter (UGAP) and two-dimensional shear wave elastography (2D-SWE) in patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD).

This study included consecutive adult patients with MASLD who underwent ultrasound with UGAP, 2D-SWE and percutaneous liver biopsy. The median values of 12 consecutive UGAP measurements were acquired by two independent radiologists (R1 and R2). Hepatic steatosis was graded by liver biopsy as: (0) < 5%; (1) 5-33%; (2) > 33-66%; (3) > 66%. Areas under the curve (AUCs) were calculated to determine the diagnostic performance. Inter- and intra-observer reliability was assessed with intraclass correlation coefficient (ICC).

A hundred patients (median age 55.0 years old) with MASLD were prospectively enrolled. At histopathology, 70 and 42 patients had grade ≥ 2 and 3 steatosis, respectively. Median UGAP was 0.78 dB/cm/MHz (IQR/Med: 5.55%). For the diagnosis of grade ≥ 2 steatosis, the AUCs of UGAP were 0.828 (95% CI: 0.739, 0.896) for R1 and 0.779 (95% CI: 0.685, 0.856) for R2. The inter- and intra-operator reliability of UGAP were excellent, with an ICC of 0.92 (95% CI: 0.87-0.95) and 0.95 (95% CI: 0.92-0.96), respectively. The median liver stiffness was 6.76 kPa (IQR/Med: 16.30%). For the diagnosis of advanced fibrosis, 2D-SWE had an AUC of 0.862 (95% CI: 0.757, 0.934), and the optimal cutoff value was > 6.75 kPa with a sensitivity of 80.6% and a specificity of 75.7%.

UGAP and 2D-SWE provide a good performance for the staging of steatosis and fibrosis in patients with MASLD with an excellent intra-operator reliability of UGAP.

Question How well do ultrasound-guided attenuation parameter (UGAP) and two-dimensional shear wave elastography (2D-SWE) perform for quantifying hepatic steatosis and fibrosis? Findings UGAP had a maximum AUC of 0.828 for the diagnosis of grade ≥ 2 steatosis, and 2D-SWE had an AUC of 0.862 for diagnosing advanced fibrosis. Clinical relevance UGAP and 2D-SWE allow rapid, reproducible, and accurate quantification of hepatic steatosis and fibrosis that can be used for the noninvasive assessment of patients with metabolic dysfunction-associated steatotic liver disease.

Quantitative magnetic resonance imaging metrics iron-corrected T1 (cT1) and liver fat from proton density fat-fraction (PDFF) are both commonly used as noninvasive biomarkers for metabolic dysfunction-associated steatohepatitis (MASH); however, their repeatability in this population has rarely been characterized.

To quantify the variability of cT1 and liver fat fraction from PDFF in patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH.

Prospective, single center.

Twenty-one participants (female = 11, mean age 53 ± 24 years) with biopsy-confirmed MASLD, including 6 with MASH and fibrosis ≥2.

3 T; T1 and T2* mapping for the generation of cT1 (shMOLLI: CardioMaps and 2D MDE, T1map-FIESTA and LMS MOST: StarMap, 2D Multi-Echo FSPGR) and magnitude-only PDFF sequence for liver fat quantification (LMS IDEAL: StarMap, 2D Multi-Echo FSPGR).

T1 mapping and PDFF scans were performed twice on the same day for all participants (N = 21), with an additional scan 2-4 weeks later for MASH patients with fibrosis ≥2 (N = 6). Whole liver segmentation masks were generated semi-automatically and average pixel counts within these masks were used for the calculation of cT1 and liver fat fraction.

Bland-Altman analysis for repeatability coefficient (RC) and 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC).

Same-day RC was 32.1 msec (95% LOA: -36.6 to 24.2 msec) for cT1 and 0.6% (95% LOA: -0.5% to 0.7%) for liver fat fraction; the ICCs were 0.98 (0.96-0.99) and 1.0, respectively. Short-term RC was 65.2 msec (95% LOA: -63.8 to 76.5 msec) for cT1 and 2.6% (95% LOA: -2.8% to 3.1%) for liver fat fraction.

In participants with MASLD and MASH, cT1 and liver fat fraction measurements show excellent test-retest repeatability, supporting their use in monitoring MASLD and MASH.

2 TECHNICAL EFFICACY: Stage 2.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking.

Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established noninvve fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, homeostatic model assessment of insulin resistance index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels.

Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in nonselected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

We retrospectively examined the benefits and disadvantages of adding imeglimin to metformin therapy in patients with type 2 diabetes.

Ninety-four patients with type 2 diabetes who had been administered imeglimin were included in the safety analysis set (SAS). Sixty-four patients who had been treated with imeglimin for over 6 months were included in the full analysis set (FAS). The primary outcome was the change in HbA1c levels in the FAS. The secondary outcomes were gastrointestinal adverse events (AEs) in the SAS and changes in body weight and FIB-4 in theFAS.

In the SAS, gastrointestinal AEs occurred in 15 of 40 (38%) metformin users and 6 of 54 (11%) non-users. In the FAS, HbA1c levels were significantly reduced in both metformin users (n = 27, baseline, 8.5 ± 1.1%;6 months, 7.7 ± 1.2%) and non-users (n = 37, baseline, 8.0 ± 0.9%; 6 months,7.4 ± 0.9%). While body weight (from 72.0 ± 20.5 kg to 70.9 ± 20.8 kg) and FIB-4 (from 1.27 ± 0.57 to 1.17 ± 0.49) significantly decreased in metformin users, they did not significantly differ in non-users.

Adding imeglimin to metformin therapy demonstrated favorable reductions in HbA1c, body weight, and FIB-4 in patients with type 2 diabetes, although it was associated with the incidence of gastrointestinal AEs.

UMIN000055241.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.

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liver fibrosis (FH) is one of the main risks and mortality factors for many patients. Metabolic syndrome, MASLD, alcoholism or hepatotropic viruses are the main causes of the development of FH. Due to the wide range of patients affected, FH screening is the order of the day. Furthermore, it is of enormous nutritional interest given that the only effective treatment today is diet and physical exercise. Metabolic syndrome and MASLD are closely linked. The prevalence of these is increasing and consequently, so is FH. Therefore, finding less invasive diagnostic strategies than liver biopsy (gold standard) is a priority.

this study analyzes the relationship between age, sex, diabetes mellitus, hypertension, obesity and dyslipidemia with the development of FH.

the diagnostic capacity of the main non-invasive markers available today is analyzed, as well as their confounding factors. Finally, a score with FIB4, NFS and APRI is proposed to improve their individual diagnostic capacity.

the prevalence of FH in the study is 44 %. Diabetes mellitus and hypertension are significant in the development of FH. For their part, FIB4, NFS and APRI show acceptable specificity, although in all of them platelets are an important confounding factor.

the score of the three markers improves specificity (89.28 %), leaving fewer indeterminates than any of the indices. Therefore, it improves the diagnostic capacity compared to individual use.

Changes in FIB-4 levels after the initiation of luseogliflozin therapy were compared between patients with type 2 diabetes according to the presence or absence of alcohol consumption.

A total of 192 patients with type 2 diabetes who continued luseogliflozin therapy for over 12 months were retrospectively investigated. The primary outcome was the change in FIB-4. The secondary outcomes were changes in HbA1c, body weight, and serum albumin concentration. A current drinker was defined as an individual consuming >20 g ethanol equivalent/day. Patients were classified according to their risk of developing liver fibrosis into the low-risk (FIB-4 < 1.3) and intermediate/high-risk (FIB-4 ≥ 1.3) groups.

In the low-risk group, while FIB-4 increased dramatically from 0.91 ± 0.30 at the baseline to 1.14 ± 0.34 at 12 months in drinkers (n = 27), non-drinkers (n = 79) showed no significant change (0.87 ± 0.22-0.91 ± 0.26). In the intermediate/high-risk group (n = 63), although the FIB-4 in drinkers (n = 23) showed no significant change (2.18 ± 1.00-2.16 ± 0.93), it significantly decreased from 2.10 ± 0.87 to 1.80 ± 0.68 in non-drinkers (n = 63). In both the low- and intermediate/high-risk groups, HbA1c and body weight significantly decreased in both drinkers and non-drinkers. Serum albumin concentrations significantly increased in both drinkers and non-drinkers in the low-risk group. Although serum albumin concentration did not significantly change in drinkers, it dramatically increased in non-drinkers in the intermediate/high-risk group.

HbA1c levels and body weight decreased in patients with type 2 diabetes after initiating luseogliflozin therapy, regardless of drinking habits. However, it is desirable to limit alcohol consumption when considering its effects on liver fibrosis.

Metabolic dysfunction leading to non-alcoholic fatty liver disease (NAFLD) exhibits distinct molecular and immune signatures that are influenced by factors like gut microbiota. The gut microbiome interacts with the liver via a bidirectional relationship with the gut-liver axis. Microbial metabolites, sirtuins, and immune responses are pivotal in different metabolic diseases. This extensive review explores the complex and multifaceted interrelationship between sirtuins and gut microbiota, highlighting their importance in health and disease, particularly metabolic dysfunction and hepatocellular carcinoma (HCC). Sirtuins (SIRTs), classified as a group of NAD+-dependent deacetylases, serve as crucial modulators of a wide spectrum of cellular functions, including metabolic pathways, the inflammatory response, and the process of senescence. Their subcellular localization and diverse functions link them to various health conditions, including NAFLD and cancer. Concurrently, the gut microbiota, comprising diverse microorganisms, significantly influences host metabolism and immune responses. Recent findings indicate that sirtuins modulate gut microbiota composition and function, while the microbiota can affect sirtuin activity. This bidirectional relationship is particularly relevant in metabolic disorders, where dysbiosis contributes to disease progression. The review highlights recent findings on the roles of specific sirtuins in maintaining gut health and their implications in metabolic dysfunction and HCC development. Understanding these interactions offers potential therapeutic avenues for managing diseases linked to metabolic dysregulation and liver pathology.

Epidemiological evidence suggests that non-alcoholic fatty liver disease (NAFLD) may increase the risk of atrial fibrillation (AF). However, the findings are inconsistent, and the causality remains to be established.

We conducted two-step, two-sample Mendelian randomization (MR) analysis to assess the association between genetically predicted NAFLD (i.e. chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and AF. Subsequently, we further performed Mendelian randomization to investigate the causal relationship between non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, and AF. The inverse variance weighted (IVW) method was used as the primary approach to reveal the potential causation between the exposure and outcome.

There was no significant causal association between NAFLD diagnosed based on cALT, confirmed by imaging, or verified by biopsy, and an increased risk of atrial fibrillation. Furthermore, the results of the IVW method revealed a positive causal effect of NASH on AF (OR=1.113, 95% CI=1.025-1.209, P = 0.011). In the reverse analysis, however, no evidence supported a significant genetic association between AF and NASH (OR=0.974, 95% CI=0.934-1.016, P = 0.214).

A causal relationship existed between NASH and the risk of AF. However, no significant genetic association has been observed between NAFLD and AF risk. This suggests that managing the progression of NAFLD may hold potential value in preventing the onset of AF.

Heart failure with reduced ejection fraction (HFrEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both associated with liver fibrosis. HFrEF patients may develop liver fibrosis due to hepatic congestion, MASLD, or a combination of both. The Fibrosis-4 (FIB-4) score calculated using age, aspartate aminotransferase, alanine aminotransferase, and platelet count, serves as a screening tool for advanced liver fibrosis. This study examines the association between the FIB-4 score and all-cause mortality, cardiovascular mortality, and major adverse liver outcomes (MALO) in patients with HFrEF.

This study included 4523 HFrEF patients from the Danish Heart Failure Registry. Based on FIB-4 score, 25.5 % were low-risk, 45.7 % were indeterminate-risk, and 28.8 % were high-risk for advanced liver fibrosis. After five years, the cumulative incidence of all-cause mortality was 43 % for the high-risk group, 36 % for the indeterminate-risk group, and 23 % for the low-risk group. The indeterminate-risk and high-risk group had an increased hazard ratio (HR) for all-cause mortality (HR 1.33, 95 % confidence interval [CI] 1.16-1.52; HR 1.51, 95 % CI 1.31-1.74) compared to the low-risk group. Similarly, HRs were elevated for cardiovascular mortality (HR 1.61, 95 % CI 1.27-2.05; HR 2.14, 95 % CI 1.67-2.74) and MALO (HR 1.77, 95 % CI 1.01-3.31; HR 2.54, 95 % CI 1.43-4.52).

A high FIB-4 score in patients with HFrEF is associated with increased mortality and MALO.

BackgroundThe prevalence of hepatosteatosis, or fatty liver disease, has been increasing globally in recent years largely due to increasing rates of obesity, diabetes, and metabolic syndrome.PurposeTo examine the platelet to lymphocyte ratio (PLR) reflection on the hepatosteatosis stage.Material and MethodsWe evaluated healthy individuals who applied to the check-up department in our hospital. The platelet and lymphocyte counts from blood tests, along with upper abdominal ultrasound results obtained as part of routine diagnostic check-ups, results recorded retrospectively, between November 2022 and April 2024.ResultsA total 748 participants were included in the study. All participants were divided in three groups according to hepatosteatosis stages.The PLR levels were highest in the stage 1 hepatosteatosis group. There was statistical significance in PLR levels between stage 1 and 3 hepatosteatosis (P = 0003). In addition, PLR levels were higher in stage 2 than in stage 3, which was also statistically significant (P = 0037).ConclusionThese results could help in early detection and monitoring of disease progression in patients with hepatoteatosis. Lower PLR values (<115.26) in advanced stages might prompt closer monitoring or more aggressive interventions to prevent progression to fibrosis.

Cholecystectomy increases the incidence of metabolic associated fatty liver disease and fibrosis. Dietary antioxidants protect the liver from oxidative stress and inhibit the development of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the epidemiological evidence that links antioxidants intake to hepatic steatosis and fibrosis in patients underwent cholecystectomy is not available. Therefore, the present study aimed to investigate the association of composite dietary antioxidant index (CDAI) with the risk of hepatic steatosis and fibrosis in the cholecystectomy population. Data of 773 participants from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were analyzed. Dietary and supplementary intake of antioxidants were collected to calculate CDAI. The controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) assessed by the vibration controlled transient elastography (VCTE) were used to identify hepatic steatosis and hepatic fibrosis, respectively. Weighted multivariate logistic regression and restricted cubic spline (RCS) regression were conducted to analyze the association. Weighted multivariate logistic regression analysis with full adjustment for confounding variables showed a negative association between CDAI and hepatic fibrosis in individuals underwent Scholecystectomy [OR (95%CI) = 0.87 (0.79, 0.94), P = 0.010], while non-significant association was found between CDAI and MASLD. Moreover, compared to the lowest quartile, the highest quartile of CDAI was associated with a lower risk of hepatic fibrosis [OR (95%CI) = 0.28 (0.13, 0.60), P = 0.007]. The RCS analysis further indicated a linear negative relationship between intake of CDAI, vitamin E, and selenium and the risk of hepatic fibrosis, whereas vitamin A was non-linearly negatively correlated with the risk of hepatic fibrosis (all P overall < 0.001). Our findings suggest that higher antioxidants intake, especially vitamin E, may be associated with a lower risk of hepatic fibrosis among individuals underwent cholecystectomy. Further studies are needed to validate current findings and explore the underlying mechanisms.

Polycystic ovary syndrome (PCOS) is linked to non-alcoholic fatty liver disease (NAFLD). Biochemical, sex hormonal, and anthropometric indicators have been explored for screening NAFLD in PCOS patients. However, the accuracy of NAFLD screening using these indicators in PCOS patients remains uncertain. This study aimed to identify biochemical, sex hormonal, and anthropometric indicators associated with NAFLD in overweight and obese PCOS patients and assess the diagnostic efficacy of combined indicators.

This cross-sectional study (Clinical trial number ChiCTR1900020986; Registration date January 24th, 2019) involved 87 overweight or obese women with PCOS (mean age 29 ± 4 years). Measurements included anthropometric indices, biochemistry, sex hormone levels, and liver proton density fat fraction (PDFF). Correlation analysis, intergroup comparisons, and logistic regression analysis were used to identify risk factors for NAFLD (PDFF > 5.1%). The receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value were used to determine cut-off values and evaluate diagnostic accuracy.

Liver PDFF was 7.69% (3.93%, 14.80%) in overweight and obese PCOS patients, with 67.8% diagnosed with NAFLD. NAFLD was associated with increased body mass index (BMI), abdominal circumference (AC), and triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), glucose, insulin, and free testosterone (FT) levels, and with decreased high-density lipoprotein-cholesterol (HDL-C) and sex hormone-binding globulin (SHBG) levels (P < 0.05). Risk factors for NAFLD in PCOS included BMI > 26.8 kg/m2, AC > 88.3 cm, triglyceride > 1.57 mmol/L, TC > 4.67 mmol/L, LDL-C > 3.31 mmol/L, glucose > 4.83 mmol/L, insulin > 111.35 pmol/L, FT > 7.6 pg/mL and SHBG < 25 nmol/L (β = 1.411-2.667, P < 0.005). A multi-indicator model including triglycerides, LDL-C, glucose, insulin, and SHBG showed higher diagnostic accuracy (AUC = 0.899, P < 0.001) for screening NAFLD in PCOS patients than single indicators (AUC = 0.667-0.761, P < 0.05).

Overweight and obese PCOS patients have higher incidences of liver PDFF and NAFLD. A multi-indicator model including triglycerides > 1.57 mmol/L, LDL-C > 3.31 mmol/L, glucose > 4.83 mmol/L, insulin > 111.35 pmol/L, and SHBG < 25 nmol/L is highly accurate for screening NAFLD in overweight and obese PCOS patients.

Psoriasis (Pso) is an inflammatory skin disease associated with Metabolic Syndrome (MetS), Steatotic Liver Disease (SLD) and cardiovascular risk. However, the effect of anti-inflammatory therapy on cardiovascular risk is uncertain.

To determine the relationship between anti-inflammatory therapy and subclinical atherosclerosis in individuals with Pso, using the gold standard carotid-femoral Pulse Wave Velocity (cf-PWV) measurement. Additionally, to evaluate the association between cf-PWV, steatosis and Advanced Fibrosis (AF) using Transient Elastography (TE) by Fibroscan®.

Cross-sectional study including Pso patients submitted to cf-PWV and TE. Steatosis was defined as a controlled attenuation parameter ≥ 275 dB/m, AF as liver stiffness measurement ≥ 10 kPa, and increased Aortic Stiffness (AoS) as cf-PWV ≥ 10 m/s. Significant cumulative methotrexate dose was ≥ 1500 mg (MTX1500). Logistic regression analysis evaluated the independent variables associated with increased AoS.

Eighty patients were included (mean age 56.2 ± 11.5-years, 57.5% female, BMI 28.6 ± 5.3 kg/m2). Prevalences of MetS, diabetes mellitus, dyslipidemia, systemic arterial hypertension, steatosis and AF were 57.5%, 40.0%, 67.5%, 70.0%, 50.0% and 16.3%, respectively. MTX1500 was present in 45%, immunobiological treatment in 33.8%, and cf-PWV ≥ 10 m/s in 21.2%. On logistic regression analysis, age was independently related to cf-PWV ≥ 10 m/s (OR = 1.21; 95% CI 1.06‒1.38; p = 0.003) and MTX1500 was a protective cardiovascular factor (OR = 0.18; 95% CI 0.038‒0.87; p = 0.033). No association was observed between steatosis, AF or immunobiological therapy and cf-PWV ≥10 m/s.

Sample size.

In patients with Pso, increased AoS was associated with age, but not with steatosis or AF. A protective cardiovascular effect of MTX was found in a Pso population with a high prevalence of MetS and its components.

Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Metabolic-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There is a critical lack of reliable non-invasive diagnostic methods and effective pharmaceutical treatments for MAFLD/MASH, emphasizing the need for further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there is a significant gap in literature regarding the roles of EVs from hosts, plants, and microbiota in MAFLD. This review explores the potential of EVs from various sources-host, plants, and microbiota-as biomarkers, therapeutic agents, drug carriers, and treatment targets for MAFLD. Firstly, the roles of host-derived extracellular vesicles (EVs) in MAFLD, with a focus on cell-type specific EVs and their components-proteins, miRNAs, and lipids-for disease diagnosis and monitoring were discussed. Moreover, it highlighted the therapeutic potential of mesenchymal stem cell (MSC)-derived EVs in reducing lipid accumulation and liver injury, and immune cell-derived EVs in mitigating inflammation and fibrosis. The review also discussed the use of host-derived EVs as drug carriers and therapeutic targets due to their ability to deliver bioactive molecules that impact disease mechanisms. Additionally, it summarized research on plant-derived EVs, which help reduce liver lipid accumulation, inflammation, and enhance gut barrier function in MAFLD. Also, the review explored microbial-derived EVs as novel therapeutic targets, particularly in relation to insulin resistance, liver inflammation, and dysfunction in MAFLD. Overall, by exploring the diverse roles of EVs from host, plant, and microbiota sources in MAFLD, this review offers valuable insights into their potential as non-invasive biomarkers and novel therapeutic strategies, which could pave the way for more effective diagnostic and treatment options for this increasingly prevalent liver disease. Notably, the challenges of translating EVs into clinical practice were also thoroughly discussed, aiming to provide possible directions and strategies for future research.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a hepatic form of metabolic syndrome, often co-occurs with type 2 diabetes (T2D) and now affects approximately 30% of the global population. MASLD encompasses conditions from simple steatosis to metabolic dysfunction-associated steatohepatitis, with oxidative stress (OS) driving progression through inflammation. This study analyzes the expression levels of circulating miRNAs and redox status markers in MASLD patients with and without T2D, exploring their potential as disease biomarkers. The expressions of miR-21, miR-34a, and miR-122 were analyzed in the platelet-poor plasma of 147 participants, divided into three groups: MASLD + T2D (48), MASLD (50), and a control group (49). Total oxidant status (TOS), total antioxidant status (TAS), ischemia-modified albumin (IMA), and superoxide anion radical (O2•-) were measured in serum and plasma. Logistic regression showed that miR-21, miR-34a, TOS, TAS, O2•-, and IMA were positive predictors of MASLD, while miR-21 and TAS were negative predictors of T2D in MASLD. Although miR-122 did not show a significant association with either condition, in combination with miR-34a and other markers such as lipid status and liver enzymes, a new significant predictor of MASLD was identified. Circulating miRNAs in combination with redox status markers, lipid status and liver enzymes show potential as MASLD biomarkers.

Lifestyle-induced weight reduction remains crucial for managing type 2 diabetes and steatotic liver disease, but its effectiveness varies. We postulated that the G allele in the rs738409 single nucleotide polymorphism within patatin-like phospholipase domain-containing protein 3 (PNPLA3), which associates with metabolic dysfunction-associated steatotic liver disease, also modulates diet-related metabolic effects.

Participants with type 2 diabetes were randomized to 8-week hypocaloric diets (energy intake: -1,256 kJ/d of, <30 kcal% fat): high in cereal fiber and coffee excluding red meat (HF-RM + C; n = 16), or low in cereal fiber, devoid of coffee, but high in red meat (LF + RM-C; n = 15). Whole-body insulin sensitivity (M value) was assessed using [2H]glucose and hyperinsulinemic-normoglycemic clamps, hepatic lipid content (HCL) and body fat volumes by magnetic resonance spectroscopy/imaging before and after intervention.

Despite comparable weight loss, HCL decreased more in non-carriers (-65 %) than in G-allele carriers (-36 %) upon HF-RM + C diet (both p < 0.05 vs baseline and between groups), but only among non-carriers (-46 %, p < 0.05 vs baseline) upon LF + RM-C. Upon HF-RM + C diet, increase in insulin sensitivity was not different between carriers (+27 % p = 0.051 from baseline) and non-carriers (+21 %, p = 0.032 from baseline), p > 0.05 for between-group comparison. Upon LF + RM-C diet, both groups equally improved their whole-body insulin sensitivity (+42 % for non-carriers and +37 % for carriers, p < 0.05 vs baseline). Upon HF-RM + C diet, non-carriers decreased circulating interleukin-18 from baseline by -31 %, whereas, upon LF + RM-C diet, non-carriers decreased circulating anti-inflammatory interleukin-1 receptor antagonist levels by 14 % (both p < 0.05 vs baseline).

Humans with the PNPLA3 G-allele show modified dietary-induced effects on steatotic liver disease in type 2 diabetes despite body weight reduction. Registration at Clinicaltrials.gov, Identifier number: NCT01409330.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Naringenin (NAR) possesses various pharmacological activities including antioxidant, anti-inflammatory, and hepatoprotective effects. However, its therapeutic efficacy is limited by its hydrophobic and crystalline nature. This study aimed to investigate the therapeutic potential and molecular mechanisms of NAR efficiently loaded into cationic nanoparticles (NP-NAR) for treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a mouse model. The results demonstrated that NP-NAR effectively ameliorated lipid metabolism dysbiosis, oxidative stress, insulin resistance, and inflammation in MASLD mice. Transcriptomic analysis and molecular data revealed that NP-NAR promoted fatty acid oxidation via activation of the PPAR signaling pathway, reduced hepatic lipid uptake and lipogenesis by inhibiting the expressions of key genes including CD36, ACC, and FASN. Moreover, NP-NAR modulated cholesterol metabolism by inhibiting the classical bile acid synthesis pathway. 16 S rDNA gene sequencing revealed a disbalanced gut microbiota in MASLD mice, whereas NP-NAR treatment statistically reversed the abundance changes of several intestinal bacteria at the phylum and genus levels, which partly contributed to the balance in intestinal metabolite production, including short-chain fatty acids. In conclusion, these findings suggest that NP-NAR may be a promising candidate for the treatment of obesity-associated MASLD, offering new insight into the mechanisms underlying NAR's efficacy against MASLD.

We aimed to recognize the burden of NAFLD and support public health policy development for its prevention and management.

A cross-sectional analysis of GBD 2021 results was conducted.

We collected incidence data on NAFLD from 1990 to 2021 using Global Burden of Disease Study in 2021. Estimated annual percentage changes (EAPCs) in NAFLD age standardized incidence rate (ASR) were calculated to quantify the temporal trends in NAFLD ASR. Bayesian age-period-cohort models were constructed to project NAFLD incidence rates and cases up to 2050. Additionally, we assessed the percentage of cirrhosis and liver cancer attributable to NAFLD.

Globally, the newly-occurred cases of NAFLD increased by 94.49 % from 24, 856, 159 in 1990 to 48, 353, 272 in 2021. The case number will further increase to 78,602,984 in 2050, and ASR will increase from 5.93 per 1000 in 2021 to 7.26 per 1000 in 2050. The most pronounced increases were observed in young people and men. In 2021, NAFLD accounted for 82.7 % of cirrhosis and other chronic liver diseases and 8.0 % of liver cancer cases.

From 1990 to 2021, the incidence of NAFLD has been continuously increasing and is expected to continue rising until 2050. The increases in young people and men highlight their priority in future schedules. The rising proportions of cirrhosis and liver cancer caused by NAFLD further underscore the serious health risks.

Non-alcoholic fatty liver disease is a liver condition that is increasing globally. Unfortunately, there are no successful or approved pharmacological treatments for non-alcoholic fatty liver disease. Hence, this study aimed to investigate the effect of therapeutic lifestyle changes on patients with overweight/obesity and non-alcoholic fatty liver disease.

A prospective, parallel-group, randomized controlled trial was conducted. The patients were randomized into intervention and control groups using tables with random numbers. In the control group, routine health guidance was provided for 3 months, while in the intervention group, diversified lifestyle intervention was provided. The body composition, visceral fat area, abdominal circumference, and body mass index of the control and intervention groups were compared before and after the intervention. Descriptive statistics, paired t-tests, and linear regression models were used for data analysis.

A total of 115 participants (57 in the intervention group and 58 in the control group) completed the study. The intervention groups had significantly greater high-density lipoprotein cholesterol levels, basal metabolic rate, muscle mass, and questionnaire scores than the control groups (P < 0.05). Furthermore, the intervention participants had lower body mass index, abdominal circumference, triglyceride levels, low-density lipoprotein cholesterol levels, and fatty liver index (P < 0.05).

Therapeutic lifestyle changes therapy for non-alcoholic fatty liver disease patients with overweight/obesity can significantly control body mass index, improve blood lipid levels, reduce fatty liver and body fat rates, improve basic metabolism, alleviate disease, and improve quality of life. More research is needed to determine the long-term impact of therapeutic lifestyle changes in high-risk groups.

The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a broad and continuous spectrum of liver diseases ranging from fatty liver to steatohepatitis. The intricate interactions of genetic, epigenetic, and environmental factors in the development and progression of MASLD remain elusive. Here, we aimed to achieve an integrative understanding of the genomic and transcriptomic alterations throughout the progression of MASLD.

RNA-Seq profiling (n = 146) and whole-exome sequencing (n = 132) of MASLD liver tissue samples identified 3 transcriptomic subtypes (G1-G3) of MASLD, which were characterized by stepwise pathological and molecular progression of the disease. Macrophage-driven inflammatory activities were identified as a key feature for differentiating these subtypes. This subtype-discriminating macrophage interplay was significantly associated with both the expression and genetic variation of the dsDNA sensor IFI16 (rs6940, A>T, T779S), establishing it as a fundamental molecular factor in MASLD progression. The in vitro dsDNA-IFI16 binding experiments and structural modeling revealed that the IFI16 variant exhibited increased stability and stronger dsDNA binding affinity compared to the wild-type. Further downstream investigation suggested that the IFI16 variant exacerbated DNA sensing-mediated inflammatory signals through mitochondrial dysfunction-related signaling of the IFI16-PYCARD-CASP1 pathway.

This study unveils a comprehensive understanding of MASLD progression through transcriptomic classification, highlighting the crucial roles of IFI16 variants. Targeting the IFI16-PYCARD-CASP1 pathway may pave the way for the development of novel diagnostics and therapeutics for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is, increasingly, a major threat to human health, yet without any approved drug. β-carotene (BC) contributes to alleviating several metabolic diseases. However, the bioavailability of BC is hindered by hydrophobicity and environmental sensitivity. Herein, we explore the utilization of cationic lipid-assisted nanoparticles to achieve efficient delivery of BC. In the MASLD model, NP-BC ameliorated the development of metabolic disorders, insulin resistance, inflammatory injury and hepatic steatosis. Transcriptomic analysis showed that NP-BA rectifies various pathways involved in steatosis development by inhibiting the PI3K/AKT/mTOR pathway and PPARγ gene expression. Meanwhile, NP-BC also reshaped the composition of gut microbiota in MASLD mice by reducing the Firmicutes/Bacteroidetes ratio and increasing the abundance of beneficial bacteria. Taken together, our study demonstrates that NP-BC can improve MASLD and may be a promising candidate for treating MASLD.

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing at an alarming rate. To date, only one therapy has been provisionally approved for the treatment of MASH and liver fibrosis, and novel strategies are urgently needed. In addition, the frequent coexistence of MASH and type 2 diabetes has further intensified interest in devising comprehensive therapies to simultaneously tackle both diseases. We have recently shown that increasing hepatic and/or circulating levels of hexosaminidase A (HEXA), a lysosomal enzyme that remodels GM2 to GM3 gangliosides within lipid rafts, offers therapeutic benefits for metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Taking advantage of the MUP-uPA mouse model of MASH, including both wild-type (WT) mice with mild MASH and MUP-uPA mice with severe MASH and fibrosis, we show that biweekly treatment with a long-lasting HEXA-FC analog improves features of MASLD, including hepatic steatosis and hepatocyte ballooning, in mice with mild MASH, as well as glycemic control across both mouse models. Mechanistically, HEXA-FC enhances hepatic fatty acid oxidation and peripheral glucose disposal while not impacting endogenous glucose production. Together, these outcomes suggest that while HEXA-FC treatment may offer therapeutic benefits in mild MASH and insulin resistance, it is ineffective against severe MASH and liver fibrosis.NEW & NOTEWORTHY The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. Here, we show that chronic FC-HEXA recombinant protein treatment reduces hepatic lipid accumulation and improves blood glucose control in mice with mild MASH and insulin resistance.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

Exercise is a key component of lifestyle management in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but neither its therapeutic effect on the active stage of the disease, that is metabolic dysfunction-associated steatohepatitis (MASH) nor the mediating mechanisms have been characterized. Therefore, we performed multi-omic phenotyping of patients with MASLD-MASH on an exercise program.

Fifteen patients with MASLD conducted high-intensity interval training (HIIT) combined with home-based training for 12 weeks. MASLD was evaluated using histology, transient elastography, and multiparametric magnetic resonance imaging (MRI) before and after the intervention. Change in maximal oxygen consumption (VO2max) and MRI-determined liver fat were compared with a control group of patients with MASLD (n = 22). RNA sequencing was performed on liver, muscle, and fat biopsies of patients in the exercise group. Stool was analyzed by shotgun metagenomics and untargeted metabolomics was performed on plasma, urine, adipose, and stool.

HIIT increased VO2max by 10.1% and improved mitochondrial metabolism in skeletal muscle, indicating improved cardiorespiratory fitness and adherence. VO2max increased significantly in the exercise group compared with controls. Histologically, no reduction in steatosis, MASH, or liver fibrosis was observed; however, transient elastography tended to improve. MRI-determined liver fat did not change in the exercise group compared with controls. HIIT induced changes in mRNA expression of genes related to beiging of adipose tissue and fibrogenesis in liver. In addition, specific gut microbial taxa and metabolites changed.

HIIT increased cardiorespiratory fitness and induced beneficial gene expression changes in muscle, adipose tissue, and liver, but without translation into histological improvement of MASLD. Longer exercise intervention trials are warranted to validate or refute current recommendations for exercise as a cornerstone treatment for MASLD-MASH.

Despite exercise being considered as a key component of lifestyle management for steatotic liver disease, neither the clinical effects nor the mechanisms involved are completely understood. We show that a high-intensity interval training (HIIT) program in 15 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) improved cardiorespiratory fitness, compared with 22 control patients with MASLD who did not participate in an exercise program, however, it did not improve MASLD. HIIT induced a positive effect on fat tissue and muscle metabolism which was accompanied with changes in certain gut bacteria and metabolites in blood and urine. These findings improve our understanding of the effects of exercise on the whole-body metabolism in relation to steatotic liver disease. As such, this study provides a basis for future exercise interventions in patients with MASLD, required to thoroughly test current guideline advice for exercise as a cornerstone treatment for MASLD of all stages.

Dutch Trial Register (registration number NL7932).

The purpose of this study was to compare levels of pain and anxiety during percutaneous ultrasound-guided liver biopsy between patients receiving standard of care and those receiving standard of care plus the support of Ericksonian hypnosis.

This prospective, single-center, single-blind, randomized controlled superiority trial included 70 participants. Participants were randomly assigned to either the standard of care group and received oral anxiolytic medications with reassuring conversational support, or to the experimental group, and received Ericksonian hypnosis (i.e., conversational hypnosis) in addition to standard of care. The primary outcome was the level of pain experienced during the biopsy, measured on a 10-point visual analog scale (0 indicating no pain to 10 indicating excruciating pain). Secondary outcomes included anxiety level during the biopsy, pain level within one hour of the biopsy measured using the same 10-point visual analog scale, amount of analgesic medication taken in the 24 h following the biopsy, and patient willingness to undergo another ultrasound-guided percutaneous liver biopsy in the future.

Thirty-six participants were included in the standard of care group, and 34 were included in the experimental group. The mean score of pain experienced during the biopsy was lower in the experimental group (2.4 ± 1.9 [standard deviation (SD)]) compared to the standard of care group (4.4 ± 2.6 [SD]) (P = 0.001). The level of anxiety experienced during the biopsy was lower in the hypnosis group (2.1 ± 1.8 [SD]) compared to the standard of care group (4.8 ± 2.4 [SD]) (P < 0.001). No significant differences in other secondary outcomes were observed between the two groups.

The addition of Ericksonian hypnosis to standard of care reduces the pain experienced by patients during percutaneous ultrasound-guided percutaneous liver biopsy by comparison with standard of care alone.

The increasing prevalence of the spectrum of Steatotic Liver Disease (SLD), including Metabolic-Associated Steatotic Liver Disease (MASLD), Metabolic-Associated Steatohepatitis (MASH), and progression to Cirrhosis and Hepatocellular Carcinoma (HCC) has led to intense research in disease pathophysiology, with many studies focusing on the role of iron. Iron overload, which is often observed in patients with SLD as a part of metabolic hyperferritinaemia (MHF), particularly in the reticuloendothelial system (RES), can exacerbate steatosis. This imbalance in iron distribution, coupled with a high-fat diet, can further promote the progression of SLD by means of oxidative stress triggering inflammation and activating hepatic stellate cells (HSCs), therefore leading to fibrosis and progression of simple steatosis to the more severe MASH. The influence of iron overload in disease progression has also been shown by the complex role of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. Ferroptosis depletes the liver's antioxidant capacity, further contributing to the development of MASH, while its role in MASH-related HCC is potentially linked to alternations in the tumour microenvironment, as well as ferroptosis resistance. The iron-rich steatotic hepatic environment becomes prone to hepatocarcinogenesis by activation of several pro-carcinogenic mechanisms including epithelial-to-mesenchymal transition and deactivation of DNA damage repair. Biochemical markers of iron overload and deranged metabolism have been linked to all stages of SLD and its associated HCC in multiple patient cohorts of diverse genetic backgrounds, enhancing our daily clinical understanding of this interaction. Further understanding could lead to enhanced therapies for SLD management and prevention.