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Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD), in the context of autoimmune hepatitis (AIH) among liver transplantation (LT) candidates or recipients remains poorly understood. This study compares waitlist and post‐LT outcomes in patients with MASLD/AIH to MASLD and AIH alone. Methods: Using the united network organ sharing database (2002–2022), we compared waitlist outcomes and post‐LT survival among patients with MASLD/AIH (n = 282), AIH (n = 5812), and MASLD (n = 33 331). Competing risk, Kaplan Meier estimates and Cox proportional hazard analyses were performed. Results: MASLD/AIH group had the highest rates of encephalopathy and ascites, and highest MELD scores. MASLD/AIH patients had higher transplantation incidence (adjusted subdistribution hazard ratio [aSHR] 1.64, 95% CI 1.44–1.85; p <.001) and lower waitlist removal risk (aSHR.30, 95% CI.20–.44; p <.001) compared to MASLD alone. One‐year post‐LT survival favoured MASLD compared to AIH (patient: 92% vs. 91%, p <.001; graft: 89% vs. 88%, p <.001) and MASLD/AIH (patient: 92% vs. 90%, p =.008; graft: 89% vs. 88%, p =.023). Recipients with MASLD/AIH showed no significant difference in survival at 10‐year post‐LT compared to MASLD (patient: 63% vs. 61%, p =.68; graft 60% vs. 59%, p =.83) and AIH (patient: 63% vs. 70%, p =.07; graft: 60% vs. 64%, p =.42). Conclusions: Our study showed that MASLD/AIH patients demonstrate higher LT incidence and lower dropout rates. Long‐term post‐LT outcomes did not significantly differ between groups. Further prospective multicenter studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Introduction: The cumulative impact of metabolic syndrome (MetS) components on micro‐ and macrovascular disease in metabolic dysfunction‐associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro‐ and macrovascular disease in patients with MASLD. Methods: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow‐up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex. Results: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55–22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45–8.13)). MASLD with all MetS components carried greatest risk of both micro‐ (31.20 (28.88–33.70) (n = 462 789)) and macrovascular (8.04 (7.33–8.82) (n = 336 010)) disease. Conclusion: We demonstrate a differential effect of MetS components on micro‐ and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro‐ and macrovascular complications. [ABSTRACT FROM AUTHOR]

Background & Aims: There is an unmet need for a reliable and reproducible non‐invasive measure of fatty liver content (FLC) for monitoring steatotic liver disease in clinical practice. Sonographic FLC assessment is qualitative and operator‐dependent, and the dynamic quantification range of algorithms based on a single ultrasound (US) parameter is unsatisfactory. This study aims to develop and validate a new multiparametric algorithm based on B‐mode images to quantify FLC using Magnetic Resonance (MR) values as standard reference. Methods: Patients with elevated liver enzymes and/or bright liver at US (N = 195) underwent FLC evaluation by MR and by US. Five US‐derived quantitative features [attenuation rate(AR), hepatic renal‐ratio(HR), diaphragm visualization(DV), hepatic‐portal‐vein‐ratio(HPV), portal‐vein‐wall(PVW)] were combined by mixed linear/exponential regression in a multiparametric model (Steatoscore2.0). One hundred and thirty‐four subjects were used for training and 61 for independent validations; score‐computation underwent an inter‐operator reproducibility analysis. Results: The model is based on a mixed linear/exponential combination of 3 US parameters (AR, HR, DV), modelled by 2 equations according to AR values. The computation of FLC by Steatoscore2.0 (mean ± std, 7.91% ± 8.69) and MR (mean ± std, 8.10% ± 10.31) is highly correlated with a low root mean square error in both training/validation cohorts, respectively (R = 0.92/0.86 and RMSE = 5.15/4.62, p <.001). Steatoscore2.0 identified patients with MR‐FLC≥5%/≥10% with sensitivity = 93.2%/89.4%, specificity = 86.1%/95.8%, AUROC = 0.958/0.975, respectively and correlated with MR (R = 0.92) significantly (p <.001) better than CAP (R = 0.73). Conclusions: Multiparametric Steatoscore2.0 measures FLC providing values highly comparable with MR. It is reliable, inexpensive, easy to use with any US equipment and qualifies to be tested in larger, prospective studies as new tool for the non‐invasive screening and monitoring of FLC. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Metabolic dysfunction‐associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction‐associated steatotic liver disease (LC‐MASLD) by geographical region, age and sex during 1990–2021.Global Burden of Diseases Study 2021 data were analysed to assess LC‐MASLD incidence, prevalence, mortality and disability‐adjusted life years (DALYs). Temporal trends during 1990–2021 were measured by ‘estimated annual percentage change’ (EAPC). Inequalities of LC‐MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI).During 1990–2021, LC‐MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC‐MASLD incidence was earliest in the 15–19 age group, both prevalence and DALY rates peaked at 75–79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990–2021, demonstrated by a decline in SII from −0.09 to −0.56 per 100 000 for mortality and from 1.41 to −7.74 per 100 000 for DALYs. RCI demonstrated similar findings.The LC‐MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990–2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations. [ABSTRACT FROM AUTHOR]

Computational quantification reduces observer‐related variability in histological assessment of metabolic dysfunction‐associated steatotic liver disease (MASLD). We undertook stain‐free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second‐harmonic generation/two‐photon excitation fluorescence (TPEF) microscopy, and all‐cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all‐cause mortality (index >.14 vs. .31 vs.

Background: Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects approximately 20%–30% of the general population and is linked to high‐caloric western style diet. However, there are little data that specific nutrients might help to prevent steatosis. Methods: We analysed the UK Biobank (ID 71300) 24 h‐nutritional assessments and investigated the association between nutrient intake calculated from food questionnaires and hepatic steatosis indicated by imaging or ICD10‐coding. The effect of manganese (Mn) on subgroups with risk single nucleotide polymorphism carriage as well as the effect on metabolomics was investigated. All analyses are corrected for age, sex, body mass index, Townsend index for socioeconomic status, kcal, alcohol, protein intake, fat intake, carbohydrate intake, energy from beverages, diabetes, physical activity and for multiple testing. Results: We used a random forest classifier to analyse the feature importance of 63 nutrients and imaging‐proven steatosis in a cohort of over 25 000 UK Biobank participants. Increased dietary Mn intake was associated with a lower likelihood of MRI‐diagnosed steatosis. Subsequently, we conducted a cohort study in over 200 000 UK Biobank participants to explore the relationship between Mn intake and hepatic or cardiometabolic outcomes and found that higher Mn intake was associated with a lower risk of ICD‐10 coded steatosis (OR =.889 [.838–.943], p <.001), independent of other potential confounders. Conclusion: Our study provides evidence that higher Mn intake may be associated with lower odds of steatosis in a large population‐based sample. These findings underline the potential role of Mn in the prevention of steatosis, but further research is needed to confirm these findings and to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of bile acids (BAs), as important signalling molecules in regulating lipid and glucose metabolism, contributes to the development of non‐alcoholic fatty liver disease (NAFLD). However, static BA profiles during fasting may obscure certain pathogenetic aspects. In this study, we investigate the dynamic alterations of BAs in response to an oral glucose tolerance test (OGTT) among children with NAFLD. Methods: We recruited 230 subjects, including children with overweight/obesity, or complicated with NAFLD, and healthy controls. Serum BAs, 7‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19 (FGF19) were quantified during OGTT. Clinical markers related to liver function, lipid metabolism and glucose metabolism were assessed at baseline or during OGTT. Findings: Conjugated BAs increased while unconjugated ones decreased after glucose uptake. Most BAs were blunted in response to glucose in NAFLD (p >.05); only glycine and taurine‐conjugated chenodeoxycholic acid (CDCA) and cholic acid (CA) were responsive (p <.05). Primary BAs were significantly increased while secondary BAs were decreased in NAFLD. C4 and FGF19 were significantly increased while their ratio FGF19/C4 ratio was decreased in NAFLD. The dynamic pattern of CDCA and taurine‐conjugated hyocholic acid (THCA) species was closely correlated with glucose (correlation coefficient r =.175 and −.233, p <.05), insulin (r =.327 and −.236, p <.05) and c‐peptide (r =.318 and −.238, p <.05). Among which, CDCA was positively associated with liver fat content in NAFLD (r =.438, p <.05). Additionally, glycochenodeoxycholic acid (GCDCA), CDCA and THCA were potential biomarkers to discriminate paediatric NAFLD from healthy controls and children with obesity. Interpretation: This study provides novel insights into the dynamics of BAs during OGTT in paediatric NAFLD. The observed variations in CDCA and HCA species were associated with liver dysfunction, dyslipidaemia and dysglycaemia, highlighting their potential roles as promising diagnostic and therapeutic targets in NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction‐associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention‐induced fibrosis changes in MASH. Methods: We examined unstained sections from paired liver biopsies (baseline and end‐of‐intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. Results: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI‐induced liver fibrosis regression was concentrated in the periportal region. Conclusion: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle‐induced fibrosis regression and placebo responses, which is not captured by conventional histological staging. [ABSTRACT FROM AUTHOR]

Background and Aims: We examined the impact of a co‐diagnosis of metabolic dysfunction‐associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes. Methods: Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time‐to‐event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper.1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes‐related, and cancer events over 5 years. Results: Analysis 1 (n = 95 275): a co‐diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver‐related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co‐diagnosis of MASLD significantly increased risk of all‐cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation. Conclusions: T2D significantly potentiates the risk of cardiovascular, malignancy and liver‐related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Previous studies have reported an association between metabolic dysfunction‐associated steatotic liver disease (MASLD) and the risk of serious bacterial infections. However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain. We performed a meta‐analysis of observational studies to quantify the association between MASLD and serious bacterial infections requiring hospital admission.We systematically searched PubMed, Scopus, Web of Science and Embase from database inception to 1 April 2024, using predefined keywords to identify studies examining the risk of serious bacterial infections among individuals with and without MASLD. MASLD was diagnosed using liver biopsy, imaging or International Classification of Diseases codes. Meta‐analysis was performed using random‐effects modelling.We identified six cross‐sectional and two prospective cohort studies with aggregate data on ~26.6 million individuals. MASLD was significantly associated with higher odds of serious bacterial infections (pooled random‐effects odds ratio 1.93, 95% confidence interval [CI] 1.44–2.58; I2 = 93%). Meta‐analysis of prospective cohort studies showed that MAFLD was associated with an increased risk of developing serious bacterial infections (pooled random‐effects hazard ratio 1.80, 95% CI 1.62–2.0; I2 = 89%). This risk further increased across the severity of MASLD, especially the severity of fibrosis (pooled random‐effects hazard ratio 2.42, 95% CI 1.89–2.29; I2 = 92%). These results remained significant after adjusting for age, sex, obesity, diabetes and other potential confounders. Sensitivity analyses did not modify these findings. The funnel plot did not reveal any significant publication bias.This meta‐analysis shows a significant association between MASLD and an increased risk of serious bacterial infections requiring hospital admission. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction–associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction–associated steatohepatitis, fibrosis and liver‐related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex‐specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex‐specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusion Metabolic dysfunction‐associated steatohepatitis (MASH) with bridging fibrosis is a critical stage in the evolution of fatty liver disease. Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) provides sensitive and reproducible quantitation of liver fibrosis. This methodology was applied to gain an in‐depth understanding of intra‐stage fibrosis changes and septa analyses in a homogenous, well‐characterised group with MASH F3 fibrosis.Paired liver biopsies (baseline [BL] and end of treatment [EOT]) of 57 patients (placebo, n = 17 and tropifexor n = 40), with F3 fibrosis stage at BL according to the clinical research network (CRN) scoring, were included. Unstained sections were examined using SHG/TPEF microscopy with AI. Changes in liver fibrosis overall and in five areas of liver lobules were quantitatively assessed by qFibrosis. Progressive, regressive septa, and 12 septa parameters were quantitatively analysed.qFibrosis demonstrated fibrosis progression or regression in 14/17 (82%) patients receiving placebo, while the CRN scoring categorised 11/17 (65%) as ‘no change’. Radar maps with qFibrosis readouts visualised quantitative fibrosis dynamics in different areas of liver lobules even in cases categorised as ‘No Change’. Measurement of septa parameters objectively differentiated regressive and progressive septa (p < .001). Quantitative changes in individual septa parameters (BL to EOT) were observed both in the ‘no change’ and the ‘regression’ subgroups, as defined by the CRN scoring.SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post‐LT setting of patients transplanted for metabolic dysfunction‐associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings.This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1‐year after LT.In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16–46) and 26.0 (IQR: 16.8–41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0–5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post‐LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8–80.4, p = .010) and post‐LT dyslipidaemia (OR: 7.9, 95% CI: 1.3–47.1, p = .024) with LSM (OR: 1.7, 95% CI: 1.1–2.8, p = .030) was independently associated with MASLD.Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) in patients with alcohol‐associated hepatitis (AH) has rapidly increased following the coronavirus disease 2019 pandemic and the implementation of the Acuity Circle policy, raising questions of equity and utility. Waitlist mortality among high (≥37) Model for End‐Stage Liver Disease LT candidates with AH and post‐transplant survival were assessed with a semiparametric survival regression and a generalized linear mixed‐effect model with LT centre‐ and listing date‐level random intercepts. These models demonstrate a lower mortality for the candidates listed with AH (adjusted sub‐hazard ratio.58_.72_.90 and odds ratio.44_.66_.99) when compared to other diagnoses (autoimmune hepatitis, metabolic dysfunction‐associated fatty liver disease and primary biliary cholangitis). Post‐LT survival was comparable. This study highlights the limitations of current tools in characterizing the risk of mortality, and thus need for the modifications in prioritizing LT candidates with AH. Policy revision may be needed to ensure equivalent access to LT regardless of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Glucosamine is a dietary supplement commonly used to support joint health. However, there has been interest in exploring other effects of glucosamine on health outcomes due to its ant‐inflammation effect. Objective: This study compared the risks of major adverse liver outcomes (MALOs) between regular users and non‐users of glucosamine among patients with type 2 diabetes and metabolic dysfunction associated steatotic liver disease (MASLD) using the data from a large prospective cohort study. Methods: Demographic, anthropometric, laboratory and medication prescription information among 18 753 patients with type 2 diabetes and MASLD was obtained from the UK Biobank. MASLD was identified based on hepatic steatosis defined by fatty liver index ≥60 plus the presence of any clues of metabolic dysregulation and cardio‐metabolic risk factors, excluding patients with moderate to severe alcohol consumption. Results: During a mean follow‐up of 11.4 years, 826 incident MALOs events were recorded. Patients not regularly using glucosamine compared with patients using glucosamine showed a significantly higher risk of the composite MALOs (HR 1.36, 95% confidence interval [CI] 1.09–1.69) as well as most individual MALOs except for ascites. The multivariable‐adjusted HRs of MALOs within 3, 5 and 10 years among non‐users of glucosamine compared with regular users were 1.79 (95% CI.69–2.03), 1.88 (95% CI 1.21–2.54) and 1.32 (95% CI 1.05–1.72), respectively. Further subgroup analyses in participants with different baseline characteristics and sensitivity analyses excluding participants who regularly took any other supplements and participants who used self‐reports to diagnose diabetes confirmed the findings. Conclusions: The present study indicated that habitual use of glucosamine was associated with a low risk of individual and composite MALOs among patients with type 2 diabetes and MASLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non‐coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. Methods: RNA‐binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y‐Box binding protein 1 (YBX1) were identified by RNA‐seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin‐like phospholipase domain containing 3 (PNPLA3) in MASLD progression. Results: Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up‐regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction‐associated steatohepatitis development. Conclusions: In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise is recommended for the management of metabolic dysfunction‐associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12–20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI‐measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Results: Eighty‐eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5‐fold (OR [95%CI]: 4.86 [1.72, 13.8], p =.002) greater odds of ≥30% relative reduction in MRI‐measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum‐ and imaging‐based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight‐neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non‐alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter‐organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra‐ and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver‐gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra‐hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH. [ABSTRACT FROM AUTHOR]

Background and Aims: Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction‐associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy‐1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. Methods: The impact of Thy‐1 on the development of SLD and progression to fibrosis was investigated in high‐fat diet (HFD)‐induced SLD wild‐type and Thy‐1‐deficient mice. In addition, the serum soluble Thy‐1 (sThy‐1) concentration was analysed in patients with metabolic dysfunction‐associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. Results: We demonstrated that Thy‐1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD‐induced SLD mice. Mechanistically, Thy‐1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy‐1 prevents palmitic acid‐mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy‐1‐deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy‐1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. Conclusion: Our data strongly suggest that Thy‐1 may function as a fibrosis‐protective factor in mouse and human SLD. [ABSTRACT FROM AUTHOR]

Background and Aims: Non‐invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction‐associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice. Methods: We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis. Results: Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system‐level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost‐effectiveness to payers. Conclusions: This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system‐level barriers. Multi‐level interventions are likely required to address these barriers. [ABSTRACT FROM AUTHOR]

Background and Aims: The presence of steatosis in a donor liver and its relation to post‐transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro‐ and macro‐steatosis of a donor graft on post‐transplantation outcomes. Methods: The UNOS‐STAR registry (2005–2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro‐ or micro‐vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all‐cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. Results: There were 9184 with no macro‐steatosis (control), 150 with grade 3 macro‐steatosis, 822 with grade 2 macro‐steatosis and 12 585 with grade 1 macro‐steatosis. There were 10 320 without micro‐steatosis (control), 478 with grade 3 micro‐steatosis, 1539 with grade 2 micro‐steatosis and 10 404 with grade 1 micro‐steatosis. There was no significant difference in all‐cause mortality or graft failure among recipients who received a donor organ with any evidence of macro‐ or micro‐steatosis, compared to those receiving non‐steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro‐steatosis donor organ. Conclusion: This study shows no significant difference in all‐cause mortality or graft failure among recipients who received a donor liver with any degree of micro‐ or macro‐steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro‐ and micro‐steatosis. [ABSTRACT FROM AUTHOR]

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as an alternative for the validated definition of metabolic dysfunction-associated fatty liver disease (MAFLD). We compared the abilities of MAFLD and MASLD to predict the risk of atherosclerotic cardiovascular disease (ASCVD). Methods: Six thousand and ninety six participants from the 2017 to 2020 National Health and Nutrition Examination Survey cohort who received a thorough medical health check-up were chosen for the study. The associations between fatty liver status and coronary risk surrogates, such as 10-year ASCVD risk and self-reported cardiovascular events, were analysed. Results: MAFLD and MASLD were identified in 2911 (47.7%) and 2758 (45.2%) patients, respectively. MAFLD (odds ratio [OR]: 2.14, 95% confidence interval [CI], 1.782.57, p < .001) was more strongly independently associated with high ASCVD risk than MASLD (OR: 1.82, 95% CI, 1.52-2.18, p < .001) was in comparison with the absence of each condition. However, compared with MAFLD, MASLD alone was not associated with increased ASCVD risk. Multiple logistic regression revealed that MAFLD alone was significantly more strongly associated with a high risk of ASCVD (OR: 2.82; 95% CI: 1.13-7.01; p<.03) than MASLD alone. Conclusions: Although both MAFLD and MASLD were associated with different ASCVD risks, MAFLD predicted the ASCVD risk better than MASLD. The higher predictive ability of MAFLD compared to MASLD was attributed to metabolic dysfunction rather than moderate alcohol use. [ABSTRACT FROM AUTHOR]

Background & Aims: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. Methods: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. Results: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF >5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF ≥-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa). Conclusions: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa). [ABSTRACT FROM AUTHOR]

This article discusses the role of genetic factors in the development of liver diseases, specifically steatotic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The study focuses on a case study of a patient with familial hypobetalipoproteinemia (FHBL), a genetic disorder characterized by low levels of LDL-cholesterol and ApoB. The patient had a heterozygous mutation in the APOB gene, as well as common genetic variants in the PNPLA3 and TM6SF2 genes. These genetic factors contributed to the development of liver disease, which was successfully treated with a liver transplant. The study emphasizes the importance of genetic analysis in understanding and treating liver diseases. [Extracted from the article]

Background and Aims: Abnormal liver chemistries are common in Turner syndrome (TS). Guidelines suggest that TS patients undergo annual screening of liver enzymes, but the role of non‐invasive screening for steatosis and fibrosis is not clearly defined. We compared the prevalence of hepatic steatosis and fibrosis among TS patients to healthy controls using ultrasound with shear‐wave elastography (SWE) and assessed for risk factors associated with steatosis and fibrosis in TS. Methods: Prospective case–control study of TS versus control patients from 2019 to 2021. All patients underwent abdominal ultrasound with doppler and SWE to assess hepatic fibrosis and steatosis. Risk factors were compared between TS and controls, as well as within the TS group. Results: A total of 55 TS and 50 control patients were included. Mean age was 23.6 years vs. 24.6 years in the control group (p =.75). TS patients had significantly more steatosis (65% vs. 12%, stage 1 vs. 0, p <.0001) and fibrosis (39% vs. 2%, average Metavir F2 vs. F0, p <.00001) than controls. These findings remained significant after adjusting for body mass index (BMI) (p <.01). GGT is more sensitive than AST or ALT in identifying these changes. Conclusion: TS is associated with an increased prevalence of hepatic steatosis and fibrosis compared to healthy controls. Our findings suggest that serum GGT and ultrasound with SWE may help identify TS patients with liver disease. Early risk factor mitigation including timely oestrogen replacement, weight control, normalization of lipids and promoting multidisciplinary collaboration should be encouraged. [ABSTRACT FROM AUTHOR]

The article discusses the newly proposed definition of metabolic dysfunction-associated fatty liver disease (MAFLD) and its ability to identify three distinct groups of patients. The study analyzed data from a national health survey and categorized individuals into four groups: no MAFLD, MAFLD-overweight/obese, MAFLD-diabetes, and MAFLD-lean. The comparison of clinical and biochemical features among the groups revealed distinct characteristics, with the MAFLD-diabetes group showing the highest risk factors. The study also found that participants in the MAFLD-lean group had a lower risk of all-cause mortality compared to the other groups. The findings support the utility of the MAFLD definition in identifying homogeneous patient groups and predicting outcomes. [Extracted from the article]

Background: Metabolic dysfunction‐associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N‐terminal propeptide of collagen type 3 (PRO‐C3) is a biomarker of advanced fibrosis in MAFLD and PRO‐C3 may be involved in renal fibrosis. We aimed to use PRO‐C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD–CKD). Methods: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy‐confirmed MAFLD were included. Serum PRO‐C3 concentration was measured and regression analyses were performed to examine associations with MAFLD–CKD. A derivative algorithm for MAFLD–CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. Results: The study included two Asian cohorts (n = 180 with MAFLD–CKD; mean‐eGFR: 94.93 mL/min/1.73 m2; median‐urinary albumin‐to‐creatinine ratio: 6.58 mg/mmol). PRO‐C3 was associated with the severity of MAFLD‐CKD and independently associated with MAFLD–CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08–1.23, p <.001). A new non‐invasive score (termed PERIOD) including PRO‐C3 efficiently predicted MAFLD‐CKD (AUROC =.842, 95% CI:.805–.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC =.807, 95% CI:.691–.893) with similar results in all patient subgroups. In the MAFLD–CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO‐C3‐based ADAPT with the Agile 3+ scores (AUROC =.90, 95% CI:.836–.964). Conclusions: The PERIOD score is helpful for accurately predicting the risk of MAFLD–CKD. PRO‐C3 can also be used to assess liver fibrosis in people with MAFLD–CKD. [ABSTRACT FROM AUTHOR]

Background and Aims: The beneficial effect of Hepatitis C virus (HCV) eradication by direct antiviral agents (DAAs) on liver fibrosis is well defined. Despite this, the impact of viral eradication in both hepatic and extra‐hepatic metabolic features is underreached. This systematic review aimed to synthesize the evidence on the impact of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, glucidic impairment, dyslipidaemia, and weight gain. Methods: A systematic search of the existing literature (up to December 2022) identified 97 original studies that fulfilled the inclusion criteria. Results: Whereas total cholesterol and low‐density lipoprotein (LDL) seem to increase after viral eradication, the cardiovascular damage expressed as carotid plaques and intima‐media thickness seems to improve. Otherwise, the effect on liver steatosis, glucidic homeostasis, and weight seems to be strictly dependent on the presence of baseline metabolic disorders. Conclusion: Despite high heterogeneity and relatively short follow‐up of included studies, we can conclude that the presence of metabolic risk factors should be strictly evaluated due to their impact on liver steatosis, glucidic and lipid homeostasis, and on weight gain to better identify patients at risk of liver disease progression despite the virus eradication. [ABSTRACT FROM AUTHOR]

Background and Aims: Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non‐alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross‐validation approach to assess this interaction in bariatric patients. Methods: 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non‐alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. Results: We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3‐(3‐hydroxyphenyl)‐3‐hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3–F4) versus F0 had lower abundance of anti‐inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol‐10 biosynthesis and Peptidoglycan biosynthesis IV. Conclusions: In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity. [ABSTRACT FROM AUTHOR]

Background & Aims: FibroScan® Expert 630 and FibroScan® Mini+430 are novel vibration‐controlled transient elastography devices equipped with the same SmartExam software, which allows continuous measurement of controlled attenuation parameter (CAP) during the entire examination. This study aims to compare the CAP variabilities and the quantification for liver fibrosis and steatosis between the conventional FibroScan and the SmartExam‐equipped machines in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods: This retrospective study included 118 patients with biopsy‐proven MASLD who underwent liver biopsy at two tertiary centres between 2021 and 2023. Liver stiffness and steatosis measurements were performed using both FibroScan machines and M and XL probes for each individual. Liver histology was used as the reference standard for liver fibrosis and steatosis staging. Results: Standard deviations of continuous CAP (cCAP) were significantly lower than those of CAP for all probes (p <.0001). CAP variability was significantly associated with body mass index (p <.01), probe selection (p <.001) as well as the random effect of centre. Only the effect of probe selection (p <.001) was significantly associated with cCAP variability. No significant difference was found in the performance of staging liver fibrosis and steatosis between two types of machines at the same cut‐offs. Conclusions: The SmartExam‐based VCTE reduces the variability of CAP measurement and achieves a similar accuracy as the FibroScan 502 device for the estimation of both hepatic steatosis and fibrosis. Future studies should determine if cCAP is a better tool to monitor changes in steatosis than the original CAP. [ABSTRACT FROM AUTHOR]

Background and Aims: Emerging evidence suggests a detrimental impact of high red meat intake on hepatic steatosis. We investigated the potential interplay between red meat intake and gut microbiome on circulating levels of trimethylamine N‐oxide (TMAO) and hepatic steatosis risk. Methods: This cross‐sectional study was conducted in a representative sample of 754 community‐dwelling adults in Huoshan, China. Diet was collected using 4 quarterly 3 consecutive 24‐h dietary (12‐day) recalls. We profiled faecal microbiome using 16S ribosomal RNA sequencing and quantified serum TMAO and its precursors using LC‐tandem MS (n = 333). We detected hepatic steatosis by FibroScan. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Results: TMAO levels but not its precursors were positively associated with the likelihood of hepatic steatosis (aOR per 1‐SD increment 1.86, 95% CI 1.04–3.32). We identified 14 bacterial genera whose abundance was associated with TMAO concentration (pFDR <.05) belonging to the phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria families. Per 10 g/day increase in red meat intake was positively associated with TMAO levels among participants who had higher red meat intake (>70 g/day) and higher TMAO‐predicting microbial scores (TMS, β =.045, p =.034), but not among others (pinteraction =.030). TMS significantly modified the positive association between red meat and steatosis (pinteraction =.032), with a stronger association being observed among participants with higher TMS (aOR 1.30, 95% CI 1.07–1.57). Conclusions: The bacterial genera that predicted TMAO levels may jointly modify the association between red meat intake and TMAO levels and the subsequent risk of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime‐reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization. Methods: We overexpressed the human MARC1 A165 (wild‐type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH‐7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization. Results: MARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild‐type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine‐48 ubiquitin‐mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization. Conclusions: This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Following the classification of metabolic dysfunction‐associated fatty liver disease (MAFLD), non‐alcoholic fatty liver disease (NAFLD) has recently been redefined again as metabolic dysfunction‐associated steatotic liver disease (MASLD). However, the distinctions in characteristics and mortality outcomes between NAFLD, MAFLD and MASLD remain unclear. Methods: We analysed data from 7519 participants in the third National Health and Nutrition Examination Surveys of United States (US) and their linked mortality until 2019. Survey weight‐adjusted multivariable Cox proportional model was used to study the mortality over three terms. Results: The prevalence of NAFLD, MAFLD and MASLD was 18.5%, 19.3% and 20.8%, respectively. Most individuals with NAFLD (94.5%) or MAFLD (100%) can be classified as MASLD, while a relatively low percentage of those with MASLD were also diagnosed with either NAFLD (84.1%) or MAFLD (92.7%). During a median follow‐up of 26.9 years, both MAFLD and MASLD were associated with increased risk of all‐cause mortality (adjusted hazard ratio [aHR] 1.18, 95% CI 1.04–1.33 and 1.19, 1.06–1.34, respectively), this association was mainly observed in NAFLD−/MASLD+ subgroups. NAFLD was not associated with all‐cause mortality. However, all three terms were associated with an increased risk of all‐cause mortality in individuals with advanced fibrosis (aHR: 1.71–1.81). Subgroup analyses showed that higher risk of all‐cause mortality for both MAFLD and MASLD were observed among older adults (≥65 year), non‐Hispanic whites and those without diabetes. Conclusions: Both MASLD and MALFD were linked to higher all‐cause mortality risk, but MASLD identified a greater number of individuals compared to MAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: The cost‐effectiveness to screen hepatic fibrosis in at‐risk population as recommended by several professional societies has been limited. This study aimed to investigate the cost‐effectiveness of this screening strategy in the expanded at‐risk population recently proposed by several societies. Methods: A combined model of the decision tree and Markov models was developed to compare expected costs, quality‐adjusted life‐years (QALYs) and incremental cost‐effectiveness ratio (ICER) between screening and no screening groups. The model included liver disease‐related health states and cardiovascular disease (CVD) states as a base‐case analysis. Screening strategy consisted of fibrosis‐4 index (FIB‐4) followed by vibration‐controlled transient elastography (VCTE) and intensive lifestyle intervention (ILI) as a treatment for diagnosed patients. Results: Cost‐effectiveness analysis showed that screening the at‐risk population entailed $298 incremental costs and an additional 0.0199 QALY per patient compared to no screening (ICER $14 949/QALY). Screening was cost‐effective based on the implicit ICER threshold of $25 000/QALY in Korea. When the effects of ILI on CVD and extrahepatic malignancy were incorporated into the cost‐effectiveness model, the ICER decreased by 0.85 times from the base‐case analysis (ICER $12 749/QALY). In contrast, when only the effects of liver disease were considered in the model, excluding cardiovascular disease effects, ICER increased from the baseline case analysis to $16 305. Even when replacing with medical costs in Japan and U.S., it remained cost‐effective with the estimate below the countries' ICER threshold. Conclusions: Our study provides compelling evidence supporting the cost‐effectiveness of FIB‐4‐based screening the at‐risk population for advanced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aims: The relationship between moderate alcohol intake and health outcomes among individuals with metabolic dysfunction‐associated fatty liver disease (MAFLD) is complex. Our aim was to investigate the association of minimal alcohol consumption with all‐cause and cause‐specific mortality among MAFLD individuals of different genders. Methods: Our study included 2630 MAFLD individuals from the Third National Health and Nutrition Examination Survey. Cox regression analysis was performed to assess the association between alcohol use measures and all‐cause and cause‐specific mortality. Restricted cubic spline curves were used to evaluate the relationship between alcohol consumption per week and all‐cause mortality. Results: In the entire MAFLD cohort, we observed significant disparities in clinical characteristics between male and female individuals with MAFLD. Higher weekly alcohol consumption was significantly associated with all‐cause and cause‐specific mortality (male, hazard ratios [HRs]: 1.009, 95% CIs: 1.004–1.014; female, HRs: 1.032, 95% CIs: 1.022–1.042). In males with MAFLD, a linear association with all‐cause mortality was observed for weekly alcohol consumption (p for non‐linearity =.21). Conversely, in females with MAFLD, the risk of all‐cause mortality remained relatively stable until 2 drinks per week, after which it rapidly increased with each additional drink consumed, and the increase in mortality risk was higher than that observed in males (p for non‐linearity <.05). Conclusions: Our findings indicate that any increase in weekly alcohol consumption was associated with increased all‐cause mortality in men with MAFLD. Conversely, consuming less than 2 drinks per week had minimal impact on the risk of mortality among female. [ABSTRACT FROM AUTHOR]

Metabolic‐associated steatotic liver disease (MASLD) encompasses a wide spectrum of metabolic conditions associated with an excess of fat accumulation in the liver, ranging from simple hepatic steatosis to cirrhosis and hepatocellular carcinoma. Finding appropriate tools to study its development and progression is essential to address essential unmet therapeutic and staging needs. This review discusses advantages and shortcomings of different dietary, chemical and genetic factors that can be used to mimic this disease and its progression in mice from a hepatic and metabolic point of view. Also, this review will highlight some additional factors and considerations that could have a strong impact on the outcomes of our model to end up providing recommendations and a checklist to facilitate the selection of the appropriate MASLD preclinical model based on clinical aims. [ABSTRACT FROM AUTHOR]

Background and Aims: Thyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction‐associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease. Methods: Subjects were recruited and had liver biopsies in two Gastroenterology‐Hepatology Clinics (Greece and Australia) and one Bariatric‐Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid‐stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to <2.5 uIU/mL); euthyroidism with relatively high (2.5–4.0 uIU/mL); subclinical hypothyroidism (>4 uIU/mL). Results: TSH as a continuous variable was positively associated with significant fibrosis (F ≥ 2), metabolic dysfunction‐associated steatohepatitis (MASH) and at‐risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p =.02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p =.001) and at‐risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p =.001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor‐15 were examined as moderators, significance was lost. Sex‐specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes (p‐values <.01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at‐risk MASH being 6.96. Conclusions: These observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver‐specific thyroid receptor agonists for subjects across the TSH continuum. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction‐associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. Methods: This nationwide cohort study included 9 298 497 patients who participated in a health‐screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non‐MAFLD, diabetes mellitus (DM)‐MAFLD, overweight/obese‐MAFLD and lean‐MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all‐cause and extrahepatic malignancy‐related mortality. Results: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow‐up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM‐MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11–1.14; p <.001) and the lean‐MAFLD (aSHR = 1.12; 95% CI = 1.10–1.14; p <.001) groups were associated with higher risks of extrahepatic malignancy than the non‐MAFLD group. However, the overweight/obese‐MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non‐MAFLD group (aSHR = 1.00; 95% CI =.99–1.00; p =.42). These findings were reproduced in several sensitivity analyses. The DM‐MAFLD was an independent risk factor for all‐cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40–1.43; p <.001) and extrahepatic malignancy‐related mortality (aHR = 1.20; 95% CI = 1.17–1.23; p <.001). Conclusion: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non‐MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required. [ABSTRACT FROM AUTHOR]

Background & Aims: Gut–vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli (E. coli) NF73‐1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB. Methods: C57BL/6J mice were fed with high‐fat diet (HFD) or normal diet in the presence or absence of E. coli NF73‐1 for the indicated time periods. Intestinal barrier function and infiltration of immune cells were evaluated in these mice. Endothelial cells were exposed to E. coli NF73‐1 for barrier integrity analysis. Results: HFD‐induced GVB disruption preceded the damage of intestinal epithelial barrier (IEB) as well as intestinal and hepatic inflammatory changes and can be reversed by vascular endothelial growth factor A blockade. Antibiotic treatment prevented mice from HFD‐induced liver steatosis by restoration of the GVB. Notably, E. coli NF73‐1 caused a more conspicuous damage of GVB than that of the IEB and contributed to NAFLD development. Mechanistically, E. coli NF73‐1 dismantled the GVB by inhibiting the Wnt/β‐catenin signalling pathway. Activation of Wnt/β‐catenin improved the GVB and impeded the translocation of E. coli NF73‐1 into the liver in vitro and in vivo. Conclusions: E. coli NF73‐1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β‐catenin signalling pathway. Targeting E. coli NF73‐1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are potential risk factors for severe pneumonia and other infections. Available data on the role of NAFLD/NASH in worsening outcomes for COVID‐19 are controversial and might be confounded by comorbidities. Methods: We used the PINC AI™ Healthcare Data Special Release (PHD‐SR) to identify patients with COVID‐19 (ICD‐10) at approximately 900 hospitals in the United States. We performed exact matching (age, gender, and ethnicity) for patients with or without NAFLD/NASH, adjusting for demographics (admission type, region) and comorbidities (e.g., obesity, diabetes) through inverse probability of treatment weighting and then analysed hospitalisation‐related outcomes. Results: Among 513 623 patients with SARS‐CoV‐2 (COVID‐19), we identified 14 667 with NAFLD/NASH who could be matched to 14 667 controls. Mean age was 57.6 (±14.9) years, 50.8% were females and 43.7% were non‐Hispanic whites. After matching, baseline characteristics (e.g., age, ethnicity, and gender) and comorbidities (e.g., hypertension, obesity, diabetes, and cardiovascular disease) were well balanced (standard difference (SD) <.10), except for cirrhosis and malignancies. Patients with COVID‐19 and NAFLD/NASH had higher FIB‐4 scores, a significantly longer hospital length of stay (LOS) and intensive care LOS than controls (9.4 vs. 8.3 days, and 10.4 vs. 9.3, respectively), even after adjusting for cirrhosis and malignancies. Patients with COVID‐19 and NAFLD/NASH also had significantly higher risk of needing invasive mandatory ventilation (IMV) (odds ratio 1.0727; 95% CI 1.0095–1.1400). Other outcomes were similar in both groups. Conclusions: In this large real‐world cohort of patients hospitalised for COVID‐19 in the United States, NAFLD/NASH were obesity‐independent risk factors for complicated disease courses. [ABSTRACT FROM AUTHOR]

The article explores the debate between the definitions of metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated fatty liver disease (MAFLD) in relation to predicting cardiovascular disease (CVD) risk. A cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) found that the MAFLD-only group had a higher proportion of patients at high CVD risk compared to the MASLD-only group. However, further cohort studies are needed to determine which definition is more effective in predicting CVD events. The article also discusses the ongoing debate surrounding the definition of metabolic health and the diagnosis of metabolic syndrome, highlighting the uncertainty and concerns about over-medicalization. The study suggests that the current criteria for metabolic dysfunction may be highly sensitive but not specific enough, and that the number of metabolic abnormalities present in a patient determines their overall CVD risk. Further research is required to determine whether MAFLD is a better predictor of cardiovascular events compared to MASLD. [Extracted from the article]

This article explores the role of thyroid hormones (THs) in chronic liver diseases such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. The authors present evidence that THs regulate the activation of hepatic stellate cells (HSCs) through thyroid hormone receptor (TR) α and modulation of transforming growth factor (TGF) β downstream signaling. They also discuss the potential for using TGFβ signaling and TRα-dependent mechanisms to develop new treatments for liver fibrosis. However, the study is limited to in vitro cell lines and a non-physiologic mouse model, suggesting the need for further research. The article also acknowledges the challenges of targeting HSCs and TGFβ for antifibrotic therapy and suggests that future treatments may involve cell type-specific or liver-directed strategies, as well as innovative drug delivery systems or micro-RNA-based approaches. [Extracted from the article]

Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached epidemic proportions worldwide and is the most frequent cause of chronic liver disease in developed countries. Within the spectrum of liver disease in MAFLD, steatohepatitis is a progressive form of liver disease and hepatocyte ballooning (HB) is a cardinal pathological feature of steatohepatitis. The accurate and reproducible diagnosis of HB is therefore critical for the early detection and treatment of steatohepatitis. Currently, a diagnosis of HB relies on pathological examination by expert pathologists, which may be a time-consuming and subjective process. Hence, there has been interest in developing automated methods for diagnosing HB. This narrative review briefly discusses the development of artificial intelligence (AI) technology for diagnosing fatty liver disease pathology over the last 30 years and provides an overview of the current research status of AI algorithms for the identification of HB, including published articles on traditional machine learning algorithms and deep learning algorithms. This narrative review also provides a summary of object detection algorithms, including the principles, historical developments, and applications in the medical image analysis. The potential benefits of object detection algorithms for HB diagnosis (specifically those combined with a transformer architecture) are discussed, along with the future directions of object detection algorithms in HB diagnosis and the potential applications of generative AI on transformer architecture in this field. In conclusion, object detection algorithms have huge potential for the identification of HB and could make the diagnosis of MAFLD more accurate and efficient in the near future. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. Methods: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. Results: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (--61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. Conclusion: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weightneutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level. [ABSTRACT FROM AUTHOR]

Background and Aims: Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone- to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. Methods: A cross-sectional analysis using the 2013--2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. Results: Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. Conclusion: The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: If alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are now the two main indications for liver transplantation (LT), it has been recognized that both conditions can coexist in varying degrees and the concept of dual-aetiology fatty liver disease (DAFLD) has been proposed. This retrospective study aimed to evaluate, in a cohort of patients transplanted for ALD and NAFLD, the prevalence of DAFLD before LT and the impact on liver graft outcome. Methods: From 1990 to 2010, all patients who underwent LT for the so-called ALD or NAFLD in our centre were included. Before LT, DAFLD was defined as patients with a history of excessive alcohol consumption and obesity associated with either diabetes or hypertension. Before LT, patients were separated into three groups: DAFLD, ALD, and NAFLD. Fatty liver graft disease was classified according to the FLIP algorithm. Results: Out of 907, adult LT recipients were identified: 33 DAFLD patients, 333 ALD patients, and 24 NAFLD patients. After LT, ALD patients experienced significantly more alcohol relapse than DAFLD patients, who had twice more post-LT metabolic syndrome. Out of 926, post-LT biopsies, DAFLD patients had significantly more fatty liver graft disease due to metabolic syndrome features than ALD patients. Conclusion: Our results support that DAFLD recently emerged as an indication of LT. In the future, this particular population needs to be identified as a specific entity since post-LT outcome on the graft is different from ALD and more similar to NAFLD patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Diagnosis of metabolic dysfunction‐associated steatohepatitis (MASH) requires histology. In this study, a magnetic resonance imaging (MRI) score was developed and validated to identify MASH in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Secondarily, a screening strategy for MASH diagnosis was investigated. Methods: This prospective multicentre study included 317 patients with biopsy‐proven MASLD and contemporaneous MRI. The discovery cohort (Spain, Portugal) included 194 patients. NAFLD activity score (NAS) and fibrosis were assessed with the NASH‐CRN histologic system. MASH was defined by the presence of steatosis, lobular inflammation, and ballooning, with NAS ≥4 with or without fibrosis. An MRI‐based composite biomarker of Proton Density Fat Fraction and waist circumference (MR–MASH score) was developed. Findings were afterwards validated in an independent cohort (United States, Spain) with different MRI protocols. Results: In the derivation cohort, 51% (n = 99) had MASH. The MR–MASH score identified MASH with an AUC =.88 (95% CI.83–.93) and strongly correlated with NAS (r =.69). The MRI score lower cut‐off corresponded to 88% sensitivity with 86% NPV, while the upper cut‐off corresponded to 92% specificity with 87% PPV. MR–MASH was validated with an AUC =.86 (95% CI.77–.92), 91% sensitivity (lower cut‐off) and 87% specificity (upper cut‐off). A two‐step screening strategy with sequential MR–MASH examination performed in patients with indeterminate‐high FIB‐4 or transient elastography showed an 83–84% PPV to identify MASH. The AUC of MR–MASH was significantly higher than that of the FAST score (p <.001). Conclusions: The MR–MASH score has clinical utility in the identification and management of patients with MASH at risk of progression. [ABSTRACT FROM AUTHOR]

Background & Aims: Obesity and non‐alcoholic fatty liver disease (NAFLD) are known risk factors for gastrointestinal (GI) cancers. However, GI carcinogenesis in lean NAFLD patients remains unclear. This systematic review and meta‐analysis aims to investigate the association between lean NAFLD and GI cancer risk. Methods: PubMed, Embase and Cochrane Library databases were systematically searched (from inception date to April 2023) for cohort studies assessing GI cancers in lean (body mass index [BMI] < 25 kg/m2 or < 23 kg/m2 in Asians) and non‐lean (BMI ≥25 kg/m2 or ≥ 23 kg/m2 in Asians) NAFLD individuals. Data from eligible studies were extracted, and meta‐analysis was carried out using a random effects model to obtain risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup analyses, meta‐regressions and sensitivity analyses were also performed. This study was registered in PROSPERO (CRD42023420902). Results: Eight studies with 56,745 NAFLD individuals (11% were lean) and 704 cases of incident GI cancers were included. Lean NAFLD was associated with higher risk of hepatic (RR 1.77, 95% CI 1.15–2.73), pancreatic (RR 1.97, 95% CI 1.01–3.86) and colorectal cancers (RR 1.53, 95% CI 1.12–2.09), compared to non‐lean NAFLD. No significant differences were observed for oesophagus, gastric, biliary and small intestine cancers. Conclusions: This study shows that lean NAFLD patients have an increased risk of liver, pancreatic and colorectal cancers compared to non‐lean NAFLD patients, emphasizing the need to explore tailored cancer prevention strategies for this specific patient group. Further research is required to explore the mechanisms underlying the association between lean NAFLD and specific GI cancers. [ABSTRACT FROM AUTHOR]