Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by metabolic triggers and genetic predisposition. Among the genetic MASLD risk variants identified today, the common PNPLA3 148M variant exerts the largest effect size of MASLD heritability. The PNPLA3 148M protein is causatively linked to the development of liver steatosis, inflammation and fibrosis in experimental studies and is therefore an appealing target for therapeutic approaches to treat this disease. Several PNPLA3 targeted approaches are currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the most severe form of MASLD and promising proof of principle data with reduced liver fat content in homozygous PNPLA3 148M risk allele carriers has been reported from phase 1 trials following hepatic silencing of PNPLA3. Thus, targeting PNPLA3, the strongest genetic determinant of MASH may hold promise as the first precision medicine for the treatment of this disease. A histological endpoint-based phase 2b study has been initiated and several more are expected to be initiated to evaluate treatment effects on histological MASH and liver fibrosis in participants being homozygous for the PNPLA3 148M risk allele variant. The scope of this mini-review is to briefly describe the PNPLA3 148M genetics, function and preclinical experimental evidence with therapeutic approaches targeting PNPLA3 as well as to summarise the PNPLA3 based therapies currently in clinical development.

Steatotic liver disease (SLD) is influenced by both genetics and lifestyle factors, with lifestyle effects varying by genetic susceptibility. We aimed to evaluate gene-lifestyle interactions on SLD risk.

We included 28,215 UK Biobank participants with available data. Predictors were healthy lifestyle patterns, PNPLA3-rs738409, TM6SF2-rs58542926, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. Primary outcome was liver fat content (LFC); secondary outcomes were cT1 (a measure of liver inflammation/fibrosis) and SLD-related events.

Lifestyle predictors, except smoking, reduced LFC, while genetic predictors increased it. Genetic predictors significantly interacted with healthy lifestyle patterns, sedentary behavior and social connection. Lifestyle effects on lower LFC were up to 6.3-fold stronger in PNPLA3-rs738409-GG vs. -CC individuals, and 1.5-7.0 times higher in the top vs. bottom PRS quartile. PRS and PNPLA3 also interacted with alcohol consumption, diet, and PNPLA3 further interacted with physical activity. These interactions were more pronounced in overweight participants. Genetic factors and physical activity interacted to influence cT1, while PRS, PNPLA3 and sleep duration were associated with cardiovascular events.

Lifestyle effects on LFC, cT1 and cardiovascular events were accentuated in individuals at higher SLD genetic risk, implying lifestyle interventions may be more impactful in these populations.

Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable.

This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (n = 41/85), F2 (n = 47), and F3/4 (n = 72/24)) according to fibrosis stage. We performed serum N-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure N-glycosylation changes of carrier protein.

Comprehensive N-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral N-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer (M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect N-glycan. A sandwich ELISA based on N-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum.

A2F bisect N-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice.

UMIN000030720.

To evaluate the concordance between vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) for staging liver fibrosis and assessing hypothetical eligibility for resmetirom treatment in a cohort of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A secondary objective was to assess the performance of VCTE for liver fat quantification.

This retrospective study included 103 patients (61 males; mean age 54.7 years) with suspected MASLD who underwent VCTE and MRI/MRE. The following parameters were extracted: liver stiffness (LS) from both techniques, controlled attenuation parameter (CAP) from VCTE, and MRI-proton density fat fraction (PDFF). Agreement and fibrosis stage distributions were assessed using Cohen's Kappa and McNemar's tests. ROC analysis assessed the performance of CAP against MRI-PDFF (considered the reference for steatosis).

A significant difference was observed in assigned fibrosis stage distributions between VCTE and MRE across all combinations (F0-F1 vs F2-F4, F0-F2 vs F3-F4, F0-F3 vs F4, all p < 0.001) with fair to moderate agreement between modalities (Cohen's Kappa values 0.305-0.554). VCTE assigned a higher fibrosis stage in 42 patients (40.7%). Thirty-three vs eighteen patients were classified as F2-F3 (qualified for resmetirom treatment) with VCTE vs MRE (Cohen's Kappa 0.215), which was associated with estimated cost savings of $707,701/year with MRE. VCTE-CAP achieved AUCs of 0.547, 0.754, and 0.813 for diagnosing mild, moderate, and severe steatosis, respectively.

VCTE and MRE have fair to moderate agreement for fibrosis staging, with VCTE tending to assign a higher fibrosis stage compared to MRE. VCTE-CAP reliably detects only severe steatosis.

Question What is the agreement between VCTE and MRE in staging fibrosis in MASLD and identifying patients with F2-F3 disease? Findings Limited concordance was found between VCTE and MRE for staging liver fibrosis and identifying F2-F3 disease; VCTE tended to assign higher fibrosis stages compared to MRE. Clinical relevance MRE could represent the modality of choice for selecting patients with metabolic dysfunction-associated steatohepatitis for resmetirom therapy as it potentially offers high cost-savings compared to VCTE.

Recent evidence indicates that metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD), a newly defined subgroup of steatotic liver disease (SLD), may have a worse prognosis than metabolic dysfunction-associated steatotic liver disease (MASLD). This study examines the clinical factors influencing the severity of MetALD to inform and improve future management strategies.

Data from the 2017-2020 National Health and Nutrition Examination Surveys (NHANES), involving 7745 adults with valid elastography measurements, were utilized to define and estimate the prevalence of MASLD, MetALD, and alcohol liver disease (ALD). Controlled attenuation parameter (CAP) ≥285 dB/m, liver stiffness measurement (LSM) ≥8 kPa, and ≥12 kPa indicated the presence of hepatic steatosis, clinically significant fibrosis, and advanced fibrosis, respectively.

The prevalence of MetALD was 4 % (N=287), compared to 24 % (N=2049) for MASLD and 7 % (N=486) for ALD. The prevalence of significant fibrosis and advanced fibrosis in MetALD was 10.8 % and 3.1 %, respectively, compared to 24.7 % and 9.8 % in MASLD, and 15 % and 8 % in ALD. Logistic regression analysis among MetALD patients showed that higher body mass index (BMI) (odds ratio [OR]: 1.15, 95 % CI: 1.08-1.23, P<0.01) and diabetes mellitus (DM) (OR: 3.0, 95 % CI: 1.06-6.2, P<0.01) were associated with an increased risk of fibrosis. These factors were also identified as independent risk factors for fibrosis in patients with MASLD and ALD.

MetALD had the lowest prevalence and fibrosis severity among the three groups of SLD. Elevated BMI and DM were associated with the severity of liver disease, and these findings provide a rationale for the use of obesity- and diabetes-targeted medications in these individuals.

The Information Technology (IT) sector is a leading industry that fuels India's economic growth. However, the work culture in this sector often promotes sedentary lifestyle, inadequate physical activity, and unhealthy dietary patterns which are risk factors for various non-communicable disease (NCD). This study aims to assess the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) among IT employees and its association with behavioural and biological risk factors. This cross-sectional study involved 345 IT employees in Hyderabad, India, who responded to a questionnaire on their occupational sitting, shift work, stress, sleep duration, smoking, physical activity, and food habits. Anthropometric, biochemical, metabolic, and liver function parameters were evaluated. MAFLD was diagnosed using a Vibration-Controlled Transient Elastography FibroScan. Chi-square test and Spearman's rank correlation were performed to analyse the associations and correlations between risk factors. The median age of the employees was 38 years (34-43 years) with a body mass index (BMI) of 244 (70.72%) obese. Approximately, 248 (71.88%), 89 (25.80%), 241 (69.86%) and 131 (37.97%) of employees were found to sit for long hours at work, had shift work, sleep deprivation and stress, respectively. Almost 72 (20.87%) of IT employees had elevated fasting blood glucose (FBG) and 264 (76.52%) had high low-density lipoprotein (LDL-C). Metabolic Syndrome (MetS) was present in 118 (34.20%) of the employees. A total of 290 (84.06%) employees had increased liver fat accumulation indicating MAFLD. There is high prevalence of MAFLD among IT employees, highlighting the urgent need for workplace interventions and health promotion initiatives addressing MAFLD risk in the IT workforce.

Environmental pollutants significantly impact liver disease development, progression, and outcomes. This review examines the complex relationship between environmental exposures and liver pathology, from malignant conditions like hepatocellular carcinoma to steatotic and cholestatic liver diseases. Key environmental factors include air pollutants, volatile organic compounds, persistent organic pollutants, heavy metals, and per- and polyfluoroalkyl substances. These compounds can act through multiple mechanisms, including endocrine disruption, metabolic perturbation, oxidative stress, and direct hepatotoxicity. The impact of these exposures is often modified by factors such as sex, diet, and genetic predisposition. Recent research has revealed that even low-level exposures to certain chemicals can significantly affect liver health, particularly when combined with other risk factors. The emergence of exposomics as a research tool promises to enhance our understanding of how environmental factors influence liver disease. Importantly, exposure effects can vary by demographic and socioeconomic factors, highlighting environmental justice concerns. Implementation of this knowledge in clinical practice requires new diagnostic approaches, healthcare system adaptations, and increased awareness among medical professionals. In conclusion, this review provides a comprehensive examination of current evidence linking environmental exposures to liver disease and discusses implications for clinical practice and public health policy.

To address the need for a simple model to predict ≥ F2 fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, a study utilized data from 791 biopsy-proven MASLD patients from the NASH Clinical Research Network and Jinan University First Affiliated Hospital. The data were divided into training and internal testing sets through randomized stratified sampling. A multivariable logistic regression model using key categorical variables was developed to identify ≥ F2 fibrosis. External validation was performed using data from the FLINT trial and multiple centers in China. The DA-GAG score, incorporating diabetes, age, GGT, aspartate aminotransferase/ platelet ratio, and globulin/ total protein ratio, demonstrated superior performance in distinguishing ≥ F2 fibrosis with an area under the receiver operating characteristic curve of 0.79 in training and over 0.80 in testing datasets. The DA-GAG score efficiently identifies MASLD patients with ≥ F2 fibrosis, significantly reducing the medical burden.

To evaluate the utility of deep learning-based automated attenuation measurements on contrast-enhanced CT (CECT) for diagnosing moderate-to-severe hepatic steatosis (HS), using histology as reference standard.

This retrospective study included 3,620 liver donors (2,393 men and 1,227 women; mean age, 31.7 ± 9.4 years), divided into the development (n = 2,714) and test (n = 906) cohorts. Attenuation values of the liver and spleen on CECT were measured both manually and using a deep learning algorithm (before and after radiologists' correction of segmentation errors). Performance of: (1) liver attenuation and (2) liver-spleen attenuation difference for diagnosing moderate-to-severe HS (> 33%) was assessed using the area under the receiver operating characteristic curve (AUC). Three different criteria targeting 95% sensitivity, 95% specificity, and the maximum Youden's index, respectively, for diagnosing moderate-to-severe HS, were developed and validated.

The performance of deep learning-based measurements did not differ significantly, with or without radiologists' corrections (p = 0.13). Liver-spleen attenuation difference outperformed liver attenuation alone in diagnosing moderate-to-severe HS in both deep learning-based (AUC, 0.868 vs. 0.821; p = 0.001) and manual (AUC, 0.871 vs. 0.823; p = 0.001) measurements. In the test cohort, the criterion targeting 95% sensitivity for diagnosing moderate-to-severe HS (liver-spleen attenuation difference ≤ 2.8 HU) yielded 92.0% (69/75) sensitivity and 48.5% (403/831) specificity. The criterion targeting 95% specificity (liver-spleen attenuation difference ≤ -18.8 HU) yielded 53.3% (40/75) sensitivity and 95.7% (795/831) specificity. The criterion targeting the maximum Youden's index (liver-spleen attenuation difference ≤ -8.2 HU) yielded 82.7% (62/75) sensitivity and 80.7% (671/831) specificity.

Deep learning-based automated measurements of liver and spleen attenuation on CECT can be used reliably to detect moderate-to-severe HS.

To evaluate the association between a new definition of metabolic dysfunction-associated steatotic liver disease (MASLD), different metabolic dysfunction subtypes and risk of colorectal cancer(CRC).

A total of 99,979 participants who met the criteria were included from the Kailuan Study. Participants were categorized into three groups based on fatty liver disease and metabolic status: Non-SLD with metabolic normal group(NMN), Non-SLD with metabolic abnormal group(NMA) and MASLD group. Incident of CRC were confirmed by review of medical records. The Cox proportional hazard regression models were used to assess the association MASLD with the risk of CRC by calculating the hazard ratios (HR) and 95 % confidence interval (CI).

During a mean 13.54 ± 2.78 years of follow-up, we documented 669 CRC. Multivariate Cox regression analysis showed that compared with the NMN group, MASLD participants demonstrated an increased risk of developing CRC (HR 1.54 95 %CI 1.12-2.13). The greater the number of metabolic dysfunctions, the greater the risks of CRC (P < 0.05). The HR for CRC was 1.93 (95 % CI 1.27-2.92) in MASLD participants with 4-5 items of metabolic dysfunctions. In the subtype analysis, the HR for CRC was 1.97 (95 % CI 1.13-3.45) in lean-MASLD participants and 1.55(95 %CI 1.12-2.15) in diabetes-MASLD participants.

MASLD was associated with increased risk of CRC. Moreover, MASLD individuals who complicated by lean or diabetes have an increased risk of developing CRC.

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.

The current subclassification of steatotic liver disease (SLD) relies on validated questionnaires, such as Alcohol Use Disorders Identification Test (AUDIT) and Lifetime Drinking History (LDH), which, while useful, are impractical and lack precision for their use in routine clinical practice. Phosphatidylethanol (PEth) is a quantitative, objective alcohol biomarker with high sensitivity and specificity.

To assess the diagnostic accuracy of PEth for differentiating metabolic dysfunction and alcohol-associated liver disease (MetALD) from metabolic dysfunction-associated steatotic liver disease (MASLD) in a large, population-based, prospective, multiethnic cohort of individuals with overweight or obesity.

This is a cross-sectional analysis of a prospective study including 374 adults with overweight or obesity residing in Southern California who had SLD as defined by MRI-PDFF ≥ 5%. The clinical research visit included medical history, biochemical and PEth testing, standardised validated questionnaires (including AUDIT and LDH), physical examination, and advanced imaging using MRI-PDFF and MRE.

Among 374 adults with SLD, the prevalence of MASLD, MetALD, and ALD was 90.1%, 6.4%, and 3.5%, respectively. PEth had a robust diagnostic accuracy in the detection of MetALD (AUROC 0.81, 95%CI 0.73-0.89) and the Youden cut-off was 25 ng/mL. In head-to-head comparative efficacy analysis, PEth was both statistically and clinically superior to all previously used indirect alcohol biomarkers for diagnosing MetALD, including aspartate aminotransferase/alanine aminotransferase ratio, mean corpuscular volume, gamma glutamyltransferase, and ALD/NAFLD index (p < 0.05).

PEth outperforms previously used non-invasive tests in differentiating MetALD from MASLD and has the potential to change clinical practice by enhancing the subclassification of SLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) challenges traditional paradigms by manifesting in lean individuals. The link between MASLD and inflammatory bowel disease (IBD) underscores the importance of the gut-liver axis in disease progression and chronic inflammation. This study evaluates MASLD prevalence, clinical characteristics, and diagnostic predictors in lean individuals with and without IBD. This prospective study included 387 lean patients. Hepatic steatosis and fibrosis were assessed using vibration-controlled transient elastography (VCTE). Anthropometric, clinical and biological data were compared. The subgroup analyses focused on MASLD patients with and without IBD. MASLD was present in 34.1% of lean individuals and 46.3% of those who were lean with IBD. MASLD patients had increased visceral adiposity (CUN-BAE: 31.21 ± 5.42 vs. 24.57 ± 6.49, p < 0.001) and metabolic dysfunction, including dyslipidemia and elevated fasting glucose. IBD-MASLD patients exhibited greater hepatic steatosis and systemic inflammation. CUN-BAE outperformed FLI and HSI in predicting liver steatosis, especially in IBD patients (AUC = 0.806). Lean MASLD, particularly in IBD patients, highlights the need for tailored diagnostic and management strategies. The gut-liver axis plays a key role in disease progression, and the CUN-BAE index demonstrates superior accuracy for identifying liver steatosis.

The past decade has witnessed transformative changes in our understanding of various lipid or lipid-related biomarkers (Table 1) and their relationships with cardiometabolic diseases [...].

Non-alcoholic steatohepatitis (NASH), an advanced manifestation of non-alcoholic fatty liver disease (NAFLD), is characterized by hepatocyte injury, inflammation, and fibrosis. Saturated fatty acids (SFAs) have emerged as key contributors to hepatocyte lipotoxicity and disease progression. Toll-like receptor 4 (TLR4) acts as a sentinel for diverse ligands, including lipopolysaccharide (LPS) and endogenous molecules like palmitic acid (PA)-induced ceramide (CER) accumulation, promoting hepatocyte demise. However, the intricate mechanisms underlying TLR4's modulation of ceramide metabolism and their concerted effect on SFA-mediated hepatotoxicity remain elusive.

A NASH mouse model with liver-specific TLR4 knockdown was established through palm oil feeding and AAV2/8 tail vein injection. Histological and biochemical assessments were conducted to evaluate the mice's condition and liver damage extent. Liquid chromatography-mass spectrometry (LC-MS) was employed to quantify ceramide levels in liver tissues, offering insights into NASH mechanisms.

The PO-fed model exhibited elevated serum ALT, AST, and liver TG levels, enhancing lipid accumulation and hepatocellular damage. TLR4 knock-down reduced liver mass and the liver-to-body weight ratio, signifying a decreased hepatic burden. Histopathological evaluations revealed substantial improvement in hepatic steatosis in TLR4-silenced PO-fed mice, with diminished lipid droplets and inflammatory infiltrates. LC-MS analysis showed a marked decrease in long-chain ceramides (C14, C16, C20) in TLR4-knockdown PO-fed mice. Furthermore, expression of MyD88, SPTLC1, SPTLC2, and inflammatory markers IL-1β, IL-6, TNF-α were significantly attenuated.

SFAs activate the TLR4 signaling pathway via MyD88, fostering ceramide de novo synthesis, which exacerbates hepatocyte lipotoxicity and accelerates NASH progression.

International guidelines suggest screening for advanced fibrosis due to metabolic dysfunction-associated steatotic liver disease in people with type 2 diabetes, but how to implement these guidelines in clinical care remains unclear. We hypothesise that examination with VCTE could be implemented simultaneously with retina scanning with a high acceptance rate in people with type 2 diabetes.

In this cross-sectional study, we offered VCTE to people with type 2 diabetes referred to routine retina scanning in a large retina scanning facility in Stockholm, Sweden. We excluded people with type 1 diabetes, currently pregnant, with known liver disease, reporting high alcohol consumption, who did not speak Swedish, or younger than 18 years. Between Nov 6, 2020, and June 20, 2023, we conducted surveys with included participants and collected data from medical records on diabetes retinopathy, sex, and VCTE measurements. Increased liver stiffness was defined as at least 8·0 kPa, and possible advanced fibrosis as more than 12·0 kPa. Presence of metabolic dysfunction-associated steatotic liver disease was defined as a controlled attenuation parameter (CAP) value of 280 dB/m or higher. Participants with a liver stiffness measurement of at least 8·0 kPa or those with unreliable measurements were subsequently referred for a secondary evaluation at a liver specialist, including a follow-up liver stiffness measurement with VCTE. The primary outcome was the proportion of eligible people approached for screening who accepted. Secondary outcomes were the prevalence of elevated liver stiffness (≥8·0 kPa or >12·0 kPa), presence of metabolic dysfunction-associated steatotic liver disease, and the proportion of elevated liver stiffness readings at the first VCTE examination that were not elevated in the secondary evaluation with a liver specialist. Secondary outcomes were assessed in all participants who accepted screening, except false positives, which were assessed only in participants who had a second examination.

1301 participants were eligible to undergo assessment with VCTE, which was accepted by 1005 (77·2%). 973 (96·8%) participants had complete measurements, of whom 504 (51·8%) had CAP values of 280 dB/m or higher, indicating metabolic dysfunction-associated steatotic liver disease. Of 977 participants with reliable liver stiffness measurements, 154 (15·8%) had values of at least 8·0 kPa, suggestive of liver fibrosis, and 49 (5·0%) had values higher than 12·0 kPa, indicating possible advanced fibrosis. However, upon reassessment with a second VCTE after referral, 56 (45·2%) of 124 individuals had values less than 8·0 kPa. 74 (7·4%) of 1005 participants had a final liver stiffness of at least 8·0 kPa; 29 (2·9%) had values greater than 12·0 kPa.

Simultaneous examination with VCTE alongside retina scanning had a high acceptance rate among people with type 2 diabetes and could be a strategy for case-finding of people with fibrosis due to metabolic dysfunction-associated steatotic liver disease. However, a high proportion of participants in our study with elevated liver stiffness measurement at the screening visit did not have an elevated liver stiffness measurement at secondary evaluation, suggesting false-positive findings were common.

Gilead Sciences, Pfizer, Region Stockholm, Åke Wiberg Foundation, and Bengt Ihre Foundation.

To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice.

A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included.

Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P < 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P < 0.001). Resmetirom's ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis.

Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies.

Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors.

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7-14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to more than 55%. Although MASLD does not always develop into progressive liver disease, it has become the top indication for liver transplant in the United States for women and those with hepatocellular carcinoma (HCC). Nonetheless, the most common cause of mortality among patients with MASLD remains cardiovascular disease. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with an increased risk of developing de novo T2D, chronic kidney disease, sarcopenia, and extrahepatic cancers. Furthermore, MASLD is associated with decreased health-related quality of life, decreased work productivity, fatigue, increased healthcare resource utilization, and a substantial economic burden. Similar to other metabolic diseases, lifestyle interventions such as a heathy diet and increased physical activity remain the cornerstone of managing these patients. Although several obesity and T2D drugs are available to treat co-morbid disease, resmetirom is the only MASH-targeted medication for patients with stage 2-3 fibrosis that has approved by the Food and Drug Administration for use in the United States. This review discusses MASLD epidemiology and its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD incidence could continue to increase.

Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), which have a reciprocal relationship compounded by obesity, are highly prevalent in the Middle East affecting morbidity, mortality, and healthcare costs.

This study aimed to assess the severity of MASLD and liver fibrosis among adult Emirati patients with long-standing T2DM.

This cross-sectional study used noninvasive methods to assess the severity of MASLD and fibrosis progression in an adult cohort of Emirati patients (N = 546) with a mean T2DM duration of 16 years.

Fatty liver infiltration was assessed by hepatic steatosis index (HSI), while fibrosis was assessed by the fibrosis-4 (FIB-4) index and aspartate aminotransferase/platelet ratio index (APRI). Of those, 108 patients were randomly subjected to ultrasound-based FibroScan® to assess controlled attenuation parameter (CAP) and liver stiffness measurement (LSM).

All patients had fatty liver with ~ 83% being categorized as having severe steatosis. Serum-based fibrosis biomarker panels detected significant liver fibrosis in ~ 2.5% of these patients. The APRI appeared to be more restrictive in detecting moderate fibrosis (1.5%) than the FIB-4 index (25.5%). CAP significantly correlated with the LSM, indicating that the two methods contributed to the same underlying pathophysiology. Liver steatosis was more severe in female patients, who were older and had a higher body mass index (BMI) than those with moderate or no significant fibrosis. They also had higher serum liver enzymes and were more likely to have age-related changes in kidney function. Interestingly, severity of both steatosis and fibrosis remained unaffected by age and duration of T2D except for fibrosis severity detected by FibroScan®.

This study highlights the critical need for routine screening of MASLD among Emirati patients with long-standing T2DM, given the high point prevalence of severe steatosis (~ 83%), predominantly among women in this population.

Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and affects nearly 30% of the adult population and 10% of the pediatric population. It is estimated that this number will double by 2030. MASLD is one of the leading causes of hepatocellular carcinoma, cirrhosis, and liver transplantation, as well as a significant risk factor for cardiovascular disease and mortality. Due to the ever-increasing number of patients, the long-term asymptomatic course of the disease, serious complications, and lack of preventive programs, as well as insufficient awareness of the disease among patients and doctors themselves, MASLD is a growing interdisciplinary problem and a real challenge for modern medicine. The main cause of MASLD is an inappropriate lifestyle-inadequate nutrition and insufficient physical activity, which lead to various components of metabolic syndrome. Lifestyle changes-appropriate diet, weight reduction, and systematic physical activity-are also the basis for the prevention and treatment of MASLD. Hence, in recent years, so much importance has been attached to lifestyle medicine, to non-pharmacological treatment as prevention of lifestyle diseases. The narrative review presents possible therapeutic options for non-pharmacological management in the prevention and treatment of MASLD. The best documented and available diets used in MASLD were discussed, focusing on the benefits and drawbacks of the Mediterranean, high-protein, ketogenic, and intermittent fasting diets. In addition, the most recent recommendations regarding physical activity are summarized.

Although numerous noninvasive steatosis indices have been developed to assess hepatic steatosis, whether they can be applied to young adults in the evaluation of metabolic dysfunction-associated steatotic liver disease (MASLD) remains uncertain.

Data from patients under 35 years of age who visited the Liver Health Clinic at the Armed Forces Goyang Hospital between July 2022 and January 2024 were retrospectively collected. Steatosis was diagnosed on the basis of a controlled attenuation parameter score ≥250 dB/m. MASLD was defined as the presence of steatosis in patients with at least one cardiometabolic risk factor.

Among the 1,382 study participants, 901 were diagnosed with MASLD. All eight indices for diagnosing steatosis differed significantly between the MASLD and non-MASLD groups (p<0.001). Regarding the predictive performance, the hepatic steatosis index (HSI), fatty liver index (FLI), Framingham steatosis index, Dallas steatosis index, Zhejiang University index, lipid accumulation product, visceral adiposity index, and triglyceride glucose-body mass index exhibited an area under the curve of 0.898, 0.907, 0.899, 0.893, 0.915, 0.869, 0.791, and 0.898, respectively. The cutoff values for the FLI and HSI were re-examined, indicating a need for alternative cutoff values for the HSI, with a rule-in value of 42 and a rule-out value of 36 in this population.

This study presents novel findings regarding the predictive performance of established steatosis markers in young adults. Alternative cutoff values for the HSI in this population have been proposed and warrant further validation.

The incidence of steatotic liver disease (SLD) is increasing across all age groups as the incidence of obesity increases worldwide. The existing noninvasive prediction models for SLD require laboratory tests or imaging and perform poorly in the early diagnosis of infrequently screened populations such as young adults and individuals with healthcare disparities. We developed a machine learning-based point-of-care prediction model for SLD that is readily available to the broader population with the aim of facilitating early detection and timely intervention and ultimately reducing the burden of SLD.

We retrospectively analyzed the clinical data of 28,506 adults who had routine health check-ups in South Korea from January to December 2022. A total of 229,162 individuals were included in the external validation study. Data were analyzed and predictions were made using a logistic regression model with machine learning algorithms.

A total of 20,094 individuals were categorized into SLD and non-SLD groups on the basis of the presence of fatty liver disease. We developed three prediction models: SLD model 1, which included age and body mass index (BMI); SLD model 2, which included BMI and body fat per muscle mass; and SLD model 3, which included BMI and visceral fat per muscle mass. In the derivation cohort, the area under the receiver operating characteristic curve (AUROC) was 0.817 for model 1, 0.821 for model 2, and 0.820 for model 3. In the internal validation cohort, 86.9% of individuals were correctly classified by the SLD models. The external validation study revealed an AUROC above 0.84 for all the models.

As our three novel SLD prediction models are cost-effective, noninvasive, and accessible, they could serve as validated clinical tools for mass screening of SLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of histological findings from the generally benign simple steatosis to steatohepatitis (MASH) which can progress to fibrosis and cirrhosis. Several factors, including the microbiome, may contribute to disease progression.

Here, we demonstrate links between the presence and abundance of specific bacteria in the adipose and liver tissues, inflammatory genes, immune cell responses, and disease severity. Overall, in MASLD patients, we observed a generalized obesity-induced translocation of gut bacteria to hepatic and adipose tissues. We identified microbial patterns unique to more severely diseased tissues. Specifically, Enterococcus, Granulicatella, and Morganellaceae abundance is positively correlated with immune cell counts and inflammatory gene expression levels, and both genera are significantly enriched in MASH patients. Brevibacterium is enriched in adipose tissues of patients with liver fibrosis.

Together, these results provide further insight into the microbial factors that may be driving disease severity. Video Abstract.

Metabolic-associated steatohepatitis and liver fibrosis (MASLD) is a growing public health concern, with environmental factors potentially playing a role in its development. This study aimed to investigate the associations between serum cadmium and mercury levels and the risk of MASLD in a nationally representative sample from the United States.

Data from the National Health and Nutrition Examination Survey from 1999 to 2018 were analyzed. Serum cadmium and mercury concentrations were measured, and MASLD was defined based on established criteria. Logistic regression models were used to assess the associations between serum metal levels and MASLD, with adjustments for potential confounders. Stratified analyses and restricted cubic spline curves were employed to examine subgroup differences and nonlinear relationships.

The study revealed significant inverse associations between serum cadmium and mercury levels and the likelihood of MASLD. Individuals in the highest quartiles of cadmium and mercury had lower odds of MASLD compared to those in the lowest quartiles (Model 3: Cadmium Q4 vs. Q1, Mercury Q4 vs. Q1). Stratified analyses showed stronger inverse associations in older adults, males, and never smokers for cadmium, and in females and individuals without diabetes for mercury. Nonlinear dose-response curves indicated critical thresholds beyond which the risk dynamics changed.

Higher serum levels of cadmium and mercury were associated with a lower risk of MASLD, with notable variations across subgroups. These findings challenge the conventional understanding of these heavy metals as universally harmful and highlight the need for further research to unravel the complex interplay between environmental exposures and MASLD pathophysiology.

US tools to quantify hepatic steatosis have recently been made clinically available by different manufacturers, but comparative data on their consistency are lacking.

US tools to quantify hepatic steatosis have recently been made clinically available by different manufacturers, but comparative data on their consistency are lacking. The aim of our study was to compare the diagnostic consistency for evaluating hepatic steatosis by two different US techniques, hepatorenal index by B-mode Ratio and attenuation coefficient by attenuation imaging (ATI).

Patients with suspicion or previously diagnosed of metabolic dysfunction-associated steatotic liver disease (MASLD) who attended fatty liver consulting room from June 2023 to September 2023 were prospectively recruited. Patients underwent two different US techniques of B-mode Ratio and ATI, and laboratory test were collected. According to previously proposed cut-off values, B-mode Ratio ≥ 1.22, 1.42, 1.54, and ATI ≥ 0.62, 0.70, and 0.78 dB/cm/MH were used for assessing of mild, moderate, and severe hepatic steatosis, respectively. Kappa consistency test was used to evaluate the consistency of hepatic steatosis.

A total of 62 patients were enrolled, including 44 males (71.0%) with an age of (41 ± 13) years and a body mass index of (27.0 ± 3.5) kg/m2. In the hyperlipidemia group, the B-mode Ratio and ATI were significantly higher than those in the non-hyperlipidemia group, with values of 1.68 ± 0.39 vs. 1.28 ± 0.35 (p = 0.001) and 0.74 ± 0.12 dB/cm/MH vs. 0.64 ± 0.11 dB/cm/MH (p = 0.005), respectively. The correlation coefficient between B-mode Ratio and ATI was 0.732 (p < 0.001). Using B-mode Ratio and ATI as diagnostic criteria for MASLD, the proportion of patients with MASLD was 79% and 82%, respectively. The Kappa coefficient for assessing MASLD was 0.90 (p < 0.001). Furthermore, these two different US techniques were used for grading hepatic steatosis, with no, mild, moderate, and severe steatosis accounting for 21%, 18%, 13%, and 48%, as well as 18%, 29%, 22%, and 31%, respectively. The linear weighted Kappa coefficient for staging hepatic steatosis was 0.78 (95% confidence interval: 0.68-0.87, p < 0.001).

The non-invasive methods of two different US techniques based on B-mode Ratio and ATI have good consistency for evaluating hepatic steatosis, and can be used for large-scale community screening.

Abdominal point-of-care ultrasound is an essential diagnostic tool for internal medicine physicians. It can identify intraperitoneal free fluid, evaluate the liver for size, presence of steatosis, and assessment for possible cirrhosis. Diagnosing cholelithiasis or cholecystitis can expedite care. Physical examination for mild splenomegaly may be insensitive. In such cases, sonographic measurements may provide a more definitive diagnosis. With the proper training, these organs can be evaluated at the bedside and guide clinical decision making.

In recent years, there has been a rise in cryptogenic hepatocellular carcinoma (c-HCC) cases in Japan, posing a detection challenge due to an unknown etiology. This study aims to enhance diagnostic strategies for c-HCC by analyzing its characteristics and exploring current opportunities for detection.

A retrospective study was conducted from April 2012 to March 2022, enrolling 372 newly diagnosed hepatocellular carcinoma (HCC) patients. Excluding cases associated with hepatitis viral infection, alcoholic liver disease, non-alcoholic fatty liver disease/steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and congestive hepatopathy, the study specifically focused on genuine c-HCC. The analysis delved into the characteristics, detection opportunities, and survival outcomes associated with c-HCC.

Among the non-viral HCC cases, 55 patients (29.3%) (34 men and 21 women) were diagnosed with c-HCC, making it the second-highest etiology. Notably, individuals with c-HCC, typically aged 60 and above (median age 76.0), exhibited a women predominance and presented with larger tumors (4.5 cm vs. 2.5 cm), correlating with a poorer prognosis. Cirrhosis was notably absent in most c-HCC cases (72.7%), and more than half (56.4%) did not have diabetes mellitus (DM). Diagnostic pathways for c-HCC primarily involved incidental imaging (47%) and symptoms (24%). Within the cohort of c-HCC, the prognosis for symptomatic cases is notably unfavorable compared to other cases [median survival time 19.0 (7.0-45.0) months vs. 47.0 (29.0-76.0) months, p = 0.029]. In the multivariate regression analysis, age and women emerged as independent factors associated with c-HCC. Rather than a significant increase in women, there is a narrowing gender gap.

Patients with c-HCC were predominantly elderly, without cirrhosis or diabetes, and exhibited minimal gender differences. Detection often occurred incidentally through abdominal imaging. Considering the limitations of conventional surveillance, it seems reasonable to propose that abdominal imaging be included in cancer screening, particularly for individuals aged 60 and older.

1610A127.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated at 32.4%, reflecting its growing clinical significance. MASLD, which includes MASLD and metabolic dysfunction-associated steatohepatitis (MASH) has been linked to increased metabolic, cardiovascular, and malignant morbidity. Progression into fibrotic stages of MASLD is also strongly associated with liver-related mortality. The past few years have seen a heightened focus on creating innovative therapeutic strategies for MASH management. GLP-1 receptor agonists (RA) have also emerged as a potential treatment option. Studies on GLP-1 agonists, such as liraglutide and semaglutide, have demonstrated efficacy in MASH management, albeit with limited histological improvement of fibrosis. However, recent investigations into GLP-1/GIP RA (tirzepatide) and Glucagon/GLP-1 RA (survodutide) have shown even more encouraging results, with higher rates of MASH resolution and fibrosis improvement. The tolerability of these medications due to their gastrointestinal side effects remains a major concern. Future research should focus on optimizing drug regimens, identifying patients most likely to benefit, and balancing efficacy with tolerability. The evolving landscape of MASH therapeutics suggests a bright future, with the potential for combination therapies to further enhance patient outcomes.

Steatotic liver disease (SLD) is a significant public health burden. Previously, we estimated prepandemic SLD prevalence determined by transient elastography-assessed hepatic steatosis and fibrosis in the United States. We now estimate the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and examine associations with lifestyle, socioeconomic, and other factors.

Liver stiffness and controlled attenuation parameters were assessed on 13,538 non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey 2017 to March 2020 and August 2021 to August 2023. The prevalence of SLD (controlled attenuation parameter >300 dB/m) was 28.7%, fibrosis (liver stiffness >8 kPa) was 11.3%, and MASLD was 25.6%. Between the 2 survey cycles, the age-standardized SLD prevalence was not significantly different, MASLD prevalence decreased (26.8%-23.6%), and fibrosis prevalence increased (10.4%-12.7%). In multivariable-adjusted analysis, both MASLD and fibrosis were associated with diabetes, higher body mass index, higher waist-to-hip ratio, elevated blood pressure, and inversely associated with non-Hispanic Black race-ethnicity. MASLD was also associated with male sex, non-Hispanic Asian race-ethnicity, prediabetes, higher total cholesterol, lower HDL cholesterol, and greater sedentary lifestyle. Fibrosis was also associated with SLD, lower total cholesterol, and less education.

In the US population, MASLD and fibrosis prevalence are high along with obesity and diabetes. Our findings suggest that early detection of chronic liver disease and targeting lifestyle and other modifiable risk factors may slow disease progression toward advanced fibrosis and cirrhosis.

Alcohol-related liver disease is the third cause of hepatocellular carcinoma worldwide and the leading cause in Europe. Additionally, the recent definition of Metabolic dysfunction-Associated Steatotic Liver Disease with increased alcoholic intake will enrich this population with a more nuanced phenotype, reflecting recent epidemiological trends. In these patients, hepatocellular carcinoma diagnosis is often delayed and less frequently detected through screening programs. Moreover, at the time of diagnosis, patients with alcohol-related hepatocellular carcinoma tend to have a poorer general condition, more severely impaired liver function, and a higher prevalence of comorbidities, leading to increased competitive mortality. However, when hepatocellular carcinoma is diagnosed during surveillance programs in patients with alcohol-related liver disease or metabolic dysfunction-Associated steatotic liver disease with increased alcoholic intake, the rate of allocation to first-line curative treatments is high (56%) and comparable to that of patients with virus-related hepatocellular carcinoma. As a consequence, the etiology of the underlying cirrhosis cannot be considered an independent prognostic factor in patients with hepatocellular carcinoma. Instead, prognosis is driven by liver function, general condition, and tumor burden. This underscores the crucial role of early diagnosis through periodic surveillance in patients with Alcohol-related liver disease or Metabolic dysfunction-Associated Steatotic Liver Disease with increased alcoholic intake -related cirrhosis.

Mitochondrial uncouplers are small molecule protonophores that act to dissipate the proton motive force independent of adenosine triphosphate (ATP) synthase. Mitochondrial uncouplers such as BAM15 increase respiration and energy expenditure and have potential in treating a variety of metabolic diseases. In this study, we disclose the structure-activity relationship profile of 6-substituted [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol derivatives of BAM15. Utilizing an oxygen consumption rate assay as a measure of increased cellular respiration, SHO1122147 (7m) displayed an EC50 of 3.6 μM in L6 myoblasts. Pharmacokinetic studies indicated a half-life of 2 h, Cmax of 35 μM, and no observed adverse effects at 1,000 mg kg-1 dose in mice. In a Gubra-Amylin (GAN) mouse model of MASH, SHO1122147 was efficacious in decreasing body weight and liver triglyceride levels at 200 mg kg-1 day-1 without changes in body temperature. These findings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol mitochondrial uncouplers for treatment of fatty liver disease and obesity.

Background/Objectives: This study investigates the gut microbiota's role in metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on microbial and functional signatures and sex-based differences. Methods: Using baseline data from 98 MASLD patients and 45 controls from the Fatty Liver in Obesity (FLiO) study, the gut microbiota was profiled with 16S gene sequencing, followed by statistical and machine learning analyses to identify disease-associated microbial signatures. Results: Notable alpha and beta diversity differences were observed between MASLD patients and the controls, varying by sex. Machine learning models highlighted specific microbial signatures for each sex, achieving high accuracy (area under the receiver operating characteristic curves of 0.91 for women and 0.72 for men). The key microbial taxa linked to MASLD included Christensenella and Limosilactobacillus in women and Beduinibacterium and Anaerotruncus in men. Functional profiling showed that MASLD patients had increased pathways for amine biosynthesis and amino acid degradation, while the controls exhibited enhanced fermentation pathways. These microbial features were associated with systemic inflammation, insulin resistance, and metabolite production linked to gut dysbiosis. Conclusions: The findings support the potential of gut microbiota signatures to be used as non-invasive indicators of MASLD and highlight sex-specific variations that could inform personalized diagnostic and therapeutic approaches.

The aim was to examine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a risk factor for atherosclerotic cardiovascular disease, and its association with glycaemic control metrics in children and adolescents with type 1 diabetes (T1D).

We enrolled 244 children and adolescents with T1D (115 girls, mean age: 16.2 ± 3.2 years). The diagnosis of MASLD was defined by the presence of hepatic steatosis on ultrasonography in combination with at least one of five common cardiometabolic risk factors. Metrics of short-term and long-term glycaemic control, blood pressure, lipids, anthropometric characteristics and three genetic variants strongly related to MASLD susceptibility (rs738409 [patatin-like phospholipase domain-containing 3], rs58542926 [transmembrane 6 superfamily member 2] and rs1260326 [glucokinase regulator]) were assessed. Characteristics of these subjects with and without MASLD were compared using the unpaired Student t test, Mann-Whitney test or χ2 test as appropriate. Logistic regression analyses were performed to determine the main independent predictors of MASLD.

The prevalence of MASLD was 27.5% in children and adolescents with T1D. Blood pressure, total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein cholesterol, HbA1c and time above range (TAR) were significantly higher in subjects with MASLD than in those without MASLD. Mean HbA1c values from diabetes onset (adjusted odds ratio [OR]: 1.703, 95% confidence interval [CI]: 1.040-2.787, p = 0.034), TAR (adjusted OR: 1.028, 95% CI: 1.009-1.047, p = 0.006) and plasma LDL cholesterol (adjusted OR: 1.045, 95% CI: 1.013-1.078, p = 0.004) were independently associated with the presence of MASLD.

MASLD is a common condition in children and adolescents with T1D. The mean HbA1c values from diabetes onset, TAR and LDL cholesterol levels were the independent predictors of MASLD.