To inform clinical monitoring of children and young adults with metabolic dysfunction-associated steatotic liver disease (MASLD) by characterizing the real-world natural history of MASLD and identifying baseline predictors of liver disease progression.

This retrospective study included consecutive patients ages < 23 years with MASLD who underwent serial MR elastography (MRE) and/or MR fat fraction (FF) examinations between 09/2009 and 11/2022. Outcomes of MASLD were defined based on maximum ratio values. A relative change ≥ 19% in liver stiffness measures (LSM) and an absolute change ≥ 5% for liver FF were considered clinically meaningful. Random intercept models characterized the yearly rate of change in LSM (kilopascals per year) and FF (percentage per year).

One hundred twenty-one patients (87 males, mean age at baseline: 12 ± 3 [SD] years) underwent 297 MRE examinations. The mean interval between the first and last MRE was 34 (± 24) months (range: 1-120 months). Among the 114 patients with serial LSM, 33% (38/114) showed progression, 46% (53/114) remained stable, and 21% (23/114) showed regression. Among the 88 patients with serial FF measures, 57% (50/88) showed progression, 2% (2/88) remained stable, and 41% (36/88) showed regression. LSM progression was associated with Hispanic ethnicity, baseline BMI-for-age percentile, baseline mean liver FF, and GGT changes over time. Predictors for liver FF progression included ALT, AST, GGT, and LDL.

In a real-world sample of children and young adults with MASLD who underwent serial liver MRI, a minority of patients demonstrated improvements in liver stiffness or FF over time.

Question In children, there is scarce data regarding the natural history of MASLD. Findings In this retrospective study, most children and young adults with MASLD had either unchanged or worsening liver stiffness (n = 91/114, 79%) and liver fat (n = 52/88, 59%). Clinical relevance Our findings emphasize the need for optimized care in pediatric MASLD. The identified risk factors for the progression of liver fat and stiffness may help to identify children who require interventions beyond changes in lifestyle.

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common disease in children. Lifestyle modification is the primary treatment but difficult to achieve and maintain. Topiramate is a component of an approved weight loss medication (topiramate-phentermine) in children aged 12 years and older but is more commonly used as a single agent, off-label, for pediatric obesity. Our aim is to describe change in anthropometrics and laboratory values while providing topiramate treatment of pediatric MASLD.

Descriptive cohort study including patients aged <18 years with MASLD and body mass index (BMI) >95th percentile treated with topiramate for weight loss for ≥3 months from January 1, 2010, to December 30, 2023. The primary outcome was change in serum alanine aminotransferase (ALT) levels from baseline to 3-6 months. Secondary outcomes were changes in BMI z score, glycated hemoglobin, and lipid profile.

Of 43 patients prescribed topiramate, 11 were excluded for nonadherence, leaving 32 (56% boys, 72% non-Hispanic) for further analyses. With topiramate, ALT levels improved (76 vs 50 U/L, p = 0.001). Further, 43% of patients had either ALT normalization or reduction by >50% from baseline. BMI z score decreased by 0.1 from baseline to 3-6 months. There were no improvements in glycated hemoglobin or lipids. Eight patients (25%) reported mild side effects.

Topiramate, as an adjunct to lifestyle intervention, may be considered in the treatment of pediatric MASLD, specifically in the context of failed lifestyle modification and inability to tolerate or qualify for other obesity pharmacotherapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease in children. MASLD encompasses a spectrum of liver disease and can be severe, with 10% of affected children presenting with advanced fibrosis. While biopsy remains the most accurate method for diagnosing and staging the disease, MRI proton density fat fraction and magnetic resonance elastography are the most reliable non-invasive measures for assessing steatosis and fibrosis, respectively. MASLD is associated with multiple comorbidities including type 2 diabetes, hypertension, dyslipidaemia, decreased bone mineral density, obstructive sleep apnoea, anxiety and depression. Currently, there are no pharmacological treatments available for children, highlighting the urgent need for paediatric clinical trials. A diet low in free sugars is promising for reducing steatosis and decreasing alanine aminotransferase, a surrogate marker for hepatic inflammation. Emerging data indicate that steatosis can be present in children under 6 years of age, which was previously considered rare. The intricate interplay of genetics may inform future therapeutics and prognostication, with the PNPLA3 gene showing the most evidence for association with the risk and severity of steatotic liver disease and steatohepatitis. MASLD is a complex disease affecting one in ten children and is associated with increased early mortality risk. More dedicated studies are needed in children to advance our understanding of this disease and find effective treatments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, and dyslipidemia. MASLD often leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, offers a promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated its capacity to reduce hepatic triglyceride accumulation and improve lipid profiles. Early- and advanced-phase studies, including the MAESTRO program, highlight significant reductions in hepatic fat content and favorable impacts on noninvasive biomarkers of fibrosis with minimal side effects. This review highlights evidence from pivotal studies, explores resmetirom's mechanism of action, and compares its efficacy and safety with other emerging therapeutic agents. While resmetirom marks a breakthrough in non-cirrhotic MASH management, further long-term studies are essential to fully evaluate its clinical benefits and potential regulatory approval for broader use in MASLD and MASH.

The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).

Vitamin E is an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) but associated with hemorrhagic complications when used for other indications. We aimed to determine the risk of developing iron deficiency during treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) with vitamin E. Iron status was monitored prospectively in 20 people with MASLD treated with 200 - 800 IU/d vitamin E (https://clinicaltrials.gov/study/NCT01792115). To gain mechanistic insights liver histology, hepatic gene expression, hepatic 4-hydroxynonenal, haptoglobin genotype and plasma vitamin E levels were assessed. We found iron deficiency to occur in 11/20 subjects (55%) after a median 11 weeks (range 4-13) of vitamin E treatment, and anemia to occur in 6 of the 11 (30% of study population) after 23 weeks (16-36). Ferritin (84.5 ± 85.2 to 47.8 ± 54.9μg/L, p < 0.001) and mean corpuscular volume (MCV, 86.2 ± 4.9 to 84.3±4.3fL, p = 0.003) significantly decreased, with a concomitant rise in red-cell distribution width (RDW, 13.4 ± 1.3 to 14.4 ± 1.9%, p = 0.003). A gastrointestinal bleeding source was found in 75% of subjects with complete work-up. Iron deficiency occurred in all diabetics vs. 47% of non-diabetics (p 0.007). Iron deficiency risk was not associated with cirrhosis, platelet count, prothrombin time, haptoglobin genotype, or plasma vitamin E level. Changes in hepatic gene expression and oxidative stress were suggestive of an extrahepatic effect. Iron deficiency resolved with appropriate care even with continued vitamin E treatment. We conclude that occult gastrointestinal bleeding and iron deficiency were frequently observed during vitamin E treatment, possibly reflecting an effect on platelet function. Close monitoring is warranted during the first months of treatment, especially in diabetics and subjects with risk factors for gastrointestinal bleeding.

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease with an increasing incidence worldwide. Single drug therapy may have toxic side effects and disrupt gut microbiota balance. Polyphenols are widely used in disease intervention due to their distinctive nutritional properties and medicinal value, which a potential gut microbiota modulator. However, there is a lack of comprehensive review to explore the efficacy and mechanism of combined therapy with drugs and polyphenols for NAFLD.

Based on this, this review firstly discusses the link between NAFLD and gut microbiota, and outlines the effects of polyphenols and drugs on gut microbiota. Secondly, it examined recent advances in the treatment and intervention of NAFLD with drugs and polyphenols and the therapeutic effect of the combination of the two. Finally, we highlight the underlying mechanisms of polyphenol combined drug therapy in NAFLD. This is mainly in terms of signaling pathways (NF-κB, AMPK, Nrf2, JAK/STAT, PPAR, SREBP-1c, PI3K/Akt and TLR) and gut microbiota. Furthermore, some emerging mechanisms such as microRNA potential biomarker therapies may provide therapeutic avenues for NAFLD.

Drawing inspiration from combination drug strategies, the use of active substances in combination with drugs for NAFLD intervention holds transformative and prospective potential, both improve NAFLD and restore gut microbiota balance while reducing the required drug dosage. This review systematically discusses the bidirectional interactions between gut microbiota and NAFLD, and summarizes the potential mechanisms of polyphenol synergistic drugs in the treatment of NAFLD by modulating signaling pathways and gut microbiota. Future researches should develop multi-omics technology to identify patients who benefit from polyphenols combination drugs and devising individualized treatment plans to enhance its therapeutic effect.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

The prevalence of obesity, along with that of its associated health conditions, including cardiovascular diseases, diabetes mellitus, and liver diseases, such as non-alcoholic fatty liver disease (NAFLD), is increasing annually. Bariatric surgery is indicated for the treatment of obesity if conservative treatment fails. While various liver fibrosis scores have been proposed for assessing liver function, they are typically used prior to bariatric surgery. This study aimed to determine whether fibrosis scores calculated from non-invasive parameters are effective in monitoring liver function after bariatric surgery.

This study analyzed data from 151 patients who underwent sleeve gastrectomy (SG) and were followed up at 3, 6, 9, 12, 24, and 36 months postoperatively. From the routinely collected parameters, liver fibrosis scores (APRI, Fib-4, BARD, Forns index [FORNS], Lok score [LOK], and NAFLD scores) were calculated retrospectively and compared to diabetes status % excess weight loss (%EWL) and % total weight loss (%TWL) over a 3-year follow-up period.

After SG, APRI, FORNS, and NAFLD scores showed significant improvements, whereas Fib-4, BARD, and LOK scores did not improve. Similarly, body mass index, %EWL, %TWL, and diabetes status also improved significantly. Throughout the 3-year follow-up period, only the APRI and NAFLD scores showed significant improvement.

Only APRI and NAFLD scores changed significantly after SG. Thus, these two scores may be used to reflect and monitor liver function in patients who have undergone SG.

Longitudinal outcomes in children with metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear due to the absence of a standardized monitoring approach. This study aimed to (1) define improvement and worsening in children with MASLD, (2) estimate rates of improvement or deterioration with the standard of care (SOC) over 1 and 2 years, and (3) identify baseline and longitudinal factors associated with improvement or worsening.

Using data from 2 large randomized controlled trials, we derived definitions for composite improvement and worsening of MASLD based on associations between changes in ALT, GGT, and liver histology after 1 and 2 years. Improvement was defined as ≥40% decrease in ALT and ≥20% decrease in GGT and worsening as ≥20% increase in both ALT and GGT. We applied definitions to a cohort of 440 children with MASLD. After 1 year of SOC, 22% of children with MASLD showed improvement, increasing to 31% after 2 years. However, 20% showed worsening after both 1 and 2 years despite receiving SOC. Logistic regression analysis, employing stepwise model selection, identified changes in body mass index z-score and cholesterol to be most associated with improvement or deterioration.

This study developed criteria for improvement and worsening in children with MASLD over 1 and 2 years of follow-up. With SOC, over one-quarter of children are likely to improve while one-fifth of children are likely to worsen. Targeting interventions that affect body mass index and lipid parameters may help improve MASLD over time.

Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.

Current research efforts in polymer and nanotechnology applications are primarily focused on cargo delivery to enhance the therapeutic index, with limited attention being paid to self-molecularly targeted nanoparticles, which may also exhibit significant therapeutic potential. Long-term and anomalous lipid accumulation in the liver is a highly relevant factor contributing to liver diseases. However, the development of the reliable medications and their pharmacological mechanisms remain insufficient. Herein, a polyguanide nanoinhibitors (PGNI) depot is constructed by copolymerizing biguanide derivatives in different proportions onto prepolymers. The nanoinhibitors for their ability to ameliorate lipid accumulation in vitro and in vivo is screened, and subsequently demonstrated that covalently polymeric guanidine chains exhibit superior efficacy in ameliorating hepatic lipid accumulation via heterogeneous mechanisms compared to small-molecule guanidine. It is found that PGNIs stabilize guanidine metabolism in the liver, preferably for biosafety. More importantly, PGNI is ingested and localized in hepatocyte lysosomes and is locked to interact with vesicular adenosine triphosphatase (V-ATPase) on lysosomes, leading to the inhibition of V-ATPase and lysosomal acidification, thereby activating the AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and fatty acid oxidation. These results imply that polymer-formed nanoparticles can serve as targeted inhibitors, offering a novel approach for therapeutic applications.

Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.

Steatotic liver disease affects approximately 1 in 10 children in the U.S. and increases the risk of cirrhosis, diabetes, and cardiovascular disease. Lifestyle modification centered on increased physical activity and dietary improvement is the primary management approach. However, significant gaps in the literature hinder the establishment of exercise as a targeted therapeutic strategy for pediatric metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD). We performed a systematic review of studies assessing the impact of exercise interventions on validated hepatic outcomes in children with NAFLD.

We searched CENTRAL, PubMed, Embase, Web of Science, CINAHL, and Google Scholar on June 5 and 6, 2023, for studies in English involving children aged 0 to 19 years diagnosed with NAFLD or at increased risk for NAFLD due to overweight or obesity. We updated the search on August 8, 2024. Eligible studies were required to examine the impact of exercise interventions on hepatic steatosis or liver chemistry. The risk of bias was assessed with RoB2 and ROBINS-I. Data extraction was performed by two independent reviewers.

After screening 1578 unique records, 16 studies involving 998 children were included. This comprised seven studies comparing exercise intervention with non-exercising controls, three uncontrolled studies of exercise intervention, two studies comparing exercise plus lifestyle interventions with lifestyle interventions alone, and nine studies comparing different types of exercise interventions. Five of the 11 studies that evaluated hepatic steatosis reported an absolute decrease of 1% to 3%. In the nine studies that evaluated liver chemistry, no significant changes were observed.

Evidence supporting exercise intervention for the treatment of pediatric MASLD is limited. Existing studies were constrained by their methodological approaches; thus, there is a pressing need for high-quality future research. This will enable the development of precise, evidence-based exercise guidelines crucial for the effective clinical management of this condition.

Liver disorders present a significant global health challenge, necessitating the exploration of innovative treatment modalities. Liposomal nanocarriers have emerged as promising candidates for targeted drug delivery to the liver. This review offers a comprehensive examination of the mechanisms and applications of liposomal nanocarriers in addressing various liver disorders. Firstly discussing the liver disorders and the conventional treatment approaches, the review delves into the liposomal structure and composition. Moreover, it tackles the different mechanisms of liposomal targeting including both passive and active strategies. After that, the review moves on to explore the therapeutic potentials of liposomal nanocarriers in treating liver cirrhosis, fibrosis, viral hepatitis, and hepatocellular carcinoma. Through discussing recent advancements and envisioning future perspectives, this review highlights the role of liposomal nanocarriers in enhancing the effectiveness and the safety of liver disorders and consequently improving patient outcomes and enhances life quality.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent hepatic condition linked to metabolic alterations. It gradually causes liver damage and potentially progresses to cirrhosis. Despite its significance, research, especially in the pediatric population, is limited, leading to contradictory findings in diagnosis and treatment. This meta-analysis aims to synthesize existing literature on therapeutic interventions for MASLD in children and adolescents.

A comprehensive search of randomized controlled clinical trials yielded 634 entries from PubMed, Scopus, and Web of Science up to 2023. Interventions included medications, behavioral modifications, dietary changes, probiotics, supplements, surgical procedures, or combinations. The analysis focused on studies with treatment duration of at least 3 months, employing a random-effects REML meta-analysis model. Treatment effects on anthropometric measurements and biochemical components were examined and adjusted for heterogeneity factors analysis. A bibliometric analysis for insights into research contributors was performed.

The systematic review incorporated 31 clinical trials, with 24 meeting criteria for meta-analysis. These comprised 3 medication studies, 20 with supplements, 4 focusing on lifestyle, and 4 centered on diets. Significant overall treatment effects were observed for ALT, AST, BMI, and HOMA-IR mainly by supplements and lifestyle. Meta-regression identified age, BMI changes, and treatment duration as factors modifying ALT concentrations. Bibliometric analysis involving 31 linked studies highlighted contributions from 13 countries, with the USA, Spain, and Chile being the most influential.

We conclude that supplementation and lifestyle changes can effectively impact ALT and AST levels, which can help address liver issues in obese children. However, the evaluation of risk bias, the high heterogeneity, and the bibliometric analysis emphasize the need for more high-quality studies and broader inclusion of diverse child populations to provide better therapeutic recommendations.

PROSPERO, CRD42023393952. Registered on January 25, 2023.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disease in children in industrialized countries mainly due to the rise in obesity and overweight. Besides risk of progressive liver damage, MASLD also carries an increased risk of extra-hepatic morbidity, most importantly type 2 diabetes mellitus and cardiovascular disease. Important challenges remain in the prevention, detection, and treatment of this prevalent disorder. This review outlines the epidemiology and risk factors of MASLD and provides an approach to screening, diagnosis, and treatment based on current best available evidence and expert opinion. What is known: • NAFLD/MASLD is a common disorder in children strongly related to obesity/overweight and insulin resistance. • This silent disorder is underdiagnosed due to lack of awareness and lack of simple diagnostic criteria. What is new: • New diagnostic criteria have transformed NAFLD/MASLD from a diagnosis of exclusion to a positive diagnosis with simple criteria. • Effective treatments are emerging for adults and will likely become available for children. • Identifying children with NAFLD/MASLD has become even more important due to this new treatment perspective.

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

The relationship between dietary antioxidants and fatty liver disease remains a topic of debate. This study aimed to examine the association between the Composite Dietary Antioxidant Index (CDAI) and nonalcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD).

The study analyzed data from the 2003-2018 cycles of the National Health and Nutrition Examination Survey. The study included 16,321 individuals aged 20-85 years. Food and nutrient intake data were based on the 24-h recall method. Multivariate logistic regression models were employed to examine the relationship between CDAI and NAFLD/MAFLD.

In the fully adjusted multivariate logistic regression model, CDAI demonstrated a significant negative correlation with NAFLD and MAFLD. Mediation analysis showed that inflammatory factors partially mediated the relationship between CDAI and NAFLD/MAFLD prevalence. The combination of high CDAI levels with effective physical activity was associated with a greater reduction in NAFLD/MAFLD prevalence than high CDAI levels alone.

Our study highlighted a negative association between CDAI and NAFLD/MAFLD, mediated by inflammatory factors. Additionally, participants with characteristics of active physical activity and high levels of CDAI were more strongly correlated with the reduced prevalence of NAFLD/MAFLD. Further research in clinical cohorts should be conducted to comprehensively investigate the impact of CDAI on NAFLD/MAFLD prevalence.

To summarize the literature on pharmacotherapy for managing paediatric obesity.

A systematic review and meta-analysis were conducted of randomized controlled trials (RCTs) with <18-year-olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy-reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs).

Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon-like peptide-1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3-24 months). Metformin had little to no benefit on PROMs (e.g., health-related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z-score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA-IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL-cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions.

Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long-term effectiveness and safety of GLP1RAs remain to be evaluated.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in children. We hypothesized environmental toxins could drive progression to metabolic dysfunction-associated steatohepatitis (MASH), and assayed serum toxins and metabolites in children with histologically characterized MASLD/MASH.

Environmental chemicals, common in household items, perfluoroalkyl substances (PFAS), polybrominated flame retardants (polybrominated diphenyl ethers [PBDEs]), and metabolic profiles were assayed in children enrolled in the multicenter NASH Clinical Research Network Pediatric Database 2. Mixture models, using repeated holdout weighted quantile sum regression (WQSrh) were run in addition to single chemical/metabolite logistic regression. For metabolomic analyses, random subset version of WQSrh was used for the large number of predictors versus participants. Nominal and false discovery rate (FDR) p-values (two-sided) were computed.

Four hundred and thirty-five children distributed across MASH (n = 293) and MASLD (n = 142), with 304 (69.9%) males. Mean (standard deviation) for Nonalcoholic Steatohepatitis Score (NAS) and alanine aminotransferase (ALT) for MASLD were 3.1 (1.0), 67.9 (43.4), and for MASH 4.2 (1.4), 144 (121). There was an inverse association between PFAS/PBDE mixture and MASH versus MASLD, lobular inflammation (p = 0.026), NAS (p = 0.009, FDR p = 0.04), and log-transformed ALT (p = 0.005, FDR p = 0.025) driven by perfluorohexane sulfonate (PFHXS). Metabolites from positive hydrophilic interaction liquid chromatography mode, biliverdin (p = 0.002) and 1-methylhistidine (associated with meat ingestion, p = 0.02) and reverse phase negative mode, hippuric acid (solvent exposure, p = 0.022) significantly associated with MASH.

Significant negative PFAS/PBDE mixture effect and odds of MASH were dominated by PHFXS. Several metabolites are significantly associated with MASH which inform mechanistic pathways and could drive key therapeutic and diagnostic strategies in children.

To determine the association between dietary antioxidant sources and non-alcoholic fatty liver disease (NAFLD).

In this observational study, we utilized NHANES 2017-2020 data to identify the factors associated with NAFLD in dietary antioxidant sources via weighted multivariate logistic regression models. Then, Mendelian randomization (MR) was applied to investigate the effect of dietary antioxidant sources on NAFLD at the genetic level.

Of the six dietary sources of antioxidants, only vitamin E (Vit E) was significantly associated with NAFLD (OR = 0.98; 95% CI: 0.97-0.99; p = 0.001). Upon adjusting for all covariates, it was determined that the highest quartile of dietary Vit E intake was associated with a decreased NAFLD occurrence compared with the lowest quartile of dietary Vit E intake (p < 0.001). The results of IVW-MR analysis revealed an association between Vit E and NAFLD (OR = 0.028; p = 0.039).

Our research indicates a negative and linear relationship between daily vitamin E intake and NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), also called non-alcoholic fatty liver disease, is the most epidemic chronic liver disease worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is the critical stage of MASLD, and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications. So far, pharmacotherapeutics for the treatment of MASH are still a major challenge, because of the complexity of the pathogenesis and heterogeneity of MASH. Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways, including the attenuation of steatohepatitis or fibrosis or both. It is notable that thyroid hormone receptor-β agonist, resmetirom has become the first officially approved drug for treating MASH with fibrosis. Other agents such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 analogs, and fibroblast growth factor 21 analogs are awaiting approval. This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials, and presents the future directions and difficulties of new drug research for MASH.

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, affecting an estimated 3 in 10 people. The available treatment is far from optimal. Diet and lifestyle changes to promote weight loss and weight loss maintenance are the basic management of NAFLD, but these are difficult to achieve and maintain. Vitamin E has shown beneficial effects on oxidative stress, which plays a major role in the pathogenesis of NAFLD. However, there is uncertainty about the effects of vitamin E for people with NAFLD.

To evaluate the beneficial and harmful effects of vitamin E alone, or vitamin E in combination with other vitamins or minerals, versus placebo or no intervention in people with NAFLD.

We used recommended Cochrane search methods. The latest search was performed on 2 February 2024.

We included randomised clinical trials that compared vitamin E alone, or in combination with other vitamins or minerals, at any dose, duration, and route of administration, versus placebo or no intervention, in people with NAFLD of any age, sex, or ethnic origin. We included participants with imaging techniques or histology-proven NAFLD and minimal alcohol intake, and participants with steatohepatitis who had liver biopsies.

Our critical outcomes were all-cause mortality, liver-related mortality, and serious adverse events. Our important outcomes were liver-related morbidity, health-related quality of life, non-serious adverse events, biochemical response, and imaging assessment of the degree of fatty liver.

We used Cochrane's RoB 2 tool to assess risk of bias for each of the predefined outcomes.

We used standard Cochrane methods. We used GRADE to assess the certainty of evidence.

We included 16 randomised clinical trials involving 1066 paediatric and adult participants with NAFLD. Experimental groups received vitamin E alone (14 trials) or vitamin E in combination with vitamin C (2 trials). Control groups received placebo in 13 trials and no intervention in three trials. Daily dosages of oral vitamin E ranged from 298 international units (IU) to 1000 IU. Co-interventions were lifestyle and low-calorie diet interventions in 13 trials, ursodeoxycholic acid in one trial, unchanged diet and physical activity in one trial, and baseline treatments for type 2 diabetes in one trial. Nine trials had more than two intervention groups, but we used only the groups in which vitamin E alone or vitamin E in combination with vitamin C were compared with placebo or no intervention. In total, 7.9% (84/1066) of participants dropped out. Follow-up ranged from 2 months to 24 months.

Vitamin E versus placebo or no intervention The effects of vitamin E versus placebo or no intervention on all-cause mortality (risk ratio (RR) 3.45, 95% confidence interval (CI) 0.57 to 20.86; 3 trials, 351 participants; very low certainty evidence) and serious adverse events (RR 1.91, 95% CI 0.30 to 12.01; 2 trials, 283 participants; very low certainty evidence) are very uncertain. There were no data on liver-related mortality or liver-related morbidity. The effects of vitamin E versus placebo or no intervention on physical health-related quality of life (mean difference (MD) 0.74, 95% CI -0.52 to 2.01; 2 trials, 251 participants; higher scores indicate better quality of life; very low certainty evidence); psychosocial health-related quality of life (MD -0.57, 95% CI -4.11 to 2.97; 2 trials, 251 participants; higher scores indicate better quality of life; very low certainty evidence); and non-serious adverse events (RR 0.86, 95% CI 0.64 to 1.17; 2 trials, 283 participants; very low certainty evidence) are also very uncertain. There were no data on proportion of participants without a decrease in liver enzymes. Vitamin E likely slightly reduces serum alanine transaminase (ALT) (MD -9.29, 95% CI -13.69 to -4.89; 11 trials, 708 participants; moderate certainty evidence) and aspartate aminotransferase (AST) (MD -4.90, 95% CI -7.24 to -2.57; 11 trials, 695 participants; moderate certainty evidence) levels compared with placebo or no intervention. Vitamin E may slightly reduce serum alkaline phosphatase (ALP) levels (MD -5.21, 95% CI -9.88 to -0.54; 5 trials, 416 participants; very low certainty evidence), but the evidence is very uncertain. Vitamin E plus vitamin C versus placebo There were no data on all-cause mortality, liver-related mortality, serious adverse events, liver-related morbidity, health-related quality of life, and non-serious adverse events. The effects of vitamin E plus vitamin C on reducing serum ALT (MD -0.50, 95% CI -4.58 to 3.58; 2 trials, 133 participants; very low certainty evidence), AST (MD 0.09, 95% CI -3.39 to 3.57; 1 trial, 88 participants; very low certainty evidence), and gamma-glutamyl transferase (GGT) levels (MD 1.58, 95% CI -3.22 to 6.38; 1 trial, 88 participants; very low certainty evidence) are very uncertain. We identified three ongoing trials, and six trials are awaiting classification.

Given the very low certainty evidence, we do not know if long-term treatment (18 months to 24 months) with vitamin E administered alone affects all-cause mortality, serious adverse events, quality of life, or non-serious adverse events in people with NAFLD when compared with placebo or no intervention. We found no data on liver-related mortality, liver-related morbidity, or proportion of participants without a decrease in liver enzymes. Vitamin E likely reduces ALT and AST slightly when compared with placebo, but whether this has any impact on the clinical course in people with NAFLD is unknown. The trials on vitamin E plus vitamin C did not report on all-cause mortality, liver-related mortality, serious adverse events, liver-related morbidity, health-related quality of life, or non-serious adverse events. Given the very low certainty evidence, we do not know the effects of vitamin E plus vitamin C on liver enzymes in people with NAFLD when compared with placebo.

Three trials disclosed no external funding. Five trials were industry funded. Five trials were funded by organisations with no vested interests. Three trials did not provide any information on clinical trial support or sponsorship.

Protocol: doi.org/10.1002/14651858.CD015033.

There has been an alarming increase in metabolic dysfunction-associated steatotic liver disease (MASLD) and it is now the most common chronic liver disease worldwide, in both adult and pediatric populations. The lack of regional guidelines has hampered the formulation of national policies for prevention and management of MASLD in children. Therefore, we formulated recommendations for steatotic liver disease in children.

To review the existing literature on the burden and epidemiology of pediatric MASLD and formulate recommendations for diagnostic evaluation, prevention, and management strategies.

The Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition invited national and international stakeholders to participate in a consensus meeting held on April 20, 2024, in Mumbai, Maharashtra, India. Various aspects of pediatric steatotic liver disease were deliberated upon and a consensus document and recommendations were formulated after several rounds of discussion.

Metabolic dysfunction-associated steatotic liver disease (MASLD) should be used as the preferred term in place of non-alcoholic fatty liver disease (NAFLD). There is a high prevalence of steatotic liver disease (SLD) among Indian children and adolescents, especially those who are overweight or obese. This condition may be progressive in childhood and associated with increased morbidity and mortality in adulthood. Various lifestyle, dietary, and genetic factors may predispose individuals to MASLD, including an increased intake of calorie-dense processed foods, sweetened sugar beverages, excessive screen time, higher sedentary time and lack of moderate to vigorous physical activity. MASLD is usually asymptomatic or presents with mild, non-specific symptoms and therefore, a high degree of suspicion is required for early diagnosis. MASLD is usually associated with cardiometabolic factors (hypertension, insulin resistance/diabetes mellitus, and/or dyslipidemia) and secondary causes should be excluded in all cases, particularly in the presence of red flag signs. Screening for MASLD should be considered in all obese children (body mass index or BMI ≥95th percentile) and in all overweight children (BMI ≥ 85th and <95thpercentile) with additional risk factors, such as prediabetes/diabetes, dyslipidemia, positive family history of metabolic syndrome, obstructive sleep apnea, and hypopituitarism. Abdominal ultrasound in combination with alanine aminotransferase (ALT) levels should be used as a screening test for MASLD in Indian children as per the proposed algorithm. Diet (any hypocaloric diet) and exercise (aerobic, resistance, or a combination of both; moderate to high intensity; regular in frequency) remain the cornerstones of pediatric MASLD management. Pharmacotherapy and/or endoscopic/surgical techniques for obesity should be considered as adjuncts and should be considered only after a failed adequate trial of lifestyle modifications.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population. Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD, progress in drug development for this condition remains limited. This review highlights the potential of drug-target Mendelian randomisation (MR), a study design that leverages human genetics and genomics, for the discovery, repositioning and safety assessment of drug targets in MASLD. We summarised key aspects of designing and appraising a drug-target MR study, discussing its inherent assumptions and considerations for instrument selection. Furthermore, we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets, repositing existing drug targets, informing adjunctive treatments and addressing issues in paediatric MASLD.

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, with a prevalence of 38%. In these patients, cardiovascular disease (CVD) is the number one cause of mortality rather than liver disease. Liver abnormalities per se due to MASLD contribute to risk factors such as dyslipidemia and obesity and increase CVD incidents. In this review we discuss hepatic pathophysiological changes the liver of MASLD leading to cardiovascular risks, including liver sinusoidal endothelial cells, insulin resistance, and oxidative stress with a focus on glutathione metabolism and function. In an era where there is an increasingly robust recognition of what causes CVD, such as the factors included by the American Heart Association in the recently developed PREVENT equation, the inclusion of liver disease may open doors to how we approach treatment for MASLD patients who are at risk of CVD.

The historical use of the term non-alcoholic fatty liver disease (NAFLD) in obese/overweight children has been controversial as to the appropriateness of this terminology in children, and lately, in adults too. Newer game-changer terminology, metabolic (dysfunction)-associated fatty liver disease (MAFLD), for this condition signifies a positive step forward that addresses the limitations of the previous definition for both adults and children. The prevalence of MAFLD has surged in tandem with the global rise in obesity rates, establishing itself as a predominant cause of chronic liver disease in both adult and pediatric populations. The adoption of the recently proposed nomenclature reflects a more encompassing comprehension of the disease and its etiology compared to its predecessor, NAFLD. Notably, the revised terminology facilitates the recognition of MAFLD as an autonomous condition while acknowledging the potential coexistence of other systemic fatty liver disorders. Particularly in children, this includes various paediatric-onset genetic and inherited metabolic disorders, necessitating thorough exclusion, especially in cases where weight loss interventions yield no improvement or in the absence of obesity. MAFLD presents as a multifaceted disorder; evidence suggests its origins lie in a complex interplay of nutritional, genetic, hormonal, and environmental factors. Despite advancements, current non-invasive diagnostic biomarkers exhibit limitations in accuracy, often necessitating imaging and histological evaluations for definitive diagnosis. While dietary and lifestyle modifications stand as cornerstone measures for MAFLD prevention and management, ongoing evaluation of therapeutic agents continues. This article provides an overview of the latest developments and emerging therapies in the realm of paediatric MAFLD.

In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.

Studies on adults have shown an association between overt or subclinical hypothyroidism and metabolic dysfunction-associated steatotic liver disease (MASLD). The goal of this study was to assess the relationship between thyroid-stimulating hormone (TSH) levels and the histological characteristics of MASLD in youth.

This observational study used prospectively collected liver biopsy and clinical data from youth enrolled in 2 pediatric clinical trials in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Thyroid assays were compared between youth with MASLD and population-based controls aged ≤18 years from the National Health and Nutrition Examination Survey. Individuals with overt hypothyroidism, abnormal antithyroid antibodies, or thyroid-related medications were excluded. Subclinical hypothyroidism was defined as TSH between 4.5 and 10.0 uIU/L. Multinomial logistic regression was used to test the association between TSH and MASLD histological changes at baseline, adjusting for age, sex, race/ethnicity, and body mass index. Mixed-effect models, including treatment and time, were used for the longitudinal analysis.

Mean TSH, total thyroxine (T4), total triiodothyronine (T3), and free T4 levels were higher ( p < 0.001) in the NASH CRN cohort (n = 218; 421 observations) than in the National Health and Nutrition Examination Survey cohort (n = 2198). TSH levels were positively associated with increased steatosis over time ( p = 0.03). Subclinical hypothyroidism was associated with borderline or definite metabolic-associated steatohepatitis on histology at baseline ( p = 0.03) and with changes in fibrosis over time ( p = 0.01).

The association between TSH and steatosis severity in individuals with normal thyroid hormone concentrations suggests an independent role of TSH in MASLD.