Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Elafibranor, a dual PPARα and PPARδ agonist, reduces alcoholassociated liver disease: Lessons from a mouse model

Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists have been under scrutiny as potential pharmacological targets and as of today,resmetirom,a thyroid hormone receptor b agonist,is the only approved agent.The dual PPARαandδagonist elafibranor has also undergone extensive clinical testing,which reached the phase III clinical trial but failed to demonstrate a beneficial effect on MASLD.As alcohol-associated liver disease and MASLD can be interconnected,whether elafibranor might be affective against liver disease caused by alcohol consumption is worth investigating.Writing recently in the World Journal of Gastroenterology,Koizumi et al reported using a mouse model of alcoholassociated liver disease and found that hepatic steatosis,liver fibrosis,and hepatocyte apoptosis were alleviated by administration of elafibranor.Although preclinical in nature,these data support the potential beneficial action of elafibranor in alcohol-induced MASLD,warranting the testing of this molecule in patients with steatotic liver disease caused by alcohol consumption.

Critical assessment of the reported bidirectional associations between gallstone, non-alcoholic fatty liver, and kidney stone diseases

The recent article by Jiang et al published in World Journal of Gastroenterology reports substantial bidirectional associations between gallstone disease(GSD),non-alcoholic fatty liver disease(NAFLD),and kidney stone disease(KSD),based on multicenter cross-sectional studies and a systematic review with meta-analysis.While the findings have the potential to significantly impact clinical and pre-ventive strategies,several methodological issues merit closer examination.This letter critiques key aspects of the study,including sample population hetero-geneity,potential confounding variables,and the reliance on cross-sectional data that may limit causal inferences.We also discuss the generalizability of these results to broader populations given the study's focus on the Chinese demogra-phic.By addressing these concerns,we suggest a more nuanced interpretation of the associations between GSD,NAFLD,and KSD,advocating for longitudinal studies to validate these findings and enhance their applicability in global health contexts.

Assessment of skeletal muscle alterations and circulating myokines in metabolic dysfunction-associated steatotic liver disease:A crosssectional study

BACKGROUND Skeletal muscle alterations(SMAs)are being increasingly recognized in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD)and appear to be associated with deleterious outcomes in these patients.However,their actual prevalence and pathophysiology remain to be elucidated.AIM To determine the prevalence of SMAs and to assess the significance of circulating myokines as biomarkers in patients with MASLD.METHODS Skeletal muscle strength and muscle mass were measured in a cross-sectional study in a cohort of 62 patients fulfilling MASLD criteria,recruited from the outpatient clinics of a tertiary level hospital.The degree of fibrosis and liver steatosis was studied using abdominal ultrasound and transitional elastography.Anthropometric and metabolic characteristics as well as serum levels of different myokines were also determined in the MASLD cohort.Statistical analysis was performed comparing results according to liver fibrosis and steatosis.RESULTS No significant differences were found in both skeletal muscle strength and skeletal muscle mass in patients with MASLD between different stages of liver fibrosis.Interestingly,serum levels of fibroblast growth factor-21(FGF21)were significantly higher in patients with MASLD with advanced hepatic fibrosis(F3-F4)than in those with lower fibrosis stages(F0-F2)(197.49±198.27 pg/mL vs 95.62±83.67 pg/mL;P=0.049).In addition,patients with MASLD with severe hepatosteatosis(S3)exhibited significantly higher serum levels of irisin(1116.87±1161.86 pg/mL)than those with lower grades(S1-S2)(385.21±375.98 pg/mL;P=0.001).CONCLUSION SMAs were uncommon in the patients with MASLD studied.Higher serum levels of irisin and FGF21 were detected in patients with advanced liver steatosis and fibrosis,respectively,with potential implications as biomarkers.

Hepatitis B virus infection and metabolic dysfunction associated steatotic liver disease:Rising pandemic with complex interaction

Due to sedentary lifestyle and rising prevalence of obesity,patients with general population and those who are infected with chronic hepatitis B are found to have metabolic dysfunction associated steatotic liver disease(MASLD).Both chronic hepatitis B virus(HBV)infection and MASLD can damage hepatocytes in their own way,but concomitant HBV-MASLD has its own clinical implications.Cherry on top is the presence of diabetes mellitus,hypertension or obesity which added more chances of unfavorable outcomes in these patients.In this article,we co-mment on the article by Wang et al published in the recent issue.This article provides a comprehensive overview of the complex interaction between HBV-MASLD,HBV alone and MASLD alone patients.We discuss key findings from recent studies,including the promising outcomes observed in patients with concurrent HBV and MASLD,warrants further research.The insights presented here offer renewed understanding of this complex interaction.

High metabolic dysfunction-associated steatotic liver disease prevalence in type 2 diabetes: Urgent need for integrated screening and lifestyle intervention

This letter discusses the recent study by Mukherjee et al,which identifies a significant prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)among newly diagnosed type 2 diabetes mellitus(T2DM)patients in Bihar,India,and underscores the pressing need for integrated MASLD mana-gement within T2DM care.With 72.3%of the study cohort affected by MASLD,implementing routine liver function tests and ultrasound screenings is recom-mended as a standard practice in diabetes care,especially in regions with high prevalence rates.The study also advocates for dietary and lifestyle modifications,particularly the reduction of saturated fats,to slow MASLD progression.Patient education on monitoring body mass index and waist circumference,coupled with the integration of these metrics into digital health records,could enhance patient involvement and support proactive health management.Moreover,the letter emphasizes the advantages of developing a region-specific MASLD risk model that incorporates local dietary patterns and socioeconomic factors.Continued research into genetic and environmental determinants of MASLD remains es-sential for advancing our understanding of its etiology and informing targeted public health strategies.

What is the role of nonalcoholic fatty liver disease in pulmonary carcinoma development?

This article summarizes the epidemiological characteristics and clinical manifest-ations of nonalcoholic fatty liver disease(NAFLD).The incidence of NAFLD has been increased dramatically and become the leading cause of chronic liver disease worldwide.In addition to its adverse outcomes of liver fibrosis,cirrhosis,and hepatocellular carcinoma,and related complications,NAFLD has recently been found to be associated with the high-risk extrahepatic carcinomas,such as various types of lung cancer(i.e.,lung adenocarcinoma,squamous cell carcinoma,and small cell lung cancer).The presence of hepatic steatosis also predisposes lung cancer to liver metastasis,but has better response to immune checkpoint inhibi-tors.Whether other factors(i.e.,gender,smoking,etc.)are associated with NAFLD and lung cancer remains controversial.We also comment on the reciprocal rela-tionships between NAFLD and components of metabolic syndrome.Most meta-bolic syndrome components are suggested to facilitate lung cancer development via activating insulin/insulin-like growth factor axis.In addition,suppressed anti-tumor immunity and accelerated tumor progression could be attributed to the cell-specific metabolic reprogramming in condition of high-fat diet and related obesity.These findings may reveal the role of NAFLD in pulmonary carcinoma and help develop new treatment strategies for this disease.

Adenosine triphosphate-binding pocket inhibitor for mixed lineage kinase domain-like protein attenuated alcoholic liver disease via necroptosis-independent pathway

BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.

Research hotspots and trends in gut microbiota and nonalcoholic fatty liver disease: A bibliometric study

BACKGROUND Recent research indicates that the intestinal microbial community,known as the gut microbiota,may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).To understand this relationship,this study used a compre-hensive bibliometric analysis to explore and analyze the currently little-known connection between gut microbiota and NAFLD,as well as new findings and possible future pathways in this field.AIM To provide an in-depth analysis of the current focus issues and research deve-lopments on the interaction between gut microbiota and NAFLD.METHODS In this study,all data were collected from the Web of Science Core Collection,and the related searches were completed on one day(February 21,2024).The data were stored in plain text format to facilitate subsequent analysis.VOSviewer 1.6.20 and CiteSpace 6.1R6 Basic were used for knowledge graph construction and bibliometric analysis.RESULTS The study included a total of 1256 articles published from 2013 to 2023,and the number of published papers demonstrated an upward trend,reaching a peak in the last two years.The University of California,San Diego held the highest citation count,while Shanghai University of Traditional Chinese Medicine in China led in the number of published works.The journal"Nutrients"had the highest publication count,while"Hepatology"was the most frequently cited.South Korean author Suk Ki Tae was the most prolific researcher.The co-cited keyword cluster labels revealed ten major clusters,namely cortisol,endothelial dysfunction,carbohydrate metabolism,myocardial infarction,non-alcoholic steatohepatitis,lipotoxicity,glucagon-like peptide-1,non-islet dependent,ethnicity,and microRNA.Keyword outbreak analysis highlighted metabolic syndrome,hepatic steatosis,insulin resistance,hepatocellular carcinoma,cardiovascular disease,intestinal permeability,and intestinal bacterial overgrowth as prominent areas of intense research.CONCLUSION Through the quantitative analysis of relevant literature,the current research focus and direction of gut microbiota and NAFLD can be more clearly understood,which helps us better understand the pathogenesis of NAFLD,and also opens up innovative solutions and strategies for the treatment of NAFLD.

Small bites,big impact:The importance of evening snacks in patients with advanced chronic liver disease

People with advanced chronic liver disease(ACLD)have an enhanced risk of malnutrition,which has multifactorial etiology and is mainly linked to a reduced energy and protein intake;malnutrition is critical for patients with cirrhosis since it is often associated with sarcopenia,a skeletal muscle depletion with a loss of muscle mass and function.Late-evening snacks have been extensively studied,and guidelines are recommended to counteract the effects of prolonged fasting at night in patients with ACLD.However,it has not been fully explored whether late evening snacking is clarified as a milestone to address the nutritional needs of people with ACLD or whether it has a potential role in improving body compo-sition.In this randomised control trial,Yu et al demonstrated that long-term nocturnal snacks have the potential to significantly improve body composition by body fat mass,visceral fat area and body cell mass in patients with ACLD.While the improvement in skeletal muscle mass was minor,the promising results in other compositions provide hope for future research and patient care.

Exploring the links between gallstone disease, non-alcoholic fattyliver disease, and kidney stones: A path to comprehensiveprevention

The recent study exploring the bidirectional associations between gallstone disease,non-alcoholic fatty liver disease,and kidney stone disease highlights a critical concern in chronic disease management.Given the rising global prevalence of these conditions,understanding their interconnections is essential.The study emphasizes the importance of shared risk factors,such as obesity,type 2 diabetes,dyslipidemia,and oxidative stress,and calls for multidisciplinary screening strategies.This approach would improve patient outcomes and reduce the socio-economic burden.While the study contributes valuable insights from a Chinese population,further research across diverse populations is necessary to validate and extend these findings globally.Ultimately,the research underscores the need for integrated prevention programs to better manage these interconnected diseases and improve health outcomes.

Effectiveness of RESET care program: A real-world-evidence on managing non-alcoholic fatty liver disease through digital health interventions

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)management requires sustainable lifestyle modifications.This study aimed to evaluate the effectiveness of the RESET care plan,a comprehensive program that is an integrated personalized diet,exercise,and cognitive behavior therapy,delivered via MyTatva’s digital health application enabled through a body composition analyzer(BCA)and smartwatch.AIM To evaluates the effectiveness of the comprehensive program delivered via My-Tatva’s digital health app enabled through internet of thing devices.METHODS This retrospective observational study analyzed deidentified data from 22 par-ticipants enrolled in the MyTatva RESET care program.Participants were divided into three groups:Group A,diet plan;Group B,diet+exercise plan;and Group C,diet+exercise+cognitive behavioral therapy plan.Participants were provided with a BCA and smartwatch for continuous monitoring of anthropometric para-meters.Statistical analysis,including one-way ANOVA and post-hoc Tukey’s Honest Significant Difference test,was conducted to compare mean changes in anthropometric parameters across the groups.INTRODUCTION Non-alcoholic fatty liver disease(NAFLD)has emerged as a global health burden,affecting approximately 1 in 4 in-dividuals worldwide.NAFLD ranges from simple steatosis(fat accumulation)to non-alcoholic steatohepatitis(NASH),and its global prevalence in the general population is estimated between 6.3%and 33%,with NASH affecting 3-5%[1,2].Obesity is a major risk factor of NAFLD,with studies showing that the likelihood of developing NAFLD increases 5-fold at a body mass index(BMI)of 30-32.5 kg/m²and up to 14-fold at BMI of 37.5-40 kg/m²compared to a BMI of 20-22.5 kg/m²[3,4].Effective NAFLD management requires both dietary and physical activity modifications.Healthy weight loss with sustained muscle mass plays a pivotal role,with a reduction of 3%-5%decreasing hepatic steatosis,5%-7%improving NASH conditions,and 10%or more needed to reverse hepatic fibrosis[5].Management also normalizes elevated liver enzymes(aspartate aminotransferase and alanine aminotransferase),enhances insulin sensitivity,and thereby reduces cardiovascular risk by improving endothelial function and increasing cardiorespiratory fitness[6].However,diet or exercise alone is often not as effective as a combined approach.Integrating both balanced dietary changes and increased physical activity yields more sustainable improvements in NAFLD and overall metabolic health[1,7].Traditional intervention methods usually involve in-person consultations,which often lack real-time and continuous patient monitoring.The recommendation of drastic changes in diet and exercise can also be overwhelming for patients,leading to low adherence rates.Many patients struggle to maintain these changes in the long-term due to a lack of con-tinuous motivational support[8,9].In recent years,the health ecosystem has witnessed a significant shift toward digital health platforms,which complement pharmacological treatments in chronic disease management,and increase scala-bility.These platforms provide continuous monitoring and personalized support,helping to bridge the gap between health care setups and patients[10].Recent digital advances enable internet of things(IoT)devices to be integrated into such management plans to track health metrics,to address the limitations of traditional methods[11,12].The MyTatva digital health application offers the RESET plan,a novel comprehensive approach for NAFLD mana-gement by integrating personalized support from nutrition,physiotherapy,and cognitive behavioral therapy(CBT)coaches.We aimed to evaluate the effectiveness of the RESET plan by analyzing the reduction in anthropometric para-meters across three different digital intervention groups.

Bletilla striata polysaccharides alleviate metabolic dysfunctionassociatedsteatotic liver disease through enhancing hepatocyteRelA/HNF1αsignal

BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease(MASLD)have not been fully understood.AIMTo investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclearfactor kappa B p65(RelA)/hepatocyte nuclear factor-1 alpha(HNF1α)signaling.METHODSA mouse model of MASLD was induced by feeding with a high-fat-diet(HFD)and a hepatocyte model of steatosiswas induced by treatment with sodium oleate(SO)and sodium palmitate(SP).The therapeutic effects of BSP onMASLD were examined in vivo and in vitro.The mechanisms underlying the action of BSP were analyzed for theireffect on lipid metabolism disorder,endoplasmic reticulum(ER)stress,and the RelA/HNF1αsignaling.RESULTSHFD feeding reduced hepatocyte RelA and HNF1αexpression,induced ER stress,lipid metabolism disorder,andnecroptosis in mice,which were significantly mitigated by treatment with BSP.Furthermore,treatment with BSP orBSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate(SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation,and lipid peroxidation,and enhancing theexpression of RelA,and HNF1α.The therapeutic effects of BSP on MASLD were partially abrogated by RELAsilencing in mice and RELA knockout in hepatocytes.RELA silencing or knockout significantly down-regulatedHNF1αexpression,and remodeled ER stress and oxidative stress responses during hepatic steatosis.CONCLUSIONTreatment with BSP ameliorates MASLD,associated with enhancing the RelA/HNF1αsignaling,remodeling ERstress and oxidative stress responses in hepatocytes.

Muscle strength and non-alcoholic fatty liver disease/metabolicassociated fatty liver disease

This editorial comments on an article published in a recent issue of World Journal of Gastroenterology,entitled“Association of low muscle strength with metabolic dysfunction-associated fatty liver disease:A nationwide study”.We focused on the association between muscle strength and the incidence of non-alcoholic fatty liver disease(NAFLD)and metabolic-associated fatty liver disease(MAFLD),as well as the mechanisms underlying the correlation and related clinical applications.NAFLD,which is now redefined as MAFLD,is one of the most common chronic liver diseases globally with an increasing prevalence and is characterized by malnutrition,which may contribute to decreased muscle strength.Reduction of muscle strength reportedly has a pathogenesis similar to that of NAFLD/MAFLD,including insulin resistance,inflammation,sedentary behavior,as well as insufficient vitamin D.Multiple studies have focused on the relationship between sarcopenia or muscle strength and NAFLD.However,studies investigating the relationship between muscle strength and MAFLD are limited.Owing to the shortage of specific medications for NAFLD/MAFLD treatment,early detection is essential.Furthermore,the relationship between muscle strength and NAFLD/MAFLD suggests that improvements in muscle strength may have an impact on disease prevention and may provide novel insights into treatments including dietary therapy,as well as tailored physical activity.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range,elevated alanine aminotransferase(ALT)levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively.METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected.The incidence rate,cumulative times,and equally and unequally weighted cumulative effects of excess high-normal ALT levels(ehALT)were measured.Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD.RESULTS A total of 83.13%of participants with MAFLD had normal ALT levels.The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group.Compared with those in the low-normal ALT group,the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651[95%confidence interval(CI):1.199-2.273]and 1.535(95%CI:1.119-2.106)in the third quartile and 1.616(95%CI:1.162-2.246)and 1.580(95%CI:1.155-2.162)in the fourth quartile,respectively.CONCLUSION Most participants with MAFLD had normal ALT levels.Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Excess cardiovascular mortality in men with non-alcoholic fatty liver disease:A cause for concern!

Non-alcoholic fatty liver disease(NAFLD)has emerged as the commonest cause of chronic liver disease worldwide in recent years.With time,our understanding of NAFLD has evolved from an isolated liver condition to a systemic disease with significant manifestations beyond the liver.Amongst them,cardiovascular diseases(CVDs)are the most important and clinically relevant.Recent research supports a strong independent link between NALFD and CVD beyond the shared risk factors and pathophysiology.Female sex hormones are well known to not only protect against CVD in pre-menopausal females,but also contribute to improved adipose tissue function and preventing its systemic deposition.Recent research highlights the increased risk of major adverse cardiovascular-cerebral events(MACCE)amongst male with NAFLD compared to females.Further,racial variation was observed in MACCE outcomes in NAFLD,with excess mortality in the Native Americans and Asian Pacific Islanders compared to the other races.

Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease

In this editorial,we comment on Yin et al’s recently published Letter to the editor.In particular,we focus on the potential use of glucagon-like peptide 1 receptor agonists(GLP-1RAs)alone,but even more so in combination therapy,as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease(MASLD),the new definition of an old condition,non-alcoholic fatty liver disease,which aims to better define the spectrum of steatotic pathology.It is well known that GLP-1RAs,having shown outstanding performance in fat loss,weight loss,and improvement of insulin resistance,could play a role in protecting the liver from progressive damage.Several clinical trials have shown that,among GLP-1RAs,semaglutide is a safe,well-studied therapeutic choice for MASLD patients;however,most studies demonstrate that,while semaglutide can reduce steatosis,including steatohepatitis histological signs(in terms of inflammatory cell infiltration and hepatocyte ballooning),it does not improve fibrosis.Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease.In particular,GLP-1RAs associated with antifibrotic drug therapy,dual glucose-dependent insulinotropic polypeptide(GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis,liver biochemistry,and non-invasive fibrosis tests than monotherapy.Therefore,although to date there are no definitive indications from international drug agencies,there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD,one that will certainly include the use of GLP-1RAs as combination therapy.

Metabolic disease and the liver: A review

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common liver disease worldwide,with an estimated prevalence of 31%in Latin America.The presence of metabolic comorbidities coexisting with liver disease varies substantially among populations.It is acknowledged that obesity is boosting the type 2 diabetes mellitus“epidemic,”and both conditions are significant contributors to the increasing number of patients with MASLD.Nonalcoholic steatohepatitis represents a condition of chronic liver inflammation and is considered the most severe form of MASLD.MASLD diagnosis is based on the presence of steatosis,noninvasive scores and altered liver tests.Noninvasive scores of liver fibrosis,such as serum biomarkers,which should be used in primary care to rule out advanced fibrosis,are simple,inexpensive,and widely available.Currently,guidelines from international hepatology societies recommend using noninvasive strategies to simplify case finding and management of high-risk patients with MASLD in clinical practice.Unfortunately,there is no definite pharmacological treatment for the condition.Creating public health policies to treat patients with risk factors for MASLD prevention is essential.

Exploring non-invasive diagnostics for metabolic dysfunctionassociated fatty liver disease

The population with metabolic dysfunction-associated fatty liver disease(MAFLD)is increasingly common worldwide.Identification of people at risk of progression to advanced stages is necessary to timely offer interventions and appropriate care.Liver biopsy is currently considered the gold standard for the diagnosis and staging of MAFLD,but it has associated risks and limitations.This has spurred the exploration of non-invasive diagnostics for MAFLD,especially for steatohepatitis and fibrosis.These non-invasive approaches mostly include biomarkers and algorithms derived from anthropometric measurements,serum tests,imaging or stool metagenome profiling.However,they still need rigorous and widespread clinical validation for the diagnostic performance.