Elafibranor:A promising therapeutic approach for liver fibrosis and gut barrier dysfunction in alcohol-associated liver disease

This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.

Red cell distribution width/platelet ratio predicts decompensation of metabolic dysfunction-associated steatotic liver disease-related compensated advanced chronic liver disease

Prognostication of compensated advanced chronic liver disease(cACLD)is of paramount importance for the physician-and-patient communication and for rational clinical decisions.The paper published by Dallio et al reports on red cell distribution width(RDW)/platelet ratio(RPR)as a non-invasive biomarker in predicting decompensation of metabolic dysfunction-associated steatotic liver disease(MASLD)-related cACLD.Differently from other biomarkers and algorithms,RPR is inexpensive and widely available,based on parameters which are included in a complete blood count.RPR is computed on the grounds of two different items,one of which,RDW,mirrors the host’s response to a variety of disease stimuli and is non-specific.The second parameter involved in RPR,platelet count,is more specific and has been used in the hepatological clinic to discriminate cirrhotic from non-cirrhotic chronic liver disease for decades.Cardiovascular disease is the primary cause of mortality among MASLD subjects,followed by extra-hepatic cancers and liver-related mortality.Therefore,MASLD biomarkers should be validated not only in terms of liver-related events but also in the prediction of major adverse cardiovascular events and cardiovascular mortality and extra-hepatic cancers.Adequately sized multi-ethnic confirmatory investigation is required to define the role and significance of RPR in the stratification of MASLD-cACLD.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

Effects of Lactobacillus paracasei N1115 on gut microbial imbalance and liver function in patients with hepatitis B-related cirrhosis

BACKGROUND Hepatitis B cirrhosis(HBC)is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction.Although the relationship between certain single probiotics and HBC has been explored,the impact of the complex ready-to-eat Lactobacillus paracasei N1115(LP N1115)supplement on patients with HBC has not been determined.AIM To compare the changes in the microbiota,inflammatory factor levels,and liver function before and after probiotic treatment in HBC patients.METHODS This study included 160 HBC patients diagnosed at the General Hospital of Ningxia Medical University between October 2018 and December 2020.Patients were randomly divided into an intervention group that received LP N1115 supplementation and routine treatment and a control group that received routine treatment only.Fecal samples were collected at the onset and conclusion of the 12-wk intervention period.The structure of the intestinal microbiota and the levels of serological indicators,such as liver function and inflammatory factors,were assessed.RESULTS Following LP N1115 intervention,the intestinal microbial diversity significantly increased in the intervention group(P<0.05),and the structure of the intestinal microbiota was characterized by an increase in the proportions of probiotic microbes and a reduction in harmful bacteria.Additionally,the intervention group demonstrated notable improvements in liver function indices and significantly lower levels of inflammatory factors(P<0.05).CONCLUSION LP N1115 is a promising treatment for ameliorating intestinal microbial imbalance in HBC patients by modulating the structure of the intestinal microbiota,improving liver function,and reducing inflammatory factor levels.

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.

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.

Short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function

BACKGROUND Hepatectomy is the first choice for treating liver cancer.However,inflammatory factors,released in response to pain stimulation,may suppress perioperative immune function and affect the prognosis of patients undergoing hepatectomies.AIM To determine the short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function.METHODS Clinical data from patients with liver cancer admitted to Suzhou Ninth People’s Hospital from January 2020 to December 2023 were retrospectively analyzed.Thirty-five patients underwent laparoscopic hepatectomy for liver cancer(liver cancer resection group)and 35 patients underwent medical image-guided microwave ablation(liver cancer ablation group).The short-term efficacy,complications,liver function,and immune function indices before and after treatment were compared between the two groups.RESULTS One month after treatment,19 patients experienced complete remission(CR),8 patients experienced partial remission(PR),6 patients experienced stable disease(SD),and 2 patients experienced disease progression(PD)in the liver cancer resection group.In the liver cancer ablation group,21 patients experienced CR,9 patients experienced PR,3 patients experienced SD,and 2 patients experienced PD.No significant differences in efficacy and complications were detected between the liver cancer ablation and liver cancer resection groups(P>0.05).After treatment,total bilirubin(41.24±7.35 vs 49.18±8.64μmol/L,P<0.001),alanine aminotransferase(30.85±6.23 vs 42.32±7.56 U/L,P<0.001),CD4+(43.95±5.72 vs 35.27±5.56,P<0.001),CD8+(20.38±3.91 vs 22.75±4.62,P<0.001),and CD4+/CD8+(2.16±0.39 vs 1.55±0.32,P<0.001)were significantly different between the liver cancer ablation and liver cancer resection groups.CONCLUSION The short-term efficacy and safety of microwave ablation and laparoscopic surgery for the treatment of liver cancer are similar,but liver function recovers quickly after microwave ablation,and microwave ablation may enhance immune function.

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

Clinical effect of spleen aminopeptide on improving liver function damage and immune function in children with infant hepatitis syndrome

BACKGROUND Infant hepatitis syndrome(IHS)is a clinical syndrome in infants less than one year of age with generalized skin jaundice,abnormal liver function,and hepato-megaly due to various etiologies such as infection.AIM To investigate the effect of IHS patients,after treatment with arsphenamine-based peptides,on patients'liver function damage and immune function.METHODS Of 110 patients with IHS treated in our hospital from January 2019 to January 2021 were grouped according to the randomized residual grouping method,with 5 cases in each group shed due to transfer,etc.Ultimately,50 cases remained in each group.The control group was treated with reduced glutathione,and the treat-ment group was treated with sesquiterpene peptide based on the control group.Observe and compare the differences in indicators after treatment.RESULTS The comparison of serum total bilirubin,direct bilirubin,and serum alanine transferase after treatment was significantly different and lower in the treatment group than in the control group(P<0.05).The comparison of CD4+,CD3+,CD4+/CD8+after treatment was significantly different and higher in the treatment group than in the control group,and the comparison was statist-ically significant(P<0.05).The complication of the two groups showed that the rash,cough and sputum,elevated platelets,and gastrointestinal reactions in the treatment group were significantly lower than those in the control group,and the differences were statistically significant by test(P<0.05).CONCLUSION The comparative study of IHS treated with arsphenamine combined with reduced glutathione is more effective.

Update in lean metabolic dysfunction-associated steatotic liver disease

BACKGROUND A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease(MAFLD).They are now defined as metabolic dysfunction-associated steatotic liver disease(MASLD),which includes cardiometabolic criteria in adults.This condition,extensively studied in obese or overweight patients,constitutes around 30%of the population,with a steady increase worldwide.Lean patients account for approximately 10%-15%of the MASLD population.However,the pathogenesis is complex and is not well understood.AIM To systematically review the literature on the diagnosis,pathogenesis,characteristics,and prognosis in lean MASLD patients and provide an interpretation of these new criteria.METHODS We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023,specifically focusing on lean NAFLD,MAFLD,or MASLD patients.We include original articles with patients aged 18 years or older,with a lean body mass index categorized according to the World Health Organization criteria,using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population.RESULTS We include 85 studies in our analysis.Our findings revealed that,for lean NAFLD patients,the prevalence rate varied widely,ranging from 3.8%to 34.1%.The precise pathogenesis mechanism remained elusive,with associations found in genetic variants,epigenetic modifications,and adaptative metabolic response.Common risk factors included metabolic syndrome,hypertension,and type 2 diabetes mellitus,but their prevalence varied based on the comparison group involving lean patients.Regarding non-invasive tools,Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients.Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles,with some medications showing efficacy to a lesser extent.However,lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart.CONCLUSION MASLD is a complex disease comprising epigenetic,genetic,and metabolic factors in its pathogenesis.Results vary across populations,gender,and age.Limited data exists on clinical practice guidelines for lean patients.Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

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.

Omics-based biomarkers as useful tools in metabolic dysfunctionassociated steatotic liver disease clinical practice:How far are we?

Unmet needs exist in metabolic dysfunction-associated steatotic liver disease(MASLD)risk stratification.Our ability to identify patients with MASLD with advanced fibrosis and at higher risk for adverse outcomes is still limited.Incorporating novel biomarkers could represent a meaningful improvement to current risk predictors.With this aim,omics technologies have revolutionized the process of MASLD biomarker discovery over the past decades.While the research in this field is thriving,much of the publication has been haphazard,often using single-omics data and specimen sets of convenience,with many identified candidate biomarkers but lacking clinical validation and utility.If we incorporate these biomarkers to direct patients’management,it should be considered that the roadmap for translating a newly discovered omics-based signature to an actual,analytically valid test useful in MASLD clinical practice is rigorous and,therefore,not easily accomplished.This article presents an overview of this area’s current state,the conceivable opportunities and challenges of omics-based laboratory diagnostics,and a roadmap for improving MASLD biomarker research.

Effect of Shuanghuanglian Oral Solution on Liver Function in a Mouse Model of Non-alcoholic Steatohepatitis

[Objectives]To observe the effect of Shuanghuanglian oral solution on liver function in BABL/cJ mice in non-alcoholic steatohepatitis(NASH)model.[Methods]The BABL/cJ mice were randomly divided into three groups:a control group,a model group,and an experimental group.The experimental group was administered with 10%Shuanghuanglian oral solution at a dose of 0.1 mL/(10 g·d),while the control group and experimental group received an equivalent dosage of normal saline.All three groups were treated for a period of 28 d.The liver function of the mice in each group was examined after the treatment.[Results]The body mass,liver index,triacylglycerol(TG),total cholesterol(TC),aspartate aminotransferase(AST),and alanine aminotransferase(ALT)levels were all significantly reduced compared to the model group(P<0.05).[Conclusions]Shuanghuanglian oral solution has a beneficial effect on liver function in BABL/cJ mice.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

Biochemical Liver Functions and Molecular Identification of Fasciola hepatica from Experimentally Infected Rat Model

The current study was performed to evaluate the liver function status as well as molecular characterization of the recovered worms in rats experimentally infected with F. hepatica. Sixteen male Wister rats aged 30 days were randomly allocated into two groups (n = 8). The first group was infected orally with 15 viable encysted metacercaria of F. hepatica per animal. The other group was kept non-infected (control group). At zero time (before infection), the 2nd, 4th, 6th, 8th, 10th, 12th and 14th weeks post-infection (WPI), blood and serum samples were collected via puncture of retro-orbital plexus of veins from each rat. Serum enzyme level (AST and ALT) and total protein were measured, and the serum protein profile was carried out using agarose gel electrophoresis. During the period of the experiment, serum ALT and AST activities and serum total globulins significantly increased while serum total proteins and albumin markedly decreased in the infected group. On the 14th WPI, the data of the electropherogram showed that globulin fractions (α1-, β- and γ-globulin) levels were significantly increased while α2-globulin was markedly decreased in the infected group. The molecular analysis confirmed the amplification of the ITS1, ITS2 and NDI genes of F. hepatica recovered from the infected liver of rats with amplicon sizes of 630, 510 and 560 bp, respectively. Sequencing of the amplified ITS gene resulted in the determination of 3 strains (PP108836, PP108837, and PP108838). Also, analysis of the ITS2 gene resulted in obtaining 3 isolates under the accession numbers (PP109065, PP109066, and PP109067). In conclusion, fasciolosis in the rat model is suitable for routine experimental infections and caused a pronounced liver dysfunction with discharging of the Fasciola eggs in the faeces and the development of adult stages in the bile ducts. Furthermore, molecular techniques are a sensitive tool for the identification and characterisation of the Fasciola parasite.

Metabolic dysfunction-associated steatotic liver disease:A silent pandemic

The worldwide epidemiology of non-alcoholic fatty liver disease(NAFLD)is showing an upward trend,parallel to the rising trend of metabolic syndrome,owing to lifestyle changes.The pathogenesis of NAFLD has not been fully understood yet.Therefore,NAFLD has emerged as a public health concern in the field of hepatology and metabolisms worldwide.Recent changes in the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease have brought a positive outlook changes in the understanding of the disease process and doctor-patient communication.Lifestyle changes are the main treatment modality.Recently,clinical trial using drugs that target‘insulin resistance’which is the driving force behind NAFLD,have shown promising results.Further translational research is needed to better understand the underlying pathophysiological mechanism of NAFLD which may open newer avenues of therapeutic targets.The role of gut dysbiosis in etiopathogenesis and use of fecal microbiota modification in the treatment should be studied extensively.Prevention of this silent epidemic by spreading awareness and early intervention should be our priority.

Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease:Clinical implications

In this editorial,we comment on the article by Chen et al recently published in 2024.We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase(ALT)would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease(MAFLD).This is important given the increasing prevalence of MAFLD and obesity globally.Currently,a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT.The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered,particularly as their study found that 83.12%of their study population with a diagnosis of MAFLD had a normal ALT.The main advantages of screening would be to identify patients and provide intervention early,the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis.However,there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered.Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity,although studies have not yet shown a significant improvement in fibrosis regression.It would also require a huge amount of resource if a reduced ALT level alone was used as criteria;it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk.Currently,there is not a good argument to recommend wide-spread screening with a reduced ALT level as this is unlikely to be cost-effective.This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories.Although studies previously have suggested a more pragmatic approach in screening those over the age of 60,this is likely to change with the increasing incidence of obesity within the younger age groups.The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

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.

Multifunctional role of oral bacteria in the progression of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)encompasses a spectrum of liver disorders of varying severity,ultimately leading to fibrosis.This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis.The pathogenesis of NAFLD is closely associated with disturbances in the gut micr-obiota and impairment of the intestinal barrier.Non-gut commensal flora,particularly bacteria,play a pivotal role in the progression of NAFLD.Notably,Porphyromonas gingivalis,a principal bacterium involved in periodontitis,is known to facilitate lipid accumulation,augment immune responses,and induce insulin resistance,thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD.The influence of oral microbiota on NAFLD via the“oral-gut-liver”axis is gaining recognition,offering a novel perspective for NAFLD management through microbial imbalance correction.This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms,emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.

Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.