Nomogram based on liver stiffness and spleen area with ultrasound for posthepatectomy liver failure:A multicenter study

BACKGROUND Liver stiffness(LS)measurement with two-dimensional shear wave elastography(2D-SWE)correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve.The size of the spleen increases due to tissue proliferation,fibrosis,and portal vein congestion,which can indirectly reflect the situation of liver fibrosis/cirrhosis.It was reported that the size of the spleen was related to posthepatectomy liver failure(PHLF).So far,there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF.This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area(SPA)for the prediction of PHLF in hepatocellular carcinoma(HCC)patients and to develop a risk prediction model.AIM To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model.METHODS This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022.Within 1 wk before partial hepatectomy,ultrasound examination was performed to measure LS and SPA,and blood was drawn to evaluate the patient’s liver function and other conditions.Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram.Nomogram performance was validated further.The diagnostic performance of the nomogram was evaluated with receiver operating charac-teristic curve compared with the conventional models,including the model for end-stage liver disease(MELD)score and the albumin-bilirubin(ALBI)score.RESULTS A total of 562 HCC patients undergoing hepatectomy(500 in the training cohort and 62 in the validation cohort)were enrolled in this study.The independent predictors of PHLF were LS,SPA,range of resection,blood loss,international normalized ratio,and total bilirubin.Better diagnostic performance of the nomogram was obtained in the training[area under receiver operating characteristic curve(AUC):0.833;95%confidence interval(95%CI):0.792-0.873;sensitivity:83.1%;specificity:73.5%]and validation(AUC:0.802;95%CI:0.684-0.920;sensitivity:95.5%;specificity:52.5%)cohorts compared with the MELD score and the ALBI score.CONCLUSION This PHLF nomogram,mainly based on LS by 2D-SWE and SPA,was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.

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.

Discussion on Traditional Chinese Medicine Treatment of Liver-Depression-Spleen-Deficiency Type Insomnia Based on the State-Target Theory and the Regulation of Microbiome-Gut-Brain Axis

Insomnia has become an urgent clinical problem in modern society.Current research has found that the gut flora-gut-brain axis plays an important role in regulating insomnia.The state-target theory is a product of the combination of traditional Chinese medicine and modern molecular biology technology.This paper clarifies the correlation between the state-target theory,the intestinal flora-gut-brain axis,and liver-depression-spleen-deficiency insomnia.The use of traditional Chinese medicine to regulate the structure and abundance of intestinal flora was also explored,aiming to integrate traditional Chinese medicine with Western medicine for the prevention and treatment of liver-depression-spleen-deficiency insomnia.

Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness

BACKGROUND Acute bleeding due to esophageal varices(EVs)is a life-threatening complication in patients with cirrhosis.The diagnosis of EVs is mainly through upper gastrointestinal endoscopy,but the discomfort,contraindications and complications of gastrointestinal endoscopic screening reduce patient compliance.According to the bleeding risk of EVs,the Baveno VI consensus divides varices into high bleeding risk EVs(HEVs)and low bleeding risk EVs(LEVs).We sought to identify a non-invasive prediction model based on spleen stiffness measurement(SSM)and liver stiffness measurement(LSM)as an alternative to EVs screening.AIM To develop a safe,simple and non-invasive model to predict HEVs in patients with viral cirrhosis and identify patients who can be exempted from upper gastrointestinal endoscopy.METHODS Data from 200 patients with viral cirrhosis were included in this study,with 140 patients as the modelling group and 60 patients as the external validation group,and the EVs types of patients were determined by upper gastrointestinal endoscopy and the Baveno Ⅵ consensus.Those patients were divided into the HEVs group(66 patients)and the LEVs group(74 patients).The effect of each parameter on HEVs was analyzed by univariate and multivariate analyses,and a noninvasive prediction model was established.Finally,the discrimination ability,calibration ability and clinical efficacy of the new model were verified in the modelling group and the external validation group.RESULTS Univariate and multivariate analyses showed that SSM and LSM were associated with the occurrence of HEVs in patients with viral cirrhosis.On this basis,logistic regression analysis was used to construct a prediction model:Ln[P/(1-P)]=-8.184-0.228×SSM+0.642×LSM.The area under the curve of the new model was 0.965.When the cut-off value was 0.27,the sensitivity,specificity,positive predictive value and negative predictive value of the model for predicting HEVs were 100.00%,82.43%,83.52%,and 100%,respectively.Compared with the four prediction models of liver stiffness-spleen diameter to platelet ratio score,variceal risk index,aspartate aminotransferase to alanine aminotransferase ratio,and Baveno VI,the established model can better predict HEVs in patients with viral cirrhosis.CONCLUSION Based on the SSM and LSM measured by transient elastography,we established a non-invasive prediction model for HEVs.The new model is reliable in predicting HEVs and can be used as an alternative to routine upper gastrointestinal endoscopy screening,which is helpful for clinical decision making.

Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges

Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.

Diagnostic and therapeutic role of endoscopic ultrasound in liver diseases:A systematic review and meta-analysis

BACKGROUND In hepatology,the clinical use of endoscopic ultrasound(EUS)has experienced a notable increase in recent times.These applications range from the diagnosis to the treatment of various liver diseases.Therefore,this systematic review summarizes the evidence for the diagnostic and therapeutic roles of EUS in liver diseases.AIM To examine and summarize the current available evidence of the possible roles of the EUS in making a suitable diagnosis in liver diseases as well as the therapeutic accuracy and efficacy.METHODS PubMed,Medline,Cochrane Library,Web of Science,and Google Scholar databases were extensively searched until October 2023.The methodological quality of the eligible articles was assessed using the Newcastle-Ottawa scale or Cochrane Risk of Bias tool.In addition,statistical analyses were performed using the Comprehensive Meta-Analysis software.RESULTS Overall,45 articles on EUS were included(28 on diagnostic role and 17 on therapeutic role).Pooled analysis demonstrated that EUS diagnostic tests had an accuracy of 92.4%for focal liver lesions(FLL)and 96.6%for parenchymal liver diseases.EUS-guided liver biopsies with either fine needle aspiration or fine needle biopsy had low complication rates when sampling FLL and parenchymal liver diseases(3.1%and 8.7%,respectively).Analysis of data from four studies showed that EUS-guided liver abscess had high clinical(90.7%)and technical success(90.7%)without significant complications.Similarly,EUS-guided interventions for the treatment of gastric varices(GV)have high technical success(98%)and GV obliteration rate(84%)with few complications(15%)and rebleeding events(17%).CONCLUSION EUS in liver diseases is a promising technique with the potential to be considered a first-line therapeutic and diagnostic option in selected cases.

Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions

Intrahepatic cholangiocarcinoma(iCCA)is a rare biliary tract cancer with high mortality rate.Complete resection of the iCCA lesion is the first choice of treatment,with good prognosis after margin-negative resection.Unfortunately,only 12%-40% of patients are eligible for resection at presentation due to cirrhosis,portal hypertension,or large tumor size.Liver transplantation(LT)offers margin-negative iCCA extirpation for patients with unresectable tumors.Initially,iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes.Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA.Another selection criterion is the tumor response to neoadjuvant therapy.Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy.Another index that helps predict the treatment outcome is the biomarker.Improved survival outcomes have also opened the door for living donor LT for iCCA.Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection.The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease worldwide,affecting about 1/4th of the global population and causing a huge global economic burden.To date,no drugs have been approved for the treatment of NAFLD,making the correction of unhealthy lifestyles the principle method of treatment.Identifying patients with poor adherence to lifestyle correction and attempting to improve their adherence are therefore very important.AIM To develop and validate a scale that can rapidly assess the adherence of patients with NAFLD to lifestyle interventions.METHODS The Exercise and Diet Adherence Scale(EDAS)was designed based on com-pilation using the Delphi method,and its reliability was subsequently evaluated.Demographic and laboratory indicators were measured,and patients completed the EDAS questionnaire at baseline and after 6 months.The efficacy of the EDAS was evaluated in the initial cohort.Subsequently,the efficacy of the EDAS was internally verified in a validation cohort.RESULTS The EDAS consisted of 33 items in six dimensions,with a total of 165 points.Total EDAS score correlated significantly with daily number of exercise and daily reduction in calorie intake(P<0.05 each),but not with overall weight loss.A total score of 116 was excellent in predicting adherence to daily reduction in calorie intake(>500 kacl/d),(sensitivity/specificity was 100.0%/75.8%),while patients score below 97 could nearly rule out the possibility of daily exercise(sensitivity/specificity was 89.5%/44.4%).Total EDAS scores≥116,97-115,and<97 points were indicative of good,average,and poor adherence,respectively,to diet and exercise recommendations.CONCLUSION The EDAS can reliably assess the adherence of patients with NAFLD to lifestyle interventions and have clinical application in this population.

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.

Liver transplantation as an alternative for the treatment of neuroendocrine liver metastasis: Appraisal of the current evidence

Background:Liver transplantation(LT)for neuroendocrine liver metastases(NELM)is still in debate.Studies comparing LT with liver resection(LR)for NELM are scarce,as patient selection is heterogeneous and experience is limited.The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM.Data sources:A scoping literature search on LT and LR for NELM was performed with PubMed,including English articles up to March 2023.Results:International guidelines recommend LR for NELM in resectable,well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies.Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival.In highly selected patients(based on the Milan criteria)with unresectable NELM,oncologic results of LT are promising.Prognostic factors include tumor biology(G1/G2)and burden,waiting time for LT,patient age and extrahepatic spread.Based on low-level evi-dence,LT for low-grade NELM within the Milan criteria resulted in improved disease-free survival and overall survival compared to LR.The benefits of LT were lost in patients beyond the Milan NELM-criteria.Conclusions:With adherence to strict selection criteria especially tumor biology,LT for NELM is becoming a valuable option providing oncologic benefits compared to LR.Recent evidence suggests even stricter selection criteria with regard to tumor biology.

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 albumin-bilirubin score in non-malignant liver disease

The albumin-bilirubin(ALBI)score,which was proposed to assess the prognosis of patients with hepatocellular carcinoma,has gradually been extended to other liver diseases in recent years,including primary biliary cholangitis,liver cirrhosis,hepatitis,liver transplantation,and liver injury.The ALBI score is often compared with classical scores such as the Child-Pugh and model for end-stage liver disease scores or other noninvasive prediction models.It is widely employed because of its immunity to subjective evaluation indicators and ease of obtaining detection indicators.An increasing number of studies have confirmed that it is highly accurate for assessing the prognosis of patients with chronic liver disease;additionally,it has demonstrated good predictive performance for outcomes beyond survival in patients with liver diseases,such as decompensation events.This article presents a review of the application of ALBI scores in various non-malignant liver diseases.

Letter to editor‘Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness’

predicting high-risk esophageal varices based on liver and spleen stiffness".Acute bleeding caused by esophageal varices is a life-threatening complication in patients with liver cirrhosis.Due to the discomfort,contraindications,and associated complications of upper gastrointestinal endoscopy screening,it is crucial to identify an imaging-based non-invasive model for predicting high-risk esophageal varices in patients with cirrhosis.

Histopathological impact of SARS-CoV-2 on the liver:Cellular damage and long-term complications

Coronavirus disease 2019(COVID-19),caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome,multiple organ failure,and death.Despite extensive studies on the pathogenicity of SARS-CoV-2,its impact on the hepatobiliary system remains unclear.While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels,the exact source of this damage is not fully understood.Proposed mechanisms for injury include direct cytotoxicity,collateral damage from inflammation,drug-induced liver injury,and ischemia/hypoxia.However,evidence often relies on blood tests with liver enzyme abnormalities.In this comprehensive review,we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients,drawing from liver biopsies,complete autopsies,and in vitro liver analyses.We present evidence of the direct impact of SARS-CoV-2 on the liver,substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes,including mitochondrial swelling,endoplasmic reticulum dilatation,and hepatocyte apoptosis.Additional ly,we describe the diverse liver pathology observed during COVID-19 infection,encompassing necrosis,steatosis,cholestasis,and lobular inflammation.We also discuss the emergence of long-term complications,notably COVID-19-related secondary sclerosing cholangitis.Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Clinical Observation on Modified Huan'gan Lipi Decoction Combined with Acupuncture in Treating Spleen Deficiency and Liver Hyperactivity Type Tic Disorders

[Objectives]To observe the clinical efficacy of Modified Huan'gan Lipi Decoction combined with acupuncture in the treatment of spleen deficiency and liver hyperactivity type tic disorders(TD).[Methods]Sixty patients with spleen deficiency and liver hyperactivity type TD were randomly divided into a treatment group of 40 cases and a control group of 20 cases.The treatment group received Modified Huan'gan Lipi Decoction combined with acupuncture,and the control group received Haloperidol Tablets.After 4 weeks of treatment,the Yale Global Tic Severity Scale(YGTSS)score,the total score of TCM syndrome and the clinical efficacy were compared between the two groups before and after treatment.[Results]After treatment,the total effective rate of 87.5%in the treatment group was higher than 80.0%in the control group(P>0.05);the total score of YGTSS and the total score of TCM syndromes in the two groups were compared within groups,P﹤0.01;between groups,P﹤0.01.The recurrence rates of the treatment group and the control group were 11.1%and 71.4%,respectively.The difference between the two groups was statistically significant(P﹤0.01).[Conclusions]Modified Huan'gan Lipi Decoction combined with acupuncture in the treatment of spleen deficiency and liver hyperactivity type TD can significantly improve the patient's tic symptoms,and its long-term efficacy is stable.

Protective mechanism of Coprinus comatus polysaccharide on acute alcoholic liver injury in mice,the metabolomics and gut microbiota investigation

Coprinus comatus polysaccharide(CCP)has significant hepatoprotective effect.To explore hepatoprotective mechanism of CCP,the study analyzed preventive effect of CCP on acute alcoholic liver injury in mice by histopathological examination and biochemical analysis.Simultaneously,hepatoprotective mechanism was also analyzed in conjunction with metabolomics and proliferation of gut microbiota.The results showed that CCP significantly decreased alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)levels in serum of alcoholic liver disease(ALD)mice.Histopathological examination showed that CCP can significantly improve liver damage.Metabolomics results showed that there were significant differences in the level of metabolites in liver tissue of control group,ALD group and CCP group,including taurine,xanthosine,fumaric acid and arachidonic acid,among others.Metabolites pathways analysis showed that hepatoprotective effect of CCP was related to energy metabolism,biosynthesis of unsaturated fatty acids,amino acids metabolism and lipid metabolism.Additionally,CCP inhibited an increase in the number of Clostridium perfringens,Enterobacteriaceae and Enterococcus,and a decrease in the number of Lactobacillus and Bifidobacterium in the gut of ALD mice.All these findings suggested that CCP treatment reversed the phenotype of ethanol-induced liver injury and the associated metabolites pathways.

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.

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.