Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B

Background and Aims:The impact of nonalcoholic fatty liver disease(NAFLD)on the treatment outcome of chronic hepatitis B(CHB)is undefined and deserves an in-depth investigation.Methods:Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD,and followed up at six monthly intervals.Therapeutic response related data were recorded and compared at multiple time points.Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response(CVR).Results:We enrolled 267 patients(CHB:164;CHB with NAFLD:103)with comparable follow-up durations.They were also comparable in baseline HBV DNA levels and HBeAg positivity.Patients with concomitant NAFLD showed less significant decline in HBV DNA,qHBsAg,pgRNA,and liver enzyme levels over time;moreover,their cumulative incidences of CVR were significantly lower and that of low-level viremia(LLV)were significantly higher at 6,12,18,24 months.First CVR of CHB was delayed with the presence NAFLD(11.0 vs.7.0 months,p<0.001)and further prolonged with higher grade of liver steatosis(Grade 2–3 vs.1:13.0 vs.9.0 months).On multivariate analysis,HBeAg positivity(HR:0.650,p=0.036),grade of steatosis(G2[HR:0.447,p=0.004];G3[HR:0.085,p=0.002])and HBV DNA(log10 IU/mL)(HR:0.687,p<0.001)were significantly associated with delayed CVR,whereas grade of necroinflammation(HR:1.758,p<0.001)accelerated the CVR.Conclusions:In CHB patients receiving initial antiviral therapy,NAFLD was associated with higher levels of HBV DNA,pgRNA,and liver enzymes,and higher incidence of LLV and delayed CVR.

Impact of COVID-19 on Liver Transplant Activity in the USA: Variation by Etiology and Cirrhosis Complications

Background and Aims:The COVID-19 pandemic has impacted the care of patients with liver disease.We examined impact of COVID-19 on liver transplant(LT)activity in the USA.Methods:LT listings in the United Network for Organ Sharing(UNOS)database(April 2018–May 2021)were analyzed to examine the impact of COVID-19 pandemic on the LT activity based on etiology:hepatitis C virus(HCV),alcohol-associated liver disease(ALD),alcoholic hepatitis(AH),and nonalcoholic steatohepatitis(NASH)complications:hepatocellular carcinoma(HCC)and acute-on-chronic liver failure(ACLF)grade 2 or 3 and Model for End-Stage Liver Disease(MELD)score.Joinpoint regression models assessed time trend changes on a log scale.Results:Of 23,871 recipients(8,995 in the COVID era,April 2018–February 2020),mean age 52 years,62% men,61% Caucasian,32%ALD,15%HCC,30%ACLF grades 2–3,and mean MELD score 20.5,monthly LT changes were a decrease of 3.4%for overall LTs and 22%for HCC after September 2020,and increase of 4.5%for ALD since 11/2020 and 17%since 03/2021 for ACLF grade 2–3.Monthly MELD scores increased by 0.7 and 0.36 after June 2020 for HCV and HCC respectively.Conclusions:The COVID-19 pandemic has impacted LT activity,with a decrease of LTs especially for HCC,and an increase of LTs for ALD and severe ACLF.Strategies are needed to reorganize cirrhosis patients to overcome the aftereffects of COVID-19 pandemic.

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

A Novel Prognostic Biomarker LPAR6 in Hepatocellular Carcinoma via Associating with Immune Infiltrates

Background and Aims:LPAR6 is the most recently deter-mined G protein-coupled receptor of lysophosphatidic acid,and hardly any study has demonstrated the performance of LPAR6 in cancers.We sought to clarify the relationship of LPAR6 to prognosis potential and tumor infiltration im-mune cells in different cancers.Methods:The expression of LPAR6 and its clinical characteristics were evaluated on various databases.The association between LPAR6 and im-mune infiltrates of various types of cancer were investigated via TIMER.Results:We determined that higher LPAR6 ex-pression level was associated with a better overall survival.Additionally,high LPAR6 expression level was significantly associated with better disease-specific survival(DSS)in bladder cancer,and better overall survival(OS)/progres-sion-free survival(PFS)/distant metastasis-free survival(DMFS)/relapse-free survival(RFS)in breast cancer and some other types of cancers.Moreover,LPAR6 significant-ly affects the prognosis of various cancers via The Cancer Genome Atlas(TCGA).Further research exposed that the mRNA level of LPAR6 was positively coordinated with in-filtrating levels of devious immune cells in hepatocellular carcinoma.Conclusions:Our results imply that LPAR6 is associated with prognosis potential and immune infiltration levels in liver cancer.Moreover,LPAR6 expression possibly contributes to the activation of CD8+T,naive T,effector T cells and natural killer cells and inactivates T regulatory cells,decreases T cell exhaustion and regulate T helper cells in liver cancer.These discoveries imply that LPAR6 could be a novel biomarker of prognosis for indicating progno-sis potential and immune-infiltrating level in hepatocellular carcinoma.

Roles of SET7/9 and LSD1 in the Pathogenesis of Arsenicinduced Hepatocyte Apoptosis

Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury.To investigate whether histone H3 lysine 4(H3K4)methyltransferase(SET7/9)and histone H3K4 demethyltransferase(LSD1/KDM1A)can regulate endoplasmic reticulum stress(ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.Methods:Apoptosis,proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer.The expression of ERS-and epigenetic-related proteins was detected by Western blot analysis.The antisense SET7/9 expression vector and the overexpressed LSD1 plasmid were used for transient transfection of LO_(2) cells.The effects of NaAsO_(2) on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein,activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.Results:The protein expression of LSD1(1.25±0.08 vs.1.77±0.08,p=0.02)was markedly decreased by treatment with 100μM NaAsO_(2),whereas the SET7/9(0.68±0.05 vs.1.10±0.13,p=0.002)expression level was notably increased,which resulted in increased H3K4me1/2(0.93±0.64,1.19±0.22 vs.0.71±0.13,0.84±0.13,p=0.03 and p=0.003).After silencing SET7/9 and overexpressing LSD1 by transfection,apoptosis rate(in percentage:3.26±0.34 vs.7.04±0.42,4.80±0.32 vs.7.52±0.38,p=0.004 and p=0.02)was significantly decreased and proliferation rate was notably increased,which is reversed after inhibiting LSD1(in percentage:9.31±0.40 vs.7.52±0.38,p=0.03).Furthermore,the methylation levels of H3 in the promoter regions of GRP78(20.80±2.40 vs.11.75±2.47,20.46±2.23 vs.14.37±0.91,p=0.03 and p=0.01)and CHOP(48.67±4.04 vs.16.67±7.02,59.33±4.51 vs.20.67±3.06,p=0.004 and p=0.001)were significantly increased in LO_(2) cells exposed to 100μM NaAsO_(2) for 24 h.Conclusions:Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis.NaAsO_(2) induces apoptosis in LO_(2) cells by activating the ERS-mediated apoptotic signaling pathway,at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes,including GRP78 and CHOP.

Development and Validation of a Prognostic Model for One-year Survival of Cirrhosis Patients with First-ever Spontaneous Bacterial Peritonitis

Background and Aims: Spontaneous bacterial peritonitis(SBP) is one of the leading causes of death in patients withliver cirrhosis. We aimed to establish a prognostic model toevaluate the 1-year survival of cirrhosis patients after thefirst episode of SBP. Methods: A prognostic model was developedbased on a retrospective derivation cohort of 309cirrhosis patients with first-ever SBP and was validated in aseparate validation cohort of 141 patients. We used Uno’sconcordance, calibration curve, and decision curve (DCA)analysis to evaluate the discrimination, calibration, and clinicalnet benefit of the model. Results: A total of 59 (19.1%)patients in the derivation cohort and 42 (29.8%) patientsin the validation cohort died over the course of 1 year. Aprognostic model in nomogram form was developed withpredictors including age [hazard ratio (HR): 1.25;95% confidenceinterval (CI): 0.92–1.71], total serum bilirubin (HR:1.66;95% CI: 1.28–2.14), serum sodium (HR: 0.94;95%CI: 0.90–0.98), history of hypertension (HR: 2.52;95% CI:1.44–4.41) and hepatic encephalopathy (HR: 2.06;95%CI: 1.13–3.73). The nomogram had a higher concordance(0.79) compared with the model end-stage liver disease(0.67) or Child-Turcotte-Pugh (0.71) score. The nomogramalso showed acceptable calibration (calibration slope, 1.12;Bier score, 0.15±0.21) and optimal clinical net benefit in thevalidation cohort. Conclusions: This prediction model developedbased on characteristics of first-ever SBP patientsmay benefit the prediction of patients’ 1-year survival.

COVID-19 in Liver Transplant Recipients-A Series with Successful Recovery

The severe acute respiratory syndrome corona virus-2 (referred to as SARS-CoV-2) pandemic had a great impact on public life in general as well as on populations with pre-existing disease and co-morbidities. Liver transplant and immunosuppressant medication predisposes to more severe disease and is often associated with poor outcome. The clinical features, disease course, treatment and process of modulating the immunosuppression is challenging. Here, we describe the clinical presentation, treatment and outcomes in six liver transplant recipients. Out of those six patients, three had mild, one had moderate and one had severe COVID-19, and one was asymptomatic. The immunosup-pression minimization or withdrawal was done based upon the clinical severity. Consideration of tocilizumab and/or convalescent plasma as well as antivirals i.e. remdesvir done in severe cases. The routine practice of prophylactic anti-coagulation, consideration of repurposed drugs (i.e. teico-planin and doxycycline), and watchful monitoring of asymptomatic recipients helped to achieve an uneventful recovery.

Chylous Ascites:A Review of Pathogenesis,Diagnosis and Treatment

Chylous ascites(CA)is a rare form of ascites that results from the leakage of lipid-rich lymph into the peritoneal cavity.This usually occurs due to trauma and rupture of the lymphatics or increased peritoneal lymphatic pressure secondary to obstruction.The underlying etiologies for CA have been classified as traumatic,congenital,infectious,neoplastic,postoperative,cirrhotic or cardiogenic.Since malignancy and cirrhosis account for about two-thirds of all the cases of CA in Western countries,in this article we have attempted to reclassify CA based on portal and non-portal etiologies.The diagnosis of CA is based on the distinct characteristic of the ascitic fluid which includes a milky appearance and a triglyceride level of>200 mg/dL.The management consists of identifying and treating the underlying disease process,dietary modification,and diuretics.Some studies have also supported the use of agents such as orlistat,somatostatin,octreotide and etilefrine.Paracentesis and surgical interventions in the form of transjugular intrahepatic portosystemic shunt(commonly known as TIPS),peritoneal shunt,angiography with embolization of a leaking vessel,and laparotomy remain as treatment options for cases refractory to medical management.

Information

JCTH is a new,comprehensive specialist journal focusing on the recent progress in clinical and basic research with direct applications to clinical management of liver diseases.The studies published in JCTH will represent the most current trends in the field of hepatology,highlighting the topically relevant subjects of nations worldwide.Publications in JCTH will be presented in formats that emphasize clarity of the study’s objectives and implications of its findings,using high quality visual aids to enhance the manuscript’s esthetic appeal as well as its impact.For our upcoming issue,we encourage you and your group to submit original articles that showcase your work in hepatology and topically relevant reviews to promote our readers’understanding of the field.

Assessment of the Visual Analogue Score in the Evaluation of the Pruritus of Cholestasis

Background and Aims:A visual analogue score (VAS),based on application of a visual analogue scale,has been widely used to assess pruritus in clinical studies of patients with cholestatic liver disease.A VAS is a numerical score of the severity of the perception of pruritus,and,hence,is inherently subjective.The objective of this study was to assessthe reliability of a VAS as an index of pruritus in cholestatic patients.Methods:In 8 patients with chronic pruritus due to primary biliary cholangitis,values for a VAS of pruritus were compared with corresponding measurements of scratching activity,which were generated by a monitoring system specifically designed to quantitate this activity.The relationship between individual values for the VAS and corresponding values for scratching activity during a specific interval immediately preceding the recording of the VAS was examined by determining the Spearman's rank correlation coefficient.Results:The mean Spearman's rank correlation coefficient between individual values for the VAS and corresponding mean values for scratching activity was 0.072;the range of these coefficients was-0.04 to 0.26.A VAS of pruritus is an unreliable index of scratching activity,and,hence,of the pathophysiological process responsible for the pruritus of cholestasis.Conclusion:It is concluded that the use of a VAS as a primary quantitative endpoint in trials of the efficacy of potential therapies for the pruritus of cholestasis may be inappropriate.

IGF2BP3 Enhances the Growth of Hepatocellular Carcinoma Tumors by Regulating the Properties of Macrophages and CD8^(+)T Cells in the Tumor Microenvironment

Background and Aims:Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma(HCC).However,its role in regulating tumor immune microenvironment(TME)is not well characterized.Here,we investigated the effects of IGF2BP3 on macrophages and CD8^(+)T cells within the TME of HCC.Methods:The relationship between IGF2BP3 and immune cell infiltration was analyzed using online bioinformatics tools.Knockout of IGF2BP3 in mouse hepatoma cell line Hepa1-6 was established using CRISPR/Cas9 technology.In vitro cell coculture and subcutaneously implanted hepatoma mice model were used to explore the effects of IGF2BP3 on immune cells.Expression of CCL50l transforming growth factor beta 1(TGF-β1)was detected with quantitative real-time polymerase chain reaction,western blotting,and enzyme-linked immunosorbent assay.The binding of IGF2BP3 and its target RNA was verified by trimolecular fluorescence complementation system and RNA immunoprecipitation followed by quantitative or semiquantitative polymerase chain reaction.Results:IGF2BP3 expression was elevated in HCC and was positively correlated with macrophage infiltration.Patients with higher IGF2BP3 expression and lower macrophage infiltration had a better survival rate.We found that IGF2BP3 could bind to the mRNA of CCL5 or TGF-β1,increasing their expression,and inducing macrophage infiltration and M2 polarization while inhibiting the activation of CD8^(+)T cells.Furthermore,inhibition of IGF2BP3 combined with anti-CD47 antibody treatment significantly suppressed the growth of hepatoma in Hepa1-6 xenograft tu-mor mice.Conclusions:IGF2BP3 promoted the infiltration and M2-polarization of macrophages and suppressed CD8^(+)T activation by enhancing CCL5 and TGF-β1 expression,which facilitated the progression of Hepa1-6 xenograft tumor.

Current Status and Analysis of Machine Learning in Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is a common tumor.Although the diagnosis and treatment of HCC have made great progress,the overall prognosis remains poor.As the core component of artificial intelligence,machine learning(ML)has developed rapidly in the past decade.In particular,ML has become widely used in the medical field,and it has helped in the diagnosis and treatment of cancer.Different algorithms of ML have different roles in diagnosis,treatment,and prognosis.This article reviews recent research,explains the application of different ML models in HCC,and provides suggestions for follow-up research.

Role of Ras-related Nuclear Protein/Polypyrimidine Tract Binding Protein in Facilitating the Replication of Hepatitis C Virus

Background and Aims:Ras-related nuclear(RAN)protein is a small GTP-binding protein that is indispensable for the translocation of RNA and proteins through the nuclear pore complex.Recent studies have indicated that RAN plays an important role in virus infection.However,the role of RAN in hepatitis C virus(HCV)infection is unclear.The objective of this study was to investigate the role and underlying mechanisms of RAN in HCV infection.Methods:Huh7.5.1 cells were infected with the JC1-Luc virus for 24 h and then were incubated with complete medium for an additional 48 h.HCV infection and RAN expression were determined using luciferase assay,quantitative reverse transcription-PCR and western blotting.Small interfering RNA was used to silence RAN.Western blotting and immunofluorescence were used to evaluate the cytoplasmic translocation of polypyrimidine tract-binding(PTB),and coimmunoprecipitation was used to examine the interaction between RAN and PTB.Results:HCV infection significantly induced RAN expression and cytoplasmic redistribution of PTB.Knockdown of RAN dramatically inhibited HCV infection and the cytoplasmic accumulation of PTB.Colocalization of RAN and PTB was determined by immunofluorescence,and a direct interaction of RAN with PTB was demonstrated by coimmunoprecipitation.Conclusions:PTB in the host cytoplasm is directly associated with HCV replication.These findings demonstrate that the involvement of RAN in HCV infection is mediated by influencing the cytoplasmic translocation of PTB.

Re-evaluating Transarterial Chemoembolization Failure/Refractoriness:A Survey by Chinese College of Interventionalists

Background and Aims:The recognition of transarterial chemoembolization(TACE)failure/refractoriness among Chinese clinicians remains unclear.Using an online survey conducted by the Chinese College of Interventionalists(CCI),the aim of this study was to explore the recognition of TACE failure/refractoriness and review TACE application for hepatocellular carcinoma(HCC)treatment in clinical practice.Methods:From 27 August 2020 to 30 August 2020 during the CCI 2020 annual meeting,a survey with 34 questions was sent by email to 264 CCI clinicians in China with more than 10 years of experience using TACE for HCC treatment.Results:A total of 257 clinicians participated and responded to the survey.Most participants agreed that the concept of“TACE failure/refractoriness”has scientific and clinical significance(n=191,74.3%).Nearly half of these participants chose TACE-based combination treatment as subsequent therapy after so-called TACE failure/refractoriness(n=88,46.1%).None of the existing TACE failure/refractoriness definitions were widely accepted by the participants;thus,it is necessary to re-define this concept for the treatment of HCC in China(n=235,91.4%).Most participants agreed that continuing TACE should be performed for patients with preserved liver function,presenting portal vein tumor thrombosis(n=242,94.2%)or extrahepatic spread(n=253,98.4%),after the previous TACE treatment to control intrahepatic lesion(s).Conclusions:There is an obvious difference in the recognition of TACE failure/refractoriness among Chinese clinicians based on existing definitions.Further work should be carried out to re-define TACE failure/refractoriness.

Elastography for Longitudinal Assessment of Liver Fibrosis after Antiviral Therapy:A Review

Chronic hepatitis B or C viral infection is a common cause of liver cirrhosis and hepatocellular carcinoma. Fibrosis regres-sion can be achieved after long-term antiviral therapy (AVT). Monitoring of dynamic changes in liver fibrosis after treat-ment is essential for establishing prognosis and formulation of a follow-up surveillance program. Routine surveillance of fibrosis after AVT by liver biopsy, the gold standard for fibrosis assessment, is hindered by its invasive nature, sampling error and observer variability. Elastography is a noninvasive quan-titative alternative that has been widely used and validated for the staging of liver fibrosis prior to treatment. Recently, increasing research interest has been focused on the role of elastography in longitudinal assessment of liver fibrosis after AVT. In this review, the basic principles, acquisition techni-ques, diagnostic performances, and strengths and limitations of ultrasound elastography and magnetic resonance elastog-raphy are presented. Emerging evidence regarding the use of elastography techniques for the monitoring of liver fibrosis after AVT is summarized. Current challenges and future directions are also discussed, designed to optimize the application of these techniques in clinical practice.

Association of GCKR Gene Polymorphisms with the Risk of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in a Chinese Northern Han Population

Background and Aims: Accumulated studies have eval-uated the effects of glucokinase regulatory protein(GCKR)gene polymorphisms on the risk of nonalcoholic fatty liver disease(NAFLD)and coronary artery disease(CAD),but the association of GCKR polymorphisms with the risk of NAFLD and CAD in the Chinese Han population have remained un-clear.The aim of this study was to investigate the association between GCKR gene polymorphisms(rs780094 and rs1260326)and the risk of NAFLD and CAD in NAFLD patients in a Chinese Northern Han population.Methods: GCKR rs780094 and rs1260326 gene polymorphisms were geno-typed by polymerase chain reaction sequencing for B-type ultrasonography-proven NAFLD patients with(n = 82)or without(n = 142)CAD,and in healthy controls(n = 152).Serum lipid profiles'levels were determined using biochemi-cal methods.Statistical analyses were conducted using SPSS 22.0 statistical software.Results: As the results showed,sig-nificant differences in the serum lipid profiles existed between each group.No significant differences were observed in the distributions of genotypes and alleles of GCKR rs780094 and rs1260326 in each group.The GCKR rs780094 T and rs1260326 T allele carriers possessed decreased body mass index value,and serum fasting plasma glucose and TG levels in the overall subjects,respectively.In addition,the GCKR rs780094 T allele carriers possessed decreased serum fasting plasma glucose level in the controls and NAFLD+CAD patients.Conclusions: GCKR rs780094 and rs1260326 poly-morphisms were found to be not associated with the risk of NAFLD nor of CAD in NAFLD patients in this Chinese Northern Han population.GCKR rs780094 T and rs1260326 T alleles could affect the body mass index value and serum fasting plasma glucose and triglyceride levels.

An Improved Method for Preparation of Uniform and Functional Mitochondria from Fresh Liver

Background and Aims:As the major energy source for mammalian cells,mitochondria have been the subject of numerous studies.However,the isolation and purification of healthy mitochondria,especially from fresh tissue,remains challenging.The most popular methods and kits involve various centrifugation steps which require substantial time and equipment but do not consistently provide pure preparations of functional mitochondria.The aim of this study was to determine whether methods could be devised to improve the purity and yield of functional mitochondria from fresh tissue.Methods:Fresh mouse liver was homogenized,and cells lysed.Particle size analysis,quantitation of mitochondrial DNA,mitochondrial oxygen consumption,and purity of mitochondria(by electron microscopy)were measured in samples after various purification steps and significant differences determined.Results:A two-step procedure consisting of centrifugation followed by filtration through 1.2μand 0.8μfilters resulted in uniform mitochondrial preparations with diameters between 520-540 nm,and approximately 5-times more pure samples.The mitochondria thus obtained had oxygen consumption and sensitivities to mitochondrial inhibitors that were indistinguishable from those purified by centrifugation alone.Electron microscopy confirmed the presence of more uniform and 4-5 times greater concentrations of mitochondria compared to centrifugation alone.Conclusions:A two-step procedure consisting of sequential centrifugation followed by filtration is a rapid method for the production of highly purified,uniform and functional mitochondria.

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis,'Inside Any Deep Asking Is the Answering'

Liver cirrhosis progresses through multiple clinical stages which culminate in either death or liver transplantation.Availability of organs,timely listing and prompt receipt of donor-livers pose difficulties in improving transplant-listed and transplant outcomes.In this regard,regenerative therapies,particularly with granulocyte colony-stimulating factor(GCSF),has become a lucrative option for improving transplant-free survival.However,the literature is confusing with regards to patient selection and real outcomes.In this exhaustive review,we describe the basics of liver fibrosis and cirrhosis through novel insights from a therapeutic point of view,discuss preclinical studies on GCSF in advanced liver disease to improve on clinical utility,shed light on the pertinent literature of GCSF in advanced cirrhosis,and provide astute inputs on growth factor therapy in decom-pensated cirrhosis.

Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

Non-alcoholic steatohepatitis(NASH)results from inflammation and hepatocyte injury in the setting of hepatic steatosis.Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis,and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA.Weight loss and lifestyle modification remain the standard first-line treatment,as no USA Food and Drug Administration-approved pharmacotherapy currently exists.The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis,with numerous phase 2 and 3 trials currently in progress.Here,we concisely review the major targets and mechanisms of action by class,summarize results from com-pleted pivotal phase 2 studies,and provide a detailed outline of key active studies with trial data for drugs in development,including obeticholic acid,elafibranor,cenicriviroc and selonsertib.

Non-alcoholic Fatty Liver Disease in Lean Subjects:Characteristics and Implications

Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects;however,it is not rare among lean individuals.Given the absence of traditional risk factors,it tends to remain under-recognised.The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients.Though results from several studies have been mixed,it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD.Several genetic variants are associated with NAFLD without insulin resistance.Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD;however,the former tend to have less severe disease at presentation.The underlying pathophysiology of lean NAFLD may be quite different.Genetic predispositions,fructose-and cholesterol-rich diet,visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings.Lean NAFLD may pose a risk for metabolic disturbances,cardiovascular morbidity or overall mortality.Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD.The effectiveness of various treatment modalities,such as exercise and pharmacotherapy,on lean NAFLD is not known.Weight loss is expected to help lean NAFLD patients who have visceral obesity.Further investigation is needed for many aspects of lean NAFLD,including mechanistic pathogenesis,risk assessment,natural history and therapeutic approach.