There is rapidly increasing uptake of GLP-1 (glucagon-like peptide-1) agonistssuch as semaglutide worldwide for weight loss and management of non-alcoholicsteatohepatitis (NASH). remains a paucity of safety data in th...There is rapidly increasing uptake of GLP-1 (glucagon-like peptide-1) agonistssuch as semaglutide worldwide for weight loss and management of non-alcoholicsteatohepatitis (NASH). remains a paucity of safety data in the vulnerable NASHcirrhotic population. We report herein the first documented case of liver decompensationand need for liver transplant waitlisting in a patient with NASHcirrhosistreated with semaglutide. Rapid weight loss led to the development ofascites and hepatic encephalopathy and an increase in the patients Model forEndstage Liver Disease-Na (MELD-Na) score from 11 to 22. Aggressive nutritionalsupplementation was commenced and the semaglutide was stopped. Overthe following months she regained her weight and her liver recompensated andher MELD-Na decreased to 13, allowing her to be delisted from the transplantwaitlist. This case serves as a cautionary tale to clinicians using semaglutide in thecirrhotic population and highlights the need for more safety data in this patientgroup.展开更多
Cirrhosis is an emerging major cause of the development of hepatocellular carcinoma(HCC),but in non-alcoholic fatty liver disease(NAFLD),up to 50%of patients with HCC had no clinical or histological evidence of cirrho...Cirrhosis is an emerging major cause of the development of hepatocellular carcinoma(HCC),but in non-alcoholic fatty liver disease(NAFLD),up to 50%of patients with HCC had no clinical or histological evidence of cirrhosis.It is currently challenging to propose general recommendations for screening patients with NAFLD without cirrhosis,and each patient should be evaluated on a caseby-case basis based on the profile of specific risk factors identified.For HCC screening in NAFLD,a valid precision-based screening is needed.Currently,when evaluating this population of patients,the use of non-invasive methods can guide the selection of those who should undergo a screening and surveillance program.Hence,the objective of the present study is to review the epidemiology,the pathophysiology,the histopathological aspects,the current recommendations,and novel perspectives in the surveillance of non-cirrhotic NAFLD-related HCC.展开更多
BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively p...BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.展开更多
Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role ...Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for(non-liver)cancer therapy,treatment of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis is still limited.Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.展开更多
AIM:To characterize the histopathologic specifications of non-alcoholic steatohepatitis(NASH)according to age and gender.METHODS:An analytical cross-sectional study was conducted in two private gastroenterology clinic...AIM:To characterize the histopathologic specifications of non-alcoholic steatohepatitis(NASH)according to age and gender.METHODS:An analytical cross-sectional study was conducted in two private gastroenterology clinics on biopsy proven patients suffering from NASH.Biopsy histopathologic findings as well as demographic and laboratory data of the patients at the time of biopsy were gathered retrospectively from clinical records.The grading and staging of histopathologic findings were performed according to the Brunt method after reevaluation of the slides by a pathologist.Patients were divided into two groups according to age(belowand above 55 years).Mean quantitative grade of all pathologic findings were also calculated according to Brunt scoring values.RESULTS:A total number of 77 NASH patients,consisting of 58 males(75.3%)and 19(24.7%)females with a mean age of 41.99±11.80 years(range,18-70 years),were enrolled.The mean age(48.72±13.99 years vs 39.74±10.16 years,P=0.004)and aspartate aminotransferase level(75.11±29.68 U/L vs 52.78± 25.00 U/L,P=0.002)was significantly higher in female patients.Mean quantitative grade of hepatosteatosis was significantly higher in females(2.00±0.82 vs 1.59 ±0.68,P=0.031)compared to males.Fifty four percent(34/65)of young patients had mild hepatosteatosis (GradeⅠ)while only one patient(11.2%)in the older group had gradeⅠhepatosteatosis.Patients aged≥55 had significantly more severe hepatosteatosis(GradeⅢ) (44.4%vs 9.5%,P=0.007)and the mean quantitative grade of hepatosteatosis was significantly higher among them(2.33±0.71 vs 1.56±0.67,P=0.002).Multivariate analysis after omitting the confounding role of age revealed a higher grade of hepatosteatosis in female patients(P=0.010).CONCLUSION:These findings point toward the possible influence of age in the severity of steatohepatitis,portal and lobar inflammation in patients suffering from NASH while gender independently might contribute to the level of steatohepatitis.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in t...Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage.Histologically,NAFLD is divided into several periods:simple steatosis,non-alcoholic steatohepatitis(NASH),hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.With the increasing prevalence of obesity and hyperlipidemia,NAFLD has become the main cause of chronic liver disease worldwide.As a result,the pathogenesis of this disease is drawing increasing attention.Ductular reaction(DR)is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes,cholangiocytes,and hepatic progenitor cells.Recently,DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis,providing new research and treatment options.This study reviews several DR signaling pathways,including Notch,Hippo/YAP-TAZ,Wnt/β-catenin,Hedgehog,HGF/c-Met,and TWEAK/Fn14,and their role in the occurrence and development of NASH.展开更多
BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines ...BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content.AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein.METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group(MR-G)with soy-yogurt-honey preparation or to guided lifestyle change group(LC-G)with endurance activity and nutrition counselling. Serum alanine transaminase(ALT), aspartate transaminase(AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod? device. Pre-and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median(interquartile range).RESULTS Twenty-two subjects(MR-G, n = 11 and LC-G, n = 11) completed the study(9 women, 13 men; age 52.1(15.0) years, body mass index(BMI) 32.3(3.3) kg/m^2).In both groups a significant weight loss was achieved(MR-G:-6.4(3.6) kg, P <0.01; LC-G:-9.1(10.4) kg, P < 0.01). BMI dropped in both groups(MR-G:-2.3(1.5)kg/m^2, P = 0.003; LC-G:-3.0(3.4) kg/m^2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT.Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes.CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and no...Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.展开更多
AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65...AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65% fat, 1% cholesterol) or standard diet(STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d postPH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio(RPR), prothrombin-proconvertin ratio(PP), and m RNA expression of genes related to regeneration.RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline(P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH(P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline,(P < 0.0001), day 2 after PH(P = 0.06) and day 5 after PH(P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes(e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups(P < 0.05).CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.展开更多
Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH ...Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients.To date,vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D,and its expression can be induced by fatty acids,and insulin.It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation.Thus,the multiplicity of VDR ligands,together with the cell type-specificity of VDR activation,must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.To this end,we have evaluated the relationship between VDR activation and various contributing factors,such as gut microbiota,bile acid,fatty acids,and insulin,in addition to vitamin D,with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.展开更多
BACKGROUND Autoimmune markers including plasma cells(PC),anti-smooth-muscle antibody(ASMA),anti-nuclear antibody(ANA),and raised immunoglobulin G(IgG)are commonly observed in non-alcoholic steatohepatitis(NASH),howeve...BACKGROUND Autoimmune markers including plasma cells(PC),anti-smooth-muscle antibody(ASMA),anti-nuclear antibody(ANA),and raised immunoglobulin G(IgG)are commonly observed in non-alcoholic steatohepatitis(NASH),however their clinical significance is unknown.AIM To determine if autoimmune markers in NASH patients are independently associated with poorer clinical outcomes.METHODS Consecutive patients with biopsy proven NASH from Christchurch Hospital,New Zealand and Singapore General Hospital(SGH)were included between 2005 to 2016 in a prospective multi-centre cohort study.Patients with other causes of chronic liver disease were excluded.IgG>14 g/L or globulin fraction>50%,ANA≥1:40,SMA≥1:40 were considered positive.Multivariate analysis was performed to assess which markers were independently associated with mortality and hepatic decompensation.RESULTS Total 261 patients were included of which 201 were from SGH.The median age was 53 and 51.9%were male.Advanced fibrosis was present in 31.4%at diagnosis.PC,ASMA,ANA and raised IgG were observed in 13.1%,4.9%,27.8%and 30.1%of patients respectively.After multivariate analysis,elevated IgG[Hazard Ratio(HR)6.79,95%CI:2.93-17.15]and fibrosis stage(HR 1.37,95%CI:1.03-1.87)were found to be independently associated with increased risk of liver decompensation.Age(HR 1.06,95%CI:1.02-1.10)and elevated IgG(HR 3.79,95%CI:1.90-7.68)were independent factors associated with higher mortality risk.CONCLUSION Elevated IgG,rather than ANA,ASMA or plasma cells,is independently associated with increased risk of hepatic decompensation and mortality in NASH.It could hence be important for prognostication.展开更多
Recently,the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma(HCC),even ...Recently,the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma(HCC),even in the absence of cirrhosis.Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC.The composition of the gut microbiota differs significantly in obese and lean individuals,especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla,and,after establishing steatohepatitis,it undergoes minor changes during the progression of the disease toward advanced fibrosis.Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice.On the contrary,the transplantation of healthy microbiota to obese mice relieves steatosis.However,further studies are needed to confirm these findings and the mechanisms involved.In this review,we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis(NASH).Furthermore,a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed,and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.展开更多
BACKGROUND Non-invasive assessment of non-alcoholic steatohepatitis(NASH)is increasing in desirability due to the invasive nature and costs associated with the current form of assessment;liver biopsy.Quantitative mult...BACKGROUND Non-invasive assessment of non-alcoholic steatohepatitis(NASH)is increasing in desirability due to the invasive nature and costs associated with the current form of assessment;liver biopsy.Quantitative multiparametric magnetic resonance imaging(mpMRI)to measure liver fat(proton density fat fraction)and fibroinflammatory disease[iron-corrected T1(cT1)],as well as elastography techniques[vibration-controlled transient elastography(VCTE)liver stiffness measure],magnetic resonance elastography(MRE)and 2D Shear-Wave elastography(SWE)to measure stiffness and fat(controlled attenuated parameter,CAP)are emerging alternatives which could be utilised as safe surrogates to liver biopsy.AIM To evaluate the agreement of non-invasive imaging modalities with liver biopsy,and their subsequent diagnostic accuracy for identifying NASH patients.METHODS From January 2019 to February 2020,Japanese patients suspected of NASH were recruited onto a prospective,observational study and were screened using noninvasive imaging techniques;mpMRI with LiverMultiScan®,VCTE,MRE and 2DSWE.Patients were subsequently biopsied,and samples were scored by three independent pathologists.The diagnostic performances of the non-invasive imaging modalities were assessed using area under receiver operating characteristic curve(AUC)with the median of the histology scores as the gold standard diagnoses.Concordance between all three independent pathologists was further explored using Krippendorff’s alpha(a)from weighted kappa statistics.RESULTS N=145 patients with mean age of 60(SD:13 years.),39%females,and 40%with body mass index≥30 kg/m2 were included in the analysis.For identifying patients with NASH,MR liver fat and cT1 were the strongest performing individual measures(AUC:0.80 and 0.75 respectively),and the mpMRI metrics combined(cT1 and MR liver fat)were the overall best non-invasive test(AUC:0.83).For identifying fibrosis≥1,MRE performed best(AUC:0.97),compared to VCTE-liver stiffness measure(AUC:0.94)and 2D-SWE(AUC:0.94).For assessment of steatosis≥1,MR liver fat was the best performing non-invasive test(AUC:0.92),compared to controlled attenuated parameter(AUC:0.75).Assessment of the agreement between pathologists showed that concordance was best for steatosis(a=0.58),moderate for ballooning(a=0.40)and fibrosis(a=0.40),and worst for lobular inflammation(a=0.11).CONCLUSION Quantitative mpMRI is an effective alternative to liver biopsy for diagnosing NASH and non-alcoholic fatty liver,and thus may offer clinical utility in patient management.展开更多
De novo lipogenesis(DNL)plays an important role in the pathogenesis of hepatic steatosis and also appears to be implicated in hepatic inflammation and fibrosis.Accordingly,the inhibition of acetyl-CoA carboxylase,whic...De novo lipogenesis(DNL)plays an important role in the pathogenesis of hepatic steatosis and also appears to be implicated in hepatic inflammation and fibrosis.Accordingly,the inhibition of acetyl-CoA carboxylase,which catalyzes the ratelimiting step of DNL,might represent a useful approach in the management of patients with nonalcoholic fatty liver disease(NAFLD).Animal studies and preliminary data in patients with NAFLD consistently showed an improvement in steatosis with the use of these agents.However,effects on fibrosis were variable and an increase in plasma triglyceride levels was observed.Therefore,more longterm studies are needed to clarify the role of these agents in NAFLD and to determine their risk/benefit profile.展开更多
BACKGROUND Aloe vera exerts several biological activities,such as,anti-inflammatory,antioxidant,and antimicrobial effects.It was recently shown to reduce insulin resistance and triglyceride level.We hypothesized that ...BACKGROUND Aloe vera exerts several biological activities,such as,anti-inflammatory,antioxidant,and antimicrobial effects.It was recently shown to reduce insulin resistance and triglyceride level.We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH)in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n=6 in each group).Rats in the control group were fed ad libitum with a standard diet for 8 wk.Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD)for 8 wk.Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg)by gavage daily for 8 wk.Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA)levels increased significantly in the NASH group as compared with the control group(377±77 nmol/mg vs 129±51 nmol/mg protein,respectively,P<0.001).Glutathione(GSH)levels were significantly lower in the NASH group than the control group(9±2 nmol/mg vs 24±8 nmol/mg protein,respectively,P=0.001).The expression of interleukin-18 (IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisomeproliferator-activated receptor gamma decreased in the NASH group comparedwith the controls. Following aloe vera administration, MDA levels decreased (199± 35 nmol/mg protein) and GSH increased (18 ± 4 nmol/mg protein) markedly.Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyteapoptosis were observed in the NASH group. Aloe vera treatment attenuatedthese changes in liver histology.CONCLUSIONAloe vera attenuated oxidative stress, hepatic inflammation and hepatocyteapoptosis, thus improving liver pathology in rats with NASH.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a spectrum of disease ranging from simple steatosis to non-alcoholic steatohepatitis(NASH), through to advanced fibrosis and cirrhosis. Many patients with NAFLD r...BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a spectrum of disease ranging from simple steatosis to non-alcoholic steatohepatitis(NASH), through to advanced fibrosis and cirrhosis. Many patients with NAFLD remain undiagnosed and recognizing those at risk is very crucial. Although liver biopsy is the gold standard method for diagnosing and staging NAFLD, non-invasive imaging and lab modalities are also very promising in diagnosing these diseases.AIM To explore some of these non-invasive modalities in this context and assess how they hold up in terms of making a diagnosis while avoiding an invasive procedure like a liver biopsy.METHODS This study was conducted on NAFLD/NASH patients(n = 73) who underwent Fibroscan examinations at Saint George Hospital University Medical Center over 17 mo in order to assess liver fibrosis. Obtained Fibroscan results were correlated to laboratory tests and calculated aspartate transaminase(AST)/alanine transaminase(ALT) ratio, AST platelet ratio index(APRI) score and Fibrosis-4 score.RESULTS A significant age difference was observed across fibrosis stages of investigated patients. The mean stiffness score was 9.48 ± 11.77 KPa. A significant negative correlation was observed between ALT, AST, Albumin, gamma-glutamyl transferase, cholesterol, LDL, HDL, triglycerides, and ALP when compared across fibrosis stages. On the other hand, a significant positive correlation was found between Bilirubin, PT INR, partial thromboplastin time, glucose, and Platelet count when compared across fibrosis stages, in addition to AST/ALT ratio, APRI, and Fib-4 scores.CONCLUSION This study showed that Ultrasound alone is not efficient in the assessment of advancement of liver disease. Furthermore, the high positive relation between AST/ALT ratio, APRI and Fib-4 scores with fibrosis stages in NAFLD patients suggests that they could be used clinically in combination with Fibroscan to predict significant fibrosis and cirrhosis and to avoid liver biopsy.展开更多
BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Unders...BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies.The inflammatory cytokine tumor necrosis factor alpha(TNF-α)is important for the progression of liver disease.TNF signaling via TNF receptor 1(TNFR1)has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes(TNFR1ΔHEP)and their wild-type littermates(TNFR1fl/fl).Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding.After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight,liver steatosis,liver fibrosis and markers of liver inflammation.RESULTS Obesity,liver injury,inflammation,steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice.However,Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH.However,improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.展开更多
BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a systemic disease with bidirectionalrelationships with cardiovascular disease (CVD). Non-alcoholic steatohepatitis(NASH) is a more severe subtype of NAFLD. Patie...BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a systemic disease with bidirectionalrelationships with cardiovascular disease (CVD). Non-alcoholic steatohepatitis(NASH) is a more severe subtype of NAFLD. Patients with NASH exhibit moreintra and extrahepatic inflammation, procoagulant imbalances andproatherogenic lipid profiles. Whether NASH increases the risk of ischemic heartdisease is currently unclear.AIMTo investigate the relationship between acute myocardial infarction (MI) andNASH in a large cohort of subjects in the United States.METHODSWe reviewed data from a large commercial database (Explorys IBM) thataggregates electronic health records from 26 large nationwide healthcare systems.Using systemized nomenclature of clinical medical terms (SNOMED CT), weidentified adult with the diagnosis of NASH from 1999-2019. We includedpatients with the diagnosis of acute MI from 2018-2019. Comorbidities known tobe associated with NASH and MI such as obesity, diabetes mellitus,hyperlipidemia, smoking, male gender, and hypertension were collected.Univariable and multivariable analyses were performed to investigate whetherNASH is independently associated with the risk of MI.RESULTSOut of 55099280 patients, 43170 were diagnosed with NASH (0.08%) and 107000(0.194%) had a MI within 2018-2019. After adjusting for traditional risk factors,NASH conferred greater odds of MI odds ratio (OR) 1.5 [95% confidence interval(CI): 1.40-1.62]. Hyperlipidemia had the strongest association with MI OR 8.39(95%CI: 8.21-8.58) followed by hypertension OR 3.11 (95%CI: 3.05-3.17) andsmoking OR 2.83 (95%CI: 2.79-2.87). NASH had a similar association with MI asthe following traditional risk factors like age above 65 years OR 1.47 (95%CI: 1.45-1.49), male gender OR 1.53 (95%CI: 1.51-1.55) diabetes mellitus OR 1.89 (95%CI:1.86-1.91).CONCLUSIONMI appears to be a prevalent disease in NASH. Patients with NASH may needearly identification and aggressive cardiovascular risk modification.展开更多
BACKGROUND There is an acute need to raise awareness of non-alcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH)among primary care physicians,endocrinologists and diabetologists to improve patient id...BACKGROUND There is an acute need to raise awareness of non-alcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH)among primary care physicians,endocrinologists and diabetologists to improve patient identification and address the current difficulties in NASH clinical trial enrollment.We examined the extent of knowledge and practice regarding NASH diagnosis and management guidelines.A randomized online convenience survey of 12869 physicians drawn from a national physician database of primary care physicians(PCPs),and gastroenterology and endocrinology specialists were queried via online survey.Our results,based on a cohort of 185 respondents,showed gaps in knowledge and practice between these three groups of practitioners,with primary care providers having the lowest adherence to published guidelines for diagnosis of NASH.Without clear knowledge and patient identification at the point of presentation-which is often in primary care or with specialties other than hepatology–many patients with NAFLD and NASH will remain undiagnosed and untreated,and clinical studies will continue to struggle with patient recruitment,hindering clinical development and optimal patient care.AIM To determine knowledge base concerning NASH diagnosis amongst gastroenterologists,endocrinologists and primary care physicians to improve referrals into clinical trials.METHODS A randomized online convenience survey of 12869 physicians drawn from a national physician database of PCPs,and gastroenterology and endocrinology specialists was conducted yielding a sample of 185 respondents.RESULTS The survey revealed that many physicians are either unaware of testing options other than biopsy,or do not use them in practice.Only 46%of endocrinologists and 42%of primary care physicians indicated they would refer a patient for specialist workup if they suspected NASH.Risk(25%)and inconvenience to patients(18%)are given as reasons for not referring those with suspected NASH for biopsy.For standard diagnostic algorithms such as Fibrosis-4 score,18%of PCPs,30%of endocrinologists and 65%gastroenterologists reported using these tests in clinical practice.CONCLUSION Substantial gaps in knowledge of the differences between NAFLD and NASH exist between these physician groups,with knowledge being particularly low among primary care doctors and endocrinologists.The use of a simple noninvasive screening algorithm may help to identify the right patients for clinical trials,which in turn will be vital to the development of effective and welltolerated treatments for this increasingly ubiquitous condition.展开更多
Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may...Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.展开更多
文摘There is rapidly increasing uptake of GLP-1 (glucagon-like peptide-1) agonistssuch as semaglutide worldwide for weight loss and management of non-alcoholicsteatohepatitis (NASH). remains a paucity of safety data in the vulnerable NASHcirrhotic population. We report herein the first documented case of liver decompensationand need for liver transplant waitlisting in a patient with NASHcirrhosistreated with semaglutide. Rapid weight loss led to the development ofascites and hepatic encephalopathy and an increase in the patients Model forEndstage Liver Disease-Na (MELD-Na) score from 11 to 22. Aggressive nutritionalsupplementation was commenced and the semaglutide was stopped. Overthe following months she regained her weight and her liver recompensated andher MELD-Na decreased to 13, allowing her to be delisted from the transplantwaitlist. This case serves as a cautionary tale to clinicians using semaglutide in thecirrhotic population and highlights the need for more safety data in this patientgroup.
文摘Cirrhosis is an emerging major cause of the development of hepatocellular carcinoma(HCC),but in non-alcoholic fatty liver disease(NAFLD),up to 50%of patients with HCC had no clinical or histological evidence of cirrhosis.It is currently challenging to propose general recommendations for screening patients with NAFLD without cirrhosis,and each patient should be evaluated on a caseby-case basis based on the profile of specific risk factors identified.For HCC screening in NAFLD,a valid precision-based screening is needed.Currently,when evaluating this population of patients,the use of non-invasive methods can guide the selection of those who should undergo a screening and surveillance program.Hence,the objective of the present study is to review the epidemiology,the pathophysiology,the histopathological aspects,the current recommendations,and novel perspectives in the surveillance of non-cirrhotic NAFLD-related HCC.
基金the Natural Science Foundation of Zhejiang Province,No.LZ21H030002。
文摘BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.
文摘Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for(non-liver)cancer therapy,treatment of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis is still limited.Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.
文摘AIM:To characterize the histopathologic specifications of non-alcoholic steatohepatitis(NASH)according to age and gender.METHODS:An analytical cross-sectional study was conducted in two private gastroenterology clinics on biopsy proven patients suffering from NASH.Biopsy histopathologic findings as well as demographic and laboratory data of the patients at the time of biopsy were gathered retrospectively from clinical records.The grading and staging of histopathologic findings were performed according to the Brunt method after reevaluation of the slides by a pathologist.Patients were divided into two groups according to age(belowand above 55 years).Mean quantitative grade of all pathologic findings were also calculated according to Brunt scoring values.RESULTS:A total number of 77 NASH patients,consisting of 58 males(75.3%)and 19(24.7%)females with a mean age of 41.99±11.80 years(range,18-70 years),were enrolled.The mean age(48.72±13.99 years vs 39.74±10.16 years,P=0.004)and aspartate aminotransferase level(75.11±29.68 U/L vs 52.78± 25.00 U/L,P=0.002)was significantly higher in female patients.Mean quantitative grade of hepatosteatosis was significantly higher in females(2.00±0.82 vs 1.59 ±0.68,P=0.031)compared to males.Fifty four percent(34/65)of young patients had mild hepatosteatosis (GradeⅠ)while only one patient(11.2%)in the older group had gradeⅠhepatosteatosis.Patients aged≥55 had significantly more severe hepatosteatosis(GradeⅢ) (44.4%vs 9.5%,P=0.007)and the mean quantitative grade of hepatosteatosis was significantly higher among them(2.33±0.71 vs 1.56±0.67,P=0.002).Multivariate analysis after omitting the confounding role of age revealed a higher grade of hepatosteatosis in female patients(P=0.010).CONCLUSION:These findings point toward the possible influence of age in the severity of steatohepatitis,portal and lobar inflammation in patients suffering from NASH while gender independently might contribute to the level of steatohepatitis.
基金Supported by the National Natural Science Foundation of China,No. 81770582the Graduates’ Innovation FundHuazhong University of Science and Technology,No. 2021yjsCXCY106
文摘Non-alcoholic fatty liver disease(NAFLD)is a disease spectrum caused in part by insulin resistance and genetic predisposition.This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage.Histologically,NAFLD is divided into several periods:simple steatosis,non-alcoholic steatohepatitis(NASH),hepatic fibrosis,cirrhosis,and hepatocellular carcinoma.With the increasing prevalence of obesity and hyperlipidemia,NAFLD has become the main cause of chronic liver disease worldwide.As a result,the pathogenesis of this disease is drawing increasing attention.Ductular reaction(DR)is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes,cholangiocytes,and hepatic progenitor cells.Recently,DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis,providing new research and treatment options.This study reviews several DR signaling pathways,including Notch,Hippo/YAP-TAZ,Wnt/β-catenin,Hedgehog,HGF/c-Met,and TWEAK/Fn14,and their role in the occurrence and development of NASH.
基金(in part)Almased^(®)? Wellness Company,Bienenbuettel,GermanyThe planning,organisation,monitoring and analysis of the study were performed independently by the investigators+1 种基金a study grant from Almased^(®)? Wellness Companya study grant from Helmholtz Alliance ICEMED
文摘BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content.AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein.METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group(MR-G)with soy-yogurt-honey preparation or to guided lifestyle change group(LC-G)with endurance activity and nutrition counselling. Serum alanine transaminase(ALT), aspartate transaminase(AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod? device. Pre-and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median(interquartile range).RESULTS Twenty-two subjects(MR-G, n = 11 and LC-G, n = 11) completed the study(9 women, 13 men; age 52.1(15.0) years, body mass index(BMI) 32.3(3.3) kg/m^2).In both groups a significant weight loss was achieved(MR-G:-6.4(3.6) kg, P <0.01; LC-G:-9.1(10.4) kg, P < 0.01). BMI dropped in both groups(MR-G:-2.3(1.5)kg/m^2, P = 0.003; LC-G:-3.0(3.4) kg/m^2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT.Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes.CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.
文摘Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.
基金Supported by NOVO Nordisk Foundation(grant number 1013267)Savværksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat to Gr?nb?k HVillum Fonden to Nyengaard JR
文摘AIM To evaluate the liver regeneration capacity(LRC) after partial hepatectomy(PH) in experimental non-alcoholic steatohepatitis(NASH).METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet(HFCD, 65% fat, 1% cholesterol) or standard diet(STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d postPH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio(RPR), prothrombin-proconvertin ratio(PP), and m RNA expression of genes related to regeneration.RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline(P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH(P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline,(P < 0.0001), day 2 after PH(P = 0.06) and day 5 after PH(P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes(e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups(P < 0.05).CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
基金Supported by the National Natural Science Foundation of China,No.81774084 and 81804020and Young Talent Promotion Project of Chinese Medicine Association,No.2019-QNRC2-C04.
文摘Nonalcoholic steatohepatitis(NASH)is a progressed stage of non-alcoholic fatty liver disease,and available therapeutic strategies for NASH are limited.Vitamin D receptor(VDR)is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients.To date,vitamin D supplementation has not consistently conferred expected therapeutic benefits,raising the question of whether VDR can serve as a proper drug target for NASH.It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D,and its expression can be induced by fatty acids,and insulin.It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis,activation of VDR in hepatocytes could accelerate lipid accumulation.Thus,the multiplicity of VDR ligands,together with the cell type-specificity of VDR activation,must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.To this end,we have evaluated the relationship between VDR activation and various contributing factors,such as gut microbiota,bile acid,fatty acids,and insulin,in addition to vitamin D,with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue-and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.
文摘BACKGROUND Autoimmune markers including plasma cells(PC),anti-smooth-muscle antibody(ASMA),anti-nuclear antibody(ANA),and raised immunoglobulin G(IgG)are commonly observed in non-alcoholic steatohepatitis(NASH),however their clinical significance is unknown.AIM To determine if autoimmune markers in NASH patients are independently associated with poorer clinical outcomes.METHODS Consecutive patients with biopsy proven NASH from Christchurch Hospital,New Zealand and Singapore General Hospital(SGH)were included between 2005 to 2016 in a prospective multi-centre cohort study.Patients with other causes of chronic liver disease were excluded.IgG>14 g/L or globulin fraction>50%,ANA≥1:40,SMA≥1:40 were considered positive.Multivariate analysis was performed to assess which markers were independently associated with mortality and hepatic decompensation.RESULTS Total 261 patients were included of which 201 were from SGH.The median age was 53 and 51.9%were male.Advanced fibrosis was present in 31.4%at diagnosis.PC,ASMA,ANA and raised IgG were observed in 13.1%,4.9%,27.8%and 30.1%of patients respectively.After multivariate analysis,elevated IgG[Hazard Ratio(HR)6.79,95%CI:2.93-17.15]and fibrosis stage(HR 1.37,95%CI:1.03-1.87)were found to be independently associated with increased risk of liver decompensation.Age(HR 1.06,95%CI:1.02-1.10)and elevated IgG(HR 3.79,95%CI:1.90-7.68)were independent factors associated with higher mortality risk.CONCLUSION Elevated IgG,rather than ANA,ASMA or plasma cells,is independently associated with increased risk of hepatic decompensation and mortality in NASH.It could hence be important for prognostication.
文摘Recently,the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma(HCC),even in the absence of cirrhosis.Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC.The composition of the gut microbiota differs significantly in obese and lean individuals,especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla,and,after establishing steatohepatitis,it undergoes minor changes during the progression of the disease toward advanced fibrosis.Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice.On the contrary,the transplantation of healthy microbiota to obese mice relieves steatosis.However,further studies are needed to confirm these findings and the mechanisms involved.In this review,we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis(NASH).Furthermore,a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed,and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.
文摘BACKGROUND Non-invasive assessment of non-alcoholic steatohepatitis(NASH)is increasing in desirability due to the invasive nature and costs associated with the current form of assessment;liver biopsy.Quantitative multiparametric magnetic resonance imaging(mpMRI)to measure liver fat(proton density fat fraction)and fibroinflammatory disease[iron-corrected T1(cT1)],as well as elastography techniques[vibration-controlled transient elastography(VCTE)liver stiffness measure],magnetic resonance elastography(MRE)and 2D Shear-Wave elastography(SWE)to measure stiffness and fat(controlled attenuated parameter,CAP)are emerging alternatives which could be utilised as safe surrogates to liver biopsy.AIM To evaluate the agreement of non-invasive imaging modalities with liver biopsy,and their subsequent diagnostic accuracy for identifying NASH patients.METHODS From January 2019 to February 2020,Japanese patients suspected of NASH were recruited onto a prospective,observational study and were screened using noninvasive imaging techniques;mpMRI with LiverMultiScan®,VCTE,MRE and 2DSWE.Patients were subsequently biopsied,and samples were scored by three independent pathologists.The diagnostic performances of the non-invasive imaging modalities were assessed using area under receiver operating characteristic curve(AUC)with the median of the histology scores as the gold standard diagnoses.Concordance between all three independent pathologists was further explored using Krippendorff’s alpha(a)from weighted kappa statistics.RESULTS N=145 patients with mean age of 60(SD:13 years.),39%females,and 40%with body mass index≥30 kg/m2 were included in the analysis.For identifying patients with NASH,MR liver fat and cT1 were the strongest performing individual measures(AUC:0.80 and 0.75 respectively),and the mpMRI metrics combined(cT1 and MR liver fat)were the overall best non-invasive test(AUC:0.83).For identifying fibrosis≥1,MRE performed best(AUC:0.97),compared to VCTE-liver stiffness measure(AUC:0.94)and 2D-SWE(AUC:0.94).For assessment of steatosis≥1,MR liver fat was the best performing non-invasive test(AUC:0.92),compared to controlled attenuated parameter(AUC:0.75).Assessment of the agreement between pathologists showed that concordance was best for steatosis(a=0.58),moderate for ballooning(a=0.40)and fibrosis(a=0.40),and worst for lobular inflammation(a=0.11).CONCLUSION Quantitative mpMRI is an effective alternative to liver biopsy for diagnosing NASH and non-alcoholic fatty liver,and thus may offer clinical utility in patient management.
文摘De novo lipogenesis(DNL)plays an important role in the pathogenesis of hepatic steatosis and also appears to be implicated in hepatic inflammation and fibrosis.Accordingly,the inhibition of acetyl-CoA carboxylase,which catalyzes the ratelimiting step of DNL,might represent a useful approach in the management of patients with nonalcoholic fatty liver disease(NAFLD).Animal studies and preliminary data in patients with NAFLD consistently showed an improvement in steatosis with the use of these agents.However,effects on fibrosis were variable and an increase in plasma triglyceride levels was observed.Therefore,more longterm studies are needed to clarify the role of these agents in NAFLD and to determine their risk/benefit profile.
基金Supported by the Grant of Ratchadaphiseksomphot,Faculty of Medicine,Chulalongkorn University,Bangkok,Thailand,No.RA59/035.
文摘BACKGROUND Aloe vera exerts several biological activities,such as,anti-inflammatory,antioxidant,and antimicrobial effects.It was recently shown to reduce insulin resistance and triglyceride level.We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH)in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n=6 in each group).Rats in the control group were fed ad libitum with a standard diet for 8 wk.Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD)for 8 wk.Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg)by gavage daily for 8 wk.Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA)levels increased significantly in the NASH group as compared with the control group(377±77 nmol/mg vs 129±51 nmol/mg protein,respectively,P<0.001).Glutathione(GSH)levels were significantly lower in the NASH group than the control group(9±2 nmol/mg vs 24±8 nmol/mg protein,respectively,P=0.001).The expression of interleukin-18 (IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisomeproliferator-activated receptor gamma decreased in the NASH group comparedwith the controls. Following aloe vera administration, MDA levels decreased (199± 35 nmol/mg protein) and GSH increased (18 ± 4 nmol/mg protein) markedly.Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyteapoptosis were observed in the NASH group. Aloe vera treatment attenuatedthese changes in liver histology.CONCLUSIONAloe vera attenuated oxidative stress, hepatic inflammation and hepatocyteapoptosis, thus improving liver pathology in rats with NASH.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a spectrum of disease ranging from simple steatosis to non-alcoholic steatohepatitis(NASH), through to advanced fibrosis and cirrhosis. Many patients with NAFLD remain undiagnosed and recognizing those at risk is very crucial. Although liver biopsy is the gold standard method for diagnosing and staging NAFLD, non-invasive imaging and lab modalities are also very promising in diagnosing these diseases.AIM To explore some of these non-invasive modalities in this context and assess how they hold up in terms of making a diagnosis while avoiding an invasive procedure like a liver biopsy.METHODS This study was conducted on NAFLD/NASH patients(n = 73) who underwent Fibroscan examinations at Saint George Hospital University Medical Center over 17 mo in order to assess liver fibrosis. Obtained Fibroscan results were correlated to laboratory tests and calculated aspartate transaminase(AST)/alanine transaminase(ALT) ratio, AST platelet ratio index(APRI) score and Fibrosis-4 score.RESULTS A significant age difference was observed across fibrosis stages of investigated patients. The mean stiffness score was 9.48 ± 11.77 KPa. A significant negative correlation was observed between ALT, AST, Albumin, gamma-glutamyl transferase, cholesterol, LDL, HDL, triglycerides, and ALP when compared across fibrosis stages. On the other hand, a significant positive correlation was found between Bilirubin, PT INR, partial thromboplastin time, glucose, and Platelet count when compared across fibrosis stages, in addition to AST/ALT ratio, APRI, and Fib-4 scores.CONCLUSION This study showed that Ultrasound alone is not efficient in the assessment of advancement of liver disease. Furthermore, the high positive relation between AST/ALT ratio, APRI and Fib-4 scores with fibrosis stages in NAFLD patients suggests that they could be used clinically in combination with Fibroscan to predict significant fibrosis and cirrhosis and to avoid liver biopsy.
基金Supported by the Swiss National Science Foundation,No.P2SKP3_158649,No.P3400PB_171581,and No.P3P3PB_171582(to Bluemel S)NIH grants(in part),No.R01 AA24726,No.U01 AA026939,and services provided by P30 DK120515(to Schnabl B).
文摘BACKGROUND End-stage liver disease caused by non-alcoholic steatohepatitis(NASH)is the second leading indication for liver transplantation.To date,only moderately effective pharmacotherapies exist to treat NASH.Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies.The inflammatory cytokine tumor necrosis factor alpha(TNF-α)is important for the progression of liver disease.TNF signaling via TNF receptor 1(TNFR1)has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.AIM To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH.METHODS NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes(TNFR1ΔHEP)and their wild-type littermates(TNFR1fl/fl).Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding.After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight,liver steatosis,liver fibrosis and markers of liver inflammation.RESULTS Obesity,liver injury,inflammation,steatosis and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice.However,Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance.CONCLUSION Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH.However,improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis.
基金We gratefully acknowledge Dr.Joseph Sudano for ensuring the data analysis is appropriate for this research.
文摘BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is a systemic disease with bidirectionalrelationships with cardiovascular disease (CVD). Non-alcoholic steatohepatitis(NASH) is a more severe subtype of NAFLD. Patients with NASH exhibit moreintra and extrahepatic inflammation, procoagulant imbalances andproatherogenic lipid profiles. Whether NASH increases the risk of ischemic heartdisease is currently unclear.AIMTo investigate the relationship between acute myocardial infarction (MI) andNASH in a large cohort of subjects in the United States.METHODSWe reviewed data from a large commercial database (Explorys IBM) thataggregates electronic health records from 26 large nationwide healthcare systems.Using systemized nomenclature of clinical medical terms (SNOMED CT), weidentified adult with the diagnosis of NASH from 1999-2019. We includedpatients with the diagnosis of acute MI from 2018-2019. Comorbidities known tobe associated with NASH and MI such as obesity, diabetes mellitus,hyperlipidemia, smoking, male gender, and hypertension were collected.Univariable and multivariable analyses were performed to investigate whetherNASH is independently associated with the risk of MI.RESULTSOut of 55099280 patients, 43170 were diagnosed with NASH (0.08%) and 107000(0.194%) had a MI within 2018-2019. After adjusting for traditional risk factors,NASH conferred greater odds of MI odds ratio (OR) 1.5 [95% confidence interval(CI): 1.40-1.62]. Hyperlipidemia had the strongest association with MI OR 8.39(95%CI: 8.21-8.58) followed by hypertension OR 3.11 (95%CI: 3.05-3.17) andsmoking OR 2.83 (95%CI: 2.79-2.87). NASH had a similar association with MI asthe following traditional risk factors like age above 65 years OR 1.47 (95%CI: 1.45-1.49), male gender OR 1.53 (95%CI: 1.51-1.55) diabetes mellitus OR 1.89 (95%CI:1.86-1.91).CONCLUSIONMI appears to be a prevalent disease in NASH. Patients with NASH may needearly identification and aggressive cardiovascular risk modification.
文摘BACKGROUND There is an acute need to raise awareness of non-alcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH)among primary care physicians,endocrinologists and diabetologists to improve patient identification and address the current difficulties in NASH clinical trial enrollment.We examined the extent of knowledge and practice regarding NASH diagnosis and management guidelines.A randomized online convenience survey of 12869 physicians drawn from a national physician database of primary care physicians(PCPs),and gastroenterology and endocrinology specialists were queried via online survey.Our results,based on a cohort of 185 respondents,showed gaps in knowledge and practice between these three groups of practitioners,with primary care providers having the lowest adherence to published guidelines for diagnosis of NASH.Without clear knowledge and patient identification at the point of presentation-which is often in primary care or with specialties other than hepatology–many patients with NAFLD and NASH will remain undiagnosed and untreated,and clinical studies will continue to struggle with patient recruitment,hindering clinical development and optimal patient care.AIM To determine knowledge base concerning NASH diagnosis amongst gastroenterologists,endocrinologists and primary care physicians to improve referrals into clinical trials.METHODS A randomized online convenience survey of 12869 physicians drawn from a national physician database of PCPs,and gastroenterology and endocrinology specialists was conducted yielding a sample of 185 respondents.RESULTS The survey revealed that many physicians are either unaware of testing options other than biopsy,or do not use them in practice.Only 46%of endocrinologists and 42%of primary care physicians indicated they would refer a patient for specialist workup if they suspected NASH.Risk(25%)and inconvenience to patients(18%)are given as reasons for not referring those with suspected NASH for biopsy.For standard diagnostic algorithms such as Fibrosis-4 score,18%of PCPs,30%of endocrinologists and 65%gastroenterologists reported using these tests in clinical practice.CONCLUSION Substantial gaps in knowledge of the differences between NAFLD and NASH exist between these physician groups,with knowledge being particularly low among primary care doctors and endocrinologists.The use of a simple noninvasive screening algorithm may help to identify the right patients for clinical trials,which in turn will be vital to the development of effective and welltolerated treatments for this increasingly ubiquitous condition.
基金supported by grants from the National Natural Science Foundation of China(No.82070588)High-Level Creative Talents from the Department of Public Health in Zhejiang Province(No.S2032102600032)+4 种基金Project of New Century 551 Talent Nurturing in Wenzhou.G.Targher is supported in part by grants from the University School of Medicine of Verona,Verona,ItalyC.D.Byrne is supported in part by the Southampton NIHR Biomedical Research Centre(No.IS-BRC-20004),UK.MEJG are supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(No.APP1053206)Project and ideas grants(Nos.APP2001692,APP1107178,and APP1108422).
文摘Background:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis(NASH)is limited by its inherent invasiveness and possible sampling errors.Some studies have shown that cytokeratin-18(CK-18)concentrations may be useful in diagnosing NASH,but results across studies have been inconsistent.We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.Methods:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease(NAFLD),and in all patients,circulating CK-18 M30 levels were measured.Individuals with a NAFLD activity score(NAS)≥5 with a score of≥1 for each of steatosis,ballooning,and lobular inflammation were diagnosed as having definite NASH;individuals with a NAS≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver(NAFL).Results:A total of 2571 participants were screened,and 1008(153 with NAFL and 855 with NASH)were finally enrolled.Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL(mean difference 177 U/L;standardized mean difference[SMD]:0.87[0.69–1.04]).There was an interaction between CK-18 M30 levels and serum alanine aminotransferase,body mass index(BMI),and hypertension(P<0.001,P=0.026 and P=0.049,respectively).CK-18 M30 levels were positively associated with histological NAS in most centers.The area under the receiver operating characteristics(AUROC)for NASH was 0.750(95%confidence intervals:0.714–0.787),and CK-18 M30 at Youden’s index maximum was 275.7 U/L.Both sensitivity(55%[52%–59%])and positive predictive value(59%)were not ideal.Conclusion:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
