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

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

Liver decompensation after rapid weight loss from semaglutide in a patient with non-alcoholic steatohepatitis -associated cirrhosis

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.

Hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis

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.

Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis:A trans-cellular crosstalk

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.

Commonly used animal models of non-alcoholic steatohepatitis

BACKGROUND: Animal models are an essential tool in non-alcoholic steatohepatitis (NASH) studies. Ideally, such models should reflect the etiology, disease progression, and the established pathology of human NASH. To date, no single animal model displays the range of histopathologic and pathophysiologic features associated with human NASH. The currently available models do not or only partially reflect the real picture of human NASH. In particular, insulin resistance and fibrosing steatohepatitis are rarely reproduced by the currently available models. Consequently, it is necessary to establish NASH models that can best mimic the real etiology, disease progression, and pathogenesis of human NASH. DATA SOURCES: We reviewed the major currently available animal models published in the literature (PubMed) and briefly commented on the pros and cons of these models. RESULT: Three major categories of animal models, genetic, dietary, and combination models, were reviewed and discussed. CONCLUSIONS: Animal models are not only useful in revealing the etiology of NASH, but also are important platforms for the assessment of therapeutic strategies. Currently available models do not reflect the full picture of NASH in patients. Better animal models are needed for a full understanding of human NASH and the development of efficient therapies for this condition. (Hepatobiliary Pancreat Dis Int 2009; 8:233-240)

Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis:Paving the way to hepatocellular carcinoma

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.

Mechanisms of ductular reaction in non-alcoholic steatohepatitis

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.

Immunoglobulin G in non-alcoholic steatohepatitis predicts clinical outcome:A prospective multi-centre cohort study

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.

Non-alcoholic steatohepatitis and influence of age and gender on histopathologic findings

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.

Acetyl-CoA carboxylase inhibitors in non-alcoholic steatohepatitis: Is there a benefit?

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.

Comprehensive lifestyle intervention vs soy protein-based meal regimen in non-alcoholic steatohepatitis

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.

Preserved liver regeneration capacity after partial hepatectomy in rats with non-alcoholic steatohepatitis

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.

Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

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.

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

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.

Quantitative multiparametric magnetic resonance imaging can aid non-alcoholic steatohepatitis diagnosis in a Japanese cohort

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.

Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis

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.

Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis

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.

Non-alcoholic steatohepatitis and the risk of myocardial infarction: Apopulation-based national study

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.

Correlation between Fibroscan and laboratory tests in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis patients for assessing liver fibrosis

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.

Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice

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.