Sulforaphane ameliorates non-alcoholic steatohepatitis by KLF4-mediated macrophage M2 polarization

Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.

Non-invasively differentiate non-alcoholic steatohepatitis by visualizing hepatic integrinαvβ3 expression with a targeted molecular imaging modality

BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrinαvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrinαvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrinαvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrinαvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrinαvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrinαvβ3 expression with MRI.

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.

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% &#x000b1; 0.4% vs 7.9% &#x000b1; 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 &#x000b1; 3.5 &#x003bc;g/mL vs 3.9 &#x000b1; 2.7 &#x003bc;g/mL, P = 0.06) and triglyceride levels (1.26 &#x000b1; 0.43 mmol/L vs 2.80 &#x000b1; 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 &#x003bc;g/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002.CONCLUSIONSitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

AIM： TO evaluate insulin resistance, cytolysis and nonalcoholic steatohepatitis （NASH） score （NAS） using the Kleiner and Brunt criteria in 54 patients with NASH and mild-to-moderate hypertension, treated with telmisartan vs valsartan for 20 mo. METHODS： All patients met the NCEP-ATP Ⅲ criteria for metabolic syndrome. Histology confirmed steatohepatitis, defined as a NAS greater than five up to 3 wk prior inclusion, using the current criteria. Patients with viral hepatitis, chronic alcohol intake, drug abuse or other significant immune or metabolic hepatic pathology were excluded. Subjects were randomly assigned either to the valsartan （V） group （standard dose 80 mg o.d., n = 26）, or to the telmisartan （T） group （standard dose 20 mg o.d., n = 28）. Treatment had to be taken daily at the same hour with no concomitant medication or alcohol consumption allowed. Neither the patient nor the medical staff was aware of treatment group allocation. Paired liver biopsies obtained at inclusion （visit 1） and end of treatment （EOT） were assessed by a single blinded pathologist, not aware of patient or treatment group. Blood pressure, BMI, ALT, AST, HOMA-IR, plasma triglycerides （TG） and total cholesterol （TC） were evaluated at inclusion and every 4 mo until EOT （visit 6）. RESULTS： At EOT we noticed a significant decrease in ALT levels vs inclusion in all patients and this decrease did not differ significantly in group T vs group V. HOMA-IR significantly decreased at EOT vs inclusion in all patients but in group T, the mean HOMA-IR decrease per month was higher than in group V. NAS significantly diminished at EOT in all patients with a higher decrease in group T vs group V. CONCLUSION： Angiotensin receptor blockers seem to be efficient in hypertension-associated NASH. Telmisartan showed a higher efficacy regarding insulin resistance and histology, perhaps because of its specific PPAR-gamma ligand effect.

Visceral fat and insulin resistance as predictors of non-alcoholic steatohepatitis

AIM： To examine whether visceral fat is associated with non-alcoholic steatohepatitis （NASH）, to assess for parameters associated with visceral adiposity and to investigate for factors associated with fibrotic severity in NASH. METHODS： Thirty NASH and 30 control subjects underwent biochemical tests, anthropometric assessment, bioelectrical impedance, dual energy X-ray absorptiometry and abdominal fat study by CT scan. Liver biopsies were graded according to the Brunt criteria. RESULTS： NASH subjects had elevated blood pressure, body mass index, waist circumference and waist-to-hip ratio. A greater number of diabetes rnellitus, impaired glucose tolerance test and HOMA-IR 〉 3.5 were found in NASH patients. HOMA-IR 〉 2.8 （OR 20.98, 95% CI 3.22-136.62; P 〈 0.001） and visceral fat area 〉 158 cm^2 （OR 18.55, 95% CI 1.60-214.67; P = 0.019） were independent predictors for NASH. Advanced stage of NASH was found in 15 （50%） patients. HOMA-IR 〉 3.5 （OR 23.12, 95% CI 2.00-266.23; P = 0.012） and grading of portal inflammation （OR 7.15, 95% CI 1.63-31.20; P = 0.009） were determined as independent risk factors for advanced stage of NASH. CONCLUSION： Obesity （especially central obesity） and metabolic syndrome are common in Thai NASH. Insulin resistance and elevated visceral fat are risk factors for the presence of NASH. The advanced stage of thedisease is related to insulin resistance.

Change of intestinal mucosa barrier function in the progress of non-alcoholic steatohepatitis in rats

AIM: To explore the change of intestinal mucosa barrier function in the progress of non-alcoholic steatohepatitis (NASH) in rats. METHODS: Thirty-two Sprague-Dawley (SD) rats were randomly divided into control group and model group. Rats in the control group were given normal diet, and rats in the model group were given fat-rich diet. Eight rats in each group were killed at end of the 8th and 12th wk, respectively. The levels of endotoxin, D-xylose, TG, TC, ALT and AST, intestinal tissue SOD and MDA as well as intestinal mucus secretory IgA (sIgA) were measured. The pathology of liver was observed by HE staining. RESULTS: At end of the 8th wk, there was no marked difference in the levels of endotoxin, D-xylose and sIgA between the two groups. At end of the 12th wk, rats in the model group developed steatohepatitis and had a higher serum level of endotoxin (P = 0.01) and D-xylose (P = 0.00) and a lower serum level of sIgA (P = 0.007). CONCLUSION: Intestinal mucosa barrier malfunction may exist in NASH rats and may be an important promoter of NASH in rats.

Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis

The nonalcoholic fatty liver disease(NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis(NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes(Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a na?ve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis

AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18expression and HOMA-R were signifi cantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.

Hepatocellular carcinoma in non-alcoholic steatohepatitis:Current knowledge and implications for management

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma(HCC) related to non-alcoholic steatohepatitis(NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASHrelated HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

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)

A comparison of survival and pathologic features of non-alcoholic steatohepatitis and hepatitis C virus patients with hepatocellular carcinoma

AIM： To compare the clinical outcome and pathologic features of non-alcoholic steatohepatitis （NASH） patients with hepatocellular carcinoma （HCC） and hepatitic C virus （HCV） patients with HCC （another group in which HCC is commonly seen） undergoing liver transplantation. METHODS： Patients transplanted for HCV and NASH at our institution from January 2000 to April 2011 were analyzed. All explanted liver histology and pre-trans- plant liver biopsies were examined by two specialist liver histopathologists. Patient demographics, disease free survival, explant liver characteristics and HCC features （tumour number, cumulative tumour size, vascular invasion and differentiation） were compared between HCV and NASH liver transplant recipients. RESULTS： A total of 102 patients with NA^SH and 283 patients with HCV were transplanted. The incidence of HCC in NASH transplant recipients was 16.7% （17/102）. The incidence of HCC in HCV transplant recipients was 22.6% （64/283）. Patients with NASH-HCC were statisti- cally older than HCV-HCC patients （P 〈 0.001）. A signif- icantly higher proportion of HCV-HCC patients had vas- cular invasion （23.4% vs 6.4%, P = 0.002） and poorly differentiated HCC （4.7% vs 0%, P 〈 0.001） compared to the NASH-HCC group. A trend of poorer recurrence free survival at 5 years was seen in HCV-HCC patients compared to NASH-HCC who underwent a Liver trans- plantation （P = 0.11）. CONCLUSION： Patients transplanted for NASH-HCC appear to have less aggressive turnout features com- pared to those with HCV-HCC, which likely in part ac- counts for their improved recurrence free survival.

Effect of Sinai San decoction on the development of non-alcoholic steatohepatitis in rats

AIM: To explore the effect of Sinai san decoction on the development of non-alcoholic steatohepatitis induced by CCL4 combined with a fat-rich diet in rats.METHODS: Twenty-seven Sprague-Dawley rats were divided into three groups randomly: control group (n = 9),model group (n = 9) and treatment group (n = 9). The rats of model group and treatment group were given small dosage of CCL4 combined with a fat-rich diet, andthose of control group were given normal diet. After four weeks of fat-rich diet feeding, the rats of treatment group were given Sinai san decoction. The serum levels of aminotransferase and lipid were measured, and the pathology of livers was observed by HE staining after the rats were sacrificed at eight weeks.RESULTS: The rats' livers presented the pathology of steatosis and inflammation with higher serum levels of ALT and AST in the model group. In the treatment group the serum ALT and AST levels decreased significantly and were close to the control group. The hepatic inflammation scores also decreased markedly, but were still higher than those of control group. And the degree of hepatocyte steatosis was similar to that of model group.CONCLUSION: Sinai san decoction may ameliorate the hepatic inflammation of rats with steatohepatitis induced by small dosage of CCL4 combined with a fat-rich diet,but does not prevent the development of hepatocyte steatosis.

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.

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.

Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

Non-alcoholic fatty liver disease(NAFLD)is a major cause of liver disease around the world.It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis(NASH)and can lead to fibrosis,cirrhosis,liver failure,and/or hepatocellular carcinoma.NAFLD is also associated with other medical conditions such as obesity,diabetes mellitus(DM),metabolic syn-drome,hypertension,insulin resistance,hyperlipidemia,and cardiovascular disease(CVD).In diabetes,chronic hyperglycemia contributes to the development of both macro-and microvascular conditions through a variety of metabolic pathways.Thus,it can cause a variety of metabolic and hemodynamic conditions,including upregulated advanced glycation end-products(AGEs)synthesis.In our previous study,the most abundant type of toxic AGEs(TAGE);i.e.,glyceraldehyde-derived AGEs,were found to make a significant contribution to the pathogenesis of DM-induced angiopathy.Furthermore,accumulating evidence suggests that the binding of TAGE with their receptor(RAGE)induces oxidative damage,promotes inflammation,and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells.All of these effects could facilitate the pathogenesis of hypertension,cancer,diabetic vascular complications,CVD,dementia,and NASH.Thus,inhibiting TAGE synthesis,preventing TAGE from binding to RAGE,and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH.Here,we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.

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.