Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis

The global incidence of nonalcoholic fatty liver disease(NAFLD)is escalating considerably.NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis,which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix,leading to fibrosis.Hepatocyte ballooning is a key catalyst for fibrosis progression,potentially advancing to cirrhosis and its decompensated state.Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD;therefore,those with substantial fibrosis require timely intervention.Although liver biopsy is the most reliable method for fibrosis detection,it is associated with certain risks and limitations,particularly in routine screening.Consequently,various noninvasive diagnostic techniques have been introduced.This review examines the increasing prevalence of NAFLD,evaluates the noninvasive diagnostic techniques for fibrosis,and assesses their efficacy in staging the disease.In addition,it critically appraises current and emerging antifibrotic therapies,focusing on their mechanisms,efficacy,and potential in reversing fibrosis.This review underscores the urgent need for effective therapeutic strategies,given the dire consequences of advanced fibrosis.

Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma

Liver cancer is the sixth most commonly diagnosed cancer worldwide,with hepatocellular carcinoma(HCC)comprising most cases.Besides hepatitis B and C viral infections,heavy alcohol use,and nonalcoholic steatohepatitis(NASH)-associated advanced fibrosis/cirrhosis,several other risk factors for HCC have been identified(i.e.old age,obesity,insulin resistance,type 2 diabetes).These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection.HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease(NAFLD)patients,and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment.Patients with NASHcirrhosis should undergo systematic HCC surveillance,while this might be considered in patients with advanced fibrosis based on individual risk assessment.In this context,interventions that potentially prevent NAFLD/NASH-associated HCC are needed.This paper provided an overview of evidence related to lifestyle changes(i.e.weight loss,physical exercise,adherence to healthy dietary patterns,intake of certain dietary components,etc.)and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms.However,well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.

Research Progress of Noninvasive Diagnostic Methods for Nonalcoholic Steatohepatitis

Distinguishing between nonalcoholic steatohepatitis(NASH) and advanced liver fibrosis is the key for clinical diagnosis of non-alcoholic fatty liver disease(NAFLD). Liver biopsy, which is widely used for diagnosis of liver diseases at present, has many drawbacks, such as being invasive, expensive and unstable. This article compares and summarizes the commonly used non-invasive diagnostic methods, including their diagnostic parameters, advantages and disadvantages, in order to provide a useful reference for the diagnosis of NASH.

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.

Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis

AIM:To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis(NASH).METHODS:In total 26 patients,23 NASHs and 3 normal controls were enrolled in this study.NASH was staged based on Brunt criterion.At a region of interest(ROI),a shear wave was evoked by implementing an acoustic radiation force impulse(ARFI),and the propagation velocity was quantif ied.RESULTS:Shear wave velocity(SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases,in which a reliable SWV value was not calculated at several ROIs.An average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4,respectively,but was not significantly different from 1.79 ± 0.78 m/s in stage 2.When a cutoff value was set at 1.47 m/s,receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1(P=0.0092) with sensitivity,specificity and area under curve of 100%,75% and 94.2%,respectively.In addition,the correlation between SWV and hyaluronic acid was significant(P<0.0001),while a tendency toward negative correlation was observed with serum albumin(P=0.053).CONCLUSION:The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position,which has the potential to shed new light on NASH management.

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma(HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC(SH-HCC), showsfeatures that resemble non-neoplastic steatohepatitis,and is thought to be strongly associated with underlying NASH.In this report,we review the histopathological features of NAFLD/NASH.

Nonalcoholic steatohepatitis-associated hepatocellular carcinoma:Our case series and literature review

Recently,nonalcoholic steatohepatitis(NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma(HCC).The natural history and prognosis of NASH are controversial.Accordingly,we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC.We experienced 11 patients with NASH-associated HCC(6 male,5 female;mean age 73.8 ± 4.9 years) who received curative treatments.Most(91%) patients had been diagnosed with obesity,diabetes,hypertension,or dyslipidemia.Seven patients(64%) also had a non-cirrhotic liver.The recurrence-free survival rates at 1,3 and 5 years were 72%,60%,and 60%.We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature(64 male;mean age 66 years).The majority of patients(68%) were obese,66% of patients had diabetes,and 24% had dyslipidemia.Furthermore,26% of the HCCs arose from the non-cirrhotic liver.In conclusion,patients with non-cirrhotic NASH may be a high-risk group for HCC,and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.

Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model

AIM: To investigate Kupffer cell dynamics and phagocytic activity,using a rat nonalcoholic steatohepatitis (NASH) model. METHODS: Male F344 rats were fed either a control diet or a choline-deficient L-amino acid-defined (CDAA) diet,followed by contrast enhanced ultrasonography (CEUS) using Levovist. The uptake of latex beads by the Kupffer cells was determined by fluorescent microscopy. The status of the Kupffer cells was compared between the two groups,using the immunohistochemical staining technique. RESULTS: After 4 or more wk of the CDAA diet,CEUS examination revealed a decrease in the signal intensity,20 min after intravenous Levovist. Fluorescent microscopic examination showed that the uptake of latex beads by the Kupffer cells was reduced at week 1 and 2 in the study group,compared with the controls,with no further reduction after 3 wk. Immunohistochemical staining revealed no significant difference in the Kupffer cell counts between the control group and the CDAA group. CONCLUSION: CEUS examination using Levovist demonstrated reduced contrast effect and phagocytic activity in the liver parenchymal phase,although the Kupffer cell numbers were unchanged,indicating reduced phagocytic function of the Kupffer cells in the rat NASH model. We believe that CEUS examination using Levovist is a useful screening modality,which can detect NASH in fatty liver patients.

A rabbit model of pediatric nonalcoholic steatohepatitis: The role of adiponectin

AIM： To create a rabbit model of pediatric nonalcoholic steatohepatitis （NASH） and to evaluate the role of adiponectin in the process. METHODS： Thirty-two specific pathogen-free male New Zealand rabbits were divided randomly into three groups： （1） the normal control group （n = 10） was fed with standard diet for 12 wk; （2） the model group A （n = 11）; and （3） model group B （n = 11） were fed with a highfat diet （standard diet ＋ 10% lard ＋ 2% cholesterol） for 8 and 12 wk, respectively. Hepatic histological changes were observed and biochemical parameters as well as serum levels of adiponectin, interleukin （IL）-6, IL-10 and tumor necrosis factor （TNF）-α were measured. RESULTS： Typical histological hepatic lesions of NASH were observed in both model groups described as liver steatosis, liver inflammatory infiltration, cytologic ballooning, perisinusoidal fibrosis and overall fibrosis. Compared with the normal control group, there were significant increases in model groups A and B in weight gain （1097.2 ± 72.3, 1360.5± 107.6 vs 928.0 ±58.1, P 〈 0.05, P 〈 0.01）, liver weight （93.81±6.64, 104.6±4.42 vs 54.4±1.71, P 〈 0.01）, Lg （ALT） （1.9±0.29, 1.84± 0.28 vs 1.60±0.17, P 〈 0.01）, and Lg （TG） （1.03 ±0.24, 1.16 ±0.33 vs 0.00 ±0.16, P 〈 0.01）. Weight gain was much more in model group B than in model group A （1360.5± 107.6 vs 1097.2 ±72.3, P 〈 0.05）. But, there was no significant difference between the two groups concerning the other indexes. Pro-inflammatory cytokines （IL-6 and TNF-α） increased in model group B compared with that of control and model group A （IL-6：1.86±0.21 vs 1.41 ±0.33, 1.38± 0.42, P 〈 0.01; TNF-α： 1.18±0.07 vs 0.66 ±0.08, 0.86 ±0.43, P 〈 0.01, P 〈 0.05）, whereas serum adiponectin and IL-10 decreased in model groups compared with that in the control （adiponectin： A： 21.87±4.84 and B： 21.48 ±4.60 vs 27.36 ±7.29, P 〈 0.05. IL-10： A： 1.72± 0.38 and B： 1.83 ±0.39 vs 2.26±0.24, P 〈 0.01）. Lg （TC） and the degree of liver fatty infiltration was an independent determinant of serum adiponectin level analyzed by stepwise multiple regressions, resulting in 29.4% of variances. CONCLUSION： This rabbit model produces the key features of pediatric NASH and may provide a realistic model for future studies. Adiponectin level partially reflects the severity of liver steatosis, but not the degree of liver inflammation.

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.

Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

Betaine and nonalcoholic steatohepatitis: Back to the future?

Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries. Obesity and insulin resistance are the two most common risk factors for NASH, which can lead to recurrent NASH after liver transplantation. There is currently no approved therapy for NASH, and treatment is directed at risk factor modification and lifestyle changes. Betaine has been used for NASH, with mixed results, and may show promise in conjunction with other agents in clinical trials.

Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis

AIM: To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). METHODS: All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). RESULTS: At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). CONCLUSION: BMI helps identify children with NASH who might have fibrotic deposition in the liver.

Potential risk factors for nonalcoholic steatohepatitis related to pancreatic secretions following pancreaticoduodenectomy

AIM: To identify risk factors for nonalcoholic steatohepatitis following pancreaticoduodenectomy, with a focus on factors related to pancreatic secretions. METHODS: The medical records of 228 patients who had a pancreaticoduodenectomy over a 16-mo period were reviewed retrospectively. The 193 patients who did not have fatty liver disease preoperatively were included in the final analysis. Hepatic steatosis was diagnosed using the differences between splenic and hepatic attenuation and liver-to-spleen attenuation as measured by non-enhanced computed tomography. RESULTS: Fifteen patients (7.8%) who showed postoperative hepatic fatty changes were assigned to Group A, and the remaining patients were assigned to Group B. Patient demographics, preoperative laboratory findings (including levels of C-peptide, glucagon, insulin and glucose tolerance test results), operation types, and final pathological findings did not differ significantly between the two groups; however, the frequency of pancreatic fistula (P = 0.020) and the method of pancreatic duct stenting (P = 0.005) showed significant differences between the groups. A multivari- ate analysis identified pancreatic fistula (HR = 3.332, P = 0.037) and external pancreatic duct stenting (HR = 4.530, P = 0.017) as independent risk factors for the development of postoperative steatohepatitis. CONCLUSION: Pancreatic fistula and external pancreatic duct stenting were identified as independent risk factors for the development of steatohepatitis following pancreaticoduodenectomy.

Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression

AIM: To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats.METHODS: Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150-200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9th week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor-α (TNF-α) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-β1 (TGF-β1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined.RESULTS: Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-β1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-α compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-β1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-α were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content.CONCLUSION: When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.

Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138

AIM:To investigate the possible use of the multiple cytokine production modulator,Y-40138,as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS:We allocated 6-wk-old male F344 rats to choline-supplemented,L-amino acid-defined (CSAA) diet (control group),CSAA diet + Y-40138 (control + Y-40138 group),choline-def icient,L-amino acid-def ined (CDAA) diet (NASH group),or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group,we measured the plasma alanine aminotransferase (ALT) levels,and the plasma and liver levels of tumor necrosis factor-α (TNF-α),interferon-γ (IFN-γ),and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining,Azan staining,Sirius red staining,and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method,and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit.RESULTS:In comparison to the NASH group,serumALT elevation was mild,production of serum and liver TNF-α and IFN-γ was inhibited,and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups,whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group.CONCLUSION:Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator,Y-40138,is promising as a novel treatment for NASH.

Treating nonalcoholic steatohepatitis with antidiabetic drugs： Will GLP-1 agonists end the struggle？

Nonalcoholic fatty liver disease(NAFLD) is highly associated with insulin resistance(IR), type 2 diabetes mellitus and metabolic syndrome, being characterized as the hepatic component of metabolic syndrome. Despite its high prevalence, no pharmacological treatment has been established, as of yet. A growing body of evidence, however, shows that reducing IR can result in improvement of the biochemical and histological features of nonalcoholic steatohepatitis(NASH)-the aggressive form of NAFLD that can lead to cirrhosis and hepatocellular carcinoma. Unfortunately, the several trials that have assessed the effect of various antidiabetic agents to date have failed to establish an effective and safe treatment regimen for patients with NAFLD. Glucagon-like peptide-1(commonly known as GLP-1) agonists are a novel class of antidiabetic drugs that improve insulin sensitivity and promote weight loss. They also appear to have a direct effect on the lipid metabolism of hepatocytes, reducing hepatic steatosis. Several trials have demonstrated that GLP-1 agonists can reduce aminotransferase levels and improve liver histology in patients with NAFLD, suggesting that these agents could serve as an alternative treatment option for these patients. This manuscript discusses the role and potential mechanisms of GLP-1 agonists in the treatment of NASH.

Oral administration of a non-absorbable plant cellexpressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis

AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model.METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant antitumor necrosis factor alpha fusion protein(PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS.RESULTS The orally administered non-absorbable PRX-106 w a s b i o l o g i c a l l y a c t i v e. A l t e r e d d i s t r i b u t i o n o f CD4+CD25+Fox P3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+Fox P3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+Fox P3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice.CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.

Cisapride decreasing orocecal transit time in patients with nonalcoholic steatohepatitis

BACKGROUND : Altered small-intestine motility, lengthening of orocecal transit time (OCTT), and small-intestinal bacterial overgrowth (SIBO) have been detected in patients with nonalcoholic steatohepatitis (NASH). These changes might be related to the progressive course and poor prognosis of the disease. This study was undertaken to investigate the effect of 4-week treatment with cisapride on OCTT. METHODS: Ten NASH patients without diabetes were included. Ten healthy individuals served as controls. OCTT was measured by lactulose breath test (LBT). Anti- endotoxin core antibodies (EndoCAb) IgG were also examined. The effect of cisapride (10 mg TID during 4 weeks) on LBT and serum EndoCAb IgG levels in NASH patients was investigated. RESULTS: The NASH patients had more significantly prolonged OCTT (95±17 min) than the controls (59±18 min, P=0.00032). Cisapride administration decreased OCTT (from 95±17 min to 83±19 min, P=0.037), basal breathed H2 (from 9.87±1.60 ppm to 8.61±1.63 ppm, P=0.046) and EndoCAb IgG titers (from 5.24±0.68 GMU/ ml to 4.20±0.72 GMU/ml, P=0.013) in NASH patients. CONCLUSIONS: The present data suggest the existence of deranged intestinal motility and endotoxemia in NASH patients. Cisapride administration during 4 weeks possibly restore intestinal motility and ameliorate endotoxemia in NASH patients.