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.

Influence of nonalcoholic fatty liver disease on response to antiviral treatment in patients with chronic hepatitis B:A meta-analysis

BACKGROUND Although hepatitis B virus infection is the leading cause of chronic liver injury globally,nonalcoholic fatty liver disease(NAFLD)is gradually gaining attention as another major chronic liver disease.The number of patients having chronic hepatitis B(CHB)with concomitant hepatic steatosis has increased.AIM To analyze the effect of NAFLD on the response to antiviral treatment in patients with CHB.METHODS Relevant English studies were systematically searched across PubMed,EMBASE,Web of Science,and Cochrane Library until October 2023.Studies in which the treatment outcomes were compared between patients with CHB only and those with CHB and hepatic steatosis were included.RESULTS Of the 2502 retrieved studies,11 articles were finally included.Biochemical response until 48 wk(OR=0.87,95%CI:0.50–1.53,P=0.000)and 96 wk(OR=0.35,95%CI:0.24–0.53,P=0.24)and virological response until 96 wk(OR=0.80,95%CI:0.43–1.49,P=0.097)were lower in patients with hepatic steatosis than in patients with CHB alone.CONCLUSION Hepatic steatosis lowers the biochemical response to antiviral treatment in patients with CHB.

Prevalence of nonalcoholic fatty liver disease in patients with hepatitis B:A meta-analysis

BACKGROUND The prevalence of nonalcoholic fatty liver disease(NAFLD)in patients with chronic hepatitis B(CHB)has increased in recent clinical practice;however,the relationship between CHB and hepatic steatosis(HS)remains controversial.AIM To shed light on the potential association between NAFLD and hepatitis B virus(HBV)infection.METHODS We conducted a systematic literature search using multiple databases,including PubMed,the Cochrane Library,Web of Science,and EMBASE,to identify relevant studies.Predefined inclusion criteria were used to determine the eligibility of the studies for further analysis.RESULTS Comprehensive meta-analysis software was used for statistical analysis,which covered 20 studies.The results indicated a lower NAFLD susceptibility in HBVinfected individuals(pooled OR=0.87;95%CI=0.69-1.08;I2=91.1%),with diabetes(P=0.015),body mass index(BMI;P=0.010),and possibly age(P=0.061)as heterogeneity sources.Of note,in four studies(6197 HBV patients),HBV-infected individuals had a reduced NAFLD risk(OR=0.68,95%CI=0.51-0.89,P=0.006).A positive link between hyperlipidemia and metabolic syndrome emerged in hepatitis B patients,along with specific biochemical indicators,including BMI,creatinine,uric acid,fasting blood glucose,and homeostasis model assessment of insulin resistance.CONCLUSION HBV infection may provide protection against HS;however,the occurrence of HS in patients with HBV infection is associated with metabolic syndrome and specific biochemical parameters.

Influence of nonalcoholic fatty liver disease on the therapeutic effect of nucleoside(acid)analogs for hepatitis B virus

BACKGROUND The effect of nonalcoholic fatty liver disease(NAFLD)on the efficacy of nucleoside analogues(NAs)in antiviral therapy for patients with chronic hepatitis B(CHB)remains controversial.AIM To investigate the influence of NAFLD on virological response in CHB patients undergoing NAs treatment.METHODS Logistic regression analysis was conducted on a cohort of 465 CHB patients from two hospitals to determine whether NAFLD was a risk factor for adverse reactions to NAs.CHB patients were followed up for more than 28 months after initial antiviral treatment,and further validation was performed using different viral load populations.RESULTS NAFLD was identified as an independent risk factor for partial virological response following antiviral therapy with NAs(odds ratio=1.777,P=0.017).In our subsequent analysis focusing on CHB patients with high viral load,the NAFLD group exhibited significantly longer virus shedding time and lower proportion of the complete virological response compared with the non-NAFLD group(16.8±6.1 vs 13.0±6.8,P<0.05).During the 24-month period of antiviral treatment with NAs,hepatitis B virus(HBV)DNA levels decreased slowly in the NAFLD group,and the negative conversion rate of HBV was notably lower than that observed in non-NAFLD group(P=0.001).Similar results were obtained when analyzing patients with low baseline HBV viral load within the NAFLD group.CONCLUSION Coexistence of NAFLD may diminish virological response among CHB patients receiving antiviral treatment with NAs.

Disease-specific mi R-34a as diagnostic marker of nonalcoholic steatohepatitis in a Chinese population

AIM To assess disease-specific circulating micro RNAs(mi RNAs) in non-alcoholic steatohepatitis(NASH) patients.METHODS A total of 111 biopsy-proven non-alcoholic fatty liver disease(NAFLD) or chronic hepatitis B(CHB) patients and healthy controls from China's Mainland were enrolled to measure their serum levels of mi R-122,-125 b,-146 b,-16,-21,-192,-27 b and-34 a. The correlations between serum mi RNAs and histological features of NAFLD were determined. The diagnostic value of mi RNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18(CK-18), fibrosis-4(FIB-4), and aspartate aminotransferase to platelet ratio index(APRI), respectively.RESULTS Circulating mi R-122,-16,-192 and-34 a showed differential expression levels between NAFLD and CHB patients, and mi R-34 a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples(P < 0.01). Serum mi R-122,-192 and-34a levels were correlated with steatosis(R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity(R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum mi R-16 levels were associated with fibrosis(R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of mi R-34 a for NASH(area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but mi R-16 showed a limited performance in the diagnosis of significant fibrosis in NASH.CONCLUSION Circulating mi R-34 a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH.

Pathogenesis and research progress of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

In this editorial,we comment on the article by Mei et al.Nonalcoholic steatohep-atitis(NASH)is a severe inflammatory subtype of nonalcoholic fatty liver disease(NAFLD)with pathological features including steatosis,hepatocellular damage,and varying degrees of fibrosis.With the epidemic of metabolic diseases and obesity,the prevalence of NAFLD in China has increased,and it is now similar to that in developed countries;thus,NAFLD has become a major chronic liver disease in China.Human epidemiological data suggest that estrogen has a protective effect on NASH in premenopausal women and that sex hormones influence the development of liver disease.This review focuses on the path-ogenesis,treatment,and relationship between NASH and other diseases as well as on the relationship between NASH and sex hormone metabolism,with the aim of providing new strategies for the treatment of NASH.

Chronic hepatitis B, nonalcoholic steatohepatitis and physical fitness of military males: CHIEF study

AIM To investigate the association of chronic hepatitis B and nonalcoholic steatohepatitis with physical fitness in a Taiwan Residents military male cohort.METHODS We made a cross-sectional examination of this association using 3669 young adult military males according to cardiorespiratory fitness and hospitalization events recorded in the Taiwan Armed Forces study. Cases of chronic hepatitis B(n = 121) were defined by personal history and positive detection of hepatitis B surface antigen. Cases of nonalcoholic steatohepatitis(n = 129) were defined by alanine transaminase level > 60 U/L, liver ultrasound finding of steatosis, and absence of viral hepatitis A, B or C infection. All other study participants were defined as unaffected(n = 3419). Physical fitness was evaluated by performance in 3000-m run, 2-min sit-ups, and 2-min push-ups exercises, with all the procedures standardized by a computerized scoring system. Multiple linear regression analysis was used to determine the relationship.RESULTS Chronic hepatitis B negatively correlated with 2-min push-up numbers(β =-2.49, P = 0.019) after adjusting for age, service specialty, body mass index, systolic and diastolic blood pressures, current cigarette smoking, alcohol intake status, serum hemoglobin, and average weekly exercise times. Nonalcoholic steatohepatitis was borderline positively correlated with 3000-m running time(β = 11.96, P = 0.084) and negatively correlated with 2-min sit-up numbers(β =-1.47, P = 0.040). CONCLUSION Chronic hepatitis B viral infection and nonalcoholic steatohepatitis affects different physical performances in young adult military males, and future study should determine the underlying mechanism.

Γ-Aminobutyric acid promotes methionine-choline deficient diet-induced nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis（NASH） is one of the most common liver diseases and a major cause of liver fibrosis worldwide.r-Aminobutyric acid（GABA） is one of the most abundant inhibitory neurotransmitters in the central nervous system.Recently,it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role.In the present study,we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects.To test this hypothesis,C57BL/6 mice were fed a methionine-choline-deficient（MCD） diet for 8 weeks.After four weeks into MCD feeding,mice were provided with plain water（control） or water containing 2 mg/mL of GABA for the subsequent 4 weeks.Using this MCD diet-induced NASH model,we found that mice receiving GABA showed more severe steatohepatitis and liver fibrosis than control mice.This increased liver damage was confirmed by higher levels of serum alanine transaminase（ALT） and aspartate aminotransferase（AST） compared to the control group.In accordance with increased liver steatohepatitis,NASH-related and inflammatory gene expression（collagen al,tissue inhibitor of metalloproteinase-1,TNF-α） in the liver was markedly increased in GABA-treated mice.Furthermore,GABA directly enhanced production of inflammatory cytokines including IL-6 and TNF-α in LPS activated RAW macrophage cells and increased TIB-73 hepatocyte death.Such effects were abolished when GABA was treated with bicuculline,a competitive antagonist of GABA receptors.These results suggest that oral administration of GABA may be involved in changes of the liver immune milieu and conferred detrimental effects on NASH progression.

Baseline hepatocyte ballooning is a risk factor for adverse events in patients with chronic hepatitis B complicated with nonalcoholic fatty liver disease

BACKGROUND Although many studies have investigated the impact of chronic hepatitis B virus(HBV)infection and nonalcoholic fatty liver disease(NAFLD)on liver disease,few have investigated the relationship between nonalcoholic steatohepatitis(NASH)defined by liver pathology and the prognosis of chronic HBV infection.Most patients were followed up for a short time.This study aimed to further explore the impact of NAFLD and the pathological changes confirmed by liver pathology in patients with chronic HBV infection.AIM To study the effect of NAFLD confirmed using liver pathology on the outcomes of long-term serious adverse events[cirrhosis,hepatocellular carcinoma(HCC),and death]in patients with chronic hepatitis B(CHB)virus infection.METHODS We enrolled patients with chronic hepatitis B virus(HBV)infection who underwent liver biopsy at the Third People’s Hospital of Zhenjaing Affiliated Jiangsu University between January 2005 and September 2020.Baseline clinical and pathological data on liver pathology and clinical data at the end of follow-up were collected.Propensity score matching(PSM)was used to balance baseline parameters,Kaplan-Meier(K-M)survival analysis was used to evaluate the risk of clinical events,and Cox regression was used to analyze the risk factors of events.RESULTS Overall,456 patients with chronic HBV infection were included in the study,of whom 152(33.3%)had histologically confirmed NAFLD.The median follow-up time of the entire cohort was 70.5 mo.Thirty-four patients developed cirrhosis,which was diagnosed using ultrasound during the follow-up period.K-M survival analysis showed that NAFLD was not significantly associated with the risk of cirrhosis(log-rank test,P>0.05).Patients with CHB with fibrosis at baseline were more prone to cirrhosis(log-rank test,P=0.046).After PSM,multivariate analysis showed that diabetes mellitus,ballooning deformation(BD),and platelet(PLT)were independent risk factors for cirrhosis diagnosed using ultrasound(P<0.05).A total of 10 patients(2.2%)developed HCC,and six of these patients were in the combined NAFLD group.K-M survival analysis showed that the cumulative risk of HCC in the NAFLD group was significantly higher(log-rank test,P<0.05).Hepatocyte ballooning,and severe liver fibrosis were also associated with an increased risk of HCC(log-rank test,all P<0.05).Cox multivariate analysis revealed that hepatocyte ballooning,liver fibrosis,and diabetes mellitus were independent risk factors for HCC.CONCLUSION There was no significant correlation between chronic HBV infection and the risk of cirrhosis in patients with NAFLD.Diabetes mellitus,BD,and PLT were independent risk factors for liver cirrhosis.Patients with chronic HBV infection and NASH have an increased risk of HCC.BD,liver fibrosis,and diabetes mellitus are independent risk factors for HCC.

Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis?

The liver involvement in alcoholic liver disease(ALD) classically ranges from alcoholic steatosis, alcoholic hepatitis or steatohepatitis, alcoholic cirrhosis and even hepatocellular carcinoma. The more commonly seen histologic features include macrovesicular steatosis, neutrophilic lobular inflammation, ballooning degeneration, Mallory-Denk bodies, portal and pericellular fibrosis. Nonalcoholic steatohepatitis(NASH) is a condition with similar histology in the absence of a history of alcohol intake. Although the distinction is essentially based on presence or absence of a history of significant alcohol intake, certain histologic features favour one or the other diagnosis. This review aims at describing the histologic spectrum of alcoholic liver disease and at highlighting the histologic differences between ALD and NASH.

Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B

AIM:To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B(CHB) and nonalcoholic fatty liver disease(NAFLD).METHODS:A cohort of Han patients with biopsyproven CHB,with or without NAFLD(CHB group,n = 51;CHB + NAFLD group,n = 57),and normal controls(normal group,n = 47) were recruited from Northern(Tianjin),Central(Shanghai),and Southern(Zhangzhou) China.Their PNPLA3 polymorphisms were genotyped by gene sequencing.The association between PNPLA3 polymorphisms and susceptibility to NAFLD,and clinical characteristics of NAFLD were evaluated on the basis of physical indices,liver function tests,glycolipid metabolism,and histopathologic scoring.The association of PNPLA3 polymorphisms and hepatitis B virus(HBV) load was determined by the serum level of HBV DNA.RESULTS:After adjusting for age,sex,and body mass index,we found that four linked single nucleotide polymorphisms(SNPs) of PNPLA3,including the rs738409 G allele(CHB + NAFLD group vs CHB group:odds ratio[OR]= 2.77,95%confidence interval[CI]:1.18-6.54;P = 0.02),rs3747206 T allele(CHB+ NAFLD group vs CHB group:OR = 2.77,95%CI:1.18-6.54;P = 0.02),rs4823173 A allele(CHB +NAFLD group vs CHB group:OR = 2.73,95%CI:1.16-6.44;P= 0.02),and rs2072906 G allele(CHB+ NAFLD group vs CHB group:OR = 3.05,95%CI:1.28-7.26;P = 0.01),conferred high risk to NAFLD in CHB patients.In patients with both CHB and NAFLD,these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis(NASH)(NAFLD activity score ≥3;P =0.01-0.03) and liver fibrosis(>1 Metavir grading;P =0.01-0.04).As compared to those with C/C and C/G at rs738409,C/C and C/T at rs3747206,G/G and G/A at rs4823173,and A/A and A/G at rs2072906,patients in the CHB + NAFLD group with G/G at rs738409,T/T at rs3747206,A/A at rs4823173,and G/G at rs2072906 showed significantly lower serum levels of HBV DNA(P< 0.01-0.05).CONCLUSION:Four linked SNPs of PNPLA3(rs738409,rs3747206,rs4823173,and rs2072906) are correlated with susceptibility to NAFLD,NASH,liver fibrosis,and HBV dynamics in CHB patients.

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.

Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis(NASH) development in mice fed a methionine-choline-deficient(MCD) diet. METHODS Twenty-four male C57 BL/6 J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk(Control 2 w group,n = 6) or 4 wk(Control 4 w group,n = 6) or the MCD diet for 2 wk(MCD 2 w group,n = 6) or 4 wk(MCD 4 w group,n = 6). Liver injury,fibrosis,and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16 s r RNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet,however,the mice developed prominent NASH with liver fibrosis,and the intestinal barrier was more impaired. Compared with the control diet,the MCD diet induced gradual gut microbiota dysbiosis,as evidenced by a marked decrease in the abundance of Alistipes and the(Eubacterium) coprostanoligenes group(P < 0.001 and P < 0.05,respectively) and a significant increase in Ruminococcaceae UCG 014 abundance(P < 0.05) after 2 wk. At 4 wk,the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance(P < 0.05,and P < 0.01,respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk,arachidic acid,hexadecane,palmitic acid,and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group,and at 4 wk,cholic acid,cholesterol,arachidic acid,tetracosane,and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome.

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.

Effects of salvianolic acid B on liver mitochondria of rats with nonalcoholic steatohepatitis

AIM: To investigate the effects of salvianolic acid B(Sal B) on the morphological characteristics and functions of liver mitochondria of rats with nonalcoholic steatohepatitis(NASH).METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into three groups:(1) a normal group fed a normal diet;(2) an NASH model group; and(3) a Sal B-treated group fed a high-fat diet. Two rats from each group were executed at the end of the 12 th week to detect pathological changes. The rats in the Sal B-treated group were gavaged with 20 m L/kg Sal B(1 mg/m L) daily. The model group received an equal volume of distilled water as a control. At the end of the 24 th weekend, the remaining rats were executed. Serum biochemical parameters and liver histological characteristics were observed. Malondialdehyde(MDA) and superoxide dismutase(SOD) in the liver were determined. Protein expression of Cyt C and caspase-3 was determined by immunohistochemistry. The m RNA transcripts of mitofusin-2(Mfn2) and NF-κB in the liver tissue were detected by real-time PCR. Mitochondrial membrane potential was detected using a fluorescence spectrophotometer. Mitochondrial respiratory function was detected using a Clark oxygen electrode.RESULTS: The model group showed significantly higher ALT, AST, TG, TC and MDA but significantly lower SOD than the normal group. In the model group,the histological characteristics of inflammation and steatosis were also evident; mitochondrial swelling and crest were shortened or even disappeared. Cyt C(18.46 ± 1.21 vs 60.01 ± 3.43, P < 0.01) and caspase-3 protein expression(30.26 ± 2.56 vs 83.31 ± 5.12, P < 0.01) increased significantly. The m RNA expression of NF-κB increased(0.81 ± 0.02 vs 0.91 ± 0.03, P < 0.05), whereas the m RNA expression of Mfn2 decreased(1.65 ± 0.31 vs 0.83 ± 0.16, P < 0.05). Mitochondrial membrane potential also decreased and breathing of rats was weakened. Steatosis and inflammation degrees in the treatment group were significantly alleviated compared with those of the model group. In the treatment group, mitochondrial swelling was alleviated. Cyt C(60.01 ± 3.43 vs 30.52 ± 2.01, P < 0.01) and caspase-3 protein expression(83.31 ± 5.12 vs 40.15 ± 3.26, P < 0.01) significantly decreased. The m RNA expression of NF-κB also decreased(0.91 ± 0.03 vs 0.74 ± 0.02, P < 0.01), whereas the m RNA expression of Mfn2 increased(0.83 ± 0.16 vs 1.35 ± 0.23, P < 0.01). Mitochondrial membrane potential increased and respiratory function was enhanced. CONCLUSION: Sal B can treat NASH by protecting the morphological characteristics and functions of liver mitochondria, regulating lipid metabolism, controlling oxidative stress and lipid peroxidation and inhibiting apoptosis.

Liver fibrosis markers of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD) is one of themajor causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis(NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury(e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albuminto-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including 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.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.

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.

Nonalcoholic steatohepatitis in nonalcoholic fatty liver disease patients of Bangladesh

AIM: To explore the prevalence and risk factors for nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD) patients. METHODS: We have included 493 patients with sonographic evidence of a fatty change, and 177 of these individuals were evaluated and confirmed after liver biopsy. The exclusion criteria consisted of significant alcohol abuse (【 20 g daily), evidence of hepatitis B and C, evidence of drug-induced fatty liver disease and other specific liver diseases such as hemochromatosis, Wilson’s disease or autoimmune liver disease. The patients were assessed for metabolic syndrome, and biochemical, anthropometric and histopathological evaluations were carried out. The degree of disease activity in the NAFLD patients was evaluated using the NAFLD Activity Score. The data were analyzed by SPSS, version 16.0. RESULTS: Females predominated among the study participants (250, 57.0%), and the mean age was 40.8 ± 10.2 years. The numbers of overweight, obeseⅠ and obese Ⅱ patients were 58 (13.2%), 237 (53.9%) and 93 (21.2%), respectively. However, there were 422 (96.2%) centrally obese patients. NASH was absent in 10 (5.6%) cases, borderline in 92 (52.6%) cases and present in 75 (42.4%) cases. The presence of diabetes could significantly (P = 0.001) differentiate NASH from simple steatosis. The following parameters did not influence the development of NASH: age, sex, basal metabolic index, waist circumference, serum high-density lipoprotein, triglyceride, insulin resistance index, hypertension and metabolic syndrome. The serum gammaglutamyl transpeptidase (GGT) level was significantly higher (P = 0.05, 51.7 ± 32.8 and 40.4 ± 22.6 U/L) in the NASH patients, with a sensitivity of 45% and a specificity of only 68%. The serum alanine aminotransferase and aspartate aminotransferase levels were not able to predict NASH. CONCLUSION: Females were the predominant sufferers of NAFLD in Bangladesh. The prevalence of NASH was high. Diabetes was found to be the main culprit in developing NASH. GGT was the only biochemical marker of NASH. We recommend liver biopsy in NAFLD patients who have diabetes and elevated GGT.