胆汁酸核受体FXR在非酒精性脂肪性肝病中的作用

背景:肝细胞内三酰甘油堆积和胰岛素抵抗是非酒精性脂肪性肝病(NAFLD)的基本特征,贯穿NAFLD的整个病程。胆汁酸对食物性脂类的吸收和胆同醇代谢具有重要调控作用,亦是平衡糖脂代谢的重要信号分子,其主要通过法尼酯衍生物X受体(FXR)发挥作用。目的:评估FXR激动剂GW 4064对肝细胞内脂质堆积和三酰甘油含量的潜在作用,同时探讨FXR在NAFLD患者肝组织中的表达情况。方法:以软脂酸和油酸(2:1)混合液处理人张氏肝细胞株,建立肝细胞脂肪变性模型,干预组予FXR激活剂GW 4064(10μmol/L)处理。以油红染色测定细胞内脂质含量,并检测三酰甘油含量。以免疫组化法检测正常对照组和NAFLD患者肝组织中的FXR表达情况。结果:FXR激活剂GW 4064可明显减少脂肪变肝细胞中脂滴和三酰甘油含量。FXR在NAFLD患者肝组织中的表达率显著低于正常对照组(P0.01)。结论:FXR激动剂GW 4064可有效缓解肝细胞的脂肪变程度;FXR在NAFLD患者中的表达受抑制。FXR改善NAFLD的分子机制值得进一步研究。     

Non-Invasive Histologic Markers of Liver Disease in Patients With Chronic Hepatitis B

Background:

An exact histologic staging of liver fibrosis is essential for identifying the best therapeutic strategy and determining the disease prognosis in patients with chronic hepatitis B (CHB). While liver biopsy has a vital role in the management of liver diseases, it also sustains some limitations hampering its widespread use.

Objectives:

In this study, we evaluated and compared several available indices of the severity of liver diseases in patients with hepatitis.

Patients and Methods:

Exclusion criteria were as follows: decompensated liver disease, alcoholic liver disease or alcohol intake of 40 g or more per week; co-infection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus.

Results:

Results showed that AST to platelet ratio index (APRI) (odds ratio = 2.35, P = 0.01) and age (odds ratio = 1.04, P = 0.007) were independently predictive of the presence of significant liver necrosis and inflammation. On the other hand, AARPRI (odds ratio = 3.8, P = 0.07), age (odds ratio = 1.04, P = 0.02), and ALT levels (odds ratio = 1.01, P = 0.007) were predictive of a significant liver fibrosis. Further analysis with receiver-operating curve showed that none of these predictors had a fair diagnostic value (area under the curve < 70).

Conclusions:

The APRI had the highest sensitivity and specificity (64% and 71%, respectively) for prediction of the presence of liver disease. We suggest that APRI may be applicable for the detection of a severe liver disease.     

Occult Hepatitis B Virus Infection in Patients With Chronic Hepatitis C Treated With Antiviral Therapy

Background

Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the liver and/or in the serum of patients with negative results of hepatitis B s antigen (HBsAg) test with or without serological markers of previous viral exposure. The impact of OBI in patients with chronic hepatitis C (CHC) is still unclear.

Objectives

The Aim of this study was to assess OBI prevalence and its potential implications on treatment outcome in a cohort of patients with CHC underwent standard antiviral therapy.

Patients and Methods

Baseline serum samples from 137 HBsAg-negative CHC patients treated with pegylated-interferon and ribavirin (73 Responders/74 Non Responders),were retrospectively analyzed for HBV status.

Results

Seventy-three patients (53.3%) showed markers of previous exposure to HBV. HBV DNA was detected in 2 of 137 serum samples (1.5%), both carrying HBV antibodies. Liver biopsies and post-therapy sera were available for 35 patients (12 Responders/23 Non Responders). HBV DNA sequences were found in 13 of 35 specimens (37.1%), all of patients with HBV DNA negativity in basal and post-therapy serum samples. Among OBI-positive patients, 5 (38.5%) carried serological markers of HBV infection. Regarding therapy outcome, in the OBI-positive group there were 5 of 13 (38.5%) sustained virological responders (SVR) compared to 7 of 22 (31.8%) in the OBI-negative one.

Conclusions

Despite the high prevalence rate of liver HBV DNA in patients with CHC, SVR was not affected by occult HBV infection.     

HBsAg阳性慢性肝病患者肝组织HBV DNA分子状态与血清HBV标志物关系的研究

采用分子杂交技术对28例慢性肝病患者进行肝组织和血清HBV对比研究,结果表明:①肝组织HBV DNA阳性率显著高于血清HBV DNA阳性率,②血清DNA-P反映乙肝病毒的早期复制;③血清HBeAg阴性、Anti-HBe阳性时肝组织内可发现游离型HBV DNA及小片段DNA,表明肝内HBV正处于活跃复制状态,从分子水平证实了Anti-HBe阳性时部分患者可有传染性,需积极有效治疗:④慢迁肝和慢活肝中发现整合型HBV DNA较少,提示慢活肝经治疗后有希望达到从肝内清除乙肝病毒的目的。另外,也提示乙肝病毒在肝内的复制状态与病理损伤无直接关系。     

Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B

Background and AimsThe impact of nonalcoholic fatty liver disease (NAFLD) on the treatment outcome of chronic hepatitis B (CHB) is undefined and deserves an in-depth investigation.MethodsHistologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD, and followed up at six monthly intervals. Therapeutic response related data were recorded and compared at multiple time points. Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response (CVR).ResultsWe enrolled 267 patients (CHB: 164; CHB with NAFLD: 103) with comparable follow-up durations. They were also comparable in baseline HBV DNA levels and HBeAg positivity. Patients with concomitant NAFLD showed less significant decline in HBV DNA, qHBsAg, pgRNA, and liver enzyme levels over time; moreover, their cumulative incidences of CVR were significantly lower and that of low-level viremia (LLV) were significantly higher at 6, 12, 18, 24 months. First CVR of CHB was delayed with the presence NAFLD (11.0 vs. 7.0 months, p<0.001) and further prolonged with higher grade of liver steatosis (Grade 2–3 vs. 1: 13.0 vs. 9.0 months). On multivariate analysis, HBeAg positivity (HR: 0.650, p=0.036), grade of steatosis (G2 [HR: 0.447, p=0.004]; G3 [HR: 0.085, p=0.002]) and HBV DNA (log10 IU/mL) (HR: 0.687, p<0.001) were significantly associated with delayed CVR, whereas grade of necroinflammation (HR: 1. 758, p<0.001) accelerated the CVR.ConclusionsIn CHB patients receiving initial antiviral therapy, NAFLD was associated with higher levels of HBV DNA, pgRNA, and liver enzymes, and higher incidence of LLV and delayed CVR.     

Impact of Nucleotide Mutations at the HNF3- and HNF4-Binding Sites in Enhancer 1 on Viral Replication in Patients with Chronic Hepatitis B Virus Infection

Background/Aims

The hepatitis B virus (HBV) genome contains binding sites for hepatocyte nuclear factors (HNF) 3 and 4 in the core domain of enhancer 1 (Enh1), and mutations in this domain have a strong impact on virus replication. We aimed to identify frequent base-mutation sites in the core domain of Enh1 and to examine the impact of these mutations on viral replication.

Methods

We studied virological characteristics and genetic sequences in 387 patients with chronic hepatitis B. We evaluated functional differences associated with specific mutations within the core domain of Enh1.

Results

Mutations in the core domain were found with significant frequency in C1126 (122/387 [31.5%], the binding site for HNF3) and in C1134 (106/387 [27.4%], the binding site for HNF4). A single mutation at nt 1126 (C1126) was identified in 17/123 (13.8%), and 105/123 (85.4%) had double mutations (C1126/1134). The level of HBV DNA (log10 copies/mL) was lower in single mutants (C1126, 5.81±1.25) than in wild (6.80±1.65) and double mutants (C1126/1134, 6.81±1.54). Similarly, the relative luciferase activity of C1126 and C1126/C1134 was 0.18 and 1.12 times that of the wild-type virus, respectively.

Conclusions

Mutations in the HNF3 binding site inhibit viral replication, whereas mutations at the HNF4 binding site restore viral replication.     

Expert Panel Review on Nonalcoholic Fatty Liver Disease in Persons With Human Immunodeficiency Virus

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Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

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Weight Change and the Development of Nonalcoholic Fatty Liver Disease in Metabolically Healthy Overweight Individuals

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Trends in Etiology-based Mortality From Chronic Liver Disease Before and During COVID-19 Pandemic in the United States

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