HBV突变与HBV相关慢加急性肝衰竭相关性研究

目的探讨HBV突变与慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)之间的相关性。方法以87例HBV相关ACLF患者为研究对象,另选取52例慢性乙型肝炎(chronic hepatitis B,CHB)患者和51例HBV肝硬化(liver cirrhosis,LC)患者为对照,应用聚合酶链反应及基因测序对患者血清标本进行HBV基本核心启动子区、前C区和C区13个位点的突变检测,分析HBV突变与ACLF发生的相关性。结果 CHB、LC、ACLF组人均核苷酸变异检出位点分别为2.31、3.55和3.86个。nt1762、nt1846、nt1899和nt1913 4个突变位点的核苷酸突变率比较,ACLF组高于CHB组;nt1764位点突变率组间比较LC组高于ACLF组,而nt1846和nt1913位点突变率比较LC组低于ACLF组;nt1753、nt1762、nt1764和nt1899 4个突变位点的核苷酸突变率比较,LC组高于CHB组。多因素分析提示A1846T和C1913(A/G)核苷酸突变是预测ACLF的有效指标。结论 CHB或LC患者HBV基因序列的A1846T和C1913(A/G)核苷酸突变可能与其发生ACLF密切相关。     

乙型肝炎相关慢加急性肝衰竭患者乙型肝炎病毒前C/C区联合突变特点分析

目的分析乙型肝炎相关慢加急性肝衰竭（HBV-ACLF）患者HBV前C/C区联合突变的特征。方法入选166名慢性HBV感染者,其中ACLF 49人,慢性乙型肝炎（CHB）45人,肝硬化（LC）45人,肝细胞癌（HCC）27人,对HBV前C/C区片段进行PCR扩增,分析突变数量及联合突变状况。结果 ACLF患者多联突变比例明显高于其他组患者。4组之中,ACLF组5联突变和7联突变者比例最高,分别是20.4%（10/49）和12.2%（6/49）,6联突变者与HCC组相近分别为14.3%（7/49）和14.8%（4/27）,明显高于CHB和LC组。联合突变组合形式的分析结果提示,ACLF组患者,含nt1846和nt1913突变的联合突变组合阳性率在4组患者中最高。结论 ACLF患者HBV前C/C区多联突变比例高于其他慢性HBV感染者;以nt1846和nt1913为基础的联合突变率最高。     

Correlation Between Patatin-Like Phospholipase Domain-Containing Protein 3 Gene Polymorphisms and Liver Cirrhosis in a Chinese Han Population With Chronic Hepatitis B

Background:

A single nucleotide polymorphism (SNP) of patatin-like phospholipase domain-containing 3 (PNPLA3) genes (rs738409) is associated with the severity of fibrosis and cirrhosis in patients with fatty liver disease. However, in a small group of Italian patients, there was no significant correlation between the rs738409 SNP and hepatitis B virus (HBV) infection-associated liver cirrhosis.

Objectives:

This study aimed to investigate whether PNPLA3 polymorphisms are a risk factor for liver cirrhosis in a Chinese Han population with chronic hepatitis B (CHB).

Patients and Methods:

The study population consisted of 344 Chinese Han patients with CHB, among which 203 presented with liver cirrhosis (LC group) and 141 had no sign of liver cirrhosis (CHB group). TaqMan genotyping assay was used to investigate the association of two PNPLA3 SNPs (rs738409 and rs2281135) with the risk of liver cirrhosis.

Results:

The allele and genotype distributions of PNPLA3 rs738409 and rs2281135 were not significantly different between the CHB and LC groups. After segregation on the basis of sex, no significant correlation between PNPLA3 (rs738409 and rs2281135) genotypes/alleles and liver cirrhosis was detected. Moreover, none of the haplotypes in PNPLA3 (rs738409 and rs2281135) was found to be statistically different between the two groups.

Conclusions:

Our results showed no association between PNPLA3 polymorphisms (rs738409 and rs2281135) and the susceptibility to HBV-related liver cirrhosis in a Chinese Han population.     

G1896A Precore Mutation and Association With HBeAg Status,Genotype and Clinical Status in Patients With Chronic Hepatitis B

Background:

Precore stop codon (G1896A) mutation is one of the commonest mutations found in patients with chronic hepatitis B. However, over the years, this mutation was not reported much in Malaysia.

Objectives:

We therefore investigated the presence of G1896A mutation in Malaysian population and its association with HBeAg status, clinical stage, hepatitis B virus (HBV) genotype and e-seroconversion rate.

Patients and Methods:

Serum samples from 93 patients confirmed as hepatitis B carriers were collected for molecular assay. The whole genome of HBV was amplified by polymerase chain reaction and directly sequenced. The precore and basal core promoter regions were analyzed for presence of mutations.

Results:

The most commonly observed mutation in the precore region was C1858T with 64.5% prevalence. The precore mutation of interest (G1896A) was identified in 25.8% of isolates. The basal core promoter mutations detected were A1762T-G1764A (26.9%), C1653T (8.6%), A1752G (10.8%) and C1766T (2.2%). No significant association was observed between G1896A mutation and HBeAg-negativity. Nonetheless, G1896A was highly prevalent among HBV genotype B. Clinical association revealed that subjects with G1896A mutations were mainly detected in asymptomatic chronic hepatitis B (58.3%) and liver cirrhosis (41.7%). One subject was diagnosed with fulminant hepatitis (4.2%) and 8.3% had hepatocellular carcinoma (HCC).

Conclusions:

Our data suggested an intermediate prevalence of G1896A mutation among Malaysian hepatitis B carriers. The stop codon mutation has a significant association with genotype B and patients with chronic hepatitis B and liver cirrhosis.     

HLA-DPB1 Variant Effect on Hepatitis B Virus Clearance and Liver Cirrhosis Development Among Southwest Chinese Population

Background:

Previous studies have shown that genetic variants in HLA-DP genes affect disease progression in hepatitis B virus (HBV) infection.

Objectives:

We aimed to evaluate possible association between HLA-DPB1 rs9277534 polymorphism and different clinical complications of hepatitis B virus (HBV) infection.

Materials and Methods:

Snapshot assay was used to investigate the association of rs9277534 polymorphism in 342 patients with persistent HBV infection and 342 age and gender-matched HBV spontaneous clearance controls. Patients were categorized into asymptomatic HBV carriers (AsC, n = 104), chronic hepatitis B (CHB, n = 116), and liver cirrhosis (LC, n = 122) subgroups.

Results:

There was a significantly higher proportion of the rs9277534 minor allele A in HBV spontaneous clearance control than that in HBV persistent infection group (OR = 0.58, 95%CI = 0.46-0.73, P < 0.0001). Genotypic analysis showed that GA and AA genotypes were associated with HBV spontaneous clearance (GA: OR = 0.56, 95%CI = 0.40-0.79, P = 0.019; AA: OR = 0.24, 95%CI = 0.14-0.44, P < 0.0001). A significant difference was found between AsC and LC groups in the distribution of AA genotype (OR = 9.32, 95%CI = 1.293-67.14, P = 0.027).

Conclusions:

Variant at rs9277534 could affect both the spontaneous clearance of HBV infection and progression from asymptomatic HBV carriers to HBV-related liver cirrhosis in Southwest Han Chinese population.     

The Expression of Programmed Death-1 in Circulating CD4+ and CD8+ T Cells during Hepatitis B Virus Infection Progression and Its Correlation with Clinical Baseline Characteristics

Background/Aims

Programmed death-1 (PD-1) expression was investigated in CD4⁺ and CD8⁺ T cells from hepatitis B virus (HBV)-infected patients at the chronic hepatitis B (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) stages.

Methods

PD-1 expression in circulating CD4⁺ and CD8⁺ T cells was detected by flow cytometry. The correlations between PD-1 expression and HBV viral load, alanine aminotransaminase (ALT) levels and aspartate aminotransferase (AST) levels were analyzed using GraphPad Prism 5.0.

Results

PD-1 expression in CD4⁺ and CD8⁺ T cells was significantly increased in both the CHB group and advanced-stage group (LC plus HCC). In the CHB group, PD-1 expression in both CD4⁺ and CD8⁺ T cells was positively correlated with the HBV viral load, ALT, and AST levels. However, in the LC plus HCC group, significant correlations between PD-1 expression and the clinical parameters were nearly absent.

Conclusions

PD-1 expression in peripheral CD4⁺ and CD8⁺ T cells is dynamic, changes with HBV infection progression, and is related to HBV viral load and liver function, especially in CHB. PD-1 expression could be utilized as a potential clinical indicator to determine the extent of virus replication and liver injury.     

Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: a multicenter cross-sectional study in China

Background and aim

In China, acute-on-chronic liver failure (ACLF) is mostly caused by hepatitis B virus (HBV). However, the mechanism remains unclear. This study aims to investigate the association between both HBV genotype and mutations in basal core promoter (BCP) and pre-core/core (pre-C/C) regions with the development of HB-ACLF.

Methods

A multicenter cross-sectional study was performed in China. Serum samples from 522 patients were analyzed, including 231 patients with mild-chronic hepatitis B (CHB-M), 84 with severe-chronic hepatitis B (CHB-S) and 207 with HB-ACLF. HBV genotype and related mutations in the BCP and pre-C/C regions were determined by direct sequencing.

Results

A significantly higher ratio of HBV genotype B to C was detected in HB-ACLF patients than in CHB-M or CHB-S patients. The A1762T/G1764A, A1846T and G1896A mutations were significantly more common in HB-ACLF patients infected with either genotype B or C as compared with CHB-M, whereas the C1913A/G and A2159G mutations were more associated with HB-ACLF in genotype C patients. Comparing with CHB-S, the A1762T/G1764A mutation in genotype B and the A2159G mutation in genotype C were significantly more common in HB-ACLF patients. A multivariate analysis showed that factors such as HBV genotype B, age ≥40 years and A1762T/G1764A, A1846T and G1896A mutations were independently associated with the development of HB-ACLF.

Conclusion

Chronic HBV infection with genotype B, A1762T/G1764A, A1846T and G1896A mutations has a higher possibility to develop HB-ACLF. These virological factors could serve as possible molecular markers for prediction of the clinical outcomes of chronic HBV infection.     

Association between hepatitis B virus basal core promoter/precore region mutations and the risk of hepatitis B-related acute-on-chronic liver failure in the Chinese population: an updated meta-analysis

Background

The relationship between hepatitis B virus (HBV) mutations in basal core promoter (BCP) and precore (PC) regions and the risk of hepatitis B-related acute-on-chronic liver failure (HB-ACLF) remains uncertain.

Methods

Databases were searched for papers that were published in English or Chinese until April 31, 2015. The odds ratios (ORs) of HBV mutation were pooled by using a fixed or random-effects model according to heterogeneity.

Results

Data for 13 studies with a total of 1,149 HB-ACLF and 1,867 chronic hepatitis B (CHB) cases were retrieved. Statistically significant summary ORs for HB-ACLF were obtained for T1753V (1.99; 95 % confidence interval 1.30–3.02) and A1762T/G1764A (2.11; 95 %, 1.75–2.54) in the BCP region and for A1846T (3.33; 95 %, 2.23–4.97), G1896A (2.78; 95 %, 2.07–3.74), and G1899A (3.09; 95 %, 1.82–5.25) in the PC region. In subgroup analysis, BCP mutations were found to have higher ORs in age-matched studies, but PC mutations were found to have higher ORs in age-unmatched studies; patients with the mutations in HBV genotype C were more susceptible to HB-ACLF; patients with pre-existing liver cirrhosis had a higher risk of HB-ACLF occurrence. In sensitivity, specificity, and accuracy analysis, A1762T/G1764A had the highest sensitivity (67.43 %); A1762T/G1764A + G1896A triple mutations had the highest specificity (93.70 %); and T1753V + A1762T + G1764A mutation had the highest accuracy (65.42 %).

Conclusions

HBV T1753V, A1762T/G1764A, A1846T, G1896A, and G1899A mutations are correlated with an increase in the risk of HB-ACLF. These mutations alone and in combination may be predictive of the susceptibility of patients with CHB to developing HB-ACLF.

     

Clinical and virological implications of A1846T and C1913A/G mutations of hepatitis B virus genome in severe liver diseases

Objective: Mutations occurring within different genes of hepatitis B virus (HBV) genome may have different clinical implications. This study aimed to observe the clinical and virological implications of the A1846T and C1913A/G mutations of HBV genome in the development and treatment outcome of severe liver diseases, which has not been previously determined.

Materials and methods: A total of 438 cases of patients with liver diseases were retrospectively reviewed, including 146 with mild chronic hepatitis B infection (CHB-M), 146 with severe chronic hepatitis B infection (CHB-S), and 146 with acute-on-chronic liver failure (ACLF). Partial or full-length HBV genome was directly sequenced. Replicons containing A1846T, C1913A or other mutant sequences, or the wild-type counterparts were constructed respectively, and then transfected into HepG2 cells for phenotype analysis.

Results: There was significant difference in the detection rates of A1846T (30.82%, 40.41% and 55.48%, respectively) and C1913A/G (15.52%, 28.77%, and 35.62%, respectively) among patients with CHB-M, those with CHB-S, and those with ACLF (p?p?=?.041). In vitro experiment revealed that A1846T mutant resulted in 3.20-fold and 1.85-fold increase of replication capacity and promoter activity, respectively compared with wild type counterpart (p?p?Conclusion: Occurrence of A1846T and C1913A is positively associated with clinical presentations of severe liver disease. A1846T mutation is significantly associated with poor prognosis of ACLF.     

The Effect of HBV Genotype C on the Development of HCC Differs Between Wild-Type Viruses and Those With BCP Double Mutations (T1762A1764)

Background:

Association of hepatitis B virus (HBV) genotype C with hepatocellular carcinoma (HCC) development remains controversial. HBV basal core promoter (BCP) double mutations (T¹⁷⁶²A¹⁷⁶⁴) are very strong confounding factors of genotypes B and C in HCC development.

Objectives:

To investigate the association of HBV genotype C with HCC development after controlling for BCP double mutations.

Materials and methods:

Four hundred and two serum samples from patients with HCC, liver cirrhosis (LC) and chronic hepatitis (CH) and also from asymptomatic HBsAg carriers were analyzed.

Results:

Genotypes B (31.1%), C (62.8%), and I (6.1%) were detected. With the severity of liver disease the prevalence of genotype B decreased, but genotype C increased. No trend was found for genotype I. The prevalence of BCP double mutations in genotypes C and I viruses was significantly higher than genotype B. BCP double mutations are risk factors for CH, LC and HCC. Genotype C was not identified as a particular risk factor for HCC prior to the stratification analysis but after that genotype C viruses with BCP double mutations were found to be a particular risk factor for HCC (P = 0.008, OR = 17.19 [95% CI: 2.10 - 140.41]), but those with the wild-type BCP were not. In the interaction analysis, genotype C and BCP double mutations were found to have a synergistic effect on HCC development (P < 0.0001, OR = 52.56 [95% CI: 11.49-240.52]).

Conclusions:

The effect of HBV genotype C on the development of HCC differs between wild-type viruses and those with BCP double mutations, suggesting that not all individuals infected with genotype C HBV are at increased risk of HCC.     

Hepatitis B learning needs assessment of family medicine trainees in Canada: results of a nationwide survey

BACKGROUND:

An estimated 350 million people worldwide have chronic hepatitis B (CHB), which is a major cause of cirrhosis and hepatocellular carcinoma.

OBJECTIVE:

To assess the level of knowledge among family medicine trainees regarding the identification and management of CHB.

METHODS:

A questionnaire to assess knowledge regarding screening and management of patients with CHB and cirrhosis was developed. The questionnaire was pilot tested among primary care physicians, subsequently revised and distributed to family medicine trainees across Canada through an online survey program (QuestionPro).

RESULTS:

A total of 158 trainees completed the questionnaire. Of these, 54% to 56% routinely offered vaccination against hepatitis A or hepatitis B virus (HBV), and 42% regularly screened patients for HBV risk factors. The percentage who recognized the need to screen high-risk populations for CHB, ie, individuals from an HBV-endemic country, men who have sex with men, or intravenous drug users was 73%, 66% and 74%, respectively. While less than 50% of respondents used the appropriate HBV screening tests, 86% to 91% correctly interpreted various HBV serological patterns. Only 3% recognized cirrhosis in our case scenario. Almost 80% of respondents inappropriately preferred prescribing a narcotic or nonsteroidal anti-inflammatory drug over acetaminophen (4%) for pain control in a patient with cirrhosis. While less than 60% recognized HBeAg negative CHB as an indication for referral and treatment, 90% would have referred a patient in the immune-tolerant phase, even though treatment is not indicated.

CONCLUSIONS:

Knowledge gaps regarding CHB among family medicine trainees in the areas of primary prevention, disease recognition and management of cirrhosis were identified. Results suggest that opportunities to prevent potentially life-threatening complications are being missed.     

Relationship Between HBV Genotypes B,C and Follicular Helper T Cells in Patients with Chronic Hepatitis B and its Significance

Background

Clinical observations have shown that patients infected with chronic hepatitis B virus (HBV) genotype C versus genotype B had a higher load of the virus, more serious illness, and poorer responses to antiviral therapy and prognosis. However, the disparity between the two has not been clarified.

Objectives

To explore possible relationship between HBV genotypes B and C and peripheral blood follicular helper T cells (Tfh) and its significance in treating chronic hepatitis B (CHB) patients.

Patients and Methods

One hundred and fifty CHB patients were enrolled into this study, including 70 cases infected with HBV genotype C and 79 cases with genotype B. One patient had suffered from both genotypes B and C. The levels of Tfh, also known as interleukin-21 (IL-21), HBV specific cytotoxic T lymphocytes (CTL), HBV DNA and alanine transaminase (ALT) were evaluated and compared in patients infected with genotype B and C.

Results

Levels of Tfh, IL-21 and HBV specific CTL of patients infected with HBV genotype C were significantly lower than those of patients infected with HBV genotype B, P < 0.01. Levels of HBV DNA and ALT of patients infected with genotype C were significantly higher than those of the patients infected with HBV genotype B, P < 0.01.

Conclusions

Compared with chronic hepatitis B (CHB) patients infected with genotype B, higher levels of serum HBV DNA, ALT and TBil of patients infected with HBV genotype C may be related to their lower level of peripheral blood Tfh, which may result in lower IL-21, and it may result in lower HBV specific CTL.     

Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B‐related acute‐on‐chronic liver failure without pre‐existing liver cirrhosis

Summary. The study was undertaken to investigate the features and clinical implications of hepatitis B virus (HBV) genotypes, basal core promoter (BCP) and precore (PC) mutations in hepatitis B‐related acute‐on‐chronic liver failure (HB‐ACLF). Samples from 75 patients with HB‐ACLF and without pre‐existing liver cirrhosis and 328 age‐matched patients with chronic hepatitis B (CHB) were analyzed. HBV genotype and BCP/PC mutations were determined by direct sequencing. Mutations at 8 sites of the BCP/PC region were compared between the two groups of patients. A significantly higher ratio of genotype B to C was found in patients with HB‐ACLF than in patients with CHB (30.7–69.3%vs16.5–82.6%, P < 0.01). Single mutations including T1753V (C/A/G), A1762T, G1764A, G1896A and G1899A and triple mutations T1753V/A1762T/G1764A and A1762T/G1764A/C1766T (or T1768A) were more frequently detected in patients with HB‐ACLF than in patients with CHB. Correspondingly, BCP/PC wild‐type sequences were absent in patients with HB‐ACLF in contrast to 27.1% in patients with CHB. The BCP/PC mutations were found to be associated with increased HBeAg negativity, higher alanine aminotransferase level and lower viral load. Patients with HB‐ACLF infected with the PC mutant virus had a higher mortality. The findings suggest that patients with CHB infected with genotype B with BCP/PC mutations were more likely to develop HB‐ACLF than those with genotype C with wild‐type BCP/PC regions, and patients with HB‐ACLF with the PC mutation had increased risk of a fatal outcome.     

Prevalence of Hepatitis D Virus Infection Among Patients With Chronic Hepatitis B Attending Birjand Hepatitis Clinic (East of Iran) in 2012

Background

Hepatitis delta virus (HDV) is a defective RNA virus dependent on Hepatitis B virus (HBV) infection for its replication and expression. All patients with HBV infection should be tested for the presence of HDV infection. It is estimated that approximately 5% of hepatitis B surface antigen (HbsAg) carriers in the world are HDV infected patients. HBV-HDV co-infection may lead to more severe acute disease and higher risks of fulminant hepatitis, cirrhosis, and hepatocellular carcinoma than those having HBV infection alone. Also, HBV infected patients with HDV super-infection have a higher rate of progression to chronic disease and serious complications.

Objectives

Our aim was to determine the prevalence of HDV infection among chronic hepatitis B (CHB) patients attending Birjand Hepatitis Clinic, East of Iran.

Materials and Methods

A cross-sectional analytical study was conducted on 413 CHB patients in 2012. Serology test for anti-HDV was measured by ELISA in these patients. CHB patients had positive hepatitis B surface antigen for at least 6 months before the study entrance.

Results

The mean age of CHB patients was 38.5± 11.9 years and 55.9% of them (231 patients) were male. There were 13 cases (3.1%) with HDV infection. There was no association between positive anti-HDV serology and factors such as age, gender, carrier state, liver enzymes, and positive hepatitis B e antigen (HBeAg) serology.

Conclusions

Although HDV had a low prevalence in our area, it is important for healthcare providers and policy makers to plan preventive strategies for HDV spread as well as HBV prevention programs among high risk population.     

Adiponectin and Its Receptors in Chronic Hepatitis B Patients With Steatosis in China

Background

HBV infection is a serious public health problem worldwide, which can contribute to the incidence of chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC).

Objectives

In the present report, we assessed the association between adiponectin, its receptors and hepatic steatosis, fibrosis, and inflammation with hepatitis B virus.

Patients and Methods

Liver biopsies from 89 patients with untreated chronic hepatitis B (34 steatosis vs. 55 without steatosis) were analyzed; liver biopsies from 50 healthy adults were used as control. The liver biopsies were subjected to routine histological examination, and stained immunohistochemically for adiponectin and adiponectin receptor2 (adipoR2).

Results

The two groups were found to be comparable with respect to demographic, biochemical, metabolic, histological, and viral characteristics. BMI, γ-GT, FPG, insulin, and insulin sensitivity estimated by the HOMA index were significantly higher in patients with steatosis. The viral load of HBV and HBeAg positivity was higher in patients with steatosis than those without steatosis. High serum adiponectin levels were significantly correlated with abnormal serum ALT level (vs. normal ALT, P = 0.000), and HBV genotype C (vs. genotype B, P = 0.018). In patients with chronic HBV, the insulin sensitizing adipokine adiponectin, and its receptor AdipoR2were associated with steatosis. While adiponectin may becorrelated with inflammation, adiponectin, and its receptors were not associated with viral factors.

Conclusions

Our results suggest that the role of adiponectin might be impaired in chronic hepatitis B with steatosis. Reduced hepatic expression of adiponectin and adipoR2 might be of pathophysiological relevance in CHB patients with steatosis. These findings indicated that reduced liver adiponectin expression may play an important role in the pathogenesis, and progression of CHB patients with steatosis. However, hepatic expression of adiponectin, and adipoR2 was not associated with various measures of HBV infection.     

Isolated Tuberculosis of Transplanted Liver,A Case Report and Review of the Literature

Introduction

Recipients of liver transplantation are prone to different types of infections such as tuberculosis (TB).

Case Presentation

Herein we report a 59-year-old man with liver transplantation due to HBV cirrhosis who developed isolated hepatic TB, 18 months after OLT (orthotropic liver transplantation). He has been successfully treated with anti-TB regimen and now after 12 months he is completely symptom-free.

Conclusions

Organ transplantation and treatment of transplanted patients with immunosuppressive drugs would prone them to various unusual infections. One of these is unusual primary involvement of liver by tuberculosis which has been extremely rare in the previous reports.     

Drug-Resistance Associated Mutations in Polymerase (P) Gene of Hepatitis B Virus Isolated From Malaysian HBV Carriers

Background:

Mutations in the polymerase (P) gene of hepatitis B virus are often associated with drug resistance. The pattern of mutations varies geographically, thus giving rise to genotypes diversity.

Objectives:

This study was carried out to detect mutations in P gene of hepatitis B virus isolated from Malaysian HBV carriers.

Materials and Methods:

A total of 58 sera samples were analyzed by PCR and sequencing, of which the P gene of isolated HBV was successfully amplified and sequenced from 40 samples.

Results:

Genotyping of these samples revealed that the predominant genotype was genotype C (22/40, 55.0%), followed by genotype B (17/40, 42.5%), and only 1 sample showed genotype D (2.5%). A number of significant drug resistant mutations were found in five patients including S202I, N236T, M250L, L180M/V, M204I, A181T, T184G, M250V, and V173L. Of these, L180M/V and M204I were most frequently detected (80%) and associated with lamivudine in combination with emtricitabine and telbivudine drug resistance. Association with age, sex, and clinical symptoms revealed that these patients were all male, mid to elderly age and almost all hadcirrhotic liver disease.

Conclusions:

Detection and surveillance of the significant sites of mutations in HBV is crucial for clinicians to decide on the choice of antiviral treatment and further management of hepatitis B carriers.     

Serum Levels of Annexin A2 as a Candidate Biomarker for Hepatic Fibrosis in Patients With Chronic Hepatitis B

Background:

Hepatologists have studied serologic markers of liver injury for decades. Annexins are a prominent group of such markers and annexin A2 (AnxA2) is one of the best characterized annexins. AnxA2 inhibits HBV polymerase among other functions. Its expression is up-regulated in regenerative hepatocytes.

Objectives:

To determine if serum AnxA2 level has a role in estimating liver damage in chronic HBV infection and investigate whether AnxA2 levels correlate with hepatic fibrosis.

Patients and Methods:

This study included 173 patients with chronic hepatitis B (CHB) and 51 healthy controls. Liver fibrosis was graded histologically on liver biopsy samples. Blood samples were taken from patients during biopsy and serum AnxA2 levels were measured with ELISA.

Results:

In a group of adult patients with CHB, AnxA2 values were far higher than those of the control group (P = 0.001). When we assessed AnxA2 levels based on fibrosis stages, serum AnxA2 levels of patients with early stage fibrosis (stages 1 - 3) were significantly higher than those of patients with advanced stage fibrosis (stages 4 - 5; P = 0.001).

Conclusions:

AnxA2 is a useful biomarker for early stage fibrosis in patients with CHB.     

Association of Proton Pump Inhibitor Therapy with Hepatic Encephalopathy in Hepatitis B Virus-related Acute-on-Chronic Liver Failure

Background:

Hepatic encephalopathy (HE) is an important neuropsychiatry complication of acute-on-chronic liver failure (ACLF). PPI therapy may increase the intestinal bacterial overgrowth and infections.

Objectives:

The aim of this study was to assess whether PPI use in ACLF is associated with HE.

Patients and Methods:

A retrospective case-control study was performed. Fifty five admitted patients with hepatitis B virus (HBV)-related ACLF complicated by Stage II-IV HE developed after admission between January 2008 and December 2012 were matched (by sex, age, and MELD score) with comparable HBV-related ACLF patients (n = 110) who did not develop this complication during hospitalization. We excluded combined HE upon admission and other neurological disorders in patients with ACLF. Univariate and multivariate analyses of 30 variables (laboratory examination, predisposition, treatment, etc.) before the occurrence of HE were carried out to identify the factors predictive of HE.

Results:

In univariate analysis, patients with HE in ACLF had a significantly higher rate of PPI use (89.1%) compared with non-HE (63.6%, P = 0.001). In addition, clinical and standard laboratory variables were significantly different between the two groups regarding the infection rate, hyponatremia, alpha-fetoprotein (AFP), Arginine Hydrochloride use and Lactulose use. Logistic regression analysis was used to examine the combined effects of the variables with HE as the outcome. HE in ACLF was associated with hyponatremia (odds ratio (OR) = 6. 318, 95% confidence interval (CI) = 2. 803-14.241; P = 0. 000), PPI use was independently associated with HE (OR = 4. 392, CI = 1. 604-12.031; P = 0. 004), and lactulose use was protective (OR = 0. 294, CI = 0. 136-0.675; P = 0. 003).

Conclusions:

The occurrence of HE is associated with hyponatremia and PPI use in patients with ACLF.     

Association Between TT Virus Infection and Cirrhosis in Liver Transplant Patients

Background:

Cirrhosis is one of the most severe liver complications, with multiple etiologies. The torque teno virus (TTV), also known as transfusion transmitted virus, which has a high incidence in the world population, is one of the possible increasing risk factors in patients with idiopathic fulminant hepatitis and cryptogenic cirrhosis.

Objectives:

The aim of this study was to evaluate solitary and co-infection with TTV, in patients with cryptogenic and determined cause of cirrhosis.

Patients and Methods:

In this cross-sectional study, 200 liver transplant patients were consecutively recruited between years 2007 and 2011. Patients were classified, based on recognition of the etiology of cirrhosis to determined (n = 81) and cryptogenic (n = 119) patient groups. The existence of TTV infection was analyzed, using a semi-nested polymerase chain reaction method. The presence of hepatitis B virus (HBV) infective markers, including HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B core antibody (HBcAb), and hepatitis B e antibody (HBeAb), was evaluated using qualitative polymerase chain reaction and enzyme linked immunosorbent assay protocols, respectively.

Results:

The TTV infection was found in 37 of 200 (18.5%) and 53 of 200 (26.5%) plasma and tissue samples of studied liver transplanted patients, respectively. The TTV genomic DNA was found in 32 (26.9%) and 28 (23.5%) of 119 liver tissue and plasma samples of transplanted patients with cryptogenic cirrhosis, respectively. The genomic DNA of TTV was also diagnosed in 21 (25.9%) and nine (11.1%) of the 81 liver tissue and plasma samples of patients with determined cirrhosis, respectively. Significant associations were found between TTV infection with HBV molecular and immunologic infective markers, in liver transplanted patients, with determined and cryptogenic cirrhosis.

Conclusions:

The diagnosis of the high frequency of solitary TTV and co-infection with HBV, in both liver transplanted patients with cryptogenic and determined cirrhosis, emphasized on the importance of TTV infection in the development of cirrhosis, especially in the cases of cryptogenic ones, prompting for further studies the confirm this agent in the etiology of determined cirrhosis.