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1.  Prevalence of Hepatitis C Virus Genotypes in Iranian Patients: A Systematic Review and Meta-Analysis 
Hepatitis Monthly  2014;14(12):e22915.
Context:
Hepatitis C virus (HCV) is a global public health problem and a major etiology of chronic liver disease, which may develop into cirrhosis and hepatocellular carcinoma. Genotypes of HCV indicate the route of acquisition, the clinical outcome, response to treatment, prognosis and control strategies.
Objectives:
The aim of this study was to estimate the overall prevalence and trend of HCV genotypes or subtypes in Iran
Data Sources:
A literature review was done for papers reporting HCV genotypes in Iranian patients in PubMed, Magiran, IranMedex, Scientific Information Databank, and Google scholar databases.
Study Selection:
Data were selected according to inclusion and exclusion criteria.
Data Extraction:
Data were abstracted by two independent authors. Data were analyzed based on random-effects model using the Meta R. Pooled statistical software. Prevalence of HCV genotypes in cities and provinces of Iran with 95% confidence interval (CI) were calculated.
Results:
Fifty-three articles published between 1999 and 31 June 2014 including 22952 HCV infected individuals were included in the meta-analysis. Subtype 1a was predominant with a rate of 39% (95% CI: 34-44%); followed by subtype 3a, 32% (95% CI: 26-39%); subtype 1b, 13% (95% CI: 10-15%); genotype 4, 5.18% (95% CI: 3.27-7.5%); and genotype 2, 3.6% (95% CI: 1.6-8.3%). Untypeable HCV had a rate of 0.11% (95% CI: 0.07-0.16%).
Conclusions:
The most frequent subtypes of HCV in Iran were 1a, 3a and 1b, respectively. This frequency differed in various provinces of Iran and fluctuated with time. It is important to determine the distribution of HCV genotypes in different geographical areas and its trend with time for epidemiological and patients’ management purposes.
doi:10.5812/hepatmon.22915
PMCID: PMC4310018
Hepatitis C virus; Genotypes; Molecular Epidemiology; Iran
2.  Association of Upregulated HMGB1 and c-IAP2 Proteins With Hepatocellular Carcinoma Development and Progression 
Hepatitis Monthly  2014;14(12):e23552.
Background:
Hepatocellular carcinoma (HCC) is one of the most important health problems in China.
Objectives:
This study analyzed expression of high-mobility group protein B1 (HMGB1) and inhibitor of apoptosis protein-2 (c-IAP2) proteins in HCC compared to paired para-tumor tissue samples to assess the association with HCC pathogenesis and progression.
Materials and Methods:
Sixty-eight HCC and para-tumor tissue samples were collected for Western blot, qRT-PCR and immunohistochemical analyses of HMGB1 and c-IAP2.
Results:
HMGB1 and c-IAP2 proteins were highly expressed in HCC tissue samples [85.3% (58/68) and 82.4% (56/68), respectively] compared to para-tumor tissue samples [32.3% and 27.9%, respectively]. Furthermore, expression of HMGB1 was significantly associated with enhanced c-IAP2 expression in HCC tissue samples (r = 0.878, P < 0.01). Expression of HMGB1 was associated with tumor multiplicity and size, alpha-fetoprotein (AFP) level and advanced TNM stage, while expression of c-IAP2 was associated with tumor size, AFP level and advanced TNM stage.
Conclusions:
Expression of HMGB1 and c-IAP2 proteins was associated with HCC development and progression, and the expression of HMGB1 and c-IAP2 proteins in HCC were significantly associated with each other. Additionally, these proteins may show promise as biomarkers to predict HCC progression.
doi:10.5812/hepatmon.23552
PMCID: PMC4310020
Hepatocellular Carcinoma; HMGB1; c-IAP2 Protein; Biomarkers
3.  Distribution of Hepatitis B Virus Genotypes in Azerbaijani Patients With Chronic Hepatitis B Infection 
Hepatitis Monthly  2014;14(12):e25105.
Background:
Hepatitis B virus (HBV) has been classified into ten genotypes (A-J) based on genome sequence divergence, which is very important for etiological and clinical investigations. HBV genotypes have distinct geographical distributions worldwide.
Objectives:
The aim of this study was to investigate the distribution of HBV genotypes among Azerbaijani patients with chronic hepatitis B, came from the Republic of Azerbaijan country to Iran to receive medical care.
Patients and Methods:
One hundred and three patients with chronic HBV infection, referred to hospitals related to Iran University of Medical Sciences and Tehran Hepatitis Center from August 2011 to July 2014, were enrolled in this cross sectional study. About 3-milliliter of peripheral blood was taken from each patient. After viral DNA extraction, HBV genotypes were tested using the INNO-LiPA™ HBV kit (Innogenetics, Ghent, Belgium). HBV genotyping was confirmed using sequencing of hepatitis B surface antigen (HBsAg) and polymerase (pol) regions of HBV.
Results:
The mean age of patients was 35.9 ± 11.7 years (19-66). Of 103 patients, 72 (69.9%) were male. In the present study, the predominant HBV genotype was D (93.2%) followed by genotype A (5.8%) and concurrent infection with A and D genotypes (0.97%).
Conclusions:
The main and frequent HBV genotype among Azerbaijani patients with chronic hepatitis B virus infection was genotype D followed by genotype A.
doi:10.5812/hepatmon.25105
PMCID: PMC4310019
Hepatitis B virus; Genotype; Patients
4.  Enhanced-Transient Expression of Hepatitis C Virus Core Protein in Nicotiana tabacum, a Protein With Potential Clinical Applications 
Hepatitis Monthly  2014;14(11):e20524.
Background:
Hepatitis C virus (HCV) is major cause of liver cirrhosis in humans. HCV capsid (core) protein (HCVcp) is a highly demanded antigen for various diagnostic, immunization and pathogenesis studies. Plants are considered as an expression system for producing safe and inexpensive biopharmaceutical proteins. Although invention of transgenic (stable) tobacco plants expressing HCVcp with proper antigenic properties was recently reported, no data for “transient-expression” that is currently the method of choice for rapid, simple and lower-priced protein expression in plants is available for HCVcp.
Objectives:
The purpose of this study was to design a highly codon-optimized HCVcp gene for construction of an efficient transient-plant expression system for production of HCVcp with proper antigenic properties in a regional tobacco plant (Iranian Jafarabadi-cultivar) by evaluation of different classes of vectors and suppression of gene-silencing in tobacco.
Materials and Methods:
A codon-optimized gene encoding the Kozak sequence, 6xHis-tag, HCVcp (1-122) and KDEL peptide in tandem (from N- to C-terminal) was designed and inserted into potato virus-X (PVX) and classic pBI121 binary vectors in separate cloning reactions. The resulted recombinant plasmids were transferred into Agrobacterium tumefaciens and vacuum infiltrated into tobacco leaves. The effect of gene silencing suppressor P19 protein derived from tomato bushy stunt virus on the expression yield of HCVcp by each construct was also evaluated by co-infiltration in separate groups. The expressed HCVcp was evaluated by dot and western blotting and ELISA assays.
Results:
The codon-optimized gene had an increased adaptation index value (from 0.65 to 0.85) and reduced GC content (from 62.62 to 51.05) in tobacco and removed the possible deleterious effect of “GGTAAG” splice site in native HCVcp. Blotting assays via specific antibodies confirmed the expression of the 15 kDa HCVcp. The expression level of HCVcp was enhanced by 4-5 times in P19 co-agroinfiltrated plants with better outcomes for PVX, compared to pBI121 vector (0.022% versus 0.019% of the total soluble protein). The plant-derived HCVcp (pHCVcp) could properly identify the HCVcp antibody in HCV-infected human sera compared to Escherichia coli-derived HCVcp (eHCVcp), indicating its potential for diagnostic/immunization applications.
Conclusions:
By employment of gene optimization strategies, use of viral-based vectors and suppression of plant-derived gene silencing effect, efficient transient expression of HCVcp in tobacco with proper antigenic properties could be possible.
doi:10.5812/hepatmon.20524
PMCID: PMC4286711  PMID: 25598788
Hepatitis C Virus Core; Transgenic; Transient Expression; Tobacco
5.  Epidemiology of Hepatitis B in the Reproductive-Age Female Farmworkers of Southeastern Turkey 
Hepatitis Monthly  2014;14(11):e22120.
Background:
There are limited data on the prevalence of the hepatitis B virus (HBV) infection in the agricultural population worldwide.
Objectives:
This study aimed to determine the prevalence of HBV infection and associated risk factors in the reproductive-age female farmworker.
Materials and Methods:
This cross-sectional study was conducted between January and April 2013 in southeastern region (SAR) of Turkey. A community-based representative agricultural sample (n = 705) from the agricultural areas of nine provinces of SAR was randomly determined by clustering method using Epi Info software. Questionnaires including demographic information and risk factors of HBV were administered to participants. The presence of HBsAg, anti-HBs, anti-HBc, and anti-HBe antibodies in blood samples were measured by ELISA.
Results:
The prevalence of the HBsAg, anti-HBs, anti-HBc, anti-HBe antibodies, and seropositivity were 5.7%, 25.9%, 28.9%, 16.4%, and 36.7%, respectively. There was no association between the HBsAg and the size of the household, age, education level, parity, and place of birth while the prevalence of HBsAg was higher in seasonal migratory farmworkers and people living in urban areas and the prevalence of anti-HBs antibody was significantly higher in women ≥ 35 years of age, those with a high parity, and those who gave birth without the assistance of health professionals (P < 0.05). The risk for HBV infection in the seasonal migratory group was 4.3 times higher in comparison to local workers (P = 0.00; OR = 4.3; 95% CI, 2.2-8.4), with a prevalence rate of 11%.
Conclusions:
The monitoring of at-risk groups like seasonal migratory farmworkers is necessary to strengthen the healthcare service provided to this population.
doi:10.5812/hepatmon.22120
PMCID: PMC4286707  PMID: 25598790
HBsAg; ELISA; Agriculture
6.  Sofosbuvir vs. Combination of Pegylated Interferon and Ribavirin; How Much Shall Pay for Iranian Patients? 
Hepatitis Monthly  2014;14(11):e25540.
doi:10.5812/hepatmon.25540
PMCID: PMC4286709  PMID: 25598793
Hepatitis C; Therapy; Sofosbuvir; Cost; Peginterferon
7.  Risk Factors of Hepatitis C Virus Infection in Drug Users From Eleven Methadone Maintenance Treatment Clinics in Xi’an, China 
Hepatitis Monthly  2014;14(11):e19601.
Background:
Hepatitis C virus (HCV) infection rates in drug users vary among different regions of China. Drug users who are unaware of their HCV serostatus tend to engage in more risky behaviors.
Objectives:
This prospective study aimed to assess risk factors of HCV infection in drug users among 11 methadone maintenance treatment (MMT) clinics in Xi’an, China.
Patients and Methods:
Baseline characteristics and drug use information of patients were collected upon enrollment in the study and anti-HCV tests were performed within one month after the enrollment. Data on daily medication, monthly random urine morphine test results, illicit drug use and MMT retention time were recorded during a 5-year follow-up.
Results:
Of 10243 patients, 58.0% had positive results for anti-HCV. Injection drug use, longer duration of drug abuse, older age, female gender, unmarried status and unemployment were independent risk factors of HCV infection. Urine test positivity rate was lower (14.8% vs. 16.7%, χ2 = 100.235, P < 0.05), but MMT retention rate was higher (log-rank χ2 = 4.397, P < 0.05) in the anti-HCV positive group than anti-HCV negative one. However, multivariate regression revealed no significant association between anti-HCV serostatus and either MMT retention time or illicit drug use.
Conclusions:
The major risk factor of HCV infection was injection drug use. The patient’s awareness of his or her HCV status had a minor effect in reduction of illicit drug use and improvement in MMT retention. Therefore, adequate counseling is necessary for drug users in MMT clinics in Xi’an.
doi:10.5812/hepatmon.19601
PMCID: PMC4286713  PMID: 25598787
Methadone; Maintenance; Treatment; Injection; Drug User
8.  Characterization of HCV Genotype 5a Envelope Proteins: Implications for Vaccine Development and Therapeutic Entry Target 
Hepatitis Monthly  2014;14(11):e23660.
Background:
Hepatitis C virus (HCV) is one of the major causes of cirrhosis and hepatocellular carcinoma with an estimation of 185 million people with infection. The E2 is the main target for neutralizing antibody responses and the variation of this region is related to maintenance of persistent infection by emerging escape variants and subsequent development of chronic infection. While both E1 and E2 are hypervariable in nature, it is difficult to design vaccines or therapeutic drugs against them.
Objectives:
The objective of this study was to characterize genotype 5a E1 and E2 sequences to determine possible glycosylation sites, conserved B-cell epitopes and peptides in HCV that could be useful targets in design of vaccine and entry inhibitors.
Patients and Methods:
This study was conducted through PCR amplification of E1 and E2 regions, sequencing, prediction of B-cell epitopes, analysis of N-linked glycosylation and peptide design in 18 samples of HCV genotype 5a from South African.
Results:
Differences in the probability of glycosylation in E1 and E2 regions were observed in this study. Three conserved antigenic B-cell epitopes were predicted in the E2 regions and also 11 short peptides were designed from the highly conserved residues.
Conclusions:
This study provided conserved B-cell epitopes and peptides that can be useful for designing entry inhibitors and vaccines able to cover a global population, especially where genotype 5a is common.
doi:10.5812/hepatmon.23660
PMCID: PMC4286708  PMID: 25598792
Hepatitis C Virus; Genotype; Epitopes; Peptides
9.  Entecavir Versus Lamivudine Therapy for Patients With Chronic Hepatitis B-Associated Liver Failure: A Meta-Analysis 
Hepatitis Monthly  2014;14(11):e19164.
Background:
Nucleoside analogues are recommended as antiviral treatments for patients with hepatitis B virus (HBV)-associated liver failure. Clinical data comparing entecavir (ETV) and lamivudine (LAM) are inconsistent in this setting.
Objectives:
To compare the efficacy and safety of ETV and LAM in patients with chronic hepatitis B (CHB)-associated liver failure.
Patients and Methods:
A literature search was performed on articles published until January 2014 on therapy with ETV and LAM for patients with CHB-associated liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was the primary efficacy measure, while total bilirubin (TBIL), prothrombin activity (PTA) changes and HBV DNA negative change rates were secondary efficacy measures. A quantitative meta-analysis was performed to compare the efficacy of the two drugs. Safety of ETV and LAM was observed.
Results:
Four randomized controlled trials and nine retrospective cohort studies comprising a total of 1549 patients were selected. Overall analysis revealed comparable survival rates between patients received ETV and those received LAM (4 weeks: RR = 1.03, 95%CI [0.89, 1.18], P = 0.73; 8 weeks: RR = 0.98, 95% CI [0.85, 1.14], P = 0.84; 12 weeks: RR = 0.98, 95% CI [0.90, 1.08], P = 0.70; 24 weeks: RR = 1.02, 95% CI [0.94, 1.10], P = 0.66). After 24 weeks of treatment, patients treated with ETV had a significantly lower TBIL levels (MD = -37.34, 95% CI [-63.57, -11.11], P = 0.005), higher PTA levels (MD = 11.10, 95% CI [2.47, 19.73], P = 0.01) and higher HBV DNA negative rates (RR = 2.76, 95% CI [1.69, 4.51], P < 0.0001) than those treated with LAM. In addition, no drug related adverse effects were observed in the two treatment groups.
Conclusions:
ETV and LAM treatments had similar effects to improve 24 weeks survival rate of patients with CHB-associated liver failure, but ETV was associated with greater clinical improvement. Both drugs were tolerated well during the treatment. It is suggested to perform further studies to verify the results.
doi:10.5812/hepatmon.19164
PMCID: PMC4286714  PMID: 25598786
Entecavir; Lamivudine; LAM; Hepatitis B; Liver Failure
10.  Association of Hepcidin mRNA Expression With Hepatocyte Iron Accumulation and Effects of Antiviral Therapy in Chronic Hepatitis C Infection 
Hepatitis Monthly  2014;14(11):e21184.
Background:
Iron overload is frequently observed in patients with chronic hepatitis C (CHC) and is associated with the increased risk of liver fibrosis and carcinogenesis. Hepcidin is a regulator of iron homeostasis and a component of innate immunity. Based on experimental studies, iron overload might be a result of low hepcidin synthesis in CHC.
Objectives:
The aim of this case-control study was to assess hepcidin mRNA expression in liver tissue of patients with CHC in terms of iron metabolism parameters, hemochromatosis (HFE) gene mutations, disease activity, and efficacy of antiviral treatment with pegylated interferon and ribavirin.
Patients and Methods:
A total of 31 patients with CHC, who were qualified for antiviral therapy, were compared with 19 patients with chronic hepatitis B (CHB). In both groups, liver function tests and serum iron parameters were assayed and hepcidin mRNA expression was measured in liver specimens using real time PCR with normalization to reference genes mRNA of stable expression.
Results:
Patients with CHC had lower hepcidin mRNA expression and more frequently iron deposits in hepatocytes than subjects with CHB did. In CHC group, hepcidin mRNA expression was positively correlated with alanine aminotransferase activity and serum iron concentration. Low expression of hepcidin had no correlation with tissue iron overload in those with CHC. In univariate analysis, HCV viral load and efficacy of antiviral treatment were not significantly associated with hepcidin mRNA expression.
Conclusions:
Further studies on the role of hepcidin in pathogenesis of CHC are needed to assess the potency of its use in antiviral treatment.
doi:10.5812/hepatmon.21184
PMCID: PMC4286710  PMID: 25598789
Hepatitis C; Hepcidin; Iron Overload; Liver; Interferon-alpha
11.  Are Women With Polycystic Ovarian Syndrome at a High Risk of Non-Alcoholic Fatty Liver Disease; A Meta-Analysis 
Hepatitis Monthly  2014;14(11):e23235.
Context:
Insulin resistance is a hallmark of metabolic syndrome (MS). It has been proposed that both polycystic ovarian syndrome (PCOS) and nonalcoholic fatty liver disease (NAFLD) are correlated with Insulin resistance. Therefore, PCOS and NAFLD can be attributed with insulin resistance and therefore MS. The aim of this meta-analysis was to determine whether PCOS patients are at a high risk of NAFLD.
Evidence Acquisition:
Google scholar, Scopus, ISI Web of Science, Embase, MEDLINE, and some Iranian databases such as scientific information database (SID), IranMedex, and MagIran were searched to identify relevant studies. We included all papers regardless of their language from January 1985 to June 2013. By using data on prevalence of NAFLD in patients with and without PCOS, odds ratio (OR) with 95% confidence intervals (CIs) were calculated in each study. Chi-squared test was used to assess heterogeneity between studies.
Results:
We finally included seven eligible studies. According to chi-squared test, there was a significant heterogeneity (73.6%) between studies (P = 0.001). NAFLD prevalence was significantly higher in patients with PCOS compared to healthy control, with an overall OR of 3.93 (95% CI: 2.17, 7.11).There was no significant publication bias based on Begg's and Egger's tests.
Conclusions:
According to the results of this meta-analysis, there was a high risk of NAFLD in women with PCOS. We suggest evaluating patients with PCOS regarding NAFLD.
doi:10.5812/hepatmon.23235
PMCID: PMC4286712  PMID: 25598791
Polycystic Ovary Syndrome; Non-alcoholic Fatty Liver Disease; Insulin Resistance; Metabolic Syndrome; Meta-Analysis
12.  Hepatitis B Virus Core Promoter Mutations in Patients With Chronic Hepatitis B and Hepatocellular Carcinoma in Bucharest, Romania 
Hepatitis Monthly  2014;14(10):e22072.
Background:
Accurate and personalized molecular virological diagnosis of hepatitis B virus (HBV) infection is crucial for individualized selection of patients for antiviral therapy in Romania.
Objectives:
We aimed to investigate HBV mutations in Romanian patients with chronic HBV infection, also to match HBV genotypes with HBV mutations identified and clinical outcomes.
Patients and Methods:
This was a cross-sectional study. A total of 484 Romanian patients with chronic HBV infection and hepatocellular carcinoma (HCC) were investigated. This was performed in Fundeni Clinical Institute, Bucharest, Romania during January 2005 to August 2010. HBsAg positive patients with chronic HBV infection admitted to Fundeni Clinical Institute were randomly enrolled in the study. Analysis was performed in the Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. Indirect diagnosis was performed with enhanced chemiluminescence method using Architect i2000SR and HBV-DNA was quantified with COBAS TaqMan HBV PCR. Direct sequencing of the PCR-products was performed with the PCR-product sequencing kit. HBV genotyping was performed with INNO-LiPA DR Amplification and INNO-LiPA HBV precore-core.
Results:
We detected two HBV genotypes; A (8.1%) and D (60.5%), and a mixture of genotypes A and D (31.4%) (P < 0.001). Basal core promoter (BCP) A1762T/G1764A and precore (PC) G1896A mutations were detected in these Romanian patients with chronic HBV infection. HBV chronic carriers had mainly genotype D (54.4%) and HBV WT (64.0%). BCP A1762T, G1764A and PC G1896A were significantly associated with HCC-tissue HBV sequencing (75.3%) (P < 0.001). PC G1896A alone was detected in HCC-serum HBV sequencing group (66.7%).
Conclusions:
Genotype D was the main genotype detected in Romanian patients with chronic HBV infection. Genotype D presented both BCP and PC mutations more frequently.
doi:10.5812/hepatmon.22072
PMCID: PMC4250966  PMID: 25477976
Hepatitis B Virus; Hepatocellular carcinoma; Genotype; Mutations
13.  Immunogenicity of Multi-Epitope DNA and Peptide Vaccine Candidates Based on Core, E2, NS3 and NS5B HCV Epitopes in BALB/c Mice 
Hepatitis Monthly  2014;14(10):e22215.
Background:
Hypervariability of HCV proteins is an important obstacle to design an efficient vaccine for HCV infection. Multi-epitope vaccines containing conserved epitopes of the virus could be a promising approach for protection against HCV.
Objectives:
Cellular and humoral immune responses against multi-epitope DNA and peptide vaccines were evaluated in BALB/c mice.
Materials and Methods:
In this experimental study, multi-epitope DNA- and peptide-based vaccines for HCV infection harboring immunodominant CD8+ T cell epitopes (HLA-A2 and H2-Dd) from Core (132-142), NS3 (1073-1081) and NS5B (2727-2735), a Th CD4+ epitope from NS3 (1248-1262) and a B-cell epitope from E2 (412-426) were designed. Multi-epitope DNA and peptide vaccines were tested in two regimens as heterologous DNA/peptide (group 1) and homologous peptide/peptide (group 2) prime/boost vaccine in BALB/c mice model. Electroporation was used for delivery of the DNA vaccine. Peptide vaccine was formulated with Montanide ISA 720 (M720) as adjuvant. Cytokine assay and antibody detection were performed to analyze the immune responses.
Results:
Mice immunized with multi-epitope peptide formulated with M720 developed higher HCV-specific levels of total IgG, IgG1 and IgG2a than those immunized with multi-epitope DNA vaccine. IFN-γ levels in group 2 were significantly higher than group 1 (i.e. 3 weeks after the last immunization; 37.61 ± 2.39 vs. 14.43 ± 0.43, P < 0.05). Moreover, group 2 had a higher IFN-γ/IL-4 ratio compared to group 1, suggesting a shift toward Th1 response. In addition, in the present study, induced immune responses were long lasting and stable after 9 weeks of the last immunization.
Conclusions:
Evaluation of multi-epitope DNA and peptide-vaccines confirmed their specific immunogenicity in BALB/c mice. However, lower Th1 immune responses in mice immunized with DNA vaccine suggests further investigations to improve the immunogenicity of the multi-epitope DNA vaccine through immune enhancers.
doi:10.5812/hepatmon.22215
PMCID: PMC4238154  PMID: 25419219
Vaccine; Epitope; Electroporation; Prime-Boost
14.  Rapamycin Enhances HBV Production by Inducing Cellular Autophagy 
Hepatitis Monthly  2014;14(10):e20719.
Background:
Some reports revealed that rapamycin could reactivate HBV infection. However, the mechanism has not been clearly explained.
Objectives:
In this report, we studied the mechanism by which rapamycin enhances HBV replication and expression by inducing cellular autophagy.
Materials and Methods:
HepG2.2.15 cells were treated with rapamycin to induce autophagy. Autophagosomes were observed by fluorescence microscopy and transmission electron microscopy. Autophagy marker protein LC3-Ⅱ/LC3-Ⅰwas detected by Western blotting. HBV DNA and mRNA were determined by real time PCR and Southern blotting. HBsAg was evaluated by ELISA.
Results:
In HepG2.2.15 cells, HBV DNA and HBsAg increased when host cells were treated with rapamycin and the effect was reversed by autophagy inhibitor, 3-methyladenine (3-MA).
Conclusions:
These results indicated a potential explanation for reactivation of HBV infection when patients with hepatitis receive rapamycin.
doi:10.5812/hepatmon.20719
PMCID: PMC4238155  PMID: 25419217
HBV; Rapamycin; Autophagy
15.  Apolipoprotein C3 Gene Polymorphisms Are Not a Risk Factor for Developing Non-Alcoholic Fatty Liver Disease: A Meta-Analysis 
Hepatitis Monthly  2014;14(10):e23100.
Context:
Our objective was to evaluate the effect of gene polymorphisms of apolipoprotein C3 (APOC3) on the development of non-alcoholic fatty liver disease (NAFLD) in different populations.
Evidence Acquisition:
We performed a meta-analysis of all relevant studies published in the literature. A total of 115 clinical trials or reports were identified, but only seven trials met our inclusion criteria. A meta-analysis was performed according to the Cochrane Reviewers’ Handbook recommendations.
Results:
Five hospital-based and two population-based case-control studies were included in the final analysis. The overall frequency of APOC3 gene polymorphisms was 67.5% (1177/1745) in NAFLD and 68.8% (988/1437) in controls. The summary odds ratio for the association of gene polymorphisms of APOC3 and the risk of NAFLD was 1.03 (95% CI: 0.89-1.22),which was not statistically significant (P > 0.05).
Conclusions:
Our meta-analysis, while not ruling out possible publication bias, showed no association between gene polymorphisms of APOC3 and the risk of NAFLD development in different populations in the world.
doi:10.5812/hepatmon.23100
PMCID: PMC4250968  PMID: 25477977
Apolipoprotein; Polymorphisms; NAFLD
16.  The Therapeutic Use of Analgesics in Patients With Liver Cirrhosis: A Literature Review and Evidence-Based Recommendations 
Hepatitis Monthly  2014;14(10):e23539.
Context:
Pain management in cirrhotic patients is a major clinical challenge for medical professionals. Unfortunately there are no concrete guidelines available regarding the administration of analgesics in patients with liver cirrhosis. In this review we aimed to summarize the available literature and suggest appropriate evidence-based recommendations regarding to administration of these drugs.
Evidence Acquisition:
An indexed MEDLINE search was conducted in July 2014, using keywords “analgesics”, “hepatic impairment”, “cirrhosis”, “acetaminophen or paracetamol”, “NSAIDs or nonsteroidal anti-inflammatory drugs”, “opioid” for the period of 2004 to 2014. All randomized clinical trials, case series, case report and meta-analysis studies with the above mentioned contents were included in review process. In addition, unpublished information from the Food and Drug Administration are included as well.
Results:
Paracetamol is safe in patients with chronic liver disease but a reduced dose of 2-3 g/d is recommended for long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided because of risk of renal impairment, hepatorenal syndrome, and gastrointestinal hemorrhage. Most opioids can have deleterious effects in patients with cirrhosis. They have an increased risk of toxicity and hepatic encephalopathy. They should be administrated with lower and less frequent dosing in these patients and be avoided in patients with a history of encephalopathy or addiction to any substance.
Conclusions:
No evidence-based guidelines exist on the use of analgesics in patients with liver disease and cirrhosis. As a result pain management in these patients generates considerable misconception among health care professionals, leading under-treatment of pain in this population. Providing concrete guidelines toward the administration of these agents will lead to more efficient and safer pain management in this setting.
doi:10.5812/hepatmon.23539
PMCID: PMC4250965  PMID: 25477978
Adverse Drug Events; Hepatic Cirrhosis; Pain Management; Acetaminophen
17.  Geographic Distribution of Hepatitis C Virus Genotypes in Pakistan 
Hepatitis Monthly  2014;14(10):e20299.
Background:
Distribution of Hepatitis C Virus (HCV) genotypes may be changed over time. Epidemiological Studies on distribution patterns of HCV genotypes in Pakistani population might assist for better treatment options and preventive strategies.
Objectives:
This study was conducted to determine distribution patterns of HCV genotypes in different geographical regions of Pakistan.
Patients and Methods:
In this cross-sectional study, 1818 randomly selected patients from different geographical regions of Pakistan, diagnosed with HCV infection by the third generation Enzyme Linked Immunosorbent Assay (ELISA), were included between April 2011 and December 2013. HCV RNA was detected in serum samples of patients by Reverse Transcription Polymerase Chain Reaction (RT- PCR) of the core region. Qualitative PCR was performed to determine viral load. HCV genotyping was performed by RT-nested PCR using type-specific primers of the core region. Frequency of different genotypes among patients was assessed according to gender, age and geographical region at the time of sampling.
Results:
Of 1818 HCV RNA positive samples, HCV genotypes PCR fragments were detected in 1552 (85.5%) samples. HCV genotype 3a was the predominant genotype (39.4%) followed by genotype 2a (24.93%). HCV genotype 3 was the predominant genotype in Punjab and Sindh regions, while genotype 2 was the most predominant genotype in Khyber Pakhtunkhwa region and the second predominant genotype after genotype 3 in Sindh region. The incidence of genotype 2a is increasing in our country with decrease in the incidence of genotype 3a. A higher incidence of HCV various genotypes were observed among male patients and those younger than 45 years.
Conclusions:
This study may facilitate treatment options and preventive strategies in Pakistan.
doi:10.5812/hepatmon.20299
PMCID: PMC4250967  PMID: 25477975
HCV Genotypes; Distribution Patterns; Geographical Regions; Pakistan
18.  The Impact of IFNL4 rs12979860 Polymorphism on Spontaneous Clearance of Hepatitis C; A Case-Control Study 
Hepatitis Monthly  2014;14(10):e22649.
Background:
About 30% of individuals with hepatitis C virus (HCV) infection are able to clear HCV spontaneously. Differences in host genetics affect the outcome of HCV infection. Single nucleotide polymorphisms (SNPs) of the Interferon lambda (IFNL) genes were associated with spontaneous and treatment-induced clearance of HCV infection.
Objectives:
The aim of this study was to evaluate the association between the IFNL4 rs12979860 SNP and spontaneous clearance of HCV infection in Iranian population.
Materials and Methods:
A case-control study was designed on 91 cases with spontaneous HCV infection clearance and 259 patients with persistent HCV infection as the control group. The rs12979860 SNP was assessed as the most common IFNL polymorphism by PCR-RFLP method.
Results:
Distribution of rs12979860 CC genotype in the spontaneous clearance group was around two folds of its distribution in chronic hepatitis C group (P < 0.001, OR = 4.09, 95% CI = 2.44-6.86).
Conclusions:
The rs12979860 SNP was observed as a strong host genetic factor associated with spontaneous clearance of hepatitis C infection.
doi:10.5812/hepatmon.22649
PMCID: PMC4238152  PMID: 25419220
Genetic polymorphism; Hepatitis C; Human IFNL4 Protein
19.  NAFLD Prevalence in a Young Cadaveric Organ Donor Population 
Hepatitis Monthly  2014;14(10):e21574.
Background:
Liver transplantation is a critical survival point for patients with end stage liver diseases. It can dramatically increase patients’ survival if the donor liver is intact. One aspect of liver health is absence of steatosis. Nonalcoholic Steato Hepatitis (NASH) and Nonalcoholic Fatty Liver Disease (NAFLD) are increasing among young adults and patients living with chronic liver diseases.
Objectives:
In this study, we determined the prevalence of NALFD in livers of brain-dead donors in Imam-Khomeini hospital Complex, Tehran, Iran. We assumed that the calculated prevalence would represent NAFLD prevalence in Iranian population in the age range of 20-60 years.
Materials and Methods:
All eligible brain dead liver transplant donors were enrolled in the survey from March 21, 2011 to March 21, 2013 in Imam-Khomeini hospital Complex. Eligible participants were donors aged 20 to 60 years without any obvious history of liver disease. Liver needle biopsy was performed at the end of the transplant operation; time zero biopsy. We calculated the prevalence of NAFLD among brain-dead donors. Moreover, the frequency of NASH was calculated based on the NAS (NAFLD Activity Score).
Results:
Among 116 cases, two were diagnosed as probable NASH. There was a significant association between NAFLD and male gender (P = 0.04). Moreover, we found a higher steatosis level in male gender. There was a significant association between NAFLD and BMI (P = 0.05). Those with BMI more than 27 had severe steatosis.
Conclusions:
Our comprehensive literature review showed that our study was the first investigation in Iran and the region, which determined the prevalence of NAFLD based on tissue diagnosis. We believe that the prevalence of NAFLD/NASH in our donors can represent the overall prevalence in this age group in Iran.
doi:10.5812/hepatmon.21574
PMCID: PMC4238153  PMID: 25419218
Steatosis; NASH; NAFLD; Prevalence; Cadaver
20.  Serological Assay and Genotyping of Hepatitis C Virus in Infected Patients in Zanjan Province 
Hepatitis Monthly  2014;14(9):e17323.
Background:
Hepatitis C Virus (HCV), a public health problem, is an enveloped, single-stranded RNA virus and a member of the Hepacivirus genus of the Flaviviridae family. Liver cancer, cirrhosis, and end-stage liver are the outcomes of chronic infection with HCV. HCV isolates show significant heterogeneity in genetics around the world. Therefore, determining HCV genotypes is a vital step in determining prognosis and planning therapeutic strategies.
Objectives:
As distribution of HCV genotypes is different in various geographical regions and HCV genotyping of patients has not been investigated in Zanjan City, this study was designed for the first time, to determine HCV genotypes in the region and to promote the impact of the treatment.
Materials and Methods:
Serum samples of 136 patients were collected and analyzed for anti-HCV antibodies using ELISA (The enzyme-linked immunosorbent assay) method. Then, positive samples were exposed to RT-PCR, which was performed under standard condition. Afterwards, they investigated for genotyping using allele-specific PCR (AS-PCR), and HCV genotype 2.0 line probe assay (LiPA).
Results:
Samples indicated 216 bp bands on 2% agarose gel. Analyses of the results demonstrated that the most dominant subtype was 3a with frequency of 38.26% in Zanjan Province followed by subtypes of 1b, 1a, 2, and 4 with frequencies of 25.73%, 22.05%, 5.14%, and 4.41%, respectively. The frequency of unknown HCV genotypes was 4.41%.
Conclusions:
According to the results, it was found that HCV high prevalent genotype in Zanjan is subtype 3a. Analysis of the results provides identification of certain HCV genotypes, and these valuable findings could affect the type and duration of the treatment.
doi:10.5812/hepatmon.17323
PMCID: PMC4214121  PMID: 25368655
Anti-HCV Antibody; Hepatitis C Virus; Genotype; RT-PCR; AS-PCR
21.  An Unusual Cause for a Hepatic Flare in a Chronic HBV Carrier 
Hepatitis Monthly  2014;14(9):e20099.
Introduction:
Hepatitis E is an emerging disease in developed countries with an increasing incidence. In developed countries, HEV genotype 3 prevails as a zoonotic disease carried by wild boars or pigs, which usually causes asymptomatic infection.
Case Presentation:
An asymptomatic HBsAg carrier was tested regularly at a German university hospital and showed no signs of chronic hepatitis B (CHB) activity. At a routine visit, elevated aminotransferases were detected while HBV DNA remained low and the patient was clinically asymptomatic. The laboratory signs of acute hepatitis resolved spontaneously. When aminotransferases returned to normal limits, the patient showed a flare of HBV-replication, which resolved spontaneously. In follow-up, further investigations revealed a resolved hepatitis E (HEV) superinfection causing an acute hepatitis before the HBV flare. No potential risk factors for HEV infection were identified.
Conclusions:
Elevated aminotransferases in CHB patients are most commonly caused by exacerbation of CHB. Nevertheless, when HBV DNA is not elevated, other reasons should be excluded. Amongst others, superinfection with another hepatotropic virus can be the reason for decompensation of chronic hepatitis B. This case report describes an asymptomatic HEV superinfection followed by a flare in HBV replication in an HBsAg carrier without signs of HBV replication for eight years. In CHB carriers with signs of acute hepatitis, rare causes should be considered as well. HEV should be a part of routine laboratory evaluation for hepatitis flares given the rising number of infections.
doi:10.5812/hepatmon.20099
PMCID: PMC4221959  PMID: 25386198
Hepatitis E; Chronic Hepatitis B; Risk Factors; Hepatic Flare; Superinfection
22.  Analytical Assessment of Interleukin - 23 and -27 Cytokines in Healthy People and Patients With Hepatitis C Virus Infection (Genotypes 1 and 3a) 
Hepatitis Monthly  2014;14(9):e21000.
Background:
The immune system plays important roles in determining the outcomes of hepatitis C virus (HCV) infection. Interleukin-23 and -27 (IL-23 and IL-27) are two novel IL-12 cytokine family members known to enhance the T-lymphocyte response, but their precise involvement in HCV infection is not well known.
Objectives:
We investigated the serum IL-27 and IL-23 levels in patients with HCV infection and in healthy individuals.
Patients and Methods:
In this case-control study, we assessed IL-23 and IL-27 levels in serum of 37 healthy individuals and 64 patients with chronic HCV using Enzyme-linked immunosorbent assay (ELISA). The relationship of cytokines level with liver enzymes (ALT, AST, and ALP), HCV genotype and viral load were analyzed. The differences of these cytokine levels in the groups of treatment and no treatment was compared. HCV genotypes were classified by HCV-specific primers methods. HCV RNA loads were determined by fluorescence quantitative PCR.
Results:
Serum level of IL-23 was higher in HCV infected patients compared to control group (P = 0.005). However, no significant difference was seen in IL-27 serum level between patients compared to the control group (P = 0.65). There was no significant difference in IL-23 and IL-27 level between genotype 1 HCV-infected- and 3a HCV-infected- patients. Positive moderate correlation between IL-23 and IL-27 with viral load was found in type 3a and 1 HCV-infected patient. Positive relative correlation was seen between ALT and IL-23 in 1a HCV-infected patients, which was higher than 3a HCV-infected patients; but there were no significant difference between serums liver enzymes with IL-23 and IL-27 in respect to genotype 3a and 1a HCV-infected patients
Conclusions:
These findings may reflect a vigorous pro-inflammatory reaction orchestrated by the host immune system against chronic HCV. Also, a better understanding of the involvement mechanism considering the correlation between other genotypes with inflammatory cytokines in various stages of disease can be obtained.
doi:10.5812/hepatmon.21000
PMCID: PMC4221962  PMID: 25386199
Hepatitis C; Interleukin–23; Interleukin-27; Cytokines; Genotypes; Hepacivirus
23.  Estrogen Receptor Alpha Expression and Liver Fibrosis in Chronic Hepatitis C Virus Genotype 1b: A Clinicopathological Study 
Hepatitis Monthly  2014;14(9):e21885.
Background:
Hepatic damage due to chronic hepatitis C virus (HCV) genotype 1b infection varies widely.
Objectives:
We aimed to investigate whether estrogen receptor alpha (ERα) plays a role in liver fibrosis in patients infected with HCV genotype 1b.
Patients and Methods:
All the consecutive patients who received the same standard treatment protocol for HCV genotype 1b were subdivided into two subgroups according to their fibrosis scores as fibrotic stages < 2 in mild fibrosis group and fibrotic stages ≥ 2 in advanced fibrosis group, depending on the presence of septal fibrosis. ERα was stained in liver biopsy specimens. Demographics and clinical properties were compared between the groups. Multivariate logistic regression analysis was performed to predict advanced fibrosis.
Results:
There were 66 patients in the mild fibrosis group and 24 in the advanced fibrosis group. Among the mild and advanced fibrosis groups, 65.1% and 50%were female, respectively (P = 0.19). There was an inverse correlation between ERα and fibrotic stage (r: -0.413; P < 0.001). Age, platelet counts, neutrophil counts, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transferase (GGT) and ERα were statistically significant in the univariate analysis. In multivariate logistic regression analyses, ERα expression continued to be an independent predicting factor of liver fibrosis in patients infected with chronic HCV genotype 1b (OR: 0.10; 95% CI: 0.018-0.586; P < 0.001).
Conclusions:
ERα expression in liver was inversely correlated with liver fibrosis among patients infected with chronic HCV genotype 1b.
doi:10.5812/hepatmon.21885
PMCID: PMC4214133  PMID: 25368658
Estrogen Receptors Alpha; Genotype; Hepatitis C Virus, Liver Fibrosis
24.  Diagnostic Value of Serum Level of Soluble Tumor Necrosis Factor Receptor IIα in Egyptian Patients With Chronic Hepatitis C Virus Infection and Hepatocellular Carcinoma 
Hepatitis Monthly  2014;14(9):e19346.
Background:
The prognosis of hepatocellular carcinoma (HCC) is unfavorable and needs serum markers that could detect it early to start therapy at a potentially curable phase.
Objectives:
The aim of this study was to determine the value of serum soluble tumor necrosis factor (TNF) receptor-IIα (sTNFR-IIα) in diagnosis of HCC in patients with chronic hepatitis C virus (HCV) infection.
Patients and Methods:
The study was performed on 110 subjects who were classified into five groups. Group I included 20 patients with chronic noncirrhotic HCV infection and persistently normal transaminases for ≥6 months. Group II included 20 patients with chronic noncirrhotic HCV infection and elevated transaminases. Group III included 20 patients with Chronic HCV infection and liver cirrhosis. Group IV included 20 patients with chronic HCV infection with liver cirrhosis and HCC. Group V included 30 healthy age and sex-matched controls. Medical history was taken from all participants and they underwent clinical examination and abdominal ultrasonography. in addition, the following laboratory tests were requested: liver function tests, complete blood count, HBsAg, anti-HCVAb, HCV-RNA by qualitative PCR, and serum levels of α-fetoprotein (AFP) and sTNFR-IIα.
Results:
The serum level of sTNFR-IIα was significantly higher in patients with HCC in comparison to the other groups. A positive correlation was found between the serum levels of sTNFR-IIα and AST and ALT in patients of group-II. Diagnosis of HCC among patients with HCV infection and cirrhosis could be ascertained when sTNFR-IIα is assessed at a cutoff value of ≥ 250 pg/mL.
Conclusions:
Serum sTNFR-IIα could be used as a potential serum marker in diagnosing HCC among patients with HCV infection.
doi:10.5812/hepatmon.19346
PMCID: PMC4221961  PMID: 25386197
Liver Cirrhosis; Hepatocellular Carcinoma; Hepatitis C Virus; s TNF-RII
25.  Long-Term T-Cell-Mediated Immunologic Memory to Hepatitis B Vaccine in Young Adults Following Neonatal Vaccination. 
Hepatitis Monthly  2014;14(9):e22223.
Background:
The long-term duration of cell-mediated immunity induced by neonatal hepatitis B virus (HBV) vaccination is unknown.
Objectives:
Study was designed to determine the cellular immunity memory status among young adults twenty years after infantile HB immunization.
Patients and Methods:
Study subjects were party selected from a recent seroepidemiologic study in young adults, who had been vaccinated against HBV twenty years earlier. Just before and ten to 14 days after one dose of HBV vaccine booster injection, blood samples were obtained and sera concentration of cytokines (interleukin 2 and interferon) was measured. More than twofold increase after boosting was considered positive immune response. With regard to the serum level of antibody against HBV surface antigen (HBsAb) before boosting, the subjects were divided into four groups as follow: GI, HBsAb titer < 2; GII, titer 2 to 9.9; GIII, titer 10 to 99; and GIV, titers ≥ 100 IU/L. Mean concentration level (MCL) of each cytokines for each group at preboosting and postboosting and the proportion of responders in each groups were determined. Paired descriptive statistical analysis method (t test) was used to compare the MCL of each cytokines in each and between groups and the frequency of responders in each group.
Results:
Before boosting, among 176 boosted individuals, 75 (42.6%) had HBsAb 10 IU/L and were considered seroprotected. Among 101 serosusceptible persons, more than 80% of boosted individuals showed more than twofold increase in cytokines concentration, which meant positive HBsAg-specific cell-mediated immunity. MCL of both cytokines after boosting in GIV were decreased more than twofold, possibly because of recent natural boosting.
Conclusions:
Findings showed that neonatal HBV immunization was efficacious in inducing long-term immunity and cell-mediated immune memory for up to two decades, and booster vaccination are not required. Further monitoring of vaccinated subjects for HBV infections are recommended.
doi:10.5812/hepatmon.22223
PMCID: PMC4214124  PMID: 25368659
Cell-Mediated Immunity; Hepatitis B Vaccine; Booster Vaccination

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