Hepatitis Monthly
Year:2011 | Volume:11 | Issue:5 (34)|Papers Count:15

Although the name for cancer as a disease was coined by ancient Greeks and Persians, and in spite of billions of euros, dollars, and other currencies invested in cancer research, the disease remains a major killer, particularly in Western countries (1). Over half of anticancer drugs, including acetogenins, alkaloids, and terpenes, are derived from natural products, especially from the plant kingdom (2-6). Annonaceous acetogenins (ACGs) include a series of natural products isolated from Annonaceae plants. ACGs are white, waxy derivatives of longchain (C35 or C37) fatty acids, characterized by a long aliphatic chain bearing a terminal methyl substituted a, b –unsaturated γ -lactone ring with one-, two- or three tetrahydropyran (THP) rings (5). ACGs are a likely source of potential drugs as they exhibit various biological activities such as cytotoxic, antitumor, antiparasitic, pesticidal, pisicidal, antihelmenthic, antiviral, antimicrobial, and immunosuppressive activities. They are known to be powerful inhibitors of complex I (NADH: biquinone oxidoreductases) in the mitochondrial electron transport system.

Celiac disease (CD) is characterized by sensitivity to gluten, which is found in dietary wheat, barley, and rye. Many extra-intestinal manifestations have been described in association with CD. Liver disease and CD share widespread risk factors. Liver disorders such as autoimmune hepatitis, elevation of liver enzyme levels, primary biliary cirrhosis, nonspecific hepatitis, primary sclerosing cholangitis, and nonalcoholic fatty liver disease have been reported in patients with CD. In this review, we provide information regarding liver disorders that may be found in association with celiac disease and the effect of the treatment of CD on these disorders.

Background: Viral load has been used to diagnose and monitor patients who are being treated for chronic hepatitis B (CHB). The Diagnosis methods are molecular-based and expensive. Quantitation of hepatitis B surface antigen (HBsAg) by automated chemiluminescent micro-particle immunoassay has been proposed to be a surrogate marker.Quantitating HBV DNA levels molecularly is expensive; thus, a cheaper laboratory test as a surrogate diagnostic marker might simplify our management.Objectives: We determined whether quantitative HBsAg levels correlate with HBV DNA levels in CHB.Patients and Methods: In this cross-sectional study, all CHB patients who were referred by a gastroenterologist to undergo quantitative HBV DNA assay in a qualified laboratory in Mashhad, Iran in 2009 were enrolled, and blood samples was obtained. Patients who were positive for antibodies to HCV and HDV were excluded. HBV DNA was measured by real-time polymerase chain reaction, and serum HBsAg was quantified byelectrochemiluminescence assay (Roche Diagnostic).Results: Of 97 patients, 70 were male (72%) and 27 were female (28%); the mean age was 39 ± 11 years. Eighty-seven percent wasHBeAg-negative. By Mann-Whitney test, HBSAg titer differed significantly between HBeAg-positive and -negative patients (P=0.001), as did HBV DNA levels (P=0.009). By Spearman test, there was no significant correlation between HBsAg and HBV DNA levels (P=0.606 and r=0.53).Conclusions: HBeAg-negative patients have higher levels of HBsAg and lower levels of HBV DNA. By electrochemiluminescence assay, HBsAg has no significant correlation with HBV DNA levels in CHB with predominant genotype D and HBeAg negativity in Iran.

Background: Hepatitis B virus (HBV) infection is a significant health problem throughout the world.Objectives: We aimed to evaluate the prevalence of hepatitis B antigen (HBsAg) seropositivity in the general population of Mashhad, northeast of Iran.Patients and Methods: One thousand six hundred fifty-two healthy individuals aged 1 to 90 (Mean; 29.1 ± 18.5) from all 12 municipalities of Mashad were selected randomly by multistage cluster sampling. Informed consent was obtained, and demographics and medical histories were collected. Twice-reactive samples were considered HBsAgpositive by ELISA. Chi-square test and logistic regression were applied to analyze the factors related to HBsAg positivity using SPSS 16.0.Results: The overall prevalence of HBsAg positivity was 1.39% (95% CI, 0.91% to 2.12%); 2.0% and 0.89% among men and women, respectively (p=0.054). Infection was more prevalent in older (p=0.019) and married persons (p=0.001), Afghanis (p=0.046), and those with a history of traditional cupping (p=0.005). There was no association between HBV infection and gender; literacy; income; employment; family size; or history of blood transfusion, dental procedure, surgery, hospitalization, or tattooing. By logistic regression analysis, age was the only variable that had a significant association with infection (p=0.026).Conclusion: It seems that the prevalence of HBV infection in Mashhad is slightly lower than that of the nation.

Background: Patients with HBeAg-negative chronic hepatitis B (CHB) has a significantly different prognosis than inactive carriers; there is however, no reliable strategy for accurately differentiating these two disease conditions.Objectives: To determine a strategy for discriminating patients with HBeAg-negative CHB from inactive carriers.Materials and Methods: Consecutive inactive carriers (i.e. HBeAg-negativity, anti-HBepositivity, normal ALT levels, and HBV DNA<2000 IU/mL) were enrolled. HBV reactivation was defined as the elevation of the HBV DNA level to ³ 2000 IU/mL. Patients were classified into true inactive carriers when their HBV DNA levels remained at<2000 IU/mL or false inactive carriers when their HBV DNA levels increased to ³ 2000 IU/mL during the first year.Results: The Mean ± SD age of 208 inactive carriers (140 males) was 47.7 ± 12.6 years.The Mean ± SD serum ALT and HBV DNA levels were 22.8 ± 8.6 IU/L and 360 ± 482 IU/ mL, respectively. HBV reactivation developed in 41 (19.7%) patients during the first year.Baseline HBV DNA and ALT levels differed significantly between true inactive and false inactive carriers. The AUROCs of the baseline ALT and HBV DNA levels for predicting a false inactive carrier were 0.609 and 0.831, respectively. HBV reactivation developed more often in patients with a baseline HBV DNA level of ³ 200 IU/mL than in those with a baseline HBV DNA level of<200 IU/mL during a Mean ± SD follow-up of 622 ±199 days.Conclusions: The HBV DNA level was useful for discriminating patients with HBeAgnegative CHB from true inactive carriers. The follow-up strategies applied to inactive carriers need to vary with their HBV DNA levels.

Background: HBV is still a worldwide health problem. Annually about 0.5–1.2 million patients die of HBV-related diseases such as liver cirrhosis and hepatocellular carcinoma.Lamivudine (LAM) is the first nucleoside analog used in the treatment of chronic hepatitis B. As LAM has been clinically used for a long time, increasing clinical experience has been achieved showing that the resistance mutation rate is relatively high.Numerous studies have also focused on the predictive factors of long-term efficacy of LAM treatment.Objectives: To determine the optimal cutoff values of baseline hepatitis B virus (HBV) DNA and alanine transaminase (ALT) levels as predictors for the long-term efficacy of LAM treatment in patients with chronic hepatitis B.Patients and Methods: A total of 163 HBeAg-positive chronic hepatitis B patients receiving LAM treatment were recruited into the present study. Logistic regression analysis was performed to find out the independent predictors of 2-year on-treatment virological response among the baseline parameters. The receiver operating characteristic (ROC) curve was used to evaluate the optimal cutoff values of these independent predictors.The accuracy of the prediction was assessed using the area under curve (AUC) and optimal cutoff values were determined through maximizing the Youden’s index.Results: After 2 years of LAM treatment, undetectable HBV DNA was maintained in 114 (69.9%) patients. LAM-related resistance mutation (YMDD mutation) was detected in 45 (27.6%) patients. Logistic regression analysis indicated that the baseline ALT and HBV DNA levels were the independent predictors of the efficacy. ROC curve analysis suggested the integration parameter derived from the baseline ALT and HBV DNA levels had the maximal predictive value for a 2-year on-treatment virological response.The optimal cutoff values of ALT and HBV DNA were 220 IU/L and 8.2 log10 copies/mL, respectively.Conclusions: The incidence of LAM-resistant mutations in HBeAg-positive chronic hepatitis B patients may be significantly reduced and long-term efficacy improved when the baseline ALT was greater than 220 IU/L and HBV DNA was less than 8.2 log10 copies/ mL.

Background: Previous studies suggest that annonaceous may cause permeability glycoprotein (P-gp) function to abate, leading to cell apoptosis. It has also been reported that annonaceous acetogenins affect hepatocellular carcinoma (HCC) cells in the G1 phase, leading to apoptosis. Desacetyluvaricin (Des), a new type of annonaceous acetogenin monomer, has a significant effect on HCC, with few side effects.Objectives: To investigate the effect of Des on the expression of Toll-like receptor 4 (TLR4) and P53 protein in HCC.Materials and Methods: HCC HepG2.2.15 cell was cultured by routine method. HepG2.2.15 cells were divided into three groups: control group, treated with Des and DDP (cisplatin) which were examined by immunofluorescence flow cytometry for expression of TLR4 and P53.Results: TLR4 was expressed by more cells in the Des group than in the cisplatin or serum-only groups (71.94%, 42.64%, and 37.16%, respectively; Des vs.cisplatin: p<0.05; Des vs. serum only: p<0.05), with no difference between the cisplatin and serum-only groups (p>0.05). P53 was expressed by more cells in the Des and cisplatin groups than in the serum-only group (32.6%, 31.5% and 3.3%, respectively; Des vs. serum only, p<0.05; cisplatin vs. serum only, p<0.05), with no difference between the Des and cisplatin groups (p>0.05).Conclusions: Des increases TLR4 and P53 expression in HCC cells. Improved immune recognition by the former effect and induction of apoptosis by the latter could be the mechanisms of Des’s clinical effects on HCC.

Background: In Iran, there is limited evidence on the prevalence of hepatitis B and C viruses (HBV and HCV) among females who engage in illegal sexual behavior.Objectives: To determine the prevalence of HBV and HCV infections and their associated factors in this population in Isfahan-Iran.Patients and Methods: In this cross-sectional study, 100 females who engaged in illegal sexual behavior during 2009-2010 in Isfahan were recruited from welfare to the DIC for women, and referrals were made among those who knew others who engaged in prostitution. Markers for HBV and HCV-Ab were measured by ELISA, and recombinant immunoblot assay was used for confirmation of HCV infection. Also, a questionnaire on demographics and prostitution-associated risk data in a face-to-face interview was completed for each participant. Chi-square and multivariate logistic regression models were used for data analysis.Results: Of the 100 samples collected, 91 were sufficient for testing. The mean age and time spent in sex work were 30.84 ± 9.34 years and 36 ± 28.5 months, respectively. HBsAg was detected in 1 (1.1%), anti-HBc in 4 (4.4%), anti-HBs in 60 (65.9%), and HCV Ab in 9 (9.9%) subjects. The evidence of vaccination was seen in 54 subjects (59.3%). There were no significant differences in the prevalence of HBV or HCV infection by estimated risk factors, and there was no independent risk factor for these infections.Conclusions: The high prevalence of HCV infection in this study indicates the need to implement preventive interventions for female sex workers and, perhaps more importantly, to involve their male clients.

Background: Extrahepatic cholestasis that is caused by benign and malignant diseases has been reported to increase liver stiffness (LS), as measured by transient elastography (TE).Objectives: The aim of this study was to evaluate LS in patients with extrahepatic cholestasis due to choledocholithiasis before and after endoscopic sphincterotomy and stone removal.Patients and Methods: LS was measured by TE (Fibroscan) in patients with extrahepatic cholestasis that was caused by choledocholithiasis before and 1 month after endoscopic sphincterotomy and successful stone removal.Results: We studied 12 patients (7 females, 5 males), aged 36 to 76 years (mean age 57.1 ± 11.6 years), with extrahepatic cholestasis that was caused by choledocholithiasis.LS was increased in all patients (range: 6.2–18.4 kPa; mean: 8.9 ± 3.5 kPa) before endoscopic therapy. Successful biliary drainage was effected by sphincterotomy and stone removal in all patients, which led to a significant decline in LS to 3.9–8.1 kPa (Mean: 5.6 ± 1.2 kPa; p<0.001) within a mean observation time of 29 days. The decrease in LS values correlated significantly with a decline in serum total bilirubin levels (r=0.691; p<0.0001).Conclusions: Extrahepatic cholestasis due to choledocholithiasis increases LS and should be excluded before assesing liver fibrosis by transient elastography.

Hepatitis Monthly has recently published an interesting and practically valuable original report from Yilmaz, et al.(1). That was a retrospective study investigating the ability of the aspartate transaminase to platelet ratio index (APRI) in diagnosing and predicting the extent of fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD). This relatively large scale study was conducted on a cohort of 207 CHB patients, 108 CHC patients, and 140 NAFLD patients. The results of that study were apparently reliable and potentially useful with clinical significance.The authors, by comparing with the results from liver biopsy, concluded that APRI has an acceptable accuracy for the assessment of the extent of liver fibrosis in patients with CHC and NAFLD, but not in those with CHB.

We enjoyed reading the excellent article by Yilmaz and colleagues on noninvasive assessment of liver fibrosis using aspartate transaminase to platelet ratio index (APRI) in adult patients with chronic liver disease (CLD) (1). They performed their tests on adults with chronic hepatitis C (CHC), B (CHB), and non-alcoholic fatty liver disease (NAFLD).We definitely need to develop serological markers that have satisfactory sensitivity, specificity, and high predictive values, which can be used either instead of liver biopsy or to reduce the frequency of needed biopsies for monitoring the evolution of CHC and defining the right moment for commencing treatment. Despite the study results showing that APRI has an acceptable accuracy for the assessment of liver fibrosis in adults with CHC and NAFLD, this was not the case in CHB patients. We believe that the study results would have been more valid if the researchers have used a combination of non-invasivetests to assess liver fibrosis. A similar study conducted in Hungary used APRI and liver stiffness (LS) measurements to assess fibrosis in CHC (2). The combination of both fibrosis markers was useful for non-invasive assessment of fibrosis in CHC. Forestier and colleagues found that LS measurements, APRI score, 13C-amniopyrine breath test and indocyanine green plasma clearance were reliable markers for assessing cirrhosis in patients with CLD (3).APRI was also found to be a simple and readily available tool for assessing liver fibrosis in patients with biliary atresia during post-operative follow-up care (4).

I read with great interest the article by Yusuf Yilmazet al. (1) published in a recent issue of of Hepatitis Monthly.The authors retrospectively studied 207 patients with chronic hepatitis B (CHB), 108 with chronic hepatitis C (CHC), and 140 patients with non-alcoholic fatty liver disease (NAFLD). All participants underwent liver biopsy.The stage of liver fibrosis in patients with chronic viral hepatitis was graded using the METAVIR scale. The Kleiner system for grading fibrosis was used in patients with NAFLD.

The article published in Hepatitis Monthy on noninvasive assessment of liver fibrosis with the aspartate transaminasis to platelet ratio index (APRI) in patients with chronic liver disease by Yilmazet al. (1), is interesting and very useful to permit a diagnosis and staging of fibrosis, although this index does not seem to have a high sensitivity and specificity. In recent years, efforts have been made to develop non-invasive predictive models that may correlate with stage of fibrosis. One of the first non-invasive predictive models for patients with chronic hepatitis C (CHC) was the Fibrotest, which includes a2-macroglobulin, haptoglobin, g -glutamil-transferase (GGT), apolipoprotein A1 and total bilirubin. However, considerable expenses and use of uncommon parameters reduce their clinical applicability. A few years later, the Forns’ score (age, GGT, cholesterol, platelets and prothrombin) and the APRI index (AST and platelets) overcame these draw-backs by use of only standard laboratory tests in the development of their predictive models.

The prospective randomized clinical trial of Malaguarnera and colleagues, published in the current issue of Hepatitis Monthly, investigates the potential role of a commercially available HMG Co-A reductase agent—rosuvastatin (Crestor, Astra Zeneca) —in combination with non-pegylated interferon and ribavirin in the treatment of chronic hepatitis C (HCV). HMG Co-A reductase agents, commonly referred to as statins, are popular agents prescribed throughout the world, for their cholesterol lowering effects in order to reduce the risk of cardiovascular morbidity and mortality. They are well-recognized to improve liver biochemistry in dyslipidemic patients with non-alcoholic fatty liver disease (1); but recent reports have suggested that they may possess an antiviral effect on HCV independent of their lipid lowering activity. In an in vitro study (2), various statin agents were reported to have differing effects on HCV replication in combination with interferon with fluvastatin (Lescol, Novartis) exhibiting the strongest anti-HCV activity, atorvastatin (Lipitor, Pfizer) had moderate activity whereas pravastatin (Pravachol, Bristol Myers Squibb) had no activity. Likewise, the combination of statins—specifically simvistatin and mevastatin—in combination with protease/polymerase inhibitor agents were found to clear HCV replicons from culture (3). It is interesting that this in vitro study also found that pravastatin exhibited no antiviral activity (3). Clinically, the experience of statin agents in the treatment of HCV has not been very well-studied and the reported outcomes have been interesting yet at times conflicting. Fluvastatin monotherapy was reported to produce a modest 1.75 log decrease in HCV viral load in HCV monoinfected patients (4).

At the beginning of the third millennium, Hepatitis C virus (HCV) infection continues to be a major health hazard, with 170 million chronically infected people worldwide (1). Recent research has found that the prevalence of HCV infection in Iran is 1% and 0.1% in males and females, respectively (2). Although a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) has been established as a standard anti-HCV therapy, treatment responses vary. Numerous factors, including gender, age, HCV RNA level prior to treatment, liver cirrhosis, and HCV genotypes have been determined to contribute to this discrepancy (1). In addition, a number of recently published, genome-wide association studies (GWAS) have shown that polymorphisms within the IL28B locus result in differences between patients’ responses to anti-HCV treatment (3-6). In this regard, rs8099917 (8 kb upstream of the IL28B gene) and rs12979860 (3 kb upstream of the IL28B gene) have been identified asrelevant single nucleotide polymorphisms (SNPs) that significantly impact treatment response to HCV infection (7). Although both SNPs are known to be independent predictors of response to anti-HCV therapy, a recent, extensive meta-analysis has reported that rs12979860 is more closely related to treatment responses (8). The prevalence of these SNPs and the rate of sustained viral response (SVR) have been found to vary across Caucasian, African American, and Japanese ethnicities (1).