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Steven T Wiersma,
Brian McMahon,
Jean-Michel Pawlotsky,
Chloe L Thio, Mark Thursz,
Seng Gee Lim,
Ponsiano Ocama,
Gamal Esmat,
Maimuna Mendy,
Mendy Maimuna,
David Bell,
Marco Vitoria,
Irina Eramova,
Daniel Lavanchy,
Geoff Dusheiko
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ABSTRACT: Most of the estimated 350 million people with chronic hepatitis B virus (HBV) infection live in resource-constrained settings. Up to 25% of those persons will die prematurely of hepatocellular carcinoma (HCC) or cirrhosis. Universal hepatitis B immunization programmes that target infants will have an impact on HBV-related deaths several decades after their introduction. Antiviral agents active against HBV are available; treatment of HBV infection in those who need it has been shown to reduce the risk of HCC and death. It is estimated that 20-30% of persons with HBV infection could benefit from treatment. However, drugs active against HBV are not widely available or utilized in persons infected with HBV. Currently recommended antiviral agents used for treatment of human immunodeficiency virus (HIV) infection do not adequately suppress HBV, which is of great concern for the estimated 10% of the HIV-infected persons in Africa who are co-infected with HBV. Progressive liver disease has been shown to occur in co-infected persons whose HBV infection is not suppressed. In view of these concerns, an informal World Health Organization consultation of experts concluded that: chronic HBV is a major public health problem in emerging nations; all HIV-infected persons should be screened for HBV infection; HIV/HBV co-infected persons should be treated with therapies active against both viruses and that reduce the risk of resistance; standards for the management of chronic HBV infection should be adapted to resource-constrained settings. In addition, a research agendum was developed focusing on issues related to prevention and treatment of chronic HBV in resource-constrained settings.
Liver international: official journal of the International Association for the Study of the Liver 07/2011; 31(6):755-61. · 3.82 Impact Factor
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ABSTRACT: HFE hemochromatosis (HFE-H) is the most common and well-defined inherited cause for iron-related morbidity and mortality. Majority of patients with HFE-H are homozygote for C282Y mutation. Recent studies suggest that iron accumulation in most types of hemochromatosis is due to deficiency of hepcidin, a central iron regulator. However, the precise link between hepcidin levels and iron absorption in HFE-H patients has been poorly understood.
To measure hepcidin response to oral iron challenge (200 mg ferrous sulphate), in HFE-H (C282Y/C282Y) patients and compare with healthy controls (HCs).
Nine patients with C282Y/C282Y HFE-H along with 15 HC were recruited for the study. All HFE-H were iron depleted and studied at a time distant to phlebotomy. Hepcidin was measured using a published immunoassay method after ingestion of 65 mg oral iron challenge. Serum iron, ferritin and transferrin saturation were measured using standard methods. The area under the curve was calculated and compared between the two groups.
The basal serum hepcidin levels in patients with HFE-H were significantly low as compared with HC (P=0.0002). Incremental serum hepcidin response seen in HC reached significance at 4 h post iron challenge (P=0.0085) returning to baseline only at 24 h. There was no significant hepcidin response in HFE-H at 4 h (P=0.294). The overall hepcidin response was significantly lower in HFE-H compared with HC (area under the curve: P=0.0127).
Failure to mount a rapid hepcidin response to an oral iron challenge is the key mechanisms of iron accumulation despite prevailing excess body iron in patients with HFE-H with C282Y/C282Y mutation.
European journal of gastroenterology & hepatology 06/2011; 23(8):721-4. · 1.66 Impact Factor
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ABSTRACT: The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory.
Seminars in Liver Disease 05/2011; 31(2):115-27. · 7.05 Impact Factor
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Gut 04/2011; 60(8):1025-6. · 10.11 Impact Factor
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ABSTRACT: Polymorphisms in the interleukin-28B (IL28B) gene are associated with outcomes from infection with hepatitis C virus (HCV). However, the role of these polymorphisms in protecting injection drug users who are at high risk for HCV infection but do not have detectable antibodies against HCV or HCV RNA (exposed uninfected) has not been demonstrated. We investigated whether these individuals have the IL28B genotype rs12979860-CC, which protects some individuals against HCV infection.
Seventy-four exposed uninfected individuals, 89 spontaneous resolvers, and 234 chronically infected individuals were genotyped to determine single nucleotide polymorphisms at IL28B.rs12979860.
Exposed, uninfected individuals had a significantly lower frequency of the protective genotype (rs12979860-CC) than anti-HCV-positive spontaneous resolvers (41.9% vs 69.7%, respectively; P=.0005; odds ratio [OR], 0.31; 95% confidence interval [CI]: 0.16-0.60) but a similar frequency to patients who were chronically infected (41.9% vs 43.6%, respectively; P=ns). However, exposed, uninfected individuals had a significantly higher frequency of homozygosity for killer cell immunoglobulin-like receptor 2DL3:group 1 HLA-C (KIR2DL3:HLA-C1) than those with chronic infection (31.1% vs 13.3%, respectively; P=.0008; OR, 2.95; 95% CI: 1.59-5.49). For patients who spontaneously resolved infection, IL28B and KIR:HLA protected, independently, against chronic HCV infection, based on logistic regression and synergy analyses (synergy factor, 1.3; 95% CI: 0.37-4.75; P synergy=.6).
IL28B and KIR2DL3:HLA-C1 are independently associated with spontaneous resolution of viremia following HCV exposure. Resistance to HCV infection in exposed uninfected cases is associated with homozygosity for KIR2DL3:HLA-C1 but not the single nucleotide polymorphism IL28B.rs12979860. Uninfected individuals are therefore a distinct population from patients who spontaneously resolve HCV infection. Distinct, nonsynergistic innate immune mechanisms can determine outcomes of HCV exposure.
Gastroenterology 04/2011; 141(1):320-5, 325.e1-2. · 11.68 Impact Factor
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ABSTRACT: Background & Aims. Assess the clinical utility of the Prati criteria and normal ALT (<40 IU/L) in a cohort of patients with chronic hepatitis B infection (CHB). Methods. Serology, radiology, and histology were obtained in 140 patients with CHB. Results. HBeAg(+) group: 7 patients (7/56-12% HBeAg(+) group) misclassified as "immunotolerant", with HBV DNA > 6 log copies/ml and normal ALT, who in fact had moderate/severe fibrosis on liver biopsy. HBeAg(-) group: 10 patients with normal ALT and moderate/severe fibrosis on liver biopsy; 4 of these patients had >3 log copies/ml HBV DNA levels and 6 patients misclassified as "inactive carriers" with negative HBV DNA levels normal ALT and moderate/severe fibrosis (6/84-7% HBeAg(-) group). Two male HBeAg(+) and three male HBeAg(-) patients with ALT between 20 and 30 IU/L and moderate/severe fibrosis on liver biopsy would have been further mischaracterised using the Prati criteria for normal ALT. Age and ethnic group were more important predictors of moderate/severe fibrosis in multivariate analysis. Conclusion. HBeAg status, age, ethnic origin with longitudinal assessment of LFTs and viral load should be studied in patients with "normal ALT" at the upper end of normal range (ALT 20-40 IU/L) to appropriately classify patients and identify patients for liver fibrosis assessment to inform treatment decisions.
Hepatitis research and treatment 01/2011; 2011:524027.
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ABSTRACT: To study the role of hepcidin in hereditary hyperferritinemia cataract syndrome (HHCS).
Six patients from two families with HHCS, confirmed by genetic analysis showing A to G mutation at position +40 in the L-ferritin gene, were recruited to undergo serum hepcidin and prohepcidin measurements using radioimmunoassay and enzyme linked immunoassay, respectively, and measurements were compared with levels in serum from 25 healthy volunteers (14 females), mean age 36 +/- 11.9 years.
The serum hepcidin and prohepcidin levels in patients with HHCS were 19.1 +/- 18.6 and 187 +/- 120.9 ng/mL, respectively. Serum ferritin was 1716.3 +/- 376 microg/L. Liver biopsy in one patient did not show any evidence of iron overload. Serum hepcidin and prohepcidin values in healthy controls (HCs) were 15.30 +/- 15.71 and 236.88 +/- 83.68 ng/mL, respectively, while serum ferritin was 110 +/- 128.08 microg/L. There was no statistical difference in serum hepcidin level between the two cohorts (19.1 +/- 18.6 ng/mL vs 15.30 +/- 15.71 ng/mL, P = 0.612) using two-tailed t-test.
Serum hepcidin levels in HHCS patients is similar to that in HCs. Our study suggests that circulating ferritin is not a factor influencing hepcidin synthesis and does not have a role in the iron-sensing mechanism in hepatocytes.
World Journal of Gastroenterology 07/2010; 16(28):3541-5. · 2.47 Impact Factor
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ABSTRACT: To examine body fluids such as ascitic fluid (AF), saliva, bile and pleural effusions for the presence of hepcidin using a novel radioimmunoassay (RIA).
Serum samples were collected from 25 healthy volunteers (mean age: 36 +/- 11.9 years, 11 males, 14 females). In addition bile was obtained from 12 patients undergoing endoscopic retrograde cholangiopancreatography (mean age: 66.9 +/- 16.7 years, M:F = 5:7). Saliva was collected from 17 healthy volunteers (mean age: 35 +/- 9.9 years, M:F = 8:9). Pleural and AF were collected from 11 and 16 patients [(mean age: 72 +/- 20.5 years, M:F = 7:4) and (mean age: 67.32 +/- 15.2 years, M:F = 12:4)], respectively. All biological fluid samples (serum, exudative and transudative fluids) were tested for the presence of hepcidin-25 molecule using RIA.
Hepcidin-25 was detected in all biological fluids tested. The mean +/- SD hepcidin-25 in serum was 15.68 +/- 15.7 ng/mL, bile 7.37 +/- 7.4 ng/mL, saliva 3.4 +/- 2.8 ng/mL, exudative fluid 65.64 +/- 96.82 ng/mL and transudative fluid 14.1 +/- 17.8 ng/mL.
We provide clear evidence that hepcidin-25 is present in bile, saliva, pleural and ascitic fluids. Hepcidin is likely to play a role here in innate immunity.
World Journal of Gastroenterology 05/2010; 16(17):2129-33. · 2.47 Impact Factor
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Journal of Hepatology 04/2010; · 9.26 Impact Factor
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ABSTRACT: Hepatitis B vaccination is successful in 95% of individuals. In the remainder, despite repeated attempts, immunization often remains unsuccessful. 'Non-response' leaves the individual susceptible to infection. Various strategies have been employed to overcome this. These include the use of adjuncts alongside conventional vaccines which activate immune responses. In this case report we demonstrate the successful use of the hematopoietic growth factor Granulocyte colony-stimulating factor (G-CSF) as a vaccine adjunct in an individual who had previously failed conventional vaccination three times. The patient tolerated the regimen without any side effects and achieved a hepatitis B surface antibody titer greater than 100 IU/L. Use of G-CSF as a vaccine adjunct for hepatitis B has not previously been reported and the outcome in this case suggests that the use of G-CSF in this context warrants further exploration.
World journal of hepatology. 03/2010; 2(3):136-8.
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ABSTRACT: Chronic hepatitis B virus infection is common cause of morbidity and mortality in resource poor settings. Now that effective drugs are available, international action is needed to implement treatment programmes.
Tropical Medicine & International Health 10/2009; 15(1):2-4. · 2.80 Impact Factor
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Heiner Wedemeyer,
Elisabeth Schuller,
Verena Schlaphoff,
Rudolf E Stauber,
Johannes Wiegand,
Ingolf Schiefke,
Christa Firbas,
Bernd Jilma, Mark Thursz,
Stefan Zeuzem,
Wolf P Hofmann,
Holger Hinrichsen,
Erich Tauber,
Michael P Manns,
Christoph S Klade
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ABSTRACT: We examined the effect of the hepatitis C virus (HCV) peptide vaccine IC41 on HCV-specific T-cell responses and virological relapse rates in patients with chronic HCV genotype 1 infection when added to pegylated interferon plus ribavirin standard therapy. 35 patients received 6 vaccinations with IC41 from weeks 28 to 48 of standard antiviral treatment and were followed-up for another 6 months. IC41 vaccination did not prevent HCV-RNA relapse in patients with ongoing interferon standard treatment but HCV-specific T-cell responses were inducible and were associated with lower relapse rates. An increase of HCV-specific T-cell responses occurred in 73% of patients, responses were more frequent and stronger in patients with sustained virologic response than in patients who relapsed. Optimized vaccine responses may enhance sustained virologic response rates obtained with standard treatment of chronic hepatitis C.
Vaccine 07/2009; 27(37):5142-51. · 3.77 Impact Factor
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Jeremy F L Cobbold,
Quentin M Anstee,
Robert D Goldin,
Horace R T Williams,
Helen C Matthews,
Bernard V North,
Nathan Absalom,
Howard C Thomas, Mark R Thursz,
Roger D Cox,
Simon D Taylor-Robinson,
I Jane Cox
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ABSTRACT: NAFLD (non-alcoholic fatty liver disease) is a common cause of chronic liver disease associated with the metabolic syndrome. Effective techniques are needed to investigate the potential of animal models of NAFLD. The present study aimed to characterize murine models of NAFLD by metabolic profiling of intact liver tissue. Mice of three strains (BALB/c, C3H and the novel mutant, Gena/263) were fed a control or high-fat diet. Biometric, biochemical and histological analysis demonstrated a spectrum of NAFLD from normal liver to steatohepatitis. Metabolic profiling of intact liver tissue, using (1)H MAS (proton magic angle spinning) MRS (magnetic resonance spectroscopy), showed an increase in the total lipid-to-water ratio, a decrease in polyunsaturation indices and a decrease in total choline with increasing disease severity. Principal components analysis and partial least-squares discriminant analysis showed separation of each model from its control and of each model from the total dataset. Class membership from the whole dataset was predicted with 100% accuracy in six out of eight models. Those models with steatosis discriminated from those with steatohepatitis with 100% accuracy. The separation of histologically defined steatohepatitis from simple steatosis is clinically important. Indices derived from (1)H MAS MRS studies may inform subsequent in vivo MRS studies at lower field strengths.
Clinical Science 09/2008; 116(5):403-13. · 4.61 Impact Factor
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Patrick T F Kennedy,
Heather C Lee,
Lukshmy Jeyalingam,
Raza Malik,
Peter Karayiannis,
David Muir,
Janice Main, Mark Thursz,
Robert Goldin,
Belinda Smith,
Ashley Brown,
Howard C Thomas
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ABSTRACT: Treatment strategies in chronic hepatitis B (CHB) are evolving as more potent oral antivirals become available. However, drug resistance remains a major challenge and policy guidelines on management are limited by the evidence base. This study aims to review the implications of the National Institute for Health and Clinical Excellence (NICE) guidelines in a cohort of unselected CHB patients in the United Kingdom and to evolve a management algorithm for their treatment.
In total, 783 unselected hepatitis B surface antigen-positive patients, were assessed of whom 212 (27%) underwent liver biopsy. Age, alanine aminotransferase, hepatitis B virus DNA and necroinflammatory score were analysed to determine their value as predictors of fibrosis. Patients with biopsy evidence of fibrosis were offered treatment and followed longitudinally. Six-month on-treatment virologic response was evaluated to determine the validity of this strategy in predicting the early emergence of resistance.
Age, gender and necroinflammatory score were predictors of fibrosis in CHB patients, whereas age > 40 years was a predictor of cirrhosis in both hepatitis B e antigen (HBeAg)-positive (P < 0.03) and HBeAg-negative patients (P < 0.003). A total of 81% of HBeAg-positive and 65% of HBeAg-negative CHB patients who required adefovir add-on therapy were identifiable after 6 months of lamivudine monotherapy, by continuing HBV DNA positivity (P < 0.002 and P < 0.0001, respectively).
Advanced liver disease was present in patients falling outside current treatment guidelines, highlighting the importance of liver histology in identifying fibrosis and the need for antiviral therapy. While 6 month on-treatment virologic response as a trigger for instituting add-on therapy may be an improvement on the current recommendations, such a strategy should be integrated into any new treatment algorithm, likely to consist of entecavir and tenofovir.
Antiviral therapy 01/2008; 13(8):1067-76. · 3.16 Impact Factor
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ABSTRACT: Tissue injury leads to activation of coagulation and generation of thrombin. Inhibition of thrombin receptor protease-activated receptor 1 (PAR-1) has been shown to reduce liver fibrosis in animals. This study aimed to evaluate the effect of PAR-1 gene polymorphism on rate of liver fibrosis (RF) in chronic hepatitis C.
Polymorphisms studied: C > T transition 1426 bp upstream of translation start site (-1426C/T), 13 bp repeat of preceding -506 5'-CGGCCGCGGGAAG-3' sequence (-506I/D), and A > T transversion in intervening sequence (IVS) 14 bp upstream of exon-2 start site (IVS-14A/T). A total of 287 European and 90 Brazilian patients were studied.
1426C/T polymorphism: There was a trend to higher RF in patients with the TT genotype (P = 0.06) and an association between genotype CC and slow fibrosis (P = 0.03) in Europeans. In males, RF was significantly higher in those with the TT genotype compared to CT (P = 0.003) and CC (P = 0.007). There was a significant association between TT and fast fibrosis (P = 0.04). This was confirmed in an independent cohort of Brazilians where RF was higher in TT than in CC (P = 0.03). Analysis of -506I/D showed no difference in RF and distribution of slow/fast fibrosis among different genotypes in both populations. Analysis of IVS-14A/T showed no difference between genotypes.
In conclusion, these findings suggest that PAR-1 receptor polymorphisms influence the progression of liver fibrosis.
Journal of Gastroenterology and Hepatology 11/2007; 23(9):1403-9. · 2.87 Impact Factor
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ABSTRACT: Two receptor chains, IL-10RA and IL-10RB, are known to mediate the functions of interleukin-10 (IL-10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL-10 receptor genes and outcome of HCV infection. IL-22, an IL-10 homologue, shares the IL-10RB receptor chain with IL-10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL-10RA and IL-22 genes in hepatitis C disease pathogenesis.
This study population consisted of 631 HCV patients, recruited from several hepatology clinics across Europe. We genotyped four single-nucleotide polymorphisms (SNPs) in the IL-10RA and six SNPs in the IL-22 gene by ligation detection reaction or restriction fragment length polymorphism. Outcome of HCV infection was assessed according to viral clearance, treatment response, severity of fibrosis and overall inflammation.
Variation in IL-10RA appeared to be correlated with response to treatment and inflammation. Two SNPs in IL-22 affected treatment response and viral clearance respectively. We furthermore report on allele and haplotype frequencies and linkage disequilibrium for IL-10RA and IL-22. Our results indicate that genetic variation in these genes may play a modulatory role in the outcome of hepatitis C infection.
Liver international: official journal of the International Association for the Study of the Liver 11/2007; 27(8):1134-43. · 3.82 Impact Factor
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ABSTRACT: Background: Two receptor chains, IL-10RA and IL-10RB, are known to mediate the functions of interleukin-10 (IL-10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL-10 receptor genes and outcome of HCV infection. IL-22, an IL-10 homologue, shares the IL-10RB receptor chain with IL-10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL-10RA and IL-22 genes in hepatitis C disease pathogenesis.Methods: This study population consisted of 631 HCV patients, recruited from several hepatology clinics across Europe. We genotyped four single-nucleotide polymorphisms (SNPs) in the IL-10RA and six SNPs in the IL-22 gene by ligation detection reaction or restriction fragment length polymorphism. Outcome of HCV infection was assessed according to viral clearance, treatment response, severity of fibrosis and overall inflammation.Conclusions: Variation in IL-10RA appeared to be correlated with response to treatment and inflammation. Two SNPs in IL-22 affected treatment response and viral clearance respectively. We furthermore report on allele and haplotype frequencies and linkage disequilibrium for IL-10RA and IL-22. Our results indicate that genetic variation in these genes may play a modulatory role in the outcome of hepatitis C infection.
Liver international: official journal of the International Association for the Study of the Liver 07/2007; 27(8):1134 - 1143. · 3.82 Impact Factor
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Mark Thursz
Gut 06/2007; 56(5):613-4. · 10.11 Impact Factor
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ABSTRACT: Countries in the the Asia-Pacific region and Africa tend to have the highest prevalence of hepatitis B infection worldwide. Hepatitis B infection progresses from an asymptomatic persistently infected status to chronic hepatitis B, cirrhosis, decompensated liver disease and/or hepatocellular carcinoma. The aim of this review was to summarize rates and risk factors for progression between disease states in the Asia-Pacific region and Africa. A literature search was conducted employing MEDLINE and EMBASE (1975-2003) using the following key words: hepatitis B, natural history, disease progression, cirrhosis, hepatocellular carcinoma, mortality, Africa and the Asia-Pacific region. Bibliographies of articles reviewed were also searched. Ranges for annual progression rates were: (i) asymptomatic persistent infection to chronic hepatitis B, 0.84-2.7%; (ii) chronic hepatitis B to cirrhosis, 1.0-2.4%; and (iii) cirrhosis to hepatocellular carcinoma, 3.0-6.6%. Patients with asymptomatic persistent infection and chronic hepatitis B had relatively low 5-year mortality rates (<4%); rates (>50%) were much higher in patients with decompensated liver disease and hepatocellular carcinoma. No data were found for progression rates in African populations. Hepatitis B e antigen was a risk factor for chronic hepatitis B, and bridging hepatic necrosis in chronic hepatitis B increased the risk of cirrhosis. Risk factors for hepatocellular carcinoma included cirrhosis, co-infection with hepatitis C virus, and genetic and environmental factors. In this review, wide ranges of disease progression estimates are documented, emphasizing the need for further studies, particularly in Africa, where progression rates are largely not available. Summarizing information on factors associated with disease progression should assist in focusing efforts to arrest the disease process in those at most risk.
Journal of Gastroenterology and Hepatology 07/2005; 20(6):833-43. · 2.87 Impact Factor
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ABSTRACT: Interferon-alpha2 (IFN-alpha2) is used as standard treatment of patients with chronic hepatitis C (cHCV), but little is known about the immunomodulatory effects of this cytokine in vivo. We have studied immunologic parameters in freshly isolated peripheral blood mononuclear cells (PBMC) of 26 patients with cHCV 12 h before and 12 h after the first s.c. injection of 5-6 MU IFN-alpha2. In PBMC obtained after IFN injection, a substantial increase in IL-10 production after antigen-specific and nonspecific stimulation was observed, whereas IFN-gamma production and proliferation were significantly diminished compared with PBMC obtained before IFN injection. Patients were stratified according to single nucleotide polymorphisms (SNPs) in the interleukin-10 (IL-10) promoter, which have been associated with the response to IFN therapy. Induction of IL-10 and suppression of IFN-gamma levels were more prominent in patients with genotype CC at position -592 (n = 15) compared with patients with genotype AA/AC (n = 11). In conclusion, our data indicate that IFN-alpha2 therapy can potently enhance IL-10 and suppress IFN-gamma production of PBMC, which is, at least partially, dependent on an SNP in the IL-10 promoter. This suggests an autoregulatory role of IL-10 in IFN therapy.
Journal of Interferon & Cytokine Research 11/2004; 24(10):585-93. · 3.06 Impact Factor
