Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C

Bonkovsky, Herbert L.; Troy, Nicole; McNeal, Kristina; Banner, Barbara F.; Sharma, Ashish; Obando, Jorge; Mehta, Savant; Koff, Raymond S.; Liu, Qin; Hsieh, Chung‐Cheng

doi:10.1016/s0168-8278(02)00305-7

Cited by 106 publications

(77 citation statements)

References 27 publications

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“…Data on the possible relationship between carriage of the HFE gene mutations and response to IFN based therapy have been controversial (5,22,24,32,35,37) . Previous studies showed an association between H63D HFE polymorphism and higher SVR rates in patients with chronic hepatitis C (6) .This relationship could be due to the fact that the HFE gene is located on the short arm of chromosome 6, close to the major histocompatibility complex (MHC).…”

Section: Discussionmentioning

confidence: 99%

“…Feder et al (13) , in 1996, discovered the HFE gene and two of its polymorphisms, C282Y and H63D, which were clearly associated with higher prevalence of elevated serum ferritin, transferrin saturation, and genetic hemochromatosis. It is well known that 20%-30% of patients with chronic hepatitis C have serum markers of iron overload, but not an increased prevalence of HFE polymorphisms (4,5,10) . Elevated serum ferritin has long been recognized as a marker of poor response to antiviral treatment in chronic HCV infected patients (3,12,16) , however the mechanism underlying this effect is not clear and the role of HFE polymorphisms has not yet been established.…”

Section: Introductionmentioning

confidence: 99%

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Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin

Coelho-Borges¹,

Cheinquer

Wolff

et al. 2012

Arq. Gastroenterol.

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-Context -Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. Objective -To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. Methods -A total of 44 treatment naïve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. Results -Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). Conclusion -Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin

Coelho-Borges¹,

Cheinquer

Wolff

et al. 2012

Arq. Gastroenterol.

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“…Iron overload is, by itself, a risk factor for liver fibrosis, cirrhosis, and hepatocellular carcinoma (17), and it appears to aggravate the clinical picture of chronic hepatitis C. A pathogenic synergism is evident in the combination of HCV infection and the common disease of iron overload hereditary hemochromatosis, which is associated with accelerated liver damage (18,19). The most prevalent form of hereditary hemochromatosis is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex class I type molecule that appears to control dietary iron absorption and body iron reutilization (20).…”

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confidence: 99%

Iron Inactivates the RNA Polymerase NS5B and Suppresses Subgenomic Replication of Hepatitis C Virus

Fillebeen

Rivas-Estilla

Bisaillon

et al. 2005

Journal of Biological Chemistry

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Clinical data suggest that iron is a negative factor in chronic hepatitis C; however, the molecular mechanisms by which iron modulates the infectious cycle of hepatitis C virus (HCV) remain elusive. To explore this, we utilized cells expressing a HCV replicon as a wellestablished model for viral replication. We demonstrate that iron administration dramatically inhibits the expression of viral proteins and RNA, without significantly affecting its translation or stability. Experiments with purified recombinant HCV RNA polymerase (NS5B) revealed that iron binds specifically and with high affinity (apparent K d : 6 and 60 M for Fe 2؉ and Fe 3؉ , respectively) to the protein's Mg 2؉ -binding pocket, thereby inhibiting its enzymatic activity. We propose that iron impairs HCV replication by inactivating NS5B and that its negative effects in chronic hepatitis C may be primarily due to attenuation of antiviral immune responses. Our data provide a direct molecular link between iron and HCV replication.

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“…This might be ascribed to the predominance of the HFE H63D heterozygous variant among our patients, which affects iron homeostasis in CVH to a lower extent than the C282Y variant. 32,33 Moreover, the presence of other, still poorly characterized, factors that interfere with the phenotypical expression of mutated HFE genes cannot be excluded. 34 Furthermore, hepatic iron concentration could not be determined in our study that is the most important limitation of this study although Lin et al showed that ferritin, iron and transferrin saturation were all excellent predictors for presence of hepatic iron overload in patients with CHC.…”

Section: Discussionmentioning

confidence: 99%

Relationship Between Hemochromatosis Gene Mutations and Degree of Fibrosis in Liver Disease Associated with Chronic Hepatitis B and C

Bağır¹,

Öksüz²,

Doğan³

et al. 2012

Turkiye Klinikleri J Med Sci

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Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C

Cited by 106 publications

References 27 publications

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin

Iron Inactivates the RNA Polymerase NS5B and Suppresses Subgenomic Replication of Hepatitis C Virus

Relationship Between Hemochromatosis Gene Mutations and Degree of Fibrosis in Liver Disease Associated with Chronic Hepatitis B and C

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