Reduced serum hepcidin levels in patients with chronic hepatitis C

Girelli, Domenico; Pasino, Michela; Goodnough, Julia B.; Nemeth, Elizabeta; Guido, Maria; Castagna, Annalisa; Busti, Fabiana; Campostrini, Natascia; Martinelli, Nicola; Vantini, Italo; Corrocher, Roberto; Ganz, Tomas; Fattovich, Giovanna

doi:10.1016/j.jhep.2009.06.027

Cited by 153 publications

(142 citation statements)

References 54 publications

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“…Serum hepcidin-25 levels in our Japanese patients were relatively high at 30.7 ± 14.5 ng/mL compared to those in Italian HFE-hemochromatosis patients. Our findings, including the reduced hepcidin/ferritin ratio and correlation between hepcidin and ferritin concentrations fit well with reports showing that hepcidin induction was relatively impaired in CHC patients, but also that its regulation by iron stores was maintained (13,14). These findings are also in agreement with recent studies in animal and cellular models suggesting that HCV suppresses hepcidin production and may contribute to the development of iron overload in CHC (19,20).…”

Section: Discussionsupporting

confidence: 92%

“…Investigation of hepcidin regulation has been limited due to the lack of reliable methods. Recently serum hepcidin levels of CHC patients were measured in 2 studies using different methods (13,14). Both studies indicated that hepcidin regulation by iron stores is maintained in CHC and suggested that HCV infection can impair hepcidin production, which may be an important factor in hepatic iron accumulation.…”

Section: Introductionmentioning

confidence: 99%

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Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

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Aim In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFEhemochromatosis. Methods Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFEhemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre-and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume. Results In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. Conclusion Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

et al. 2010

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“…15,17,45,46 Three of our patients coinfected with HCV had a hepcidin-resistant iron overload syndrome without the evidence of a genetic basis for the latter.…”

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confidence: 88%

“…2,13,14 Evidence suggests that functional disruption of the hepcidin system might be a molecular basis for hemochromatosis, but few reports on the active form of serum hepcidin-25 have been published to date owing to the lack of reliable methods for quantitative determination. 15,16,17 Aceruloplasminemia is a neurological disorder characterized by heavy iron overload in the liver and brain with clinical manifestations of ataxia, involuntary movement, retinal degeneration, and dementia around the age of 50. 18 It results from a mutation in the ceruloplasmin gene (CP).…”

Section: Introductionmentioning

confidence: 99%

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

et al. 2010

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Background. Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes.Methods. We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE-hemochromatosis. Results.One patient with HJV-hemochromatosis, 2 with TFR2-hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion.Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. (231 words)

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“…11 Thus, the link between altered iron state and HCV infection could be hepcidin, due to its role as a potent regulator in iron homeostasis. However, in most cases, hepcidin was found suppressed during chronic HCV infection, 12,13 possibly because of ROS-mediated reduction in HAMP gene expression. 14 On the other hand, HCV-driven inflammation may counteract ROS-induced hepcidin repression, since elevated IL-6 stimulates HAMP gene transcription.…”

Section: Introductionmentioning

confidence: 99%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to na€ ıve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells.

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Reduced serum hepcidin levels in patients with chronic hepatitis C

Cited by 153 publications

References 54 publications

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

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