Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis

Valenti, Luca; Pulixi, E.A.; Arosio, Paolo; Cremonesi, Laura; Biasiotto, Giorgio; Dongiovanni, Paola; Maggioni, Marco; Fracanzani, Anna Ludovica

doi:10.3324/haematol.11281

Cited by 64 publications

(51 citation statements)

References 32 publications

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“…Despite similar demographic features and prevalence of viral hepatitis, the MDM2 mutated G allele was significantly associated with alcohol abuse (P ϭ 0.02) and the presence of HFE mutations (P ϭ 0.05), known risk factors for iron overload in patients with cirrhosis 4,69 (Table 3). These data suggest an interaction between high MDM2 levels, low p53 activity, and iron overload in the pathogenesis of HCC.…”

Section: Association Between the ϫ309 T ͼ G Mdm2 Promoter Polymorphismentioning

confidence: 99%

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Dongiovanni

Fracanzani

Cairo

et al. 2010

The American Journal of Pathology

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Iron overload is a risk factor for hepatocarcinoma, but the pathways involved are poorly characterized. Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53. Regulation of MDM2 by iron status was observed at protein levels in mouse hepatocytes and rat liver, and was associated with specular changes in p53 expression. Iron dependent regulation of MDM2/ p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis. Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. Furthermore, nutlin enhanced the antiproliferative activity of deferoxamine in HepG2 hepatoblastoma cells. The MDM2 ؊309T > G promoter polymorphism, determining increased MDM2 and lower p53 activity, was associated with higher risk of hepatocarcinoma in cirrhotic patients with hemochromatosis, and with HFE mutations in patients with hepatocarcinoma without hemochromatosis, suggesting an interaction between MDM2 and iron in the pathogenesis of hepatocarcinoma. In conclusion, iron status influences p53 activity and antioxidant response by modulating MDM2 expression. MDM2 inhibitors may enhance the antiproliferative activity of iron chelators. (Am J Pathol

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Section: Association Between the ϫ309 T ͼ G Mdm2 Promoter Polymorphismentioning

confidence: 99%

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Dongiovanni

Fracanzani

Cairo

et al. 2010

The American Journal of Pathology

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“…However, the frequency and severity of iron overload in chronic hepatitis C, which oscillates between broad limits, from 7 to 32% (2,(5)(6)(7)(8), remains controversial. Iron accumulation in the liver may aggravate tissue damage by generating free radicals, releasing proinflammatory and profibrogenic cytokines, and interfering with the immune system (9,10).…”

Section: Introductionmentioning

confidence: 99%

Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C

Ladero

López-Alonso

Devesa

et al. 2009

Rev. esp. enferm. dig.

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Background: hyperferritinemia is often found in patients with chronic hepatitis C (CHC) and is predictive of poorer response to antiviral therapy.Objective: to investigate changes in ferritinemia during and after antiviral therapy.Patients and methods: serum ferritin levels were measured in 262 CHC patients (163 males, mean age 48.5 years ± 10.1) before and during antiviral therapy, and six months post-treatment in all 154 patients whit undetectable serum HCV-RNA after therapy completion.Results: baseline serum ferritin was higher in patients with primary therapeutic failure than in those reaching sustained viral response (330 ± 291 ng/mL vs. 211 ± 192 ng/mL, p = 0.002). Serum ferritin transiently increased during therapy from baseline (257 ± 242 ng/mL vs. 875 ± 630 ng/mL, p < 0.001). Six months after finishing therapy, serum ferritin decreased under baseline values both in sustained responders (117 ± 102 ng/mL vs. 211± 192 ng/mL, p < 0.001) and, to a lesser extent, in relapsers (217 ± 174 ng/mL vs. 257 ± 221 ng/mL, p = 0.047).Conclusions: baseline serum ferritin may predict response to antiviral treatment in chronic hepatitis C. Combined antiviral therapy induces a marked increase in serum ferritin that falls below baseline values after sustained viral response, suggesting that the cause of hyperferritinemia in many patients is HCV infection itself rather than iron overload.

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“…[4,10]. Wir selbst haben Polymorphismen im Exon 2 des Adiponektin-Gens untersucht und gefunden, dass Patienten mit einer chronischen Hepatitis C und Steatohepatitis mit Entzün-dungsgrad 3 bis 4 Polymorphismen in diesem Lokus aufweisen [13].…”

Section: Hepatitis Bunclassified

Aktuelle Probleme der Hepatitis

Dienes

Drebber

2008

Pathologe

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In den letzten Jahren hat sich das Bild der Virushepatitis, bedingt durch den raschen Fortschritt in der molekularen Virologie, erheblich geändert. Es wurden verschiedene neue Formen der Hepatitis heraus gearbeitet, die einer speziellen Diagnostik vor allem mit den modernen Mitteln der Molekularbiologie bedürfen, wobei diese auch am Paraffinmaterial der Biopsien angewendet werden können. Im Folgenden sollen die neuen Erkenntnisse auf dem Gebiet der Virushepatitiden B, C, D und E sowie bei Erkrankungen mit nichthepatotropen Viren, wie Epstein-Barr-Virus (EBV) und Zytomegalievirus (CMV), besprochen werden.Für die Diagnose der autoimmunen Hepatitis wurden kürzlich neue Kriterien vorgeschlagen, die hier kurz eingeführt und kommentiert werden. Hepatitis BDer natürliche Verlauf der chronischen Hepatitis B wird inzwischen besser verstanden, weil die modernen molekularbiologischen Methoden noch einzelne Virusgenome nachweisen können und das Schicksal des Virus im Organismus inzwischen so beschrieben wird, dass mit dem Fortgang der Erkrankung die Menge an replizierenden Viren allmählich und kontinuierlich abnimmt. Es gibt also eine späte Phase, in der das Virus im Serum unter die Nachweisgrenze fallen kann.

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Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis

Cited by 64 publications

References 32 publications

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C

Aktuelle Probleme der Hepatitis

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