Surival and Prognostic Factors in 212 Italian Patients With Genetic Hemochromatosis

Fargion, Silvia; Mandelli, C.; Piperno, Alberto; Cesana, Bruno Mario; Fracanzani, Anna Ludovica; Fraquelli, Mirella; Bianchi, Paolo; Fiorelli, G.; Conte, Dario

doi:10.1002/hep.1840150417

Cited by 196 publications

(102 citation statements)

References 23 publications

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“…76,77 In line with our hypothesis, we observed that the G allele, previously linked to increased MDM2 expression and lower p53 activity, 78,79 was associated with increased cancer risk, indicating that a preserved ability to downregulate MDM2 expression may protect from iron-induced carcinogenesis through p53 upregulation. Moreover, the MDM2 Ϫ309G allele was significantly associated with the presence of HFE mutations in a case-only cohort of Italian patients with HCC, suggesting an interaction between iron overload and the failure to adequately down-regulate MDM2 expression in the pathogenesis of the disease in a subset of patients.…”

Section: Discussionsupporting

confidence: 87%

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: Discussionsupporting

confidence: 87%

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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“…77 Clinical studies have shown that hepatic iron overload is a risk factor for the development of HCC in hemochromatosis, alcoholic liver disease, posttransplant patients, and in patients with HCC developed in a noncirrhotic liver. [78][79][80][81] A recent retrospective study by Sorrentino et al implicates iron deposition as a risk factor for HCC development in patients with NASHrelated cirrhosis. 82 Fifty-one patients with HCC in the setting of NASH-related cirrhosis were compared with 102 age-matched, sex-matched, and disease-matched HCC-free patients with NASH-related cirrhosis.…”

Section: Iron Deposition and Hccmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection

2010

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Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

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“…The degree of iron overload was mild in more than 50% of these patients [27]. Iron overload may also act synergistically with other risk factors for HCC, such as chronic hepatitis B virus (HPB) infection and alcohol abuse, in causing the tumor [30].…”

Section: Hepatocellular Carcinoma In Hereditary Hemochromatosismentioning

confidence: 99%

Hepatic iron overload and hepatocellular carcinoma

Kew

2009

Cancer Letters

111

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In recent years it has become increasingly evident that excess body iron may be complicated by the supervention of hepatocellular carcinoma (HCC). Hereditary hemochromatosis (HH) was the first condition in which hepatic iron overload was shown to predispose to the development of HCC. The inherited predisposition to excessive absorption of dietary iron in HH is almost always the result of homozygosity of the C282Y mutation of the HFE gene, which causes inappropriately low secretion of hepcidin. HCC develops in 8-10% of patients with HH and is responsible for approximately 45% of deaths in the HCC patients. Cirrhosis is almost always present when HCC is diagnosed. Dietary iron overload is a condition which occurs in rural-dwelling Black Africans in southern Africa as a result of the consumption, over time, of large volumes of alcohol home-brewed in iron containers and having, as a consequence, a high iron content. Iron loading of the liver results and may be complicated by malignant transformation of the liver (relative risk of approximately 10.0). Accompanying cirrhosis does occur but is less common than that in HH. The development of HCC as a consequence of increased dietary iron, and the fact that it may develop in the absence of cirrhosis, has been confirmed in an animal model. Drinking water with a high iron content might contribute to the high incidence of HCC in parts of Taiwan. The metabolic syndrome [obesity, insulin resistance type 2 (or diabetes mellitus type 2), non-alcoholic fatty liver or non-alcoholic steatohepatitis] has in recent years become a major public health problem in some resource-rich countries. A link between excess body iron and insulin resistance or the metabolic syndrome has become apparent. The metabolic syndrome may be complicated by the supervention of HCC, and recent evidence suggests that increased body iron may contribute to this complication.

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Surival and Prognostic Factors in 212 Italian Patients With Genetic Hemochromatosis

Cited by 196 publications

References 23 publications

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

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

Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection

Hepatic iron overload and hepatocellular carcinoma

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