Hepatocellular carcinoma caused by iron overload: A possible mechanism of direct hepatocarcinogenicity

Asare, George Awuku; Mossanda, Kensese S.; Kew, Michael C.; Paterson, Alan C.; Kahler-Venter, Christina P.; Siziba, Kwanele

doi:10.1016/j.tox.2005.11.006

Cited by 87 publications

(59 citation statements)

References 52 publications

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“…1,7,12 Despite previous suggestions that lemurs with increased tissue iron deposition (hemosiderosis) may be at risk for developing liver cancer, 3,19 there was no correlation in this study between liver iron levels and the presence or absence of hepatic neoplasia. The fact that inflammation and fibrosis was not seen in animals with higher liver iron levels also suggests that iron is not a causative factor leading to tumor production in the animals in the population studied.…”

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confidence: 79%

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Spontaneous Hepatocellular Carcinoma in Captive Prosimians

Zadrozny

Williams

Remick³

et al. 2009

Vet Pathol

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Spontaneous hepatocellular carcinoma has been reported as a relatively common neoplasm in prosimians; however, the cause is unknown. To investigate possible pathogenic mechanisms, the authors performed a review of all adult animals from a captive prosimian population that had postmortem examinations over the past 10 years. They performed a detailed histologic evaluation of all suspected proliferative liver lesions and diagnosed hepatocellular carcinoma in 14 of 145 lemurs (9.7%). Affected animals ranged between the ages of 6 and 40 years old. The tumors had an unusually aggressive growth pattern for animal species; metastasis to the lungs or mediastinum was evident in 7 of 14 animals. Thirty-one animals-9 with hepatocellular carcinomas and 22 age-matched controls without hepatic neoplasia-were tested to evaluate the relationship between hepatic iron stores (as well as other trace metals) and the presence of hepatocellular carcinoma. There was no difference between the hepatic iron, copper, or molybdenum in lemurs with hepatocellular carcinoma and those without, suggesting that iron is not a key element in the pathogenesis of liver tumor formation. Analysis of 22 serum samples from animals with and without liver tumors indicated no evidence of active infection with a hepadnavirus, the virus family that includes hepatitis B virus. Hepatitis C virus and aflatoxin B1 were considered as potential causes and ruled out owing to lack of associated histopathologic lesions. In conclusion, hepatocellular neoplasia is relatively common in captive prosimians, although previously suspected etiologies seem unlikely. KeywordsHepadnaviridae, hepatocellular carcinoma, iron, lemur, liver cell adenoma, neoplasms, prosimiansLemurs and lorises are members of the suborder Prosimii, the most primitive members of the Primate family. 15 Lemurs are native to the island of Madagascar, whereas lorises are found in southern Asia. 15 Most of these species are endangered in their natural habitat, and small breeding populations are maintained at various sites around the globe. Our understanding of the general background of neoplastic disease in prosimians is limited to a few publications. 17 In a recent publication, hepatocellular neoplasia was identified as the most common spontaneous neoplasm in prosimians.17 Before this review article, spontaneous hepatic neoplasms were sporadically reported in the literature with only occasional mention of metastasis.Liver tumors in domestic animals are uncommon, representing approximately 1% of overall tumor incidence. Similarly, malignant hepatic neoplasia in anthropoid primates is uncommon. Review of the literature reveals descriptions of fewer than 16 hepatocellular carcinomas (HCCs) and 5 cholangiocarcinomas in nonhuman primates. 16 Only 5 chimpanzees with hepatocellular neoplasia have been reported. Three of the tumors were carcinomas: One occurred in a chimpanzee with chronic hepatitis B virus (HBV), a member of the hepadnaviral family, with concurrent hepatitis D virus, a satellite virus of ...

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“…11,16 Known risk factors for HCC in humans include chronic viral infections with HBV or hepatitis C virus (HCV), 6,24 excessive hepatic iron levels, 1,2,12 excessive alcohol consumption, and aflatoxin B1 contamination of the diet.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Hepatocellular Carcinoma in Captive Prosimians

Zadrozny

Williams

Remick³

et al. 2009

Vet Pathol

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“…Reactive oxygen species production, in physiologic conditions controlled by antioxidant intracellular defense mechanisms, can lead to lipid peroxidation and oxidative damage to several cellular membranes and organelles, including DNA. Thus, excess free iron with reactive oxygen species overproduction in hepatic tissue, exceeding the cellular defenses, could be responsible for mutagenesis and hepatocarcinogenesis, overcoming the protective effect of activation of tumor suppressor genes and critical DNA repair genes orchestrated by p53 [5][6][7] (Fig. 1).…”

Section: Mechanisms Of Iron Toxicity In Hccmentioning

confidence: 99%

Role of iron in hepatocellular carcinoma

Valenti

Fracanzani

2014

Clinical Liver Disease

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“…Oxidative stress also leads to increased lipid peroxidation of unsaturated fatty acids in membranes and cells. The mechanisms by which the cytotoxic and genotoxic by-products contribute to hepatocarcinogenesis have been mentioned in the section on iron overload in HH [53][54][55].…”

Section: Hepatocellular Carcinoma In Dietary Iron Overloadmentioning

confidence: 99%

Hepatic iron overload and hepatocellular carcinoma

Kew

2009

Cancer Letters

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110

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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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Hepatocellular carcinoma caused by iron overload: A possible mechanism of direct hepatocarcinogenicity

Cited by 87 publications

References 52 publications

Spontaneous Hepatocellular Carcinoma in Captive Prosimians

Spontaneous Hepatocellular Carcinoma in Captive Prosimians

Role of iron in hepatocellular carcinoma

Hepatic iron overload and hepatocellular carcinoma

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