Hepatocellular carcinoma in the thalassaemia syndromes

Borgna‐Pignatti, Caterina; Vergine, Gianluca; Lombardo, Turiddu; Cappellini, Maria Domenica; Cianciulli, Paolo; Maggio, Aurelio; Renda, Disma; Lai, Maria Eliana; Mandas, Antonella; Forni, Gianluca; Piga, Antonio; Bisconte, Maria Grazia

doi:10.1046/j.1365-2141.2003.04732.x

Cited by 161 publications

(146 citation statements)

References 14 publications

(12 reference statements)

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“…Two such studies from the United States and Sweden showed a strong association of HCC and HH [64,135]. In addition to HH, the hepatic iron overload owing to other causes, such as homozygous beta thalassemia [136] and the dietary form observed in South African blacks [137], is also associated with an increased risk of HCC. There is also evidence that marked iron overload in the setting of end-stage liver disease is also associated with HCC.…”

Section: Hemochromatosis and Hccmentioning

confidence: 99%

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

et al. 2010

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Introduction The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. Methods The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. 123Hepatol Int (2010) 4: 439-474 DOI 10.1007/s12072-010-9165-7 Results Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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Section: Hemochromatosis and Hccmentioning

confidence: 99%

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

et al. 2010

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“…HCC is known to occasionally complicate hepatic iron accumulation in patients with thalassemia major, sideroblastic anemias, or spherocytosis [46][47][48].…”

Section: Hepatocellular Carcinoma In Dietary Iron Overloadmentioning

confidence: 99%

Hepatic iron overload and hepatocellular carcinoma

Kew

2009

Cancer Letters

108

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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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“…Thalassemia patients have about 5.5-fold elevated relative risk for developing hepatocellular carcinoma. 26 We previously discovered that b-Thal/Hb E patients excrete high amounts of the LPOderived DNA adducts, edA and edC, in their urine. 27 These are thought to be excision products following elimination by DNA repair in the affected internal organs.…”

Section: Random Generation Of Eda In All Liver Cell Nucleimentioning

confidence: 99%

“…24 Iron overload in primary hemochromatosis patients leads to 200-fold increased relative risk for hepatocellular carcinoma, 25 whereas in b-thalassemia patients it was estimated to be about 5.5-fold. 26 We had earlier reported a 9-to 13-fold increase in urinary excretion of edA and edC in b-Thal/Hb E patients, suggesting massive DNA damage in internal organs, mostly in the liver. The edC level in urine was strongly and positively correlated with serum NTBI; edA level showed a trend.…”

mentioning

confidence: 99%

Accumulation of lipid peroxidation‐derived DNA lesions in iron‐overloaded thalassemic mouse livers: Comparison with levels in the lymphocytes of thalassemia patients

Meerang¹,

Nair²,

Sirankapracha³

et al. 2009

Intl Journal of Cancer

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In thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of b-Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. edA, edC and M 1 dG residues were quantified by 32 P-postlabeling-TLC/ HPLC. M 1 dG levels in lymphocyte DNA from patients were 4 times as high as in controls, while the increase in edA and edC was not significant. Adducted DNA accumulated in the liver of thalassemic mice having >2.7 mg Fe/g tissue dry weight; DNA adducts and iron were highly correlated. edA was not specifically generated in certain mouse liver cell types as revealed by immunohistochemical staining. We found elevated LPO-induced DNA damage in the liver of thalassemic mouse and in lymphocytes, implicating that massive DNA damage occurs in the liver of thalassemia patients. We conclude that promutagenic LPO-derived DNA lesions are involved in the onset of hepatocellular carcinoma in these patients. ' 2009 UICC Key words: iron overload; lipid peroxidation; thalassemia; etheno-DNA adducts Iron overload, one of the major causes of morbidity and mortality in thalassemia patients, results from multiple, life-long transfusions and enhanced iron absorption as a response to increased erythropoiesis. [1][2][3] Iron overload in these patients is indicated by significantly increased levels of serum ferritin, saturated transferrin (the iron carrier protein) 4 and iron deposition in many organs. 5,6 Administration of the iron chelators, desferrioxamine and deferiprone, is commonly used in therapy. These drugs can cause serious side effects and are expensive. For desferrioxamine, a special infusion equipment is needed and, therefore, not all patients can benefit from iron-chelating therapy. In addition, patients who receive iron chelators still encounter a milder or shorter period of iron overload. As a result of iron overload, high levels of plasma iron in the form of nontransferrin bound iron (NTBI) can be found in both transfusion-dependent and transfusion-independent thalassemia patients. 7 NTBI plays a crucial role in the production of hydroxyl radicals (HO • ) in vivo that occurs through the biological Fenton-type and Haber-Weiss reactions. The resulting hydroxyl radicals can induce oxidative stress and, as a consequence, damage of cellular nucleic acids, proteins, lipids and carbohydrates, which in turn can potentiate tissue damage. 8 Previous studies demonstrated increased oxidative stress in thalassemia patients, including increased antioxidant enzyme activities and decreased nonenzymatic antioxidants. 9-12 Moreover, increase in modified DNA bases such as 8-oxodG, resulting from direct attack of hydroxyl radical to DNA, 13 increase in ortho-and meta-tyrosine, which are products of hydroxyl radical attack on phenylalanine, 14 and increase in lipid peroxidation (LPO) products, such as malondialdehyde (MDA) 10 and F 2 -isoprostane, 15 have been reported.LPO end-products such as 4-hydroxy-2-nonenal (HNE) and 1...

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Hepatocellular carcinoma in the thalassaemia syndromes

Cited by 161 publications

References 14 publications

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

Hepatic iron overload and hepatocellular carcinoma

Accumulation of lipid peroxidation‐derived DNA lesions in iron‐overloaded thalassemic mouse livers: Comparison with levels in the lymphocytes of thalassemia patients

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