Hepatocellular Carcinoma in Hemochromatosis

Bradbear, R. A.; Halliday, June W.; Bassett, Mark L.; Cooksley, W. G. E.; Powell, Lawrie W.

doi:10.1007/978-4-431-68349-0_14

Cited by 3 publications

(6 citation statements)

References 45 publications

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“…(a) In half the patients with IFF at the time of GH diagnosis, HCC developed, compared with 8% of control GH patients. This control group was carefully selected; each IFF-positive patient was matched with two IFF-negative patients according to factors suggested to be involved in the development of HCC in GH, such as age ( > 50 yr), sex (male), amount of total iron (heavy overload) and liver fibrosis or cirrhosis (7,(21)(22)(23). Therefore we assumed that the two groups were comparable according to putative known carcinogenic risk factors, especially because they did not differ with respect to associated putative causes of liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

et al. 1993

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Sublobular nodules of hepatocytes free of iron or exhibiting much less iron than the surrounding parenchyma, referred to in this study as iron-free-foci, are frequently found in the livers of patients with genetic hemochromatosis complicated by hepatocellular carcinoma. To test the hypothesis that such nodules are preneoplastic lesions, iron-free foci were sought in the initial liver biopsy specimens of 185 patients with untreated and uncomplicated genetic hemochromatosis. Iron-free foci were found in 14 (7.6%) patients, all men, aged from 38 to 76 yr, with heavy iron overload and with fibrosis or cirrhosis. Twelve patients with iron-free foci were followed for 0.9 to 15 yr (7 +/- 6 yr). In six (50%), HCC developed, compared with 2 (8%) from a control group consisting of 24 patients without IFF matched according to age, sex, degree of fibrosis, liver iron amount and follow-up duration. The mean number of iron-free foci per iron-free foci-positive specimen was 3.2 +/- 2.1. Ten patients had dysplastic aspects in their iron-free foci, and four had intrahepatocytic iron-positive inclusions at the periphery of iron-free foci. Proliferative cell nuclear antigen was positive in 75% of iron-free foci and in 24% +/- 21% of hepatocyte nuclei in iron-free foci. This study clearly demonstrates that iron-free foci are proliferative lesions and strongly suggests that such nodules are preneoplastic foci. Therefore the finding of IFF in the initial liver biopsy specimen from a patient with genetic hemochromatosis should lead to regular screening for hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 99%

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

et al. 1993

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“…Further studies of hemochromatosis may be useful in clarifying the relation of non-hepatic malignancies to body iron stores in the general population. o 1995 Wiley-Liss, Inc. * Primary hemochromatosis is a genetic disorder with an autosomal recessive mode of inheritance (Bradbear et al, 1992). It is characterized by excessive absorption and accumulation of iron in most organs, especially in hepatocytes, leading to hepatic cirrhosis, diabetes mellitus.…”

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confidence: 99%

“…It is characterized by excessive absorption and accumulation of iron in most organs, especially in hepatocytes, leading to hepatic cirrhosis, diabetes mellitus. arthritis, cardiomyopathy and hypogonadism (Bradbear et al, 1992). The clinically apparent disease is more common in men, who generally consume more food and thus absorb more iron, while women tend t a lose iron intermittently during menstruation and pregnancy.…”

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“…In addition to autopsy and clinical reports, 2 follow-up studies have shown that the risk of primary liver cancer (PLC), especially hcpatocellular carcinoma (HCC), is very high among patients with hemochromatosis complicated by liver cirrhosis (Niederau ef al., 1985;Bradbear et al, 1985). Earlier surveys of hemochromatosis patients indicated that about 7% developed PLC, although more recently the proportion has risen to almost 30% (Bradbear et al, 1992). This increase probably reflects longer survival of hemochromatosis patients due to earlier detection and more effective therapy by periodic venesections.…”

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Cancer risk following primary hemochromatosis: A population‐based cohort study in Denmark

Hsing

McLaughlin

Olsen

et al. 1995

Intl Journal of Cancer

126

118

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A population-based cohort of 120 Danish men, discharged with a hospital diagnosis of primary hemochromatosis from 1977 to 1989, was followed up to 1989 for subsequent cancer risk. Nineteen subjects (including 6 with primary liver cancers) were excluded from the analysis, either because they died within the same month of hemochromatosis diagnosis or because they had cancer prior to diagnosis of hemochromatosis. Among the 101 remaining subjects, 4 primary liver cancers occurred one year or more after the diagnosis of hemochromatosis, far surpassing the expected number based on incidence rates from the Danish population (standardized incidence ratio 92.9, 95% confidence interval 25.0 to 237.9). The excess of liver cancer was associated with cirrhosis and included cholangiocarcinoma as well as hepatocellular carcinoma. Significantly elevated risks were also observed for non-hepatic cancers (13 cases; SIR 3.5, 95% CI 1.9 to 6.0), notably esophageal cancer (2 cases; SIR 42.9, 95% CI 4.8 to 154.9) and skin melanoma (2 cases; SIR 27.8, 95% CI 3.1 to 100.3). The results of this population-based study are in accordance with the hypothesis that patients with primary hemochromatosis have a substantial risk of primary liver cancer. Further studies of hemochromatosis may be useful in clarifying the relation of non-hepatic malignancies to body iron stores in the general population.

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“…In fact, the risk for primary hepatocellular carcinoma in idiopathic hemochromatosis is more than 200 times greater than that of the control population [2,3]. Awai et al [4] originally developed an experimental model of iron overload using ferric ion chelated with nitrilotriacetate (NTA).…”

Section: Introductionmentioning

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Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α_2U‐globulin to the kidney fatty acid‐binding protein

et al. 1995

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The mechanism of acute nephrotoxicity of an iron chelate in vivo has been investigated. Administration of a renal carcinogen ferric nitrilotriacetate (Fe-NTA) (15 mg Fe/kg body weight, intraperitoneally) led to selective loss of a renal protein with an apparent molecular mass of 17 kDa. Analysis of the 17 kDa protein by NH2-terminal sequence demonstrated its identity over 16 NH2-terminal residues as a kidney fatty acid-binding protein (k-FABP) that is a proteolytically modified form of a2u-globulin, a major urinary protein of adult male rats. An immunochemical study using anti-a2u-globulin polyclonal antibodies confirmed that a single injection of Fe-NTA led to a decrease in k-FABP levels. However, a 19-kDa protein identical to the C~zu-globulin progressively appeared in the kidney, suggesting that the proteolytic processing of azu-globnlin in the renal proximal tubules was suppressed by the treatment with Fe-NTA. By monitoring k-FABP and its precursor Ot2u-globulin , it was determined that repeated exposure to Fe-NTA caused suppression of both proteolytic and endocytotic activity of the kidney. The implications of these data in relation to the nephrotoxicity of Fe-NTA are discussed.renal carcinogenesis mediated by Fe-NTA treatment, the role of iron or Fe-NTA has not been fully established, except for the induction of lipid peroxidation. Okada and his co-workers have shown that membrane lipid peroxidation, as seen biochemically by 2-thiobarbituric acid-reactive substances (TBARS) and histochemically by cold Schiff's method (detection of aldehydes), is one of the basic mechanisms of Fe-NTAinduced renal injury and is closely associated with renal carcinogenesis [10][11][12][13][14]. It can therefore be assumed that these renal oxidative injuries are associated with the alteration of the fundamental functions of the kidney, including reabsorption of filtered proteins from glomerular ultrafiltrate and their proteolysis.In the present paper, based on the identification of a major kidney-specific protein, we demonstrate the alteration of proteolytic and endocytotic functions of the renal brush border membrane caused by Fe-NTA treatment. Materials and methods

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Hepatocellular Carcinoma in Hemochromatosis

Cited by 3 publications

References 45 publications

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

Cancer risk following primary hemochromatosis: A population‐based cohort study in Denmark

Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α_2U‐globulin to the kidney fatty acid‐binding protein

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Hepatocellular Carcinoma in Hemochromatosis

Cited by 3 publications

References 45 publications

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: A study of 185 patients

Cancer risk following primary hemochromatosis: A population‐based cohort study in Denmark

Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α2U‐globulin to the kidney fatty acid‐binding protein

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Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α_2U‐globulin to the kidney fatty acid‐binding protein