Iron Metabolism. Iron Stores in Man as Measured by Phlebotomy 1

Haskins, Donald; Stevens, Alexander R.; Finch, Stuart C.; Finch, Clement A.

doi:10.1172/jci102639

Cited by 160 publications

(72 citation statements)

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“…The significant correlations of TfSat and SF we observed herein confirm these observations. Similarly, Hb and MCV decrease predictably in C282Y homozygotes during therapeutic phlebotomy [3,10,11] and in control subjects undergoing experimental phlebotomy [12][13][14][15] to achieve iron depletion. Therapeutic phlebotomy is associated with decreasing values of MCV in C282Y homozygotes [3,10,11].…”

Section: Discussionmentioning

confidence: 99%

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 lg/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P 5 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P 5 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women. Am. J. Hematol. 82:898-905, 2007. V V C 2007 Wiley-Liss, Inc. IntroductionElevated values of mean corpuscular volume (MCV) are common in persons with hemochromatosis. In early series of hemochromatosis cases, this was attributed to hepatic cirrhosis [1], a then-current diagnostic criterion of hemochromatosis and a common sequel of severe iron overload [1,2]. In Alabama hemochromatosis probands diagnosed in medical care, mean MCV and hemoglobin concentration (Hb) were significantly greater in HFE C282Y homozygotes than in probands with other HFE genotypes or in control subjects, and 44% of all probands had prephlebotomy values of MCV greater than the upper reference limit [3]. Further, there was a significant positive association of MCV in HFE C282Y homozygotes with serum transferrin saturation (TfSat) at diagnosis and with quantities of iron removed by phlebotomy to achieve iron depletion, but not with the presence of human leukocyte antigen-A*03 [3]. In a southern California hemochromatosis screening program that evaluated persons who attended a health appraisal clinic, mean TfSat, mean serum ferritin concentration (SF), mean MCV, and mean Hb were higher than the corresponding measures in participants without common HFE mutations [4].

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Section: Discussionmentioning

confidence: 99%

Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study

McLaren

Barton²,

et al. 2007

American J Hematol

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“…When iron stores are reduced and erythropoiesis is normal, iron absorption is increased. 21,22 The store regulator also acts to reduce absorption when iron stores are increased. Erythropoiesis clearly affects iron absorption and the effects of the "erythroid regulator" seem more pronounced than those of the store regulator.…”

Section: Discussionmentioning

confidence: 99%

Regulation of iron absorption in Hfe mutant mice

Ajioka

Levy

Andrews

et al. 2002

Blood

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Hereditary hemochromatosis is most commonly caused by homozygosity for a point mutation (C282Y) in the human hemochromatosis gene (HFE). The mechanism by which HFE regulates iron absorption is not known, but the C282Y mutation results in loss of cell surface expression of the human hemachromatosis protein (HFE) and hyperabsorption of iron by the duodenal enterocyte. Mice homozygous for a deletion in the mouse hemochromatosis gene (Hfe) or a mutation equivalent to that seen in human hereditary hemochromatosis IntroductionHereditary hemochromatosis is one of the most common inherited disorders of whites, affecting nearly 5 per 1000 people of Northern European extraction. 1 The gene mutated in hereditary hemochromatosis, the human hemochromatosis gene (HFE), is a major histocompatibility complex (MHC) class I-like gene. 2 The HFE mutation most frequently found in hereditary hemochromatosis results in a cysteine-to-tyrosine conversion at amino acid 282 in a region of the human hemachromatosis protein (HFE) corresponding to the ␣3 domain in class I proteins. This mutation results in the loss of interaction with ␤ 2 -microglobulin and decreased cell surface expression of HFE. 3 The HFE-␤ 2 microglobulin heterodimer interacts with the transferrin receptor (TfR), resulting in a conformational change causing a reduction in the affinity of the receptor for diferric transferrin (Tf (Fe) 2 ). 4-6 Despite increasing information regarding HFE structure and expression, 7,8 the mechanism by which HFE regulates iron absorption remains undefined.Iron absorption is mediated by the duodenal enterocyte. Absorption is affected by the rate at which iron is imported from the gut lumen into the enterocyte and the rate at which it is exported to the plasma. An importer (natural resistance-associated macrophage protein 2 (Nramp2), divalent cation transporter 1 (DCT1), divalent metal transporter 1 (DMT1)) and an exporter (ferroportin1, ironregulated transporter 1 (Ireg1), metal transporter protein 1 (MTP1)) in enterocytes have been identified, but whether or not HFE directly affects the activity of these iron transporters is not known. 9-13 The murine hemochromatosis gene (Hfe) has been altered by recombination to produce both knockout mice and mice homozygous for the C282Y mutation (knockin). 14,15 Both mutant strains develop iron overload with aging and serve as useful models for hemochromatosis. We used Hfe knockout and knockin mice to determine the contribution of mouse hemachromatosis protein (Hfe) to the regulation of intestinal iron absorption in iron-replete, iron-loaded, and iron-deficient states and in mice with stimulated erythropoiesis. Materials and methods Mice and dietsAll mice used in these experiments were of the 129/SvEvTac strain. 15 Mice were maintained in the Animal Resource Center at the University of Utah following approved guidelines. For dietary studies, mice were maintained on a standard rodent diet (Harlan Teklad TD 8640) containing approximately 0.33 g of iron per kilogram, a diet supplemented with 20 g carbony...

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“…Supplementary medicinal iron seems indicated for individuals who undergo chronic blood loss, have increased physiological requirements, or have an absorptive defect due to an operative procedure, e.g., subtotal gastrectomy, or steatorrhea (7,26,38,39). Therapy should be continued after the hemoglobin level has been restored to normal since it has been shown that depleted iron stores are not easily reconstituted (40).…”

Section: Experimental Subjects and Methodsmentioning

confidence: 99%