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. 1989 Jan;83(1):261–267. doi: 10.1172/JCI113868

Duodenal iron proteins in idiopathic hemochromatosis.

P Whittaker 1, B S Skikne 1, A M Covell 1, C Flowers 1, A Cooke 1, S R Lynch 1, J D Cook 1
PMCID: PMC303670  PMID: 2910911

Abstract

This study was undertaken to assess the relationship between iron absorption and the concentration of duodenal iron proteins in normal subjects and patients with idiopathic hemochromatosis (IH). Biopsies were obtained endoscopically from the duodenum in 17 normal subjects, 3 of whom were mildly iron deficient, and 7 patients with untreated IH. The absorption of both heme and nonheme iron was increased in IH despite a 20-fold elevation in serum ferritin. Immunoassays using MAb were used to measure transferrin, H-rich ferritin, and L-rich ferritin in mucosal samples. Mucosal transferrin concentrations in normal subjects did not correlate with either iron status or iron absorption, indicating that mucosal transferrin plays no physiological role in iron absorption. Mucosal transferrin was significantly lower in IH, presumably because of a decrease in mucosal transferrin receptors. Mucosal H and L ferritin concentrations were directly related to body iron stores and inversely related to iron absorption in normal subjects. In IH, mucosal H and L ferritin failed to increase in parallel with the serum ferritin, but were appropriate for the level of iron absorption. The relationship of mucosal H/L ferritin in IH did not differ from that observed in normal subjects. Our findings indicate that the major abnormality in duodenal iron proteins in IH is a parallel decrease in the concentration of H- and L-rich ferritin. It is not evident whether this is the result or the cause of the absorptive abnormality.

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Selected References

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  1. Arosio P., Adelman T. G., Drysdale J. W. On ferritin heterogeneity. Further evidence for heteropolymers. J Biol Chem. 1978 Jun 25;253(12):4451–4458. [PubMed] [Google Scholar]
  2. Banerjee D., Flanagan P. R., Cluett J., Valberg L. S. Transferrin receptors in the human gastrointestinal tract. Relationship to body iron stores. Gastroenterology. 1986 Oct;91(4):861–869. doi: 10.1016/0016-5085(86)90687-6. [DOI] [PubMed] [Google Scholar]
  3. Beamish M. R., Walker R., Miller F., Worwood M., Jacobs A., Williams R., Corrigall A. Transferrin iron, chelatable iron and ferritin in idiopathic haemochromatosis. Br J Haematol. 1974 Jun;27(2):219–228. doi: 10.1111/j.1365-2141.1974.tb06788.x. [DOI] [PubMed] [Google Scholar]
  4. Blight G. D., Morgan E. H. Ferritin and iron uptake by reticulocytes. Br J Haematol. 1983 Sep;55(1):59–71. doi: 10.1111/j.1365-2141.1983.tb01224.x. [DOI] [PubMed] [Google Scholar]
  5. Boyd D., Vecoli C., Belcher D. M., Jain S. K., Drysdale J. W. Structural and functional relationships of human ferritin H and L chains deduced from cDNA clones. J Biol Chem. 1985 Sep 25;260(21):11755–11761. [PubMed] [Google Scholar]
  6. Broxmeyer H. E., Bognacki J., Dorner M. H., de Sousa M. Identification of leukemia-associated inhibitory activity as acidic isoferritins. A regulatory role for acidic isoferritins in the production of granulocytes and macrophages. J Exp Med. 1981 Jun 1;153(6):1426–1444. doi: 10.1084/jem.153.6.1426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. CROSBY W. H. THE CONTROL OF IRON BALANCE BY THE INTESTINAL MUCOSA. Blood. 1963 Oct;22:441–449. [PubMed] [Google Scholar]
  8. Cartwright G. E., Edwards C. Q., Kravitz K., Skolnick M., Amos D. B., Johnson A., Buskjaer L. Hereditary hemochromatosis. Phenotypic expression of the disease. N Engl J Med. 1979 Jul 26;301(4):175–179. doi: 10.1056/NEJM197907263010402. [DOI] [PubMed] [Google Scholar]
  9. Cook J. D., Layrisse M., Finch C. A. The measurement of iron absorption. Blood. 1969 Mar;33(3):421–429. [PubMed] [Google Scholar]
  10. Cook J. D., Layrisse M., Martinez-Torres C., Walker R., Monsen E., Finch C. A. Food iron absorption measured by an extrinsic tag. J Clin Invest. 1972 Apr;51(4):805–815. doi: 10.1172/JCI106875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cook J. D., Palmer H. E., Pailthorp K. G., Finch C. A. The measurement of iron absorption by whole-body counting. Phys Med Biol. 1970 Jul;15(3):467–473. doi: 10.1088/0031-9155/15/3/007. [DOI] [PubMed] [Google Scholar]
  12. Covell A. M., Einspahr D. E., Skikne B. S., Cook J. D. Specific binding of acidic isoferritins to erythroleukemia K562 cells. J Lab Clin Med. 1987 Dec;110(6):784–790. [PubMed] [Google Scholar]
  13. Cox T. M., Mazurier J., Spik G., Montreuil J., Peters T. J. Iron binding proteins and influx of iron across the duodenal brush border. Evidence for specific lactotransferrin receptors in the human intestine. Biochim Biophys Acta. 1979 Nov 15;588(1):120–128. doi: 10.1016/0304-4165(79)90377-5. [DOI] [PubMed] [Google Scholar]
  14. Dadone M. M., Kushner J. P., Edwards C. Q., Bishop D. T., Skolnick M. H. Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am J Clin Pathol. 1982 Aug;78(2):196–207. doi: 10.1093/ajcp/78.2.196. [DOI] [PubMed] [Google Scholar]
  15. Dawson R. B., Rafal S., Weintraub L. R. Absorption of hemoglobin iron: the role of xanthine oxidase in the intestinal heme-splitting reaction. Blood. 1970 Jan;35(1):94–103. [PubMed] [Google Scholar]
  16. Dezza L., Cazzola M., Piacibello W., Arosio P., Levi S., Aglietta M. Effect of acidic and basic isoferritins on in vitro growth of human granulocyte-monocyte progenitors. Blood. 1986 Mar;67(3):789–795. [PubMed] [Google Scholar]
  17. Eakins J. D., Brown D. A. An improved method for the simultaneous determination of iron-55 and iron-59 in blood by liquid scintillation counting. Int J Appl Radiat Isot. 1966 Jul;17(7):391–397. doi: 10.1016/0020-708x(66)90065-2. [DOI] [PubMed] [Google Scholar]
  18. Edwards C. Q., Griffen L. M., Dadone M. M., Skolnick M. H., Kushner J. P. Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A. Am J Hum Genet. 1986 Jun;38(6):805–811. [PMC free article] [PubMed] [Google Scholar]
  19. Flowers C. A., Kuizon M., Beard J. L., Skikne B. S., Covell A. M., Cook J. D. A serum ferritin assay for prevalence studies of iron deficiency. Am J Hematol. 1986 Oct;23(2):141–151. doi: 10.1002/ajh.2830230209. [DOI] [PubMed] [Google Scholar]
  20. Hallberg L., Björn-Rasmussen E. Determination of iron absorption from whole diet. A new two-pool model using two radioiron isotopes given as haem and non-haem iron. Scand J Haematol. 1972;9(3):193–197. doi: 10.1111/j.1600-0609.1972.tb00930.x. [DOI] [PubMed] [Google Scholar]
  21. Halliday J. W., Mack U., Powell L. W. Duodenal ferritin content and structure: relationship with body iron stores in man. Arch Intern Med. 1978 Jul;138(7):1109–1113. [PubMed] [Google Scholar]
  22. Halliday J. W., Powell L. W., Mack U. Iron absorption in the rat: the search for possible intestinal mucosal carriers. Br J Haematol. 1976 Oct;34(2):237–250. doi: 10.1111/j.1365-2141.1976.tb00194.x. [DOI] [PubMed] [Google Scholar]
  23. Hann H. W., Stahlhut M. W., Chung L. C. Inhibitory effects of isoferritins from tumour and non-tumour tissues on E-rosette formation. Lancet. 1984 Jan 7;1(8367):43–43. doi: 10.1016/s0140-6736(84)90201-0. [DOI] [PubMed] [Google Scholar]
  24. Huebers H. A., Huebers E., Csiba E., Rummel W., Finch C. A. The significance of transferrin for intestinal iron absorption. Blood. 1983 Feb;61(2):283–290. [PubMed] [Google Scholar]
  25. Huebers H., Huebers E., Forth W., Rummel W. Binding of iron to a non-ferritin protein in the mucosal cells of normal and iron-deficient rats during absorption. Life Sci I. 1971 Oct 15;10(20):1141–1148. doi: 10.1016/0024-3205(71)90274-8. [DOI] [PubMed] [Google Scholar]
  26. Jacobs A. Ferritin: an interim review. Curr Top Hematol. 1985;5:25–62. [PubMed] [Google Scholar]
  27. Jones B. M., Worwood M. An immunoradiometric assay for the acidic ferritin of human heart: application to human tissues, cells and serum. Clin Chim Acta. 1978 Apr 3;85(1):81–88. doi: 10.1016/0009-8981(78)90104-3. [DOI] [PubMed] [Google Scholar]
  28. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  29. Layrisse M., Martinez-Torres C., Cook J. D., Walker R., Finch C. A. Iron fortification of food: its measurement by the extrinsic tag method. Blood. 1973 Mar;41(3):333–352. [PubMed] [Google Scholar]
  30. Matzner Y., Hershko C., Polliack A., Konijn A. M., Izak G. Suppressive effect of ferritin on in vitro lymphocyte function. Br J Haematol. 1979 Jul;42(3):345–353. doi: 10.1111/j.1365-2141.1979.tb01142.x. [DOI] [PubMed] [Google Scholar]
  31. McGill J. R., Naylor S. L., Sakaguchi A. Y., Moore C. M., Boyd D., Barrett K. J., Shows T. B., Drysdale J. W. Human ferritin H and L sequences lie on ten different chromosomes. Hum Genet. 1987 May;76(1):66–72. doi: 10.1007/BF00283053. [DOI] [PubMed] [Google Scholar]
  32. Momtazi S., Herbert V. Intestinal absorption using vibration-obtained individual small bowel epithelial cells of the rat: folate absorption. Am J Clin Nutr. 1973 Jan;26(1):23–29. doi: 10.1093/ajcn/26.1.23. [DOI] [PubMed] [Google Scholar]
  33. Osterloh K. R., Simpson R. J., Peters T. J. The role of mucosal transferrin in intestinal iron absorption. Br J Haematol. 1987 Jan;65(1):1–3. doi: 10.1111/j.1365-2141.1987.tb06126.x. [DOI] [PubMed] [Google Scholar]
  34. Osterloh K., Schümann K., Ehtechami C., Forth W. Transferrin in isolated cells from rat duodenum and jejunum. Blut. 1985 Jul;51(1):41–47. doi: 10.1007/BF00320599. [DOI] [PubMed] [Google Scholar]
  35. Parmley R. T., Barton J. C., Conrad M. E. Ultrastructural localization of transferrin, transferrin receptor, and iron-binding sites on human placental and duodenal microvilli. Br J Haematol. 1985 May;60(1):81–89. doi: 10.1111/j.1365-2141.1985.tb07388.x. [DOI] [PubMed] [Google Scholar]
  36. Pollack S., Lasky F. D. Guinea pig intestinal iron binding protein. Biochem Biophys Res Commun. 1976 May 17;70(2):533–539. doi: 10.1016/0006-291x(76)91079-2. [DOI] [PubMed] [Google Scholar]
  37. Powell L. W., Campbell C. B., Wilson E. Intestinal mucosal uptake of iron and iron retention in idiopathic haemochromatosis as evidence for a mucosal abnormality. Gut. 1970 Sep;11(9):727–731. doi: 10.1136/gut.11.9.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Saddi R., Feingold J. Idiopathic haemochromatosis: an autosomal recessive disease. Clin Genet. 1974;5(3):234–241. doi: 10.1111/j.1399-0004.1974.tb01688.x. [DOI] [PubMed] [Google Scholar]
  39. Savin M. A., Cook J. D. Iron transport by isolated rat intestinal mucosal cells. Gastroenterology. 1978 Oct;75(4):688–694. [PubMed] [Google Scholar]
  40. Sciot R., Paterson A. C., Van den Oord J. J., Desmet V. J. Lack of hepatic transferrin receptor expression in hemochromatosis. Hepatology. 1987 Sep-Oct;7(5):831–837. doi: 10.1002/hep.1840070507. [DOI] [PubMed] [Google Scholar]
  41. Simon M., Bourel M., Genetet B., Fauchet R. Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing. N Engl J Med. 1977 Nov 10;297(19):1017–1021. doi: 10.1056/NEJM197711102971901. [DOI] [PubMed] [Google Scholar]
  42. Simpson R. J., Osterloh K. R., Raja K. B., Snape S. D., Peters T. J. Studies on the role of transferrin and endocytosis in the uptake of Fe3+ from Fe-nitrilotriacetate by mouse duodenum. Biochim Biophys Acta. 1986 Oct 29;884(1):166–171. doi: 10.1016/0304-4165(86)90240-0. [DOI] [PubMed] [Google Scholar]
  43. Skikne B. S. A commercial electrochemical method evaluated for measurement of iron status. Clin Chem. 1987 Sep;33(9):1645–1647. [PubMed] [Google Scholar]
  44. The measurement of total and unsaturated iron-binding capacity in serum. Br J Haematol. 1978 Feb;38(2):281–287. doi: 10.1111/j.1365-2141.1978.tb01044.x. [DOI] [PubMed] [Google Scholar]
  45. Theil E. C. Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem. 1987;56:289–315. doi: 10.1146/annurev.bi.56.070187.001445. [DOI] [PubMed] [Google Scholar]
  46. Ulvik R. J. Relevance of ferritin-binding sites on isolated mitochondria to the mobilization of iron from ferritin. Biochim Biophys Acta. 1982 Mar 15;715(1):42–51. doi: 10.1016/0304-4165(82)90047-2. [DOI] [PubMed] [Google Scholar]
  47. WENNESLAND R., BROWN E., HOPPER J., Jr, HODGES J. L., Jr, GUTTENTAG O. E., SCOTT K. G., TUCKER I. N., BRADLEY B. Red cell, plasma and blood volume in healthy men measured by radiochromium (Cr51) cell tagging and hematocrit: influence of age, somatotype and habits of physical activity on the variance after regression of volumes to height and weight combined. J Clin Invest. 1959 Jul;38(7):1065–1077. doi: 10.1172/JCI103883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Walters G. O., Jacobs A., Worwood M., Trevett D., Thomson W. Iron absorption in normal subjects and patients with idiopathic haemochromatosis: relationship with serum ferritin concentration. Gut. 1975 Mar;16(3):188–192. doi: 10.1136/gut.16.3.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. el Guindi M., Skikne B. S., Covell A. M., Cook J. D. An immunoassay for human transferrin. Am J Clin Nutr. 1988 Jan;47(1):37–41. doi: 10.1093/ajcn/47.1.37. [DOI] [PubMed] [Google Scholar]

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