Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-26T07:50:41.992Z Has data issue: false hasContentIssue false
  • English
  • Français

Iron deficiency and iron overload: effects of diet and genes

Published online by Cambridge University Press:  28 August 2007

Wylie Burke ,
Giuseppina Imperatore  and
Michelle Reyes
Wylie Burke*
Affiliation:
Department of Medical History and Ethics, University of Washington, Seattle, WA 98195, USA
Giuseppina Imperatore
Affiliation:
Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA
Michelle Reyes
Affiliation:
Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA
*
*Corresponding author: Dr Wylie Burke, fax +1 206 685 7515, email wburke@u.washington.edu
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some HFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

Keywords

Iron deficiencyIron overloadHereditary haemochromatosisIron regulatory pathway
Type
Micronutrient and Reprod. and Dev. Grps Sym. on relative contribution of diet and genotype to dev.
Information
Proceedings of the Nutrition Society , Volume 60 , Issue 1 , February 2001 , pp. 73 - 80
Copyright
Copyright © The Nutrition Society 2001

References

Adams, PC (1992) Intrafamilial variation in hereditary hemochromatosis. Digestive Diseases and Sciences 37, 361–363.CrossRefGoogle ScholarPubMed
Adams, PC, Campion, ML, Gandon, G, LeGall, JY, David, V & Jouanolle, AM (1997 a) Clinical and family studies in genetics hemochromatosis: Microsatellite and HFE studies in five atypical families. Hepatology 26, 991–995.Google Scholar
Adams, PC, Deugnier, Y, Moirand, R & Brissot, P (1997 b) The relationship between iron overload, clinical symptoms and age in 410 hemochromatosis patients. Hepatology 25, 162–166.CrossRefGoogle Scholar
Andrews, NC (1999) Disorders of iron metabolism. New England Journal of Medicine 341, 1986–1995.CrossRefGoogle ScholarPubMed
Bacon, BR & Sadiq, SA (1997) Hereditary hemochromatosis: presentation and diagnosis in the 1990s. American Journal of Gastroenterology 92, 784–789.Google Scholar
Barton, JC, Edwards, CQ, Bertoli, LF, Shroyer, TW & Hudson, SL (1995) Iron overload in African Americans. American Journal of Medicine 99, 616–623.Google Scholar
Beutler, E (2000) Evidence for multiple hemochromatosis genes. In Hemochromatosis, pp. 99–103 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.CrossRefGoogle ScholarPubMed
Bloom, PD, Burstien, GR & Gorduek, VR (2000) Iron overload in African Americans. In Hemochromatosis, pp. 475–484 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.CrossRefGoogle Scholar
Bodmer, JG, Marsh, SG, Albert, ED, Bodmer, WF, Bontrop, RE, Charron, D, Dupont, B, Erlich, HA, Fauchet, R, Mach, B, Mayr, WR, Parham, P, Sasazuki, T, Schreuder, GM, Strominger, JL, Svejgaard, A & Terasaki, PI (1997) Nomenclature for factors of the HLA system, 1996. Vox Sanguinis 73, 105–130.Google Scholar
Bothwell, TH, Charlton, RW & Motulsky, AG (1995) Hemochromatosis. In The Metabolic and Molecular Bases of Inherited Disease, 7th ed., pp. 2237–2270 [Scriver, CR, Beaudet, AL, Sly, WS and Valle, D, editors]. New York: McGraw Hill.Google Scholar
Boulton, F, Collis, D, Inskip, H, Paes, H & Garlick, M (2000) A study of iron and HFE status in blood donors, including a group who failed the initial screen for anaemia. British Journal of Haematology 108, 434–439.CrossRefGoogle ScholarPubMed
Bradley, L, Johnson, D, Palomaki, G, Haddow, J, Robertson, N & Ferrie, R (1998) Hereditary haemochromatosis mutation frequencies in the general population. Journal of Medical Screening 5, 34–36.CrossRefGoogle ScholarPubMed
Brown, KE & Bacon, BR (2000) Hepatic iron metabolism in hemochromatosis. In Hemochromatosis, pp. 157–162 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.CrossRefGoogle Scholar
Bulaj, ZJ, Griffen, LM, Jorde, LB, Edwards, CQ & Kushner, JP (1996) Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. New England Journal of Medicine 335, 1799–1805.Google Scholar
Burke, W, Imparatore, G, McDonnell, SM, Baron, RC & Khoury, MJ (2000) Contribution of different HFE genotypes to iron overload: a pooled analysis. Genetics in Medicine 2, 271–277.CrossRefGoogle ScholarPubMed
Burt, MJ, George, PM, Upton, JD, Collett, JA, Frampton, CM, Chapman, TM, Walmsley, TA & Chapman, BA (1998) The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 43, 830–836.Google Scholar
Camaschella, C, Roetto, A, Cali, A, De Gobbi, M, Garozzo, G, Carella, M, Majarano, N, Totaro, A & Gasparini, P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nature Genetics 25, 14–15.CrossRefGoogle Scholar
Centers for Disease Control and Prevention (1996) Iron overload disorders among Hispanics–San Diego, California, 1995. Morbidity and Mortality Weekly Report 45, 991–993.Google Scholar
Cogswell, ME, McDonnell, SM, Khoury, MJ, Franks, AL, Burke, W & Brittenham, G (1998) Iron overload, public health and genetics: evaluating the evidence for hemochromatosis screening. Annals of Internal Medicine 129, 971–979.CrossRefGoogle ScholarPubMed
Conrad, ME, Umbreit, JN, Moore, EG & Parmley, RT (2000) Intestinal iron absorption in hemochromatosis. In Hemochromatosis, pp. 118–130 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.Google Scholar
Edwards, CQ, Griffen, LM, Bulaj, ZJ, Ajioka, RS & Kushner, JP (2000) The iron phenotype of hemochromatosis heterozygotes. In Hemochromatosis, pp. 411–418 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.Google Scholar
Edwards, JA & Hoke, JE (1972) Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proceedings of the Society for Experimental Biology and Medicine 141, 81–84.CrossRefGoogle ScholarPubMed
Elsenstein, RS & Blemings, KP (1998) Iron regulatory proteins, iron responsive elements and iron hemostasis. Journal of Nutrition 128, 2295–2298.Google Scholar
Fargion, S, Mandelli, C, Piperno, A, Cesana, B, Fracanzani, AL, Fraquelli, M, Bianchi, PA, Fiorelli, G & Conte, D (1992) Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 15, 655–659.CrossRefGoogle ScholarPubMed
Feder, JN, Gnirke, A, Thomas, W, Tsuchihashi, Z, Ruddy, DA, Basava, A et al. . (1996) A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. Nature Genetics 13, 399–408.CrossRefGoogle Scholar
Feder, JN, Penny, DM, Irrinki, A, Lee, VK, Lebron, JA, Watson, N, Tsuchihashi, Z, Sigal, E, Bjorkman, PJ & Schatzman, RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proceedings of the National Academy of Sciences USA 95, 1472–1477.CrossRefGoogle ScholarPubMed
Feder, JN, Tsuchihashi, Z, Irrinki, A, Lee, VK, Mapa, FA, Morikang, E, Prass, CE, Starnes, SM, Wolff, RK, Parkkila, S, Sly, WS & Schatzman, RC (1997) The hemochromatosis founder mutation in HLA-H disrupts beta-2-microglobulin interactions and cell surface expression. Journal of Biological Chemistry 272, 14025–14028.CrossRefGoogle ScholarPubMed
Galan, P, Yoon, HC, Preziosi, P, Viteri, F, Valeix, P, Briancon, S, Malvy, D, Roussel, AM, Favier, A & Hercberg, S (1998) Determining factors in the iron status of adult women in the SU.VI. MAX study. European Journal of Clinical Nutrition 52, 383–388.CrossRefGoogle ScholarPubMed
Gordeuk, V, Mukiibi, J, Hasstedt, SJ, Samowitz, W, Edwards, CQ, West, G et al. . (1992) Iron overload in Africa: interaction between a gene and dietary iron content. New England Journal of Medicine 326, 95–100.Google Scholar
Halliday, JW (1998) Hemochromatosis and iron needs. Nutrition Reviews 56, Suppl. II, S30–S37.Google Scholar
Hanson, E, Imperatore, G & Burke, W (2000) HFE gene and hereditary hemochromatosis. American Journal of Epidemiology (In the Press).Google Scholar
Kaltwasser, JP (2000) Juvenile hemochromatosis. In Hemochromatosis, pp. 318–325 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.CrossRefGoogle Scholar
Lawson, MS, Thomas, M & Hardiman, A (1998) Iron status of Asian children aged 2 years living in England. Archives of Disease in Childhood 78, 420–426.Google Scholar
Looker, AC, Dallman, PR, Carroll, MD, Gunter, EW & Johnson, CL (1997) Prevalence of iron deficiency in the United States. Journal of the American Medical Association 277, 973–976.Google Scholar
Lebron, JA, Bennet, MJ, Vaughn, DE, Chirino, AJ, Snow, PM, Mintier, GA, Feder, JN & Bjorkman, PJ (1998) Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93, 111–123.Google Scholar
Levy, JE, Montross, LK & Andrews, NC (2000) Genes that modify the hemochromatosis phenotype in mice. Journal of Clinical Investigation 105, 1209–1216.CrossRefGoogle ScholarPubMed
Morse, AC, Beard, JL & Jones, BC (1999) A genetic developmental model of iron deficiency: biological aspects. Proceedings of the Society for Experimental Biology and Medicine 220, 147–152.Google Scholar
Mura, C, Raguenes, O & Ferec, C (1999) HFE mutation analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93, 2502–2506.Google Scholar
National Center for Biotechnology Information (2000) Hemochromatosis; HFE. http://www.ncbi.nlm.nih.gov/htbin-post/Omin Google Scholar
Niederau, C, Fischer, R, Purschel, A, Stremmel, W, Haussinger, D & Strohmeyer, G (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110, 1107–1119.CrossRefGoogle ScholarPubMed
Niederau, C, Niederau, CM, Lange, S, Littauer, A, Abdel-Jalil, N, Maurer, M, Haussinger, D & Strohmeyer, G (1998) Screening for hemochromatosis and iron deficiency in employees and primary care patients in Western Germany. Annals of Internal Medicine 128, 337–345.Google Scholar
Olynyk, JK, Cullen, DJ, Aquila, S, Rossi, E, Summerville, L & Powell, LW (1999) A population-based study of the clinical expression of the hemochromatosis gene. New England Journal of Medicine 341, 718–724.Google Scholar
Parkilla, S, Waheed, A, Britton, RS, Feder, JN, Tsuchihashi, Z, Schatzman, RC, Bacon, BR & Sly, WS (1997) Immunohistochemistry of HLA-H, the protein defective in patients with hemochromatosis, reveals unique pattern of expression in hereditary hemochromatosis. Proceedings of the National Academy of Sciences USA 94, 2534–2539.Google Scholar
Pietrangelo, A, Montosi, G, Totaro, A, Garuti, C, Conte, D, Cassanelli, S, Fraquelli, M, Sardini, C, Vasta, F & Gasparini, P (1998) Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. New England Journal of Medicine 341, 725–732.CrossRefGoogle Scholar
Provan, D (1999) Mechanisms and management of iron deficiency. British Journal of Haematology 105, Suppl. 1, 19–26.Google Scholar
Ramm, GA (2000) Animal models of iron overload based on excess exogenous iron. In Hemochromatosis, pp. 494–507 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.CrossRefGoogle Scholar
Roetto, A, Totaro, A, Cazzola, M, Ciciliano, M, Bosio, S, D'Ascola, G, Carella, M, Zelante, L, Kelly, AL, Cox, TM, Gasparini, P & Camaschella, C (1999) Juvenile hemochromatosis locus maps to chormosome 1q. American Journal of Human Genetics 64, 1388–1393.Google Scholar
Rossi, E, Olynyk, JK, Cullen, DJ, Papadopoulos, G, Bulsara, M, Summerville, L & Powell, LW (2000) Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clinical Chemistry 46, 162–166.Google Scholar
Simon, M, Bourel, M, Fauchet, R & Genetet, B (1976) Association of HLA-A3 and HLA-B14 with idiopathic haemochromatosis. Gut 5, 332–334.Google Scholar
Skikne, BS (2000) Intestinal iron-binding proteins. In Hemochromatosis, pp. 107–117 [Barton, JC and Edwards, CQ, editors]. New York: Cambridge University Press.Google Scholar
US Department of Agriculture, Agricultural Research Service (1997) Results from USDA's 1994–96 Continuing Survey of Food Intakes by Individuals and 1994–96 Diet and Health Knowledge Survey. http://www.barc.usda.gov/bhnrc/foodsurvey/Google Scholar
Waheed, A, Parkkila, S, Saarnio, J, Fleming, RE, Zhou, XY, Tomatsu, S, Britton, RS, Bacon, BR & Sly, WS (1999) Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proceedings of the National Academy of Sciences USA 96, 1579–1584.CrossRefGoogle ScholarPubMed
Waheed, A, Parkkila, S, Zhou, XY, Tomatsu, S, Tsuchihashi, Z, Feder, JN, Scatzman, RC, Britton, RS, Bacon, BR & Sly, WS (1997) Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta-2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proceedings of the National Academy of Sciences USA 94, 12384–12389.Google Scholar
Wharton, BA (1999) Iron deficiency in children: detection and prevention. British Journal of Haematology 106, 270–280.Google Scholar
Whitfield, JB, Cullen, LM, Jazwinska, EC, Powell, LW, Heath, AC, Zhu, G, Duffy, DL & Martin, NG (2000) Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. American Journal of Human Genetics 66, 1246–1258.Google Scholar
Yip, R, Parvanta, I, Cogswell, ME, McDonnell, SM, Bowman, BA, Gurmmer-Strawn, LM & Trowbridge, F (1998) Recommendations to prevent and control iron deficiency in the United States. Morbidity and Mortality Weekly Report 47, 1–29.Google Scholar
Zhou, XY, Tomatsu, S, Fleming, RE, Parkkila, S, Waheed, A, Jiang, J, Fei, Y, Brunt, EM, Ruddy, DA, Prass, CE, Schatzman, RC, O'Neill, R, Britton, RS, Bacon, BR & Sly, WS (1998) HFE gene knockout produces mouse model of hereditary hemochromatosis. Proceedings of the National Academy of Sciences USA 95, 2492–2497.Google Scholar