Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-02T19:52:08.974Z Has data issue: false hasContentIssue false

4 - Tests for hemochromatosis and iron overload

Published online by Cambridge University Press:  01 June 2011

James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
By
James C. Barton ,
Corwin Q. Edwards ,
Pradyumna D. Phatak ,
Robert S. Britton  and
Bruce R. Bacon
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah Medical Center
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
James C. Barton
Affiliation:
University of Alabama, Birmingham
Corwin Q. Edwards
Affiliation:
University of Utah School of Medicine, Salt Lake City
Pradyumna D. Phatak
Affiliation:
University of Rochester Medical Center, New York
Robert S. Britton
Affiliation:
St Louis University, Missouri
Bruce R. Bacon
Affiliation:
St Louis University, Missouri
Get access

Summary

Iron overload and associated abnormalities can be detected by diverse biochemical and physicochemical tests. It is also possible to predict susceptibility to develop iron overload in some persons by the appropriate selection and interpretation of molecular genetic analyses. In this chapter, the clinical and laboratory assessment of iron overload is reviewed.

Transferrin and transferrin saturation

Transferrin is a ~80 kDa metal-binding glycoprotein synthesized by hepatocytes. It is the predominant iron transporter in plasma, and is responsible for the capture, transport, and distribution of free iron. Each molecule of transferrin has two high-affinity iron-binding sites, each of which can bind one ferric ion. Iron binding to transferrin is maximal at alkaline values of pH, and in the presence of bicarbonate. Transferrin binds iron absorbed via enterocytes and iron that is released by macrophages and hepatocytes. In healthy subjects, much transferrin-bound iron is delivered to erythroblasts in the bone marrow for hemoglobin synthesis via specific transferrin receptors (Chapter 2). Transferrin also transports iron to other tissues that accept iron via similar receptors. In normal subjects, approximately eight times the amount of plasma iron quantified in static measurements is delivered by transferrin to target cells each day. Transferrin also binds and transports certain non-ferrous metals (Chapter 8).

Normal subjects

The capacity of serum transferrin to bind iron is measured by automated clinical laboratory methods as the serum total iron-binding capacity (TIBC). Typically, this is calculated as the sum of the serum iron concentration and the serum unbound iron-binding capacity (UIBC).

Type
Chapter
Information
Handbook of Iron Overload Disorders , pp. 34 - 64
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Benyamin, B, McRae, AF, Zhu, G, et al. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009; 84: 60.CrossRefGoogle ScholarPubMed
Adams, PC, Reboussin, DM, Barton, JC, et al. Hemochromatosis and iron overload screening in a racially diverse population. N Engl J Med 2005; 352: 1769–78.CrossRefGoogle Scholar
Barton, JC, Acton, RT, Dawkins, FW, et al. Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study. Genet Test 2005; 9: 231–41.CrossRefGoogle ScholarPubMed
Harris, EL, McLaren, CE, Reboussin, DM, et al. Serum ferritin and transferrin saturation in Asians and Pacific Islanders. Arch Intern Med 2007; 167: 722–6.CrossRefGoogle ScholarPubMed
Edwards, CQ, Griffen, LM, Kaplan, J, Kushner, JP.Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes. J Intern Med 1989; 226: 373–9.CrossRefGoogle ScholarPubMed
Torti, FM, Torti, SV.Regulation of ferritin genes and protein. Blood 2002; 99: 3505–16.CrossRefGoogle Scholar
Witte, DL, Crosby, WH, Edwards, CQ, Fairbanks, VF, Mitros, FA.Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis. Clin Chim Acta 1996; 245: 139–200.CrossRefGoogle ScholarPubMed
Adams, PC, Bhayana, V.Unsaturated iron-binding capacity: a screening test for C282Y hemochromatosis?Clin Chem 2000; 46: 1870–1.Google ScholarPubMed
Adams, PC, Kertesz, AE, McLaren, CE, Barr, R, Bamford, A, Chakrabarti, S.Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5211 voluntary blood donors. Hepatology 2000; 31: 1160–64.CrossRefGoogle ScholarPubMed
Witte, DL.Mild liver enzyme abnormalities: eliminating hemochromatosis as cause. Clin Chem 1997; 43: 1535–38.Google ScholarPubMed
Adams, PC, Reboussin, DM, Press, RD, et al. Biological variability of transferrin saturation and unsaturated iron-binding capacity. Am J Med 2007; 120: 999. e1–7.CrossRefGoogle ScholarPubMed
Beutler, E, Felitti, VJ, Koziol, JA, Ho, NJ, Gelbart, T.Penetrance of 845G>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211–18.CrossRefGoogle Scholar
Westerhausen, M, Meuret, G.Transferrin-immune complex disease. Acta Haematol 1977; 57: 96–101.CrossRefGoogle ScholarPubMed
Harrison, PM, Arosio, P.The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996; 1275: 161–203.CrossRefGoogle ScholarPubMed
Worwood, M.Serum ferritin. CRC Crit Rev Clin Lab Sci 1979; 10: 171–204.CrossRefGoogle ScholarPubMed
Worwood, M.Serum ferritin. Clin Sci (Lond) 1986; 70: 215–20.CrossRefGoogle ScholarPubMed
Worwood, M.Ferritin. Blood Rev 1990; 4: 259–69.CrossRefGoogle ScholarPubMed
Worwood, M.The diagnostic value of serum ferritin determinations for assessing iron status. Haematologia (Budap) 1987; 20: 229–35.Google ScholarPubMed
Herbert, V, Jayatilleke, E, Shaw, S, et al. Serum ferritin iron, a new test, measures human body iron stores unconfounded by inflammation. Stem Cells 1997; 15: 291–6.CrossRefGoogle ScholarPubMed
Morrison, ED, Brandhagen, DJ, Phatak, PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among US patients with phenotypic hemochromatosis. Ann Intern Med 2003; 138: 627–33.CrossRefGoogle Scholar
Beaumont, C, Simon, M, Fauchet, R, et al. Serum ferritin as a possible marker of the hemochromatosis allele. N Engl J Med 1979; 301: 169–74.CrossRefGoogle ScholarPubMed
Waalen, J, Felitti, VJ, Gelbart, T, Beutler, E.Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008; 111: 3373–6.CrossRefGoogle ScholarPubMed
Barton, JC.Ferritin >1000: grand for hemochromatosis screening?Blood 2008; 111: 3309.CrossRefGoogle Scholar
Cox, DW.Factors influencing serum ceruloplasmin levels in normal individuals. J Lab Clin Med 1966; 68: 893–904.Google ScholarPubMed
Tutor-Crespo, MJ, Hermida, J, Tutor, JC.Assessment of copper status in epileptic patients treated with anticonvulsant drugs by measuring the specific oxidase activity of ceruloplasmin. Epilepsy Res 2003; 56: 1473.CrossRefGoogle ScholarPubMed
Domenico, I, Word, DM, di Patti, MCet al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing EPI-ceruloplasmin. EMBOJ 2007; 26; 2823–31.CrossRefGoogle Scholar
Wilson, SAK.Progressive lenticular degeneration. A familial nervous disease associated with cirrhosis of the liver. Brain 1912; 34: 295–309.CrossRefGoogle Scholar
Davies, LP, Macintyre, G, Cox, DW.New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test 2008; 12: 139–45.CrossRefGoogle ScholarPubMed
Davies, L, Kenney, S, Cox, DW. Wilson Disease Mutation Database. University of Alberta. 01/23/2010.Google Scholar
Mak, CM, Lam, CW.Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci 2008; 45: 263–90.CrossRefGoogle ScholarPubMed
Scheinberg, I, Sternlieb, AI.Wilson's disease. Major Probl Intern Med 1984; 23: 1–24.Google Scholar
Olivarez, L, Caggana, M, Pass, KA, Ferguson, P, Brewer, GJ.Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach. Ann Hum Genet 2001; 65: 459–63.CrossRefGoogle ScholarPubMed
Owada, M, Suzuki, K, Fukushi, M, Yamauchi, K, Kitagawa, T.Mass screening for Wilson's disease by measuring urinary holoceruloplasmin. J Pediatr 2002; 140: 614–16.CrossRefGoogle ScholarPubMed
Ohura, T, Abukawa, D, Shiraishi, H, et al. Pilot study of screening for Wilson's disease using dried blood spots obtained from children seen at outpatient clinics. J Inherit Metab Dis 1999; 22: 74–80.CrossRefGoogle ScholarPubMed
Yamaguchi, Y, Aoki, T, Arashima, S, et al. Mass screening for Wilson's disease: results and recommendations. Pediatr Int 1999; 41: 405–8.CrossRefGoogle ScholarPubMed
Kim, GH, Yang, JY, Park, JY, Lee, JJ, Kim, JH, Yoo, HW.Estimation of Wilson's disease incidence and carrier frequency in the Korean population by screening ATP7B major mutations in newborn filter papers using the SYBR green intercalator method based on the amplification refractory mutation system. Genet Test 2008; 12: 395–9.CrossRefGoogle Scholar
Walshe, JM, Cox, DW.Effect of treatment of Wilson's disease on natural history of haemochromatosis. Lancet 1998; 352: 112–13.CrossRefGoogle ScholarPubMed
Hafkemeyer, P, Schupp, M, Storch, M, Gerok, W, Haussinger, D.Excessive iron storage in a patient with Wilson's disease. Clin Investig 1994; 72: 134–6.CrossRefGoogle Scholar
Shiono, Y, Wakusawa, S, Hayashi, H, et al. Iron accumulation in the liver of male patients with Wilson's disease. Am J Gastroenterol 2001; 96: 31471.CrossRefGoogle ScholarPubMed
Hayashi, H, Yano, M, Fujita, Y, Wakusawa, S.Compound overload of copper and iron in patients with Wilson's disease. Med Mol Morphol 2006; 39: 121–6.CrossRefGoogle ScholarPubMed
Fasano, A, Bentivoglio, AR, Colosimo, C.Movement disorder due to aceruloplasminemia and incorrect diagnosis of hereditary hemochromatosis. J Neurol 2007; 254: 113–14.CrossRefGoogle ScholarPubMed
Abuzetun, JY, Hazin, R, Suker, M, Porter, J.A rare case of hemochromatosis and Wilson's disease coexisting in the same patient. J Natl Med Assoc 2008; 100: 112–14.CrossRefGoogle ScholarPubMed
Sheldon, JH.Haemochromatosis. London, Oxford University Press, 1935.Google Scholar
Bacon, BR.Hemochromatosis: diagnosis and management. Gastroenterology 2001; 120: 718–25.CrossRefGoogle ScholarPubMed
Tavill, AS.Diagnosis and management of hemochromatosis. Hepatology 2001; 33: 1321–8.CrossRefGoogle ScholarPubMed
Powell, LW.Diagnosis of hemochromatosis. Semin Gastrointest Dis 2002; 13: 80–8.Google ScholarPubMed
Tavill, AS, Adams, PC.A diagnostic approach to hemochromatosis. Can J Gastroenterol 2006; 20: 535–40.CrossRefGoogle ScholarPubMed
Wheeler, CJ, Kowdley, KV.Hereditary hemochromatosis: a review of the genetics, mechanism, diagnosis, and treatment of iron overload. Compr Ther 2006; 32: 10–16.CrossRefGoogle ScholarPubMed
Deugnier, Y, Brissot, P, Loreal, O. Iron and the liver: update 2008. J Hepatol 2008; 48 Suppl 1: S113–123.CrossRefGoogle ScholarPubMed
Emond, MJ, Bronner, MP, Carlson, TH, Lin, M, Labbe, RF, Kowdley, KV.Quantitative study of the variability of hepatic iron concentrations. Clin Chem 1999; 45: 340–6.Google ScholarPubMed
Shah, S, Mayberry, JF, Wicks, AC, Rees, Y, Playford, RJ.Liver biopsy under ultrasound control: implications for training in the Calman era. Gut 1999; 45: 628–29.CrossRefGoogle ScholarPubMed
Brunt, EM.Pathology of hepatic iron overload. Semin Liver Dis 2005; 25: 392–401.CrossRefGoogle ScholarPubMed
Alla, V, Bonkovsky, HL.Iron in non-hemochromatotic liver disorders. Semin Liver Dis 2005; 25: 461–72.CrossRefGoogle Scholar
Guyader, D, Gandon, Y.Computed tomography and magnetic resonance imaging in the diagnosis of hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis. Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 219–25.CrossRefGoogle Scholar
Brittenham, GM, Badman, DG.Non-invasive measurement of iron: report of an NIDDK workshop. Blood 2003; 101: 15–19.CrossRefGoogle Scholar
Gossuin, Y, Roch, A, Muller, RN, Gillis, P.Relaxation induced by ferritin and ferritin-like magnetic particles: the role of proton exchange. Magn Reson Med 2000; 43: 237–43.3.0.CO;2-5>CrossRefGoogle ScholarPubMed
Brasch, RC, Wesbey, GE, Gooding, CA, Koerper, MA.Magnetic resonance imaging of transfusional hemosiderosis complicating thalassemia major. Radiology 1984; 150: 767–71.CrossRefGoogle ScholarPubMed
Stark, DD, Moseley, ME, Bacon, BR, et al. Magnetic resonance imaging and spectroscopy of hepatic iron overload. Radiology 1985; 154: 137–42.CrossRefGoogle ScholarPubMed
Ernst, O, Sergent, G, Bonvarlet, P, Canva-Delcambre, V, Paris, JC, L'Hermine, C.Hepatic iron overload: diagnosis and quantification with MR imaging. Am J Roentgenol 1997; 168: 1205–8.CrossRefGoogle ScholarPubMed
Gandon, Y, Guyader, D, Heautot, JF, et al. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology 1994; 193: 533–38.CrossRefGoogle ScholarPubMed
Angelucci, E, Giovagnoni, A, Valeri, G, et al. Limitations of magnetic resonance imaging in measurement of hepatic iron. Blood 1997; 90: 4736–42.Google ScholarPubMed
Olynyk, JK, St Pierre, TG, Britton, RS, Brunt, EM, Bacon, BR.Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging. Am J Gastroenterol 2005; 100: 837–41.CrossRefGoogle ScholarPubMed
Pietrangelo, A, Corradini, E, Ferrara, F, et al. Magnetic resonance imaging to identify classic and non-classic forms of ferroportin disease. Blood Cells Mol Dis 2006; 37: 192–6.CrossRefGoogle ScholarPubMed
Ptaszek, LM, Price, ET, Hu, MY, Yang, PC.Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging. J Cardiovasc Magn Reson 2005; 7: 689–92.CrossRefGoogle ScholarPubMed
Schocke, MF, Zoller, H, Vogel, W, et al. Cardiac phosphorus-31 two-dimensional chemical shift imaging in patients with hereditary hemochromatosis. Magn Reson Imaging 2004; 22: 515–21.CrossRefGoogle ScholarPubMed
He, T, Gatehouse, PD, Kirk, P, et al. Black-blood T2* technique for myocardial iron measurement in thalassemia. J Magn Reson Imaging 2007; 25: 1205–9.CrossRefGoogle ScholarPubMed
Wood, JC, Tyszka, JM, Carson, S, Nelson, MD, Coates, TD.Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood 2004; 103: 1934–6.CrossRefGoogle ScholarPubMed
Mavrogeni, SI, Markussis, V, Kaklamanis, L, et al. A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with beta-thalassemia major. Eur J Haematol 2005; 75: 241–7.CrossRefGoogle ScholarPubMed
Sparacia, G, Iaia, A, Banco, A, D'Angelo, P, Lagalla, R.Transfusional hemochromatosis: quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism. Radiology 2000; 215: 818–23.CrossRefGoogle ScholarPubMed
Karimi, M, Jamalian, N, Rasekhi, A, Kashef, S.Magnetic resonance imaging (MRI) findings of joints in young beta-thalassemia major patients: fluid surrounding the scaphoid bone: a novel finding, as the possible effect of secondary hemochromatosis. J Pediatr Hematol Oncol 2007; 29: 393–8.CrossRefGoogle ScholarPubMed
Zhang, J, Krinsky, GA.Iron-containing nodules of cirrhosis. NMR Biomed 2004; 17: 459–64.CrossRefGoogle ScholarPubMed
Rocchi, E.[Magnetic resonance and hepatic siderosis]. Recenti Prog Med 1994; 85: 4471.Google Scholar
Barton, JC, Lee, PL.Disparate phenotypic expression of ALAS2 R452H (nt 1407 G>A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. Blood Cells Mol Dis 2006; 36: 342–6.CrossRefGoogle ScholarPubMed
Borgna-Pignatti, C, Vergine, G, Lombardo, T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol 2004; 124: 114–17.CrossRefGoogle ScholarPubMed
Mancuso, A, Sciarrino, E, Renda, MC, Maggio, A.A prospective study of hepatocellular carcinoma incidence in thalassemia. Hemoglobin 2006; 30: 119–24.CrossRefGoogle ScholarPubMed
Deugnier, YM, Guyader, D, Crantock, L, et al. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology 1993; 104: 228–34.CrossRefGoogle ScholarPubMed
Hiatt, T, Trotter, JF, Kam, I.Hepatocellular carcinoma in a non-cirrhotic patient with hereditary hemochromatosis. Am J Med Sci 2007; 334: 228–30.CrossRefGoogle Scholar
Mancuso, A, Rigano, P, Renda, D, et al. Hepatocellular carcinoma on cirrhosis-free liver in a HCV-infected thalassemic. Am J Hematol 2005; 78: 158–9.CrossRefGoogle Scholar
Guyader, D, Gandon, Y, Sapey, T, et al. Magnetic resonance iron-free nodules in genetic hemochromatosis. Am J Gastroenterol 1999; 94: 1083–6.CrossRefGoogle ScholarPubMed
Bonkovsky, HL, Rubin, RB, Cable, EE, Davidoff, A, Rijcken, TH, Stark, DD.Hepatic iron concentration: non-invasive estimation by means of MR imaging techniques. Radiology 1999; 212: 227–34.CrossRefGoogle Scholar
St Pierre, TG, Clark, PR, Chua-anusorn, W, et al. Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105: 855–61.CrossRefGoogle Scholar
St Pierre, TG, Clark, PR, Chua-anusorn, W.Single spin-echo proton transverse relaxometry of iron-loaded liver. NMR Biomed 2004; 17: 4468.CrossRefGoogle ScholarPubMed
Clark, PR, Chua-anusorn, W, St Pierre, TG.Proton transverse relaxation rate (R2) images of liver tissue; mapping local tissue iron concentrations with MRI. Magn Reson Med 2003; 49: 572.CrossRefGoogle ScholarPubMed
Westwood, MA, Anderson, LJ, Firmin, DN, et al. Interscanner reproducibility of cardiovascular magnetic resonance T2* measurements of tissue iron in thalassemia. J Magn Reson Imaging 2003; 18: 616–20.CrossRefGoogle ScholarPubMed
Hankins, JS, McCarville, MB, Loeffler, RB, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood 2009; 113: 4853.CrossRefGoogle ScholarPubMed
Brittenham, GM, Farrell, , Harris, JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 1982; 307: 1671.CrossRefGoogle ScholarPubMed
Nielsen, P, Fischer, R, Engelhardt, R, Tondury, P, Gabbe, EE, Janka, GE.Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone. Br J Haematol 1995; 91: 827–33.CrossRefGoogle ScholarPubMed
Brittenham, GM, Sheth, S, Allen, CJ, Farrell, DE.Non-invasive methods for quantitative assessment of transfusional iron overload in sickle cell disease. Semin Hematol 2001; 38: 376.CrossRefGoogle Scholar
Wood, JC.Diagnosis and management of transfusion iron overload: the role of imaging. Am J Hematol 2007; 82: 1132.CrossRefGoogle ScholarPubMed
Phatak, PD, Barton, JC.Phlebotomy-mobilized iron as a surrogate for liver iron content in hemochromatosis patients. Hematology 2003; 8: 429–32.CrossRefGoogle ScholarPubMed
Olatunbosun, D, Corbett, WE, Ludwig, J, Valberg, LS.Alteration of cobalt absorption in portal cirrhosis and idiopathic hemochromatosis. J Lab Clin Med 1970; 75: 754–62.Google ScholarPubMed
Sorbie, J, Olatunbosun, D, Corbett, WE, Valberg, LS.Cobalt excretion test for the assessment of body iron stores. Can Med Assoc J 1971; 104: 777–82.Google ScholarPubMed
Valberg, LS, Ludwig, J, Olatunbosun, D.Alteration in cobalt absorption in patients with disorders of iron metabolism. Gastroenterology 1969; 56: 2411.Google ScholarPubMed
Miller, A, Zimelman, A, Brauer, MJ.A family study of a patient with idiopathic hemochromatosis. Am J Hematol 1977; 2: 41–6.CrossRefGoogle ScholarPubMed
Barton, JC.The absorption and metabolism of non-ferrous metals in hemochromatosis. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 131–3.CrossRefGoogle Scholar
Smith, TA.Human serum transferrin cobalt complex: stability and cellular uptake of cobalt. Bioorg Med Chem 2005; 13: 4576–9.CrossRefGoogle ScholarPubMed
Simon, M, Mignon, L, Fauchet, R, et al. A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population; and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 1987; 41: 89–105.Google ScholarPubMed
Simon, M, Yaouanq, J, Fauchet, R, Gall, JY, Brissot, P, Bourel, M.Genetics of hemochromatosis: HLA association and mode of inheritance. Ann N Y Acad Sci 1988; 526: 11–22.CrossRefGoogle ScholarPubMed
Simon, M, Bourel, M, Fauchet, R, Genetet, B.Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 1976; 17: 332–4.CrossRefGoogle ScholarPubMed
Simon, M, Alexandre, JL, Bourel, M, Marec, B, Scordia, C.Heredity of idiopathic haemochromatosis: a study of 106 families. Clin Genet 1977; 11: 327–41.CrossRefGoogle ScholarPubMed
Yaouanq, J.Human leukocyte antigen (HLA) association and typing in hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 63–74.CrossRefGoogle Scholar
Porto, G, Sousa, M.Variation of hemochromatosis prevalence and genotype in national groups. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 51–62.CrossRefGoogle Scholar
Barton, JC, Acton, RT.HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFE C282Y homozygosity in central Alabama. BMC Med Genet 2002; 3: 9.CrossRefGoogle Scholar
Jazwinska, EC.The ancestral haplotype in hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 91–8.CrossRefGoogle Scholar
Feder, JN, Gnirke, A, Thomas, W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399–408.CrossRefGoogle ScholarPubMed
Distante, S, Robson, KJ, Graham-Campbell, J, Arnaiz-Villena, A, Brissot, P, Worwood, M.The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 2004; 115: 269–79.CrossRefGoogle ScholarPubMed
Ajioka, RS, Jorde, LB, Gruen, JR, et al. Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. Am J Hum Genet 1997; 60: 1439–47.CrossRefGoogle ScholarPubMed
Milman, N, Pedersen, P.Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in southern Scandinavia and spread with the Vikings. Clin Genet 2003; 64: 36–47.CrossRefGoogle ScholarPubMed
Crawford, DHG, Powell, LW, Leggett, BA, et al. Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene. Am J Hum Genet 1995; 57: 362–7.Google ScholarPubMed
Barton, JC, Harmon, L, Rivers, C, Acton, RT.Hemochromatosis: association of severity of iron overload with genetic markers. Blood Cells Mol Dis 1996; 22: 195–204.CrossRefGoogle ScholarPubMed
Piperno, A, Arosio, C, Fargion, S, et al. The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients. Hepatology 1996; 24: 43–6.CrossRefGoogle ScholarPubMed
Barton, JC, Shih, WW, Sawada-Hirai, R, et al. Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis. Blood Cells Mol Dis 1997; 23: 135–45.CrossRefGoogle ScholarPubMed
Barton, JC, Wiener, HW, Acton, RT, Go, RC.HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. Blood Cells Mol Dis 2005; 34: 38–47.CrossRefGoogle ScholarPubMed
Barton, JC, Wiener, HW, Acton, RT, Go, RC.Total blood lymphocyte counts in hemochromatosis probands with HFE C282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes. BMC Blood Disord 2005; 5: 5.Google Scholar
Krayenbuehl, PA, Maly, FE, Hersberger, M, et al. Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis. Clin Chem 2006; 52: 1552–8.CrossRefGoogle ScholarPubMed
Fargion, S, Valenti, L, Dongiovanni, P, et al. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood 2001; 97: 3707–12.CrossRefGoogle ScholarPubMed
Acton, RT, Snively, BM, Barton, JC, et al. A genome-wide linkage scan for iron phenotype quantitative trait loci: the HEIRS Family Study. Clin Genet 2007; 71: 518–29.CrossRefGoogle ScholarPubMed
Meynard, D, Kautz, L, Darnaud, V, Canonne-Hergaux, F, Coppin, H, Roth, MP.Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 2009; 41: 478–81.CrossRefGoogle ScholarPubMed
Andriopoulos, B, Corradini, E, Xia, Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009; 41: 482–7.CrossRefGoogle ScholarPubMed
Cappuccio, J, Phatak, PD.Cost-effectiveness of screening for hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 525–34.CrossRefGoogle Scholar
Biasiotto, G, Belloli, S, Ruggeri, G, et al. Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload. Clin Chem 2003; 49: 1981–8.CrossRefGoogle ScholarPubMed
Dupradeau, FY, Pissard, S, Coulhon, MP, et al. An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1. Hum Mutat 2008; 29: 206.CrossRefGoogle ScholarPubMed
Mendes, AI, Ferro, A, Martins, R, et al. Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes. Ann Hematol 2009; 88: 229–34.CrossRefGoogle ScholarPubMed
Villiers, JN, Hillermann, R, Loubser, L, Kotze, MJ.Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum Mol Genet 1999; 8: 1517–22.CrossRefGoogle ScholarPubMed
Henz, S, Reichen J, Liechti-Gallati S. HLA-H gene mutations and haemochromatosis: the likely association of H63D with mild phenotype and the detection of S65C, a novel variant in exon 2 [abstract]. J Hepatol 1997; 26: 57A.Google Scholar
Beutler, E, Griffin, MJ, Gelbart, T, West, C.A previously undescribed nonsense mutation of the HFE gene. Clin Genet 2002; 61: 40–2.CrossRefGoogle ScholarPubMed
Barton, JC, Sawada-Hirai, R, Rothenberg, BE, Acton, RT.Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Mol Dis 1999; 25: 1475.CrossRefGoogle ScholarPubMed
Barton, JC, West, C, Lee, PL, Beutler, E.A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote. Clin Genet 2004; 66: 214–16.CrossRefGoogle Scholar
Cukjati, M, Koren, S, Curin, S, , V, Vidan-Jeras, B, Rupreht, R.A novel homozygous frameshift deletion c.471del of HFE associated with hemochromatosis. Clin Genet 2007; 71: 350–3.CrossRefGoogle ScholarPubMed
Pointon, JJ, Lok, CY, Shearman, JD, et al. A novel HFE mutation (c.del478) results in nonsense-mediated decay of the mutant transcript in a hemochromatosis patient. Blood Cells Mol Dis 2009; 43: 194–8.CrossRefGoogle Scholar
Oberkanins, C, Moritz, A, Villiers, JN, Kotze, MJ, Kury, F.A reverse-hybridization assay for the rapid and simultaneous detection of nine HFE gene mutations. Genet Test 2000; 4: 121–4.CrossRefGoogle ScholarPubMed
Piperno, A, Arosio, C, Fossati, L, et al. Two novel nonsense mutations of HFE gene in five unrelated italian patients with hemochromatosis. Gastroenterology 2000; 119: 441.CrossRefGoogle ScholarPubMed
Bradbury, R, Fagan, E, Payne, SJ.Two novel polymorphisms (E277K and V212V) in the haemochromatosis gene HFE. Hum Mutat 2000; 15: 120.3.0.CO;2-B>CrossRefGoogle ScholarPubMed
A simple genetic test identifies 90% of UK patients with haemochromatosis. The UK Haemochromatosis Consortium. Gut 1997; 41: 841–4.
Rosmorduc, O, Poupon, R, Nion, I, et al. Differential HFE allele expression in hemochromatosis heterozygotes. Gastroenterology 2000; 119: 1075–86.CrossRefGoogle ScholarPubMed
Gac, G, Dupradeau, FY, Mura, C, et al. Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect. Blood Cells Mol Dis 2003; 30: 231–7.CrossRefGoogle ScholarPubMed
Beutler, E, West, C.New diallelic markers in the HLA region of chromosome 6. Blood Cells Mol Dis 1997; 23: 219–29.CrossRefGoogle ScholarPubMed
Wallace, DF, Dooley, JS, Walker, AP.A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote. Gastroenterology 1999; 116: 1409–12.CrossRefGoogle Scholar
Steiner, M, Ocran, K, Genschel, J, et al. A homozygous HFE gene splice site mutation (IVS5+1 G/A) in a hereditary hemochromatosis patient of Vietnamese origin. Gastroenterology 2002; 122: 789–95.CrossRefGoogle Scholar
Gac, G, Gourlaouen, I, Ronsin, C, et al. Homozygous deletion of HFE produces a phenotype similar to the HFE p.C282Y/p.C282Y genotype. Blood 2008; 112: 5238–40.CrossRefGoogle ScholarPubMed
Pelucchi, S, Mariani, R, Bertola, F, Arosio, C, Piperno, A.Homozygous deletion of HFE: the Sardinian hemochromatosis?Blood 2009; 113: 3886.CrossRefGoogle ScholarPubMed
Cohen, AR, Galanello, R, Pennell, DJ, Cunningham, MJ, Vichinsky, E, . Thalassemia.Hematology Am Soc Hematol Educ Program 2004; 14–34.
Barton, JC, Rothenberg, BE, Bertoli, LF, Acton, RT.Diagnosis of hemochromatosis in family members of probands: a comparison of phenotyping and HFE genotyping. Genet Med 1999; 1: 89–93.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×