Genetic Diseases Associated with Iron Overload
Keywords:
Iron, HFE, hemochromatosis, hepcidinAbstract
Hereditary hemochromatosis type I is one of the most common
human genetic diseases estimating that in average around 1:260
of the Caucasian population is affected by such disease. In our
country, occurs mainly in the northern territory. Despite that,
hereditary hemochromatosis has a variable penetrance and
clinical manifestations, affecting several organs and systems,
therefore internists should be aware of such pathology. Hepcidin,
the central regulator peptide of iron metabolism, has a crucial
role on hemochromatotic genetic diseases. We present a review
about the several genetic diseases associated with iron overload.
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References
Reuben AR: Praise ye the god of iron. Hepatology. 2004 Nov;40(5):1231-4.
Deugnier Y, Brissot P, Loréal O: Iron and the liver: update 2008. J Hepatol.2008;48 Suppl 1:S113-123.
Pietrangelo A: Hepcidin in human iron disorders: therapeutic implications. J Hepatol. 2011 Jan;54(1):173-181.
Fleming RE, Britton RS, Waheed A et al: Pathophysiology of hereditary hemochromatosis. Semin Liver Dis. 2005 Nov;25(4):411-419.
Pantopoulos K: Function of the hemochromatosis protein HFE: Lessons from animal models. World J Gastroenterol. 2008 Dec 7;14(45):6893-6901.
van Dijk BA, Laarakkers CM, Klaver SM et al: Serum hepcidin levels are innately low in HFE-related haemochromatosis but differ between C282Y-homozygotes with elevated and normal ferritin levels. Br J Haematol. 2008 Sep;142(6):979-985.
Pietrangelo A: Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010 Aug;139(2):393-408, 408.e1-2.
Ryan JD, Ryan E, Fabre A et al: Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. Hepatology.2010 Oct;52(4):1266-1273.
Bridle KR, Frazer DM, Wilkins SJ et al: Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.Lancet. 2003 Feb 22;361(9358):669-673.
Gehrke SG, Kulaksiz H, Herrmann T et al: Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood. 2003 Jul 1;102(1):371-376.
Andersen RV, Tybjaerg-Hansen A, Appleyard M et al: Hemochromatosis mutations in the general population: iron overload progression rate. Blood. 2004 Apr 15;103(8):2914-2919.
Gurrin LC, Osborne NJ, Constantine CC et al: The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology. 2008 Dec;135(6):1945-1952.
Hanson EH, Imperatore G, Burke W: HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol. 2001 Aug 1;154(3):193-206.
European Association For The Study Of The Liver: EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010 Jul;53(1):3-22.
Hunt JR, Zeng H: Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Am J Clin Nutr. 2004 Oct;80(4):924-931.
Roe MA, Heath AL, Oyston SL et al: Iron absorption in male C282Y heterozygotes. Am J Clin Nutr. 2005 Apr;81(4):814-821.
Merryweather-Clarke AT, Pointon JJ, Jouanolle AM et al: Geography of HFE C282Y and H63D mutations. Genet Test. 2000;4(2):183-198.
Distante S, Robson KJ, Graham-Campbell J et al: The origin and spread of the
HFE-C282Y haemochromatosis mutation. Hum Genet. 2004 Sep;115(4):269-279.
Shiono Y, Ikeda R, Hayashi H et al: C282Y and H63D mutations in the HFE gene have no effect on iron overload disorders in Japan. Intern Med. 2001 Sep;40(9):852-856.
Adams PC, Reboussin DM, Barton JC et al: Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005 Apr 28;352(17):1769-1778.
Jain S, Agarwal S, Tamhankar P et al: Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population. Indian J Gastroenterol. 2011 Jul;30(4):161-165.
Cardoso CS, Oliveira P, Porto G et al: Comparative study of the two more frequent HFE mutations (C282Y and H63D): significant different allelic frequencies between the North and South of Portugal. Eur J Hum Genet. 2001 Nov;9(11):843-848.
Spínola C, Brehm A, Spínola H: Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal). Ann Hematol. 2011 Jan;90(1):29-32.
Baiget M, Barceló MJ, Gimferrer E et al: Frequency of the HFE C282Y and H63D mutations in distinct ethnic groups living in Spain. J Med Genet. 1998 Aug;35(8):701.
Ropero P, Briceño O, Mateo M et al: Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Ann Hematol. 2006 May;85(5):323-326.
Aranda N, Viteri FE, Montserrat C et al: Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain. Ann Hematol. 2010 Aug;89(8):767-773.
Lim EM, Rossi E, De Boer WB et al: Hepatic iron loading in patients with compound heterozygous HFE mutations. Liver Int. 2004 Dec;24(6):631-636.
Sebastiani G, Wallace DF, Davies SE et al: Fatty liver in H63D homozygotes with hyperferritinemia. World J Gastroenterol. 2006 Mar 21;12(11):1788-1792.
Lim EM, Rossi E, De Boer WB et al: Hepatic iron loading in patients with compound heterozygous HFE mutations.Liver Int. 2004 Dec;24(6):631-636.
Gurrin LC, Bertalli NA, Dalton GW et al: HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology. 2009 Jul;50(1):94-101.
Rhodes DA, Raha-Chowdhury R, Cox TM et al: Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J Med Genet. 1997 Sep;34(9):761-764.
Waalen J, Nordestgaard BG, Beutler E: The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol. 2005 Jun;18(2):203-220.
Bulaj ZJ, Ajioka RS, Phillips JD et al: Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med. 2000 Nov 23;343(21):1529-1535.
Rossi E, Jeffrey GP: Clinical penetrance of C282Y homozygous HFE haemochromatosis. Clin Biochem Rev. 2004 Aug;25(3):183-190.
Allen KJ, Gurrin LC, Constantine CC et al: Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008 Jan 17;358(3):221-230.
Fletcher LM, Dixon JL, Purdie DM et al: Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology. 2002 Feb;122(2):281-289.
Beutler E et al: Iron storage disease: facts, fiction and progress. Blood Cells
Mol Dis. 2007 Sep-Oct;39(2):140-147.
Pietrangelo A: Hereditary hemochromatosis - a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-2397.
Adams PC, Barton JC et al: Haemochromatosis. Lancet. 2007 Dec 1;370(9602):1855-1860.
McLaren GD, McLaren CE, Adams PC et al: Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening. Can J Gastroenterol. 2008 Nov;22(11):923-930.
Brissot P, Bardou-Jacquet E, Jouanolle AM et al: Iron disorders of genetic origin: a changing world. Trends Mol Med. 2011 Aug 19.
Fargion S, Mandelli C, Piperno A et al: Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology. 1992 Apr;15(4):655-659.
Kowdley KV et al: Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology. 2004 Nov;127(5 Suppl 1):S79-86.
Brissot P: Les hémochromatoses. Nouvelle compréhension, nouveaux traitements Gastroenterol Clin Biol. 2009 Aug-Sep;33(8-9):859-867.
Muñoz M, García-Erce JA, Remacha ÁF: Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol. 2011 Apr;64(4):287-296.
Adams P, Barton JC, McLaren GD et al: Screening for iron overload: lessons from the hemochromatosis and iron overload screening (HEIRS) study. Can J Gastroenterol. 2009 Nov;23(11):769-772.
Adams PC, Kertesz AE, McLaren CE et al: Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5,211 voluntary blood donors. Hepatology.2000 May;31(5):1160-1164.
Willis G, Bardsley V, Fellows IW et al: Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study. BMC Gastroenterol. 2005 Jun 1;5:17.
Ellervik C, Birgens H, Tybjaerg-Hansen A et al: Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology. 2007 Oct;46(4):1071-1080.
Jacobs EM, Hendriks JC, van Deursen CT et al: Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study. J Hepatol. 2009 Jan;50(1):174-183.
Batts KP: Iron overload syndromes and the liver. Mod Pathol. 2007 Feb;20 Suppl 1:S31-39.
Deugnier Y, Turlin B: Pathology of hepatic iron overload. World J Gastroenterol.2007 Sep 21;13(35):4755-4760.
Adams PC: Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis? Am J Gastroenterol. 2001 Feb;96(2):567-569.
Emond MJ, Bronner MP, Carlson TH et al: Quantitative study of the variability of hepatic iron concentrations. Clin Chem. 1999 Mar;45(3):340-346.
Ernst O, Sergent G, Bonvarlet P et al: Hepatic iron overload: diagnosis and quantification with MR imaging. AJR Am J Roentgenol. 1997 May;168(5):1205-1208.
Bonkovsky HL, Rubin RB, Cable EE et al: Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. 1999 Jul;212(1):227-234.
Ernst O, Rose C, Sergent G et al: Hepatic iron overload: quantification with MR imaging at 1.5 T. AJR Am J Roentgenol. 1999 Apr;172(4):1141-1142.
Gandon Y, Olivié D, Guyader D et al: Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004 Jan 31;363(9406):357-362.
Wood JC: Magnetic resonance imaging measurement of iron overload. Curr Opin Hematol. 2007 May;14(3):183-190.
Tziomalos K, Perifanis V: Liver iron content determination by magnetic resonance imaging. World J Gastroenterol. 2010 Apr 7;16(13):1587-1597.
Castiella A, Alústiza JM, Emparanza JI et al: Liver iron concentration quantification by MRI: are recommended protocols accurate enough for clinical practice? Eur Radiol. 2011 Jan;21(1):137-141.
Nash S, Marconi S, Sikorska K et al: Role of liver biopsy in the diagnosis of hepatic iron overload in the era of genetic testing. Am J Clin Pathol. 2002 Jul;118(1):73-81.
Bassett ML, Hickman PE, Dahlstrom JE: The changing role of liver biopsy in diagnosis and management of haemochromatosis. Pathology. 2011 Aug;43(5):433-9.
Morrison ED, Brandhagen DJ, Phatak PD et al: Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med. 2003 Apr 15;138(8):627-633.
Allen KJ, Bertalli NA, Osborne NJ et al: HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology. 2010 Sep;52(3):925-933.
Brissot P, de Bels F et al: Hematology Am Soc Hematol Educ Program. 2006:36-41.Current approaches to the management of hemochromatosis.
Adams PC, Barton JC: How I treat hemochromatosis. Blood. 2010 Jul
;116(3):317-325.
Cappellini MD, Taher A: Deferasirox (Exjade) for the treatment of iron overload. Acta Haematol. 2009;122(2-3):165-173.
Phatak P, Brissot P, Wurster M et al: A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis. Hepatology. 2010 Nov;52(5):1671-1779.
Nagler M, Gregor M, Wuillemin WA: Iron chelation with deferasirox in two patients with HFE hemochromatosis and chronic anemia. Acta Haematol.2011;126(2):119-121.
Kushner JP, Porter JP, Olivieri NF et al: Secondary iron overload. Hematology Am Soc Hematol Educ Program. 2001:47-61.
Fabio G, Minonzio F, Delbini P et al: Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood. 2007 Jan 1;109(1):362-364.
Preza GC, Ruchala P, Pinon R et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest. 2011 Dec;121(12):4880-4888.
Falize L, Guillygomarc’h A, Perrin M et al: Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology. 2006 Aug;44(2):472-477.
Dar FS, Faraj W, Zaman MB: Outcome of liver transplantation in hereditary hemochromatosis. Transpl Int. 2009 Jul;22(7):717-724.
Chow JK, Werner BG, Ruthazer R et al: Increased serum iron levels and infectious complications after liver transplantation. Clin Infect Dis. 2010 Aug 1;51(3):e16-23.
Lee PL, Beutler E, Rao SV et al: Blood. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. 2004 Jun 15;103(12):4669-4671.
Pietrangelo A: Juvenile hemochromatosis. J Hepatol. 2006 Dec;45(6):892-894.
Wallace DF, Subramaniam VN: Non-HFE haemochromatosis. World J Gastroenterol. 2007 Sep 21;13(35):4690-4698.
Papanikolaou G, Politou M, Roetto A et al: Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis. 2001 Jul-Aug;27(4):744-749.
Rivard SR, Lanzara C, Grimard D et al: Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet.2003 Aug;11(8):585-589.
Niederkofler V, Salie R, Arber S et al Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload.: J Clin Invest. 2005 Aug;115(8):2180-2186.
Lanzara C, Roetto A, Daraio F et al: Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood. 2004 Jun 1;103(11):4317-4321.
Pagani A, Silvestri L, Nai A, Camaschella C: Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response. Haematologica. 2008 Oct;93(10):1466-1472.
Matthes T, Aguilar-Martinez P, Pizzi-Bosman L et al: Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5’-UTR of the HAMP gene. Blood. 2004 Oct 1;104(7):2181-2183.
Majore S, Binni F, Pennese A et al: HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis. Hum Mutat. 2004 Apr;23(4):400.
Porto G, Roetto A, Daraio F et al: A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron. Blood. 2005 Oct 15;106(8):2922-2923.
Pietrangelo A, Caleffi A, Corradini E: Non-HFE Hepatic Iron Overload. Semin Liver Dis. 2011 Aug;31(3):302-318.
Mattman A, Huntsman D, Lockitch G et al: Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood. 2002 Aug 1;100(3):1075-1077.
Olynyk JK, Trinder D, Ramm GA et al: Hereditary hemochromatosis in the post-HFE era. Hepatology. 2008 Sep;48(3):991-1001.
Camaschella C, Roetto A, Calì A et al: The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000 May;25(1):14-15.
Nemeth E, Roetto A, Garozzo G et al: Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005 Feb 15;105(4):1803-1806.
Kawabata H, Fleming RE, Gui D et al: Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005 Jan 1;105(1):376-381.
Wallace DF, Summerville L, Crampton EM et al: Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis. Am J Physiol Cell Physiol. 2008 Feb;294(2):C383-390.
De Domenico I, Ward DM, Musci G et al: Iron overload due to mutations in ferroportin. Haematologica. 2006 Jan;91(1):92-95.
Mayr R, Janecke AR, Schranz M et al: Ferroportin disease: a systematic meta-analysis of clinical and molecular findings. J Hepatol. 2010 Nov;53(5):941-949.
De Domenico I, Ward DM, Nemeth E et al: The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8955-8960.
Drakesmith H, Schimanski LM, Ormerod E et al: Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood. 2005 Aug 1;106(3):1092-1097.
Fernandes A, Preza GC, Phung Y et al: The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood. 2009 Jul 9;114(2):437-443.
Papanikolaou G, Tzilianos M, Christakis JI et al: Hepcidin in iron overload disorders. Blood. 2005 May 15;105(10):4103-4105.
Barton JC, Acton RT, Lee PL et al: SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent. Blood Cells Mol Dis. 2007 Sep-Oct;39(2):206-211.
Griffiths WJ, Mayr R, McFarlane I et al: Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation. Hepatology. 2010 Mar;51(3):788-795.
Miyajima H, Takahashi Y, Kono S: Biometals. Aceruloplasminemia, an inherited
disorder of iron metabolism. 2003 Mar;16(1):205-213.
Kono S, Suzuki H, Takahashi K et al: Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia. Gastroenterology. 2006 Jul;131(1):240-245.
Finkenstedt A, Wolf E, Höfner E et al: Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol. 2010 Dec;53(6):1101-1107.
Heilmeyer L, Keller W, Vivell O et al: Die kongenitale Atransferrinamie. Schweiz Med Wochenschr. 1961;91:1203.
Beutler E, Gelbart T, Lee P et al: Molecular characterization of a case of atransferrinemia. Blood. 2000 Dec 15;96(13):4071-4074.
Aslan D, Crain K, Beutler E: A new case of human atransferrinemia with a previously undescribed mutation in the transferrin gene. Acta Haematol.2007;118(4):244-247.
Mims MP, Guan Y, Pospisilova D et al: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005 Feb 1;105(3):1337-1342.
Iolascon A, Camaschella C, Pospisilova D et al: Natural history of recessive inheritance of DMT1 mutations. J Pediatr. 2008 Jan;152(1):136-139.
Kato J, Fujikawa K, Kanda M et al: A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet. 2001 Jul;69(1):191-197.
Siah CW, Trinder D, Olynyk JK: Iron overload. Clin Chim Acta. 2005 Aug;358(1-2):24-36.
Christiansen G, Mohney BG: Hereditary hyperferritinemia-cataract syndrome. J AAPOS. 2007 Jun;11(3):294-296.
Arnold J, Sangwaiya A, Manglam V et al: Hepcidin levels in hereditary hyperferritinemia: Insights into the iron-sensing mechanism in hepatocytes. World J Gastroenterol. 2010 Jul 28;16(28):3541-3545.
Nemeth E, Ganz T: Hepcidin and iron-loading anemias. Haematologica.2006 Jun;91(6):727-732.
Koeppen AH: Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011 Apr 15;303(1-2):1-12.
Bayot A, Santos R, Camadro JM et al: Friedreich ataxia: The vicious circle hypothesis revisited. BMC Med. 2011 Oct 11;9(1):112.
Yachie A, Niida Y, Wada T et al: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999 Jan;103(1):129-135.
Kovtunovych G, Eckhaus MA, Ghosh MC et al: Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood. 2010 Dec 23;116(26):6054-606
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