Natural History and Management of HFE-Hemochromatosis

ABSTRACT

Advances in our knowledge of hereditary hemochromatosis (HH) over the past 150 years have revealed new insights into this common genetic disorder. Meticulous family and HLA association studies followed ultimately by cloning of the HFE gene have dramatically changed our understanding of the natural history and manifestations of HH. Cross-sectional studies demonstrated that HH had a highly variable clinical and biochemical penetrance in susceptible individuals of northern European descent. “State-of-the-art” large longitudinal population studies have accurately defined the natural history. We now recognize that HH is not as discreet an entity as previously thought because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical course of HH. While phlebotomy remains the cornerstone of therapy, our diagnostic approach has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches. This review aims to encapsulate this new knowledge in a framework that addresses commonly raised issues relating to the current natural history, diagnosis, and management of HH patients.

KEYWORDS

Natural history - diagnosis - management - modifiers - HFE - hemochromatosis - penetrance

REFERENCES

• 1 Feder J N, Gnirke A, Thomas W et al.. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;  13 (4) 399-408
• 2 Merryweather-Clarke A T, Pointon J J, Shearman J D, Robson K J. Global prevalence of putative haemochromatosis mutations.  J Med Genet. 1997;  34 (4) 275-278
• 3 European Association For The Study Of The Liver . EASL clinical practice guidelines for HFE hemochromatosis.  J Hepatol. 2010;  53 (1) 3-22
• 4 Whitlock E P, Garlitz B A, Harris E L, Beil T L, Smith P R. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2006;  145 (3) 209-223
• 5 Wood M J, Powell L W, Ramm G A. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis.  Blood. 2008;  111 (9) 4456-4462
• 6 Glycosurie T A. Diabete sucre. Clinique medicale de l'Hotel-Dieu de Paris. Vol. 2. 2nd ed. Paris: J.B. Bailiere; 1865: 663-698
• 7 Von Recklinghausen F D. Uber haemochromatose. Tagll Versamml Natur Artze Heidelberg.  1889;  324-325
• 8 Sheldon J H. Hemochromatosis. London: Oxford University Press; 1935
• 9 Laufberger V. Sur la cristallisation de la ferritine.  Bull Soc Chim Biol (Paris). 1937;  (19) 1575-1582
• 10 Sherlock S. Aspiration liver biopsy-Technique and diagnostic application.  Lancet. 1945;  249 397-401
• 11 Davis Jr W D, Laurens Jr H. Correlation of results of liver function tests and liver biopsy in hepatic disease.  South Med J. 1950;  43 (3) 217-223
• 12 Davis Jr W D, Arrowsmith W R. The effect of repeated phlebotomies in hemochromatosis; report of three cases.  J Lab Clin Med. 1952;  39 (4) 526-532
• 13 Finch S C, Finch C A. Idiopathic hemochromatosis, an iron storage disease. A. Iron metabolism in hemochromatosis.  Medicine (Baltimore). 1955;  34 (4) 381-430
• 14 Simon M, Pawlotsky Y, Bourel M, Fauchet R, Genetet B. [Letter: Idiopathic hemochromatosis associated with HL-A 3 tissular antigen].  Nouv Presse Med. 1975;  4 (19) 1432
• 15 Leggett B A, Halliday J W, Brown N N, Bryant S, Powell L W. Prevalence of haemochromatosis amongst asymptomatic Australians.  Br J Haematol. 1990;  74 (4) 525-530
• 16 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch H J, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.  N Engl J Med. 1985;  313 (20) 1256-1262
• 17 Niederau C, Fischer R, Pürschel A, Stremmel W, Häussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.  Gastroenterology. 1996;  110 (4) 1107-1119
• 18 Beutler E, Gelbart T, West C et al.. Mutation analysis in hereditary hemochromatosis.  Blood Cells Mol Dis. 1996;  22 (2) 187-194 discussion 194a-194b
• 19 Bacon B R, Olynyk J K, Brunt E M, Britton R S, Wolff R K. HFE genotype in patients with hemochromatosis and other liver diseases.  Ann Intern Med. 1999;  130 (12) 953-962
• 20 Sánchez M, Bruguera M, Bosch J, Rodés J, Ballesta F, Oliva R. Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls.  J Hepatol. 1998;  29 (5) 725-728
• 21 Bacon B, Adams P C, Kowdley K V et al.. Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases.  Hepatology. 2011;  54 (1) 328-343
• 22 Asberg A, Hveem K, Thorstensen K et al.. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.  Scand J Gastroenterol. 2001;  36 (10) 1108-1115
• 23 Beutler E, Felitti V J, Koziol J A, Ho N J, Gelbart T. Penetrance of 845G—A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet. 2002;  359 (9302) 211-218
• 24 Delatycki M B, Allen K J, Nisselle A E et al.. Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis.  Lancet. 2005;  366 (9482) 314-316
• 25 Olynyk J K, Hagan S E, Cullen D J, Beilby J, Whittall D E. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study.  Mayo Clin Proc. 2004;  79 (3) 309-313
• 26 Andersen R V, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard B G. Hemochromatosis mutations in the general population: iron overload progression rate.  Blood. 2004;  103 (8) 2914-2919
• 27 Allen K J, Gurrin L C, Constantine C C et al.. Iron-overload-related disease in HFE hereditary hemochromatosis.  N Engl J Med. 2008;  358 (3) 221-230
• 28 Gurrin L C, Osborne N J, Constantine C C HealthIron Study Investigators et al. The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis.  Gastroenterology. 2008;  135 (6) 1945-1952
• 29 Gurrin L C, Bertalli N A, Dalton G W HealthIron Study Investigators et al. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.  Hepatology. 2009;  50 (1) 94-101
• 30 Constantine C C, Gurrin L C, McLaren C E HealthIron Investigators et al. SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis.  BMC Med Genet. 2008;  9 18
• 31 Constantine C C, Anderson G J, Vulpe C D et al.. A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.  Br J Haematol. 2009;  147 (1) 140-149
• 32 Benyamin B, McRae A F, 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 (1) 60-65
• 33 Osterreicher C H, Datz C, Stickel F et al.. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis.  Cytokine. 2005;  31 (2) 142-148
• 34 Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype.  Blood. 2004;  103 (7) 2835-2840
• 35 Le Gac G, Scotet V, Ka C et al.. The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype.  Hum Mol Genet. 2004;  13 (17) 1913-1918
• 36 Milet J, Dehais V, Bourgain C et al.. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance.  Am J Hum Genet. 2007;  81 (4) 799-807
• 37 Van Vlierberghe H, Langlois M, Delanghe J et al.. Haptoglobin phenotype 2-2 overrepresentation in Cys282Tyr hemochromatotic patients.  J Hepatol. 2001;  35 (6) 707-711
• 38 Moirand R, Lescoat G, Delamaire D et al.. Increase in glycosylated and nonglycosylated serum ferritin in chronic alcoholism and their evolution during alcohol withdrawal.  Alcohol Clin Exp Res. 1991;  15 (6) 963-969
• 39 Cade J E, Moreton J A, O'Hara B et al.. Diet and genetic factors associated with iron status in middle-aged women.  Am J Clin Nutr. 2005;  82 (4) 813-820
• 40 Milward E A, Baines S K, Knuiman M W et al.. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations.  Mayo Clin Proc. 2008;  83 (5) 543-549
• 41 Fletcher L M, Dixon J L, Purdie D M, Powell L W, Crawford D H. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 (2) 281-289
• 42 Adams P C, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings.  Hepatology. 1996;  23 (4) 724-727
• 43 Diwakaran H H, Befeler A S, Britton R S, Brunt E M, Bacon B R. Accelerated hepatic fibrosis in patients with combined hereditary hemochromatosis and chronic hepatitis C infection.  J Hepatol. 2002;  36 (5) 687-691
• 44 Powell E E, Ali A, Clouston A D et al.. Steatosis is a cofactor in liver injury in hemochromatosis.  Gastroenterology. 2005;  129 (6) 1937-1943
• 45 Barton J C, Barton J C, Acton R T. Longer survival associated with HLA-A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA-A and -B typing and haplotyping.  Eur J Haematol. 2010;  85 (5) 439-447
• 46 Shi Z, Johnstone D, Talseth-Palmer B A et al.. Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.  Int J Cancer. 2009;  125 (1) 78-83
• 47 Osborne N J, Gurrin L C, Allen K J et al.. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer.  Hepatology. 2010;  51 (4) 1311-1318
• 48 Zacharski L R, Chow B K, Howes P S et al.. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.  J Natl Cancer Inst. 2008;  100 (14) 996-1002
• 49 Chua A C, Klopcic B, Lawrance I C, Olynyk J K, Trinder D. Iron: an emerging factor in colorectal carcinogenesis.  World J Gastroenterol. 2010;  16 (6) 663-672
• 50 Adams P C, Barton J C. Haemochromatosis.  Lancet. 2007;  370 (9602) 1855-1860
• 51 Olynyk J K, Trinder D, Ramm G A, Britton R S, Bacon B R. Hereditary hemochromatosis in the post-HFE era.  Hepatology. 2008;  48 (3) 991-1001
• 52 Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease.  N Engl J Med. 2004;  350 (23) 2383-2397
• 53 Andrews N C. Forging a field: the golden age of iron biology.  Blood. 2008;  112 (2) 219-230
• 54 Fleming R E, Britton R S, Waheed A, Sly W S, Bacon B R. Pathogenesis of hereditary hemochromatosis.  Clin Liver Dis. 2004;  8 (4) 755-773 vii
• 55 Park C H, Valore E V, Waring A J, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver.  J Biol Chem. 2001;  276 (11) 7806-7810
• 56 Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S. Hepcidin, a new iron regulatory peptide.  Blood Cells Mol Dis. 2002;  29 (3) 327-335
• 57 Nemeth E, Ganz T. Hepcidin and iron-loading anemias.  Haematologica. 2006;  91 (6) 727-732
• 58 Ganz T. Iron homeostasis: fitting the puzzle pieces together.  Cell Metab. 2008;  7 (4) 288-290
• 59 Pak M, Lopez M A, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity.  Blood. 2006;  108 (12) 3730-3735
• 60 Piperno A, Galimberti S, Mariani R HIGHCARE investigators et al. Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project.  Blood. 2011;  117 (10) 2953-2959
• 61 Nicolas G, Bennoun M, Porteu A et al.. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.  Proc Natl Acad Sci U S A. 2002;  99 (7) 4596-4601
• 62 Milward E A, Trinder D, Wilcox C E, Britton R S, Ramm G A, Olynyk J K. Is HFE involved in increased hepcidin expression and hypoferremia in inflammation and anemia of chronic disease?.  Hepatology. 2005;  41 (4) 936-938
• 63 Trinder D, Ayonrinde O T, Olynyk J K. HCV, iron, and oxidative stress: the new choreography of hepcidin.  Gastroenterology. 2008;  134 (1) 348-351
• 64 Nemeth E, Ganz T. The role of hepcidin in iron metabolism.  Acta Haematol. 2009;  122 (2-3) 78-86
• 65 Olynyk J K, Cullen D J, Aquilia S, Rossi E, Summerville L, Powell L W. A population-based study of the clinical expression of the hemochromatosis gene.  N Engl J Med. 1999;  341 (10) 718-724
• 66 McLaren C E, McLachlan G J, Halliday J W et al.. Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis.  Gastroenterology. 1998;  114 (3) 543-549
• 67 Bacon B R. Screening for hemochromatosis.  Arch Intern Med. 2006;  166 (3) 269-270
• 68 Bomford A. Genetics of haemochromatosis.  Lancet. 2002;  360 (9346) 1673-1681
• 69 Adams P C, Reboussin D M, Leiendecker-Foster C et al.. Comparison of the unsaturated iron-binding capacity with transferrin saturation as a screening test to detect C282Y homozygotes for hemochromatosis in 101,168 participants in the hemochromatosis and iron overload screening (HEIRS) study.  Clin Chem. 2005;  51 (6) 1048-1052
• 70 Powell L W, Dixon J L, Ramm G A et al.. Screening for hemochromatosis in asymptomatic subjects with or without a family history.  Arch Intern Med. 2006;  166 (3) 294-301
• 71 Power T E, Adams P C, Barton J C et al.. Psychosocial impact of genetic testing for hemochromatosis in the HEIRS Study: a comparison of participants recruited in Canada and in the United States.  Genet Test. 2007;  11 (1) 55-64
• 72 Hall M A, Barton J C, Adams P C et al.. Genetic screening for iron overload: no evidence of discrimination at 1 year.  J Fam Pract. 2007;  56 (10) 829-834
• 73 Camaschella C, Poggiali E. Rare types of genetic hemochromatosis.  Acta Haematol. 2009;  122 (2-3) 140-145
• 74 Kaneko Y, Miyajima H, Piperno A et al.. Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders.  J Gastroenterol. 2010;  45 (11) 1163-1171
• 75 Olynyk J K, St Pierre T G, Britton R S, Brunt E M, Bacon B R. 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 (4) 837-841
• 76 St Pierre T G, Clark P R, Chua-anusorn W et al.. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance.  Blood. 2005;  105 (2) 855-861
• 77 Olsson K S. Iron stores in normal men and male blood donors. As measured by desferrioxamine and quantitative phlebotomy.  Acta Med Scand. 1972;  192 (5) 401-407
• 78 Adams P C. Role of genetic testing and liver biopsy in the diagnosis of hemochromatosis.  Curr Gastroenterol Rep. 1999;  1 (1) 27-29
• 79 Crawford D HG, Murphy T L, Ramm L E et al.. Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis.  Hepatology. 2009;  49 (2) 418-425
• 80 Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography.  J Hepatol. 2008;  48 (5) 835-847
• 81 Adhoute X, Foucher J, Laharie D et al.. Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study.  Gastroenterol Clin Biol. 2008;  32 (2) 180-187
• 82 Davis Jr W D, Arrowsmith W R. The treatment of hemochromatosis by massive venesection.  Ann Intern Med. 1953;  39 (4) 723-734
• 83 Bismuth M, Peynaud-Debayle E. Management of patients with HFE-related haemochromatosis (Type 1 haemochromatosis). 2005; Available at: http://www.has-sante.fr/portail/jcms/c_432802/management-of-patients-with-hfe-related-haemochromatosis-type-1-haemochromatosis Accessed March 10, 2011
• 84 Brissot P, de Bels F. Current approaches to the management of hemochromatosis.  Hematology (Am Soc Hematol Educ Program). 2006;  36-41
• 85 Barton J C, Bottomley S S. Iron deficiency due to excessive therapeutic phlebotomy in hemochromatosis.  Am J Hematol. 2000;  65 (3) 223-226
• 86 Adams P C, Speechley M, Kertesz A E. Long-term survival analysis in hereditary hemochromatosis.  Gastroenterology. 1991;  101 (2) 368-372
• 87 Bomford A, Williams R. Long term results of venesection therapy in idiopathic haemochromatosis.  Q J Med. 1976;  45 (180) 611-623
• 88 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;  52 (5) 1671-1779
• 89 Brandhagen D J. Liver transplantation for hereditary hemochromatosis.  Liver Transpl. 2001;  7 (8) 663-672
• 90 Crawford D HG, Fletcher L M, Hubscher S G et al.. Patient and graft survival after liver transplantation for hereditary hemochromatosis: implications for pathogenesis.  Hepatology. 2004;  39 (6) 1655-1662
• 91 Brock J H, Mulero V. Cellular and molecular aspects of iron and immune function.  Proc Nutr Soc. 2000;  59 (4) 537-540
• 92 Dar F S, Faraj W, Zaman M B et al.. Outcome of liver transplantation in hereditary hemochromatosis.  Transpl Int. 2009;  22 (7) 717-724
• 93 Yu L, Ioannou G N. Survival of liver transplant recipients with hemochromatosis in the United States.  Gastroenterology. 2007;  133 (2) 489-495
• 94 Murphy C J, Oudit G Y. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.  J Card Fail. 2010;  16 (11) 888-900
• 95 Liu P, Olivieri N. Iron overload cardiomyopathies: new insights into an old disease.  Cardiovasc Drugs Ther. 1994;  8 (1) 101-110
• 96 Easley Jr R M, Schreiner Jr B F, Yu P N. Reversible cardiomyopathy associated with hemochromatosis.  N Engl J Med. 1972;  287 (17) 866-867
• 97 Arnold J M, Liu P, Demers C Canadian Cardiovascular Society et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.  Can J Cardiol. 2006;  22 (1) 23-45
• 98 Olivieri N F, Liu P P, Sher G D et al.. Brief report: combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia.  N Engl J Med. 1994;  330 (16) 1125-1127
• 99 Carroll G J, Breidahl W H, Bulsara M K, Olynyk J K. Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load.  Arthritis Rheum. 2011;  63 (1) 286-294
• 100 Carlsson A. Hereditary hemochromatosis: a neglected diagnosis in orthopedics: a series of 7 patients with ankle arthritis, and a review of the literature.  Acta Orthop. 2009;  80 (3) 371-374
• 101 Kaltwasser J P, Werner E, Schalk K, Hansen C, Gottschalk R, Seidl C. Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis.  Gut. 1998;  43 (5) 699-704
• 102 Nienhuis A W. Vitamin C and iron.  N Engl J Med. 1981;  304 (3) 170-171
• 103 Fracanzani A L, Conte D, Fraquelli M et al.. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease.  Hepatology. 2001;  33 (3) 647-651
• 104 Kallianpur A R, Hall L D, Yadav M et al.. Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer.  Cancer Epidemiol Biomarkers Prev. 2004;  13 (2) 205-212
• 105 Kovac S, Anderson G J, Baldwin G S. Gastrins, iron homeostasis and colorectal cancer.  Biochim Biophys Acta. 2011;  1813 (5) 889-895