Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Hemochromatosis Clinical Presentation

  • Author: Andrea Duchini, MD; Chief Editor: Julian Katz, MD  more...
 
Updated: Jan 02, 2016
 

History and Physical Examination

Patients with hereditary hemochromatosis may be asymptomatic or may present with general and organ-related signs and symptoms.

Symptoms from hemochromatosis usually begin between age 30 years and age 50 years, but they may occur much earlier in life.[58] Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis.

Early symptoms include severe fatigue (74%), impotence (45%), and arthralgia (44%); fatigue and arthralgia are the most common symptoms prompting a visit to a physician. The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.[4]

Clinical manifestations include the following:

  • Liver disease (hepatomegaly, 13%; cirrhosis, 13%, usually late in the disease)
  • Skin bronzing or hyperpigmentation (70%)
  • Diabetes mellitus (48%)
  • Arthropathy
  • Amenorrhea, impotence, hypogonadism
  • Cardiomyopathy

Liver disease

Liver function abnormalities occur in 35-75% of patients. Among organ-related symptoms, hepatomegaly is seen in more than 95% of patients and can be accompanied by signs of chronic liver disease, such as abdominal pain and cutaneous stigmata of liver disease (palmar erythema, spider angioma, or jaundice), and liver failure (ascites or encephalopathy). Right upper quadrant tenderness with hepatomegaly or splenomegaly may be present.

Cirrhosis is due to progressive iron deposition in the liver parenchyma, and it is one of the most common disease manifestations of the tissue damage caused by hemochromatosis. Cirrhosis may be complicated by liver cancer years later (risk > 200-fold). This condition is also the most common cause of death in patients with hereditary hemochromatosis.

Cirrhosis reversibility after iron removal has been reported, usually early in the course of liver disease, although reversal of advanced liver disease with varices has also been reported.

Some studies show that HFE mutations in patients with hepatitis C infection are associated with higher frequencies of fibrosis and cirrhosis.[59, 60] Increased fibrosis was also found in patients with nonalcoholic steatohepatitis (NASH) who had the C282Y mutation.[61, 62]

Skin bronzing or hyperpigmentation

A combination of iron deposition and melanin causes the skin bronzing or hyperpigmentation that is typical of the disease. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease, when total iron body content is 20 g (ie, > 5-times normal).

Diabetes mellitus

Diabetes, often requiring insulin therapy, occurs due to progressive iron accumulation in the pancreas. The damage appears to be relatively selective for the pancreatic beta cells. Most patients with hemochromatotic diabetes have other signs of hemochromatosis, such as liver disease or skin pigmentation.

Diabetes mellitus can be seen in 30-60% of patients with hereditary hemochromatosis; therefore, polyuria, polydipsia, and high blood and urine glucose levels may be found. In one study, the prevalence of diabetes mellitus was 21.9% in patients with hereditary hemochromatosis.[63] The type of mutations for hereditary hemochromatosis, ferritin level, or the presence of cirrhosis were not predictive for diabetes mellitus development. In the majority patients, the insulin requirements or glucose level was not influenced by iron depletion.[63]

Arthropathy

Arthropathy is due to iron accumulation in joint tissues. It is associated with characteristic radiologic findings, that is, squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints. Symptoms usually do not respond to iron removal.

Chondrocalcinosis, which involves the knees and the wrists, may occur and may be asymptomatic.

The most commonly affected joints include the following:

  • MCP joints
  • Proximal interphalangeal joints
  • Knees
  • Feet [64]
  • Wrists
  • Back
  • Neck

Amenorrhea, impotence, hypogonadism

Amenorrhea, loss of libido, impotence, and symptoms of hypothyroidism can be seen in patients with hereditary hemochromatosis. Although amenorrhea can occur in women, it is less frequent than hypogonadism in men.

Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.

Cardiomyopathy

Cardiac enlargement, with or without heart failure or conduction defects, is another mode of presentation, particularly in younger patients. Hereditary hemochromatosis C282Y/C282Y, C282Y/H63D, and C282Y/wild-type genotypes have not been associated with ischemic heart disease or myocardial infarction.[65]

Dilated cardiomyopathy is characterized by the development of heart failure and conduction disturbances, such as sick sinus syndrome. In the past, cardiac disease was the presenting manifestation in as many as 15% of patients; therefore, the absence of other manifestations of hemochromatosis should not preclude the diagnosis. Signs of fluid overload are seen with congestive heart failure.

Other manifestations

Osteopenia and osteoporosis[5] as well as hair loss and koilonychia (spoon nails) may occur in patients with hemochromatosis.

Of patients with hereditary hemochromatosis, 25% have osteoporosis, while 41% are diagnosed with osteopenia.[5] The osteoporosis is independent of genetic background and is associated with hypogonadism, increase in alkaline phosphatase, increase in body weight, and the severity of iron overload.[5]

Partial loss of body hair is evident in 62% of patients. The pubic area is affected most commonly, although total loss of body hair is seen in about 12% of patients. Hair loss and thinning may be reversed by therapy in some patients.

Koilonychia, usually of the thumb and index and middle fingers, is seen in almost half of patients. Overall, one fourth of patients with hemochromatosis have prominent spoon nails.

Next

Screening

As the most common autosomal recessive disorder in populations of northern European descent, hereditary hemochromatosis may be an almost ideal disease for which to perform population screening.[2] The advent of genetic testing for hereditary hemochromatosis focuses concern on informed consent and the ethical, legal, and social implications of screening, particularly in relation to medical and general discrimination.

The American Association for the Study of Liver Diseases (AASLD) guidelines recommend screening of high-risk groups such as those with suggestive organ involvement, a familial history of hereditary hemochromatosis, and those with biochemical or radiologic abnormalities suggestive of the possibility of iron overload, as detailed below.[7]

CDC-suggested screening guidelines

The Centers for Disease Control and Prevention (CDC) does not recommend universal screening for hemochromatosis but rather suggests evaluating iron overload in individuals with a family history and in individuals who are symptomatic.[66]

Overall, the clinical expressivity of C282Y homozygosity appears to be much lower than previously thought, and the cost effectiveness of screening has been challenged, because many people must be screened in order to prevent severe disease in only a few. During a screening program conducted in a health appraisal clinic, classic multiorgan disease was detected in only 1 of 152 homozygotes.[67, 68, 69]

Screening for hemochromatosis should be considered in the following individuals[70] :

  • All first-degree relatives of subjects known to have hemochromatosis: Human leukocyte antigen (HLA) typing is no longer necessary; family members identified as having C282Y homozygosity should be tested for transferrin saturation, serum ferritin, and liver enzymes; screening of young children of patients with hemochromatosis does not need to be performed if the spouse is tested and does not have the C282Y mutation
  • Individuals presenting for a standard medical check: Transferrin saturation should be measured; if levels are higher than 45%, the estimation should be repeated after fasting—if the fasting level still is higher than 45%, further investigation is warranted [71]
  • The general population: This group possibly should be screened, although screening is more difficult and debatable in these individuals, [72] and cost is a major consideration; a consensus stated that population screening is best performed by phenotype (using iron-binding capacity), but using genotype screening (using C282Y mutation) is considered premature until all unanswered questions are clarified
  • If a proband is negative for C282Y mutation, family members must be screened by other means, such as serum iron studies or HLA typing; HLA typing or tissue typing has been used to detect homozygous hemochromatosis in a sibling of a proband who has hemochromatosis by other means, such as liver biopsy or quantitative phlebotomy—in this setting, a sibling who is HLA-A identical and HLA-B identical to the proband is considered homozygous; if only 1 haplotype is shared with the proband, the sibling is considered heterozygous

AMA-suggested screening guidelines

As a result of the high frequency of hereditary hemochromatosis–associated mutations, the American Medical Association recommended the establishment of guidelines for population screening, as follows:

  • Screening tests for the general population comprise measurement of serum transferrin saturation or serum iron concentration; when transferrin saturation is greater than 60% or greater than 50% in women who are premenopausal, or when serum iron concentration is greater than 150 mcg/dL, other measurements are recommended
  • Screening and diagnosis cannot be based on single-measurement transferrin saturation or serum iron concentrations, because they can be falsely increased as the result of diet, alcohol consumption, or other liver diseases
  • Adams and coworkers suggested the introduction of the unbound iron-binding capacity measurement to preselect patients for genotyping [73]
  • Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutations is believed to be diagnostic; however, negative results on DNA tests do not exclude hereditary hemochromatosis, which can also be the result of other mutations [74]
  • Liver biopsy is not required for the diagnosis of hereditary hemochromatosis; however, liver biopsy may be useful in C282Y homozygotes with suspected liver disease, in C282Y homozygotes or heterozygotes with serum ferritin levels greater than 1000 mcg/L, in patients without C282Y mutations with unexplained iron overload, and in patients with additional risk factors for liver disease [75]
  • Relatives of patients with hereditary hemochromatosis should undergo DNA testing to detect subclinical cases of hereditary hemochromatosis so that early treatment for the disease can be begun [42]

AASLD-suggested screening guidelines

Measurement of transferrin saturation after an overnight fast should be considered the initial screening of individuals with suspected iron overload and first-degree relatives of patients with hereditary hemochromatosis older than 20 years. Measurement of serum ferritin at the same time increases the predictive accuracy for diagnosis of iron overload.[7]

HFE gene mutation analysis should be performed for all individuals with abnormal iron study results and on those who are first-degree relatives of identified homozygotes. Patients younger than 40 years may be treated by therapeutic phlebotomy without the need for liver biopsy.

Previous
 
 
Contributor Information and Disclosures
Author

Andrea Duchini, MD Associate Professor of Medicine and Surgery, Director of Hepatology, University of Texas Medical Branch School of Medicine; Medical Director of Liver Transplantation, Department of Surgery, University of Texas Medical Branch School of Medicine

Andrea Duchini, MD is a member of the following medical societies: American College of Physicians, International Liver Transplantation Society, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

David M Klachko, MD, MEd Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Missouri-Columbia School of Medicine

David M Klachko, MD, MEd is a member of the following medical societies: Alpha Omega Alpha, Missouri State Medical Association, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, Endocrine Society, Sigma Xi

Disclosure: Nothing to disclose.

Hady E Sfeir, MD Clinical Assistant Professor of Medicine, Department of Internal Medicine, OSF St Francis Medical Center

Hady E Sfeir, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Acknowledgements

Vivek V Gumaste, MD Associate Professor of Medicine, Mount Sinai School of Medicine of New York University; Adjunct Clinical Assistant, Mount Sinai Hospital; Director, Division of Gastroenterology, City Hospital Center

Vivek V Gumaste, MD is a member of the following medical societies: American College of Gastroenterology and American Gastroenterological Association

Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002. 64:663-80. [Medline].

  2. McCullen MA, Crawford DH, Hickman PE. Screening for hemochromatosis. Clin Chim Acta. 2002 Jan. 315(1-2):169-86. [Medline].

  3. O'Reilly FM, Darby C, Fogarty J, Tormey W, Kay EW, Leader M, et al. Screening of patients with iron overload to identify hemochromatosis and porphyria cutanea tarda. Arch Dermatol. 1997 Sep. 133(9):1098-101. [Medline].

  4. Centers for Disease Control and Prevention (CDC). Iron overload and hemochromatosis. May 2006. [Full Text].

  5. Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int. 2009 Apr. 20(4):549-55. [Medline].

  6. Swinkels DW, Jorna AT, Raymakers RA. Synopsis of the Dutch multidisciplinary guideline for the diagnosis and treatment of hereditary haemochromatosis. Neth J Med. 2007 Dec. 65(11):452-5. [Medline].

  7. [Guideline] Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul. 54(1):328-43. [Medline]. [Full Text].

  8. Worwood M. Pathogenesis and management of haemochromatosis. Br J Haematol. 1999 Apr. 105 Suppl 1:16-8. [Medline].

  9. Khanna A, Jain A, Eghtesad B, et al. Liver transplantation for metabolic liver diseases. Surg Clin North Am. 1999 Feb. 79(1):153-62, ix. [Medline].

  10. Seravalle G, Piperno A, Mariani R, et al. Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study. Eur Heart J. 2015 Dec 28. [Medline].

  11. Gattermann N. The treatment of secondary hemochromatosis. Dtsch Arztebl Int. 2009 Jul. 106(30):499-504, I. [Medline]. [Full Text].

  12. Janssen MC, Swinkels DW. Hereditary haemochromatosis. Best Pract Res Clin Gastroenterol. 2009. 23(2):171-83. [Medline].

  13. Galbraith R. Heme oxygenase: who needs it?. Proc Soc Exp Biol Med. 1999 Dec. 222(3):299-305. [Medline].

  14. Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008 Aug 15. 181(4):2723-31. [Medline]. [Full Text].

  15. Conrad ME, Umbreit JN, Moore EG. Iron absorption and transport. Am J Med Sci. 1999 Oct. 318(4):213-29. [Medline].

  16. Parkkila S, Niemelä O, Britton RS, Fleming RE, Waheed A, Bacon BR, et al. Molecular aspects of iron absorption and HFE expression. Gastroenterology. 2001 Dec. 121(6):1489-96. [Medline].

  17. Rolfs A, Bonkovsky HL, Kohlroser JG, et al. Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol. 2002 Apr. 282(4):G598-607. [Medline].

  18. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004 Jan. 36(1):77-82. [Medline].

  19. Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, et al. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis. 2001 Jul-Aug. 27(4):744-9. [Medline].

  20. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006 May. 38(5):531-9. [Medline].

  21. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001 Mar 16. 276(11):7806-10. [Medline].

  22. Fleming RE, Britton RS, Waheed A, et al. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. 2004 Nov. 8(4):755-73, vii. [Medline].

  23. Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001 Aug. 108(4):619-23. [Medline]. [Full Text].

  24. Himmelmann A, Fehr J. Cloning of the hereditary hemochromatosis gene: implications for pathogenesis, diagnosis, and screening. J Lab Clin Med. 1999 Mar. 133(3):229-36. [Medline].

  25. Bittencourt PL, Marin ML, Couto CA, et al. Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis. Clinics (Sao Paulo). 2009. 64(9):837-41. [Medline]. [Full Text].

  26. Ramrakhiani S, Bacon BR. Hemochromatosis: advances in molecular genetics and clinical diagnosis. J Clin Gastroenterol. 1998 Jul. 27(1):41-6. [Medline].

  27. Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology. 2002 Mar. 122(3):646-51. [Medline].

  28. Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE, et al. HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology. 2009 Jul. 50(1):94-101. [Medline].

  29. Wallace DF, Walker AP, Pietrangelo A, et al. Frequency of the S65C mutation of HFE and iron overload in 309 subjects heterozygous for C282Y. J Hepatol. 2002 Apr. 36(4):474-9. [Medline].

  30. Solanas-Barca M, Mateo-Gallego R, Calmarza P, et al. Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia. J Clin Endocrinol Metab. 2009 Nov. 94(11):4391-7. [Medline].

  31. 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):669-73. [Medline].

  32. Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003 May. 34(1):102-7. [Medline].

  33. Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005 Feb 15. 105(4):1803-6. [Medline].

  34. 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):371-6. [Medline].

  35. Hattori A, Wakusawa S, Hayashi H, et al. AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis. Hepatol Res. 2003 Jun. 26(2):154-156. [Medline].

  36. 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):376-81. [Medline].

  37. Powell LW. Diagnosis of hemochromatosis. Semin Gastrointest Dis. 2002 Apr. 13(2):80-8. [Medline].

  38. Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001 May 2. 285(17):2216-22. [Medline].

  39. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997 Apr. 34(4):275-8. [Medline]. [Full Text].

  40. Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for population screening?. Genet Test. 2001 Summer. 5(2):127-30. [Medline].

  41. Wood MJ, Skoien R, Powell LW. The global burden of iron overload. Hepatol Int. 2009 Jul 29. [Medline]. [Full Text].

  42. Gochee PA, Powell LW. What's new in hemochromatosis. Curr Opin Hematol. 2001 Mar. 8(2):98-104. [Medline].

  43. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med. 1999 Sep 2. 341(10):718-24. [Medline].

  44. Gehrke SG, Pietrangelo A, Kascák M, Braner A, Eisold M, Kulaksiz H, et al. HJV gene mutations in European patients with juvenile hemochromatosis. Clin Genet. 2005 May. 67(5):425-8. [Medline].

  45. Adams PC, Barton JC. Haemochromatosis. Lancet. 2007 Dec 1. 370(9602):1855-60. [Medline].

  46. 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):1769-78. [Medline].

  47. Gleeson F, Ryan E, Barrett S, et al. Clinical expression of haemochromatosis in Irish C282Y homozygotes identified through family screening. Eur J Gastroenterol Hepatol. 2004 Sep. 16(9):859-63. [Medline].

  48. Acton RT, Barton JC, Bell DS, Go RC, Roseman JM. HFE mutations in African-American women with non-insulin-dependent diabetes mellitus. Ethn Dis. 2001 Fall. 11(4):578-84. [Medline].

  49. 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):221-30. [Medline].

  50. Barton JC, Wiener HW, Acton RT, et al. 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 Jan-Feb. 34(1):38-47. [Medline].

  51. Rivers CA, Barton JC, Gordeuk VR, et al. Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Blood Cells Mol Dis. 2007 May-Jun. 38(3):247-52. [Medline].

  52. Bulaj ZJ, Ajioka RS, Phillips JD, LaSalle BA, Jorde LB, Griffen LM, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med. 2000 Nov 23. 343(21):1529-35. [Medline].

  53. Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med. 1997 Jul 15. 127(2):105-10. [Medline].

  54. Niederau C, Strohmeyer G, Stremmel W. Epidemiology, clinical spectrum and prognosis of hemochromatosis. Adv Exp Med Biol. 1994. 356:293-302. [Medline].

  55. Milman N, Pedersen P, á Steig T, Byg KE, Graudal N, Fenger K. Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients. Ann Hematol. 2001 Dec. 80(12):737-44. [Medline].

  56. Yang Q, McDonnell SM, Khoury MJ, Cono J, Parrish RG. Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data. Ann Intern Med. 1998 Dec 1. 129(11):946-53. [Medline].

  57. Bathum L, Christiansen L, Nybo H, Ranberg KA, Gaist D, Jeune B, et al. Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch Intern Med. 2001 Nov 12. 161(20):2441-4. [Medline].

  58. Bothwell TH, MacPhail AP. Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects. Semin Hematol. 1998 Jan. 35(1):55-71. [Medline].

  59. Smith BC, Gorve J, Guzail MA, Day CP, Daly AK, Burt AD, et al. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology. 1998 Jun. 27(6):1695-9. [Medline].

  60. Martinelli AL, Franco RF, Villanova MG, Figueiredo JF, Secaf M, Tavella MH, et al. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection?. Acta Haematol. 2000. 102(3):152-6. [Medline].

  61. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998 Feb. 114(2):311-8. [Medline].

  62. Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol. 1999 Sep. 31(3):421-9. [Medline].

  63. O'Sullivan EP, McDermott JH, Murphy MS, Sen S, Walsh CH. Declining prevalence of diabetes mellitus in hereditary haemochromatosis--the result of earlier diagnosis. Diabetes Res Clin Pract. 2008 Sep. 81(3):316-20. [Medline].

  64. Bailey EJ, Gardner AB. Hemochromatosis of the foot and ankle. Report of three cases and review of the literature. Clin Orthop Relat Res. 1998 Apr. 108-15. [Medline].

  65. Ellervik C, Tybjaerg-Hansen A, Grande P, Appleyard M, Nordestgaard BG. Hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study. Circulation. 2005 Jul 12. 112(2):185-93. [Medline].

  66. Wetterhall SF, Cogswell ME, Kowdley KV. Public health surveillance for hereditary hemochromatosis. Ann Intern Med. 1998 Dec 1. 129(11):980-6. [Medline].

  67. Cogswell ME, McDonnell SM, Khoury MJ, et al. Iron overload, public health, and genetics: evaluating the evidence for hemochromatosis screening. Ann Intern Med. 1998 Dec 1. 129(11):971-9. [Medline].

  68. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002 Jan 19. 359(9302):211-8. [Medline].

  69. Wojcik JP, Speechley MR, Kertesz AE, et al. Natural history of C282Y homozygotes for hemochromatosis. Can J Gastroenterol. 2002 May. 16(5):297-302. [Medline].

  70. Powell LW, Dixon JL, Ramm GA, et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med. 2006 Feb 13. 166(3):294-301. [Medline].

  71. McDonnell SM, Phatak PD, Felitti V, et al. Screening for hemochromatosis in primary care settings. Ann Intern Med. 1998 Dec 1. 129(11):962-70. [Medline].

  72. Edwards CQ, Griffen LM, Ajioka RS, et al. Screening for hemochromatosis: phenotype versus genotype. Semin Hematol. 1998 Jan. 35(1):72-6. [Medline].

  73. 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 5,211 voluntary blood donors. Hepatology. 2000 May. 31(5):1160-4. [Medline].

  74. Lyon E, Frank EL. Hereditary hemochromatosis since discovery of the HFE gene. Clin Chem. 2001. 47(7):1147-56. [Medline].

  75. Adams PC. Role of genetic testing and liver biopsy in the diagnosis of hemochromatosis. Curr Gastroenterol Rep. 1999 Feb-Mar. 1(1):27-9. [Medline].

  76. Barton JC, Acton RT. Hemochromatosis and Vibrio vulnificus wound infections. J Clin Gastroenterol. 2009 Apr 3. [Medline].

  77. Brittenham GM, Weiss G, Brissot P, Lainé F, Guillygomarc'h A, Guyader D, et al. Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism. Hematology Am Soc Hematol Educ Program. 2000. 39-50. [Medline].

  78. Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005 Oct 4. 143(7):517-21. [Medline].

  79. Bacon BR. Hemochromatosis: diagnosis and management. Gastroenterology. 2001 Feb. 120(3):718-25. [Medline].

  80. Pawlowski M, Latute F, Bardou-Jacquet E, et al. Portable hemoglobinometer is a reliable technology for the follow-up of venesections tolerance in hemochromatosis. Clin Res Hepatol Gastroenterol. 2015 Oct. 39 (5):570-5. [Medline].

  81. Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002 Mar 1. 65(5):853-60. [Medline].

  82. 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):627-33. [Medline].

  83. Powell LW, Subramaniam VN, Yapp TR. Haemochromatosis in the new millennium. J Hepatol. 2000. 32(1 Suppl):48-62. [Medline].

  84. McDonnell SM, Witte DL, Cogswell ME, et al. Strategies to increase detection of hemochromatosis. Ann Intern Med. 1998 Dec 1. 129(11):987-92. [Medline].

  85. Powell LW, George DK, McDonnell SM, et al. Diagnosis of hemochromatosis. Ann Intern Med. 1998 Dec 1. 129(11):925-31. [Medline].

  86. Turlin B, Deugnier Y. Evaluation and interpretation of iron in the liver. Semin Diagn Pathol. 1998 Nov. 15(4):237-45. [Medline].

  87. Morcos M, Dubois S, Bralet MP, Belghiti J, Degott C, Terris B. Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. Am J Clin Pathol. 2001 Nov. 116(5):738-43. [Medline].

  88. Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2015 Dec 16. 1-12. [Medline].

  89. Durupt S, Durieu I, Nové-Josserand R, Bencharif L, Rousset H, Vital Durand D. [Hereditary hemochromatosis]. Rev Med Interne. 2000 Nov. 21(11):961-71. [Medline].

  90. Bismuth M, Peynaud-Debayle E, for the Haute Autorite de Sante (HAS) guidelines department. Management of patients with HFE-related haemochromatosis (type 1 haemochromatosis) (July 2005). Available at http://www.has-sante.fr/portail/upload/docs/application/pdf/hemochromatosis_guidelines_2006_09_12__9_10_9_659.pdf. Accessed: June 10, 2011.

  91. Brissot P, Troadec MB, Bardou-Jacquet E, Le Lan C, Jouanolle AM, Deugnier Y, et al. Current approach to hemochromatosis. Blood Rev. 2008 Jul. 22(4):195-210. [Medline].

  92. van Aerts RM, van Deursen CT, Koek GH. Proton pump inhibitors reduce the frequency of phlebotomy in patients with hereditary hemochromatosis. Clin Gastroenterol Hepatol. 2016 Jan. 14 (1):147-52. [Medline].

  93. Falize L, Guillygomarc'h A, Perrin M, Lainé F, Guyader D, Brissot P, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology. 2006 Aug. 44(2):472-7. [Medline].

  94. Barton JC, McDonnell SM, Adams PC, et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med. 1998 Dec 1. 129(11):932-9. [Medline].

  95. Nick H. Iron chelation, quo vadis?. Curr Opin Chem Biol. 2007 Aug. 11(4):419-23. [Medline].

  96. Nick H, Allegrini PR, Fozard L, Junker U, Rojkjaer L, Salie R, et al. Deferasirox reduces iron overload in a murine model of juvenile hemochromatosis. Exp Biol Med (Maywood). 2009 May. 234(5):492-503. [Medline].

  97. Zhou T, Neubert H, Liu DY, Liu ZD, Ma YM, Kong XL, et al. Iron binding dendrimers: a novel approach for the treatment of haemochromatosis. J Med Chem. 2006 Jul 13. 49(14):4171-82. [Medline].

  98. Emara AM, El Kelany RS, Moustafa KA. Comparative study of the protective effect between deferoxamine and deferiprone on chronic iron overload induced cardiotoxicity in rats. Hum Exp Toxicol. 2006 Jul. 25(7):375-85. [Medline].

  99. Hazin R, Abu-Rajab Tamimi TI, Abuzetun JY, Zein NN. Recognizing and treating cutaneous signs of liver disease. Cleve Clin J Med. 2009 Oct. 76(10):599-606. [Medline].

  100. Asare GA, Bronz M, Naidoo V, Kew MC. Synergistic interaction between excess hepatic iron and alcohol ingestion in hepatic mutagenesis. Toxicology. 2008 Dec 5. 254(1-2):11-8. [Medline].

  101. Aranda N, Viteri FE, Montserrat C, Arija V. 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):767-73. [Medline]. [Full Text].

  102. Barton JC. Chelation therapy for iron overload. Curr Gastroenterol Rep. 2007 Mar. 9(1):74-82. [Medline].

  103. Imran F, Phatak P. Pharmacoeconomic benefits of deferasirox in the management of iron overload syndromes. Expert Rev Pharmacoecon Outcomes Res. 2009 Aug. 9(4):297-304. [Medline].

  104. Frenzen K, Schäfer C, Keyßer G. Erosive and inflammatory joint changes in hereditary hemochromatosis arthropathy detected by low-field magnetic resonance imaging. Rheumatol Int. 2013 Feb 12. [Medline].

  105. Lucotte G, Champenois T, Sémonin O. A rare case of a patient heterozygous for the hemochromatosis mutation C282Y and homozygous for H63D. Blood Cells Mol Dis. 2001 Sep-Oct. 27(5):892-3. [Medline].

  106. Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene. 2015 Dec 15. 574 (2):179-92. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.