eMedicine Specialties > Dermatology > Metabolic Diseases

Hemochromatosis

Author: Jacek Drobnik, MD, PhD, Assistant Professor of Physiology and Medicine, Department of Pathophysiology, Medical University of Lodz, Poland
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Oct 30, 2008

Introduction

Background

Hereditary hemochromatosis (HH) is a fairly common disease in whites and is a result of iron deposition in hepatocytes, myocardial fibers, and other visceral cells. The classic tetrad of manifestations resulting from hemochromatosis consists of (1) cirrhosis, (2) diabetes mellitus, (3) hyperpigmentation of the skin, and (4) cardiac failure. Clinical consequences also include hepatocellular carcinoma, impotence, and arthritis.

Hereditary hemochromatosis is usually inherited in an autosomal recessive manner. The prevalence of hereditary hemochromatosis is estimated to be 1.5-3 cases in 1000 persons.1 Others believe this disease occurs in approximately 1 in 200-400 whites.2 Thus, the mutation causing hereditary hemochromatosis is one of the most commonly occurring genetic abnormalities in the American population; approximately 10% of the American population carries the mutation in the HFE gene.

Two mutations in the HFE gene have been described. The first, C282Y, comprises the substitution of tyrosine for cysteine at amino acid position 282. In the second, H63D, aspartic acid is substituted for histidine in position 63. C282Y homozygosity or compound heterozygosity C282Y/H63D is found in most patients with hereditary hemochromatosis. The discovery of the C282Y mutation in the HFE gene has altered the diagnostic approach to hereditary hemochromatosis. Cases of homozygotic C282Y without hepatic iron overload may occur, but the clinical outcome of some of these cases requires further study and adds to the controversy on whether systematic population screening should be made available.

In a population of white adults of northern European ancestry, 0.5% were homozygous for the C282Y mutation in HFE.3 However, only half the homozygotes had clinical features of hemochromatosis, and a quarter had serum ferritin levels that remained within the reference range over a 4-year period. In Greece, the G320V mutation seems to be widely distributed among juvenile hemochromatosis patients from central parts of Europe.4 Therefore, detection of the G320V mutation could be a noninvasive method to identify most of the patients from these regions.

Hereditary hemochromatosis is a genetically heterogeneous disorder.5 HFE resides on chromosome 6; its mutations cause most cases of hereditary hemochromatosis in populations of northern European ancestry. The gene for hemochromatosis type 1 (HFE1) is located at band 6p22 and encodes a protein containing 343 amino acids. HFE1 is the result of the C282Y and H63D mutations. Two new types of hemochromatosis have been identified: juvenile hemochromatosis (JH) or type 2 (gene HFE2), which has been mapped to band 1q21, and an adult form defined as hemochromatosis type 3 (HFE3), which results from mutations of the transferrin receptor 2 gene (TFR2) located on band 7q22. The clinical appearance of different types of hemochromatosis could be similar. This speculation also relates to JH with late onset. Therefore, patients with hemochromatosis without HFE mutations should be evaluated for other possible types of hemochromatosis.

A study compared the frequency of HFE mutations in African American women who had type 2 diabetes mellitus to the frequency of mutations in control subjects to determine whether the mutations are associated with type 2 diabetes mellitus and iron overload.6 The frequencies of the C282Y and H63D mutations were not significantly different in patients with type 2 diabetes mellitus than in control subjects. The C282Y mutation was noted in 0.59% of patients and in 1.41% of control subjects. The H63D mutation was seen in 2.99% of patients and in 3.08% of control subjects.

All of the patients with type 2 diabetes mellitus with either a C282Y or H63D mutation had levels of serum ferritin, serum iron, and transferrin saturation in the reference range. One woman who inherited the C282Y mutation also had human leukocyte antigen A3 (HLA-A3) and human leukocyte antigen B7 (HLA-B7), which are considered part of the ancestral haplotype containing the gene predisposing whites to hemochromatosis.

The frequencies of the C282Y and H63D mutations vary in African Americans from different geographic regions of the United States, which is explained by white admixture.

Pathophysiology

Hereditary hemochromatosis is the most common cause of severe iron overload.2 The hemochromatosis gene HFE is situated within the human leukocyte antigen (HLA) class I region on chromosome 6 between the genes coding for HLA-A and HLA-B. The 2 missense mutations (C282Y and H63D) of the HFE gene are responsible for most cases of hereditary hemochromatosis in patients of European descent. HFE protein, the product of the HFE gene, is homologous to major histocompatibility complex class I proteins. However, HFE does not present peptides to T cells, and transferrin receptor (TFR) is a ligand for the HFE protein.7 This link directly associates the HFE protein to the TFR-mediated regulation of iron homeostasis. In addition, evidence is accumulating that the binding of HFE to TFR is critical for the effects of HFE.

Hereditary hemochromatosis represents an error of iron metabolism characterized by excess dietary iron absorption and iron deposition in several tissues.8 Although the mutation underlying most cases of hereditary hemochromatosis is now known, considerable uncertainty exists in the mechanism by which the normal gene product, the HFE protein, regulates iron homeostasis. Knockout mice models of the HFE gene confer the hereditary hemochromatosis phenotype. However, studies on HFE expressed in cultured cells have not clarified the mechanism by which HFE mutations produce increased dietary iron absorption. Recent data implicate other genes, including those encoding a second TFR and the circulating peptide hepcidin, which may participate in a shared pathway with HFE in the regulation of iron absorption.

All types of hemochromatosis have been found to originate from the same metabolic error: disruption of tendency for circulatory iron constancy. Severe iron overload was found in patients with mutations of genes encoding hemojuvelin. These changes correlated with a low level of hepcidin.9 Hepcidin is a peptide synthesized in the liver and is responsible for regulation of iron metabolism. The hepcidin inhibits iron absorption in the gut and iron mobilization from the hepatic stores. The degradation of cellular iron exporter (ferroportin) caused by hepcidin is the mechanism of cellular iron efflux inhibition.

Hepcidin synthesis remains under the regulatory influence of hemojuvelin, which is a member of the repulsive guidance molecule (RGM) and is the coreceptor of the bone morphogenetic protein (BMP). De-arranged BMP signaling in hemojuvelin mutants associated with hemochromatosis disturbs hepcidin synthesis in hepatocytes. Thus, decreased BMP signaling by hemojuvelin disfunction lowers hepcidin secretion. The hepcidin deficiency due to mutations of hepcidin gene or genes of hepcidin regulators is supposed to be the main factor leading to different types of hemochromatosis.

In populations of northern European ancestry, hereditary hemochromatosis is closely linked to mutations in HFE.10 In one study, more than 93% of Irish patients with hereditary hemochromatosis were homozygous for the HFE C282Y mutation, providing a reliable diagnostic marker of the disease in this population. However, the prevalence of the C282Y mutation and that of the second HFE mutation, H63D, have not been determined in the Irish population.

To identify true prevalence of the genetic form of hereditary hemochromatosis in the Irish population, DNA was extracted from 1002 randomly selected newborn screening cards and was analyzed for the C282Y and H63D mutations in HFE. Mutations were identified in 364 (46%) neonates; 8 (1%) neonates were homozygous for C282Y, and 8 (1%) were homozygous for H63D. For C282Y, 155 (19%) neonates were heterozygous, and 226 (28%) neonates were heterozygous for H63D. Of these, 33 (4%) carried 1 copy of both the C282Y and H63D mutations (compound heterozygosity). Allele frequencies for C282Y and H63D were 11% and 15%, respectively. The high C282Y allele frequency in the Irish population and its close linkage to hereditary hemochromatosis indicate that C282Y genotyping is the preferred screening strategy for this disease in Ireland.

Hereditary hemochromatosis is usually inherited in an autosomal recessive pattern and is associated with missense mutations in HFE, which is an atypical major histocompatibility class I gene. Recently, a large family was described with autosomal dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells.11 This form of the disease was mapped to band 2q32. The gene encoding ferroprotein (SLC11A3), which is a transmembrane iron export protein, is within a candidate interval defined by highly significant logarithm of odds (lod) scores.

The iron-loading phenotype in autosomal dominant hemochromatosis was shown to be associated with a nonconservative missense mutation in the ferroprotein gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D mutation), was not identified in samples from 100 unaffected control subjects. Montosi and associates11 proposed that partial loss of ferroprotein function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.

The cutaneous hyperpigmentation seen in patients with hereditary hemochromatosis is primarily due to melanin rather than iron.12

Derangement of iron homeostasis is linked with susceptibility to infectious diseases. Studies performed on Hfe knockout mice (the hemochromatosis model) showed an attenuated inflammatory response induced by lipopolysaccharide and Salmonella. Secretion of tumor necrosis factor-alpha and interleukin 6 by macrophages was lowered. However, ferroporin, the macrophage iron exporter, was up-regulated. This phenomenon was linked with the presence of a decreased level of iron in macrophages. Thus, the iron level in macrophages was reported to play the regulatory role in the inflammatory response.13

Frequency

United States

Prevalence of hereditary hemochromatosis in the United States is 1 case in 200-500 individuals. Frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Prevalence of C282Y homozygosity was estimated to be 0.26%, H63D homozygosity was estimated to be 1.89%, and compound heterozygosity was estimated to be 1.97%.14

International

Worldwide frequency of the C282Y and H63D mutations was found to be 1.9% and 8.1%, respectively.15 Marked disparity in the distribution of the C282Y mutation has been noted. Non -HFE- associated hereditary hemochromatosis was found in Mediterranean countries.16

Mortality/Morbidity

Early diagnosis obtained by population or family screening, absence of serious complications of hereditary hemochromatosis, and treatment with phlebotomy prevent tissue damage and guarantee a normal lifespan. In the United States, hemochromatosis-associated hospitalizations occurred in 2.3 cases per 100,000 individuals from 1979-1997.

  • Niederau and coworkers investigated the cause of 69 deaths in patients with hereditary hemochromatosis.17 Death occurred in 19 individuals as a result of liver cancer, 14 patients died of liver cirrhosis, 5 patients died of cardiomyopathy, and 3 patients died as a result of diabetes mellitus. The other causes of death demonstrated frequencies equal to those found in the general population.
  • Another study reported that 32% of patients died of liver cirrhosis, 23.1% died of liver cancer, and 10-33% died of cardiac disease.18
  • In the United States, age-adjusted mortality rates in patients with hereditary hemochromatosis were 1.2 per million in 1979 and 1.8 per million in 1992. The mean mortality rate was 1.5 per million for whites, while the value was 0.7 per million for individuals of other races. The mortality rate for persons aged 50 years was 5.6 per million, but for younger patients, the rate was 0.8 per million. The mortality rates increased markedly in men older than 45 years and in women older than 55 years.19
  • To further complicate matters, Bathum et al studied the significance of heterozygosity.20 Genotyping for mutations in exons 2 and 4 of the HFE gene was performed in 1784 Danish people, and a trend toward fewer heterozygotes for the C282Y mutation (the mutation most often associated with hereditary hemochromatosis) was found in exon 4 mutations. Thus, in a population with high carrier frequency, such as exists in Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for the C282Y mutation, which suggests that carrier status is associated with shorter life expectancy.

Race

  • Hereditary hemochromatosis is the most commonly inherited disorder in white patients. Hereditary hemochromatosis affects 1 in 200-300 individuals of northern European descent.
  • Marked disparity in the distribution of the C282Y mutation has been noted. In the Irish, the frequency of the C282Y mutation was 10%, while in Australian aboriginal, African, and Asian populations, the mutation has not been found. The H63D mutation is more widespread.
  • In the US population, C282Y heterozygosity was 9.54% in non-Hispanic whites, 2.33% in non-Hispanic blacks, and 2.75% in Mexican Americans. The C282Y mutation found in blacks is the result of admixture with the white population.14

Sex

Symptoms of hereditary hemochromatosis occur more frequently in males than in females, with a male-to-female ratio of 3:1.

  • In relatives of patients with hereditary hemochromatosis who are homozygous for the C282Y mutation, expression of the iron overload phenotype was noted in 85% of males and 69% of females.21
  • In a study by Olynyk et al3 of homozygotes for the C282Y mutation, one quarter of patients did not express clinical or biochemical symptoms of disease, all of whom were women of reproductive age.
  • Men had a higher incidence of serious complications of hereditary hemochromatosis, primarily diabetes mellitus and cirrhosis. In men, the incidence of cirrhosis was 25.6% (13.8% in women), and the incidence of diabetes mellitus was 15.9% (7.4% in women). Women complained more often of fatigue 64.8% (42% in men) and skin hyperpigmentation 48% (44.9% in men).22

Age

  • Symptoms of hereditary hemochromatosis develop in persons older than 40 years. However, in JH, which is unrelated to HFE mutations, symptoms appear in persons aged 10-30 years.
  • Neonatal hemochromatosis, which is more correctly termed neonatal iron overload, is a disease with unknown etiology that progresses rapidly to death after birth.
  • In women, onset of hereditary hemochromatosis begins later because menstruation causes physiologic blood loss, which increases iron removal.

Clinical

History

The tetrad of cirrhosis, diabetes mellitus, hyperpigmentation of the skin, and cardiac failure may be evident. However, symptomatology of hereditary hemochromatosis has changed in recent years, and its full clinical expression is seen in only a minority of patients.1 In addition, any patient admitted to the hospital with an isolated case of asthenia or with arthralgia or hypertransaminasemia should be examined by means of transferrin-saturation testing.

  • General symptoms comprise chronic fatigue, weakness, lethargy, and apathy.
  • 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). Liver biopsy and histologic evaluation of tissue iron accumulation was believed to be the criterion standard for diagnosis of hereditary hemochromatosis until testing of the HFE gene was introduced.16
  • Amenorrhea, loss of libido, impotence, and symptoms of hypothyroidism can be seen in patients with hereditary hemochromatosis.
  • Diabetes mellitus, often requiring insulin therapy, 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 patients with hereditary hemochromatosis, the prevalence of diabetes mellitus was 21.9%.23 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.
  • Of patients with hereditary hemochromatosis, 25% are affected with osteoporosis. In 41% of patients, osteopenia is found. The osteoporosis is independent of genetic background and is associated with hypogonadism, alkaline phosphatase, body weight, and the severity of iron overload.24
  • The hypothesis that the hereditary hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk factors for ischemic heart disease and myocardial infarction was tested.25 . Hereditary hemochromatosis C282Y/C282Y, C282Y/H63D, and C282Y/wild-type genotypes were not associated with ischemic heart disease or myocardial infarction.

Physical

Patients with hereditary hemochromatosis may be asymptomatic, or hereditary hemochromatosis may be accompanied by general or organ-related signs.

  • Cutaneous hyperpigmentation is seen in more than 90% of patients with idiopathic hemochromatosis, although it may be mild.12 Hyperpigmentation is one of the earliest signs of the disease, and it tends to be most pronounced on sun-exposed skin, particularly on the face, with a coloration of brownish bronze or, at times, slate gray. In one series of 100 patients, approximately one half had metallic gray pigmentation, one fifth had a frankly brown pigmentation, and the remainder had an intermediate shade. External genital hyperpigmentation was seen in one third of patients, and one fifth had hyperpigmentation of flexural folds, scars, and nipple areolae. Hyperpigmentation often accentuates during exacerbations and regresses with therapy.
  • Ichthyosiform alterations, skin atrophy, koilonychia, and hair loss may also be evident. In the series of 100 patients, ichthyosislike changes were evident in 46% of patients.12 Ichthyosiform changes may be mild or marked.
  • Cutaneous atrophy was observed in 42% of 100 patients, usually on the anterior surface of the leg.
  • Partial loss of body hair was evident in 62% of patients. The pubic region was affected most commonly, although total loss of body hair was seen in 12% of patients. Hair loss and thinning was reduced by therapy in some patients.
  • Koilonychia, usually of the thumb and index and middle fingers, was seen in almost one half of patients. One fourth of patients had prominent spoon nails.
  • Patients complain of arthralgias, which are accompanied by findings of subchondral arthropathy and chondrocalcinosis on radiographs.
  • Splenomegaly often occurs in patients with hereditary hemochromatosis.
  • Cardiac manifestations are common in patients with hereditary hemochromatosis and include signs of congestive heart failure.

Causes

Hereditary hemochromatosis is fairly common in whites and is a result of iron deposition in hepatocytes, myocardiac fibers, and other visceral cells. Hereditary hemochromatosis is usually inherited in an autosomal recessive manner and is caused by mutations in the HFE gene.

Iron excess is known to be responsible for hypermelanosis. However, the mechanism is not fully understood. Tsuji26 found that hyperpigmentation of the skin occurs after iron injections in hairless mice. This hyperpigmentation was accompanied by hemosiderin accumulation in the skin. Stronger pigmentation of the fascial skin rather than the dorsal skin corresponded with elevated iron accumulation in the fascial part of the skin. The study suggests that the brownish discoloration of the skin in hemochromatosis may be dependent to some degree on hemosiderin accumulation. Hemosiderin is supposed to increase activation of melanocytes. On the other hand, Smith et al27 in 1978 found normal levels of immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) in patients with hereditary hemochromatosis and concluded that elevation of beta-MSH played no role in the pathogenesis of hyperpigmentation.

More on Hemochromatosis

Overview: Hemochromatosis
Differential Diagnoses & Workup: Hemochromatosis
Treatment & Medication: Hemochromatosis
Follow-up: Hemochromatosis
References
[ CLOSE WINDOW ]

References

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

  2. 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. Sep 1997;133(9):1098-101. [Medline].

  3. 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. Sep 2 1999;341(10):718-24. [Medline].

  4. 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. May 2005;67(5):425-8. [Medline].

  5. 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. Jul-Aug 2001;27(4):744-9. [Medline].

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

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

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

  9. 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. May 2006;38(5):531-9. [Medline].

  10. 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. Summer 2001;5(2):127-30. [Medline].

  11. 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. Aug 2001;108(4):619-23. [Medline].

  12. Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hermochromatosis.Study of 100 cases. Arch Dermatol. Feb 1977;113(2):161-5. [Medline].

  13. 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. Aug 15 2008;181(4):2723-31. [Medline].

  14. 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. May 2 2001;285(17):2216-22. [Medline].

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

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

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

  18. 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. Dec 2001;80(12):737-44. [Medline].

  19. 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. Dec 1 1998;129(11):946-53. [Medline].

  20. 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. Nov 12 2001;161(20):2441-4. [Medline].

  21. 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. Nov 23 2000;343(21):1529-35. [Medline].

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

  23. 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. Sep 2008;81(3):316-20. [Medline].

  24. 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. Jul 26 2008;[Medline].

  25. 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. Jul 12 2005;112(2):185-93. [Medline].

  26. Tsuji T. Experimental hemosiderosis: relationship between skin pigmentation and hemosiderin. Acta Derm Venereol. 1980;60(2):109-14. [Medline].

  27. Smith AG, Shuster S, Bomford A, Williams R. Plasma immunoreactive beta-melanocyte-stimulating hormone in chronic liver disease and fulminant hepatic failure. J Invest Dermatol. Jun 1978;70(6):326-7. [Medline].

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

  29. 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. Jun 1998;27(6):1695-9. [Medline].

  30. 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].

  31. 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. Feb 1998;114(2):311-8. [Medline].

  32. 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. Sep 1999;31(3):421-9. [Medline].

  33. 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].

  34. Lonardo A, Neri P, Mascia MT, Pietrangelo A. Hereditary hemochromatosis masquerading as rheumatoid arthritis. Ann Ital Med Int. Jan-Mar 2001;16(1):46-9. [Medline].

  35. 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. Nov 2001;116(5):738-43. [Medline].

  36. 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. Aug 2006;44(2):472-7. [Medline].

  37. 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. Jul 13 2006;49(14):4171-82. [Medline].

  38. 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. Jul 2006;25(7):375-85. [Medline].

  39. 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. May 2000;31(5):1160-4. [Medline].

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

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

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

  43. Brady JJ, Jackson HA, Roberts AG, Morgan RR, Whatley SD, Rowlands GL, et al. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol. Nov 2000;115(5):868-74. [Medline].

  44. Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelønning K, Fjøsne U, et al. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol. Oct 2001;36(10):1108-15. [Medline].

  45. Bacon BR, Sadiq SA. Hereditary hemochromatosis: presentation and diagnosis in the 1990s. Am J Gastroenterol. May 1997;92(5):784-9. [Medline].

  46. Chitturi S, Dakkak M, Campbell AP. Skin fragility and abnormal liver function tests. Postgrad Med J. Jul 1999;75(885):435-6. [Medline].

  47. Elleder M, Chlumská A, Hadravská S, Pilát D. Neonatal (perinatal) hemochromatosis. Cesk Patol. Nov 2001;37(4):146-53. [Medline].

  48. Girouard J, Giguère Y, Delage R, Rousseau F. Prevalence of HFE gene C282Y and H63D mutations in a French-Canadian population of neonates and in referred patients. Hum Mol Genet. Jan 15 2002;11(2):185-9. [Medline].

  49. 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. Sep-Oct 2001;27(5):892-3. [Medline].

  50. Vautier G, Murray M, Olynyk JK. Hereditary haemochromatosis: detection and management. Med J Aust. Oct 15 2001;175(8):418-21. [Medline].

  51. Yamada H, Ogawa H. [Essential trace element and skin diseases]. Nippon Rinsho. Jan 1996;54(1):99-105. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

hemochromatosis, hereditary hemochromatosis, HH, bronze diabetes, iron deposition disease, cirrhosis, diabetes mellitus, hyperpigmentation, cardiac failure, iron overload, hepatic iron overload, iron homeostasis, iron metabolism, excess iron absorption, neonatal iron overload, neonatal hemochromatosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Jacek Drobnik, MD, PhD, Assistant Professor of Physiology and Medicine, Department of Pathophysiology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Peter Fritsch, MD, Chair, Department of Dermatology and Venereology, University of Innsbruck, Austria
Peter Fritsch, MD is a member of the following medical societies: American Dermatological Association, International Society of Pediatric Dermatology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Genetech Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.