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eMedicine Specialties > Dermatology > Metabolic Diseases

Hemochromatosis

Jacek Drobnik, MD, PhD, Assistant Professor of Physiology and Medicine, Department of Pathophysiology, Medical University of Lodz, Poland
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Updated: Oct 14, 2009

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 from 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.

Differential Diagnoses

Addison Disease
Postinflammatory Hyperpigmentation
Argyria
Riehl Melanosis
Phytophotodermatitis
Poikiloderma of Civatte
Polymorphous Light Eruption

Other Problems to Be Considered

The cutaneous hyperpigmentation in patients with hereditary hemochromatosis (HH) should be differentiated from drug-induced hyperpigmentation and actinic reticuloid.

The discovery of the HFE gene allows easy differentiation of hereditary hemochromatosis from other forms of hepatic iron overload, including a new syndrome termed dysmetabolic hepatosiderosis.

Serum abnormalities of iron metabolism could be seen in 50% of patients with alcoholic liver disease, nonalcoholic steatohepatitis (NASH), or chronic viral hepatitis.28 These abnormalities comprise an increased ferritin level, which is sometimes accompanied with elevated transferrin saturation. Hepatic iron concentration (HIC) could be slightly elevated, but the level of HIC in patients with hereditary hemochromatosis is much higher. Patients with chronic hepatitis C virus infection (HCV) who do not respond to interferon therapy usually have higher HIC than responders. Examination of HFE mutations is pivotal for diagnosis of hemochromatosis.

The prevalence of the C282Y and H63D mutations in patients with alcoholic liver disease and in those with chronic HCV is the same as in the control population, whereas, in patients with NASH, the prevalence of HFE mutations is higher. Moreover, 40% of patients with porphyria cutanea tarda are homozygous or heterozygous for the C282Y mutation. This finding was shown in patients from the United States, the United Kingdom, and Australia but not in Italian patients. Some studies show that HFE mutations in patients with HCV are associated with higher frequencies of fibrosis and cirrhosis.29,30 Increased fibrosis was also found in patients with NASH who had the C282Y mutation.31,32

Heart diseases are associated with hereditary hemochromatosis in one third of patients. Cardiac disease is mainly manifested by congestive heart failure accompanied by supraventricular arrhythmias. On radiographs, cardiomegaly with increased pulmonary vascular markings are seen. Echocardiography reveals the features of the restrictive type of cardiomyopathy. Cardiac manifestations of hereditary hemochromatosis could have sudden onset and could be poorly responsive to therapy. The hemochromatic etiology of the cardiomyopathy should be identified to ensure appropriate treatment. The diagnosis of hemochromatosis is based on clinical features of the disease; these features include diffuse hyperpigmentation, hepatomegaly, and diabetes mellitus accompanied with biochemical abnormalities of iron metabolism and genotypic investigation.33

Distinguishing hemochromatosis arthropathy from rheumatoid arthritis is important for several reasons. For example, patients with hereditary hemochromatosis do not require corticosteroid treatment. In addition, if a diagnosis of rheumatoid arthritis is made incorrectly, treatment with phlebotomy is not started early and familial genetic counseling is not considered.34

Workup

Laboratory Studies

  • Serum iron concentration in patients with hereditary hemochromatosis is greater than 150 mcg/dL.
  • Serum ferritin level is greater than 500 ng/mL.
  • Transferrin saturation is usually more than 45%; however, transferrin saturation greater than 62% identifies hereditary hemochromatosis in 92% of patients. If transferrin saturation is greater than 45%, the presence of the C282Y or H63D mutation may be evaluated to confirm the diagnosis of hemochromatosis.

Imaging Studies

  • Radiographs demonstrate cardiomegaly and increased pulmonary vascular markings.
  • Features of restrictive cardiomyopathy are visible on echocardiograms.

Other Tests

  • Genetic tests for the C282Y and H63D mutations are widely available. Detection of hemochromatosis-associated mutations is conducted to confirm the diagnosis or to discover asymptomatic patients. Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutation definitely confirms the diagnosis of hereditary hemochromatosis.
  • Supraventricular arrhythmias are often revealed on electrocardiograms.

Procedures

  • A skin biopsy specimen may confirm the diagnosis of hereditary hemochromatosis. Any cutaneous site, hyperpigmented or not, may be selected for biopsy, but avoid performing cutaneous skin biopsies on the legs because iron deposition in that area may be due to stasis. In healthy people, iron deposition may be evident only around apocrine glands and not around eccrine glands.
  • Liver biopsy is no longer obligatory to establish the diagnosis, but it may be helpful in patients with cirrhosis, which is the primary risk factor for hepatocellular carcinoma.

Histologic Findings

Microscopically, cutaneous hyperpigmentation appears as increased melanin within the epidermal basal layers.12 An iron stain, such as Perls Prussian blue stain, should be used to detect azure granules around the blood vessels and within the basement membrane zone of sweat glands and the connective tissue cells surrounding them. Siderosis around eccrine glands may be specific for idiopathic hemochromatosis.

Primary liver cancer in patients with hemochromatosis may have a wide histologic spectrum.35 Some tumors show frequent biliary differentiation. Others arise on a nonfibrotic or cirrhotic liver and are often associated with von Meyenburg complexes and, to a lesser extent, with bile duct adenomas.

Treatment

Medical Care

Phlebotomy remains the sole recommended treatment for hereditary hemochromatosis (HH) and should be undertaken in a case-specific manner.

In the induction phase,36 one venesection weekly is made, with blood removal of 7 mL/kg per each venesection. However, the bloodletting should not exceed 550 mL. The efficacy of treatment is controlled by ferritin level evaluation in plasma once monthly until the values remain above the upper limits of normal (300 mcg/L in men and 200 mcg/L in women). Subsequently, evaluation of ferritin concentration should be performed bimonthly until its level is reduced below 50 mcg/L. In the maintenance phase, the phlebotomy should be performed every 2-4 months. The rhythm of venesection is determined by the level of ferritin, which should be lower than 50 mcg/mL.37

To asses whether hepatic fibrosis can be reversed by venesection therapy,38 the study was performed on 36 patients affected with C282Y homozygous hemochromatosis. Severe liver fibrosis of F3 and F4 stage according to the METAVIR grading system was found in the first biopsy specimen. After venesection therapy, the second biopsy specimen showed that fibrosis regressed in 69% of patients with F3 grade and in 35% with F4 grade fibrosis. In patients with the ratio of gammaglobulin (g/l) to platelets (n/mm3) X prothrombin activity (%) above 7.5, the regression of fibrosis has not been observed. The study showed that venesection therapy can reduce liver fibrosis, and the effects of therapy are dependent on the stage of the disease. The results of venesection therapy can be predicted by the simple biochemical tests.

Venesection is generally a safe and efficient method of iron removal. In patients with heart disease, anemia, or poor venous access, treatment with iron chelation agents is recommended. The therapeutic perspectives comprise compounds inhibiting intestinal absorption of iron, chelators of iron, hepcidin, or ferroportin supplementation. In disease caused by hepcidin deficiency, protein supplementation with hepcidin is advised.

Deferasirox (Exjade) is the oral iron chelator that should be taken once daily as an adjunct to venesections or instead of phlebotomy in patients in whom these are poorly tolerated. Deferasirox is very efficacious in liver iron removal. During treatment with deferasirox, kidney function should be controlled.39

The effects of deferasirox in Hjv-/- mice (knockout animals lacking HJV, ie, an experimental model of hereditary hemochromatosis) were investigated. Deferasirox was administered once daily 5 times a week. A dose of 100 mg/kg markedly reduced the iron level in the liver and heart. In the pancreas, deferasirox was less effective. The splenic iron count was not influenced.40

The family of dendrimers, the iron-selective chelators, have recently been synthesized.41 Dendrimers terminated with hydroxypiridinone have high affinity to iron and reduce its absorption in the rat intestine. Therefore, the application of the dendrimers in the treatment of iron overload diseases is considered. Experiments performed on rats compared the protective effect of 2 iron chelators, deferoxamine and deferiprone, on iron overload in the heart. The 2 compounds were administered individually or in combination with vitamin C. The vitamin C was used as the antioxidative compound aimed at preventing heart oxidative injury. Deferiprone was found to reduce histopathological changes in the heart of rats chronically loaded with iron. Moreover, additional administration of vitamin C improved histopathological changes and biochemical markers in the heart.42

The first patient affected by juvenile hemochromatosis was successfully treated with chelation therapy. Because of severe congestive heart failure, phlebotomy was contradicted. Simultaneous administration of deferoxamine and deferiprone reduced the myocardial dysfunction and improved the clinical status of that patient.

Consultations

Consult a geneticist. Family screening is indicated in all first-degree relatives for every new case that is diagnosed.

Follow-up

Further Outpatient Care

  • Physicians should be aware of the possibility of hereditary hemochromatosis (HH), and they should perform diagnostic tests when hereditary hemochromatosis is suspected. Moreover, patient education as to the importance of early diagnosis and lifelong treatment is essential for symptom-free life.
  • Continuous observation of patients with hereditary hemochromatosis regarding the potential complications of the disease is recommended.
  • Regular monitoring of hematocrit, hemoglobin, and serum ferritin levels is necessary in patients undergoing phlebotomy.
  • Genetic testing for hereditary hemochromatosis should also be performed in family members of patients with hereditary hemochromatosis.

Deterrence/Prevention

  • As a result of the high frequency of hereditary hemochromatosis – associated mutations, the American Medical Association recommends the establishment of guidelines for population screening.
    • 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.43
    • Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutations is believed to be diagnostic. On the other hand, negative results on DNA tests do not exclude hereditary hemochromatosis, which can also be the result of other mutations.44
    • 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.45
  • 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.16
  • 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.46 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.

Complications

  • Hemochromatosis may be associated with porphyria; therefore, evaluate patients for this complication.
  • In one study, homozygosity for the C282Y hemochromatosis mutation was linked to an earlier onset of skin lesions in patients with either familial or sporadic porphyria cutanea tarda; the effect is more marked in familial porphyria cutanea tarda, in which anticipation was demonstrated in family studies.47 Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is a significant susceptibility factor in both types.

Prognosis

  • The incidence and course of hereditary hemochromatosis in 179 white Danish patients with clinically overt hemochromatosis were studied from 1948-1985.18 Survival duration was significantly reduced in patients with liver cirrhosis, diabetes mellitus, or both. In contrast, survival rate in patients without cirrhosis or diabetes was similar to rates expected in the general population. Survival rate in patients with arthropathy was higher than in patients without. Patients adequately treated with phlebotomy had a higher survival rate than patients treated inadequately. The primary causes of death were hepatic failure due to cirrhosis (32%) and cirrhosis with liver cancer (23.1%).
  • Sharpened diagnostic awareness has improved early diagnosis of hereditary hemochromatosis and increased the diagnostic frequency of clinical hemochromatosis. Adequate phlebotomy treatment was the major determinant of survival, and it markedly improved prognosis. Early detection and treatment of this common iron overload disorder is crucial and can guarantee a normal lifespan in patients with hemochromatosis.

Miscellaneous

Medicolegal Pitfalls

  • Failure to diagnose hemochromatosis early when therapy may be effective constitutes a potential pitfall. In addition, take note of the increased risk of hepatoma in cirrhotic livers of patients with hemochromatosis.

References

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  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].

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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

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, Dermatology, Professor of Pathology, Pediatrics, Medicine, and 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, Northside 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: Nothing to disclose.

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; Medicis 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.

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