- Author: Andrea Duchini, MD; Chief Editor: Julian Katz, MD more...
Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. It is the most common autosomal recessive genetic disorder and the most common cause of severe iron overload.
Signs and symptoms
Patients with hereditary hemochromatosis may be asymptomatic (75%) or may present with general and organ-related signs and symptoms. Early symptoms include severe fatigue (74%), impotence (45%), and arthralgia (44%). The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.
See Clinical Presentation for more detail.
Clinical manifestations of hemochromatosis include the following:
Liver disease (hepatomegaly, 13%; cirrhosis, 13%, usually late in the disease)
Skin bronzing or hyperpigmentation (70%)
Diabetes mellitus (48%)
Amenorrhea, impotence, hypogonadism
Osteopenia and osteoporosis 
Koilonychia (spoon nails)
The diagnosis of hemochromatosis is based on clinical features of the disease. Most patients are asymptomatic 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.
Laboratory studies used in evaluating suspected hemochromatosis include the following:
Genetic testing: Examination of HFE mutations (C282Y, H63D) is pivotal for diagnosis of hemochromatosis
Transferrin saturation levels
Serum ferritin studies
Hepatic iron concentration
Supraventricular arrhythmias are often revealed on ECGs.
Chest radiography and echocardiography may be helpful in the evaluation of patients with hemochromatosis and cardiac disease.
CT scanning is neither sensitive nor specific for the detection of mild hepatic iron overload. MRI may be more sensitive than CT scanning, but this modality has not been validated as a diagnostic test to help confirm hemochromatosis. Hepatic iron quantification with MRI might be helpful.
The following are procedures that may be used to assess patients with hemochromatosis:
Liver biopsy, with biochemical determination of hepatic iron concentration and calculation of the hepatic iron index and histologic evaluation with iron staining (Perls Prussian blue)
Indications for liver biopsy
The use of liver biopsy in hereditary hemochromatosis can be restricted to those patients with a high probability of severe fibrosis or cirrhosis.
The American Association for the Study of Liver Diseases (AASLD) guidelines include the following indications for liver biopsy :
All homozygotes with clinical evidence of liver disease
All homozygotes with serum ferritin greater than 1,000 ng/ml
All homozygotes older than 40 years with other risk factors for liver disease
Compound or C282Y heterozygotes with elevated transferrin saturation, particularly those who have had abnormal liver enzyme levels or clinical evidence of liver disease
See Workup for more detail.
Clinical suspicion and early diagnosis are essential in hemochromatosis. The goal of therapy in patients with iron overload disorders is to remove the iron before it can produce irreversible parenchymal damage.
Once diagnosed, hemochromatosis is treated by phlebotomy to rid the body of excess iron and to maintain normal iron stores. Phlebotomy remains the sole recommended treatment for hereditary hemochromatosis and should be undertaken in a case-specific manner.
In patients with hemochromatosis and heart disease, anemia, or poor venous access, treatment with iron chelation agents is recommended and includes the following agents:
Surgical procedures are used to treat 2 important complications of hemochromatosis: end-stage liver disease and severe arthropathy. Orthotopic liver transplantation is the only therapeutic option when end-stage liver disease progresses despite iron-reduction therapy. This intervention is also indicated in cases with the development of hepatocellular carcinoma.
Surgical arthroplasty is considered if joint destruction becomes severe despite medical therapy.
Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. This is the most common inherited liver disease in white persons and the most common autosomal recessive genetic disorder.
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 (See Screening under Clinical).
Italian investigators report that alterations in sympathetic nerve traffic may occur in those with genetic hemochromatosis before and after iron depletion therapy. There may be an association with an hyperadrenergic state and a baroreflex alteration, which are reversed by iron depletion and which may increase cardiovascular risk.
Secondary hemochromatosis is caused by disorders of erythropoiesis and treatment of the diseases with blood transfusions. After damage of transfused erythrocytes by macrophages, iron freed from heme is accumulated in the body (liver, heart, skin). Secondary hemochromatosis is mainly induced by diseases of erythropoiesis, including thalassemia, sickle cell anemia, X-linked sideroblastic anemia, pyruvate kinase deficiency, hereditary spherocytosis, and congenital dyserythropoietic anemia (CDA).
Hereditary hemochromatosis is an adult-onset disorder that represents an error of iron metabolism characterized by inappropriately high iron absorption resulting in progressive iron overload. This disease is the most common cause of severe iron overload. The organs involved are the liver, heart, pancreas, pituitary, joints, and skin.
Excess iron is hazardous, because it produces free radical formation. The presence of free iron in biologic systems can lead to the rapid formation of damaging reactive oxygen metabolites, such as the hydroxyl radical and the superoxide radical. These can produce DNA cleavage, impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and fibrosis.
Derangement of iron homeostasis is also 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 (TNF-alpha) and interleukin (IL)-6 by macrophages was lowered. However, ferroporin, the macrophage iron exporter, was upregulated. 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.
Daily iron losses and absorption
Adults preserve a constant level of body iron by efficient conservation, maintaining rigorous control over absorption to balance losses. An adult man loses approximately 1 mg of iron daily, mostly in desquamated epithelium and secretions from the gut and skin. During the childbearing years, healthy women lose an average of an additional milligram of iron daily from menstrual bleeding (40 mL blood loss) and approximately 500 mg with each pregnancy. In addition, normal daily fecal loss of approximately 0.7 mL of blood (0.3 mg of iron) occurs. Only a small quantity of iron is excreted in urine (< 0.1 mg/d).
In healthy adults, losses are balanced by absorption of sufficient dietary iron (1-2 mg) to maintain a relatively constant amount of body iron throughout life. Although excretion is quantitatively as important as absorption in the maintenance of iron balance, absorption usually plays the more active regulatory role. In hereditary hemochromatosis, dysregulation of intestinal iron absorption occurs, wherein iron continues to be efficiently absorbed even in the face of substantial elevation of body iron stores.
HFE gene missense mutations
The gene responsible for the disease is called HFE, and it is located within the human leukocyte antigen (HLA) class I region on chromosome 6 between the genes coding for HLA-A and HLA-B. This gene is mutated in most individuals with hereditary hemochromatosis, and 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 (MHC) class I proteins. However, HFE does not present peptides to T cells, and transferrin receptor (TfR) is a ligand for the HFE protein. HFE interacts with THR and causes a clear decrease in the affinity with which the receptor binds transferrin; thus, there's a direct association of the HFE protein and the TfR-mediated regulation of iron homeostasis, and this interaction may also modulate cellular iron uptake and decrease ferritin levels. When a mutant or nonfunctional variant of the HFE gene is present, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced accumulation of iron in peripheral tissues.
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. Findings suggestive of increased iron transport at the basolateral membrane of enterocytes in hemochromatosis have emerged from numerous studies of HFE -related hemochromatosis in humans and in mice.
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. There have been data that 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.
Hemochromatosis types 2 and 3
The gene for hemochromatosis type 1 (HFE1), the result of the C282Y and H63D mutations, is located at band 6p22 and encodes a protein containing 343 amino acids. However, 2 other types of hemochromatosis have been identified: juvenile hemochromatosis (JH) or type 2 (gene HFE2), which has been mapped to band 1q21,[18, 19] 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.
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. Hepcidin is a human antimicrobial peptide synthesized in the liver that plays a key role in the downregulation of iron release by enterocytes and macrophages (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. The absence of this peptide is associated with severe, early-onset, iron-loading phenotype. It is also inappropriately low in adult-onset HFE -related disease.
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.
SLC11A3 gene missense mutation and autosomal dominant hemochromatosis
A large family was described with autosomal dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. 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 associates proposed that partial loss of ferroprotein function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.
Hereditary hemochromatosis is a genetic heterogeneous disorder inherited as an autosomal recessive trait. The gene is tightly linked to the human leukocyte antigen (HLA)-A region on the short arm of chromosome 6. HFE, a specific gene for hemochromatosis, has been identified.[24, 25] (See Pathophysiology.)
HFE missense mutations
Homozygosity for a missense mutation, with substitution of a cysteine residue for a tyrosine residue at amino acid position 282 (C282Y) of HFE is found in 70-100% of clinically diagnosed patients. A second missense mutation, with substitution of histidine for aspartate at amino acid 63 (H63D), has also been identified. The clinical effects of this mutation appear to be limited.
C282Y homozygotes and, possibly, C282Y/H63D compound heterozygotes, appear to be at risk for clinical iron overload. The clinical significance of other rarer forms of compound heterozygosity, such as heterozygosity for C282Y and a mutation in which cysteine replaces serine at position 65 (S65C) or heterozygosity for H63D and S65C, is controversial.
The precise mechanism by which mutations in the HFE gene lead to iron overload is unknown. The outcome is increased intestinal iron absorption and predominantly hepatocellular accumulation of hepatic iron.
Although relatively few cases have been described to date, the iron-overload phenotype associated with mutations in the gene encoding transferrin receptor 2 (TfR2) appears to be very similar to that of classic HFE -related hemochromatosis.
Elevated iron storage is related to the development of metabolic syndrome, diabetes, and obesity, which are themselves associated with hypertriglyceridemia. When Solanas-Barca et al investigated whether HFE mutations that cause hereditary hemochromatosis can be linked to the development of primary hypertriglyceridemia, the investigators these mutations may be important factors in the development of several primary hypertriglyceridemia phenotypes.
Furthermore, in the hypertriglyceridemia group, the genetic predisposition to hereditary hemochromatosis was 5.9 and 4.4 times greater than in subjects who were normolipidemic and in those with familial hypercholesterolemia, respectively. Moreover, 16.8% of persons (35 cases) in the hypertriglyceridemia group had iron overload, compared with 6.5% of individuals (14 cases) who were normolipidemic and 5.6% of patients (9 cases) with familial hypercholesterolemia.
HAMP gene mutation and juvenile hereditary hemochromatosis
Rare cases of juvenile hereditary hemochromatosis have been linked to a homozygous mutation in the HAMP gene, which encodes hepcidin, a peptide that plays a key role in human iron metabolism.[31, 32] However, most juvenile-onset cases have been mapped to chromosome 1q, where the gene that produces hemojuvelin, HJV (originally called HFE2), has been identified.[18, 19]
Evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Studies suggest that TfR2 is a modulator of hepcidin production in response to iron; hepcidin was low or undetectable in most cases of patients homozygous for TfR2 mutation.[34, 35, 36]
United States statistics
Prevalence of hereditary hemochromatosis in the United States is 1 case in 200-500 individuals. Most are of northern European origin. Frequency of the C282Y mutation is 5.4% and that of the H63D mutation is 13.5%. Prevalence of C282Y homozygosity has been estimated to be 0.26%, the H63D homozygosity was estimated to be 1.89%, and compound heterozygosity was estimated to be 1.97%. The carrier state is estimated to be approximately 10%.
The worldwide frequency of the C282Y is about 1.9% and that of the H63D mutation is about 8.1%. Hemochromatosis has the same prevalence in Europe, Australia, and other Western countries, with the highest prevalence being noted in people of Celtic origin. Hemochromatosis is less common among patients of African descent.
Marked geographical disparity in the distribution of the C282Y mutation has been noted. Non -HFE- associated hereditary hemochromatosis was found in Mediterranean countries.
In populations of northern European ancestry, hereditary hemochromatosis is closely linked to mutations in HFE. 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.
In a population of white adults of northern European ancestry, 0.5% were homozygous for the C282Y mutation in HFE. However, only half the homozygotes had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained within the reference range over a 4-year period. The G320V mutation seems to be widely distributed among juvenile hemochromatosis patients from central Europe and Greece. Therefore, detection of the G320V mutation could be a noninvasive method to identify most of the patients from these regions.
Racial differences in incidence
Marked racial disparity in the distribution of the C282Y mutation has been noted. Prevalence of hemochromatosis is 6 times higher in white persons than in black persons. In the Irish, the frequency of the C282Y mutation was 10%, whereas in Australian aboriginal, African, and Asian populations, the mutation has not been found.
C282Y homozygotes account for 82-90% of clinical diagnoses of hereditary hemochromatosis among persons of northern European descent ; in a report, 1 in 227 white individuals were homozygotes for the HFE C282Y mutation. The highest reported prevalence for C282Y homozygosity is one in 83 people and was described in Ireland.
The frequency of the C282Y heterozygosity is much lower among Hispanic persons (0.27 per 1000 population), Asian Americans (< 0.001 per 1000 population), Pacific Islanders (0.12 per 1000 population), and black persons (0.14 per 1000 population) than among persons of northern European descent. The frequencies of the C282Y and H63D mutations vary in black individuals from different geographic regions of the United States as a result of white admixture.
HFE mutations in black women with diabetes
In a study that compared the frequency of HFE mutations in black women who had type 2 diabetes mellitus to the frequency of mutations in control subjects, the frequencies of the C282Y and H63D mutations were not significantly different between patients with type 2 diabetes mellitus and control subjects. The C282Y mutation was noted in 0.59% of patients and in 1.41% of control subjects, whereas 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.
Sexual differences in incidence
Men are affected with hemochromatosis nearly 2-3 times as often as women, with an estimated ratio of 1.8:1 to 3:1.
Disease related to iron overload commonly develops in men (but not in women) who are homozygous for the C282Y mutation, especially when serum ferritin levels are 1000 mcg/L or more. The increased prevalence of iron-overload–related disease in C282Y homozygous men, as compared with that in women, is frequently ascribed to recurrent physiologic blood loss and the resultant slower accumulation of iron in women.
However, disparate frequencies of HLA A*03B*07 haplotypes in men and women have also been reported in hereditary hemochromatosis probands, which may be relevant to sex-specific phenotypic expression of this disease.
Studies of iron regulatory pathways in black persons have suggested that serum ferritin levels may be genetically determined by sex differences as well as environmental factors.
In a study of 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.
Olynyk et al reported that one quarter of patients who are homozygotes for the C282Y mutation did not express clinical or biochemical symptoms of disease, all of whom were women of reproductive age.
Men have also been reported to have 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).
Age-related differences in incidence
Hemochromatosis usually becomes apparent after age 40 years in men (median age, 51 y)and after age 50 years in women (median age, 66 y). In women, onset of hereditary hemochromatosis begins later because menstruation causes physiologic blood loss, which increases iron removal.
However, in juvenile hemochromatosis, 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.
Sharpened diagnostic awareness has improved early diagnosis of hereditary hemochromatosis and increased the diagnostic frequency of clinical hemochromatosis. Early detection and treatment of this common iron overload disorder can guarantee a normal lifespan in patients with hemochromatosis.
The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. Patients without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy. Adequate phlebotomy treatment is the major determinant of survival, and it markedly improves prognosis. Early diagnosis and therapeutic phlebotomy to maintain low normal body stores is crucial and can prevent all known complications of hemochromatosis. If untreated, hemochromatosis may lead to death from cirrhosis, diabetes, malignant hepatoma, or cardiac disease.[54, 55]
Potential complications of hemochromatosis include the following:
Congestive heart failure
Mortality is estimated to be 1.7 cases per 10,000 deaths. This number increases to 3.2 cases per 10,000 deaths in autopsy series. The death rate associated with hemochromatosis increased from 0.5 persons per million population in 1968 to 0.9 persons per million population in 1992 due to improved recognition of the disease. Mortality is higher in infants and in adults older than 50 years as well as higher in men and in white persons than in women, black persons, and other groups.
In a study from Denmark, investigators evaluating the incidence and course of hereditary hemochromatosis in white Danish patients with clinically overt hemochromatosis found that 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. In addition, survival rates in patients with arthropathy were higher than in patients without arthropathy. Patients adequately treated with phlebotomy also 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%).
After liver transplantation, 1-year survival rates are 58% and 5-year survival rates are 42%, which are significantly lower than those for all other indications. Poor survival and increased posttransplant mortality are predominantly due to infectious and cardiac complications. Sepsis causes most early posttransplant mortality, whereas congestive heart failure accounts for most deaths 1 year or longer after transplantation.
When Bathum et al studied the significance of heterozygosity and mortality, the investigators found that in a population with high carrier frequency, such as the Danish, mutations in HFE show an age-related reduction in the frequency of heterozygotes for the C282Y mutation. This suggests that carrier status is associated with shorter life expectancy. In the same study, genotyping for mutations in exons 2 and 4 of the HFE gene showed a trend toward fewer heterozygotes for the C282Y mutation in exon 4 mutations.
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