Hemochromatosis: Clinical Implications

Paul C. Adams, MD, Professor of Medicine, London Health Sciences Centre, London, Ontario, Canada


Hemochromatosis is the most common genetic disease in populations of European ancestry. Despite estimates of occurrence in different countries ranging from 1 in 100 to 1 in 300, many physicians consider hemochromatosis to be a rare disease. The diagnosis can be elusive because of the nonspecific nature of the symptoms and is rare because of the incomplete penetrance of the genotype. With the discovery of the hemochromatosis gene (HFE) in 1996 [1] have come new insights into the pathogenesis of the disease and new diagnostic strategies. Also since the discovery of the HFE gene, the question of whether hemochromatosis should be defined strictly on phenotypic criteria (such as the degree of iron overload [transferrin saturation, ferritin level, liver biopsy, hepatic iron concentration, iron removed by venesection therapy]) or as a genetic disease that is most commonly associated with the C282Y mutation and varying degrees of iron overload has come to the fore. Because the genetic test for the mutation has been widely used as a diagnostic tool, most studies now employ a combination of phenotypic and genotypic criteria for the diagnosis of hemochromatosis. It is important to realize that there are many causes of iron overload other than hemochromatosis ( ).

Table 1.  Differential Diagnosis of Iron Overload

HFE-related hemochromatosis

C282Y homozygotes (95%)
C282Y/H63D compound heterozygotes (4%)
H63D homozygotes (1%)

Non-HFE-related hemochromatosis


  • Ferroportin mutation

  • Nonfamilial (may be a heterogeneous collection of conditions resulting in iron overload)

  • Juvenile hemochromatosis (young adults with cardiac and endocrine dysfunction)

  • Neonatal hemochromatosis

  • Iron overload secondary to end-stage cirrhosis

  • African-American iron overload

  • African iron overload

  • Polynesian iron overload

  • Transfusional iron overload

  • Insulin resistance-related iron overload

  • Aceruloplasminemia

  • Alcoholic siderosis

  • Porphyria cutanea tarda

  • Post portacaval shunting

Genetics of Hemochromatosis

Hemochromatosis is an autosomal recessive condition and the HFE gene is localized to chromosome 6. The typical hemochromatosis patient carries 2 copies of the C282Y mutation of the HFE gene (C282Y homozygote). A minor mutation, H63D, has also been described. Compound heterozygotes (C282Y/H63D) and H63D homozygotes most commonly have normal iron tests, but mild-to-moderate iron overload has been described with these genotypes.

Clinical Features of Hemochromatosis

Liver Disease

Although hemochromatosis is often classified as a liver disease, it should be emphasized that it is a systemic genetic disease with multisystem involvement. The liver has, however, been central both in the diagnosis and prognosis of hemochromatosis. Hepatomegaly remains one of the more common physical signs in patients with this disease, but may not be present in the young asymptomatic homozygote.

In a study of 410 homozygotes from Canada and France, 22% had cirrhosis of the liver at the time of diagnosis. The mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were within normal range in these 410 patients. Cirrhotic patients and patients with concomitant alcohol abuse were more likely to have abnormal liver enzymes. [4] It seems likely then that there are factors other than iron overload -- such as environmental factors (alcohol, diet) and comodifying genes -- that contribute to cirrhosis in hemochromatosis.

Hepatocellular carcinoma (HCC) has been described in 18.5% of cirrhotic patients with hemochromatosis. [5] (This malignancy has rarely been described in noncirrhotic hemochromatosis patients.) The relative risk of HCC in this setting is approximately 200-fold.

The effect of iron depletion therapy has generally been stabilization rather than reversal of the liver disease. This fact may account for the relatively small number of C282Y homozygotes that have needed liver transplantation. Iron overload has been a risk factor associated with a poor outcome following liver transplantation, both in hemochromatosis and nonhemochromatosis patients. [6]


The most common presenting symptom in women with hemochromatosis is often arthralgias of the metacarpophalangeal joints of the hands. This pathology can be detected on x-ray in advanced cases of disease, and resembles osteoarthritis. Nonspecific aches in the back and large joints are more difficult to interpret because of the high prevalence of these symptoms in the general population. Chondrocalcinosis in the knee can be a clue to the diagnosis, but is a less common manifestation. Treatment of the arthropathy of hemochromatosis is nonspecific, and involves anti-inflammatory drugs. Arthropathy has been shown to have a major detrimental effect on the quality of life in patients with hemochromatosis. [7]


Glucose intolerance and diabetes frequently accompany cirrhosis of all etiologies. This includes cirrhosis associated with hemochromatosis, and it is uncommon to find a hemochromatotic diabetic without liver disease. It is for this reason that screening for hemochromatosis within a diabetes clinic is not particularly effective -- because organ damage has already occurred. Metabolic studies have suggested that insulin resistance rather than pancreatic islet destruction is the most common pathogenetic mechanism for the abnormal glucose metabolism associated with hemochromatosis. [8]

There has been interest in the association of insulin resistance with iron overload independent of the diagnosis of hemochromatosis. Many of these patients are obese and may have a normal transferrin saturation with an elevated serum ferritin level. [9] Some physicians would classify these patients as having hemochromatosis based on the degree of iron overload. The latter again illustrates some of the controversies surrounding case definition.

Cardiac Disease

Congestive heart failure is a late and relatively uncommon manifestation of C282Y hemochromatosis (ie, the form of hereditary hemochromatosis associated with C282Y mutation of the HFE gene). In contrast, it is often the presenting complaint in juvenile hemochromatosis, a different genetic disease that presents in young adulthood with severe heart failure, life-threatening ventricular arrhythmias, and endocrine problems. Echocardiography is the best diagnostic tool in this setting; ventricular function can significantly improve with iron depletion.


Darker skin pigmentation is a late feature of hemochromatosis that does improve with iron-depletion therapy. The clinical syndrome of "bronze diabetes" is a very rare presentation for hemochromatosis.

Impotence is common in the late stages of hemochromatosis; it is often related to testicular atrophy. Parenteral testosterone therapy may be helpful, and may also benefit osteoporosis that has been described in advanced disease. Sildenafil has been useful for impotence in several hemochromatosis patients but should be used with caution in patients with cardiac disease. Thyroid and pituitary dysfunction have also been described in association with hemochromatosis.

Diagnosis of Hemochromatosis

A paradox of genetic hemochromatosis is the observation that the disease is underdiagnosed in the general population and overdiagnosed in patients with secondary iron overload.

North American population studies using genetic testing have demonstrated a prevalence of C282Y homozygotes ranging from 1:143 to 1:327. [10-12] These differences in reported prevalence can be explained by the percentage of white participants in the screening sample. The fact that many physicians consider hemochromatosis to be rare implies that there is either a lack of penetrance of the gene (nonexpressing homozygote) or a large number of patients who remain undiagnosed in the community. (If one considers that 50% of C282Y homozygotes may be nonexpressing, there are still a large number of cases that would remain undiagnosed.)

Diagnostic Tests for Hemochromatosis

1. Transferrin Saturation:
The transferrin saturation has a sensitivity of > 90% for hemochromatosis in referred patients and family studies. The sensitivity of transferrin saturation is much lower in population screening studies designed to detect C282Y homozygotes (50%-60%). [10,12,13]

2. Unsaturated Iron-Binding Capacity (UIBC):
The UIBC is a 1-step colorimetric assay that has been used in many reference laboratories to calculate the transferrin saturation. It is inexpensive relative to the transferrin saturation study, and has been shown to be a promising and cost-efficient initial screening test for hemochromatosis. [10]

3. Serum Ferritin:
The relationship between serum ferritin and total body iron stores has been established by correlations with hepatic iron concentration and amount of iron removed by venesection. However, ferritin can be increased secondary to chronic inflammation and histiocytic neoplasms. A major diagnostic dilemma in the past was whether the serum ferritin level was related to hemochromatosis or another underlying liver disease, such as alcoholic liver disease, chronic viral hepatitis, or nonalcoholic steatohepatitis. It is likely that most of these difficult cases will now be resolved by genetic testing. However, the detection of a heterozygote for C282Y or H63D mutations often does not resolve the cause of the serum ferritin elevation.

4. Liver Biopsy:
Liver biopsy remains the gold-standard diagnostic test for hemochromatosis. However, its use has now shifted from that of a major diagnostic tool to that for estimating prognosis and concomitant disease. The need for liver biopsy seems less clear now in the young asymptomatic C282Y homozygote, in whom there is a low clinical suspicion of cirrhosis based on history, physical examination, and liver biochemistry.

A large study conducted in France and Canada suggested that C282Y homozygotes with a serum ferritin level < 1000 mcg/L, normal serum AST, and without hepatomegaly have a very low risk of cirrhosis. [14] Patients with cirrhosis have a 5.5-fold relative risk of death compared with noncirrhotic hemochromatosis patients. Cirrhotic patients are also at increased risk of HCC. Although early detection has been demonstrated by serial ultrasound and alpha-fetoprotein determination, curative treatment options remain limited. Liver biopsy is considered in typical C282Y homozygotes with liver dysfunction and in iron overloaded patients without the typical C282Y mutation. Simple C282Y heterozygotes, compound heterozygotes (C282Y/H63D), and patients with other risk factors (alcohol abuse, chronic viral hepatitis) with moderate-to-severe iron overload (serum ferritin > 1000 mcg/L) may be considered for liver biopsy. A threshold of > 283 mcmol/g (normal range, 0-35) has been associated with cirrhosis in hemochromatosis. [15]

Prior to the availability of genetic testing, hepatic iron concentration had been useful in diagnosing hemochromatosis. The hepatic iron concentration [mcmol/g]/age [in years] is the hepatic iron index. The hepatic iron index, in my opinion, has become less useful with the advent of genetic testing. It will, however, remain a tool to aid the clinician with clinical judgment about an individual case. This measure may have the greatest utility in the unusual hemochromatosis patient who is negative by conventional genetic testing but who clinically appears to have hereditary hemochromatosis.

5. Genetic Testing for Hemochromatosis:
A major advance deriving from the discovery of the hemochromatosis gene is the availability of a diagnostic genetic test. Most studies report that over 90% of typical hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. A second minor mutation, H63D, was also described in the original report. [1] Compound heterozygotes (C282Y/H63D) and, less commonly, H63D homozygotes, may resemble C282Y homozygotes, with mild-to-moderate iron overload. It is likely that additional mutations will be found, but they will be relevant in only a minority of patients.

Some patients have a clinical picture indistinguishable from that of genetic hemochromatosis but are negative for the C282Y mutation. Most of these individuals represent isolated cases, although a few occurrences of familial iron overload have been reported with such negative C282Y testing. Several pedigrees with iron overload have been reported with mutations in the ferroportin gene, which encodes an iron transport protein. [16,17] A negative C282Y test should lead the physician to question the diagnosis of genetic hemochromatosis and reconsider secondary iron overload related to cirrhosis, alcohol abuse, viral hepatitis, or iron loading anemias. If no other risk factors are found, the patient should begin venesection treatment similar to any other hemochromatosis patient.

Interpretation of the genetic test in several clinical settings is shown in A new polymorphism on intron 4 of the HFE gene (5569A) was independently reported by 2 Canadian laboratories to promote false-positive genetic testing in which a C282Y heterozygote appears to be a homozygote. [18,19] This factor should be considered during the evaluation of a "nonexpressing" C282Y homozygote. The correct diagnosis can be confirmed by direct DNA sequencing. Genetic discrimination is a concern with the widespread use of genetic testing.

Table 2.  Interpretation of Genetic Testing for Hemochromatosis

Genotype Interpretation

C282Y homozygote

This is the classical genetic pattern seen in > 90% of typical cases. Expression of disease ranges from no evidence of iron overload to massive iron overload with organ dysfunction. Siblings have a 1 in 4 chance of being affected and should undergo genetic testing. For children to be affected, each parent must be at least a heterozygote. If iron studies are normal, false-positive genetic testing or a nonexpressing homozygote should be considered.

C282Y/H63D compound heterozygote

This patient carries 1 copy of the major mutation and 1 copy of the minor mutation. Most patients with this genetic pattern have normal iron studies. A small percentage of compound heterozygotes have been found to have mild-to-moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (alcoholism, viral hepatitis).

C282Y heterozygote

This patient carries 1 copy of the major mutation. This pattern is seen in about 10% of the white population and is usually associated with normal iron studies. In rare cases, the iron studies are high in the range expected in a homozygote rather than a heterozygote. These patients may carry an unknown hemochromatosis mutation; liver biopsy is helpful in determining the need for venesection therapy.

H63D homozygote

This patient carries 2 copies of the minor mutation. Most patients with this genetic pattern have normal iron studies, but a small percentage have been found to have mild-to-moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (alcoholism, viral hepatitis).

H63D heterozygote

This patient carries 1 copy of the minor mutation. This pattern is seen in about 20% of the white population and is usually associated with normal iron studies. This pattern is so common in the general population that the presence of iron overload may be related to another risk factor. Liver biopsy may be required to determine the cause of the iron overload and the need for treatment in these patients.

No HFE mutations

An increasing number of mutations in other genes (ferroportin, transferrin receptor 2, aceruloplasminemia) have been identified as causing iron overload. There will likely be additional hemochromatosis mutations found in the future. If iron overload is present without any mutations in the HFE gene, a careful review of the history for other risk factors must be taken. Liver biopsy may be useful in determining the cause of the iron overload and the need for treatment. Most of these patients represent isolated, nonfamilial cases.

There were no adverse psychosocial effects associated with genetic testing for hemochromatosis reported in a study that followed patients for 1 year after testing. [20]

In the case of hemochromatosis, the advantages of early diagnosis of a treatable disease outweigh the potential disadvantages of genetic discrimination. Genetic discrimination has rarely been reported with hemochromatosis in the United States and appears to be even less common in other countries. The advantages of iron depletion to prevent liver disease are established, although randomized trials have never been performed.

Once the proband case is identified and confirmed with the genetic assay for the C282Y mutation, family testing is imperative. Siblings have approximately a 1 in 4 chance of also being homozygotes and should therefore be screened for the C282Y and H63D mutations, transferrin saturation, and serum ferritin level. A cost-effective strategy that is now possible with the availability of the genetic test is testing the spouse for the C282Y mutation in order to assess the risk to the children. If the spouse is not a C282Y heterozygote or homozygote, the children will be obligate heterozygotes. This assumes paternity and excludes another gene or mutation causing hemochromatosis. This strategy is particularly advantageous in cases in which the children are geographically separated or may be under a different healthcare system.

Treatment of Hemochromatosis

The therapy of hemochromatosis continues to rely on the practice of periodic bleeding.

At our center, patients attend an ambulatory-care facility and the venesections are performed by a nurse using a kit containing a 16-gauge straight needle and collection bag (Blood Pack MR6102; Baxter; Deerfield, Illinois). Blood is removed with the patient in the reclining position, over a period of 15-30 minutes. A hemoglobin level is done at the time of each weekly venesection to ensure that levels are adequate. If the hemoglobin level is decreased to less than 10 g/dL, the venesection schedule is reduced to 500 mL every other week. Venesections are continued until the serum ferritin level is approximately 50 mcg/L. The concomitant administration of a salt-containing sport beverage (eg, Gatorade) is a simple method for maintaining plasma volume during the venesection. Maintenance venesections after iron depletion, of 3-4 per year, are done in most patients, although the rate of iron reaccumulation is highly variable.

The transferrin saturation will remain increased in many treated patients and will not normalize unless the patient approaches iron deficiency. The prognosis of hemochromatosis is primarily dependent on the presence of cirrhosis at the time of diagnosis.

Chelation therapy with desferrioxamine is not recommended for hemochromatosis. Patients are advised to avoid oral iron therapy and alcohol abuse, but there are no severe dietary restrictions. Large doses of vitamin C are to be avoided. Many patients are enthusiastic about the observation that black tea decreases intestinal iron absorption. [21]

Current patient support groups are discouraged by the practice of iron fortification of foods, but much of this iron is in an inexpensive form with poor bioavailability.

Early diagnosis and treatment of patients with hemochromatosis leads to a long-term survival similar to that of the general population. Screening tests are available and inexpensive. Large-scale population screening projects are under way in 15 countries. [22] These ongoing studies should address some of the critical issues remaining, such as the percentage of C282Y homozygotes with iron overload or symptoms and the optimal screening protocol. [7]

The HEIRS (Hemochromatosis and Iron Overload Screening) study has initiated the testing of 100,000 individuals in the United States and Canada for iron overload. Initial screening studies have suggested a high prevalence of C282Y homozygotes but a low morbidity of disease.

In the largest screening study to date, 65,238 Norwegians were screened twice by high serum transferrin saturation, and those subjects identified by this process were then confirmed by genetic testing and/or liver biopsy as having hemochromatosis. Of 147 liver biopsies performed, 4 men and no women were found to have cirrhosis. [23]

In another screening study, from San Diego, California, the prevalence of significant symptomatic hemochromatosis in C282Y homozygotes was suggested to be as low as 1%. [3] This discrepancy between the morbidity in referred patients and the lack of morbidity in screened patients is not unique to hemochromatosis, and, for example, is also seen in studies of other diseases, such as chronic hepatitis C.


Hemochromatosis is a common and often underdiagnosed disease. Early diagnosis and treatment results in an excellent long-term prognosis. The development and application of a diagnostic genetic assay has improved the feasibility of the goal of preventing morbidity and mortality associated with hemochromatosis.


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