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Hereditary Hemochromatosis

(Primary Hemochromatosis)

By Candido E. Rivera, MD, Mayo Clinic

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Hereditary hemochromatosis is a genetic disorder characterized by excessive iron accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy. Diagnosis is by an elevated serum ferritin level and elevated transferrin saturation and confirmed by a gene assay. Treatment is usually with serial phlebotomies.


There are 4 types of hereditary hemochromatosis, types 1 through 4, depending on the gene that is mutated

  • Type 1: Mutations of the HFE gene

  • Type 2 (juvenile hemochromatosis): Mutations in the HJV and HAMP genes

  • Type 3: Mutations in the TFR2 gene

  • Type 4 (ferroportin disease): Mutations in the SLC40A1 gene

Other much rarer genetic disorders are associated with hepatic iron overload, but the clinical picture is usually dominated by symptoms and signs due to failure of other organs (eg, anemia in hypotransferrinemia or atransferrinemia, or neurologic defects in aceruloplasminemia).

Although these types vary markedly in age of onset, clinical consequences of iron overload are the same in all.

Type 1 hereditary hemochromatosis

Type 1 is classic hereditary hemochromatosis, also termed HFE-related hemochromatosis. More than 80% of cases are caused by the homozygous C282Y or C282Y/H63D compound heterozygote mutation. The disorder is autosomal recessive, with a homozygous frequency of 1:200 and a heterozygous frequency of 1:8 in people of northern European ancestry. It is uncommon among blacks and rare among people of Asian ancestry. Of patients with clinical hemochromatosis, 83% are homozygous. However, for unknown reasons, phenotypic (clinical) disease is much less common than predicted by the frequency of the gene (ie, many homozygous people do not manifest the disorder).

Type 2 hereditary hemochromatosis

Type 2 hereditary hemochromatosis (juvenile hemochromatosis) is a rare autosomal recessive disorder caused by mutations in the HJV gene that affect the transcription protein hemojuvelin or mutations in the HAMPgene, which directly codes for hepcidin. It often manifests in adolescents.

Type 3 hereditary hemochromatosis

Mutations in transferrin receptor 2 (TFR2), a protein that appears to control saturation of transferrin, can cause a rare autosomal recessive form of hemochromatosis.

Type 4 hereditary hemochromatosis

Type 4 hereditary hemochromatosis (ferroportin disease) occurs largely in people of southern European ancestry. It results from an autosomal dominant mutation in the SLC40A1 gene and affects the ability of ferroportin to bind hepcidin.

Transferrin and ceruloplasmin deficiency

In transferrin deficiency (hypotransferrinemia or atransferrinemia), absorbed iron that enters the portal system not bound to transferrin is deposited in the liver. Subsequent iron transfer to sites of RBC production is reduced because of transferrin deficiency.

In ceruloplasmin deficiency (aceruloplasminemia), lack of ferroxidase causes defective conversion of Fe2+ to Fe3+; such conversion is necessary for binding to transferrin. Defective transferrin binding impairs the movement of iron from intracellular stores to plasma transport, resulting in accumulation of iron in tissues.


Normal total body iron content is about 2.5 g in women and 3.5 g in men. Because symptoms may be delayed until iron accumulation is excessive (eg, > 10 to 20 g), hemochromatosis may not be recognized until later in life, even though it is an inherited abnormality. In women, clinical manifestations are uncommon before menopause because iron loss due to menses (and sometimes pregnancy and childbirth) tends to offset iron accumulation.

The mechanism for iron overload in both HFE and non-HFEhemochromatosis is increased iron absorption from the GI tract, leading to chronic deposition of iron in the tissues. Hepcidin, a liver-derived peptide, is the critical control mechanism for iron absorption. Hepcidin is normally up-regulated when iron stores are elevated and, through its inhibitory effect on ferroportin (which participates in iron absorption), it prevents excessive iron absorption and storage in normal people. Hemochromatosis types 1 through 4 share the same pathogenic basis (eg, lack of hepcidin synthesis or activity), and key clinical features.

In general, tissue injury appears to result from reactive free hydroxyl radicals generated when iron deposition in tissues catalyzes their formation. Other mechanisms may affect particular organs (eg, skin hyperpigmentation can result from increased melanin as well as iron accumulation).

Symptoms and Signs

The clinical consequences of iron overload are the same regardless of the etiology and pathophysiology of the overload.

Historically, experts believed that symptoms did not develop until significant organ damage had occurred. However, organ damage is slow and subtle, and fatigue and nonspecific systemic symptoms often occur early.

In type 1 hereditary (HFE) hemochromatosis, symptoms relate to the organs with the largest iron deposits (see Table: Common Manifestations of Hereditary Hemochromatosis). In men, the initial symptoms may be hypogonadism and erectile dysfunction caused by gonadal iron deposition. Glucose intolerance or diabetes mellitus is another common initial presentation. Some patients present with hypothyroidism.

Liver disease is the most common complication and may progress to cirrhosis; 20 to 30% of patients with cirrhosis develop hepatocellular carcinoma. Liver disease is the most common cause of death. Cardiomyopathy with heart failure is the 2nd most common fatal complication. Hyperpigmentation (bronze diabetes) is common, as is symptomatic arthropathy.

In type 2 disease, symptoms and signs include progressive hepatomegaly and hypogonadotropic hypogonadism.

In type 3 disease, symptoms and signs are similar to type 1 hereditary (HFE) hemochromatosis.

Type 4 disease manifests in the first decade of life as increased serum ferritin levels with low or normal transferrin saturation; progressive saturation of transferrin occurs when patients are in their 20s and 30s. Clinical manifestations are milder than in type 1 disease, with modest liver disease and mild anemia.

Common Manifestations of Hereditary Hemochromatosis


Prevalence (approximate)

Systemic symptoms (eg, weakness, lethargy)


Abnormal liver function test results


Skin hyperpigmentation






Erectile dysfunction

45% (of men)




  • Serum ferritin level and transferrin saturation

  • Genetic testing

Symptoms and signs may be nonspecific, subtle, and of gradual onset, so that index of suspicion should be high. Primary hemochromatosis should be suspected when typical manifestations, particularly combinations of such manifestations, remain unexplained after routine evaluation. Although any family history is a more specific clue, it is not usually present.

Serum ferritin measurement is the simplest and most direct initial test. Elevated levels (> 200 ng/mL in women or>300 ng/mL in men) are usually present in primary hemochromatosis but can result from other abnormalities, such as inflammatory liver disorders (eg, chronic viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease), cancer, certain systemic inflammatory disorders (eg, RA, hemophagocytic lymphohistiocytosis), or obesity. Further testing is done if ferritin level is abnormal; testing includes serum iron (usually > 300 mg/dL) and iron binding capacity (transferrin saturation; levels usually >50%).

In type 2 disease, ferritin levels are >1000 ng/mL, and transferrin saturation is > 90%.

In transferrin or ceruloplasmin deficiency, serum transferrin (ie, iron-binding capacity) and ceruloplasmin levels are. profoundly low

Gene assay is diagnostic of hereditary hemochromatosis caused by HFE gene mutations. Hemochromatosis types 2 to 4 is suspected in the less common instances in which ferritin and iron blood tests indicate iron overload and genetic testing is negative for the HFE gene mutation, particularly in younger patients. Confirmation of these diagnoses is evolving.

Because the presence of cirrhosis affects prognosis, a liver biopsy is commonly done and tissue iron content is measured (when available). High-intensity MRI is a noninvasive alternative for estimating hepatic iron content that is becoming increasingly accurate.

Screening is required for first-degree relatives of people with hereditary hemochromatosis by measuring serum ferritin levels and testing for the C282Y and H63Dgenes.


  • Phlebotomy

Treatment is indicated for patients with clinical manifestations, elevated serum ferritin levels (particularly levels > 1000 ng/mL), or elevated transferrin saturation. Asymptomatic patients need only periodic (eg, yearly) clinical evaluation and measurement of serum iron, ferritin, and transferrin saturation.

Phlebotomy is the simplest and most effective method to remove excess iron. It delays progression of fibrosis to cirrhosis, sometimes even reversing cirrhotic changes, and prolongs survival, but it does not prevent hepatocellular carcinoma. About 500 mL of blood (about 250 mg of iron) is removed weekly until serum iron levels are normal and transferrin saturation is < 50%. Weekly phlebotomy may be needed for many months (eg, if 250 mg Fe are removed per week, 40 wk will be required to remove 10 g Fe). When iron levels are normal, phlebotomies can be intermittent to maintain transferrin saturation at < 30%.

Diabetes, cardiomyopathy, erectile dysfunction, and other secondary manifestations are treated as indicated.

Patients should follow a balanced diet; it is not necessary to restrict consumption of iron-containing foods (eg, red meat, liver). Alcohol should be consumed only in moderation because it can increase iron absorption and, in high amounts, increases the risk of cirrhosis.

In patients with type 4 disease, tolerance to vigorous phlebotomy is poor; serial monitoring of Hb level and transferrin saturation is required.

Treatment of transferrin deficiency and ceruloplasmin deficiency is experimental; eg, iron chelators may be better tolerated than phlebotomy because patients typically have anemia.

Key Points

  • There are 4 types of hereditary hemochromatosis, which all involve mutations that impair the ability of the body to inhibit iron absorption when iron stores are excessive.

  • The effects of iron overload are similar in all types and include liver disease (leading to cirrhosis), skin pigmentation, diabetes, arthropathy, erectile dysfunction, and sometimes heart failure.

  • Diagnose by measuring serum ferritin level; if elevated, confirm by demonstrating elevated serum iron and transferrin saturation.

  • Once diagnosis is made, do liver biopsy to identify cirrhosis and determine prognosis; consider genetic testing and screening of first-degree relatives.

  • Treat with phlebotomy and moderation of alcohol consumption.

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