COMMENTARY

Hemochromatosis: More Common Than You Think?

Rowen K. Zetterman, MD

Disclosures

October 22, 2012

In This Article

Non-HFE Hemochromatosis

Juvenile Hemochromatosis (Type 2)

Juvenile hemochromatosis is a rare[35] autosomal recessive disease[36] with equal sex prevalence that typically presents clinically before the age of 30 years.[37,38] Cardiac and endocrine effects are most common, and tachyarrhythmias from atrial fibrillation or ventricular fibrillation are potential causes of death.[36] Hypogonadotropic hypogonadism, the most frequent nondiabetic endocrinopathy associated with hemochromatosis, is a consequence of pituitary-gonadal dysfunction and may result in infantilism or delayed puberty.[38]

Two mutations in juvenile hemochromatosis result in similar clinical manifestations.[39] Hemojuvelin mutation (chromosome 1q21) is the most common cause of juvenile hemochromatosis. Hepcidin gene mutation (chromosome 19q13) has also been observed.[40] The co-occurrence of hemojuvelin mutations in patients who are also HFE homozygotes can result in markedly increased iron stores, high ferritin levels, and clinically more severe disease.[29]

Transferrin Receptor 2 Hemochromatosis (Type 3)

Type 3 hemochromatosis is uncommon. This autosomal recessive disorder develops from a gene mutation of transferrin receptor 2 on chromosome 7q22.[41] Transferrin receptor 2 plays a role in the production of hepcidin.

The presentation and resulting end-organ disease of type 3 hemochromatosis are similar to those of type 1 hemochromatosis, with liver injury, cardiac disease, diabetes, arthritis, and skin pigmentation. Clinical signs and symptoms may be apparent at an earlier age than in type 1 disease.[42] Iron deposition occurs primarily within the liver.

Ferroportin Hemochromatosis (Type 4)

Ferroportin is expressed on the basolateral cell membrane and assists in exporting iron from the cell to the circulation. This autosomal dominant disorder[43] reflects a gene mutation on chromosome 2q32.[44] Ferroportin disease is milder and ethnically more heterogeneous than type 1 hemochromatosis. The clinical onset may occur by age 20 years, and elevated ferritin levels have been identified in the first decade of life.[43]

Two forms of ferroportin disease have been described. One form, which involves iron accumulation within hepatic macrophages and not the hepatocytes, rarely presents with cirrhosis.[45] Circulating ferritin levels are lower, and the more benign disease lacks cardiac effects, hypogonadism, diabetes, or arthropathy. The second form is associated with iron accumulation in hepatocytes and marked elevations of ferritin levels with normal transferrin saturation and is otherwise similar to HFE hemochromatosis.

Treatment of Non-HFE Hemochromatosis

Like those with type 1 disease, patients with non-HFE hemochromatosis and clinical evidence of iron overload, especially those with elevated hepatic iron concentrations, should be treated with phlebotomy.[14]

Neonatal Hemochromatosis

Neonatal hemochromatosis is the most common cause of neonatal liver failure.[46] The liver injury, thought to be immune-mediated, develops in utero and is associated with iron overload of the fetal liver, pancreas, and salivary glands.[47] The newborn presents with jaundice and coagulopathy. This disorder may occur in subsequent children born to the same mother,[46] and immunoglobulin administration to the mother during pregnancy may improve fetal outcome.

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