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Hemochromatosis type 4

Synonym(s) Autosomal dominant hereditary hemochromatosis
Ferroportin disease
Hemochromatosis due to defect in ferroportin
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
Age of onset All ages
  • E83.1
  • C1853733
  • C537249
MedDRA -


Disease definition

Hemochromatosis type 4 (also called ferroportin disease) is a form of rare hereditary hemochromatosis (HH; see this term), a group of diseases characterized by excessive tissue iron deposition of genetic origin.


HH type 4 is less rare than the other rare forms of HH, hemochromatosis type 2 or type 3 (see these terms). Fewer than 200 cases have been reported in the literature. It has a worldwide distribution.

Clinical description

The disease is phenotypically heterogeneous with two sub-types. Ferroportin disease form A is the usual form and is generally asymptomatic with no tissue damage and further complications. With age, tissue damage in the liver can occur which in some cases can lead to fibrosis. Ferroportin disease form B is rarer and resembles hemochromatosis type 1, but can affect children.


Ferroportin disease is due to mutations in the SLC40A1 gene located on chromosome 2, which encodes for ferroportin (FPN), an iron exporter negatively regulated by the hepcidin hormone. In form A, the ferroportin loss of function mutants are unable to export iron from cells leading to cellular (especially macrophage) iron accumulation with decreased availability of iron for serum transferrin, which is reflected in low transferrin saturation. In form B, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to down-regulation by hepcidin (resistance to hepcidin), which leads to a phenotype similar to hepcidin deficiency-related HH (i.e. types 1, 2, and 3).

Diagnostic methods

Ferroportin disease form A displays high serum ferritin levels associated with normal or low transferrin saturation and iron accumulation within splenic and hepatic (Kupffer cells) macrophages. MRI shows iron excess mainly in the spleen and, to a lesser degree, in the liver. Ferroportin disease form B displays elevated transferrin saturation associated with tissue iron accumulation, preferentially within hepatocytes. Due to the dominant pattern of inheritance, the diagnosis is facilitated by the frequent finding of similar cases of hyperferritinemia among family members. Molecular genetic blood testing allows, in most cases, the diagnosis to be established in a non invasive way (i.e. without a liver biopsy). For form A, the diagnosis must rule out other causes of hyperferritinemia with low transferrin saturation such as inflammation, metabolic syndrome, aceruloplasminemia (see this term) and L-ferritin mutations. For form B, the diagnosis must rule out hemochromatosis types 1 and 3, but also type 2 since form B ferroportin disease can also affect children.

Genetic counseling

Transmission is autosomal dominant. Genetic counseling should be offered to affected families, informing them of the 50% risk of inheriting the disease-causing mutation.

Management and treatment

Unlike patients with ferroportin disease form B, patients with form A may not tolerate phlebotomies well, with a risk for developing anemia.


Ferroportin disease form A has a benign course. Ferroportin disease form B is expected to have a good prognosis provided that patients are treated early, before the development of visceral complications.

Expert reviewer(s)

  • Pr Pierre BRISSOT

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