The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Int J Hematol. 2018 Jan;107(1):31-43. doi: 10.1007/s12185-017-2365-3. Epub 2017 Nov 13.

Abstract

Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

Keywords: Ferroportin; HFE; Hemojuvelin; Hepcidin; Transferrin receptor 2.

Publication types

  • Review

MeSH terms

  • Alleles
  • Cardiomyopathies
  • Cation Transport Proteins / genetics
  • Diabetes Mellitus
  • GPI-Linked Proteins / genetics
  • Hemochromatosis / diagnosis
  • Hemochromatosis / genetics*
  • Hemochromatosis / metabolism*
  • Hemochromatosis / therapy
  • Hemochromatosis Protein / genetics*
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Liver Diseases
  • Mutation
  • Phlebotomy*
  • Receptors, Transferrin / genetics

Substances

  • Cation Transport Proteins
  • GPI-Linked Proteins
  • HFE protein, human
  • HJV protein, human
  • Hemochromatosis Protein
  • Receptors, Transferrin
  • TFR2 protein, human
  • metal transporting protein 1
  • Iron