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

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.

The interactions between iron and copper in genetic iron overload syndromes and primary copper toxicoses in Japan

“…Excess iron first induces ferritin molecules, followed by hemosiderin formation. Serum levels of ferritin that originate from the stored form of ferric ions are reliable biomarkers of iron overload . Hepcidin25, an active form of iron regulatory hormone, regulates iron homeostasis as a major suppressor of iron exporter ferroportin (FP) .…”

“…There are 2 phenotypes: a mild form with loss‐of function (FPD A), and a severe form with gain‐of function (FPD B) . FPD is the only autosomal dominant disease, but other genetic iron overload syndromes are all autosomal recessive in inheritance . Differing from Caucasian societies where HFE‐HH is the most prevalent among genetic disorders, it has been reported in only Japanese patient .…”

“…Parenchymal iron‐dominant HH (Fig. ) is subtyped into classical and juvenile forms . HFE and TRF2 are responsible for the classical form with the triad of cirrhosis, DM, and pigmentation at the age of about 50 yrs, while HJV and HAMP are juvenile forms with additional complications of cardiac failure and hypogonadism around the age of 20–30 yrs .…”

“…The liver is the central organ for iron and copper metabolism, and it is affected by transition metal‐induced oxidative stress when these elements are in excess . Resulting diseases include iron overload syndromes and primary copper toxicoses of Wilson disease (WD) . On the other hand, deficiencies of iron and heme proteins, including hemoglobin, and those of copper and cuproproteins, including ceruloplasmin (CP), cause a wide range of pathological conditions.…”

“…Herein, the interaction between iron and copper was reviewed to improve understanding of the pathogeneses of genetic iron overload syndromes, primary copper toxicoses of WD, and their associated pathological conditions …”