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Hemochromatosis

Accredited by EMQN EQA Hemochromatosis-HFE 2011

Hereditary hemochromatosis (HH) is a group of genetic diseases characterized by excessive accumulation of iron in tissues. There are 4 types of HH: HH type 1 (HFE), HH type 2 (HJV and HAMP genes), HH type 3 (TFR2 gene) and HH-4 (gene SLC40A1). Forms 1, 2 and 3 are autosomal recessive diseases and form 4 is dominant.

Hereditary hemochromatosis (HH) Type 1, also called classic hemochromatosis (OMIM # 235200) is the most common form of HH and is mainly due to Cys282Tyr homozygous mutation of the HFE gene. This type of HH affects men more than women. From a clinical standpoint, the disease begins between 30 and 50 years of age. Hemochromatosis type 1 causes chronic fatigue, dark pigmentation of the skin and can severely affect the liver, pancreas, joints, bones, endocrine glands, or heart, resulting in various complications that appear in adulthood, such as hepatic fibrosis (cirrhosis with hepatocellular carcinoma risk), diabetes mellitus, arthropathy, osteoporosis, hypogonadotropic hypogonadism and heart failure. Biochemical abnormalities include elevated serum iron, serum transferrin saturation and serum ferritin levels. The molecular genetic blood test, showing a homozygous Cys282Tyr, confirm the diagnosis of HH in a non invasive way. Treatment consists of phlebotomy (blood draws), initially these are made weekly, generally reducing in frequency. Hemochromatosis type 1 has a very good prognosis if diagnosed early and treated appropriately before the development of serious complications.

Juvenile hemochromatosis, or HH type 2A (OMIM # 602390) was first described in 1930 under the name “hepatorenal syndrome endocrine heart" and is due to mutation in the HFE2 gene encoding HFE2 hemojuvenil or HJV protein. This rare disease is characterized by a elevation of serum ferritin levels (hyperferritinemia), transferrin saturation and serum iron, which generate a severe iron overload, cardiac failure, and hypogonadotropic hypogonadism in young age (adults under 30 years).


Hemochromatosis type 2b, also called juvenile HH (OMIM # 602390) is a rare form of HH associated to mutations in the hepcidin gene (HAMP). Patients have elevated serum ferritin levels (hyperferritinemia), transferrin saturation and serum iron, which generates a severe iron overload, cardiac failure, and hypogonadotropic hypogonadism in young age (adults under 30 years).

Hemochromatosis type 3 (TFR2 gene) is a rare disorder (OMIM # 604250) characterized by elevated serum ferritin levels (hyperferritinemia), transferrin saturation and serum iron, which generated a severe iron overload in several tissues, especially in liver. The clinical manifestations of HH type 3 are very similar to the HH type 1 (see above), but these patients usually have more severe symptoms and at younger ages than in the case of HH type 1.

Mutations in the SLC40A1 gene coding for ferroportin (FPN1) (OMIM # 604653) causes two types of disorders of iron metabolism both autosomal dominant (OMIM # 606069):
1) Ferroportin disease 4a is the most common and usually is asymptomatic without any complications or hepatic iron overload in the future. This disease is characterized by elevated serum ferritin but normal values and / or low transferrin saturation and a tendency to anemia in patients who have been given phlebotomy. Iron overload occurs in macrophages of the reticuloendothelial system of the spleen and liver, but not in hepatocytes. The course of this disease is rather benign nature.
2) Ferroportin disease 4b presentes elevated serum ferritin and transferrin saturation and hepatic iron overload in hepatocytes can lead to hepatomegaly and cirrhosis. This type of ferroportin disease is less common than the 4a and is due to specific mutations that confer resistance to ferroportin to be degraded by interaction with the hormone hepcidin.
 


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