Causes of hemochromatosis

There are various genetic defects which can cause genetic hemochromatosis. Five types have been identified to date, depending on the mechanism of the genetic defect, the beginning of the illness, the symptoms and the heredity. It has to be noted that type 1 is by far the most common; the others are very rare and are only listed here for thoroughness.

Type 1 hemochromatosis
As already mentioned, this is the most common form of genetic hemochromatosis. It is the result of a defective gene, the HFE gene, and is autosomal recessive, i.e. the disease only occurs when both parents of the diseased carry the defective gene and pass it on. If the defective gene is carried by only one parent the disease does not occur and the offspring are merely carriers (see diagram).

Heredity 1 Heredity 2 Heredity 3

It is still not exactly clear how the HFE gene defect results in iron overload. It probably creates a shortage of iron hormones the blood. The recently discovered iron hormone is called hepcidin and determines the absorption of iron in the intestine. When one has too little of this hormone, a large quantity of iron is absorbed by the intestine. The degree of manifestation of type 1 hemochromatosis is variable, i.e. some patients have many symptoms, whereas others have barely any. This is determined less by outside factors leading to increased iron absorption (for example alcohol) than by yet unknown genetic factors which increase iron absorption. The common age at which the disease manifests itself is between 30 and 50 for men, in women normally later because of menstruation (and loss of blood and iron). The most common symptoms of type 1 hemochromatosis are tiredness and joint pain; the other symptoms listed above are less frequent. In blood analysis, as well as increased iron parameters (c.f below), liver values are often increased as well.

Type 2 hemochromatosis
This type is very rare. Normally symptoms already appear between the ages of 20 and 30. Heart and hormone problems are in evidence. The following gene defects are responsible for it: type 2A hemojuvelin (HJV), type 2B hepcidin (HAMP).

Type 3 hemochromatosis
This type is caused by a gene defect in the transferrin receptor 2. It is very rare. The manifestation and type of symptoms are very similar to type 1.

Type 4 hemochromatosis
This equally rare type is also called ferroportin disease. It is caused by a gene defect in ferroportin. It is the only type of hemochromatosis which is inherited dominantly, that is, the disease can occur when only one parents carries the defective gene and has passed it on. There are two sub-types: type 4A is characterised by normal transferrin saturation (c.f. below) and lighter symptoms. Type is very similar to type 1 and 3.