Hemochromatosis

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Hemochromatosis is a hereditary disorder that leads to an iron overload in organs due to an increased iron absorption from food. It is caused by a point mutation in one of several genes.

Phenotype

The hemocromatosis phenotype and its harmfulness varies in patients. Symptoms are caused by a toxic iron accumulation in parenchymal cells of important organs, e.g. heart, liver, endocrine glands. In general, male have a higher probability of developping hemochromatosis, supposedly because of female menstruation. The disease is usually diagnosed in midle aged patients. Based on the affected organs, the symptoms range from simple biochemical abnormalities to gonadal dysfunction, glucose intolerance, diabetes and even heart failure, liver fibrosis and cirhosis.

The individual phenotype varies that much, because the genetic background only gived a predisposition to hemochromatosis. Human and environmental factors play an important role as well.

form	male/female	age	non-/caucasian
HFE	male	40-50 years	caucasian
TfR2	male or female	30-40 years	caucasian or non-caucasian
HJV, HAMP	male or female	15-20 years	caucasian or non-caucasian
Ferroportin disease	male or female	10-80 years	caucasian or non-caucasian

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Biochemical disease mechanism

The basis for hemocromatosis is a hepcidin deficiency. Hepcidin is a protein that is responsible for the downregulation of iron entry into the bloodstream. Patients do not suffer from a perturbance of the iron metabolism, which works normal, but from an increased iron uptake into the blood.

Iron Metabolism

Iron is only able to enter the human body in the small intestines.

Genetics and Inheritance

There are several different types of hemochromatosis. Each type is connected to defects in the iron uptake regulation through hepcdin. The most common and less severe type is caused by a mutation in the HFE gene on chromosome 6. The other types are rare and based on a mutations in the TfR2 gene or, in the case of juvenile hemochromatisis, mutations in the HJV or HAMP (Hepcidin) gene. Mutations in the FPN(Ferroportin) gene can also result in hemachromatosis like symptoms, but it is often termed ferroportin disease. The mutations leads to a hepcidin resistance and thus to an iron hyperabsorbtion from the diet, although the hepcidin production is not impaired in this patients.

Homozygosity for one of the above mentioned mutations only results in a certain predisposition to hemochromatosis, but not all persons with this genetic background develop the disease.

Mutations

HFE: C282Y
TfR2: Y250X (nonsense)
HJV: G320V
HAMP:
FPN: C326S and C326Y

Diagnosis and Treatment

Hemochromatosis is diagnosed in patients with an unnormal high transferrin saturation and, in later stages, increased serum ferritin levels. The transferrin saturation denotes the concentration of free iron in proportion to the concentration of transferin in the blood serum.

Since iron can only be removed from the system by blood loss, treatment is complicated. Possible treatment is only used to reduce the iron content in the body. A low iron diet

Resources

@article{pietrangelo2010hereditary,

 title={Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment},
 author={Pietrangelo, Antonello},
 journal={Gastroenterology},
 volume={139},
 number={2},
 pages={393--408},
 year={2010},
 publisher={Elsevier}

}