Haemochromatosis
is an inherited disorder that leads to excessive absorption of iron and deposition in end organs producing tissue damage and functional insufficiency. It’s early diagnosis is important as venesection removes the excessive iron load from the body there by preventing end organ damage. In white Anglo-Saxons the disease occurs in 1 in 300 individuals (homozygous) and 1 in 10 (heterozygous) are carriers of the mutation. The HFE gene was cloned in 1996 and produces a protein that interacts with the Transferrin receptor on enterocytes to reduces it’s affinity for iron, hence a mutation of the gene leads to excessive iron absorption. Three mutations have been described: C282Y, H63D and S65C. C282Y accounts for 90% of the cases of Genetic Haemochromatosis, the other mutations are seen in <2% of cases and in 10% a gene mutation is not detected. Heterozygous mutations, including the double mutation C282Y/H63D and homozygous mutations for H63D and S65C rarely lead to iron over load but expression can be modified by the following factors: iron and Vitamin C intake, blood loss (physiological or pathological), sex (penetrance is much higher in males) and other causes of end organ dysfunction such as chronic alcoholic or viral Hepatitis.
When should the gene test be requested?
1. Raised Transferrin Saturation >55% or Ferritin >300 in males and >200 in females, the higher the levels the more specific it is. Note should be made to repeat the Transferrin Saturation in the fasting state also remember that Ferritin is an acute phase reactant and so can be raised for many reasons.
2. Testing of family members. The testing of offspring need not start until adolescence, another alternative is to test the spouse if possible. eg. If your patient is homozygous for C282Y but the spouse is homozygous normal then there is no need to test the children. Obviously siblings and parents should be advised to test also.
3. Patients with evidence of end organ damage: cirrhosis and chronically abnormal liver function tests, Cardiomyopathy or Arrhythmias, Arthropathy, Pancreatic insufficiency and Pituitary dysfunction (hypogonadism).
The gene test should be combined with fasting Transferrin Saturation, Ferritin, FBC and LFT’s .
Iron studies can be difficult to interpret, especially with abnormal liver function tests so liver biopsy with histopathology and quantitation of iron is often needed to confirm iron overload. The treatment of Haemochromatosis is venesection but this is only instituted if iron overload is present. If it is not then iron studies can be followed 2 yearly. Life expectancy is returned to normal if venesection is instituted before organ damage has occurred. The commonest causes of death are Cardiomyopathy, Cirrhosis and Hepato-cellular carcinoma.
