Hemochromatosis – Who Gets It?

Hereditary Hemochromatosis (HH) is the most common form of hemochromatosis. It is predominately a disorder of persons of northern European extraction. In this form, patients are most commonly homozygous for (carry two copies of) the C282Y mutation of the HFE gene. Sometimes patients may carry one copy of the C282Y mutation and one copy of the H63D mutation. There are other forms of hemochromatosis and iron overload which will be discussed later.

Hereditary hemochromatosis takes many years to display its true nature. This is because it takes time to load iron in the body. Men usually load more quickly than women. This is because women have monthly menstrual cycles and have children. Each pregnancy is equivalent to the loss of 1 gram of iron. So the bar is “set lower” to confirm the diagnosis of HH in women. Before the true genetic nature of the disorder was recognised the diagnosis was made if the patient could be venesected or de-ironed of 5 grams of blood (if male) without causing significant anemia. If the patient was a woman only 3 grams of iron had to be removed by venesection without causing significant anemia to make the diagnosis. Liver biopsy was not infrequently employed to confirm the diagnosis.

Now with the ready availability of genetic testing the criteria are different. Often the diagnosis can be made using genetic testing and iron studies. Liver biopsy is often now not necessary.

What Happens When A Patient Presents?

Let us assume that a patient has presented with fatigue and arthralgia (aching joints) to a doctor. Now many things can give such a presentation. Paradoxically one of them is anemia or iron deficiency. Anyhow let us assume that the patient is suspected of having hemochromatosis. The patient is a lady of some 65 years of age. She had five children and menopause at age 45 years. She is of Irish/Scottish extraction and her mother died of liver problems – yet her mother never drank a drop of alcohol in her life. The patient is quite fair skinned. However this may be a red herring as not all patients with hemochromatosis go a bronzed or grayish color. When the patient is examined by the doctor she is noted to have enlarged and painful second and third knuckles and pain at the base of her thumbs. This is known as “iron fist” and is a clue to hemochromatosis. Examination of the patient’s abdomen reveals an enlarged liver. So preliminary testing is done. This patient is found to have an enlarged liver on ultrasound – but no cirrhosis. Her ferritin level is 650 ug/L and she has a transferrin saturation of 96%. In itself these are big clues – this patient probably has HH. Genetic testing reveals the patient to be a carrier of two copies of C282Y. Liver function tests are slightly abnormal. Now this patient has HH. A liver biopsy is probably not necessary as the ferritin level is not markedly elevated. Interestingly this patient almost certainly has fibrosis of the liver which may well be reversed if the patient is properly de-ironed.

The treatment for this patient is to de-iron her down to a ferritin level of 25 to 75 ug/L and try and maintain that level. Other comorbid conditions (conditions associated with HH) must be looked for and treated. Of especial importance is diabetes. The patient’s family should also be screened for HH. Those at greatest risk are the patient’s siblings. However all first degree relatives should be screened. Initial testing consists of ferritin levels, transferrin saturations and genetic testing. In this way many early cases of HH are now being picked up and successfully treated before patients load enough iron to give the severe consequences of organ failure.

What Happens If The Patient Cannot Tolerate Venesections?

Our patient – who we shall call Mrs. Abbott – is a small lady. She weighs in at just over 110 lbs and is only 5 foot 2 inches tall. After Mrs. Abbott’s first venesection of 500 mls (which is equivalent to 250 mcg of iron) she is totally exhausted and has difficulty standing for some three days. This is despite adequate hydration before and after venesection. This lady is also known to have osteoporosis (the rate of which is increased in HH) so it is important that she not fall as she could easily break an arm or worse a hip. Another venesection is planned for a week later.

What needs to be done is to decrease the standard venesection unit down to 250 mls and probably do this every few weeks after she has adequately recovered. It will take longer to de-iron Mrs. Abbott, but her treatment overall is safer. If Mrs. Abbott had a ferritin level of say 2,000 ug/L then it would be a tougher call. She would need to be deironed more quickly.

Immediately after venesection a cold pack was applied to Mrs. Abbott’s veins. This was done to preserve the veins. This is especially important in persons with frail veins and those who will need multiple venesections.

After a further 20 venesections of only 250 mls each Mrs. Abbott has a ferritin level of 46 ug/L. She has been successfully deironed. Her liver function tests are now normal and her transferrin saturation has fallen to 45%. Proper treatment is to now monitor Mrs. Abbott and see how quickly she loads iron. She is probably a patient who may only require 2 or 3 (half) venesections per year.

Why Is It Important To Screen Relatives?

Now Mrs. Abbott is from a very large family. She has 10 siblings, all of whom are younger and still alive. There are 5 sisters and 5 brothers. All the siblings are willing to be tested and live close. Often people simply do not want to know. This is of course their right.

Because one C282Y mutation is inherited from each parent Mrs. Abbott’s parents were at least carriers of one C282Y mutation or were C282Y heterozygotes. Both her parents are deceased so they cannot be tested. If we assume that both parents were C282Y heterozygotes then the chance of each of their children carrying two copies of C282Y is 1 in 4 or 25%. If one parent was a C282Y homozygote or carried two copies of C282Y then the children have a 50% chance of carrying two copies of C282Y. If both Mrs. Abbott’s parents carried two copies of C282Y then all her siblings will carry two copies of C282Y.

Mrs. Abbott’s children need also to be tested. She has 5 children. The children live in various locales and are not immediately available for testing. So the alternative is to test Mr. Abbott and work out the possibilities for the children. When Mr. Abbott is tested he is shown to be a C282Y/H63D compound heterozygote. He carries one C282Y mutation and one H63D mutation. However Mr. Abbott is a long time blood donor so it is difficult to assess what his true iron status would have been. He appears to be a nonexpressor i.e.. he is not loading iron. This is the usual case in C282Y/H63D compound heterozygotes. Over the years it turns out that Mr. Abbott has donated 50 pints of blood. His ferritin level is 76 and his transferrin saturation is 41%. Thus it is important to continue to monitor Mr. Abbott who has just turned 65 years of age and been told that he can no longer donate blood. There is a 50% chance that the children of the Abbott’s will carry two copies of C282Y and a 50% chance that they will be compound heterozygotes like their father. So the children all need to be individually tested.