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New Treatments for Hemochromatosis

Hemochromatosis is an autosomal recessive condition of iron loading that has been predominantly described in Caucasians; people from Northern Europe. In fact, the people in Europe like to call it a Celtic disease. They think it has occurred almost exclusively in the Celtic population of Northern Europe. It has a very high prevalence. The homozygous condition is thought to be found in three to five out of 1,000 people in the Caucasian population of hemocromatosis.

And heterozygotes make up to 10-15% of the population. Now for hereditary hemochromatosis, when we read the classic medicine and pathology textbooks, there was this classic triad of hepatomegaly, diabetes and hyperpigmentation. These are the findings in somebody with advanced, long-standing iron overload that has already probably led to cirrhosis of the liver. The key now is to make the diagnosis very early before any of these findings can occur. Because if you wait to make the diagnosis until cirrhosis and diabetes have developed - even if you treat it aggressively - there is a high mortality. Whereas if you make the diagnosis before cirrhosis and diabetes have developed and treat aggressively, these patients have a completely normal life expectancy. Untreated, death usually occurs from either cirrhosis, hepatocellular carcinoma.

Now one of the biggest advances in iron metabolism in the 1990ís has been identification of the genetic defect in Caucasian hemochromatosis and this gene is a cystine to tyrosine mutation at position 282 in something called the HFE gene on chromosome 6P. Now this gene was identified through positional cloning and we still do not know exactly what the product does, but we do know that a deficiency.

What is known about the HFE gene product is that it associates with the transferrin receptor in the endocytic vesicle and it somehow decreases the affinity of transferrin receptor for transferrin bound to iron. Even though we donít know the exact pathway where that leads to increased iron absorption, we do know that deficiency of this HFE gene product leads to a very clear constellation of physiologic findings that happens very early on and can be detected even in children and adolescents.

So how do you make the diagnosis of hemochromatosis? Well, you have a compatible clinical picture of positive family history, or youíve done the screening and found the elevated transferrin saturationís, whatís the next step that you should do? Well the next step that you should do is to do a PCR analysis for the HFE mutation on the DNA; either obtained from white blood cells from peripheral blood or even from a buccal swab. If you find that the subject is a homozygote for the C282Y mutation, itís appropriate to conclude the diagnosis and proceed with phlebotomy. If the serum ferritin is less than 1,000 and if the liver function tests are normal, in this setting itís highly unlikely that they have any established damage to the liver and you can proceed with definitive treatment, even in the absence of a liver biopsy. If the person is a homozygote for the C282Y mutation and the serum ferritin is greater than 1,000 or there are abnormal liver function tests.

So how do we treat patients with phlebotomy therapy? This is a very highly effective therapy that has saved many many peopleís lives and itís very simple, very old. We remove 1-2 units of blood weekly, as along as the hematocrit is greater than 35% in men or greater than 32% in women. The idea is to get the iron out of the body as fast as we can to reduce potential toxicity. We continue this phlebotomy program on a weekly basis until mild iron deficiency has developed.

Now a quantitative phlebotomy can be very useful because sometimes a patient refuses the liver biopsy or sometimes the hepatologist refuses to do the liver biopsy because the coagulation tests are abnormal, and you still suspect iron overload. In this setting I believe you must proceed with the phlebotomy program and you should make it a quantitative phlebotomy program. That means that you maintain the weekly schedule as strictly as you can and you tally or total the quantity of whole blood that has been removed until iron deficiency develops. Then when iron deficiency develops, itís possible to calculate what the iron stores were at the beginning of the program. Because there was about 1 mg of storage iron for every 2 ml of whole blood that you removed in this program.

This graph shows the typical response to somebody who has been treated with phlebotomy therapy. Here on the horizontal axis we see the months of the treatment program. On the vertical axis we see a number of things. One is the number of phlebotomies - and this is the cumulative number of phlebotomies on the red line - and the serum ferritin concentration which gradually decreases as you phlebotomize the patient and the transferrin saturation, which is very interesting. Because it remains at nearly 100% until right at the level where iron deficiency develops and then it rapidly decreases into the normal range. The reverse happens as a young patient is developing iron overload, a homozygote for the C282Y mutation. The first thing that will happen is that the serum ferritin.