Prospective on Thalassemia
- David G. Nathan, MD
The word thalassemia comes from the Greek “thalassa” shouted by Xenophon's troops when they finally reached the Black Sea. “Thalassa, Thalassa,” they cried, thinking they were on the Mediterranean. That mistake was not really very profound because thalassemia, or the blood disease of the sea, is heavily endemic around the Black Sea, the Mediterranean, and throughout the Old World, where malaria was prevalent. Because patients who are heterozygous for thalassemia are somewhat resistant to malaria, this small edge that they have has caused this disease, a genetic disorder, to proliferate massively throughout the Old World, where it is presently a huge health problem, straining blood supplies and causing enormous problems for medical and public health facilities in that part of the world.
The disease is very rare in the United States because this is a “melting pot,” where there is far more interracial marriage, or what the veterinarians would call “outbreeding.” This has reduced the incidence of homozygosity in this country a great deal, but this is the disease that brought me into pediatrics from an internal medicine career at the Brigham and Women's Hospital. There I was privileged to see these cases as a result of Dr Louis Diamond's interest in my development as a hematologist.
When I came to Children's Hospital, I saw a boy about whom I've written a book called Genes, Blood and Courage. He had this disorder and his pediatrician said that his parents should take him home and not transfuse him, because he would die of iron overload from the transfusions. He might have a more mild form of the disease and not die in very early childhood.
By the time he was 6 years old, he was distorted with an abnormal face. He had broken every long bone in his body because thalassemia, a disorder that can now be explained at the molecular level, causes enormous disruption in hemoglobin synthesis.
There is a set of non-α hemoglobin genes on chromosome 11. The β gene that contributes to hemoglobin A is found at one end of that chromosome and the γ gene that produces fetal hemoglobin is just upstream of it. There is a deficiency of β-chain production in β-thalassemia. γ chains are made in fetal life but the fetal switch in β-thalassemia causes γ-chain synthesis to decline. So there is very little hemoglobin A, usually very little hemoglobin F, and a super abundance of α-chains coming from chromosome 16 where the α genes are located. All the red cell has in it at that point is a small amount of hemoglobin A, a small amount of hemoglobin F, and a pool of toxic-free α-chains.
The precipitated α-chains injure the red cell membrane and cause the cell to die in the marrow. This produces severe anemia, expansion of marrow space, and destruction of bones. Therefore, this young man had multiple fractures. He was profoundly anemic. When I saw him, he was in heart failure because of his anemia and had to be transfused at once, even though the parents were so worried about the iron overload. Quite justifiably worried, I might add.
At the time that I came to Children's Hospital, we were seeing a lot of children with thalassemia who looked very distorted; kids who were transfused just a little. They had gargoyle-like faces because of the bony infiltration by red cells dying in the facial bone marrow. They also had huge livers and spleens. We often took out the spleen to help these children take blood transfusions more effectively. However, we never gave them very much blood, because we were afraid of iron overload. In subsequent years it was recognized, particularly in Philadelphia, that higher transfusion levels would, in fact, prevent this terrible bony deformity. This high blood transfusion was the first key to the management of this disease in the 1960s. The life span of patients with thalassemia was on an inexorable downhill course, from iron overload. By the time these children reached the age of 15 or 16, half of them were dead. And they were all dead before the age of 25.
So the bleak outlook in thalassemia clinics in this country and in England was understandable. The children felt they had no future. They were on a death course, and they knew it, and there was nothing anybody could do about it. This was the state of affairs in 1970. It was a very frustrating one for me, coming over to Children's Hospital which, as mentioned by Dr W. Hardy Hendron, is the place where you came to solve a problem. This problem couldn't be solved, or it didn't seem to be.
At this point, a biochemist at the University of California in Berkeley was working on soil organisms. He was asking a simple question, how do these organisms get iron into them? Bacteria won't live without iron. He questioned how iron from the soil got across the bacteria when, in fact, there's such a thick wall that it would prevent the simple transport of iron into the organism. He found a series of compounds that bacteria make which he called chelators, from the Greek word claw. These compounds can reach out and literally “grab” iron molecules. After that report, scientists at Ciba Geigy isolated an iron chelator they called deferoxamine from fungi. When deferoxamine encounters iron, it curls around it into a circle. When that drug was made, the scientists actually thought that it might be a drug that could be used to treat iron deficiency. That is, they thought they might give patients feroxamine and deferoxamine with iron in it. It was thought that perhaps the iron might dissociate and come across the gut and that would be easier on patients than iron salts. But, they quickly showed that it wasn't a good idea. Neither deferoxamine nor feroxamine are absorbed. Instead, they began to observe patients with iron overload who had been given this drug to see whether or not the drug would chelate iron in the body and remove it in the urine and the stools. They gave the drug intramuscularly, and found that a small amount of iron emerged, but very little. For a few years thereafter deferoxamine fell into disrepute.
Two bright young fellows at Children's Hospital, Richard Propper and Susan Shurin, who is now chief of hematology at Rainbow Babies and Children's Hospital in Cleveland, decided to ask more about the pharmacology of this drug. First they gave two intramuscular injections and got out just a little bit of iron. They started giving it intravenously and got out more iron and this became the continuous intravenous infusion program used today for severe iron overload. Propper went on to develop subcutaneous administration of deferoxamine and showed that the route almost tripled the amount of iron that came out in the urine compared with a single intramuscular injection.
This was very encouraging. For the first time we began to realize that this drug might work, if we could only figure out a way to give it continuously and subcutaneously.
The first pump, developed by Propper and colleagues, was relatively enormous. It was made in the basement of a young man in Brooklyn who was a clever inventor. This grew into all of the portable pumps that you now see patients wearing for many diseases and treatments. It was first used for deferoxamine. A line from the pump was threaded under the clothes so the child could receive subcutaneous deferoxamine 24 hours a day. The children didn't like this at all and the schedule was finally modified so the subcutaneous drug was given only at night, which they tolerated far better.
The results of this are really quite excellent. This year Doctors Nancy Oliveri, Alan Cohen, and I summarized the experience in Toronto, Philadelphia, and Boston. We now see cardiac disease-free survival over a 15- to 16-year period. We studied a group of children who were compliant, and variably noncompliant, with the drug. It works for the compliant, and now the whole death curve of thalassemia has been changed.
The problem, of course, is that we still have noncompliant children. The second problem is that this is extremely costly. However, it is doable and there is not too much managed care difficulty in this country and in the western world. There's no question that the outlook for children with thalassemia has been massively improved.
In very poor parts of the world, blood transfusion and iron chelation is an extremely expensive approach to treatment and is not terribly practical, although it is being done and with great success.
Others have tried to develop more definitive therapies. Hardy talked about organ transplantation. Bone marrow transplantation can be used to replace the stem cells in patients with thalassemia, with about a 75% yield. Parents of very young children have to make tough decisions if they have compatible sibling donor for their child with thalassemia. Bone marrow transplantation is also a very expensive and dangerous procedure, but it is a one-time treatment that can work. It is a form of cellular gene therapy.
While all this therapeutic effort was going on, those of us who were interested in the molecular biology of this disease were busily at work. We were able to show that some cases of β-thalassemia could be ascribed to very large deletions of the chromosome that carries the β gene. It turned out that only about 10% of β-thalassemia mutations are because of deletions; almost 90% of them result from various point mutations along the β gene. There's a particular hot spot for mutation in the 51 part of the gene.
We now have molecular genetic techniques that easily and readily predict all the major genetic abnormalities that cause this disease. In fact, there are at least 150 different mutations that can lead to reduction of the output of the β gene and cause β-thalassemia. That is understandable because this disease does provide some resistance to malaria. So wherever there was a mutation, that mutation was preserved. Each community, if you will, has its own mutation, a predominant mutation.
This leads to the next and last part of the thalessemia story—prenatal diagnosis. If one examines the peripheral blood of a normal 12-week-old fetus we can detect a small amount of hemoglobin A and can even detect sickle cell trait and distinguish thalassemia trait from homozygous β-thalassemia. We first obtained the fetal red cell samples with a fetascope. With molecular techniques the prenatal test is much easier. We can eradicate this disorder and prevent it from occurring in the community, which is a far more effective way of dealing with it. This is happening in many parts of the world today.
This is a story that is reassuring to many of us who have been in this field from the very beginning. We have grappled with its molecular basis, we have grappled with its therapy, and now we are dealing effectively with its prevention. That gives me many reasons to be happy that I became a pediatrician.
There is a lot more to come, perhaps gene therapy one day. Looking back over this 25-year period, much has happened. I am proud that I came to Children's Hospital, had the opportunity to meet Dr Diamond, and then start working in this fascinating area of clinical research.
- Copyright © 1998 American Academy of Pediatrics