Iron Overload: Extremely Harmful, but Preventable!

by Titi Singer, MD
Hematologist
Children’s Hospital and Research Center at Oakland

Treating severe forms of thalassemia with regular blood transfusions has been an important advance in the management of thalassemia over the past 30 years. Transfusions are given in order to correct anemia (low hemoglobin level) and minimize the other clinical manifestations of the disease, such as bone changes and enlarged liver and spleen. In order to accomplish these goals, most patients require blood transfusions every three to four weeks with a blood amount of 10–15cc/kg (approximately two to three units of blood).

The side effects of frequent blood transfusions The primary function of red blood cells is to carry oxygen to all parts of the body. Since iron binds to oxygen, red blood cells are iron-rich. Therefore, transfused blood, called packed red blood cells, contains a large amount of iron. Unfortunately, the body does not have a mechanism to remove this excess amount of iron, which comes with each transfusion. As a result, a regular transfusion schedule will result in rapid increase of the body iron load. Each unit of blood contains approximately 200 milligrams of iron. It is estimated that by the age of 10 years, a transfused child will accumulate approximately 25grams of iron, while an adult unaffected by thalassemia has a total of only about 5grams of body iron. In addition, even more iron can accumulate from the diet and absorption in the gut, since the thalassemic body “thinks” it needs more iron to make more of its own blood.

Why is too much iron so bad? In healthy people, iron is bound to storage proteins, but when there is excess iron coming from blood transfusions, it stays free (unbound) in the blood. This free iron generates extremely toxic elements called “free radicals” which cause tissue damage. If excess iron is not regularly removed with medication, it deposits in many body organs, where it causes gradual tissue damage. In some organs, the damage is more profound and can cause serious medical problems.

Iron deposits in the heart muscle, and over time, it makes the heart muscle stiffer and less elastic, so that it cannot pump out the blood so well. This results in cardiac failure. Iron can also cause serious problems with the rhythm of the heartbeat. Iron overload in the heart is still the most common cause of death for people with thalassemia. Without regular chelation therapy to remove the iron, a regularly transfused child with thalassemia will die during the second decade of life, most likely from heart disease.

A lot of iron also accumulates in the liver, which acts like a sponge in absorbing high amounts of iron. The iron gradually damages the liver tissue, making it stiffer (fibrotic) and less healthy. Iron also tends to damage the sensitive endocrine glands; these are the organs that secrete hormones which regulate many bodily functions. Iron-loaded patients can therefore develop diabetes, since the pancreas gland, which produces insulin, is affected by excess iron. (Insulin is the hormone that regulates blood sugar; the pancreas does not make sufficient insulin in people with diabetes, so they require treatment with insulin shots to maintain safe blood sugar levels.)

Patients may suffer from a variety of other hormone deficiencies, including the following: thyroid hormone, which affects the level of metabolism and energy; parathyroid hormone, which controls bone calcium; growth hormone, which results in slow growth and short stature; and sex hormones, which cause delayed maturation and growth, thus making it extremely difficult for females to get pregnant.

Patients can have one or more of these hormone deficiencies, depending on the level and length of time of their iron overload. As a result, many patients need to get medications in the forms of tablets or regular shots to replace these hormones. It is thought that iron overload also causes direct damage to the bones and to the lungs, but these effects are less well studied.

Iron chelation therapy—a lifesaver Desferal, a chelator—meaning a drug that can bind metals like iron—was introduced in the early 1970s, and it is considered an extremely effective agent for the prevention of iron overload in thalassemia. Long-term studies have shown that its use allows patients to have a much longer survival and better quality of life. When Desferal binds iron, the iron becomes inactive, preventing the toxic effect of free radical formation. Unfortunately, Desferal is poorly absorbed from the gut and disappears rapidly from the blood. Therefore, only continuous, prolonged administration of infusion by pump (subcutaneous or intravenous) is effective.

Although patients may have massive iron overload in their tissues, only very small amounts of iron are available for binding to Desferal. Administration of Desferal as an infusion over a prolonged time can remove more iron. The iron slowly comes out from the tissues to the bloodstream, where it is “captured” by Desferal. The Desferal-bound iron is then removed from the body, mostly by secretion in the urine, which gives the urine a reddish color.

Desferal is usually prescribed to be taken five to seven nights a week over 8 to 12 hours. Though undoubtedly not an easy medication to use, studies have shown remarkable results. First, it was shown that adequate therapy has led to survival curves approximate to those of normal population. Second, regarding cardiac failure as the major cause of death without adequate chelation, it was demonstrated that long-term use of Desferal resulted in long-term survival free of iron-induced cardiac complications. Third, studies showed that damage to the liver can be prevented; moreover, intensive Desferal therapy can sometimes reverse liver and cardiac dysfunction. The effect on the endocrine system is also beneficial, although it seems that some endocrine glands are very sensitive to iron overload, and even adequate chelation can not always completely prevent or reverse complications. Adequate Desferal chelation, however, can reduce the likelihood of developing diabetes.

Intense research is still in progress to learn how to best use Desferal so it prevents iron overload damage while refraining from overuse because of Desferal’s own side effects. In addition, studies for finding other chelators that can be given orally, combined with or without Desferal, are in progress.