The MDS Beacon™

What is excess iron?

Iron is an essential element to all living organisms, as it is an important aspect of health and disease. Iron is essential to red blood cells since they house most of the body’s iron content. Iron is normally bound by different proteins which prevent it from reacting destructively with other cells in the body. However, excess iron can overload these proteins, leading to free iron circulating and accumulating in the body due to the lack of an active mechanism to excrete iron. Iron deposits, especially in the heart, liver, and the endocrine system, can cause cell death, tissue damage, and reduced life expectancy.

Ferritin, one iron-storage protein, is measured as an indicator of iron levels because it correlates to the body’s regulation of the metal. Ferritin levels normally range from 12 to 300 ng/mL in healthy adult males and 12 to 150 ng/mL in females, but they increase dramatically when too much iron is present in the body.

Symptoms of excess iron are often non-specific, such as abdominal discomfort and fatigue. Complications caused by excess iron include cardiac failure, pancreatic impairment leading to diabetes, muscle cramps, bronzed pigmentation of fair skin, and a weakened immune system.

Why do MDS patients suffer from excess iron?

Excess iron is a concern for myelodysplastic syndromes (MDS) patients who have repeated red blood cell transfusions. Eighty to 90 percent of MDS patients receive transfusions to treat symptoms of low blood cell levels, such as fatigue, heart palpitations, and shortness of breath. However, transfusions also introduce iron to the body without providing a means of removing excess deposits.

Some MDS patients have iron build-up without ever having received transfusions, such as those with sideroblastic anemia or the specific gene sequence HFE, because these diseases involve an inherent defect in processing iron.

Iron chelation therapy

The term chelation therapy refers to the administration of organic compounds, known as chelating agents, that bind and remove unwanted metals from the body. The goal of iron chelation therapy is to bind free iron in the blood and prevent it from forming deposits in organs. It also removes excess iron that may have already built up in the heart, liver, and endocrine cells, and thus decreases the possibility of toxic effects.

The two iron chelators currently available in the United States are Desferal (deferoxamine), which requires injection, and Exjade (deferasirox), which is taken orally. Ferriprox (deferiprone) is another oral iron chelator that is available outside of the U.S.  The U.S. Food and Drug Administration for FDA is currently reviewing an application by Ferriprox’s manufacturer, ApoPharma, to market the drug in the U.S.

Additional ways to regulate iron levels

Patients who are genetically predisposed to form iron deposits without having received blood transfusions may also be treated by phlebotomy. Phlebotomy is a procedure that removes blood from the body thereby reducing the number of iron-rich red blood cells in the body.

Regulation of dietary intake can also help decrease iron levels. Foods that contain large amounts of iron or increase iron absorption, such as red meat, alcohol, and Vitamin C, should be avoided.

Difficulty surrounding iron chelation therapy

Iron overload remains difficult to treat due to the disagreement among clinicians regarding its seriousness. There are no specific guidelines that define iron overload, and the threshold level of ferritin, an iron-storage protein, that requires iron chelation varies by physician. In addition, there are many differences regarding the optimal levels of red blood cell transfusions, type of iron chelator, and dose that should be administered.

Measurement of ferritin levels also introduces problems, as levels vary by the type of testing used. Directly testing the liver gives the most accurate measurements of body iron, but there is a high risk for infection and bleeding, due to the low blood cell counts that often accompany MDS. Accurate non-invasive measures also exist, but they are few in number and inaccessible to most patients. Magnetic resonance imaging techniques for the liver and heart have been utilized, but discrepancies have been observed.

Iron chelation is also expensive and logistically difficult to obtain. For example, Exjade costs about $5,000 per month for the average U.S. patient. In addition, iron chelators are sometimes only available by mail order, and insurance authorization can be difficult.

Side effects, such as skin, digestive, hearing, and visual abnormalities, also obscure the guarantee of iron chelation therapy as a satisfactory option. Patients who are permanently dependent on blood transfusions are also at risk for blood disease, kidney failure, and liver failure.

Some researchers believe that MDS patients who have excess iron without having ever received transfusions are good candidates for iron chelation therapy because their life expectancies are longer than those of other diagnoses. However, the disagreements among physicians about the importance of iron chelation in treating MDS remain a source of controversy.

To better understand the role of iron chelation therapy in treating MDS patients with excess iron, large, multi-year studies are needed, due to the rapid progression of MDS and the slow effects of excess iron.