H E M A T O L O G Y
C L I N I C
Iron overload in transfusion-dependent thalassemia Introduction Hemoglobin is a protein that plays an important role in the structure and the stability of red blood cells. Hemoglobin is also important for carrying oxygen throughout the body. Thalassemia is a chronic condition caused by a defective gene resulting in a reduced amount of hemoglobin and fewer red blood cells than normal. This inherited condition results in anemia that may need regular blood transfusions for survival. With the frequent transfusions, iron, which is found in red blood cell products, accumulates in the body and gets deposited in different organs, such as the heart, liver, and endocrine glands. Iron overload is a condition that could be treated by medications called iron chelators. Your physician can help you choose the best iron chelator for your condition.
Cause The major cause of iron overload in transfusiondependent thalassemia is the high intake of iron found in red blood cell products. The human body does not have an effective means to get rid of increased iron load because of blood transfusions. In addition, a state of chronic anemia stimulates dietary iron absorption through the gut. However, this amount of iron remains minor as compared to the amount accumulated from frequent transfusions. Figure 1 shows the
organs that are most commonly affected by iron overload in transfusion-dependent thalassemia. As a result, excess iron is deposited in different body organs causing (1) heart dysfunction and failure, (2) liver disease, cirrhosis, and cancer, and (3) endocrine disease, such as growth abnormalities.
Symptoms and signs As the symptoms and signs of iron overload are not sufficiently sensitive and specific, thalassemic patients should be monitored early on after the onset of transfusion therapy for the development of transfusional iron overload. Symptoms and signs related to iron overload may include hyperpigmentation (dark skin), which is a late and rare finding. Other symptoms and signs of iron overload are those related to the end organ damage that happens from iron deposition in the different organs. Heart dysfunction due to iron overload usually presents as shortness of breath on exertion and lower extremity swelling. Cardiac arrhythmias can present as palpitations, loss of consciousness (syncope), or sudden cardiac death. Patients with liver disease may present with an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly), or an abdominal fluid accumulation
Figure 1 Major mechanism of iron overload in transfusion-dependent thalassemia. As shown in the figure, the major cause of iron overload in transfusion-dependent thalassemia is the excessive accumulation of transfusional iron that is deposited in the different organs leading to different complications such as heart failure and arrhythmias, liver disease, and endocrine gland dysfunction.
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1024533215Z.000000000365
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Table 1 Characteristics of different iron chelators
How is it administered?
How many times a day should I take it? What should my doctor and I watch for when I am on treatment?
Deferoxamine
Deferiprone
Deferasirox
Under the skin (subcutaneously) Through the vein (intravenously) Usually daily over 8–24 hours
By mouth (orally)
By mouth, dispersed in water (orally)
Three times daily
Once daily
Hearing abnormalities
Gastrointestinal disturbances
Visual abnormalities
Decrease in white blood cell count (neutropenia/agranulocytosis) Joint pain
Gastrointestinal disturbances Increase in serum creatinine Increase in liver enzymes Skin rash Liver failure Kidney failure
Infections or reactions at the site of the infusion Delay in bone growth
(ascites). Jaundice is also common in thalassemia and may be worsened by liver dysfunction. Endocrine disease presents as slow growth in children. Absence of menstrual periods (amenorrhea), loss of libido, and erectile dysfunction may be a symptom of endocrine dysfunction due to iron overload. Polyuria and polydipsia may be presenting symptoms of hyperglycemia due to pancreatic iron deposition.
Tests Serum ferritin remains a valuable means to assess iron overload. However, this method is not the most reliable among the available tools as serum ferritin may fluctuate with inflammation. Liver iron load can be assessed using a liver biopsy, which is an invasive and technically demanding procedure. Therefore, the most widely used method for reliable assessment of liver iron load is magnetic resonance imaging (MRI) for the measuring liver iron concentration. However, MRI assessment of liver iron concentration is expensive and may be unavailable in certain areas where thalassemia is prevalent. Heart iron load can be measured using specific MRI techniques, the T2* or R2*.
Treatment options There are different iron chelators available for use in treating iron overload secondary to blood transfusions. Table 1 explains the characteristics of the different iron chelators. The oldest agent is deferoxamine, an iron chelator that should be administered intravenously (through the vein) or subcutaneously (under the skin). The two other chelators are deferiprone and deferasirox each with unique characteristics and side effects. Deferiprone is taken three times daily while deferasirox is a once-daily medication. Your physician will discuss with you the side effects and the benefits of each of these iron chelators. Your physician will tailor a chelation
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Increase in liver enzymes
regimen that is both convenient to you and effective in reducing iron overload. Your physician will also counsel you on how to follow up with blood and urine tests, in addition to other investigations, to monitor for side effects.
Outlook Most guidelines agree that iron chelation therapy should be started after the cumulative transfusion of 10–20 units of packed red blood cells or when serum ferritin is greater than 1000 ng/mL. With adequate screening and treatment, complications and mortality related to iron overload are significantly delayed and improved.
Additional resources You may find many resources online, but the most valuable are the following: (1) The Thalassaemia International Federation: http://www.thalassaemia.org.cy/ (2) The Center for Disease Control and Prevention: http://www.cdc.gov/ncbddd/thalassemia/ (3) Cooley’s Anemia Foundation: http://www .thalassemia.org/learn-about-thalasse mia/about-thalassemia/ (4) The Curriculum in Iron Metabolism and Related Disorders: European Society of Haematology: http://www.ironcurriculum .esh.org/
Antoine Saliba, Ali Taher Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut, Lebanon Correspondence to: Ali Taher, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Building 56, 5th floor, Cairo Street, PO Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon. Email: [email protected]
C L I N I C
Iron overload in transfusion-dependent thalassemia Introduction Hemoglobin is a protein that plays an important role in the structure and the stability of red blood cells. Hemoglobin is also important for carrying oxygen throughout the body. Thalassemia is a chronic condition caused by a defective gene resulting in a reduced amount of hemoglobin and fewer red blood cells than normal. This inherited condition results in anemia that may need regular blood transfusions for survival. With the frequent transfusions, iron, which is found in red blood cell products, accumulates in the body and gets deposited in different organs, such as the heart, liver, and endocrine glands. Iron overload is a condition that could be treated by medications called iron chelators. Your physician can help you choose the best iron chelator for your condition.
Cause The major cause of iron overload in transfusiondependent thalassemia is the high intake of iron found in red blood cell products. The human body does not have an effective means to get rid of increased iron load because of blood transfusions. In addition, a state of chronic anemia stimulates dietary iron absorption through the gut. However, this amount of iron remains minor as compared to the amount accumulated from frequent transfusions. Figure 1 shows the
organs that are most commonly affected by iron overload in transfusion-dependent thalassemia. As a result, excess iron is deposited in different body organs causing (1) heart dysfunction and failure, (2) liver disease, cirrhosis, and cancer, and (3) endocrine disease, such as growth abnormalities.
Symptoms and signs As the symptoms and signs of iron overload are not sufficiently sensitive and specific, thalassemic patients should be monitored early on after the onset of transfusion therapy for the development of transfusional iron overload. Symptoms and signs related to iron overload may include hyperpigmentation (dark skin), which is a late and rare finding. Other symptoms and signs of iron overload are those related to the end organ damage that happens from iron deposition in the different organs. Heart dysfunction due to iron overload usually presents as shortness of breath on exertion and lower extremity swelling. Cardiac arrhythmias can present as palpitations, loss of consciousness (syncope), or sudden cardiac death. Patients with liver disease may present with an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly), or an abdominal fluid accumulation
Figure 1 Major mechanism of iron overload in transfusion-dependent thalassemia. As shown in the figure, the major cause of iron overload in transfusion-dependent thalassemia is the excessive accumulation of transfusional iron that is deposited in the different organs leading to different complications such as heart failure and arrhythmias, liver disease, and endocrine gland dysfunction.
© W. S. Maney & Son Ltd 2015 DOI 10.1179/1024533215Z.000000000365
Hematology
2015
VOL.
20
NO.
5
311
H E M A T O L O G Y
C L I N I C
Table 1 Characteristics of different iron chelators
How is it administered?
How many times a day should I take it? What should my doctor and I watch for when I am on treatment?
Deferoxamine
Deferiprone
Deferasirox
Under the skin (subcutaneously) Through the vein (intravenously) Usually daily over 8–24 hours
By mouth (orally)
By mouth, dispersed in water (orally)
Three times daily
Once daily
Hearing abnormalities
Gastrointestinal disturbances
Visual abnormalities
Decrease in white blood cell count (neutropenia/agranulocytosis) Joint pain
Gastrointestinal disturbances Increase in serum creatinine Increase in liver enzymes Skin rash Liver failure Kidney failure
Infections or reactions at the site of the infusion Delay in bone growth
(ascites). Jaundice is also common in thalassemia and may be worsened by liver dysfunction. Endocrine disease presents as slow growth in children. Absence of menstrual periods (amenorrhea), loss of libido, and erectile dysfunction may be a symptom of endocrine dysfunction due to iron overload. Polyuria and polydipsia may be presenting symptoms of hyperglycemia due to pancreatic iron deposition.
Tests Serum ferritin remains a valuable means to assess iron overload. However, this method is not the most reliable among the available tools as serum ferritin may fluctuate with inflammation. Liver iron load can be assessed using a liver biopsy, which is an invasive and technically demanding procedure. Therefore, the most widely used method for reliable assessment of liver iron load is magnetic resonance imaging (MRI) for the measuring liver iron concentration. However, MRI assessment of liver iron concentration is expensive and may be unavailable in certain areas where thalassemia is prevalent. Heart iron load can be measured using specific MRI techniques, the T2* or R2*.
Treatment options There are different iron chelators available for use in treating iron overload secondary to blood transfusions. Table 1 explains the characteristics of the different iron chelators. The oldest agent is deferoxamine, an iron chelator that should be administered intravenously (through the vein) or subcutaneously (under the skin). The two other chelators are deferiprone and deferasirox each with unique characteristics and side effects. Deferiprone is taken three times daily while deferasirox is a once-daily medication. Your physician will discuss with you the side effects and the benefits of each of these iron chelators. Your physician will tailor a chelation
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Increase in liver enzymes
regimen that is both convenient to you and effective in reducing iron overload. Your physician will also counsel you on how to follow up with blood and urine tests, in addition to other investigations, to monitor for side effects.
Outlook Most guidelines agree that iron chelation therapy should be started after the cumulative transfusion of 10–20 units of packed red blood cells or when serum ferritin is greater than 1000 ng/mL. With adequate screening and treatment, complications and mortality related to iron overload are significantly delayed and improved.
Additional resources You may find many resources online, but the most valuable are the following: (1) The Thalassaemia International Federation: http://www.thalassaemia.org.cy/ (2) The Center for Disease Control and Prevention: http://www.cdc.gov/ncbddd/thalassemia/ (3) Cooley’s Anemia Foundation: http://www .thalassemia.org/learn-about-thalasse mia/about-thalassemia/ (4) The Curriculum in Iron Metabolism and Related Disorders: European Society of Haematology: http://www.ironcurriculum .esh.org/
Antoine Saliba, Ali Taher Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut, Lebanon Correspondence to: Ali Taher, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Building 56, 5th floor, Cairo Street, PO Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon. Email: [email protected]
