H E M A T O L O G Y
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 con-
dition 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 medi-
cations called iron chelators. Your physician can help
you choose the best iron chelator for your condition.
Cause
The major cause of iron overload in transfusion-
dependent 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 absorp-
tion through the gut. However, this amount of iron
remains minor as compared to the amount accumu-
lated from frequent transfusions. Figure 1 shows the
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
C L I N I C
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 hyperpigmenta-
tion (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
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Table 1 Characteristics of different iron chelators

Deferoxamine Deferiprone Deferasirox

How is it administered? Under the skin By mouth (orally) By mouth, dispersed in

(subcutaneously) water (orally)
Through the vein
(intravenously)
How many times a day should I Usually daily over 8–24 hours Three times daily Once daily
take it?
What should my doctor and I Hearing abnormalities Gastrointestinal disturbances Gastrointestinal
watch for when I am on disturbances
treatment? Visual abnormalities Decrease in white blood cell count Increase in serum
(neutropenia/agranulocytosis) creatinine
Infections or reactions at the Joint pain Increase in liver
site of the infusion enzymes
Delay in bone growth Increase in liver enzymes Skin rash
Liver failure
Kidney failure

(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 (amenor-
rhea), loss of libido, and erectile dysfunction may
be a symptom of endocrine dysfunction due to
iron overload. Polyuria and polydipsia may be pre-
senting symptoms of hyperglycemia due to pan-
creatic 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 pro-
cedure. Therefore, the most widely used method for
reliable assessment of liver iron load is magnetic res-
onance 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 transfu-
sions. Table 1 explains the characteristics of the
different iron chelators. The oldest agent is deferox-
amine, an iron chelator that should be administered
intravenously (through the vein) or subcutaneously
(under the skin). The two other chelators are deferi-
prone and deferasirox each with unique character-
istics and side effects. Deferiprone is taken three
times daily while deferasirox is a once-daily medi-
cation. Your physician will discuss with you the
side effects and the benefits of each of these iron
chelators. Your physician will tailor a chelation
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 ade-
quate 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: ataher@aub.edu.lb

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