Transfusion medicine

Transfusion reactions & complications

Iron overload

Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Maha Badawi, M.B.B.S.

Last author update: 4 October 2021
Last staff update: 4 October 2021

Copyright: 2002-2023,, Inc.

PubMed Search: Transfusion associated iron overload [title] "loattrfree full text"[sb]

Maha Badawi, M.B.B.S.
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Cite this page: Badawi M. Iron overload. website. Accessed September 21st, 2023.
Definition / general
  • Iron accumulates within various body organs after multiple transfusions
  • Patients at risk are those receiving multiple transfusions, such as patients with sickle cell disease (SCD), thalassemia and myelodysplastic syndrome (MDS)
Essential features
  • Occurs after transfusion of 10 - 20 units of red blood cells, affecting transfusion dependent patients
  • Resulting cardiac and liver dysfunction are major causes of morbidity and mortality
  • Patients on regular transfusions should be screened for iron loading after 10 units of transfusions, then regularly thereafter
  • Iron chelation therapy is the primary mode of treatment
  • Hemochromatosis (secondary)
  • Hemosiderosis
  • Each unit of red blood cells transfused contains 200 - 250 mg of iron
  • Human body lacks a mechanism for elimination of excess iron
  • Iron released from transfused red blood cells is transported by transferrin
  • After transferrin is saturated, nontransferrin bound iron (NTBI) and labile plasma iron (LPI) exert tissue damage, partly through reactive oxygen species (Hemasphere 2020;4:e357)
  • Affected organs include heart, liver, pancreas, endocrine glands, bone marrow and skin
Clinical features
  • Asymptomatic at early stages
  • Symptoms occur later after organ damage
    • Growth retardation
    • Jaundice, ascites
    • Shortness of breath on exertion, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, lower limb edema
    • Polyuria, polydipsia
    • Skin discoloration
Screening and monitoring
  • Patients who receive multiple transfusions must be screened for iron overload using serum ferritin measurement and organ assessment
  • Should take place after transfusion of 10 units of red blood cells
  • Liver iron concentration (LIC) as assessed by liver biopsy and direct absorption spectrophotometry provide a precise method for iron loading
  • Reference range for LIC is 0.2 - 2 mg Fe/g dry weight (3.6 - 36 μg Fe/kg dry weight); measurements exceeding the upper limit are diagnostic for iron overload
  • MRI T2 and T2*w of the liver also used for screening and monitoring and reported as LIC
  • References: Magn Reson Imaging Clin N Am 2010;18:359, Br J Haematol 2017;177:703, Blood Transfus 2013;11:128
  • High serum ferritin
    • Serum ferritin above 1,000 ng/ml is usually considered an indication for initiation of treatment
    • However, serum ferritin may not be accurate for prediction of iron loading in all organs (Hematology Am Soc Hematol Educ Program 2019;2019:337)
    • Since ferritin is an acute phase reactant, trends, rather than single values are usually used
  • Elevated transferrin saturation
  • Liver biopsy used to be the gold standard method for evaluation of liver iron concentration
  • MRI T2 and T2* considered a reliable, noninvasive method for assessment of liver and myocardial iron loading; access to an MRI machine and special software required (Blood 2005;105:855, European Heart Journal 2001;22:2171)
  • Features of organ dysfunction:
    • Diabetes (high fasting and random blood glucose and high hemoglobin A1c)
    • Hypoparathyroidism (low parathyroid hormone, low calcium)
    • Hypothyroidism (high thyroid stimulating hormone, low T3 and T4)
Case reports
  • Treatment is through iron chelators, including (Transfus Clin Biol 2017;24:223):
    • Desferrioxamine, also known as deferoxamine (subcutaneously through a pump or intravenous infusion)
    • Deferiprone (oral)
    • Deferasirox (oral)
  • Combinations can also be used specially for those with severe iron loading or iron loading in specific organs (liver or heart)
  • Phlebotomy (venesection) is a primary treatment for hereditary hemochromatosis and can be used in patients with hemoglobinopathies or MDS after stem cell transplantation
  • Automated red cell exchange has a therapeutic effect on iron loading in patients with SCD, in comparison with manual exchange transfusion
Sample note / clinical documentation in the patient’s medical record
  • Note for venesection (therapeutic phlebotomy) procedure in a patient post SCT
    • Mr. X underwent therapeutic phlebotomy for iron overload secondary to (diagnosis). Whole blood volume removed: 400 ml. No replacement fluids were required. He tolerated the procedure well with no complications. The next procedure is set for [date].
Differential diagnosis
  • Hereditary hemochromatosis:
    • Genetic (autosomal recessive with variable penetrance)
    • Related to hepcidin deficiency
    • Most commonly due to HFE gene mutation but could also result from mutations in the following genes: HJV, HAMP, TFR2, SLC40A1
  • Ferroportin disease:
    • Genetic (autosomal dominant)
    • Related to defects of cellular iron export
    • Hepatic Kupffer cells show marked iron accumulation; low transferrin saturation
    • Due to loss of function mutations of the ferroportin gene (SLC40A1)
Board review style question #1
In addition to liver biopsy, the severity of liver iron content can be accurately evaluated by

  1. Computerized tomography (CT)
  2. Liver enzymes (AST, ALT, GGT)
  3. Magnetic resonance imaging (MRI)
  4. Serum ferritin levels
Board review style answer #1
C. Magnetic resonance imaging (MRI)

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Reference: Iron overload
Board review style question #2
Which of the following is a common complication of transfusional iron overload?

  1. Diabetes insipidus
  2. Hyperparathyroidism
  3. Hypogonadism
  4. Lung fibrosis
Board review style answer #2
C. Hypogonadism

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Reference: Iron overload
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