Transfusion medicine
Transfusion reactions & complications
Iron overload
Author: Maha Badawi, M.B.B.S.
Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Last author update: 4 October 2021
Last staff update: 4 October 2021
Copyright: 2002-2025, PathologyOutlines.com, Inc.
PubMed Search: Transfusion associated iron overload [title] "loattrfree full text"[sb]
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Symptoms | Screening and monitoring | Laboratory | Case reports | Treatment | Sample note / clinical documentation in the patient’s medical record | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Badawi M. Iron overload. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedironoverload.html. Accessed April 2nd, 2025.
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
Terminology
- Hemochromatosis (secondary)
- Hemosiderosis
Pathophysiology
- 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
- Heart failure, liver cirrhosis, diabetes, hypothyroidism, hypoparathyroidism, hypogonadism and skin hyperpigmentation
- Cardiac iron loading was the leading cause of death in thalassemia before effective treatments were available
- References: Hematol Am Soc 2017;2017:265, Acta Biomed 2018;88:435, Mediterr J Hematol Infect Dis 2016;8:e2016058, PLoS One 2019;14:e0214148
Symptoms
- 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
Laboratory
- High serum ferritin
- Serum ferritin above 1,000 ng/ml is usually considered an indication for initiation of treatment
- Typical normal range (μg/L): 30 - 300 (male); 10 - 200 (female) (N Engl J Med 2004;351:1548)
- 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
- Serum ferritin above 1,000 ng/ml is usually considered an indication for initiation of treatment
- 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
- 14 year old boy with hypoparathyroidism secondary to transfusional iron overload (J ASEAN Fed Endocr Soc 2020;35:129)
- 35 year old woman and 42 year old man with sickle cell disease and cardiomyopathy secondary to iron overload (Transfusion 2017;57:700)
- 56 year old woman with transfusional iron overload and end stage renal disease (Case Rep Oncol 2020;13:760)
Treatment
- 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)
Additional references
Board review style question #1
In addition to liver biopsy, the severity of liver iron content can be accurately evaluated by
- Computerized tomography (CT)
- Liver enzymes (AST, ALT, GGT)
- Magnetic resonance imaging (MRI)
- Serum ferritin levels
Board review style answer #1
Board review style question #2
Which of the following is a common complication of transfusional iron overload?
- Diabetes insipidus
- Hyperparathyroidism
- Hypogonadism
- Lung fibrosis
Board review style answer #2
