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Transfusion-Induced Iron Overload Workup

  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Mar 10, 2014

Laboratory Studies

To date, no perfect laboratory marker for iron overload exists.

Serum iron studies

Iron indices behave in a predictable fashion in states of low and high iron (see the image below).

Iron status in iron deficiency and overload. NTBI Iron status in iron deficiency and overload. NTBI = non–transferrin-bound iron; TIBC = total iron-binding capacity.

Serum ferritin has been extensively used as an easily accessible serum marker for transfusion-induced iron overload. The ferritin level that has been used as a cutoff point for iron toxicity has varied in studies from 1000 ng/mL to 3000 ng/mL.[42, 43] The major drawbacks of ferritin are a lack of specificity and interpatient variability.[43] Inflammation, disseminated malignancy, and chronic diseases can also cause large amounts of ferritin to be released in the circulation, making a single elevated reading unreliable.[44]

Low serum ferritin levels may be misleading by providing a false sense of security when patients are at risk of end-organ damage such as cardiomyopathy.[45] Ferritin has also been shown to have a prognostic value. In one study of β-thalassemia major, for patients in whom more than 67% of ferritin measurements exceeded 2500 ng/mL, the estimated disease-free survival was 38% after 10 years of therapy and 18% after 15 years.[14]

Serum iron is increased in cases of iron overload and the total iron-binding capacity (TIBC) is decreased. The relationship between serum iron and total body iron is nonlinear, and the results are dependent on the method used.[46]

Transferrin saturation can be easily measured and is a surrogate marker for NTBI, although this is far from perfect.[47] A transferrin saturation above 50% is suggestive of a high iron load, but this is a dynamic number and may vary with inflammation.

NTBI and LPI are very specific for iron overload and have promising value as monitoring parameters for clinical response to chelation therapy.[48] However, the lack of a standardized assay and limited data for general use for transfusion-induced iron overload makes it necessary to further investigate the use of NTBI and LPI.

Hepcidin measurement in serum and urine have been performed using mass spectrometry, and this may be a feasible marker in the future.[49]

The patient's complete blood cell (CBC) count should be monitored for the hemoglobin/hematocrit to maintain a high threshold for transfusion. Liver function tests, especially alanine aminotransferase (ALT) and aspartate aminotransferase (AST), should be monitored. In patients who develop diabetes mellitus, the usual parameters, such as hemoglobin A1C (HbA1C) and glucose, should be monitored.


Imaging Studies

Computed tomography (CT) scanning has a limited sensitivity (63%) for the assessment of hepatic iron overload.[50] An elevated hepatic CT density associated with an elevated serum ferritin indicates iron overload; however, a normal hepatic CT density does not exclude iron overload.[51] CT scanning is not sensitive when serum ferritin is less than 1000 mcg/L.[52]

Superconducting quantum interference device (SQUID) magnetic measurements of liver iron in patients with iron overload are quantitatively equivalent to biochemical determinations on tissue obtained by biopsy.[53] SQUID can also measure spleen iron content and can be used for monitoring the clinical response to chelation therapy.[54] However, the complexity, cost, and technical demands of the liquid helium–cooled superconducting instruments required at present necessitate restricted clinical access to this method.[55] The latest generation SQUID can be used at room temperature.[56]

Magnetic resonance imaging (MRI) is the noninvasive means of imaging choice and can detect iron deposition in the liver, heart,[57] joints, and pituitary. MRI assessment of myocardial iron loading with the use of gradient echo T2* measurements has reliable reproducibility and has been validated in multiple centers.[58] Quantitative R2* MRI using the transverse magnetic relaxation rate is useful for the measurement of hepatic iron content at facilities with experienced personnel and the proper equipment[59]

MRI is useful to assess pituitary iron overload in patients with transfusional hemochromatosis and secondary hypogonadism by detection of a significant decreased signal intensity of the anterior lobe of the pituitary gland on T2-weighted images.[60] The degree of reduction of the pituitary-to-fat signal intensity ratio correlates with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%.[61]

In addition, MRI can be used for the accurate detection of hemochromatosis in the joints of thalassemia patients receiving multiple transfusions.[62] However, iron deposition in the pancreas cannot be reliably predicted by MRI.[63] MRI mapping accurately estimates hepatic iron concentration in patients with transfusion-dependent thalassemia and sickle cell disease.[64] MRI is rapid, noninvasive, and cost effective, and could limit the use of liver biopsy to assess liver iron content.[65]


Other Tests

When peripheral flow cytometry is performed, patients with transfusion-induced iron overload seem to exhibit a high expression of CD2 and a low expression of CD38 surface markers on the helper T (Th)-cell subset.[66]

Elevated NT-proBNP levels appear to predict cardiac hemosiderosis as demonstrated by T2-weighted MRI in thalassemia even when the ejection fraction is preserved.[67]



Liver biopsy is the criterion standard for measuring iron deposition in the liver and a surrogate for other organs. The hepatic iron concentration is a reliable indicator of total body iron stores.[68] Liver iron concentration (LIC) is measured in mg/g of dry weight of liver and may vary up to 23% between fresh and paraffin-embedded samples.[69] A poor correlation is observed between serum ferritin and the quantitative iron on liver biopsy.[70] CT-guided and transjugular liver biopsies appear less risky. Complications of liver biopsies are reported in 0.06-0.32% of the patients. Death as a direct result of liver biopsy is extremely rare (0.009-0.12%).[71]

Endomyocardial biopsy is an insensitive method of determining early myocardial iron deposition because of the location of the iron and the variability of the sampling.[72]


Histologic Findings

Iron accumulation and fibrosis are the common features found in patients with thalassemia and liver damage, except that thalassemia/hemoglobin H disease exhibit lesser hepatic damage. The degrees of iron deposition and fibrosis are higher in splenectomized and cirrhotic individuals than in nonsplenectomized and noncirrhotic patients.[73]

The subcellular changes on electron microscopy are swollen mitochondria, with the presence of an electron-dense matrix and ruptured mitochondrial membrane. Proliferation of smooth endoplasmic reticulum (ER), and dilatated rough ER are observed. Increases in lysosomal hemosiderin in hepatocytes and in Kupffer cells are demonstrated. The pattern of liver cell damage is similar to that of viral hepatitis.[73]



Hepatic iron overload is classified as mild (< 7 mg/g dry weight), moderate (7-15 mg/g dry weight), or severe (>15 mg/g dry weight).[74]

Contributor Information and Disclosures

Muhammad A Mir, MD, FACP Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Muhammad A Mir, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.


Gerald L Logue, MD Professor of Medicine, Head of the Division of Hematology, Vice Chairman for Education, Department of Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Gerald L Logue, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American College of Physicians, American Society of Hematology, American Federation for Clinical Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching.

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Iron status in iron deficiency and overload. NTBI = non–transferrin-bound iron; TIBC = total iron-binding capacity.
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