eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Transfusion-Induced Iron Overload

Author: Muhammad A Mir, MBBS, Fellow, Division of Hematology, Department of Medicine, State University of New York at Buffalo
Coauthor(s): Gerald L Logue, MD, Professor of Medicine, Head of the Division of Hematology, Vice Chairman for Education, Department of Medicine, State University of New York at Buffalo
Contributor Information and Disclosures

Updated: Nov 6, 2008

Introduction

Background

The human body has no active mechanism for the excretion of iron.1 Iron homeostasis thus relies on the amount that is absorbed from the small intestine.2 During normal physiology, the amount of iron absorbed (1-2 mg/d) is lost by sloughing of intestinal mucosa and skin, as well as small amounts in the urine and bile. The day-to-day iron requirements, as iron is needed by virtually all body cells and especially erythrocytes, are met by recycling between various compartments.

In some patients, noticeably those with thalassemia major, sickle cell disease, myelodysplastic syndrome, aplastic anemia, hemolytic anemia, and refractory sideroblastic anemias, who may become transfusion-dependent and receive excess iron with each transfusion (that the body has no means to excrete), iron gradually accumulates in various tissues, causing morbidity and mortality. Each unit of transfused blood has approximately 250 mg of iron.3

Related Medscape topics:
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CME/CE The Role of Chelation Therapy in the Myelodysplastic Syndromes
Secondary Analysis of the CHOIR Trial Epoetin-alpha Dose and Achieved Hemoglobin Outcomes

Pathophysiology

The dynamics of iron regulation in the body is multifaceted and is altered in transfusion-induced iron overload.

Hepcidin, a peptide synthesized in liver, is also known as the “iron hormone."4 Circulating hepcidin reduces iron export into the plasma by binding to the iron export protein ferroportin 1 (FPN1) on the surface of enterocytes, macrophages, and other cells and causing its internalization and degradation. Thus, iron-deficiency states exhibit reduced hepcidin and iron-excess states have high levels of hepcidin to maintain the amount of iron secreted into the circulation.5 Several factors can influence hepcidin production, including the HFE gene, hypoxia, and increased erythropoietin production.6 Most forms of hereditary hemochromatosis exhibit a deficiency of hepcidin.7

In some disorders, such as β-thalassemia, excessive intestinal absorption also adds to the transfusion-induced iron overload. In thalassemia intermedia, high erythropoietic drive causes hepcidin deficiency. The lack of hepcidin results in hyperabsorption of dietary iron and body iron overload. In contrast, in thalassemia major, transfusions decrease erythropoietic drive and increase the iron load, resulting in relatively higher hepcidin levels. In the presence of higher hepcidin levels, dietary iron absorption is moderated and macrophages retain iron, but body iron stores increase due to the inability to excrete iron in transfused red blood cells.8

When the plasma iron-binding protein transferrin is oversaturated, as in transfusion-induced iron overload, the excess iron circulates as relatively free non–transferrin-bound iron (NTBI). This NTBI is rapidly taken up by liver and other tissues. Transferrin-bound iron (TBI) is also taken up by these cells through the hepcidin mechanism, which is increased in such states.9 It is this excessive iron that damages tissues.

A specific portion of NTBI is the chelatable labile plasma iron (LPI), which is not found in healthy individuals.10 This is the most toxic component due to high reduction-oxidation (redox) potential that generates oxygen-free radicals such as superoxide anion in the cells, which damages DNA, proteins, and membrane lipids in the cell.11

Hemosiderin is an abnormal, insoluble form of iron storage. It consists of ferritin trapped in lysosomal membranes.12 Unlike ferritin, it does not circulate in blood but is deposited in tissues and is unavailable when cells need iron.13

Major organs affected by this surplus iron include the heart, lung, liver, and endocrine glands.

  • Cardiac involvement is a major determinant of the prognosis in iron-overload states.14 Hypertrophy and dilatation are common. Abnormal cardiac function can be observed in the absence of overt heart failure.15 The average time for the development of heart failure in transfused, unchelated patients is 10 years.16 Iron chelation can reverse cardiac changes and improve performance.17
  • Pulmonary hypertension appears to be less common in thalassemia major patients who undergo transfusion, probably due to the correction of hypoxia, and it is more common in the less transfused thalassemia intermedia patients.18 More than one third of transfusion-dependent patients with β-thalassemia major exhibit a restrictive lung function defect, which may improve with chelation therapy.19
  • Liver involvement is common in those who undergo long-term transfusions. Early cirrhotic changes can be observed as early as age 7 years in some people with thalassemia.20 Upregulation of the transport of NTBI is observed in cultured hepatocytes and is likely to occur in vivo.21 Once cirrhosis develops, the risk of hepatocellular carcinoma (HCC) is increased.
  • Endocrine dysfunction affects virtually all glands. Pituitary involvement causes delayed puberty in more than 50% of patients.22 Up to 14% may develop insulin-dependent diabetes mellitus (IDDM).23 Even those without diabetes have impaired insulin secretion.24 Thyroid, parathyroid, and exocrine pancreas are also affected.25

Neutrophils from patients with secondary iron overload have an increased iron and ferritin content and a phagocytosis defect.26 Yersinia enterocolitica seems to have affinity for those loaded with iron, causing abdominal infections27 and hepatic abscesses.28 Deferoxamine seems to worsen the infection and should be discontinued in cases in which active abdominal symptoms are present.29

Degenerative arthropathy in thalassemia is also a sequela of iron overload.30

Frequency

United States

Amongst 342 patients with transfusion-dependent thalassemia in the National Institutes of Health (NIH) registry, 23% had iron overload as documented by a liver iron concentration of 15 mg/g dry weight or greater.31

International

In a Japanese cohort of transfusion-dependent patients with myelodysplastic syndrome and aplastic anemia, one third of all deaths were attributable to iron overload (97% of the deceased had a serum ferritin >1000 ng/mL). Cardiac failure was responsible for 24% and liver failure for 7% of all deaths. On average, each patient was transfused with more than 60 units of red blood cells per year.32

In a Greek population of thalassemia major patients who were transfusion dependent, 51% had moderate (defined as serum ferritin >2000 mcg/L) to severe iron overload (defined as serum ferritin >4000 mcg/L).33

Mortality/Morbidity

Mortality in chronically transfused patients with thalassemia and sickle cell disease is 3 times that of the general United States population. The most common cause of morbidity is cardiomyopathy (30%) that is induced by iron overload.34

Race

The prevalence of mild to moderate iron overload was similar in black and white veterans in one autopsy study that evaluated the hepatic iron concentration of 256 specimens.35

Sex

An analysis of data from 1861 patients with β-thalassemia major from Italy showed that failure of puberty was the major clinical endocrine problem in these patients, and it was present in 51% of boys and 47% of girls, all older than 15 years. Secondary amenorrhea was recorded in 23% of the patients with β-thalassemia major.36

Age

Several distinct groups can be recognized in terms of the initiation of transfusion therapy. The average age of patients undergoing transfusion initiation is 4 years in thalassemia and 13 years in sickle cell disease34 ; in adults, the average age at transfusion initiation is in the 40s for aplastic anemia,37 and in the 60s for myelodysplasia.38

Clinical

History

The clinical history surrounding transfusion-induced iron overload may include the following:

General

  • Weight loss
  • Fatigue
  • Bronze/gray skin

Hematologic

  • Underlying anemia
  • Transfusion dependence
  • Duration of transfusion dependence
  • Number of transfusions each year
  • Chelation history and compliance

Cardiac – Heart failure

  • Dyspnea
  • Orthopnea
  • Paroxysmal nocturnal dyspnea
  • Swelling of lower extremities

Gastrointestinal – Cirrhosis

  • Abdominal distention
  • Abdominal pain
  • Hematemesis
  • Melena
  • Encephalopathy

Endocrine

  • Stunted growth
  • Delayed puberty
  • Decreased libido
  • Delayed menarche
  • Diabetes mellitus
    • Polyuria
    • Polydipsia
    • Polyphagia

Musculoskeletal

  • Arthralgias

Physical

The physical examination findings in those with transfusion-induced iron overload may include the following:

General

  • Bronze/gray skin color
  • Cachexia
  • Dwarfism

Hematologic

  • Bruising

Cardiac

  • Jugular venous distention
  • S3 rhythm
  • Pleural effusion
  • Peripheral edema

Pulmonary

  • Lung crepitations
  • Loud P2

Breast

  • Delayed development

Abdominal

  • Ascites
  • Tenderness
  • Hepatomegaly
  • Splenomegaly
  • Caput medusa
  • Umbilical hernia

Neurologic

  • Asterixis
  • Encephalopathy

Genitourinary

  • Soft, small testes
 Musculoskeletal

Causes

Transfusion dependence due to the following are among the causes of transfusion-induced iron overload:

  • Sickle cell disease
  • β-thalassemia major
  • Aplastic anemia
  • Hemolytic anemia
  • Blackfan-Diamond syndrome
  • Myelodysplastic syndrome
  • Leukemia

More on Transfusion-Induced Iron Overload

Overview: Transfusion-Induced Iron Overload
Differential Diagnoses & Workup: Transfusion-Induced Iron Overload
Treatment & Medication: Transfusion-Induced Iron Overload
Follow-up: Transfusion-Induced Iron Overload
Multimedia: Transfusion-Induced Iron Overload
References
Further Reading
[ CLOSE WINDOW ]

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Further Reading

  1. Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Hematology Am Soc Hematol Educ Program. 2001;47-61. [Medline]. [Full Text].
  2. Information Center for Sickle Cell and Thalassemic Disorders. Iron transport and cellular uptake. Rev. January 29, 2001. Available at: http://sickle.bwh.harvard.edu/iron_transport.html. Accessed November 6, 2008.

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Keywords

transfusion-induced iron overload, iron overload, transfusional iron overload, transfusional hemosiderosis, secondary hemochromatosis, post-transfusion iron overload, transfusional siderosis

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Contributor Information and Disclosures

Author

Muhammad A Mir, MBBS, Fellow, Division of Hematology, Department of Medicine, State University of New York at Buffalo
Muhammad A Mir, MBBS is a member of the following medical societies: American College of Physicians and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Gerald L Logue, MD, Professor of Medicine, Head of the Division of Hematology, Vice Chairman for Education, Department of Medicine, State University of New York at Buffalo
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 Federation for Clinical Research, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

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: Novartis Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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