History

Patients with transfusion-induced iron overload typically have underlying anemia and transfusion dependence. The clinician should ask about the following:

Duration of transfusion dependenc
Number of transfusions each year
Chelation history and compliance

Patients may complain of weight loss, fatigue, and arthralgia, along with cardiac, gastrointestinal, and endocrine manifestations.

Cardiac manifestations (related to heart failure) may include the following:

Dyspnea
Orthopnea
Paroxysmal nocturnal dyspnea
Swelling of lower extremities

Gastrointestinal signs and symptoms (related to cirrhosis) may include the following:

Abdominal distention
Abdominal pain
Hematemesis
Melena
Encephalopathy

Endocrine manifestations may include the following:

Stunted growth
Delayed puberty
Decreased libido
Delayed menarche
Diabetes mellitus (ie, polyuria, polydipsia, polyphagia)

Physical

General physical examination findings in patients with transfusion-induced iron overload may include the following:

Bronze/gray skin color
Bruising
Cachexia
Dwarfism
Delayed breast development in pubertal girls
Soft, small testes in males

Cardiac findings may include the following:

Jugular venous distention
S3 rhythm
Pleural effusion
Peripheral edema

Pulmonary findings may include the following:

Lung crepitations
Loud P ₂

Abdominal findings may include the following:

Ascites
Tenderness
Hepatomegaly
Splenomegaly
Caput medusa
Umbilical hernia

Neurologic findings related to cirrhosis may include the following:

Asterixis
Encephalopathy

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

Complications

Cardiac involvement is a major determinant of the prognosis in iron-overload states.^[25] Hypertrophy and dilatation are common. Abnormal cardiac function can be observed in the absence of overt heart failure.^[26] The average time for the development of heart failure in transfused, unchelated patients is 10 years.^[27]

Iron chelation can reverse cardiac changes and improve performance.^[28] In a murine model of beta-thalassemia, the myocardial damage with increased interstitial fibrosis and remodelling appears to start before any significant myocardial iron deposits can be demonstrated, suggesting additional mechanisms of cardiac failure pathogenesis in thalassemia.^[29]

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.^[30] More than one third of transfusion-dependent patients with β-thalassemia major exhibit a restrictive lung function defect, which may improve with chelation therapy.^[31]

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.^[32] Upregulation of the transport of NTBI is observed in cultured hepatocytes and is likely to occur in vivo.^[33] 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.^[34] Destruction of pancreatic beta cells, insulin resistance, or both may result in diabetes mellitus.^[35] Even those without diabetes may have abnormal glucose metabolism.^[35] Thyroid, parathyroid, and exocrine pancreas are also affected.^[36] In one study involving patients with chronic anemia with transfusion-induced iron overload, free T3 and free T4 were decreased and thyrotropin-stimulating hormone was higher than normal.^[37]

Neutrophils from patients with secondary iron overload have an increased iron and ferritin content and a phagocytosis defect.^[38]Yersinia enterocolitica seems to have affinity for those loaded with iron, causing abdominal infections^[39] and hepatic abscesses.^[40] Deferoxamine seems to worsen the infection and should be discontinued in cases in which active abdominal symptoms are present.^[41]

Degenerative arthropathy in thalassemia is also a sequela of iron overload.^[42]

Complications of iron overload as manifested in various organs in the body

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Differential Diagnoses

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Media Gallery

Complications of iron overload as manifested in various organs in the body
Iron absorption

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Author

Geneva E Guarin, MD, MBA Resident Physician, Department of Internal Medicine, Einstein Medical Center Philadelphia

Disclosure: Nothing to disclose.

Coauthor(s)

Claudia M da Costa Dourado, MD Clinical Assistant Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Program Director, Hematology and Medical Oncology Fellowship Program, Attending Physician, Division of Hematology and Medical Oncology, Department of Medicine, Einstein Medical Center Philadelphia

Claudia M da Costa Dourado, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

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, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

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

Disclosure: Nothing to disclose.

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.

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.