eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thalassemia Intermedia: Differential Diagnoses & Workup

Author: Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
Contributor Information and Disclosures

Updated: Sep 29, 2009

Differential Diagnoses

Acrodermatitis Enteropathica

Other Problems to Be Considered

Acute leukemias
Hemolytic anemias (autoimmune, metabolic)
Hemophagocytosis
Hypersplenism
Iron-deficiency anemia
Beta thalassemia major
Thalassemia traits
Thrombocytopenia, associated with splenomegaly in various clinical entities
Anemia, hypochromic and microcytic

Workup

Laboratory Studies

  • Severe forms of thalassemia intermedia must be differentiated from β thalassemia major; this is mainly a clinical differentiation based on close monitoring to determine whether the patient's Hb level can be maintained at 6-7 g/dL without blood transfusions. The severe anemia, if associated with thrombocytopenia, hypersplenism, and the immature leukocytes often observed on peripheral blood films, raises the question of acute leukemia or metastatic lymphoma. Milder cases, on the other hand, must be differentiated from thalassemia trait or even anemias related to iron deficiency or chronic inflammation. Unlike the intermedia forms, β thalassemia trait rarely produces an Hb level less than 9 g/dL. Iron deficiency anemia is characterized by a normal Hb electrophoresis pattern and abnormal iron study results.
  • The following tests are usually adequate to suggest a diagnosis of thalassemia major or intermedia:
    • CBC count and differential reveal anemia with marked hypochromasia and microcytosis. An Hb level below 7-8 g/dL indicates a severe case; whether the thalassemia is major or intermedia can be determined only after adequate monitoring.
    • Hb electrophoresis shows an abnormal pattern. An elevated Hb A2 fraction of as much as 7% indicates β thalassemia, typically β thalassemia trait or certain forms of thalassemia intermedia. However, absence of Hb A2 does not exclude the diagnosis of β thalassemia; in fact, an Hb A2 of 0% frequently arises from a homozygous deletion of both the β and the δ chain genes because δ chains are needed to produce Hb A2. In the intermedia type overall, Hb F ranges from 20-100%, Hb A from 0-80%, and A2 up to 7% of total.
    • Peripheral blood film examination usually reveals marked hypochromasia and microcytosis, polychromasia, target cells, and significant variation in the size of the RBCs (see Media file 1).

      Peripheral blood film in thalassemia intermedia.

      Peripheral blood film in thalassemia intermedia.

      [ CLOSE WINDOW ]
      Peripheral blood film in thalassemia intermedia.

      Peripheral blood film in thalassemia intermedia.

  • Iron studies should be performed, either as baseline in anticipation of iron overload in the future or for diagnosis and management of this condition when suspected.
    • Ferritin level is an adequate tool for screening but is not the perfect test for a precise evaluation of the progress of iron overload and the development of tissue damage as a complication. It is a noninvasive test that is easy to obtain and is of value in the early stages of iron overload process; however, it becomes inaccurate when iron accumulates heavily, it lacks sensitivity and specificity, and it correlates poorly with hepatic iron concentration. It is also known to be a positive plasma reactant, which rises in association with inflammation.
    • Serum transferrin saturation may provide some information about the patient's iron status; however, it lacks sensitivity. Twenty-four–hour deferoxamine-induced urinary iron excretion is a beneficial test in deciding when chelation therapy should be started (presence of adequate iron available for chelation); it is not a practical test to evaluate iron overload, however. Urine aliquots are not usually collected correctly, the ratio of stool-to-urine iron varies, and furthermore, correlates poorly with hepatic iron deposits. 
    • Either bone marrow grading of iron stores or monitoring the numbers of nucleated red blood cells in the peripheral blood may reflect the stage of iron overload. Patients with thalassemia intermedia tend to develop iron overload somewhat later than those with thalassemia major regardless of whether they are on a transfusion schedule.
    • Once the patient is started on blood transfusions, the onset of iron overload should be expected earlier than in patients who are not receiving transfusion, and closer follow-up is required.
  • Tests to identify endocrine disturbances such as diabetes mellitus or thyroid, adrenal, or other gland dysfunction are also required.
  • Liver function tests are needed at diagnosis and during follow-up, especially in patients who are receiving blood transfusions. 

Imaging Studies

  • Chest radiography should be obtained to evaluate the size of the heart.
  • A skeletal survey should be conducted to evaluate the status of the bones and to monitor bone changes that are due to the chronic hyperactivity of the marrow.
  • CT scanning or even MRI of the liver to evaluate iron deposition has been helpful in monitoring patients on transfusion regimens and chelation therapy. Variable correlation results were reported for both. However, R2*-MRI appears to be very informative, with strong correlation with hepatic iron content (HIC) and weak but significant association with ferritin level. It is an excellent noninvasive method to assess iron overload and response to chelation therapy.17 Cardiac magnetic resonance (CMR) is used to measure cardiac T2 in patients with thalassemia. Unlike liver MRI, which correlates well with iron concentration in the liver measured by liver biopsy and with serum ferritin level, CMR does not correlate well with ferritin, liver iron level, or even echocardiographic imaging results. This suggests that surrogate measurement of cardiac iron is misleading.18
  • Echocardiography should be performed to evaluate the function of the heart.

Other Tests

  • With iron overload, ECG is necessary to monitor for cardiac conduction defects (eg, atrioventricular block).
  • Genetic counseling and DNA studies using DNA probes from known thalassemia intermedia genotypes are very useful in prenatal diagnosis and identification of new cases in selected patients at risk.
  • Study of the genotype yields no advantage and is not warranted to differentiate between thalassemia major and intermedia when, for example, a previously stable Hb level in a patient assumed to have thalassemia intermedia suddenly drops and the patient becomes transfusion dependent.
  • Genotype testing is beneficial when deciding whether to terminate a pregnancy when the fetus is affected. A thalassemia intermedia genotype probably indicates a milder disease, and parents may decide to continue the pregnancy.

Procedures

  • Examination of liver tissues obtained by ultrasonographically guided biopsy is an optimal way to evaluate body iron burden and the status of the liver itself (eg, fibrosis, inflammation). Cardiac biopsy is not sensitive because the distribution of iron in the heart is not homogeneous. A noninvasive method that correlates precisely with biopsy-determined hepatic iron levels is the susceptometry superconducting quantum interference device (SQUID).
  • Once chelation therapy is deemed necessary, evaluation of liver tissue damage from iron deposition is required. Some have suggested that liver histologic studies for iron status be obtained every 2 years.

Histologic Findings

  • Erythroid hyperplasia is the major finding in the bone marrow. In addition, excessive iron deposition is observed in later stages in both marrow and liver. Osteopenia and osteoporosis are also observed in untreated individuals with relatively low Hb levels.
  • Quantitative assessment of liver iron deposition can be used as a guideline for starting chelation; an iron concentration of 1.5 mg/g of liver (dry weight) has been suggested as an appropriate threshold.

More on Thalassemia Intermedia

Overview: Thalassemia Intermedia
Differential Diagnoses & Workup: Thalassemia Intermedia
Treatment & Medication: Thalassemia Intermedia
Follow-up: Thalassemia Intermedia
Multimedia: Thalassemia Intermedia
References
[ CLOSE WINDOW ]

References

  1. Li Q, Li LY, Mo QH. [A rare thalassemia intermedia case caused by co-existence of Hb H disease (--(SEA)/-alpha(4.2)) and beta-thalassemia major (beta (CD17A)>T/beta (IVS2-654C)>T): implications for prenatal diagnosis]. Nan Fang Yi Ke Da Xue Xue Bao. Jan 2008;28(1):16-9. [Medline].

  2. Haghi M, Feizi AA, Harteveld CL, Pouladi N, Feizi MA. Homozygosity for a rare beta 0-thalassemia mutation [frameshift codons 25/26 (+T)] causes beta-thalassemia intermedia in an Iranian family. Hemoglobin. 2009;33(1):75-80. [Medline].

  3. Harteveld CL, Refaldi C, Cassinerio E, Cappellini MD, Giordano PC. Segmental duplications involving the alpha-globin gene cluster are causing beta-thalassemia intermedia phenotypes in beta-thalassemia heterozygous patients. Blood Cells Mol Dis. May-Jun 2008;40(3):312-6. [Medline].

  4. Finkenstedt A, Bianchi P, Theurl I, Vogel W, Witcher DR, Wroblewski VJ, et al. Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Br J Haematol. Mar 2009;144(5):789-93. [Medline].

  5. [Guideline] Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older children. Br J Haematol. Feb 2004;124(4):433-53. [Medline].

  6. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. May 2007;92(5):583-8. [Medline]. [Full Text].

  7. Cappellini MD, Grespi E, Cassinerio E, Bignamini D, Fiorelli G. Coagulation and splenectomy: an overview. Ann N Y Acad Sci. 2005;1054:317-24. [Medline].

  8. Dunn J, Khan S, Ariff B, Strickland N, Al-Nahhas A. Pulmonary emboli and extramedullary haematopoiesis in beta-thalassaemia intermedia. Nucl Med Rev Cent East Eur. 2008;11(1):34-6. [Medline].

  9. Karimi M, Khanlari M, Rachmilewitz EA. Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). Am J Hematol. Jan 2008;83(1):77-9. [Medline].

  10. Morris CR, Gladwin MT, Kato GJ. Nitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders. Curr Mol Med. Nov 2008;8(7):620-32. [Medline].

  11. Parker TM, Ward LM, Johnston DL, Ventureya E, Klaassen RJ. A case of Moyamoya syndrome and hemoglobin E/beta-thalassemia. Pediatr Blood Cancer. Mar 2009;52(3):422-4. [Medline].

  12. Metarugcheep P, Chanyawattiwongs S, Srisubat K, Pootrakul P. Clinical silent cerebral infarct (SCI) in patients with thalassemia diseases assessed by magnetic resonance imaging (MRI). J Med Assoc Thai. Jun 2008;91(6):889-94. [Medline].

  13. Westerman M, Pizzey A, Hirschman J, et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br J Haematol. Jul 2008;142(1):126-35. [Medline].

  14. Goldschmidt N, Spectre G, Brill A, et al. Increased platelet adhesion under flow conditions is induced by both thalassemic platelets and red blood cells. Thromb Haemost. Nov 2008;100(5):864-70. [Medline].

  15. Singer ST, Ataga KI. Hypercoagulability in sickle cell disease and beta-thalassemia. Curr Mol Med. Nov 2008;8(7):639-45. [Medline].

  16. Aessopos A, Kati M, Farmakis D. Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. Haematologica. May 2007;92(5):658-65. [Medline].

  17. Hankins JS, McCarville MB, Loeffler RB, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. May 14 2009;113(20):4853-5. [Medline].

  18. Deborah Chirnomas S, Geukes-Foppen M, Barry K, Braunstein J, Kalish LA, Neufeld EJ, et al. Practical implications of liver and heart iron load assessment by T2*-MRI in children and adults with transfusion-dependent anemias. Am J Hematol. Oct 2008;83(10):781-3. [Medline].

  19. Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. Jul 2005;27(7):380-5. [Medline].

  20. Koren A, Levin C, Dgany O, Kransnov T, Elhasid R, Zalman L, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. May 2008;83(5):366-70. [Medline].

  21. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev. Dec 2008;22 Suppl 2:S35-41. [Medline].

  22. Atichartakarn V, Angchaisuksiri P, Aryurachai K, Chuncharunee S, Thakkinstian A. In vivo platelet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy. Int J Hematol. Apr 2003;77(3):299-303. [Medline].

  23. Blendis LM, Modell CB, Bowdler AJ. Some effects of splenectomy in thalassaemia major. Br J Haematol. Sep 1974;28(1):77-87. [Medline].

  24. Sanefuji M, Ohga S, Kira R, et al. Moyamoya syndrome in a splenectomized patient with beta-thalassemia intermedia. J Child Neurol. Jan 2006;21(1):75-7. [Medline].

  25. Cunningham MJ, Macklin EA, Neufeld EJ, et al. Complications of beta-thalassemia major in North America. Blood. Jul 1 2004;104(1):34-9. [Medline].

  26. Davison SM, Kelly DA. Management strategies for hepatitis C virus infection in children. Paediatr Drugs. 2008;10(6):357-65. [Medline].

  27. Aessopos A, Kati M, Meletis J. Thalassemia intermedia today: should patients regularly receive transfusions?. Transfusion. May 2007;47(5):792-800. [Medline].

  28. Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. Jun 1 2007;109(11):5027-35. [Medline].

  29. Lagos P, Lagona E, Kattamis C. Serum ferritin in beta-thalassaemia intermedia. Lancet. Jan 26 1980;1(8161):204-5. [Medline].

  30. Lilleyman JS, Hann IM, Blanchette V. The thalassemia. In: Pediatric Hematology. 2000:316, 325.

  31. Luyendijk W, Went L, Schaad HD. Spinal cord compression due to extramedullary hematopoiesis in homozygous thalassemia. Case report. J Neurosurg. Feb 1975;42(2):212-6. [Medline].

  32. McIntosh N. Beneficial effects of transfusing a patient with non–transfusion-dependent thalassaemia major. Arch Dis Child. Jun 1976;51(6):471-2. [Medline].

  33. Nathan DG, Oski FA. The thalassemia. In: Nathan and Oski's Hematology of Infancy and Childhood. Vol 1. Philadelphia, Pa: WB Saunders Co; 1997:847-9.

  34. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem. Jun 2003;10(12):1065-76. [Medline].

  35. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. May 2007;92(5):583-8. [Medline].

  36. Pippard MJ, Callender ST, Warner GT, Weatherall DJ. Iron absorption and loading in beta-thalassaemia intermedia. Lancet. Oct 20 1979;2(8147):819-21. [Medline].

  37. Weatherall DJ. Thalassemia. In: Stamatoyannopoulos G, et al, eds. The Molecular Basis of Blood Diseases. Philadelphia, Pa: WB Saunders Co; 1944:157-206.

  38. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. Oxford, England: Blackwell Science Publishing Co; 1981.

  39. Weizer-Stern O, Adamsky K, Amariglio N, et al. Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. Br J Haematol. Oct 2006;135(1):129-38. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

beta thalassemia intermedia, β thalassemia intermedia, beta thalassemia major, β thalassemia major, beta thalassemia trait, β thalassemia trait, hemoglobin, Hb, Hb level, globin chain synthesis, erythropoiesis, iron overload, hepcidin, anemia, growth retardation, failure to thrive, bone fractures, enlarged spleen, splenomegaly, pulmonary embolism, pulmonary hypertension, Moyamoya disease, cerebral infarction, enlarged spleen, treatment, diagnosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.