eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thalassemia: 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: Jul 29, 2009

Differential Diagnoses

Anemia, Acute
Anemia, Chronic
Hydrops Fetalis
Pyruvate Kinase Deficiency
Thalassemia Intermedia

Other Problems to Be Considered

The differential diagnoses of thalassemic states in general depend on the age of the child at the time of presentation, the type of thalassemia and its severity, and, in severe cases, whether it is treated and well controlled. Furthermore, the form of thalassemia then has to be identified once the thalassemic condition is suspected because of the numerous thalassemic conditions.

Congenital dyserythropoietic anemia is a condition that may mimic severe forms of thalassemia in children. A bone marrow examination, Hb electrophoresis, and other tests reveal the diagnosis. Diamond-Blackfan anemia may also resemble severe forms of thalassemia in young infants.

The a thalassemia trait is similar to the b thalassemia trait. Both traits should be differentiated from iron deficiency anemia, which is the most common cause of hypochromasia and microcytosis in children and should be excluded before considering thalassemia. A child with presumed iron deficiency anemia that has not responded to adequate iron treatment is a good candidate for thalassemia workup.

In b thalassemia, elevated levels of Hb A2, F, or both are usually helpful in confirming the diagnosis. However, in a thalassemia, the Hb electrophoresis results are usually normal; in this case, and in cases in which iron study results are also nondiagnostic, nonspecific tests may help to differentiate iron deficiency anemia or anemia of chronic inflammation from thalassemia. Free erythrocyte protoporphyrin (FEP) levels are usually elevated in patients with iron deficiency or anemia of chronic inflammation but not with thalassemia. The soluble transferrin receptors (sTfR) levels are high in patients with iron deficiency but not in those with anemia of chronic infection or thalassemia.

The process of differentiating thalassemia trait from iron deficiency anemia must include the patient's medical, developmental, nutritional, and family history and a review of the child's CBC count, with emphasis on the RBC indices. Proper interpretation of the CBC count may save the physician time and may save the patient from unnecessary further testing (see Laboratory Studies). The anemia in patients with thalassemia trait is usually mild; the Hb level is rarely, if ever, less than 9 g/dL, unless the cause of the anemia is multifactorial. The RBC count is almost always higher in patients with thalassemia than in those with iron deficiency anemia; in fact, it is frequently higher than the reported reference range for the age.

In thalassemia, the RBC indices, including the mean corpuscular volume (MCV) and mean corpuscular Hb (MCH), are both significantly low for an Hb level that is either normal or only slightly low. In addition, the RBC distribution width (RDW) is usually normal, reflecting the homogenous population of the RBCs in thalassemia, whereas iron deficiency anemia is known to be associated with anisocytosis. Compare the images below. A faint basophilic stippling may be seen in the RBCs of patients with thalassemia but not typically in those of patients with iron deficiency.

Peripheral blood film in thalassemia minor.

Peripheral blood film in thalassemia minor.

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Peripheral blood film in thalassemia minor.

Peripheral blood film in thalassemia minor.


Peripheral blood in iron deficiency anemia.

Peripheral blood in iron deficiency anemia.

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Peripheral blood in iron deficiency anemia.

Peripheral blood in iron deficiency anemia.


Many formulae have been introduced to help in differentiating thalassemia trait from iron deficiency. The most practical and easiest to remember is the Mentzer index, which divides the patient's MCV by the RBC count (MCV/RBC). A result of less than 13 usually suggests thalassemia trait, while a result greater than 13 is indicative of iron deficiency.

Confirmation by Hb electrophoresis in b thalassemia is essential before the patient and the family are counseled. The Mentzer index loses its value if the patient has a combination of thalassemia and iron deficiency. In such patients, Hb electrophoresis results may also be inaccurate and misleading, since iron deficiency suppresses production of all Hbs, including Hb A2. For this reason, the Hb A2 level does not rise and is typically normal in these patients, masking the diagnosis of b thalassemia. In such cases, Hb electrophoresis should be repeated after the iron deficiency has been treated to obtain an accurate Hb A2 fraction.

When b and a thalassemia coexist, the elevated levels of Hb A2 and Hb F usually present in b thalassemia may also be lost. Furthermore, a thalassemia ameliorates the severity of b thalassemia since the decrease in a chains results in less inclusions and, hence, less hemolysis.

However, the confirmation of b thalassemia is easier than that of the a trait. The Hb electrophoresis result is usually normal, and DNA testing or globin chain synthesis enumeration are the only studies that confirm the diagnosis. A moderately severe form of a thalassemia, which some consider equivalent to b thalassemia intermedia, is termed Hb H disease. The disease is characterized by moderately severe anemia, splenomegaly, some jaundice, and, possibly, some bone changes due to marrow expansion. In this form, Hb electrophoresis is diagnostic in revealing the abnormal Hb, which is unstable and may be detected on the supra vital stain as inclusions in the RBCs (Heinz bodies).

The severity of Hb H disease depends on the inherited mutation. Seventy-five percent of Hb H mutations are caused by deletions on chromosome 16, which are usually associated with the milder forms of Hb H. Nondeletional forms are usually associated with severe Hb H and require transfusion. The diagnosis of Hb H may be difficult to establish, since it is unstable and may go undetected. The b tetramers of Hb H are replaced by g tetramers in the form of Hb Bart. Patients with Hb H disease usually have more than 20% Hb Bart at birth, a finding that has helped to identify 90% of the neonates with Hb H disease in the newborns screening program in California.

Hb Constant Spring (CS) is the most common nondeletional a thalassemia mutation associated with Hb H disease. The cells that contain Hb CS are usually overhydrated, which causes the loss of the traditional microcytosis seen in patients with thalassemia. Hb H/CS disease is more severe than Hb H disease, sometimes requiring splenectomy to improve the anemia, a procedure associated with a high rate of portal vein thrombosis.

Many clinical entities associated with splenomegaly and anemia, such as storage diseases, and other forms of chronic hemolytic anemias are to be considered in the differential diagnosis. The homozygous a thalassemia is not compatible with life (unless intrauterine blood transfusion is administered), and a baby with hydrops fetalis is usually delivered.

Other causes of immune and nonimmune hydrops fetalis are also to be differentiated from the hydrops fetalis of a thalassemia major, a condition that was rarely seen in the past since the mutation that predisposes to this condition is limited to the Southeast Asian population, not the African population.

Rare forms of a thalassemia are also described. Hb CS results from a specific mutation in the a thalassemia gene, leading to the production of elongated a chains. The clinical manifestations in the homozygous state are similar to those encountered in patients with Hb H disease; however, they differ in the electrophoretic pattern. g tetramers that consist of Hb Bart replace the b tetramers of Hb H.

Thalassemia may also interact with other globin structural variants, whether they involve b, a, or other chains. In the b variants, Bs, Bc, and Be are some of the globin chain's most common mutations. For instance, the interaction of Bs with b thalassemia produces a condition associated with sickle cell disease. Conversely, when Bs (sickle trait gene) interacts with an a thalassemia gene, less Hb S is present in the RBCs than when only Bs is present. Such interactions modify the severity of each separate condition.

The incidence of Hb E/b thalassemia has increased considerably in the United States in recent years due to the immigration of individuals from Southeast Asia, where the incidence of both Hg E and b thalassemia is high (see Frequency). Clinically, the severe forms of Hb E/b thalassemia are similar to the transfusion-dependent b thalassemia major. For this reason, the diagnosis Hb E/b thalassemia should be considered in patients of Southeast Asian descent.

Other rare thalassemia variants include Hb Lepore and hereditary persistence of fetal Hb (HPFH).

Workup

Laboratory Studies

  • The CBC count and peripheral blood film examination results are usually sufficient to suspect the diagnosis. Hb evaluation confirms the diagnosis in b thalassemia, Hb H disease, and Hb E/b thalassemia.
    • In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL.
    • MCV and MCH are significantly low, but, unlike thalassemia trait, thalassemia major is associated with a markedly elevated RDW, reflecting the extreme anisocytosis.
    • The WBC count is usually elevated in b thalassemia major; this is due, in part, to miscounting the many nucleated RBCs as leukocytes. Leukocytosis is usually present, even after excluding the nucleated RBCs. A shift to the left is also encountered, reflecting the hemolytic process.
    • Platelet count is usually normal, unless the spleen is markedly enlarged.
    • Peripheral blood film examination reveals marked hypochromasia and microcytosis, hypochromic macrocytes that represent the polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes, as shown below.

      • Peripheral blood film in Cooley anemia.

        Peripheral blood film in Cooley anemia.

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        Peripheral blood film in Cooley anemia.

        Peripheral blood film in Cooley anemia.

    • Contrast this with the abnormalities associated with Hb H, an a thalassemia, shown below.

      • Supra vital stain in hemoglobin H disease that re...

        Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).

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        Supra vital stain in hemoglobin H disease that re...

        Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).

    • Hb electrophoresis usually reveals an elevated Hb F fraction, which is distributed heterogeneously in the RBCs of patients with b thalassemia, Hb H in patients with Hb H disease, and Hb Bart in newborns with a thalassemia trait. In b -0 thalassemia, no Hb A is usually present; only Hb A2 and Hb F are found.
  • Iron studies are as follows:
    • Serum iron level is elevated, with saturation reaching as high as 80%.
    • The serum ferritin level, which is frequently used to monitor the status of iron overload, is also elevated. However, an assessment using serum ferritin levels may underestimate the iron concentration in the liver of a transfusion-independent patient with thalassemia.
  • Complete RBC phenotype, hepatitis screen, folic acid level, and human leukocyte antigen (HLA) typing are recommended before initiation of blood transfusion therapy.

Imaging Studies

  • Skeletal survey and other imaging studies reveal classic changes of the bones that are usually encountered in patients who are not regularly transfused.
    • The striking expansion of the erythroid marrow widens the marrow spaces, thinning the cortex and causing osteoporosis. These changes, which result from the expanding marrow spaces, usually disappear when marrow activity is halted by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in patients whose conditions are well-controlled.
    • In addition to the classic "hair on end" appearance of the skull, shown below, which results from widening of the diploic spaces and observed on plain radiographs, the maxilla may overgrow, which results in maxillary overbite, prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic "chipmunk facies observed in patients with thalassemia major.

      • The classic "hair on end" appearance on plain sku...

        The classic "hair on end" appearance on plain skull radiographs of a patient with Cooley anemia.

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        The classic "hair on end" appearance on plain sku...

        The classic "hair on end" appearance on plain skull radiographs of a patient with Cooley anemia.

    • Other bony structures, such as ribs, long bones, and flat bones, may also be sites of major deformities. Plain radiographs of the long bones may reveal a lacy trabecular pattern. Changes in the pelvis, skull, and spine become more evident during the second decade of life, when the marrow in the peripheral bones becomes inactive while more activity occurs in the central bones.
    • Compression fractures and paravertebral expansion of extramedullary masses, which could behave clinically like tumors, more frequently occur during the second decade of life.
    • MRI and CT scanning are usually used in diagnosing such complications.
  • Chest radiography is used to evaluate cardiac size and shape.
  • MRI and CT scanning can be used as noninvasive means to evaluate the amount of iron in the liver in patients receiving chelation therapy.
  • A newer noninvasive procedure involves measuring the cardiac T2 with cardiac magnetic resonance (CMR). This procedure has shown decreased values in cardiac T2 due to iron deposit in the heart. Unlike liver MRI, which usually correlates very well with the iron concentration in the liver measured using percutaneous liver biopsy samples and the serum ferritin level, CMR does not correlate well with the ferritin level, the liver iron level, or echocardiography findings. This suggests that cardiac iron overload cannot be estimated with these surrogate measurements. This is also true in measuring the response to chelation therapy in patients with iron overload. The liver is clear of iron loading much earlier than the heart, which also suggests that deciding when to stop or reduce treatment based on liver iron levels is misleading.
  • The relationship between hepatic and myocardial iron concentration was assessed by T2-MRI in patients receiving chronic transfusion.2 A poor correlation was noted, and approximately 14% of patients with cardiac iron overload were identified who had no matched degree of hepatic hemosiderosis. Left ventricular ejection fraction was insensitive for detecting high myocardial iron. For this reason, cardiac evaluation should be addressed separately.
  • Hepatic iron content (HIC) obtained by liver biopsy, cardiac function tests obtained by echocardiography measurements, and multiple gated acquisition scan (MUGA) findings were compared to the results of iron measurements on R2-MRI in the liver and heart.3 Various iron overload patients were involved in the study that revealed that R2-MRI was strongly associated with HIC (weakly but significantly with ferritin level) and represents an excellent noninvasive method to evaluate iron overload in the liver and heart and to monitor response to chelation therapy.

Other Tests

  • ECG and echocardiography are performed to monitor cardiac function.
  • HLA typing is performed for patients for whom bone marrow transplantation is considered.
  • Eye examinations, hearing tests, renal function tests, and frequent blood counts are required to monitor the effects of deferoxamine (DFO) therapy and the administration of other chelating agents (see Treatment, Medication).

Procedures

  • Bone marrow aspiration is needed in certain patients at the time of the initial diagnosis to exclude other conditions that may manifest as thalassemia major.
  • Liver biopsy is used to assess iron deposition and the degree of hemochromatosis. However, using liver iron content as a surrogate for evaluation of cardiac iron is misleading. Many recent studies have shown very poor correlation between the two; hence, cardiac evaluation for the presence of iron overload needs to be addressed separately.
  • Measurement of urinary excretion of iron after a challenge test of DFO is used to evaluate the need to initiate chelation therapy and reflects the amount of iron overload.

Histologic Findings

  • All severe forms of thalassemia exhibit hyperactive marrow with erythroid hyperplasia and increased iron stores in marrow, liver, and other organs. In the untreated person with severe disease, extramedullary hematopoiesis in unusual anatomic sites is one of the known complications.
  • Erythroid hyperplasia is observed in bone marrow specimens. Increased iron deposition is usually present in marrow, as depicted in the image below, liver, heart, and other tissues.

    • Excessive iron in a bone marrow preparation.

      Excessive iron in a bone marrow preparation.

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      Excessive iron in a bone marrow preparation.

      Excessive iron in a bone marrow preparation.

Staging

  • Some use a relevant staging system based on the cumulative numbers of blood transfusions given to the patient to grade cardiac-related symptoms and determine when to start chelation therapy in patients with b thalassemia major or intermedia. In this system, patients are divided into 3 groups.
    • The first group contains those who have received fewer than 100 units of packed RBCs (PRBCs) and are considered to have stage I disease. These patients are usually asymptomatic; their echocardiograms reveal only slight left ventricular wall thickening, and both the radionuclide cineangiogram and the 24-hour ECG findings are normal.
    • Patients in the second group (stage II patients) have received 100-400 units of blood and may report slight fatigue. Their echocardiograms may demonstrate left ventricular wall thickening and dilatation but normal ejection fraction. The radionuclide cineangiogram findings are normal at rest but show no increase or fall in ejection fraction during exercise. Atrial and ventricular beats are usually noticed on the 24-hour ECG.
    • Finally, in stage III patients, symptoms range from palpitation to congestive heart failure, decreased ejection fraction on echocardiogram, and normal cineangiogram results or decreased ejection fraction at rest, which falls during exercise. The 24-hour ECG reveals atrial and ventricular premature beats, often in pairs or in runs.
  • A second classification, introduced by Lucarelli, is used for patients with severe disease who are candidates for hematopoietic stem cell transplantation (HSCT).4 This classification is used to assess risk factors that predict outcome and prognosis and addresses 3 elements: (1) degree of hepatomegaly, (2) presence of portal fibrosis in liver biopsy sample, and (3) effectiveness of chelation therapy prior to transplantation.
  • If one of these elements is unfavorable prior to HSCT, the chance of event-free survival is significantly poorer than in patients who have neither hepatomegaly nor fibrosis and whose condition responds well to chelation (class 1 patients). The event-free survival rate after allogeneic HSCT for class 1 patients is 90%, compared with 56% for those with hepatomegaly and fibrosis and whose condition responds poorly to chelation (class 3).

More on Thalassemia

Overview: Thalassemia
Differential Diagnoses & Workup: Thalassemia
Treatment & Medication: Thalassemia
Follow-up: Thalassemia
Multimedia: Thalassemia
References
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Further Reading

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Keywords

Mediterranean anemia, Cooley anemia, anemia, erythroblastemia, hypochromic anemia, microcytic anemia, α thalassemia, alpha thalassemia, β thalassemia, beta thalassemia, thalassemia syndromes, Hb synthesis, thalassemic hemoglobinopathy, β thalassemia major, beta thalassemia major, globin chain, Hb production, hemoglobin synthesis, hypochromasia, thalassemia minor, β+ thalassemia, beta+ thalassemia, β-0 thalassemia, beta-0 thalassemia, hypochromasia, Hb A2, Hb F, RNA-splicing mutations, Hb Malay, Hb E, Hb Knossos, Hb Lepore, red blood cell precursors, bone expansion, iron absorption

transferrin, malaria, Heinz bodies, hydrops fetalis, silent carrier β thalassemia, silent carrier beta thalassemia, cis deletion, reticulocyte, splenomegaly, frontal bossing, dental malocclusion, iron deficiency anemia, fetal Hb, HPFH, chipmunk facies, chelation, extramedullary hematopoiesis, left ventricular wall thickening, hematopoietic stem cell transplantation, HSCT, hepatitis, deferoxamine, DFO, ferritin, deferiprone, DFP, L1, vitamin C deficiency, hepatomegaly, portal fibrosis, labile iron pool, splenectomy, chorionic villus sampling, CVS, Hb H disease, Hb Constant Spring, Hb CS

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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

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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