Thalassemia Intermedia Workup

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 hemoglobin (Hb) level can be maintained at 6-7 g/dL without blood transfusions.

Increased absorption of iron in all forms of thalassemia results in hemosiderosis or iron overload regardless of whether the patient is receiving regular blood transfusions. Failure to monitor for or recognize this may end in significant organ damage. For this reason, close monitoring of iron status, ferritin level, and liver function tests is needed for evaluation. With iron overload, electrocardiography (ECG) is necessary to monitor for cardiac conduction defects (eg, atrioventricular block).

When in doubt about whether iron levels in the patient's tissues are sufficient to initiate chelation, a deferoxamine challenge test with measurement of urinary iron excreted is appropriate. 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.

A complete blood cell (CBC) count and differential in patients with thalassemia intermedia reveals anemia with marked hypochromasia and microcytosis. A hemoglobin (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.

Peripheral blood film examination usually reveals marked hypochromasia and microcytosis, polychromasia, target cells, and significant variation in the size of the red blood cells (RBCs) (see the image below).

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.

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 it is not the perfect test for a precise evaluation of the progress of iron overload and the development of tissue damage as a complication. Ferritin level 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 (RBCs) 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.

Chest radiography should be obtained to evaluate the size of the heart, and echocardiography should be performed to evaluate cardiac function. 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.

Computed tomography (CT) scanning or even magnetic resonance imaging (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.^[24]

This noninvasive procedure has not been widely used, especially in regions with limited resources, which needed it the most. This is mainly due to its limited availability and very high cost.

Renewed interest in quantitative CT as an alternative procedure for evaluation of HIC was expressed recently by comparing liver attenuation by quantitative CT with R2*-MRI–derived estimates of HIC in 37 patients with transfusional siderosis. The results have shown good correlation only at abnormally high HIC. Calculated values were equivalent around 22 mg/g of liver dry weight and quantitative CT was even superior to R2*-MRI at higher levels of iron. Therefore, the test should not to be used for evaluation of patients with good iron control or those at the early posttransfusion stage; nevertheless, it is a good alternative for HIC evaluation in patients with moderate–to-severe siderosis, particularly in regions with limited resources.^[25]

Cardiac magnetic resonance (CMR) imaging 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.^[26]

A retrospective study of a United Kingdom database of thalassemia major patients has shown that small increases in left ventricular ejection fraction by chelation therapy for cardiac siderosis are associated with a significant decrease in risk for developing heart failure. An observed improvement in left ventricular ejection fraction of 2.6-3.1% is associated with a risk reduction of 25.5-46.4% for the development of heart failure over 12 months.^[27]

Another noninvasive imaging 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.

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. However, study of the genotype at the present time yields no advantage and is not warranted to differentiate between thalassemia major and intermedia when, for example, a previously stable hemoglobin (Hb) level in a patient assumed to have thalassemia intermedia suddenly drops and the patient becomes transfusion dependent. Based on a recent study, however, genotype testing for the presence or absence of 5 severity markers may accurately determine (83.2%) whether a patient develops a severe (thalassemia major) or a mild (thalassemia intermedia) form of β-thalassemia.^[23]

Genotype testing is generally 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.

Liver biopsy is indicated in the patient receiving chelation therapy for hemosiderosis to evaluate the degree of liver involvement and iron overload. 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.

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 hemoglobin (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.