Approach

Alpha-thalassemia should be suspected in patients with the appropriate ethnic background and with microcytosis without evidence for iron deficiency, with or without accompanying anemia. Clinical manifestations are widely variable, from asymptomatic to, rarely, transfusion dependence.

Initial evaluation should focus on history and physical exam; initial laboratory testing should include a complete blood count with red cell indices, reticulocyte count, and careful review of the peripheral blood smear.[3]

History

Patients with one or two affected alpha-globin genes are likely to be asymptomatic.

Patients with hemoglobin H (Hb H) disease are variably symptomatic. In a study in patients with Hb H from Hong Kong, only 24% of those with deletional Hb H presented with symptoms, compared with 40% of those with nondeletional Hb H disease.[5]

History should include the following:

  • Presence and duration of symptoms related to anemia (fatigue, shortness of breath, dizziness)

  • Presence and duration of symptoms related to jaundice (yellow discoloration of the sclerae, skin, and mucous membranes)

  • Presence and duration of symptoms related to gallstones (nausea, gas, bloating, and abdominal pain)

  • Prior history of iron supplementation or red cell transfusion (although most patients with Hb H disease do not require chronic transfusions, in one study up to one third of those with nondeletional Hb H did require regular transfusions)[8]

  • Ethnic origin of the patient (sub-Saharan Africa, the Mediterranean basin, the Middle East, South Asia, and Southeast Asia)

  • History of other affected family members

  • Age of the patient (because alpha-thalassemia can have such wide variability in clinical manifestations, patients may present anywhere from in utero, with hydrops fetalis, to any point during adulthood, with an asymptomatic microcytosis; however, those with more severe manifestations will generally present in childhood or young adulthood).

Physical exam

Physical exam may be normal. In Hb H disease, jaundice may be present, splenomegaly is a common finding, and hepatomegaly may also be seen.[5][43]​ Clinical features of anemia may be present with symptoms including fatigue, dizziness, and shortness of breath. Symptoms of gallstones (bloating, abdominal pain, gas) may be present.

Skeletal changes due to expansion of the erythroid bone marrow may occur, with low bone mass reported in some patients.[44]​ Rarely, bone changes may lead to a milder presentation of the facial dysmorphism that is seen in suboptimally treated beta-thalassemia major, with maxillary hypertrophy, frontal bossing, and prominence of malar eminences.[43][45]​​ Growth retardation may also be seen in children.[5][45] Extramedullary hematopoiesis leading to paraspinal masses has been described.[46][47]

Initial laboratory evaluation

The initial laboratory evaluation should include a complete blood count, reticulocyte count, hemolytic tests, and red cell indices, including measurement of the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and red blood cell count.[16]​ If microcytosis (MCV <78 femtoliters) or hypochromia (MCH <27 picograms) is present, iron status should be assessed (serum iron, transferrin, transferrin saturation, and ferritin) to consider iron-deficiency anemia as the differential diagnosis. If iron studies are ambiguous or borderline, a short, well-monitored trial of iron supplementation may be warranted to rule out iron-deficiency anemia.

In Hb H disease, the reticulocyte percentage is elevated (5% to 10%) and may be further increased during acute infections or hemolytic crises.[48]​​​​ The peripheral smear should be carefully reviewed for findings consistent with alpha-thalassemia, including microcytosis, hypochromia, increased polychromasia, target cells, and anisopoikilocytosis.[48]​ Misshapen and even fragmented red cells may be found in patients with Hb H disease, and characteristic inclusion bodies may be seen on staining with a supravital dye such as brilliant cresyl blue.​[16]​​​​ [Figure caption and citation for the preceding image starts]: Hemoglobin H diseaseFrom the collection of Elizabeth A. Price and Stanley L. Schrier, Stanford University [Citation ends].com.bmj.content.model.Caption@7167e015

In homozygous Hb Constant Spring, the cells will be normal or slightly small in size, and basophilic stippling may be prominent.[6]

Subsequent laboratory evaluation

Hb H and Hb Bart can be detected as fast-moving hemoglobins. Hb H is not always reliably detectable by routine Hb electrophoresis, and some experts feel that Hb H inclusion bodies are more reliable for the diagnosis of Hb H disease.[4]

Hb fractionation and automatic measurement can also be performed with high-performance liquid chromatography (HPLC).[4][16]​​ These testing modalities will also putatively identify all common hemoglobin disorders (i.e., Hb E, Hb S, Hb C, Hb D), which may be present and impact on the clinical course. Hb electrophoresis and HPLC will not, however, detect deletions or mutations in only one or two alpha-globin genes, neither will they differentiate deletional versus nondeletional Hb H disease (except for Hb Constant Spring). Do not repeat hemoglobin electrophoresis in patients who have a prior result, unless the results of interventional therapies are being monitored or to make a more specific diagnosis.[49]

Characterization of alpha-thalassemia

Always requires DNA-based alpha-globin gene testing. Seven of the most common alpha-thalassemia deletions (-alpha(3.7), -alpha(4.2), --(FIL), --(THAI), --(MED), -(alpha)(20.5), --(SEA)) can be diagnosed by gap-polymerase chain reaction (gap-PCR).[48]​ Other deletion alleles are detected by multiplex ligation-dependent probe amplification.​​​[48]​​​​ Nondeletional alpha-thalassemia mutations are usually detected by direct sequencing or reverse dot blot.[48]​​[50]​​

If there are existing genetic test results, do not repeat a genetic test unless there is uncertainty about the existing result, for example, the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[51]​ There is no simple approach to detect all known mutations. Reference laboratories with expertise in diagnosis of hemoglobinopathies may be needed to diagnose difficult cases in a timely manner, particularly for genetic counseling purposes.

Iron overload

If iron status is significantly elevated as evident by a serum ferritin >800 nanograms/mL, hepatic iron overload should be assessed by R2 or R2* magnetic resonance imaging (MRI), superconducting quantum interference devices (SQUID), or liver biopsy (less preferred).[16][48]​​[52][53]​​​​​ Serum ferritin levels may underestimate liver iron concentration.[54]

Cardiac iron loading is assessed by T2* cardiac MRI.[48]​ Cardiac iron loading is uncommon in nontransfused patients.

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