Approach

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

Initial evaluation should focus on history and physical examination; initial laboratory testing should include a full 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 haemoglobin 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 non-deletional Hb H disease.[5]

History should include the following:

  • Presence and duration of symptoms related to anaemia (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, wind, 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 non-deletional Hb H did require regular transfusions)[8]

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

  • History of other affected family members

  • Age of the patient (because alpha-thalassaemia 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 examination

Physical examination 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 anaemia may be present with symptoms including fatigue, dizziness, and shortness of breath. Symptoms of gallstones (bloating, abdominal pain, wind) 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 sub-optimally treated beta-thalassaemia major, with maxillary hypertrophy, frontal bossing, and prominence of malar eminences.[43][45]​​ Growth retardation may also be seen in children.[5][45] Extramedullary haematopoiesis leading to paraspinal masses has been described.[46][47]

Initial laboratory evaluation

The initial laboratory evaluation should include a full blood count, reticulocyte count, haemolytic tests, and red cell indices, including measurement of the mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and red blood cell count.[16]​ If microcytosis (MCV <78 femtolitres) or hypochromia (MCH <27 picograms/cell) is present, iron status should be assessed (serum iron, transferrin, transferrin saturation, and ferritin) to consider iron-deficiency anaemia 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 anaemia.

In Hb H disease, the reticulocyte percentage is elevated (5% to 10%) and may be further increased during acute infections or haemolytic crises.​​[48]​​ The peripheral smear should be carefully reviewed for findings consistent with alpha-thalassaemia, including microcytosis, hypochromia, increased polychromasia, target cells, and anisopoikilocytosis.[48]​ Mis-shapen 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]: Haemoglobin H diseaseFrom the collection of Elizabeth A. Price and Stanley L. Schrier, Stanford University [Citation ends].com.bmj.content.model.Caption@24f9147

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 haemoglobins. 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 haemoglobin 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 non-deletional Hb H disease (except for Hb Constant Spring).

Characterisation of alpha-thalassaemia

Always requires DNA-based alpha-globin gene testing. Seven of the most common alpha-thalassaemia 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]​​​​​​ Non-deletional alpha-thalassaemia mutations are usually detected by direct sequencing or reverse dot blot.[48]​​[49]​​

There is no simple approach to detect all known mutations. Reference laboratories with expertise in diagnosis of haemoglobinopathies may be needed to diagnose difficult cases in a timely manner, particularly for genetic counselling purposes.

Iron overload

If iron status is significantly elevated as evident by a serum ferritin >1797.6 picomol/L (>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]​​[50][51]​​​​​ Serum ferritin levels may underestimate liver iron concentration.[52]

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

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