Thalassemia (Alpha and Beta)
Inherited disorders of globin chain synthesis causing microcytic hypochromic anemia of varying severity.
Also known as: alpha thalassemia, beta thalassemia, thalassemia major, thalassemia trait, Cooley anemia
Overview
Group of inherited anemias resulting from reduced or absent synthesis of one or more globin chains of hemoglobin. Alpha-thalassemia is caused by deletion of one or more of the four alpha-globin genes (chromosome 16); beta-thalassemia is caused by point mutations in one or both beta-globin genes (chromosome 11) reducing or eliminating beta-chain production.
Epidemiology
Most common monogenic disease worldwide. Alpha-thalassemia: Southeast Asian, African, Mediterranean ancestry. Beta-thalassemia: Mediterranean (Greek, Italian), Middle Eastern, North African, Indian, Southeast Asian. Heterozygote advantage against malaria.
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Risk factors
- Family history; both parents must carry the variant for severe disease
- Ethnic origin: Mediterranean, Middle Eastern, Southeast Asian, African, Indian
- Consanguinity
Pathophysiology
Imbalanced globin chain synthesis produces ineffective erythropoiesis and hemolysis. In beta-thalassemia, excess alpha chains precipitate in erythroid precursors, causing intramedullary destruction. In alpha-thalassemia, excess beta or gamma chains form unstable tetramers (HbH = beta4, Hb Barts = gamma4). Bone marrow expansion compensates (skull, facial bones), and chronic anemia drives extramedullary erythropoiesis and iron overload from increased absorption and transfusion.
Clinical presentation
Symptoms
- Alpha-thalassemia silent carrier (1 gene deleted) and trait (2 genes): asymptomatic or mild microcytosis
- HbH disease (3 alpha genes deleted): moderate hemolytic anemia, splenomegaly, gallstones; transfusions intermittent
- Hb Barts hydrops fetalis (all 4 alpha genes deleted): incompatible with extrauterine life
- Beta-thalassemia minor (heterozygous): asymptomatic mild microcytic anemia
- Beta-thalassemia intermedia: symptomatic anemia, occasional transfusions, hepatosplenomegaly
- Beta-thalassemia major (Cooley anemia): severe transfusion-dependent anemia from 6-12 months as HbF declines
Signs / physical exam
- Pallor, scleral icterus
- Hepatosplenomegaly (extramedullary erythropoiesis, iron overload)
- 'Chipmunk facies' — frontal bossing, maxillary overgrowth, prominent malar eminences (compensatory marrow expansion in major)
- Short stature, delayed puberty, skeletal deformities
- Skin bronzing (iron overload)
Classic findings
Beta-thalassemia major: 'crew-cut' skull on X-ray (vertical striations from marrow expansion) and chipmunk facies.
Differential diagnosis
- Iron deficiency anemia — Microcytic but with elevated RDW, low ferritin, high TIBC; Mentzer index (MCV/RBC) >13 suggests IDA; thalassemia has near-normal RDW and Mentzer <13
- Anemia of chronic disease — Normal or low MCV, low TIBC, normal/high ferritin, inflammatory context
- Sideroblastic anemia (congenital) — Ringed sideroblasts on marrow iron stain; iron overload from inception
- Lead poisoning — Microcytosis with basophilic stippling, elevated lead level, environmental history
- Hemoglobin C disease/trait — Target cells, HbC crystals; hemoglobin electrophoresis diagnostic
Diagnostic workup
Diagnostic criteria
Hemoglobin electrophoresis pattern (elevated HbA2 ± HbF for beta-thal; HbH band for HbH disease) or molecular genetic testing (alpha-thal gene deletions). Family studies useful.
Labs
- CBC — microcytic anemia (MCV often very low, 60-70), elevated RBC count, normal RDW, target cells
- Peripheral smear — target cells, basophilic stippling, nucleated RBCs (in major)
- Iron studies normal or elevated (distinguishes from iron deficiency)
- Hemoglobin electrophoresis (or HPLC): beta-thal trait shows elevated HbA2 (>3.5%) and often elevated HbF; beta-thal major shows mostly HbF, little or no HbA
- Alpha-thalassemia: electrophoresis typically normal in trait (silent or minor); HbH disease shows HbH band; molecular genetic testing (gap-PCR) for definitive diagnosis
- Mentzer index = MCV / RBC count; <13 suggests thalassemia, >13 suggests iron deficiency
Imaging
- Skull X-ray — 'hair-on-end' or 'crew-cut' appearance in thalassemia major
- MRI T2* of liver and heart — quantifies iron overload in chronically transfused patients
- Bone age, growth assessment
Diagnostic algorithm
| Type | Genotype | Hemoglobin Pattern | Clinical Severity |
|---|---|---|---|
| Alpha silent carrier | -α/αα (1 gene deleted) | Normal | Asymptomatic |
| Alpha trait | --/αα or -α/-α (2 genes) | Normal or mild ↑Hb Barts at birth | Mild microcytosis |
| HbH disease | --/-α (3 genes deleted) | HbH (β4) present | Moderate hemolytic anemia |
| Hb Barts hydrops | --/-- (4 genes deleted) | Hb Barts (γ4) | Hydrops fetalis, fatal |
| Beta-thal minor | β/β+ or β/β0 | ↑HbA2 (>3.5%), ↑HbF | Asymptomatic microcytic anemia |
| Beta-thal intermedia | β+/β+ (mild) | ↑HbF, variable HbA | Symptomatic, occasional transfusions |
| Beta-thal major | β0/β0 | Mostly HbF, no HbA | Transfusion-dependent from infancy |
Treatment
First-line
- Thalassemia minor/trait: no treatment; genetic counseling regarding partner carrier status and prenatal options
- Thalassemia intermedia: folic acid 1 mg daily, transfuse for growth failure, intercurrent illness, symptomatic anemia
- Thalassemia major: chronic transfusion every 2-4 weeks targeting pretransfusion Hb 9-10 g/dL to suppress endogenous erythropoiesis and prevent skeletal/extramedullary complications
- Iron chelation once ferritin >1000 ng/mL or 10-20 transfusions: deferasirox (oral once daily), deferiprone (oral TID), deferoxamine (SC/IV infusion)
- Splenectomy for hypersplenism with high transfusion requirement (with prior vaccination)
- Genetic counseling and prenatal diagnosis (chorionic villus sampling, amniocentesis, preimplantation genetic testing)
Second-line / adjunct
- Luspatercept — TGF-beta ligand trap; reduces transfusion requirement in beta-thalassemia (BELIEVE trial)
- Allogeneic HSCT — potentially curative; best results in children with matched sibling donors before iron overload
- Gene therapy — betibeglogene autotemcel (beti-cel) and exa-cel approved for transfusion-dependent beta-thalassemia
- Hydroxyurea — modest HbF induction in selected thalassemia intermedia patients
Complications
- Iron overload (cardiac, hepatic, endocrine) — leading cause of mortality without chelation
- Cardiomyopathy, arrhythmia, heart failure
- Endocrinopathies: hypogonadism, hypothyroidism, hypoparathyroidism, diabetes, growth failure
- Hepatic fibrosis, cirrhosis, hepatocellular carcinoma
- Skeletal deformity, osteoporosis, pathologic fracture
- Hypersplenism with worsening anemia and thrombocytopenia
- Alloimmunization, transfusion-transmitted infection (historic)
- Pulmonary hypertension (especially post-splenectomy thalassemia intermedia)
PANCE pearls
- Thalassemia trait shows microcytosis OUT OF PROPORTION to mild anemia, with normal RDW — contrast with iron deficiency where RDW is high and microcytosis tracks with anemia severity.
- Mentzer index = MCV/RBC: <13 suggests thalassemia, >13 suggests iron deficiency. Useful but imperfect.
- Elevated HbA2 (>3.5%) on electrophoresis is diagnostic for beta-thalassemia minor.
- Alpha-thalassemia trait often has NORMAL hemoglobin electrophoresis — diagnosis is by exclusion plus genetic testing.
- Hb Barts hydrops fetalis (no alpha genes) causes severe intrauterine anemia and hydrops; incompatible with life without intrauterine transfusion and stem cell rescue.
- Crew-cut/hair-on-end skull X-ray reflects marrow expansion in severe untreated beta-thalassemia major.
- Iron chelation is the most important intervention reducing mortality in chronically transfused thalassemia patients.
References
- TIF 2021 — Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia (4th edition)
- BSH 2016 — Significant haemoglobinopathies: guidelines for screening and diagnosis (Ryan et al., Br J Haematol)
- BELIEVE Trial — Luspatercept in Patients with Transfusion-Dependent β-Thalassemia (Cappellini et al., NEJM 2020)
- Locatelli et al. — Exagamglogene autotemcel for Transfusion-Dependent β-Thalassemia (NEJM 2024)
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