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Thalassemia

Garland E. Anderson II, MD

BASICS

DESCRIPTION

  • Group of inherited hematologic disorders

  • α-Thalassemia: due to defective α-globin chain

  • β-Thalassemia: due to defective β-globin chain synthesis

  • Unbalanced globin chain production → unstable hemoglobin tetramers → hypochromic, microcytic RBCs, and hemolytic anemia

  • α-Thalassemia: common in Mediterranean, African, Southeast Asian descent

  • β-Thalassemia: common in African and Southeast Asian descent

Types

  • Thalassemia (minor) trait (α or β): absent/mild anemia, microcytosis, hypochromia

  • α-Thalassemia major with hemoglobin Bart: usually fatal hydrops fetalis

  • α-Thalassemia intermedia with hemoglobin H (H disease): moderate hemolytic anemia, splenomegaly

  • β-Thalassemia major: severe anemia, growth retardation, hepatosplenomegaly, bone marrow expansion, deformities; transfusion required for life

  • β-Thalassemia intermedia: milder; transfusions may not be needed or delayed

  • Other: hemoglobin E/β-thalassemia (Southeast Asians), δ-thalassemia, hemoglobin H Constant Spring

Synonyms

  • Mediterranean anemia, hereditary leptocytosis, Cooley anemia

Pediatric Considerations

  • β-Thalassemia major: symptoms during early childhood (from 6 months), requires periodic transfusions

  • Screen newborn's cord blood or heel stick for hemoglobinopathies (hemoglobin electrophoresis)

Pregnancy Considerations

  • Preconception genetic counseling for at-risk couples

  • CVS at 10–11 wks or amniocentesis at 15 wks for detection via PCR

EPIDEMIOLOGY

  • Incidence: ~4.4/10,000 live births

  • Symptoms: start at 6 months (β-thalassemia major)

  • Sex: male = female

  • Prevalence:

    • ~200,000 with β-thalassemia major globally

    • <1,000 in US

    • 1.5% β-thalassemia carriers; 5% α-thalassemia carriers worldwide

ETIOLOGY AND PATHOPHYSIOLOGY

  • Inherited autosomal recessive

  • α-Thalassemia: deletion of ≥1 of 4 α-globin genes (chromosome 16);

    • 1 deletion = silent carrier

    • 2 = trait

    • 3 = H disease

    • 4 = Bart’s/hydrops fetalis

  • Nondeletional forms: rare (e.g., Hemoglobin H Constant Spring)

  • β-Thalassemia: >200 point mutations, rare deletions (chromosome 11); 20 alleles = >80% mutations

  • Degree of globin chain production varies

RISK FACTORS

  • Family history of thalassemia

GENERAL PREVENTION

  • Genetic counseling

  • Prenatal diagnostics

  • Complication prevention (severe forms):

    • Avoid sick contacts

    • Keep immunizations current

    • Promptly treat infections (esp. post-splenectomy: maintain emergency antibiotics)

    • Dental checkup every 6 months

    • Avoid bone fracture risk

DIAGNOSIS

HISTORY

  • Poor growth

  • Excessive fatigue

  • Cholelithiasis

  • Pathologic fractures

  • Shortness of breath

PHYSICAL EXAM

  • Pallor

  • Splenomegaly

  • Jaundice

  • Maxillary hyperplasia/frontal bossing (bone marrow expansion)

  • Dental malocclusion

DIFFERENTIAL DIAGNOSIS

  • Iron deficiency anemia

  • Other microcytic anemias: lead toxicity, sideroblastic

  • Other hemolytic anemias

  • Other hemoglobinopathies

DIAGNOSTIC TESTS & INTERPRETATION

  • Bone marrow aspiration: rarely needed

  • Discriminating indices: not sensitive enough for β-thalassemia exclusion

  • Hemoglobin:

    • Trait: 10–12 g/dL

    • β-thalassemia major (pre-transfusion): 3–8 g/dL

  • Hematocrit:

    • Trait: 28–40%

    • β-thalassemia major: can fall <10%

  • Peripheral blood:

    • Microcytosis (MCV <70)

    • Hypochromia (MCH <20 pg)

    • Target cells

    • Reticulocyte count elevated

    • RDW normal in trait; can be high in 50%

    • Iron deficiency anemia: RDW almost always high (90%)

  • Hemoglobin electrophoresis:

    • α-thalassemia trait: no adult pattern; newborns may show H or Bart

    • β-thalassemia major/intermedia: elevated HbA2, HbF, reduced/absent HbA

  • DNA analysis: detects deletions/point mutations; not routine (cost)

  • High-performance liquid chromatography: cost-effective

  • Mentzer index (children):

    • <13: suggests thalassemia

    • 13: suggests iron deficiency

  • MRI (FerriScan): liver iron assessment

TREATMENT

  • Outpatient for mild

  • Inpatient for transfusion therapy

GENERAL MEASURES

  • Mild (trait/minor): no therapy

  • Thalassemia intermedia: therapy only if symptoms due to low hemoglobin

  • No iron supplements unless iron deficiency proven (risk: overload)

  • Thalassemia major:

    • Regular transfusions (target post-transfusion Hb 13–14 g/L; mean >9.3 g/dL)

    • 8 transfusion events/year

    • Iron overload: therapy = chelation

MEDICATION

  • Folic acid (1 mg/day): intermedia/major

  • Iron chelation:

    • Deferoxamine (Desferal): continuous SC/IV

      • Acute: initial 1,000 mg IV, then 500 mg q4h x2; subsequent doses q4–12h (max 6,000 mg/day)

      • Chronic: 20–40 mg/kg over 8–12h daily; start age 5–8y; 3–5 years to ferritin <1,000 ng/mL

    • Deferasirox (Exjade): 20–30 mg/kg/day PO; approved for transfusion/non-transfusion dependent

      • Monitor renal/hepatic function

    • Deferiprone (Ferriprox): 25 mg/kg TID PO; alternative for deferoxamine nonresponse

      • Weekly CBC (risk agranulocytosis ~1%)

ADDITIONAL THERAPIES

  • β-Thalassemia intermedia:

    • Hydroxyurea (↑Hb 1–2 g/dL)

    • Psychological support

  • Splenectomy:

    • If hypersplenism ↑transfusion needs (>180–200 mL/kg/year)

    • Delay until age ≥4y; increased infection risk

    • Vaccinate with pneumococcal-23 1 month prior; complete conjugate series

    • Penicillin prophylaxis post-splenectomy (2 years/all patients; till 16y in children)

  • Bone marrow transplant: HLA-identical donor in children pre-hepatitis/iron overload; may impair fertility

  • Mitapivat: Small molecule, activates RBC pyruvate kinase; increases Hb (α & β)

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

  • Trait: no restrictions

  • β-Thalassemia major: avoid strenuous activity; individualize acceptable activities

  • Patient monitoring:

    • Trait: no special follow-up

    • β-thalassemia major: lifelong monitoring for therapy/complication risks

DIET

  • Trait: no restrictions

  • β-thalassemia major: limit iron-rich foods (red meats, cereals)

PATIENT EDUCATION

PROGNOSIS

  • Trait: normal lifespan

  • β-thalassemia major: avg. 17 years, usually die by 30

    • Iron overload: most morbidity/mortality (esp. cardiac)

    • MRI T2: best for myocardial iron

COMPLICATIONS

  • Chronic hemolysis

  • Infection risk post-splenectomy

  • Transfusion-related infections

  • Jaundice

  • Leg ulcers

  • Cholelithiasis

  • Osteoporosis/low-trauma fractures

  • Impaired growth

  • Delayed/absent puberty

  • Hypogonadism

  • Hepatic siderosis

  • Splenomegaly

  • Cardiac iron overload/disease

  • Thromboembolism

  • Aplastic/megaloblastic crises

  • ↑ Hematologic/abdominal cancer risk

  • ↑ Dementia risk

REFERENCES

  1. Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am Fam Physician. 2009;80(4):339-344.

  2. Peters M, Heijboer H, Smiers F, et al. Diagnosis and management of thalassaemia. BMJ. 2012;344:e228.

Codes:

  • ICD10: D56.5 Hemoglobin E-beta thalassemia

  • D56.3 Thalassemia minor

  • D56.0 Alpha thalassemia

Clinical Pearls

  • Thalassemia is a genetic condition; hemoglobin will not improve over time

  • α-Thalassemia: defective α-globin; β-thalassemia: defective β-globin

  • Electrophoresis needed for genetic counseling, not required for minor diagnosis with mild anemia/normal ferritin

  • Thalassemia minor anemia is not due to iron deficiency; iron supplements do not help and may cause overload

End of note