THALASSEMIA

Herbert L. Muncie, Jr., MD • Garland Edward Anderson, II, MD

 BASICS

DESCRIPTION

•  A group of inherited hematologic disorders that affect the synthesis of adult hemoglobin tetramer (HbA) (1,2)[C]

•  α-Thalassemia is due to a deficient synthesis of α-globin chain, whereas β-thalassemia is due to a deficient synthesis of β-globin chain:

–  The synthesis of the unaffected globin chain proceeds normally.

–  This unbalanced globin chain production causes unstable hemoglobin tetramers, which leads to hypochromic, microcytic RBCs, and hemolytic anemia.

•  α-Thalassemia is more common in persons of Mediterranean, African, and Southeast Asian descent, whereas β-thalassemia is more common in patients of African and Southeast Asian descent.

•  Types

–  Thalassemia (minor) trait (α or β): absent or mild anemia with microcytosis and hypochromia

–  α-Thalassemia major with hemoglobin Barts usually results in fatal hydrops fetalis (fluid in ≥2 fetal compartments secondary to anemia and fetal heart failure).

–  α-Thalassemia intermedia with hemoglobin H (hemoglobin H disease): results in moderate hemolytic anemia and splenomegaly

–  β-Thalassemia major: results in severe anemia, growth retardation, hepatosplenomegaly, bone marrow expansion, and bone deformities. Transfusion therapy is necessary to sustain life.

–  β-Thalassemia intermedia: Milder disease; transfusion therapy may not be needed or may be needed later in life.

•  Other variants include hemoglobin E/β-thalassemia in Southeast Asians, which often mimics the severity of α-thalassemia major; delta thalassemia; hemoglobin H Constant Spring.

•  System(s) affected: hematologic/lymphatic/immunologic, cardiac, hepatic

•  Synonym(s): Mediterranean anemia; hereditary leptocytosis; Cooley anemia

Pediatric Considerations

•  β-Thalassemia major causes symptoms during early childhood, usually starting at 6 months of age, and requires periodic transfusions to sustain life.

•  Newborn’s cord blood or heel stick should be screened for hemoglobinopathies with hemoglobin electrophoresis or comparably accurate test, although this primarily detects sickle cell disease.

Pregnancy Considerations

•  Preconception genetic counseling is advised for couples at risk for having a child with thalassemia and for parents or other relatives of a child with thalassemia (3)[A].

•  Once pregnant, a chorionic villus sample at 10 to 11 weeks’ gestation or an amniocentesis at 15 weeks’ gestation can be done to detect point mutations or deletions with polymerase chain reaction (PCR) technology.

EPIDEMIOLOGY

Incidence

•  Occurs in ∼4.4/10,000 live births

•  Predominant age: Symptoms start to appear 6 months after birth with β-thalassemia major.

•  Predominant sex: male = female

Prevalence

•  Worldwide, ∼200,000 people are alive with β-thalassemia major and <1,000 patients are in the United States.

•  In the worldwide population, an estimated 1.5% are β-thalassemia carriers and 5% α-thalassemia carriers (4).

ETIOLOGY AND PATHOPHYSIOLOGY

Unknown; it is unclear how the imbalance of β-globulin in α-thalassemia and α-globin in β-thalassemia results in ineffective red blood cell genesis and hemolysis.

Genetics

•  Inherited in an autosomal recessive pattern.

•  α-Thalassemia results from a deletion of ≥1 of the 4 genes, 2 on each chromosome 16, responsible for α-globin synthesis. 1-gene deletion is a silent carrier state, 2-gene deletion is the trait, 3-gene deletion results in hemoglobin H, and 4-gene deletion results in hemoglobin Bart, causing fatal hydrops fetalis.

•  Nondeletional forms do occur rarely. Hemoglobin H Constant Spring is the most common nondeletional form.

•  β-Thalassemia is caused by any of >200-point mutations and, very rarely, deletions on chromosome 11; 20 alleles account for >80% of the mutations.

•  Significantly disparate phenotype with the same genotype occurs because β-globin chain production can range from near-normal to absent.

RISK FACTORS

Family history of thalassemia

GENERAL PREVENTION

•  Prenatal information: genetic counseling regarding partner selection and information on the availability of diagnostic tests during the pregnancy

•  Complication prevention

–  For offspring of adult thalassemia patients, an evaluation for thalassemia by 1 year of age

–  Severe forms

  Avoid exposure to sick contacts.

  Keep immunizations up to date.

–  Promptly treat bacterial infections. (After splenectomy, patients should maintain a supply of an appropriate antibiotic to take at the onset of symptoms of a bacterial infection.)

–  Dental checkups every 6 months

–  Avoid activities that could increase the risk of bone fractures.

COMMONLY ASSOCIATED CONDITIONS

See “Complications.”

 DIAGNOSIS

Thalassemia (minor) trait has no signs or symptoms.

HISTORY

•  Poor growth

•  Excessive fatigue

•  Cholelithiasis

•  Pathologic fractures

•  Shortness of breath

PHYSICAL EXAM

•  Pallor

•  Splenomegaly

•  Jaundice

•  Maxillary hyperplasia/frontal bossing due to massive bone marrow expansion

•  Dental malocclusion

DIFFERENTIAL DIAGNOSIS

•  Iron deficiency anemia

•  Other microcytic anemias: lead toxicity, sideroblastic

•  Other hemolytic anemias

•  Other hemoglobinopathies

DIAGNOSTIC TESTS & INTERPRETATION

Special tests

•  Bone marrow aspiration to evaluate for causes of microcytic anemia is rarely needed.

•  Multiple indices have been evaluated to discriminate β-thalassemia trait from iron deficiency anemia, yet none is sensitive enough to exclude β-thalassemia.

•  Hemoglobin: usual range 10 to 12 g/dL with thalassemia trait and 3 to 8 g/dL with β-thalassemia major before transfusions.

•  Hematocrit

–  28–40% in thalassemia trait

–  May fall to <10% in β-thalassemia major

•  Peripheral blood

–  Microcytosis (MCV <70 fl)

–  Hypochromia (MCH <20 pg)

–  High percentage of target cells

–  Reticulocyte count is elevated.

•  Red cell distribution width (RDW)

–  A normal RDW with a microcytic hypochromic anemia is almost always thalassemia trait.

–  The RDW can be elevated in ∼50% of thalassemia trait patients. This is in contrast to iron deficiency anemia, where the RDW is almost always elevated (90%).

•  Hemoglobin electrophoresis

–  In α-thalassemia trait, no recognizable electrophoretic pattern occurs in adults.

–  However, in the neonatal period, 3–10% of trait patients will have hemoglobin H or hemoglobin Bart at birth, which would confirm α-thalassemia.

–  If HbA₂ is below normal (<2.5%) with a normal HbF level, the diagnosis is α-thalassemia intermedia (HbH disease).

–  In the neonatal period with β-thalassemia trait, the electrophoresis is normal. However, in adults, elevated HbA₂ levels (>4%) may be present but are usually normal (5)[C].

–  β-Thalassemia major or intermedia has elevated HbA₂, elevated HbF, and reduced or absent HbA.

•  DNA analysis

–  α-Thalassemia can definitively be diagnosed with genetic testing of hemoglobin A1 and A2 (for deletions and point mutations), but this is not routinely done due to the high cost.

–  High-performance liquid chromatography

–  Cost-effective primary screening tool for children and adolescents (6)[C]

–  Equivocal results should be confirmed with DNA analysis.

Pediatric Considerations

For children, calculate Mentzer index (mean corpuscular volume/RBC count).

•  <13: suggests thalassemia

•  >13: suggests iron deficiency anemia

•  Liver iron concentrations can be assessed with MRI (FerriScan).

 TREATMENT

•  Outpatient for mild cases

•  Inpatient for transfusion therapy

GENERAL MEASURES

•  Mild cases (trait or minor) require no therapy.

•  Thalassemia intermedia: No therapy is necessary unless hemoglobin falls to a level that causes symptoms; then transfusion therapy is needed. Decision is based on patient’s quality of life.

•  Iron supplements should not be given unless iron deficiency occurs and is confirmed with low ferritin. Supplements increase the risk of iron overload.

•  Thalassemia major

–  A regular transfusion schedule to increase posttransfusion hemoglobin to 13.0 to 14.0 g/L and maintain a mean hemoglobin level of at least 9.3 g/dL (1.4 mmol/L)

–  Patients require >8 transfusion events per year. An event may be multiple transfused units.

–  Iron overload (7)[C]

  Patients receiving transfusion therapy increase total body iron 4 times the normal amount.

  Therapy is iron chelation. (See “Medication.”)

MEDICATION

Thalassemia intermedia and major: folic acid supplements (1 mg/day)

First Line

β-Thalassemia major

•  Iron chelation with deferoxamine (Desferal)

–  Usually continuous SC or IV infusion

–  Acute toxicity: initial—1,000 mg IV, may be followed by 500 mg every 4 hours for 2 doses; subsequent doses of 500 mg every 4 to 12 hours based on response (max 6,000 mg/day)

–  Chronic: 20 to 40 mg/kg over 8 to 12 hours daily

–  Usually started by 5 to 8 years of age

–  Treatment lasts 3 to 5 years to reach serum ferritin <1,000 ng/mL.

•  Deferasirox (Exjade): 20 to 30 mg/kg/day PO acceptable alternative; approved for transfusion and non–transfussion-dependent patients with hepatic iron concentrations ≥5 mg/g of dry weight and serum ferritin >300 μg/L; renal and hepatic monitoring is recommended.

Second Line

Chelation with deferiprone (Ferriprox) 25 mg/kg TID PO initially is an acceptable alternative for patients who have not responded to deferoxamine; may provide more cardioprotection. A drawback is weekly CBC because ∼1% of patients develop agranulocytosis.

ISSUES FOR REFERRAL

Thalassemia major usually requires hematology consult.

ADDITIONAL THERAPIES

β-Thalassemia intermedia

•  Hydroxyurea may improve hemoglobin 1 to 2 g/dL.

•  Psychological support seems appropriate for this chronic disease. However, no conclusions can be made regarding specific psychological therapies.

SURGERY/OTHER PROCEDURES

•  Splenectomy

–  May be needed if hypersplenism causes an increase in the transfusion requirements (>180 to 200 mL/kg/year) (8)[C]

–  Defer surgery until patient is at least 4 years of age (due to increased infection risk).

–  Administer pneumococcal polyvalent-23 vaccine 1 month before splenectomy. Children should complete their pneumococcal conjugate vaccine series before surgery.

–  Daily penicillin prophylaxis, 250 mg BID, after splenectomy for 2 years for all patients and for children until age 16 years.

•  Bone marrow transplantation with HLA-identical related donor stem cells in children before developing hepatitis or iron overload has high likelihood of remission but may impair fertility.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  Thalassemia trait requires no restrictions.

•  β-Thalassemia major

–  Avoid strenuous activities (e.g., football, soccer).

–  Acceptable activity levels will be determined on an individual basis depending on the severity of the disorder.

Patient Monitoring

•  Thalassemia-trait patients require no special follow-up.

•  For β-thalassemia major, lifelong monitoring is necessary because the therapy and disease progression have numerous potential complications.

DIET

•  Thalassemia trait requires no restrictions.

•  β-Thalassemia major

–  Limit intake of iron-rich foods (e.g., red meats such as liver and some cereals).

PATIENT EDUCATION

Printed patient information available from Cooley Anemia Foundation, 330 7th Ave. Suite 900, New York, NY 10001; http://www.thalassemia.org or http://www.cooleysanemia.org

PROGNOSIS

•  Outlook varies depending on type.

•  Thalassemia-trait patients live a normal lifespan.

•  β-Thalassemia major patients live an average of 17 years and usually die by age 30 years.

•  Iron overload causes most of the morbidity and mortality:

–  Cardiac events are the primary cause of death.

–  Myocardial iron deposition is best assessed with MRI T2 (9)[C].

–  Effective iron chelation improves longevity.

COMPLICATIONS

•  Chronic hemolysis

•  Susceptibility to infections after splenectomy

•  Infections from blood transfusion

•  Jaundice

•  Leg ulcers

•  Cholelithiasis

•  Osteoporosis and low-trauma fractures

•  Impaired growth rate

•  Delayed or absent puberty

•  Hypogonadism

•  Hepatic siderosis

•  Splenomegaly

•  Cardiac disease from iron overload

•  Thromboembolic phenomenon

•  Aplastic and megaloblastic crises

•  Increased risk of hematologic and abdominal cancer (10)

•  Increased risk of dementia (11)

REFERENCES

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

  2.  Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012;379(9813):373–383.

  3.  Tamhankar PM, Agarwal S, Arya V, et al. Prevention of homozygous beta thalassemia by premarital screening and prenatal diagnosis in India. Prenat Diagn. 2009;29(1):83–88.

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

  5.  Mosca A, Paleari R, Ivaldi G, et al. The role of haemoglobin A(2) testing in the diagnosis of thalassaemias and related haemoglobinopathies. J Clin Pathol. 2009;62(1):13–17.

  6.  Abdel-Messih IY, Youssef SR, Mokhtar GM, et al. Clinical to molecular screening paradigm for β-thalassemia carriers. Hemoglobin. 2015;39(4):240–246.

  7.  Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med. 2012;366(4):348–359.

  8.  Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.

  9.  Pennell DJ, Udelson JE, Arai AE, et al. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013;128(3):281–308.

10.  Chung WS, Lin CL, et al. Thalassaemia and risk of cancer: a population-based cohort study. J Epidemiol Community Health. 2015;69(11):1066–1070.

11.  Chen YG, Lin TY, Chen HJ, et al. Thalassemia and risk of dementia: a nationwide population-based retrospective cohort study. Eur J Intern Med. 2015;26(7):554–559.

ADDITIONAL READING

•  Paulson RF. Targeting a new regulator of erythropoiesis to alleviate anemia. Nat Med. 2014;20(4):334–335.

•  Piel FB, Weatherall DJ. The α-thalassemias. N Engl J Med. 2014;371(20):1908–1916.

 CODES

ICD10

•  D56.9 Thalassemia, unspecified

•  D56.1 Beta thalassemia

•  D56.0 Alpha thalassemia

CLINICAL PEARLS

•  Thalassemia (group of inherited hematologic disorders that affect the synthesis of adult hemoglobin tetramer) is a genetic condition; hemoglobin will not improve over time.

•  α-Thalassemia is due to a deficient synthesis of the α-globin chain, whereas β-thalassemia is due to a deficient synthesis of the β-globin chain.

•  Hemoglobin electrophoresis is needed for genetic counseling but not to make the diagnosis of thalassemia minor when evaluating a patient with mild hypochromic, microcytic anemia, and normal serum ferritin.

•  Anemia from thalassemia minor is not due to inadequate iron availability or iron storage. Therefore, iron supplements will not improve the anemia and could be harmful due to GI distress and iron overload. If coexisting iron deficiency is proven, then iron therapy is appropriate.