Basics
Description
- Thalassemia syndromes are hereditary microcytic anemias that result from mutations that quantitatively reduce globin synthesis.
- Normal hemoglobin is a tetramer of 2α and 2 ² chains:
- α-Thalassemia: reduced or absentα-globin production
- ²-Thalassemia: reduced or absent ²-globin production
General Prevention
Thalassemia can be prevented by identifying and counseling potential parents who can have children with thalassemia. Diagnosis can be made in early pregnancy by chorionic villus sampling.
Epidemiology
- α-Thalassemia: predominantly in Chinese subcontinent, Malaysia, Indochina, and Africa and in African Americans
- ²-Thalassemia: Mediterranean countries, Africa, India, Pakistan, Middle East, and China
Genetics
- α-Thalassemia
- Normally, there are 4α-globin genes, 2 on each chromosome 16.
- Most mutations inα-thalassemia are large deletions.
- Deletions may be in trans conformation (1 deletion on each chromosome, common in African Americans) or cis conformation (2 genes deleted on same chromosome, common in Asians).
- Hemoglobin Constant Spring is anα-globin gene mutation caused by a point mutation that reduces or eliminates production ofα-globin, leading to a more severe phenotype.
- The 4α-thalassemia syndromes reflect the inheritance of molecular defects affecting the output of 1, 2, 3, or 4α genes.
- ²-Thalassemia
- Normally, there are 2 ²-globin genes, 1 on each chromosome 11.
- Most mutations in ²-thalassemia are point mutations.
- Many mutations abolish the expression completely ( ²0), whereas others variably decrease quantitative expression ( ²+).
- Heterozygous state for ²-globin mutation produces ²-thalassemia trait.
- Homozygous state produces ²-thalassemia major or ²-thalassemia intermedia.
- NOTE: Rare dominant ²-thalassemia mutations exist, causing ineffective erythropoiesis with a single mutation (due to creation of unstable ²-globin variants).
View LargeGenotypeNameDegree of anemiaα-thalassemiaαα /α ’ Silent carrierAsymptomaticα ’ /α ’ orαα/ ’ ’ α-thalassemia traitAsymptomaticα ’ / ’ ’ α-thalassemia intermedia, HbH diseaseModerate to severe ’ ’ / ’ ’ α-thalassemia majorHydrops fetalis ²-thalassemia ²/ ²+ or ²/ ²0 ²-thalassemia traitAsymptomatic ²/ ²0 or ²+/ ²+ ²-thalassemia intermediaVariable, intermittent, or chronic transfusions ²0/ ²+ or ²0/ ²0 ²-thalassemia majorSevere, chronic transfusions
Pathophysiology
- Decrease in eitherα- or ²-globin synthesis leads to fewer completedα2 " ²2 tetramers produced per RBC, which results in a decrease in intracellular hemoglobin and microcytosis.
- Unpaired globin chains precipitate, resulting in apoptosis of red cell precursors (ineffective erythropoiesis) and damage to the RBC membrane leading to hemolysis.
- Ineffective erythropoiesis causes hepatosplenomegaly and osseous changes.
- The erythrocyte 's lifespan is shortened by hemolysis and splenic trapping.
- Degree of anemia varies depending on the specific gene defect.
- Chronic transfusion therapy and, to a lesser degree, increased absorption of dietary iron in thalassemia major lead to iron accumulation.
- Increased absorption of dietary iron and intermittent transfusions in thalassemia intermedia lead to iron accumulation.
- Iron overload leads to cardiac arrhythmias and congestive heart failure (CHF) that can be fatal, liver inflammation and fibrosis, and endocrinopathies (e.g., diabetes mellitus, hypothyroidism, gonadal failure, osteoporosis).
Diagnosis
History
- Severeα-thalassemia (4 gene deletion) presents prenatally by ultrasound or at birth with hydrops fetalis and severe anemia.
- Severe ²-thalassemia usually presents between 3 and 12 months old, as production of the normal fetal hemoglobin decreases.
- α-Thalassemia syndromes will present with microcytosis in infancy. Hemoglobin H disease may present later, with mild to moderate anemia on screening or after worsening hemolysis related to intercurrent infection.
- Mediterranean, African, or Asian ethnic backgrounds are common in patients with thalassemia.
- Familial history of anemia, long-term transfusions, recurrent iron therapy for presumed iron deficiency anemia, or splenectomy
- Newborn screening varies by state but can contribute to a presumptive diagnosis ofα-thalassemia or ²-thalassemia major. Abnormal patterns include presence of Hb Barts (consistent withα-thalassemia) or isolated HbF (consistent with ²-thalassemia major). Extreme prematurity and previous blood transfusions can obscure results, and confirmatory testing is required.
Physical Exam
- Pallor indicates anemia.
- Heart murmur: Flow murmurs are often heard in significant anemia. Patients with severe anemia may present with CHF.
- Variable degrees of icterus: Hemolysis leads to increased bilirubin production.
- Abnormal facies (frontal bossing and maxillary hyperplasia): facial bone expansion by hypertrophic marrow in poorly transfused patients with ²-thalassemia
- Failure to thrive: Related to anemia and energy expended in ineffective erythropoiesis
- Variable degrees of hepatosplenomegaly (or CHF) due to extramedullary hematopoiesis
Diagnostic Tests & Interpretation
Lab
- CBC with RBC indices
- Mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) are all decreased inα- and ²-thalassemia.
- RBC volume distribution width (RDW) is usually normal.
- Peripheral smear may reveal microcytosis, hypochromia, anisocytosis, poikilocytosis, target cells, nucleated RBCs, and/or polychromasia.
- Hemoglobin 9 " 12 g/dL inα- or ²-thalassemia trait
- Hemoglobin usually 7 " 10 g/dL in HbH disease
- Hemoglobin usually 7 " 10 g/dL in ²-thalassemia intermedia
- Hemoglobin <7 g/dL in thalassemia major (without transfusions)
- Reticulocyte count: usually mildly elevated in HbH and ²-thalassemia intermedia and major
- Indirect bilirubin: may be elevated in severe thalassemia where there is significant red cell destruction
- Hemoglobin electrophoresis
- α-Thalassemia trait (2 defective genes) will have 5 " 10% Hb Barts (a tetramer of 4 ³ chains) at birth, which should be detected on the newborn 's screen. This disappears in 1 " 2 months, after which time the electrophoresis will be normal inα-thalassemia trait.
- ²-Thalassemia trait: HbF 1 " 5%, HbA2 3.5 " 8%, remainder HbA. The elevated HbA2 will distinguishα- from ²-thalassemia trait.
- HbH disease (3 defectiveα genes): 5 " 30% HbH ( ²4), remainder HbA
- Hydrops fetalis (4 defectiveα genes): mainly Hb Barts( ³4)
- ²-Thalassemia major (2 defective ² genes): HbF 20 " 100%, HbA2 2 " 7%. In most cases, little or no HbA is detected, unless recently transfused.
- Iron studies, serum ferritin: useful to help distinguish thalassemia from iron deficiency
- Mentzer Index: MCV/RBC <13 is more likely thalassemia, >13 more likely iron deficiency
Differential Diagnosis
- Iron deficiency anemia can be distinguished with iron studies.
- Anemia of chronic inflammation (can be distinguished with soluble transferrin receptor assay)
- Lead poisoning
Treatment
- Silent carriers (singleα gene deletion) andα-and ²-thalassemia trait
- Genetic counseling only
- Distinguish from iron deficiency microcytosis to avoid excess iron supplementation
- For HbH disease:
- Folic acid daily
- Transfusions whenever necessary (aplastic episode, infection)
- Splenectomy if with evidence of hypersplenism
- Cholecystectomy if necessary
- For ²-thalassemia intermedia:
- Folic acid daily
- No iron supplements
- Transfusions whenever necessary (aplastic episode, infection, acute complication)
- Splenectomy is less commonly performed due to increased risk of thrombosis and pulmonary hypertension.
- Cholecystectomy if necessary
- HbF-inducing agents such as hydroxyurea may be beneficial.
- Monitoring and treatment of iron overload
- ²-Thalassemia major
- Stem cell transplantation (umbilical cord blood or bone marrow) using histocompatible sibling donor can cure the disease and is being used more frequently.
- Regular transfusions of RBCs every 3 " 4 weeks to maintain hemoglobin at 9 " 10 g/dL
- Chelation therapy: It is important to balance the treatment of iron overload with the dangers of overchelation (toxicity to ears, eyes, bone).
- Chelation options include the following:
- Deferoxamine (SC or IV infusion over 8 " 24 hours)
- Deferasirox (once daily PO chelator). Side effects include GI discomfort, rash, renal failure +/ ’ proteinuria, hepatic failure
- Deferiprone (t.i.d. PO chelator), FDA approved for iron overload in thalassemia syndromes. Especially useful for cardiac iron removal. Side effects include arthropathy, GI upset, and agranulocytosis.
- Folic acid daily
- Penicillin V potassium oral prophylaxis (125 " 250 mg b.i.d.) for splenectomized patients
- Pneumococcus, Meningococcus, and Haemophilus influenzae vaccines before splenectomy and annual influenza A vaccination
- Cholecystectomy if indicated
- No iron supplements
- Genetic counseling for those with any thalassemia syndrome
Alert
Thalassemia trait is often treated incorrectly as presumptive iron deficiency anemia. Iron studies should be performed to confirm the diagnosis if there is no improvement in hemoglobin level after a few weeks of iron therapy.
Ongoing Care
For patients with thalassemia major and intermedia:
- Serum ferritin, blood chemistries, and liver function tests should be monitored.
- Annual monitoring for cardiac complications (echocardiogram, EKG) and endocrine function is recommended.
- Liver iron quantitation by biopsy, MRI, or other techniques are necessary intermittently to quantitate the status of iron overload accurately.
- Newer cardiac T2* MRI techniques to assess the degree of cardiac iron loading, which correlates with risk of cardiac complications.
- Annual audiologic and ophthalmologic screening is recommended for persons receiving chelation therapy (to monitor for chelator toxicity).
- Dual-energy x-ray absorptiometry (DEXA) scan or bone peripheral quantitative computed tomography (PQCT) annually
Prognosis
- Life expectancy for patients with ²-thalassemia major has improved over the years because of regular transfusions and chelation therapy.
- Bone marrow transplant from a histocompatible sibling donor may be curative.
Complications
Most complications occur in patients with ²-thalassemia intermedia or major and can be divided into 2 categories:
- Complications related to anemia/ineffective erythropoiesis and hemolysis (seen mostly in thalassemia intermedia):
- Skeletal abnormalities secondary to hyperplastic marrow
- Osteopenia, osteoporosis, and fractures
- Growth retardation
- Extramedullary hematopoiesis
- Leg ulcers
- CHF owing to severe anemia
- Thrombophilia, particularly in thalassemia intermedia after splenectomy
- Hypercoagulability: DVT, PE
- Gallstones from hemolysis
- Pulmonary hypertension
- Allo- or autoimmunization with RBC antibodies
- Complications of iron overload:
- Cardiac abnormalities: pericarditis, arrhythmias, CHF
- Hepatic abnormalities: cirrhosis and liver failure (onset usually after 2nd decade)
- Endocrine disturbances: delayed puberty, growth retardation, diabetes mellitus, hypothyroidism, hypoparathyroidism
- Infection: particularly Yersinia species
Additional Reading
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012;379(9813):373 " 83. [View Abstract]
- Olivieri NF, Brittenham GM. Management of the thalassemias. Cold Spring Harb Perspect Med. 2013;3(6):a011767. [View Abstract]
- Peters M, Heijboer H, Smiers F, et al. Diagnosis and management of thalassaemia, BMJ. 2012;344:e228. [View Abstract]
- Rachmilewitz EA, Giardina P. How I treat thalassemia. Blood. 2011;118(13):3479 " 3488. [View Abstract]
- Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005;353(11):1135 " 1146. [View Abstract]
Codes
ICD09
- 282.40 Thalassemia, unspecified
- 282.43 Alpha thalassemia
- 282.44 Beta thalassemia
ICD10
- D56.9 Thalassemia, unspecified
- D56.0 Alpha thalassemia
- D56.1 Beta thalassemia
SNOMED
- 40108008 Thalassemia (disorder)
- 68913001 alpha Thalassemia (disorder)
- 65959000 beta Thalassemia (disorder)
- 75451007 Thalassemia major
FAQ
- Q: Is prenatal testing available?
- A: Yes.
- Q: In a transfused patient, when does iron overload become a problem and when is chelation started?
- A: Usually after the age of 3 " 4 years.
- Q: At what age should monitoring for cardiac iron overload begin in ²-thalassemia major?
- A: 6 " 10 years of age.