Thalassemia

Thalassemias are a group of hereditary hemoglobin disorders characterized by mutations on the α- or β-globin chains (resulting in alpha or beta thalassemia). Thalassemias can be further classified according to the specific genotype: the α-chain is coded by four alleles, resulting in four possible variants depending on the number of alleles affected, while the β-chain is coded by two alleles, resulting in two possible variants. The number of alleles affected is directly related to the severity of the disease (minor/intermedia/major). Thalassemia mutations are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in individuals of Asian or African descent, whereas beta thalassemias are predominant in individuals of Mediterranean descent. The key feature in all forms of thalassemia is microcytic hypochromic anemia (which may be very mild in minor forms), but more severe forms may also manifest with hemolysis, splenomegaly, delay in growth and development, and skeletal deformities. The diagnostic workup for suspected thalassemia includes a blood smear, hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), and, possibly, genetic testing. Minor forms of thalassemia usually require no treatment, while patients with thalassemia intermedia/major typically require regular blood transfusions and management of disease and treatment-related complications (e.g., chelating agent for transfusion-mediated iron overload).

• Beta thalassemia: most commonly seen in people of Mediterranean descent
• Alpha thalassemia: most commonly seen in people of Asian and African descent
• Thalassemia provides partial resistance against malaria.

Alpha thalassemia is common in Asia and Africa.

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

General

• Cause: gene mutations
  • Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites
    • β-globin locus - short arm of chromosome 11
  • Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles
    • The α-globin gene cluster is located on chromosome 16
• Inheritance pattern: autosomal recessive

Beta thalassemia

In a normal cell, the β-globin chains are coded by a total of two alleles. Thus, there are two main forms of the disease.

• Beta thalassemia minor (trait): one defective allele
• Beta thalassemia major (Cooley anemia): two defective alleles
• Sickle cell beta thalassemia: a combination of one defective β-globin allele and one defective HbS allele
• Hemoglobin E/beta thalassemia: a combination of one allele with a hemoglobin E (HbE) variant and one defective β-globin allele. Produces a highly heterogeneous clinical spectrum, and in severe cases patients present with features of beta thalassemia major. ^[3]
• Hemoglobin E disease: a condition characterized by homozygosity to the HbE variant. Patients can present with mild features resembling beta thalassemia minor (i.e., mild anemia).

Alpha thalassemia

In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.

• Silent carrier (minima form): one defective allele (-α/αα)
• Alpha thalassemia trait (minor form)
  • Two defective alleles (-α/-α or --/αα)
  • Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
  • Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.
• Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH
• Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers))

References:^{[4][5][6][7][8]}

Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype.

• Inefficient erythropoiesis → anemia
  • Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
    • HbF protects infants up to the age of 6 months, after which HbF production declines and symptoms of anemia appear.
  • Alpha thalassemia intermedia (HbH disease) and alpha thalassemia major (Bart disease): faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart's
  • In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.
• Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
• Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities

References:^[9][10][11]

Beta thalassemia

• Minor variant: unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)
• Major variant
  • Severe hemolytic anemia that often requires transfusions; → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
  • Hepatosplenomegaly
  • Growth retardation
  • Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)
  • Transient aplastic crisis (secondary to infection with parvovirus B19)
• Sickle cell beta thalassemia
  • Features of sickle cell disease
  • Severity depends on the amount of β-globin synthesis.

Alpha thalassemia

• Silent carrier: asymptomatic
• Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW
• Hemoglobin H disease
  • Jaundice and anemia at birth
  • Chronic hemolytic anemia that may require transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
  • Hepatosplenomegaly
  • Skeletal deformities (less common)
  • Compared to thalassemia beta, symptoms in adults are generally less severe.
• Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia)
  • Intrauterine ascites and hydrops fetalis; , severe hepatosplenomegaly, and often cardiac and skeletal anomalies
  • Incompatible with life (death in utero or shortly after birth)

References:^{[1][2][12][13]}

The presentation of thalassemia is highly variable, ranging from incidental findings to life-threatening forms.Thalassemia is more like to be diagnosed in patients with the following:

Family history plays an important role in diagnosing patients with clinically silent thalassemia. Consider the possibility of minor forms/traits if a family member is diagnosed with a more severe form.

Initial investigations ^[14][15]

• CBC
  • Characteristic finding: microcytic hypochromic anemia (i.e., MCV < 80, MCH < 27) present regardless of Hb level
  • Hb levels: variable depending on the subtype
  • Other red cell indices
    • Normal RDW ^[16]
    • Higher RBC count than iron deficiency anemia
  • See also “Diagnostics of anemia” for further evaluation of microcytosis.
• Hemolysis evaluation: nonimmune-mediated hemolytic anemia
  • Coombs test: negative
  • ↓ Haptoglobin, ↑ LDH, ↑ reticulocytes
  • Liver chemistries: hyperbilirubinemia (indirect)
  • Iron studies (particularly ferritin) : expected to be normal in thalassemia
• Peripheral blood smear findings include:
  • HbH inclusion bodies
  • Target cells
  • Teardrop cells
  • Anisopoikilocytosis
  • Erythroblasts

CBC parameters can help differentiate thalassemia minor/trait from iron deficiency anemia. IDA is frequently associated with a high RDW, low RBC count, and low MCV typically occurring once the Hb is < 10 g/dL. In thalassemia, microcytosis is always present regardless of the Hb level, the RDW is typically normal, and compared to IDA, the RBC count is higher and the MCV is lower. ^[16]

Low ferritin suggests iron deficiency anemia and patients should receive iron supplementation. Suspect thalassemia if there is no significant response after three months. ^[14][15]

Confirmatory diagnostic studies ^[14][15]

• Detection of hemoglobin variants
  • Hb-electrophoresis (qualitative analysis)
  • Automated HPLC (qualitative and quantitative analysis)
  • Findings (vary depending on the subtype)
    • Hemoglobin A (and subtypes): hemoglobin A2 values are helpful to determine the diagnosis (i.e., to distinguish alpha from beta thalassemia)
    • Hemoglobin F: may be elevated in some children and adults with thalassemia
    • See “Hemoglobin variants” for findings of other hemoglobinopathies.

• Genetic studies (PCR-based): to determine specific diagnosis and mutations
• Bone marrow aspiration (not routinely indicated)
  • Usually performed to rule out other hematologic conditions
  • Findings in thalassemia are nonspecific (e.g., reactive hyperplasia).

Beta thalassemia minor should be strongly suspected if HbA2 is > 3.5%. ^[17]

Imaging

• Skull x-ray (AP and lateral)
  • Indication: assessment of craniofacial abnormalities
  • Findings include:
    • High forehead
    • Prominent zygomatic bones and maxilla (referred to as “chipmunk facies”)
    • Hair-on-end (also known as “crew cut”) sign
• CXR
  • Indication: suspected extramedullary hematopoiesis in the thorax
  • Findings include:
    • Mediastinal or pulmonary masses
    • Subperiosteal extension in the ribs (also known as “rib within a rib”)
• MRI spine: helpful to evaluate mass effect symptoms due to extramedullary hematopoietic pseudotumors

• All patients
  • Patient education and genetic counseling.
  • Screening tests for relatives
• Thalassemia minor
  • Usually no treatment required
  • Episodic folic acid supplementation may be indicated (e.g., during pregnancy, acute infections)
• Thalassemia major and intermedia
  • Transfusion therapy (erythrocyte concentrates)
    • Indication (for transfusion-dependent thalassemias): Hb < 7 g/dL or marked clinical symptoms
    • Target: Hb > 9–10 g/dL
  • Surveillance and treatment of complications
    • Iron overload diseases: chelating agents, e.g., deferasirox, indicated when iron accumulation reaches toxic levels
    • Other complications: e.g., gallstones, asplenia, extramedullary hematopoietic pseudotumors
• Select patients
  • Splenectomy
  • Potentially curative treatment
    • Stem cell transplantation: allogenic HSCT
    • Gene therapy

References: ^[14][15]

Transfusion therapy ^[14][15][19]

This is the mainstay of management for thalassemia major and intermedia (see “Transfusion” for more information about pretransfusion testing and transfusion reactions).

• Transfusion dependency: can fluctuate for individual patients depending on the subtype, severity, and external factors.
• Non-transfusion-dependent patients: only require either occasional or short-term regular blood transfusions for acute needs.
• Transfusion-dependent patients: require lifelong regular transfusions (e.g., every 2–5 weeks).

Additional therapies

• Folic acid should be considered in patients with: ^[19]
  • Thalassemia major or intermedia: regular supplementation
  • Thalassemia minor during periods of acute physiological stress (e.g., infections): episodic supplementation
• Fetal hemoglobin induction: hydroxyurea may help induce fetal hemoglobin, reducing symptoms and the need for transfusions

Splenectomy ^[14][15]

• Limited use: risks may outweigh benefits (see “Asplenia”).
• Indications include:
  • Hypersplenism causing recurrent infections or bleeding
  • Clinically significant splenomegaly
    • Symptomatic (e.g., abdominal pain)
    • Massive splenomegaly (> 20 cm) at risk of splenic rupture
  • Uncontrollable iron overload disease
  • Uncontrollable anemia affecting growth and development
• Post-operative care: See “Management of asplenic patients.”

Avoid splenectomy in patients < 5 years old due to the risk of overwhelming postsplenectomy sepsis.

All patients receiving transfusion therapy should be periodically evaluated for iron overload disease and subsequent organ damage. ^[14][15][17]

• Clinical features of iron overload diseases: e.g., bronze skin, growth delay, signs of organ damage
• Diagnosis of iron overload diseases
  • Liver biopsy (gold standard test)
  • MRI (noninvasive alternate test)
• General monitoring: serum ferritin
• Monitoring for organ damage
  • Endocrinopathies: Screen patients for the following conditions and refer to endocrinology as needed.
    • DM
    • Hypothyroidism/hypoparathyroidism
    • Hypogonadism
    • Osteoporosis
  • Liver cirrhosis and hepatocarcinoma: liver chemistries (every 3 months) and MRI (annually)
  • Cardiac siderosis: regular imaging (echocardiogram or MRI) ^[15][20]
• Treatment: Chelation therapy is typically recommended when iron accumulates to toxic levels and may be required from a very early age. ^[14][15][17]
  • Deferasirox (first-line)
  • Deferoxamine
  • Deferiprone

Iron overload can seriously affect the liver and cardiac function, as well as several endocrine glands, and is potentially lethal in the long term. Once organ damage occurs, it is often irreversible.

The objective of chelation therapy is to prevent organ damage resulting from iron overload disease and requires good adherence to treatment, continuous monitoring by specialists, and frequent dosing adjustment.

In addition to iron overload disease, patients may develop other long-term complications secondary to the disease or its treatment.

HSCT can have good outcomes and be considered curative, however, its use is limited due to high mortality and morbidity. Specialist evaluation and shared decision-making (involving patients and/or surrogate decision-makers) are essential and should weigh each patient's individual risks and benefits. ^[15]

• Modalities
  • Compatible sibling donor (preferred): most successful alternative; mortality rate of ∼ 5%
  • Matched unrelated donor (alternative): can be considered; higher chances of rejection
• Limitations
  • Requires the availability of a compatible donor and access to an HSCT specialized center
  • Must be performed during early childhood, before iron overload is present (which decreases success) ^[15]
  • Aggressive pretransplant myeloablation → ↑ transfusion requirement → ↑ risk of iron overload disease
  • Posttransplant immunosuppression → ↑ infection risk

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