How is thalassemia classified based on the affected globin chain and clinical severity?

Classification of Thalassemia

Thalassemia is classified based on two key dimensions: (1) which globin chain is affected (alpha vs. beta) and (2) clinical severity (transfusion-dependent vs. non-transfusion-dependent disease).

Classification by Affected Globin Chain

Beta-Thalassemia

• Beta-thalassemia results from mutations in the HBB gene on chromosome 11, with over 200 pathogenic variants identified, predominantly single-nucleotide substitutions, small deletions, or insertions 1, 2.
• Mutations produce either a β⁺ phenotype (reduced beta-globin synthesis) or a β⁰ phenotype (complete absence of beta-globin) 1.
• The disorder follows an autosomal recessive inheritance pattern, requiring homozygosity or compound heterozygosity for severe disease 1.

Alpha-Thalassemia

• Alpha-thalassemia results from reduced or absent synthesis of alpha-globin chains and is most prevalent among individuals of Southeast Asian ancestry 1, 3.
• Clinical manifestations range from no symptoms to severe transfusion-dependent anemia, depending on the number of alpha-globin genes deleted (humans have four alpha-globin genes) 4.

Classification by Clinical Severity

Beta-Thalassemia Clinical Categories

Beta-Thalassemia Trait (Carrier State)

• Results from heterozygosity for beta-thalassemia and is clinically asymptomatic 5.
• Presents with microcytic, hypochromic anemia (MCV typically <80 fL) that does not improve with iron supplementation 1, 2.
• Defined by specific hematological features without clinical symptoms 5.

Beta-Thalassemia Intermedia

• Encompasses a clinically and genotypically heterogeneous group ranging in severity from the asymptomatic carrier state to severe disease 5.
• Patients do not require regular transfusions to survive 6.

Beta-Thalassemia Major (Transfusion-Dependent)

• Represents severe transfusion-dependent anemia requiring more than 8 red-cell transfusions per year in adults 1, 2.
• Requires lifelong regular red-cell transfusions starting before age 2, accompanied by continuous iron-chelation therapy 1, 2.
• Without therapeutic intervention, becomes life-threatening by the end of the second year of life 1, 2.

Alpha-Thalassemia Clinical Categories

Silent Carrier (One-Gene Deletion)

• Deletion of 1 alpha-globin gene results in no symptoms or minimal hematological changes 4.

Alpha-Thalassemia Trait (Two-Gene Deletion)

• Deletion of 2 alpha-globin genes causes mild microcytic anemia, typically asymptomatic 4.
• MCV <80 fL suggests possible carrier status 3.

Hemoglobin H Disease (Three-Gene Deletion)

• Represents alpha-thalassemia intermedia with vastly heterogeneous clinical spectrum 4.
• Classified as mild, moderate, or severe based on symptoms and need for intervention 4.
• Requires CBC monitoring every 3-6 months to assess for worsening hemolytic anemia 3.

Alpha-Thalassemia Major/Hb Bart's Hydrops Fetalis (Four-Gene Deletion)

• Deletion of all 4 alpha genes leads to hydrops fetalis and fetal demise due to profound hemolytic anemia 1.
• Results in severe intrauterine hypoxia and non-immune hydrops fetalis presenting in late second or early third trimester 3.
• Represents the most common cause of non-immune hydrops fetalis in Southeast Asian populations, accounting for 28-55% of cases 3.

Modern Clinical Classification Framework

The current classification system categorizes all thalassemias into two functional groups 6:

• Transfusion-Dependent Thalassemia (TDT): Patients require regular blood transfusions to survive, including beta-thalassemia major, severe HbH disease, and severe HbE/beta-thalassemia 6.

• Non-Transfusion-Dependent Thalassemia (NTDT): Patients do not require regular transfusions, including beta-thalassemia intermedia, most HbH disease, and mild HbE/beta-thalassemia 6.

Clinical Timing and Presentation

• Newborns are asymptomatic because fetal hemoglobin (α₂γ₂) does not require beta-globin chains 1, 2.
• Clinical symptoms of beta-thalassemia typically appear between 1-2 years of age as fetal hemoglobin production declines and adult hemoglobin synthesis begins 1, 2.
• For alpha-globin variants causing methemoglobinemia (HbM variants), dusky color is evident at birth, while beta-globin variants become evident only after 6-9 months of age 7.

Critical Clinical Pitfall

• Iron supplementation should be avoided in patients with confirmed thalassemia trait, as it provides no therapeutic benefit and may contribute to unnecessary iron accumulation 1, 2.
• Each transfused red-cell unit delivers approximately 200-250 mg of elemental iron, and humans lack a physiological mechanism for iron excretion 1, 2.
• Cardiac iron deposition accounts for roughly 70% of mortality in transfusion-dependent thalassemia patients 1, 2.