What is beta thalassemia, including its inheritance pattern, clinical presentation, diagnostic criteria, and management?

Beta Thalassemia Overview

Beta thalassemia is an autosomal recessive genetic disorder caused by mutations in the HBB gene on chromosome 11 that result in reduced or absent beta-globin chain production, leading to ineffective erythropoiesis, chronic hemolytic anemia, and life-threatening complications—most notably cardiac iron overload, which accounts for 70% of deaths in transfusion-dependent patients. 1, 2

Genetic Basis and Inheritance

• Inheritance pattern: Autosomal recessive, requiring homozygosity or compound heterozygosity for severe disease manifestation 3
• Molecular defects: Over 200 pathogenic variants have been identified in the HBB gene on chromosome 11, most commonly single-nucleotide substitutions, small deletions, or insertions 3, 4
• Mutation types produce two phenotypes:
  • β⁰ phenotype: Complete absence of beta-globin synthesis 3
  • β⁺ phenotype: Reduced beta-globin synthesis 3
• Geographic distribution: Most prevalent in Mediterranean regions, Middle East, Southeast Asia, and Africa—areas with historical endemic malaria exposure 5

Pathophysiology

The fundamental defect is an imbalance in the α/β-globin chain ratio, with excess free α-globin chains precipitating as α-globin-heme complexes that trigger the disease's cardinal pathophysiological features 6, 4:

• Ineffective erythropoiesis (destruction of red cell precursors in bone marrow) 6, 7
• Chronic hemolytic anemia 6, 7
• Compensatory hematopoietic expansion 6, 4
• Progressive iron overload from both transfusions and increased gastrointestinal absorption 1, 6

Clinical Classification and Presentation

Beta Thalassemia Major (Transfusion-Dependent)

• Timing of symptom onset: Newborns are asymptomatic because fetal hemoglobin (α₂γ₂) does not require beta-globin chains; clinical symptoms appear between 1-2 years of age as fetal hemoglobin declines 3
• Without treatment: Life-threatening by end of second year of life; historically, most patients died from cardiac complications by age 10 3
• Defining characteristic: Requires >8 transfusion events per year in adults aged >16 years 1, 3
• Profound anemia: Life-threatening from approximately 1-2 years of age, requiring lifelong blood transfusions 1

Beta Thalassemia Intermedia (Non-Transfusion-Dependent)

• Clinical spectrum: Variable presentation; patients generally do not require regular transfusions to maintain hemoglobin 1, 2
• Age-related progression: As patients age, transfusions may become necessary to prevent cardiovascular complications including pulmonary hypertension and thrombosis 1, 2
• Iron overload mechanism: Develops from increased gastrointestinal iron absorption due to chronic anemia, even without transfusions 1, 6

Beta Thalassemia Trait (Carrier State)

• Hematologic findings: Microcytic hypochromic anemia with MCV typically <80 fL and reduced MCH 5
• Critical distinguishing feature: Mild anemia does NOT respond to iron supplementation despite compliance 5
• Clinical pitfall to avoid: Never prescribe iron supplementation to confirmed carriers—it provides no benefit and may contribute to unnecessary iron accumulation 3, 5

Diagnostic Criteria

• Complete blood count: Hypochromic microcytic anemia present in 100% of cases 8, 9
• Blood smear examination: Shows characteristic red cell morphology 9
• Hemoglobin electrophoresis: Definitive test showing abnormal hemoglobin patterns 5
• DNA analysis: Genetic testing identifies specific HBB gene mutations 9
• Prenatal testing: Genetic testing of amniotic fluid available for at-risk pregnancies 9
• Serum ferritin: Monitor every 3 months as a trend marker for iron overload 2

Management of Beta Thalassemia Major

Transfusion Protocol

Initiate regular blood transfusions every 3-4 weeks beginning at 1-2 years of age, maintaining pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion hemoglobin at 13-14 g/dL. 2

• Pre-transfusion target: 9-10 g/dL to balance iron loading minimization with symptom control 2
• Post-transfusion target: 13-14 g/dL to suppress ineffective erythropoiesis 2
• Transfusion schedule: Every 3-4 weeks on a regular schedule 2

Iron Chelation Therapy

Begin iron chelation immediately when regular transfusions are established, as each unit of blood contains 200-250 mg of iron with no physiological excretion mechanism 2, 3:

First-Line Options (Based on Cardiac Iron Removal Efficacy):

• Deferiprone (oral): 75 mg/kg/day—superior efficacy for cardiac iron removal compared to deferoxamine 1, 2
• Deferoxamine (subcutaneous): 50 mg/kg/day via subcutaneous infusion 5-7 nights per week—less effective than deferiprone for cardiac iron but widely used 1, 2
• Deferasirox (oral): Efficacy equivalent to deferoxamine for overall iron overload 1, 2

Combination Therapy:

• Deferiprone + deferoxamine: Superior to deferoxamine alone for reducing cardiac iron burden 1, 2

Cardiac Monitoring (Critical for Mortality Prevention)

Heart disease is the predominant cause of death in beta thalassemia major, accounting for 70% of mortality. 1, 2

• Annual cardiac MRI T2*: Detect cardiac iron deposition before symptoms develop 2
• Annual echocardiography: Assess left ventricular ejection fraction 2
• Early detection principle: Cardiac disease is easier and safer to treat at an early stage rather than late stage when hazard of death is high 1

Management of Acute Heart Failure

If acute heart failure develops, immediately transfer to a specialized thalassemia center and initiate continuous intravenous deferoxamine 50 mg/kg/day PLUS oral deferiprone 75 mg/kg/day. 2

• This aggressive combination approach improves outcomes compared to later-stage treatment 2
• Considerable care required to avoid exacerbating cardiovascular problems from overuse of diuretics or inotropes due to unusual loading conditions 1

Infection Prevention

• Hepatitis B vaccination: Before starting transfusions if not previously immunized 2
• Regular screening: For hepatitis B and C, as chronic viral hepatitis is common in transfused patients 2
• Sepsis risk: Second-leading cause of death; splenectomized patients vulnerable to encapsulated organisms 1

Dietary Modifications

• Limit red meat consumption: Reduces heme iron intake, which is highly absorbed 2
• Never take iron supplements: Or multivitamins containing iron 2, 3

Curative Treatment

Hematopoietic stem cell transplantation (HSCT) is the only currently available cure and should be performed as early as possible, ideally before age 14 years and before iron-related organ damage develops. 2, 9

• Gene therapy is emerging as an alternative that avoids graft-versus-host disease risk, though hematopoietic stem cells must be genetically modified ex vivo 6, 7

Important Comorbidities in Thalassemia Major

Iron overload affects multiple endocrine glands, and these deficiencies can mimic or exacerbate heart failure 1:

• Hypoparathyroidism and hypothyroidism: Can cause primary myocardial dysfunction 1
• Decreased adrenal reserve: Treat patients in heart failure as though they have adrenal insufficiency until proven otherwise 1
• Hypogonadotrophic hypogonadism: Most common endocrinopathy; low sex steroids may exacerbate heart failure symptoms 1
• Diabetes mellitus: Insulin resistance and type 2 diabetes strongly associated with cardiac iron deposition 1
• Metabolic deficiencies: Thiamine, B6, folate, carnitine, vitamin D, zinc, copper, and selenium deficiencies common; prudent to eliminate contributions from thiamine, carnitine, or extreme vitamin D deficiencies (<10 ng/dL) 1

Prognosis

• Without treatment: Death by age 10 from cardiac complications 3
• With optimal adherence: Survival into 40s-50s with reasonable quality of life; with modern chelation, survival into seventh decade now achievable 2, 3
• Key to improved outcomes: Early initiation of regular transfusions combined with immediate iron chelation, systematic cardiac monitoring, and early aggressive treatment of cardiac iron overload 1, 2