Beta-Thalassemia: Pathophysiology, Imaging Features, Diagnosis, Treatment, and Prognosis — A Comprehensive Radiology & Clinical Review

Keywords: Beta-thalassemia, thalassemia imaging features, hemoglobinopathy diagnosis, bone marrow expansion radiology, iron overload MRI, thalassemia treatment, prognosis of beta-thalassemia

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Introduction

Beta-thalassemia is a hereditary, quantitative hemoglobin disorder resulting from mutations in the beta (β)-globin gene, leading to reduced or absent synthesis of β-globin chains and consequent ineffective erythropoiesis, chronic anemia, and compensatory bone marrow expansion.

This condition represents one of the most common monogenic diseases globally with high carrier prevalence in populations historically exposed to malaria (Mediterranean, Middle Eastern, South and Southeast Asia).

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Pathophysiology of Beta-Thalassemia

Beta-thalassemia is caused by mutations in the HBB gene on chromosome 11 that impair β-globin production. These may include point mutations affecting transcription, splicing, or translation of the gene.

The degree of β-globin deficiency determines phenotypic severity:

• β-thalassemia minor (carrier state): one abnormal allele → mild anemia.
• β-thalassemia intermedia: compound heterozygosity with some β production → moderate symptoms.
• β-thalassemia major (Cooley’s anemia): two defective alleles → severe, transfusion-dependent anemia.

At the cellular level, a deficit of β chains leads to imbalance of globin chains: excessive α chains precipitate within erythroid precursors, causing ineffective erythropoiesis, hemolysis, and peripheral anemia.

A compensatory marrow response ensues, stimulating expansion of marrow cavities and extramedullary hematopoiesis (including in the spleen and liver), often producing pathologic skeletal and soft-tissue changes.

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Epidemiology

Beta-thalassemia carriers are estimated at 80–90 million worldwide (~1.5% of the global population). It is especially prevalent in Mediterranean, Middle Eastern, African, and Indian subcontinental populations, a distribution linked to selective malaria resistance.

Globally, ~68,000 children are born with symptomatic β-thalassemia annually, predominantly in regions with limited access to regular transfusion therapy.

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Clinical Presentation

β-Thalassemia Major

Infants typically present between 6 and 24 months with:

• Severe anemia (pallor, irritability)
• Growth failure, poor feeding
• Hepatosplenomegaly
• Jaundice
• Bone deformities (especially facial bones)
• Recurrent infections
• Failure to thrive due to hemolysis and marrow expansion

β-Thalassemia Intermedia

Symptoms may be milder and appear later:

• Moderate anemia
• Jaundice
• Moderate hepatosplenomegaly
• Bone changes
• Complications from chronic hemolysis and iron overload

β-Thalassemia Minor

Often asymptomatic or with mild microcytic anemia discovered incidentally.

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Imaging Features of Beta-Thalassemia

Figure 1 — Bone Marrow Expansion

Illustrating marrow expansion and cortical thinning in long bones of a patient with untreated β-thalassemia major.
Excessive medullary activity produces trabecular coarsening and cortical thinning on radiographs, a hallmark of ineffective erythropoiesis. 

Figure 2 — Craniofacial Changes

Skull radiograph demonstrating classic “crew-cut” appearance from marrow hyperplasia.
Prominent marrow expansion into skull diploë yields a ‘crew-cut’ pattern indicative of chronic hematopoietic stimulation. 

Figure 3 — Extramedullary Hematopoiesis

MRI showing paraspinal soft-tissue masses.
Extensive extramedullary hematopoietic tissue may present as soft-tissue masses on MRI, especially in inadequately transfused patients. 

Figure 4 — *Iron Overload (T2 MRI)

Cardiac and hepatic T2 mapping demonstrating low signal consistent with iron deposition.*
Quantitative T2* MRI is standard for assessing iron overload in liver and heart due to chronic transfusions.

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Diagnosis

Diagnosis begins with clinical suspicion and laboratory confirmation:

Hematologic findings:

• Microcytic hypochromic anemia
• Elevated HbA₂ and HbF on electrophoresis
• Anisopoikilocytosis with nucleated red cells

Hemoglobin electrophoresis & HPLC: Identifies abnormal fractions (e.g., ↑ HbA₂, ↑ HbF) supportive of β-thalassemia.

Genetic testing: Confirms specific mutations in the HBB gene.

Imaging as supportive information:

• Radiographs: skeletal deformities
• MRI: quantification of iron overload (T2*, R2*)
• CT: soft-tissue masses, organomegaly when needed

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Differential Diagnosis

Physicians should differentiate β-thalassemia from:

• Iron-deficiency anemia — typically low ferritin and normal HbA₂
• Anemia of chronic disease
• Other hemoglobinopathies (e.g., HbE/β-thalassemia, sickle cell)
• Megaloblastic anemia — macrocytosis rather than microcytosis

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Treatment

Supportive Care

• Red blood cell transfusions: Regular in β-thalassemia major.
• Iron chelation therapy: Deferoxamine, deferiprone, or deferasirox to prevent hemosiderosis.
• Folic acid supplementation.

Advanced Therapies

• Hematopoietic stem cell transplantation (HSCT): Curative in select patients.
• Gene therapy and erythropoiesis modulators (e.g., luspatercept): Emerging treatments.

Complication Management

• Endocrine evaluation
• Cardiac and liver surveillance with MRI
• Splenectomy in select intermedia cases

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Prognosis

Without definitive treatment, β-thalassemia major was historically fatal in childhood. Modern transfusion and chelation programs have dramatically improved survival into adulthood.

Prognosis depends on:

• Access to regular transfusions
• Adherence to chelation
• Early detection of iron toxicity
• Complication management

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Quiz

Q1. A 10-month-old infant presents with severe anemia, failure to thrive, and massive hepatosplenomegaly. Labs show microcytic anemia and elevated HbF with low HbA. What is the most likely diagnosis?
Answer: Beta-thalassemia major.
Explanation: Severe early anemia with ↑ HbF and ↓ HbA is classic for β-thalassemia major. Regular transfusions required.

Q2. On radiographs of a 5-year-old with chronic anemia, there is increased marrow space and cortical thinning of long bones and “crew-cut” skull. What mechanism underlies this?
Answer: Ineffective erythropoiesis leading to marrow expansion.
Explanation: Chronic anemia triggers marrow hyperplasia causing skeletal changes on imaging.

Q3. In a β-thalassemia major patient receiving regular transfusions, which imaging modality is best to assess cardiac iron overload?
Answer: T2 MRI.*
Explanation: Quantitative T2* MRI is the current gold standard for non-invasive measurement of hemosiderosis in liver and heart.

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References

[1] T. Needs, L. F. Gonzalez-Mosquera, D. T. Lynch, “Beta Thalassemia,” StatPearls, 2023. :contentReference[oaicite:27]{index=27} 

[2] “Imaging features of thalassaemia,” PMC, 2019. :contentReference[oaicite:28]{index=28} 

[3] “Beta-Thalassemia,” GeneReviews, NCBI Bookshelf, 2024. :contentReference[oaicite:29]{index=29} 

[4] “Beta thalassemia overview,” Medscape, 2024. :contentReference[oaicite:30]{index=30} 

[5] “Quantitative MRI iron load assessment in β-thalassemia patients,” Eur. J. Radiol., 2025. :contentReference[oaicite:31]{index=31} 

[6] “Beta Thalassemia Causes, Symptoms & Treatment,” Cleveland Clinic, 2021. :contentReference[oaicite:32]{index=32} 

[7] “Radiological Features of Thalassaemia,” Clinical Radiology, 2005. :contentReference[oaicite:33]{index=33}