What investigations should be performed to assess iron overload in a transfusion‑dependent beta‑thalassemia patient?

Investigations for Iron Overload in Thalassemia

Primary Screening Tests

Serial serum ferritin measurements every 3 months remain the cornerstone for monitoring iron burden trends in transfusion-dependent beta-thalassemia patients, supplemented by MRI assessment of liver iron concentration every 1-2 years using validated R2 or R2 methods.* 1, 2

Serum Ferritin Monitoring

• Measure serum ferritin every 3 months as an inexpensive trend marker to track changes in iron burden over time 3, 1
• Ferritin <1500 ng/mL indicates well-controlled iron burden, with 90% of patients having liver iron concentration <7 mg/g dry weight 1, 2
• Ferritin >2500-3000 ng/mL signals significant iron overload requiring intensified chelation therapy 1, 2
• Important caveat: Ferritin is an acute phase reactant and can be falsely elevated by inflammation, infection, malignancy, or liver disease, making it unreliable as a standalone measure 1, 2
• Despite limitations, ferritin correlates significantly with both cardiac T2* values (r = -0.34) and hepatic T2* values (r = -0.52) in beta-thalassemia major 4

Transferrin Saturation

• Measure transferrin saturation alongside ferritin as part of initial assessment 3
• This test has limited utility for ongoing monitoring due to daily variability and inflammation effects 3

Liver Iron Assessment

MRI for liver iron concentration should be performed every 1-2 years using validated R2, T2, or R2 methods to provide accurate quantification of total body iron burden.** 3, 1, 2

MRI Methodology

• Both R2 and R2* MRI methods correlate well with iron levels determined by liver biopsy 3
• Liver T2-relaxation time shows close inverse correlation with liver iron concentration based on biopsy validation 5
• Critical requirement: Use validated methods with specialized programming and expertise; if unavailable, refer to a specialized center 3
• Liver iron concentration >15 mg/g dry weight for ≥2 years identifies high-risk patients requiring cardiac iron assessment 3, 1

When to Perform Liver MRI

• Perform baseline liver MRI once transfusion dependency is established 1, 2
• Repeat every 1-2 years for ongoing monitoring in chronically transfused patients 1, 2
• More frequent assessment may be needed if ferritin >2500 ng/mL or evidence of inadequate chelation 1, 2

Cardiac Iron Assessment

Cardiac T2 MRI should be reserved for high-risk subgroups rather than routine screening, specifically those with liver iron content >15 mg/g for ≥2 years, evidence of end-organ damage from iron overload, or cardiac dysfunction.* 3, 1

Indications for Cardiac T2* MRI

• Liver iron concentration >15 mg/g dry weight sustained for ≥2 years 3, 1
• Evidence of cardiac dysfunction on echocardiography 3, 1
• Evidence of end-organ damage from transfusional iron overload 3, 1
• Ferritin persistently >4600 ng/mL with poor chelation compliance 3, 2

Interpretation of Cardiac T2*

• T2* values <10 ms indicate severe cardiac iron loading 3
• T2* values 10-20 ms indicate mild to moderate cardiac iron loading 3
• T2* values <20 ms are abnormal and predict risk of developing iron-related cardiac complications 3
• Cardiac T2* correlates with left ventricular ejection fraction in thalassemia major patients 5

Key Distinction from Sickle Cell Disease

• Unlike sickle cell disease, cardiac iron loading is common in transfusion-dependent thalassemia major, making cardiac surveillance more critical 3
• Cardiac iron overload accounts for approximately 70% of deaths in thalassemia major patients 3
• Ferritin and liver iron concentration do not predict cardiac iron loading; cardiac assessment requires direct T2* measurement 3, 2

Additional Laboratory Tests

Liver Function Assessment

• Measure ALT and AST to assess for iron-induced liver damage 1, 4
• ALT levels are significantly higher in patients with severe cardiac iron overload 4
• AST levels are significantly elevated in patients with hepatic iron overload 4

Hematologic Parameters

• Obtain complete blood count and reticulocyte count to assess transfusion requirements 1
• Track transfusion burden as patients receiving >20 units typically require chelation initiation 3

Monitoring Algorithm Summary

For newly diagnosed transfusion-dependent beta-thalassemia:

1. Baseline serum ferritin and transferrin saturation 1
2. Baseline liver MRI (R2 or R2*) once transfusion dependency established 1, 2
3. Baseline liver function tests (ALT, AST) 1, 4

For ongoing monitoring:

1. Serum ferritin every 3 months 3, 1
2. Liver MRI every 1-2 years 1, 2
3. Cardiac T2* MRI only if liver iron >15 mg/g for ≥2 years, cardiac dysfunction, or ferritin >4600 ng/mL with poor compliance 3, 1
4. Liver function tests periodically 1, 4

Critical Pitfalls to Avoid

• Never rely on ferritin alone to guide chelation decisions in thalassemia major, as it does not predict cardiac iron loading 3, 2
• Do not delay liver MRI assessment until ferritin is markedly elevated, as liver iron accumulation precedes cardiac involvement 5, 6
• Avoid using non-validated MRI methods or centers without specialized expertise, as this compromises accuracy 3
• Do not assume cardiac iron status from liver iron or ferritin levels, as these correlate poorly in thalassemia major 3, 2, 5