Iron Overload in Thalassemia: Mechanisms and Consequences
Iron overload in thalassemia occurs primarily through two mechanisms: regular blood transfusions and increased gastrointestinal iron absorption due to ineffective erythropoiesis and hepcidin suppression. 1, 2
Mechanisms of Iron Accumulation
In transfusion-dependent thalassemia (TDT), particularly β-thalassemia major, each unit of blood contains approximately 200 mg of iron, leading to significant iron accumulation over time with regular transfusions 1
Ineffective erythropoiesis (caused by excess α-globin chains in β-thalassemia) leads to increased intestinal iron absorption through hepcidin suppression, even in patients who are not receiving regular transfusions 2
In β-thalassemia major, the combination of transfusional iron and increased gastrointestinal absorption can increase total body iron by more than 2-5 grams per year 2
Non-transfusion-dependent thalassemia (NTDT) patients, including those with thalassemia intermedia, also develop iron overload primarily through increased gastrointestinal iron absorption 1
Pathophysiology of Iron Toxicity
When iron loading exceeds the iron-carrying capacity of transferrin, non-transferrin-bound iron (NTBI) appears in circulation 3
NTBI is preferentially taken up by the liver, heart, and endocrine organs at rates up to 200 times faster than transferrin-bound iron 3
Iron catalyzes the formation of free radicals, resulting in oxidative stress and damage to cellular structures including mitochondria, lysosomes, lipid membranes, proteins, and DNA 3
Threshold values for iron toxicity include liver iron concentration exceeding 440 mmoles/g dry weight, serum ferritin >2500 ng/mL, and transferrin saturation >75% 3
Organ-Specific Iron Loading
Different organs are affected at different rates by iron overload in thalassemia, depending on the underlying mechanism and rate of iron accumulation 4
Cardiac iron loading is the leading cause of death in transfusion-dependent thalassemia patients, with cardiac complications accounting for approximately 70% of deaths in the era of deferoxamine iron chelation 1
Before the introduction of chelation therapy, patients with transfused but unchelated β-thalassemia typically died by age 10, primarily from cardiac complications 1
Liver disease from iron overload can lead to cirrhosis and contributes to significant morbidity 3
Endocrine dysfunction, including hypothyroidism and diabetes, is another common complication of iron overload 3
Clinical Implications and Management
Iron chelation therapy is essential for preventing and reversing iron-related organ damage 5
Available chelation options include deferoxamine (subcutaneous), deferiprone and deferasirox (oral) 5
The introduction of oral chelation agents has improved compliance and led to greater reductions in cardiac iron levels compared to deferoxamine 5
Regular monitoring of iron status through serum ferritin measurements and non-invasive imaging techniques is crucial for guiding chelation therapy 4
Without adequate chelation therapy, patients with β-thalassemia major often die from cardiac complications of iron overload by 30 years of age 6
Special Considerations
In thalassemia intermedia, patients may not initially require transfusions but may need them later in life to prevent complications, which then contributes to iron loading 1
Iron overload in non-transfusion dependent thalassemia develops more slowly but still requires monitoring and potential chelation therapy 4
The introduction of improved chelation therapy has significantly increased life expectancy in thalassemia major, with median age at death improving to 35 years by 2000 in the UK 1
Pregnancy in women with thalassemia requires careful monitoring of iron status and cardiac function, as increased blood consumption during pregnancy combined with interruption of chelation therapy may worsen iron overload 1