Why People with Thalassemia Have Trouble Getting Rid of Excess Iron
People with thalassemia have trouble eliminating excess iron primarily because the human body lacks a physiological mechanism to excrete excess iron, which accumulates from both regular blood transfusions and increased gastrointestinal absorption due to ineffective erythropoiesis. 1, 2
Mechanisms of Iron Accumulation in Thalassemia
Transfusion-related iron overload: Each unit of packed red blood cells contains 200-250 mg of elemental iron that accumulates in the body with no active excretion mechanism. For transfusion-dependent thalassemia patients, this leads to significant iron accumulation over time 1, 2
Increased gastrointestinal absorption: Thalassemia patients experience ineffective erythropoiesis (abnormal red blood cell production), which leads to increased intestinal iron absorption even with a normal diet 1, 2
Hepcidin suppression: Ineffective erythropoiesis causes suppression of hepcidin, a hormone that regulates iron absorption, further increasing gastrointestinal iron uptake 3
Pathophysiology of Iron Accumulation
When iron levels exceed the binding capacity of transferrin (the protein that safely transports iron in blood), non-transferrin bound iron is released into circulation 1
This unbound iron enters cardiac myocytes through L-type calcium channels and can cause significant organ damage 1
Iron accumulates in various organs at different rates, with the heart, liver, and endocrine organs being particularly vulnerable 3
Consequences of Iron Overload
Without treatment, transfused but unchelated β-thalassemia patients typically died by age 10, primarily from cardiac complications 2
Iron-induced cardiomyopathy is the leading cause of death in transfusion-dependent thalassemia, accounting for approximately 70% of deaths 2
Prolonged exposure to iron toxicity leads to endocrinopathy, osteoporosis, cirrhosis, renal failure, and increased risk of malignancy 4
Management Challenges
Since the human body cannot actively excrete excess iron, therapeutic intervention is required through:
Chelation therapy aims to detoxify organs containing excess iron by binding to it and promoting excretion through urine and bile 1
Available chelators include deferoxamine (injectable), deferiprone, and deferasirox (oral), each with different efficacy profiles and side effects 1, 5
Phlebotomy is not feasible for thalassemia patients due to their underlying anemia, making chelation therapy the only option 1
Even with chelation therapy, maintaining iron balance is challenging due to the continuous nature of transfusions and increased absorption 6
Recent Advances
Introduction of oral chelators has transformed management and led to persistent improvements in iron burden 7
MRI techniques now allow non-invasive monitoring of iron loading in organs like the heart and liver 7
Modern chelation strategies aim to maintain non-transferrin-bound iron levels at a minimum 24 hours a day, 7 days a week 4
Life expectancy in thalassemia major has significantly increased with improved chelation therapy, with median age at death improving to 35 years by 2000 2
The fundamental problem remains that humans have evolved mechanisms to absorb and store iron efficiently but lack physiological pathways to eliminate excess iron, making thalassemia patients particularly vulnerable to iron overload from both transfusions and dysregulated absorption.