Which is the most common cause of death in patients with β-thalassemia major in the modern era of transfusion therapy and iron chelation?

Explanation

## Leading Cause of Death in β-Thalassemia Major **Key Point:** Cardiac arrhythmia and cardiomyopathy secondary to myocardial iron deposition are the most common causes of death in β-thalassemia major patients in the modern transfusion era. ### Evolution of Mortality Causes Over Time | Era | Primary Cause of Death | Secondary Causes | |-----|----------------------|------------------| | Pre-transfusion (1960s–70s) | Severe anemia, multi-organ failure | Infection, hemorrhage | | Early transfusion (1980s–90s) | Hepatic cirrhosis, iron overload | Cardiac involvement emerging | | Modern era (2000s–present) | **Cardiac arrhythmia/cardiomyopathy** | Sepsis, liver disease (if suboptimal chelation) | ### Mechanism of Cardiac Iron Overload 1. **Transfusional iron loading:** Each unit of PRBC contains ~250 mg iron; patients receive 10–20 units/year 2. **Myocardial iron deposition:** Iron accumulates in cardiomyocytes, causing oxidative damage via Fenton chemistry 3. **Arrhythmia generation:** Iron-induced fibrosis and conduction abnormalities → atrial fibrillation, ventricular arrhythmias 4. **Cardiomyopathy:** Progressive systolic dysfunction and sudden cardiac death **High-Yield:** Cardiac iron overload is now the **leading cause of death** in well-transfused β-thalassemia patients because improved transfusion and chelation protocols have extended survival, unmasking chronic cardiac toxicity. **Clinical Pearl:** T2* cardiac MRI is the gold standard for detecting myocardial iron and predicting arrhythmia risk; it should be performed annually in all β-thalassemia major patients. **Mnemonic:** **CARDIAC** — Chelation Absent/Inadequate, ARrhythmia, Dilated cardiomyopathy, Iron overload, Arrhythmia, Cardiomyopathy, Death ### Why Hepatic Cirrhosis Is No Longer #1 Although hepatic iron overload and cirrhosis remain significant complications, modern iron chelation (deferasirox, deferiprone, deferoxamine) has substantially reduced hepatic mortality. However, cardiac iron is more difficult to chelate and remains the leading cause.