Iron Overload Cardiomyopathy

Iron overload cardiomyopathy is myocardial disease from iron deposition in cardiomyocytes. It begins as diastolic dysfunction and arrhythmia, then progresses to dilated cardiomyopathy with heart failure.

It is mainly a complication of repeated transfusion in beta thalassaemia major, severe thalassaemia intermedia, sickle cell disease on chronic transfusion, myelodysplastic syndromes and aplastic anaemia. Each unit of red cells carries 200 to 250 mg of iron, and the body has no route to excrete it.

Hereditary haemochromatosis (HFE C282Y homozygosity) and juvenile haemochromatosis (HJV, HAMP) also cause it. Juvenile disease presents with cardiac and endocrine disease in the second and third decades.

Heart failure is a leading cause of death in transfusion dependent thalassaemia. It is reversible when chelation is intensified before irreversible fibrosis develops.

Pathophysiology. Non-transferrin-bound iron enters cardiomyocytes through L-type calcium channels and generates hydroxyl radicals, causing lipid peroxidation, mitochondrial injury and myocyte death.

Cardiac iron accumulates later than liver iron and clears more slowly. Serum ferritin correlates poorly with cardiac iron.

• Often asymptomatic while cardiac iron is rising and ejection fraction is normal.
• Exertional dyspnoea, fatigue, palpitations, oedema, orthopnoea, syncope.
• Atrial fibrillation or flutter, atrioventricular block, ventricular tachycardia and sudden death.
• Features of iron overload: bronze or grey skin, hepatomegaly, diabetes, hypogonadism, hypothyroidism, hypoparathyroidism, delayed puberty.
• Pulmonary hypertension in thalassaemia intermedia.

Red flags.

• Cardiac T2* under 10 ms
• Falling ejection fraction (under 56% in thalassaemia) or new heart failure
• Atrial fibrillation, ventricular tachycardia or syncope
• Ferritin over 2,500 microgram/L, or non-adherence to chelation
• Pregnancy or planned pregnancy
• Fever or diarrhoea on deferoxamine (Yersinia), or sore throat on deferiprone

• Cardiac MRI T2*. Over 20 ms is normal. 10 to 20 ms is mild to moderate overload. Under 10 ms is severe overload with a high risk of heart failure within a year, and under 6 ms carries the highest risk. T2* detects iron before function falls.
• Liver iron concentration by MRI. Normal under 1.8 mg/g dry weight, and over 15 mg/g is severe.
• Serum ferritin every 3 months (over 1,000 microgram/L suggests overload in the absence of inflammation), and transferrin saturation over 45% in haemochromatosis.
• Echocardiography (restrictive filling, ejection fraction, strain, pulmonary pressure), ECG and ambulatory ECG.
• Cause. Transfusion history, HFE and other genetic testing for haemochromatosis, and family screening.
• Associated disease. Glucose, thyroid function, calcium, parathyroid hormone, sex hormones, hepatitis B and C and HIV in transfused patients.

Differential diagnosis.

• Dilated and restrictive cardiomyopathy of other cause
• Cardiac amyloidosis
• Myocarditis
• High output failure from chronic anaemia
• Pulmonary hypertension in haemoglobinopathy
• Sickle cell cardiomyopathy
• Diabetic cardiomyopathy
• Hypothyroid and other endocrine heart disease

Chelation is the treatment. Intensify as soon as T2* falls under 20 ms.

• Deferoxamine 40 to 50 mg/kg/day subcutaneously over 8 to 12 hours, 5 to 7 nights weekly, maximum 60 mg/kg daily. Reduce the dose when ferritin is under 1,000 microgram/L, keeping the daily dose (mg/kg) divided by ferritin (microgram/L) under 0.025. Stop during fever or diarrhoea (Yersinia). Annual hearing and eye review.
• Deferiprone 75 mg/kg/day orally in 3 divided doses, maximum 100 mg/kg daily. It removes cardiac iron best. Check neutrophils weekly, interrupt for neutrophils under 1.5 x 109/L and stop for agranulocytosis. Contraindicated in pregnancy and previous neutropenia.
• Deferasirox film coated tablet 14 mg/kg orally once daily (dispersible tablet 20 mg/kg), increased every 3 to 6 months by 3.5 mg/kg (film coated) or 5 to 10 mg/kg (dispersible), maximum 28 mg/kg (film coated) or 40 mg/kg (dispersible) daily. Check creatinine weekly for the first month and after each dose change, then monthly, with ALT and urine protein monthly. Reduce the dose when creatinine rises by over 33% on two readings. Contraindicated at eGFR under 40 mL/min/1.73 m2 and platelets under 50 x 109/L.
• Severe cardiac overload (T2* under 10 ms) or heart failure: continuous intravenous deferoxamine 50 to 60 mg/kg/day over 24 hours by central line, often with deferiprone 75 to 100 mg/kg/day, until T2* is over 20 ms and ejection fraction is normal, then step down. Avoid vitamin C supplements in severe cardiac overload because they can provoke arrhythmia.
• Transfuse to a pre-transfusion haemoglobin of 95 to 105 g/L in thalassaemia major.

Hereditary haemochromatosis. Venesection of 400 to 500 mL weekly until ferritin is 50 to 100 microgram/L, then every 2 to 4 months. Defer when haemoglobin is under 110 g/L. Use slower, smaller removals with volume support in heart failure, or erythrocytapheresis, with deferoxamine added in severe cardiac disease. Avoid iron and vitamin C supplements, alcohol and raw shellfish (Vibrio). Screen first degree relatives.

Heart failure.

• Ramipril 2.5 mg orally once daily, increased every 2 to 4 weeks to 10 mg once daily (maximum 10 mg daily, and 5 mg daily at creatinine clearance under 30 mL/min). Check potassium and creatinine 1 to 2 weeks after each change. Contraindicated in pregnancy and bilateral renal artery stenosis.
• Bisoprolol 1.25 mg orally once daily, increased every 1 to 4 weeks to the target 10 mg once daily, maximum 10 mg daily in heart failure. Contraindicated in cardiogenic shock, second degree or third degree atrioventricular block without a pacemaker, sick sinus syndrome and severe asthma.
• Furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care). Avoid over diuresis, because the ventricle is preload dependent. Monitor sodium, potassium and creatinine.

Arrhythmia. Atrial fibrillation: rate control with bisoprolol and anticoagulation, because thrombotic risk is high after splenectomy. Apixaban 5 mg orally twice daily, reduced to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present. Also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min, and avoided under 15 mL/min. Maximum 10 mg daily. Long term. Defibrillator criteria follow the usual rules, with chelation continuing.

Endocrine disease. Treat diabetes, hypothyroidism, hypogonadism and hypoparathyroidism in the usual way.

Advanced disease. Mechanical support or transplantation, with haematopoietic stem cell transplantation considered for thalassaemia.

Special groups.

• Pregnancy: deferasirox and deferiprone are contraindicated. Intensify chelation and check T2* before conception. Deferoxamine is limited to high cardiac risk, after the first trimester.
• Region: in sub-Saharan Africa sickle cell disease is more common than thalassaemia. Cardiac iron is uncommon in sickle cell disease, but check liver iron in chronically transfused patients.

Monitoring. T2* every 1 to 2 years when over 20 ms, every 6 to 12 months at 10 to 20 ms, and every 3 to 6 months when under 10 ms. Ferritin every 3 months. Echocardiography and ambulatory ECG yearly. Ferritin, creatinine, urine protein and ALT on deferasirox, neutrophils weekly on deferiprone, and hearing and eye review yearly on deferoxamine.

Referral and escalation. Refer to a haematology centre with cardiac MRI access. Urgent for T2* under 10 ms, heart failure, arrhythmia or agranulocytosis.