Thyrotoxic Cardiomyopathy

Thyrotoxic cardiomyopathy is reversible left ventricular dysfunction, with or without dilatation, caused by excess thyroid hormone. It follows prolonged or severe hyperthyroidism and takes two forms: a high output state that progresses to heart failure, and a tachycardia mediated dilated form.

Causes of thyrotoxicosis are Graves disease, toxic multinodular goitre, toxic adenoma, thyroiditis, amiodarone induced thyrotoxicosis, excess levothyroxine and iodine loading. About 6% of hyperthyroid patients develop heart failure, and atrial fibrillation occurs in 10 to 15% (more in older adults and with male sex).

Heart failure occurs in up to a third of thyroid storm, with hypotension and shock in severe cases. Subclinical hyperthyroidism (suppressed TSH, normal free T4 and T3) also raises the risk of atrial fibrillation and heart failure. Recovery of ventricular function is usual after the euthyroid state is restored.

Thyroid storm is diagnosed with the Burch-Wartofsky score: 45 or more is highly suggestive, 25 to 44 suggests impending storm and under 25 makes it unlikely.

Pathophysiology. Tri iodothyronine increases heart rate, contractility, blood volume and myocardial oxygen use through genomic effects on contractile and calcium handling proteins, and lowers systemic vascular resistance, producing high cardiac output with wide pulse pressure.

Persistent tachycardia and volume load cause dilatation and failure, and loss of the atrial contribution in atrial fibrillation worsens this. Pulmonary hypertension and right heart failure can develop. Stroke risk is raised in atrial fibrillation.

• Palpitations, exertional dyspnoea, fatigue, weight loss, heat intolerance, sweating, tremor, anxiety, diarrhoea, oligomenorrhoea.
• Sinus tachycardia or atrial fibrillation with rapid rates, bounding pulses with a wide pulse pressure, hyperdynamic apex, systolic flow murmur, and a pulmonary systolic scratch (Means-Lerman).
• Signs of heart failure: oedema, raised venous pressure, third heart sound, ascites.
• Graves features: diffuse goitre, orbitopathy, pretibial myxoedema. Nodular goitre in older adults.
• Thyroid storm: fever over 38.5 degrees Celsius, agitation or delirium, severe tachycardia, heart failure, vomiting, jaundice, shock.

Red flags.

• Fever with delirium, tachycardia over 140/min, or shock (thyroid storm)
• Atrial fibrillation with rapid ventricular response
• Pulmonary oedema or ejection fraction under 40%
• Jaundice or liver dysfunction
• Recent iodine load, amiodarone, thyroid surgery, radioiodine or infection
• Embolic event

• Thyroid function. TSH (suppressed, usually under 0.01 mIU/L), free T4 and free T3. Isolated raised T3 in early disease.
• Cause. TSH receptor antibodies, thyroid peroxidase antibodies, thyroid ultrasound with colour Doppler, and radionuclide uptake scan (diffuse in Graves disease, focal in nodular disease, low in thyroiditis). In amiodarone induced thyrotoxicosis, colour flow Doppler and uptake scan help separate type 1 (iodine induced, increased flow) from type 2 (destructive thyroiditis, absent flow).
• ECG, echocardiography and natriuretic peptide. Ejection fraction, chamber size, pulmonary pressure. High cardiac output is shown by a raised left ventricular outflow velocity time integral.
• Laboratory. Electrolytes, creatinine, liver function, full blood count (before thionamides), glucose, troponin, calcium, blood cultures with fever.
• Burch-Wartofsky score for storm.

Differential diagnosis.

• Other high output states: anaemia, thiamine deficiency, arteriovenous fistula, Paget disease, pregnancy, sepsis, cirrhosis
• Primary atrial fibrillation and other tachyarrhythmia with tachycardia induced cardiomyopathy
• Phaeochromocytoma and sympathomimetic or stimulant toxicity
• Anxiety and panic disorder
• Dilated cardiomyopathy of other cause and ischaemic heart disease
• Sepsis and malignant hyperthermia
• Thyrotoxic periodic paralysis (weakness)
• Pulmonary embolism

Reduce adrenergic effects while thyroid hormone is brought under control.

• Propranolol 20 to 40 mg orally every 6 to 8 hours (hyperthyroid patients clear it faster), increased as needed to a heart rate under 90/min, maximum 320 mg daily. In thyroid storm, 60 to 80 mg orally every 4 hours, or 1 mg intravenously over 1 minute repeated every 2 minutes to a maximum of 10 mg. Propranolol also reduces conversion of T4 to T3. Contraindicated in asthma, severe bradycardia, high grade AV block and cardiogenic shock. Use with caution in decompensated heart failure. In heart failure with tachycardia from thyrotoxicosis, careful beta blockade often improves haemodynamics, but start low in low output states.
• Esmolol 500 microgram/kg intravenously over 1 minute, then infusion 50 microgram/kg/min, repeating the bolus and increasing the infusion by 50 microgram/kg/min every 4 to 5 minutes, maximum 200 microgram/kg/min. Use in thyroid storm or when haemodynamics are uncertain, because its effect wears off within minutes.
• Diltiazem 60 mg orally every 6 to 8 hours (maximum 360 mg daily) when a beta blocker is contraindicated, avoiding it with reduced ejection fraction.
• Heart failure: 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), with sodium, potassium and creatinine monitoring. Use intravenous 40 to 80 mg for pulmonary oedema. Digoxin is less effective and needs higher doses while thyrotoxic (125 to 250 micrograms orally once daily, maximum 250 micrograms daily), and the dose must fall when the patient becomes euthyroid.

Antithyroid therapy.

• Carbimazole 15 to 40 mg orally once daily (start 30 to 40 mg in severe disease), maximum 60 mg daily, then reduce by 5 mg every 4 to 6 weeks, or continue with levothyroxine added (block and replace). Check full blood count and liver function at baseline. Stop and check the white cell count urgently for sore throat or fever (agranulocytosis, 0.2% to 0.5%). Avoid in the first trimester of pregnancy (aplasia cutis, choanal atresia). Reduce in severe liver impairment.
• Propylthiouracil 100 to 150 mg orally every 8 hours (maximum 600 mg daily), used in the first trimester of pregnancy and when carbimazole cannot be taken. Check liver function (risk of severe hepatotoxicity) and full blood count. Avoid for long courses and in children.
• Thyroid storm (intensive care): propylthiouracil 500 to 1,000 mg orally or by nasogastric tube as a loading dose, then 250 mg every 4 hours (maximum 1,500 mg daily), or carbimazole 60 mg daily in divided doses. Give iodine at least 1 hour after the first thionamide dose: potassium iodide solution 5 drops (about 250 mg) orally every 6 hours, or Lugol solution 8 drops every 6 hours, for 5 to 7 days. Hydrocortisone 100 mg intravenously every 8 hours. Cholestyramine 4 g orally every 6 hours. Paracetamol 1 g every 6 hours (maximum 4 g daily) and cooling for fever (avoid aspirin, which displaces T4). Fluids, glucose, electrolytes, thiamine and treatment of the precipitant. Plasma exchange or dialysis for refractory storm.
• Definitive treatment once euthyroid and heart failure is controlled: radioactive iodine (contraindicated in pregnancy and breastfeeding; rate control is maintained until effect), or surgery for large goitre, suspected cancer or orbitopathy, or long term thionamides in Graves disease.
• Amiodarone induced thyrotoxicosis. Type 1: carbimazole 40 mg orally once daily with potassium perchlorate where available. Type 2: prednisolone 40 mg orally once daily, tapered over 2 to 3 months. Mixed forms need both. Stopping amiodarone is not always needed. Involve endocrinology.

Atrial fibrillation.

• Rate control with propranolol 20 to 40 mg orally every 6 to 8 hours (maximum 320 mg daily), or diltiazem 60 mg orally every 6 to 8 hours (maximum 360 mg daily) when a beta blocker is contraindicated and ejection fraction is preserved. About 60% revert to sinus rhythm within 3 months of becoming euthyroid, so delay cardioversion unless unstable.
• Anticoagulation by stroke risk (not by thyroid state): 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. Warfarin sensitivity is raised in thyrotoxicosis, so use lower doses and daily INR.

Special groups.

• Pregnancy: propylthiouracil in the first trimester, then carbimazole at the lowest effective dose, with beta blockers (propranolol) for symptoms and no radioiodine.
• Older adults: subclinical and apathetic disease can present with atrial fibrillation and heart failure alone.

Monitoring. Thyroid function every 4 to 6 weeks until stable. Heart rate and rhythm daily in storm. Echocardiography at 3 months once euthyroid, and with persistent dysfunction at 6 months. Full blood count and liver function if symptoms appear on thionamides. INR as directed.

Referral and escalation. Refer to endocrinology and cardiology. Admit to intensive care for thyroid storm or cardiogenic shock. Urgent for rapid atrial fibrillation with heart failure, jaundice or neutropenia on thionamide.