Drug-Induced Thyroiditis

Drug induced thyroiditis is thyroid inflammation caused by a medicine. It is usually painless and destructive, giving a thyrotoxic phase, then hypothyroidism, then recovery in many patients. Permanent hypothyroidism can follow.

Causes are immune checkpoint inhibitors (anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies), interferon alpha, tyrosine kinase inhibitors (sunitinib, sorafenib), lithium, amiodarone, alemtuzumab and interleukin-2.

Thyroid dysfunction develops in roughly 10 to 20% of patients given checkpoint inhibitors, more often with combined agents, and in up to 15% of those given interferon alpha. Positive thyroid peroxidase antibodies before treatment raise the risk.

Onset is usually within the first 3 months of treatment. The thyrotoxic phase lasts 2 to 8 weeks and is often missed.

Pathophysiology.

Immune activation or direct cytotoxicity damages follicular cells and releases preformed hormone, so thyrotoxicosis occurs without increased synthesis and radioiodine uptake is low.

Lithium and tyrosine kinase inhibitors also reduce hormone synthesis and release. Amiodarone adds an iodine load, which is a separate mechanism.

• Thyrotoxic phase: palpitations, tremor, weight loss, heat intolerance, anxiety, often mild or silent.
• Hypothyroid phase: fatigue, cold intolerance, constipation, weight gain, low mood.
• Small painless goitre or none. Neck pain is unusual.

Red flags.

• Atrial fibrillation, heart failure or thyroid storm in the thyrotoxic phase.
• Headache, visual change, hypotension or hyponatraemia (check for hypophysitis and adrenal insufficiency, especially with checkpoint inhibitors).

• Check thyroid stimulating hormone, free thyroxine and thyroid peroxidase antibodies before starting a causative drug, then every 4 to 6 weeks during the first months (before each cycle with checkpoint inhibitors).
• Thyrotoxic phase: suppressed thyroid stimulating hormone with raised free thyroxine and free triiodothyronine, thyrotropin receptor antibodies negative.
• Hypothyroid phase: raised thyroid stimulating hormone with low free thyroxine.
• Low thyroid stimulating hormone with low or low normal free thyroxine suggests hypophysitis; check morning cortisol before any thyroid hormone.
• Uptake scan (low uptake) only if the cause is unclear and the patient is not pregnant or breastfeeding. Ultrasound shows a hypoechoic gland with low Doppler flow.

Differential diagnosis.

• Graves disease (interferon alpha and alemtuzumab can induce it; thyrotropin receptor antibodies positive, high uptake).
• Amiodarone induced thyrotoxicosis and iodine induced thyrotoxicosis.
• Subacute granulomatous thyroiditis (painful, high ESR).
• Hypophysitis, non-thyroidal illness and assay interference.

• Most patients continue the causative drug. Stop or interrupt it only for severe thyrotoxicosis, and then in discussion with the prescribing team.
• Thyrotoxic phase: propranolol 10 to 40 mg three to four times daily (or atenolol 25 to 50 mg daily) until it settles. Antithyroid drugs do not help.
• Prednisolone 0.5 mg/kg daily, tapered over 2 to 4 weeks, only for severe or painful thyroiditis.
• Hypothyroid phase: levothyroxine if symptomatic or thyroid stimulating hormone is over 10 mU/L, at about 1.6 micrograms/kg daily (start 25 to 50 micrograms in older adults or heart disease). Recheck after 6 weeks.
• Reassess after 6 to 12 months of recovery: reduce the dose and retest thyroid stimulating hormone after 6 weeks.
• Replace cortisol first if hypophysitis or adrenal insufficiency is found.

Special groups. Older adults and heart disease: start levothyroxine at the lowest dose and increase slowly. Pregnancy: interferon alpha is avoided; check thyroid function each trimester if exposure continues.

Monitoring. Thyroid function every 4 to 6 weeks until euthyroid, then every 6 to 12 weeks during therapy and at 12 months after stopping.

Referral and escalation. Endocrinology for severe thyrotoxicosis, suspected hypophysitis or diagnostic doubt.