Levothyroxine Initiation and Titration

Levothyroxine replaces thyroid hormone in primary hypothyroidism, central hypothyroidism and after thyroid surgery or radioiodine. It has a half-life of about 7 days, so dose changes take 6 to 8 weeks to show. The aim is to relieve symptoms and normalise TSH in primary disease, without overtreatment.

Targets. In primary hypothyroidism aim for TSH in the reference range, about 0.4 to 4.0 mIU/L. In central hypothyroidism, TSH is unreliable, so aim for free T4 in the upper half of the reference range. In adults over 70 a TSH up to about 6 mIU/L is acceptable.

Check adrenal function. If adrenal insufficiency coexists, start hydrocortisone before levothyroxine to avoid an adrenal crisis.

Treat. Overt hypothyroidism (high TSH with low free T4). Subclinical hypothyroidism (high TSH with normal free T4) is treated if TSH is over 10 mIU/L, if symptoms with positive thyroid peroxidase antibodies are present, in pregnancy or when planning pregnancy, and in younger adults. In older adults with TSH under 10 mIU/L, observe.

Formulation. Levothyroxine sodium tablets 25, 50, 75, 100 and 125 micrograms. Liquid and soft-gel forms help when absorption is poor. Liothyronine is not routine.

Starting dose.

• Adults under 50 years without heart disease: 1.6 micrograms/kg/day, rounded to the nearest tablet.
• Adults over 50 years, or with heart disease: start 25 to 50 micrograms once daily and increase by 12.5 to 25 micrograms every 6 to 8 weeks.
• Cardiac disease or frailty: start 12.5 to 25 micrograms once daily.

Titration. Check TSH 6 to 8 weeks after starting and after each dose change, adjusting by 12.5 to 25 micrograms until TSH is in range. Once stable, check TSH every 6 to 12 months.

Administration. Take on an empty stomach, 30 to 60 minutes before breakfast with water, or at bedtime at least 3 hours after the last meal. Keep the timing the same each day.

Interactions. Separate by 4 hours from iron, calcium, antacids, sucralfate, cholestyramine and multivitamins. Proton pump inhibitors, orlistat and coffee reduce absorption. Rifampicin, carbamazepine, phenytoin and phenobarbital increase clearance, so doses need to rise. Warfarin effect increases as thyroid status normalises.

Pregnancy. Increase the dose by 25 to 30% as soon as pregnancy is confirmed (for example, two extra tablets weekly), check TSH every 4 weeks until 20 weeks, and keep TSH in the trimester-specific range (generally under 2.5 mIU/L). Return to the pre-pregnancy dose after delivery.

Myxoedema coma. Give levothyroxine 200 to 400 micrograms intravenously as a loading dose (lower in older adults and cardiac disease), then 1.6 micrograms/kg daily intravenously at 75% of the oral dose, with hydrocortisone 100 mg intravenously every 8 hours, passive rewarming, and supportive care.

Special groups.

• Congenital hypothyroidism: start 10 to 15 micrograms/kg daily within the first 2 weeks; dosing by paediatric endocrinology.
• Children: weight-based doses that fall with age, set by a paediatric endocrinologist.
• Older adults and cardiac disease: start low and go slow.
• Kidney and liver impairment: no routine adjustment.
• Breastfeeding: compatible.
• Malabsorption or after bariatric surgery: higher doses or liquid forms may be needed.

Monitoring. TSH 6 to 8 weeks after any change, and annually once stable. Free T4 in central hypothyroidism. Repeat TSH after starting a new interacting drug.

Overtreatment. Suppressed TSH raises the risk of atrial fibrillation and bone loss. Reduce the dose when TSH is under 0.1 mIU/L.

Persistent symptoms. Check adherence, timing with food, interacting drugs, coeliac disease and gastric causes of malabsorption before increasing the dose.

Stopping. Treatment is usually lifelong. In subclinical disease, stopping can be attempted with a repeat TSH at 6 to 8 weeks.

Referral and escalation. Refer for suspected central hypothyroidism, TSH that does not normalise on over 2 micrograms/kg, pregnancy, thyroid nodules or goitre, and myxoedema coma, which is an emergency.