Diagnosis

Diagnosis is based on the finding of an elevated free T4 or free T3 when accompanied by a suppressed TSH. Free T4 is elevated in around 75% of cases but in the remaining 25% of cases, the free T4 is normal, and only the free T3 elevated (T3 toxicosis). All patients with thyrotoxicosis (except rare cases of thyrotoxicosis due to TSH secreting pituitary adenoma) will have a suppressed TSH level. Measure FBC at start of therapy. Measurement of TSH receptor antibodies will help to identify if the aetiology of hyperthyroidism is Graves' disease.

Monitoring the effect of treatment

The success of treatment is measured by a decrease in free T4 and/or T3 levels back to normal. TSH may remain suppressed for longer and should not be used acutely to measure response to treatment in thyrotoxicosis.

Oral medication is usually with carbimazole. See 6.2.2 Antithyroid drugs

Carbimazole

• Carbimazole daily dose is 20-40mg and maintained at this dose until the patient becomes euthyroid (usually after 4 to 8 weeks).
• After euthyroidism is achieved, two different schedules can be employed termed 'block and replace' and 'reducing dose'.
• In block and replace a suppressive dose of carbimazole (40mg) is given with levothyroxine supplements added once the T4 and T3 has returned to normal.
• In a reducing dose schedule, carbimazole 15-40mg a day is given as a single daily dose depending on the severity of hyperthyroidism, with a decreasing dose as the thyroid function returns to normal.
• These treatment schedules are described in more detail below.

Propylthiouracil

• Propylthiouracil should only be used as second-line therapy due to rare reports of fulminant hepatic toxicity. An exception is early pregnancy when it is first-line treatment because carbimazole use in early pregnancy may be associated with foetal congenital abnormalities.
• Propylthiouracil is started at a dose of 300-600mg daily until the patient is euthyroid, then maintained at 50-150mg.

Block and replace schedule

• Treatment is started with carbimazole 40mg daily. This is maintained throughout treatment. 100 micrograms levothyroxine is added when the free T4 and free T3 has returned to normal, usually after about 6 weeks (TSH may still be suppressed).
• The free T4 is then monitored to assess the replacement dose of levothyroxine. If the free T4 is less than 15pmol/L after a further 6 weeks, the replacement dose of levothyroxine may be increased to 150 micrograms daily. Aim to titrate levothyroxine to keep the free T4 in the upper half of the normal range.

Hyperthyroidism in pregnancy should NOT be treated with block and replace treatment. See guidance below for hyperthyroidism in pregnancy.

Reducing dose schedule

The alternative approach of reducing dose carbimazole is used when there is concern about compliance, in pregnant women, in elderly patients or those likely to remain on treatment long term (e.g. patients who have relapse) or patient preference. In this case, once the free T4 is normal, the dose of carbimazole should be halved and, as long as thyroid function remains normal, can often be halved every 6 weeks. In patients in whom the free T4 or free T3 is only just raised (less than 25% above normal) who are not markedly symptomatic, a starting dose of 10mg carbimazole may be appropriate.

Monitoring the effect of treatment

• The success of treatment is measured by a decrease in free T4 and/or T3 levels back to normal. TSH may remain suppressed for longer and should not be used acutely to measure response to treatment in thyrotoxicosis.
• Monitoring should be initially every 6 weeks or if patient develops symptoms suggestive of hypo or hyperthyroidism. When the patient is euthyroid on stable doses, monitoring frequency can be reduced to 3 monthly (titration regime) or 6 monthly (block and replacement regime).
• The recommended duration of treatment is 18 months (range 6-24). Remission rate following oral medication is about 50%.
• After stopping medical treatment, thyroid function tests should be performed if suggested clinically and, if asymptomatic, 3 monthly for 2 years, and then yearly subsequently.

Side effects of anti-thyroid drugs

All patients must be warned about the danger of agranulocytosis (see below).

Doctors are reminded of the importance of recognising bone marrow suppression induced by carbimazole and propylthiouracil, and the need to stop treatment promptly.

1. Patients should be asked to report symptoms and signs suggestive of infection, especially sore throat, mouth ulcers and high fever.
2. A white blood cell count should be performed if there is any clinical evidence of infection.
3. Carbimazole and propylthiouracil should be stopped promptly pending results of clinical or laboratory evidence of neutropenia.

Pruritus and allergic rashes are common with carbimazole and, often respond to antihistamines without needing to stop the drug. If troublesome, patient should be referred for consideration of alternative treatments (such as, radioiodine) for thyrotoxicosis.

Patients receiving propylthiouracil should be told how to recognise signs of liver disorder and advised to seek prompt medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain, jaundice, dark urine, or pruritus develop.

Usually radioiodine and surgery are reserved for patients who relapse from medical treatment. Radioiodine should not be given to patients with active eye disease and only given to patients with inactive eye disease after careful ophthalmology assessment. Patients who relapse after 18 months treatment should be started on carbimazole if symptomatic and referred urgently to the thyroid clinic to discuss the treatment options.

• Subclinical hyperthyroidism is when the TSH is below the reference range but the free T4 and free T3 are in the normal range.
• If the free T4/T3 are in the lower half of the reference range pituitary disease (secondary hypothyroidism) should be considered.
• Non-thyroidal illness should be excluded. The tests should be repeated after 2 months (many will normalise or develop overt hyperthyroidism) then patients should be divided into:
  • TSH fully suppressed
  • Low TSH ≤ 0.4mU/L
• Tests should be repeated every 3-6 months for 1 year, then annually (if the TSH is stable and the patient is well). Consider referral if goitre is present or thyrotoxicosis develops.
• There is evidence that subclinical hyperthyroidism increases risk of osteoporosis and atrial fibrillation (AF) but evidence is limited that reversing this improves outcome.
• Subclinical hyperthyroidism with TSH 0.1-0.4mU/L generally does not require treatment. Decision to treat a fully suppressed TSH should be made on an individual basis, but patients at risk of osteoporosis and AF could be treated with low dose carbimazole or occasionally radioiodine therapy.

Hyperthyroidism in pregnancy should NOT be treated with block and replace.

Low dose propylthiouracil is probably the drug of choice for the first trimester and patients should be referred for specialist assessment and to combined antenatal endocrine clinic for close monitoring of prescription. Hyperthyroidism may improve in pregnancy with only very low doses or no anti-thyroid medication required. TSH receptor antibody titre should be checked in pregnancy to determine risk of neonatal hyperthyroidism.

• In uncomplicated first cases of hyperthyroidism, a patient should be offered an overview appointment with the local endocrine specialist. This may be a single consultation, in which a management plan is agreed between the patient, the specialist and the general practitioner.
• Patients with recurrent hyperthyroidism should also be referred to plan definitive treatment.
• Pregnant women with history of thyrotoxicosis should be referred to joint ante-natal endocrine clinic.
• Patients with thyroid eye disease should be referred for ophthalmology assessment.
• Specialist referral may be indicated where specifically requested by the patient.