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.

Carbimazole

• Carbimazole daily dose is 20-40mg and maintained at this dose until the patient becomes euthyroid (usually after 4 to 8 weeks).
• The dose may then be progressively reduced to the lowest dose which maintains the euthyroid state - usually 5mg. Therapy is usually given for 18 months.
• Pruritus and rashes can often be treated with antihistamines without discontinuing therapy.

Propylthiouracil

• Propylthiouracil is started at a dose of 300-600mg daily until the patient is euthyroid, then maintained at 50-150mg. 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 is associated with congenital malformation in the offspring.

Oral medication is usually with carbimazole, which can either be in a block and replace schedule or reducing dose schedule.

The recommended duration of treatment is 18 months (range 6-24). Remission rate following oral medication is about 50%.

• 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.
• In both cases the efficacy of treatment is monitored by serum free T₄ levels, monitored 4-6 weekly.

Side effects

All patients must be warned about the danger of agranulocytosis (3/1000) and told to see their doctor if they develop a sore throat, ulcerated mouth or high fever. The white cell count and differential should be checked in these patients.

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.

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 should be stopped promptly pending results of clinical or laboratory evidence of neutropenia.

Local Policy - Block and replace

Local policy is usually to recommend block and replace treatment, for practical reasons of thyroid function remaining stable, especially in young people. Thus:

• Treatment is started with carbimazole 40mg daily. This is maintained throughout treatment. 100mcg 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 150mcg daily. Aim to titrate levothyroxine to keep the free T4 in the upper half of the normal range.

Local policy - Reducing dose carbimazole

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.

• The recommended duration of treatment of either type for an initial episode is 18 months.
• 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).
• 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.
• Propylthiouracil is started at a dose of 300-600mg daily until the patient is euthyroid, then maintained at 50-150mg. Propylthiouracil should only be used as second-line therapy due to rare reports of fulminant hepatic toxicity.

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 assessment at the Joint Thyroid Eye Clinic. 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 less than 0.01mU/L
  • Low TSH 0.1 - 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 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 (less than 0.01mU/L) should be made on an individual basis, but patients at risk of osteoporosis and AF could be treated with low dose carbimazole or occasionally radio iodine 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 clinic (every Tuesday AM) for close monitoring of prescription. Hyperthyroidism may improve in pregnancy with only very low doses or no anti-thyroid medication required. Thyroid stimulating antibodies 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.
• Consider referring patients with hypothyroidism if the patient has active and unstable ischaemic heart disease, if there is no improvement or worsening of symptoms on levothyroxine, and if thyroid function tests remain abnormal despite full dose of levothyroxine.
• Pregnant women with history of thyrotoxicosis and hypothyroidism should be referred to joint ante-natal endocrine clinic.
• Patients with thyroid eye disease should be referred to joint thyroid eye clinic.
• Specialist referral may be indicated where specifically requested by the patient.