Thyrotoxicosis is often clinically obvious but treatment should never be instituted without biochemical confirmation. Differentiation of the mild case from anxiety states may be difficult; useful positive clinical markers are eye signs, proximal myopathy and wasting. The hyperdynamic circulation with warm peripheries seen with thyrotoxicosis can be compared with the clammy hands of anxiety.
Serum TSH is suppressed «0.1 mU litre'”) though most physicians also like to confirm the diagnosis with a raised serum T, or T4; the former is more sensitive as there are occasional cases of ‘T, toxicosis’. Microsomal (directed against thyroid peroxidase) and thyroglobulin antibodies are present in most cases of Graves’ disease. TSH receptor antibodies are not measured routinely, but are present: TSI 80% positive, TBII 60–90% in Graves’ disease.
The TRH test is now very rarely necessary. A normal TSH rise excludes the diagnosis; a flat response is characteristic but not diagnostic.
Three possibilities are available: antithyroid drugs, surgery and radioiodine. Practices and beliefs differ widely within and between countries; it also depends on patient preference and local expertise. Some general guidelines are:
PATIENTS WITH LARGE GOITRES, SINGLE OR MULTIPLE NODULAR GOITRES are unlikely to remit after a course of antithyroid drugs.
RADIOIODINE is now more widely used in the UK for those under the age of 40 years as has previously happened elsewhere; theoretical risks of carcinogenesis were not proven.
PATIENTS WITH DYSTHYROID EYE DISEASE may show worsening of eye problems after radioiodine, though this can often be prevented by steroid or early T4 administration.
PATIENTS WHO DEMONSTRATE POOR COMPLIANCE with drug therapy should probably undergo surgery.
PATIENT PREFERENCE, with informed discussion of the alternatives, must be given great weight.
Carbimazole is most often used in the UK. Occasionally propylthiouracil is also used. Methimazole, the active metabolite of carbimazole, is used in the USA. These drugs inhibit the formation of thyroid hormones and also have minor other actions; carbimazole/ methimazole is also an immunosuppressive agent. Initial doses and side-effects are detailed. Though thyroid hormone synthesis is reduced very quickly, the long half-life of T. (7 days) means that clinical benefit is not apparent for 10–20 days. As many of the manifestations of hyperthyroidism are mediated via the sympathetic system, f3-blockers are used to provide rapid partial symptomatic control; they also decrease peripheral conversion of T. to T,. Drugs preferred are those without intrinsic sympathomimetic activity. They should not be used alone for hyperthyroidism except when the condition is self-limiting, e.g. subacute thyroiditis.
Subsequent management is either by gradual dose titration or a ‘block and replace’ regimen.
GRADUAL DOSE TITRATION
Review after 4-6 weeks and reduce dose of carbimazol depending on clinical state and T./T3Ievels. TSH levels may remain suppressed for long periods. 2 When clinically and biochemically euthyroid, stop 13- blockers.
3 Review after 2-3 months and, if controlled, reduce carbimazole. Once-daily dosage is now possible.
4 Gradually reduce dose to 5 mg daily over 12-18 months if thyrotoxicosis remains controlled.
5 When euthyroid on 5 mg daily carbirnazole, discontinue.
6 About 50% of patients will relapse, mostly within the following 2 years. Long-term antithyroid therapy is then used or surgery or radiotherapy is considered (see below).
7 Propylthiouracil is used in similar fashion but doses required are tenfold higher (50-500 mg daily).
‘BLOCK AND REPLACE’ REGIMEN. With this policy, full doses of antithyroid drugs, usually carbimazole 30-45 mg daily, are given to suppress the thyroid completely while replacing thyroid activity with T. 0.1 mg daily. This is continued usually for 18 months, the claimed advantages being the avoidance of over- or under-treatment and the better use of the immunosuppressive action. Against this there is no ‘feel’ for whether the patient is likely to relapse as with the titration method.
TOXICITY. The major side-effect is agranulocytosis that occurs in approximately 1 in 1000 patients within 3 months of treatment. All patients must be warned to seek immediate medical attention if they develop unexplained fever or sore throat; this is best done with a written sheet. If toxicity occurs on carbimazole, propylthiouracil may be used and vice versa; side-effects are only occasionally repeated on the other drug. Surgery – subtotal thyroidectomy Thyroidectomy should only be performed in patients who have previously been rendered euthyroid. Conventional practice is to stop the antithyroid drug 10-14 days before operation and to give potassium iodide (60 mg three times daily), which reduces the vascularity of the gland. Particular indications for surgery are:
• Patient choice.
• A large goitre is unlikely to respond to antithyroid medication.
Indications for either surgery or radioiodine are:
• Persistent drug side-effects (also suitable for radioiodine)
• Poor compliance with drug therapy
• Recurrent hyperthyroidism after drugs
The operation should only be performed by experienced surgeons to reduce the chance of complications:
EARLY POSTOPERATIVE BLEEDING causing tracheal compression and asphyxia is a rare emergency requiring immediate removal of all clips/sutures to allow escape of the bloodlhaematoma.
LARYNGEAL NERVE PALSY (1%); vocal chord movement should be checked preoperatively. Mild hoarseness is more common and thyroidectomy is best avoided in serious singers!
TRANSIENT HYPOCALCAEMIA in up to 10% but with permanent hypoparathyroidism in less than 1%.
RECURRENT HYPERTHYROIDISM (less than 5%).
HYPOTHYROIDISM- about 10% of patients are hypothyroid within 1 year and this percentage increases with time. It is likeliest if microsomal antibodies are positive. Automated computer thyroid registers with annual TSH screening are used in some regions.
Iodine-131 in an empirical dose (usually 18-40 x 1010Bq) accumulates in the thyroid and destroys the gland by local radiation. Early discomfort in the neck and immediate worsening of hyperthyroidism are sometimes seen; again patients must be rendered euthyroid before treatment though they have to stop antithyroid drugs about 5 days before radioiodine.
If worsening occurs, the patient should not receive carbimazole for 2-3 days after radioiodine, as it will prevent radioiodine uptake by the gland. They should receive propranolol until carbimazole can be restarted if necessary; euthyroidism normally returns in 2-3 months.
Apart from the immediate problems above, a major complication is the progressive incidence in subsequent hypothyroidism affecting the majority of subjects over the following 20 years. Though 75% of patients are rendered euthyroid in the short term, a small proportion remain hyperthyroid; increasing the radioiodine dose reduces recurrence but increases the rate of hypothyroidism. Again, long-term surveillance of thyroid function is necessary with frequent tests in the first year after therapy. Special situations in hyperthyroidism.
This rare condition, with a mortality of 10%, is a rapid deterioration of thyrotoxicosis with hyperpyrexia, severe tachycardia and extreme restlessness. It is usually precipitated by stress, infection, surgery in an unprepared patient or radioiodine therapy. With careful management it should no longer occur.
Treatment is urgent. Propranolol in full doses is started immediately together with potassium iodide, antithyroid drugs, corticosteroids (which suppress many of the manifestations of hyperthyroidism) and full supportive measures.
Hyperthyroidism in pregnancy and neonatal life Maternal hyperthyroidism during pregnancy is uncommon and usually mild. Diagnosis can be difficult because of misleading thyroid function tests, although TSH is largely reliable. The pathogenesis is almost always Graves’ disease. TSI crosses the placenta to stimulate the fetal thyroid. Carbimazole also crosses the placenta, but T. does so poorly. The smallest dose of carbimazole necessary is used and the fetus must be monitored (see below). The paediatrician should be informed and the infant checked immediately after birth -overtreatment with carbimazole can cause fetal goitre.
If necessary (high doses needed, poor patient compliance or drug side-effects), surgery can be performed, preferably in the second trimester. Radioactive iodine is absolutely contraindicated.
The fetus and maternal Graves’ disease Any mother with a history of Graves’ disease may have circulating TSr. Even if she has been treated (e.g. by surgery), the immunoglobulin may still be present to
stimulate the fetal thyroid, and the fetus can thus become hyperthyroid, while the mother remains euthyroid.
Any such patient should therefore be monitored during pregnancy. Fetal heart rate provides a direct biological assay of thyroid status, and monitoring should be performed at least monthly. Rates above 160 min ” are strongly suggestive of fetal hyperthyroidism and maternal treatment with carbimazole and/or propranolol may be used. To prevent the mother becoming hypothyroid, T. may be given as this does not easily cross the placenta. Sympathomimetics, used to prevent premature labour, are contraindicated as they may provoke fatal tachycardia in the fetus.
Thyrotoxicosis may also develop in the neonatal period as TSI has a half-life of approximately 3 weeks. Manifestations in the newborn include irritability, failure to thrive and persisting weight loss, diarrhoea and eye signs. Thyroid function tests are difficult to interpret as neonatal normal ranges vary with age.
Untreated neonatal thyrotoxicosis is probably associated with hyperactivity in later childhood.
THYROID EYE DISEASE
This is also known as dysthyroid eye disease or ophthalmic Graves’ disease.
The evidence suggests that the exophthalmos of Graves’ disease is due to specific antibodies that cause retroorbital inflammation with swelling and oedema of the extraocular muscles leading to limitation of movement. This leads to proptosis which can sometimes be unilateral, and increased pressure on the optic nerve may cause optic atrophy. Histology shows a focal oedema and glycosaminoglycan deposition followed by fibrosis. While often associated with Graves’ hyperthyroidism, it need not be so and patients may be hyperthyroid, euthyroid or hypothyroid. TSH receptor antibodies are almost invariably found in the serum but their role in the pathogenesis in unclear.
The clinical appearances are characteristic. Proptosis and limitation of eye movements (by ‘tight’ muscles) are direct effects of the inflammation, while conjunctival oedema, lid lag and corneal scarring are secondary to the proptosis and lack of eye cover. The ability to close the eyes completely is important, as otherwise corneal damage may occur. Visual impairment from optic nerve pressure may occur. Eye manifestations often do not parallel the clinical course of Graves’ disease- in particular the degree of toxicosis. Only 5-10% threaten sight, but the discomfort and cosmetic problems cause great patient anxiety. There is a grading system.
Few investigations are necessary if the appearances are characteristic and bilateral. TSH and T3 or T. should be measured.
The exophthalmos should be measured to allow progress to be monitored. If appearances or measurements are markedly discrepant in the two eyes, other retroorbital space-occupying lesions should be considered: CT or MRI of the orbits will exclude other causes and show enlarged muscles and oedema.
If patients are thyrotoxic this should be normalized, but hypothyroidism must be avoided as this may exacerbate the eye problem: an increased incidence of eye problems after radioiodine treatment reflects this. Direct treatment may be either local or systemic:
METHYLCELLULOSE EYEDROPS are given to aid lubrication. Some patients gain relief by sleeping upright.SYSTEMIC STEROIDS (prednisolone 30-120 mg daily) usually reduce inflammation if more severe symptomsare present. Pulse intravenous methylprednisolone may be more rapidly effective in severe cases.
IRRADIATION OF THE ORBITS (20 Gy in divided doses) is also used in severe instances, with steroid cover. LATERAL TARSORRHAPHY will protect the cornea iflids cannot be closed.
SURGICAL DECOMPRESSION of the orbit(s) is occasionally needed.
CORRECTIVE EYE MUSCLE SURGERY may improve diplopia due to muscle changes, but should be deferred till the situation has been stable for 6 months. Plastic surgery around the eyes may also be of value.
Grade 0 No signs or symptoms
Grade 1 Only signs, no symptoms
Grade 2 Soft tissue involvement
Grade 3 Proptosis (measured with exophthalmometer)
Grade 4 Extraocular muscle involvement
Grade 5 Corneal involvement
Grade 6 Sight loss with optic nerve involvement