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Hyperthyroidism Hyperthyroidism (thyroid overactivity, thyrotoxicosis) is common, affecting perhaps 2–5% of all females at some time and with a sex ratio of 5:1, most often between ages 20 and 40 years. Nearly all cases (>99%) are caused by intrinsic thyroid disease; a pituitary cause is extremely rare (Table 16.26). Graves’ disease This is the most common cause of hyperthyroidism/ thyrotoxicosis and is due to an autoimmune process. Serum IgG antibodies bind to the thyroid TSH receptor stimulating thyroid hormone production, behaving like TSH. These TSH receptor antibodies can be measured in serum. There is an association with HLA-B8, Dw3 and 50% concordance is seen amongst monozygotic twins with a 5% concordance rate in dizygotic twins. Yersinia enterocolitica as well as Escherichia coli and other Gram-negative organisms contain TSH binding sites. This raises the possibility that the initiating event in the pathogenesis may be an infection with possible ‘molecular mimicry’ in a genetically susceptible individual, but the precise initiating mechanisms remain unproven in most cases. Associated with the thyroid disease in many cases are eye changes (see below) and other signs such as vitiligo and pretibial myxoedema. Rarely lymphadenopathy and splenomegaly may occur. Graves’ disease is also associated with other autoimmune disorders such as pernicious anaemia and myasthenia gravis. The natural history is one of fluctuation, many patients showing a pattern of alternating relapse and remission; perhaps only 40% of subjects have a single episode. Many patients eventually become hypothyroid. Other causes of hyperthyroidism/thyrotoxicosis Toxic solitary adenoma/nodule (Plummer’s disease) This is the cause of about 5% of cases of hyperthyroidism. It does not usually remit after a course of antithyroid drugs. Toxic multinodular goitre This commonly occurs in older women. Again, antithyroid drugs are rarely successful in inducing a remission. De Quervain’s thyroiditis This is transient hyperthyroidism from an acute inflammatory process, probably viral in origin. Apart from the toxicosis there is usually fever, malaise and pain in the neck with tachycardia and local thyroid tenderness. Thyroid function tests show initial hyperthyroidism, the erythrocyte sedimentation rate (ESR) is raised, and thyroid uptake scans show suppression of uptake in the acute phase, though hypothyroidism, usually transient, may then follow after a few weeks. Treatment of the acute phase is with aspirin, using short-term prednisolone in severely symptomatic cases. Postpartum thyroiditis This is described on p. 932. CLINICAL FEATURES OF HYPERTHYROIDISM The symptoms of hyperthyroidism affect many systems. Symptoms and relevant signs are shown in Fig 16.21. Symptomatology and signs vary with age and with the underlying aetiology. Important points are: •The eye signs, pretibial myxoedema and thyroid acropachy occur only in Graves’ disease. Pretibial myxoedema is an infiltration on the shin, essentially occurring only with eye disease (see below). Thyroid acropachy is very rare and consists of clubbing, swollen fingers and periosteal new bone formation. •In the elderly a frequent presentation is with atrial fibrillation, other tachycardias and/or heart failure, often with few other signs. Thyroid function tests are mandatory in any patient with atrial fibrillation. •Children frequently present with excessive height or excessive growth rate, or with behavioural problems such as hyperactivity. They may also show weight gain rather than loss. •So-called ‘apathetic thyrotoxicosis’ in some elderly patients presents with a clinical picture more like hypothyroidism. There may be very few signs and a high degree of clinical suspicion is essential. DIFFERENTIAL DIAGNOSIS Hyperthyroidism 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, a diffuse goitre, proximal myopathy and wasting. The hyperdynamic circulation with warm peripheries seen with hyperthyroidism can be contrasted with the clammy hands of anxiety. INVESTIGATIONS Serum TSH is suppressed in hyperthyroidism (<0.1 mU L–1), except for the very rare instances of TSH hypersecretion. Most physicians also like to confirm the diagnosis with a raised serum T 3 or T4; the former is more sensitive as there are occasional cases of isolated ‘T 3 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 commonly present: TSI 80% positive, TBII 60–90% in Graves’ disease (see p. 936). TREATMENT Three possibilities are available: radioiodine, antithyroid drugs, and surgery. Practices and beliefs differ widely within and between countries. Treatment also depends on patient preference and local expertise. This section gives some general guidelines. Patient preference, with informed discussion of the alternatives and long-term sequelae, must be given great weight. Where radioiodine or surgery is chosen, patients need to be rendered euthyroid with antithyroid drugs before their definitive therapy. Most patients (90%) with hyperthyroidism have a diffuse goitre. Those with large single or multinodular goitres are unlikely to remit after a course of antithyroid drugs. Severe biochemical hyperthyroidism is also less likely to respond. Radioiodine is now more widely used in the UK as has previously happened elsewhere; theoretical risks of carcinogenesis have not been proven in practice. The range of doses is from about 200 up to 500 MBq, the higher doses having greater ‘cure’ rates but also more, and quicker, subsequent hypothyroidism. Response usually takes 1–6 months. Radiation safety requirements make it usable only in specialist centres. Patients with dysthyroid eye disease may show worsening of eye problems after radioiodine, though this association remains controversial and can often be prevented by steroid or early T 4 administration. Patients who demonstrate poor compliance with drug therapy or medical supervision should probably undergo surgery. Antithyroid drugs 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 in Table 16.27. Although thyroid hormone synthesis is reduced very quickly, the long half-life of T4 (seven 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, ß-blockers may be used to provide rapid partial symptomatic control; they also decrease peripheral conversion of T 4 to T3. Drugs preferred are those without intrinsic sympathomimetic activity (Table 16.27). They should not be used alone for hyperthyroidism except when the condition is self-limiting, as in subacute thyroiditis. Subsequent management is either by gradual dose titration or a ‘block and replace’ regimen. Neither regime has been shown to be unequivocally superior. Gradual dose titration 1 Review after 4–6 weeks and reduce dose of carbimazole depending on clinical state and T 4/T3 levels. TSH levels may remain suppressed for long periods and are unhelpful at this stage. 2 When clinically and biochemically euthyroid, stop ß-blockers. 3 Review after 2–3 months and, if controlled, reduce carbimazole. 4 Gradually reduce dose to 5 mg daily over 6–24 months if hyperthyroidism remains controlled. 5 When the patient is euthyroid on 5 mg daily carbimazole, discontinue. About 50% of patients will relapse, mostly within the following two years. Long-term antithyroid therapy is then used or surgery or radiotherapy is considered (see below). Propylthiouracil is used in similar fashion but doses required are tenfold higher and must be given in split doses (50–500 mg daily). ‘Block and replace’ regimen With this policy, full doses of antithyroid drugs, usually carbimazole 40 mg daily, are given to suppress the thyroid completely while replacing thyroid activity with 100 µg of thyroxine daily once euthyroidism has been achieved. 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 of carbimazole. This regimen is contraindicated in pregnancy as T 4 crosses the placenta less well than carbimazole. Toxicity The major side-effect is agranulocytosis that occurs in approximately 1 in 1000 patients usually within three 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 be performed only 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 thrice daily), which reduces the vascularity of the gland. Particular indications for surgery are: • patient choice • a large goitre, which is unlikely to respond to antithyroid medication. Indications for either surgery or radioiodine are: • persistent drug side-effects • poor compliance with drug therapy • recurrent hyperthyroidism after drugs. The operation and complications The operation should be performed only 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 blood/haematoma. •Laryngeal nerve palsy occurs in 1%. Vocal chord movement should be checked preoperatively. Mild hoarseness is more common and thyroidectomy is best avoided in professional singers! •Transient hypocalcaemia occurs in up to 10% but with permanent hypoparathyroidism in fewer than 1%. •Recurrent hyperthyroidism occurs in 1–3% within one year, then 1% per year. •Hypothyroidism occurs in about 10% of patients within one 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, and have demonstrated that a high proportion of patients become hypothyroid in the long term. Radioactive iodine Iodine-131 in an empirical dose (usually 200–500 MBq) accumulates in the thyroid and destroys the gland by local radiation – though it takes several months to be fully effective. 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 at least four days before radioiodine, and not recommence until three days after radioiodine. It is contraindicated in children, in pregnancy and while breast-feeding. 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 (Table 16.27) 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 of 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, and at least annually thereafter. Special situations in hyperthyroidism Thyroid crisis This rare condition, with a mortality of 10%, is a rapid deterioration of hyperthyroidism 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 T4 does so poorly so a ‘block-and-replace’ regimen is contraindicated. 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. Breast-feeding while on usual doses of carbimazole or propylthiouracil appears to be safe. 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 TSI. 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 per minute are strongly suggestive of fetal hyperthyroidism and maternal treatment with carbimazole and/or propranolol may be used. To prevent the mother becoming hypothyroid, T 4 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. Hyperthyroidism may also develop in the neonatal period as TSI has a half-life of approximately three 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 hyperthyroidism is probably associated with hyperactivity in later childhood. Thyroid hormone resistance Thyroid hormone resistance is an inherited condition caused by an abnormality of the thyroid hormone receptor. Mutations to the receptor result in the need for higher levels of thyroid hormones to achieve the same intracellular effect. As a result, the normal feedback control mechanisms (see Fig 16.2) result in high blood levels of thyroxine with a normal TSH in order to maintain a euthyroid state. This has two consequences: • First, thyroid function tests appear abnormal even when the patient is euthyroid and requires no treatment; this is a particular problem if only T 4 or free T4 levels are measured and, before sensitive TSH assays were developed, some patients were treated inappropriately for hyperthyroidism. • Second, different tissues contain different thyroid hormone receptors and, in some families, receptors in certain tissues may have normal activity. In this case the level of thyroid hormones to maintain euthyroidism at pituitary and hypothalamic levels (which controls secretion of TSH) may be higher than that required in other tissues such as heart and bone, so that these tissues may exhibit ‘thyrotoxic’ effects in spite of a normal serum TSH. This ‘partial thyroid hormone resistance’ can be very difficult to manage effectively. The hypothalamic-pituitary-thyroid axis. The green line indicates negative feedback at the hypothalamic and pituitary level Thyroid eye disease This is also known as dysthyroid eye disease or ophthalmic Graves’ disease. PATHOPHYSIOLOGY The evidence suggests that the exophthalmos of Graves’ disease is due to a specific immune response that causes retro-orbital 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. The precise autoantigen which leads to the immune response remains to be identified, but appears to be an antigen in retro-orbital tissue with similar immuno-reactivity to the TSH receptor. Eye disease, while often associated with Graves’ hyperthyroidism, can also occur in patients who may be hyperthyroid, euthyroid or hypothyroid. TSH receptor antibodies are almost invariably found in the serum but their role in the pathogenesis in unclear. CLINICAL FEATURES The clinical appearances are characteristic (Fig 16.22). 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% of cases threaten sight, but the discomfort and cosmetic problems cause great patient anxiety. A grading system for disease severity is illustrated in Fig 16.22. The signs of thyroid eye disease, and its grading INVESTIGATIONS Few investigations are necessary if the appearances are characteristic and bilateral. TSH and T 3 and T4 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 retro-orbital space-occupying lesions should be considered: CT or MRI of the orbits will exclude other causes and show enlarged muscles and oedema. TREATMENT 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 probably reflects this. Direct treatment may be either local or systemic, and always requires close liaison between specialist endocrinologist and ophthalmologist: •Methylcellulose or hypromellose eyedrops are given to aid lubrication. •Some patients gain relief by sleeping upright. The eyelids can be taped to ensure closure at night. •Systemic steroids (prednisolone 30–120 mg daily) usually reduce inflammation if more severe symptoms are 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 if lids 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 until the situation has been stable for six months. Plastic surgery around the eyes may also be of value.
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