In the first of a short series of articles on endocrinology, H S Randeva and P M G Bouloux explain the various manifestations of thyrotoxicosis and tell you how to diagnose and treat it

Thyrotoxicosis or hyperthyroidism is the clinical syndrome caused by an excess of circulating free thyroxine and free triiodothyronine, or both. It is common, affecting about 2% of women and 0.2% of men.

Causes

Of the causes of thyrotoxicosis (box 1), Graves' disease is the most common (70-80%); toxic thyroid adenoma, toxic multinodular goitre, and subacute thyroiditis account for most of the remainder. Surreptitious overdosing (factitious thyrotoxicosis) is occasionally seen.

Clinical features

Thyrotoxicosis usually develops insidiously, and most patients have had symptoms for at least 3-6 months before presentation. Almost every system is affected (box 2), and patients may initially present to various medical specialists - for example, to a cardiologist with atrial fibrillation, or to a neurologist with myopathy.

Investigations

When thyrotoxicosis is suspected, the diagnosis should be confirmed by measurement of thyroid stimulating hormone and free thyroxine in the serum, which are usually present in low and high concentrations respectively. The concentration of thyroid stimulating hormone may, however, be normal or increased if the cause of thyrotoxicosis is either a pituitary adenoma secreting thyroid stimulating hormone or resistance to thyroid hormone. In the latter case the patient is clinically euthyroid. Estimation of total thyroxine concentration is not useful and may be misleading as various factors, including pregnancy, cirrhosis of the liver, and opiate drugs, alter the binding of thyroxine to thyroxine binding globulin.

When the concentration of thyroid stimulating hormone is low but that of thyroxine normal, serum concentration of free triiodothyronine should be measured to diagnose triiodothyronine (T3) toxicosis. Thyroxine (T4) toxicosis (raised concentration of free thyroxine, normal concentration of free triiodothyronine), which is unusual, may occur with high iodine intake, treatment with amiodarone, severe intercurrent illness, or starvation. Finally, euthyroid patients with Graves' ophthalmopathy, severe non-thyroidal illness, large goitres, or those who have had recent treatment for thyrotoxicosis may have a suppressed concentration of thyroid stimulating hormone.

Graves' disease

Graves' disease is an autoimmune disorder that is distinguished clinically from other forms of hyperthyroidism by the presence of a painless diffuse goitre (90%), ophthalmopathy (60%), pretibial myxoedema (1-5%), and, less often, thyroid acropachy (<1%). The disease is rare in children, but the frequency increases to a peak in the fourth decade, thereafter declining. There is a female preponderance of 10:1, and there may be a family history of thyroid disease or other autoimmune endocrine disease.

Pathogenesis

Hyperthyroidism of Graves' disease is mediated by the stimulant action of thyroid stimulating hormone receptor antibodies on thyrocytes. The major thyroid stimulating hormone receptor antibody in Graves' disease is referred to as the thyroid stimulating antibody (TsAb), which binds to and activates the thyroid stimulating hormone receptor, mimicking the effects of thyroid stimulating hormone, namely biosynthesis and secretion of thyroid hormone. Thyroid stimulating hormone receptor antibodies in Graves' disease may also stimulate thyrocyte proliferation, leading to goitre (thyroid growth stimulating antibodies), or they may block synthesis of thyroid hormone (thyroid stimulating hormone blocking antibodies).

The pathogenesis of the extrathyroidal manifestations of Graves' disease - namely ophthalmology and dermopathy - are less well understood but are thought to be immunologically mediated.¹

Natural history

The concentration of thyroid stimulating antibodies in the serum is presumed to fluctuate because the natural course of Graves' disease is one of alternating relapse and remission over many years in most patients. Some patients, however, have a single episode of hyperthyroidism, sometimes followed by the development of hypothyroidism 10-20 years later. Thyroid failure in the latter is thought to result from the presence of thyroid blocking antibodies (atrophic thyroiditis or primary myxoedema), and from tissue destruction by cell mediated immunity and cytotoxic antibodies.²

Clinical features

The clinical presentation (box 3) comprises the non-specific features of thyrotoxicosis and those specific to Graves' disease (extrathyroidal manifestations). Goitre in Graves' disease is typically symmetrical, painless, diffusely enlarged, and a bruit is often audible over the thyroid.

Thyroid associated ophthalmopathy is closely associated with Graves' hyperthyroidism, although either condition may exist without the other. It may predate (20%), coincide with (40%), or follow successful treatment of hyperthyroidism (40%). Thyroid associated ophthalmopathy results from enlargement of the extraocular muscles and an increase in retro-ocular pressure, caused by lymphocytic infiltration, oedema, and later fibrosis. This results in proptosis and an impairment of extraocular muscle function.

Thyroid associated dermopathy is generally over the shin (pretibial myxoedema) but has been seen in the toes, forehead, and neck. It presents as painless thickening of the skin in nodules or plaques. It is closely associated with ophthalmopathy, with high titres of thyroid stimulating hormone receptor antibodies, and its presence often indicates likely relapse of hyperthyroidism after treatment.

Thyroid acropachy refers to finger clubbing associated with periosteal new bone formation occurring in patients with Graves' disease; almost all patients have thyroid associated ophthalmopathy and thyroid associated dermopathy.

Diagnosis

Graves' disease is usually diagnosed on the basis of the clinical history and examination. Useful points to note are a strong family history of thyroid disease or the presence of extrathyroidal manifestations. Laboratory confirmation of thyroid overactivity is made as described above. In view of the likely need for prolonged medical or destructive treatment, a definitive diagnosis is essential and may require additional investigations in the form of autoantibodies and a thyroid isotope scan.

Autoantibodies to thyroid peroxidase or microsomal antigen can be detected in about 80-90% of patients. They are not specific for Graves' disease, however, as they occur in other types of autoimmune thyroid disease and in 10% of normal subjects.

Radioisotope thyroid scanning (technetium 99m and iodine 123) is useful to differentiate Graves' disease from the other forms of thyrotoxicosis, especially when this is not clinically obvious. In Graves' disease there is an increased uptake of technetium 99m by the thyroid uniformly, whereas with a toxic nodular goitre, the uptake may be patchy and irregular (toxic multinodular goitre), or confined to the area of the nodule, with the uptake over the remainder of the thyroid being suppressed (solitary toxic adenoma).

Treatment

The management of Graves' disease is primarily directed towards the treatment of hyperthyroidism, but also aims to prevent the development or deterioration of the extrathyroidal manifestations, particularly ophthalmopathy.

Graves' hyperthyroidism

There are three principal treatments - medical treatment (drugs), treatment with radioiodine, and surgery - all of which are effective, but the choice of treatment depends on factors such as local circumstances and experience, characteristics and preference of the patient, and access to a specialist centre.

Medical treatment

Antithyroid drugs: carbimazole, methimazole and propylthiouracil constitute the thionamide group of antithyroid drugs. They inhibit the organification of iodide and coupling of iodothyronines, thus reducing production of triiodothyronine and thyroxine. Propylthiouracil also inhibits the peripheral conversion of thyroxine to triiodothyronine. In addition to blocking thyroid hormone biosynthesis, these drugs also lower concentrations of thyroid stimulating hormone receptor antibodies and increase acitivity of suppressor T cells, which suggests that they have immunosuppressive effects.³ Carbimazole is given once daily, which makes it the drug of first choice. Once patients are taking a maintenance dose, serum concentrations of free thyroxine and thyroid stimulating hormone are measured every three months.

The duration of antithyroid treatment has been much studied and debated (6-24 months), but is usually 18 months.⁴

Adverse effects

The commonest are pruritus and a maculopapular rash (<5% of patients). These problems may resolve despite continued treatment, but it is usual to change to another antithyroid drug. Other, less common, adverse effects are shown in box 4.

Outcome

The relapse rate after 18 months' treatment is around 50%. There is some evidence that the longer the duration of treatment the lower the relapse rate (6 months: 30%, 2 years: 80%), but this is not universally accepted. No test will reliably predict relapse, although a large goitre, severe hyperthyroidism at the time of diagnosis, and a high concentration of thyroid stimulating hormone receptor antibodies are all associated with a high relapse rate.

Blockers

These are useful adjunctive agents and ameliorate some of the clinical features, such as tremor, palpitations, and anxiety. Propranolol (120-240 mg/day) is the most commonly used b blocker, although any could be used. Once a euthyroid state has been reached, the b blocker is discontinued.

Radioiodine treatment

Radioiodine acts by destroying functioning thyroid cells and inhibits their ability to replicate; iodine 123 is the isotope used. It is appropriate in nearly all types of hyperthyroidism, especially in elderly people, those with recurrent treatment for hyperthyroidism with antithyroid drugs, or those in whom drug treatment or surgery are contraindicated. Radioiodine is contraindicated in children, pregnancy, and women who are breast feeding; pregnancy is reportedly safe 4 months or more after treatment.⁵

Treatment regimens, which may vary from centre to centre, include administering either an ablative (large) dose or a cal- culated (small) dose of radioiodine; there is no evidence that the calculated dose has any advantage over the ablative dose. Antithyroid drugs are stopped 3-4 days before radioiodine to allow for its effective uptake, and resumed 4 days after treatment to prevent thyroid storm, or, more often, radiation thyroiditis. Thyroid function should be assessed 6-8 weeks after treatment. Given that radioiodine works slowly, it is usual to wait 6 months before giving a further dose of it for persistent hyperthyroidism.

Hypothyroidism, which can occur at any stage after radioiodine treatment, is usually transient in the first 3 months of treat- ment. Permanent hypothyroidism occurs in 50% of those given high doses of radioiodine by 1 year (in 10% of those given low doses); its incidence remains at 1-3% per year thereafter.

Radioiodine treatment of Graves' hyperthyroidism carries a small, but definite, risk of the development of worsening of ophthalmopathy.⁶

Surgery

It is beyond the scope of this article to go into detail about thyroidectomy. Indications are given in box 5. The two most important things to remember are: surgery can damage the recurrent laryngeal nerve, so the vocal cords must be checked preoperatively; parathyroid glands may be removed too, so repeated measurements of the serum concentration of calcium must be made in the immediate postoperative period.

Management of Graves' ophthalmopathy

The aims of treatment are to relieve the symptoms, to suppress the process of the disease, to restore muscle motility, and to improve cosmetic appearance. Fortunately, most cases are mild and require simple measures, but in some, the disease may be severe and require the collaboration of an ophthalmologist. The different aspects of the management are summarised in box 6.

Other causes of thyrotoxicosis

Toxic multinodular goiter

Like Graves' disease, this form of hyperthyroidism is more common in women. Patients tend to be older than those with Graves' disease, however, and because of this, cardiovascular features such as atrial fibrillation or cardiac failure tend to predominate. Treatment is usually with radioiodine treatment or thyroid surgery.

Toxic solitary adenoma

Most patients are female and aged over 40 years. The diagnosis is confirmed by its characteristic findings on thyroid isotope scanning as described earlier. Both radioiodine or surgical lobectomy are effective treatments.

Subacute (de Quervain's) thyroiditis

This is characterised by the presence of a small, tender goitre, systemic upset (flu-like illness), and thyrotoxicosis without hypertension. It is an inflammation of the thyroid gland induced by viruses such as Coxsackie or enteroviruses. The thyrotoxic phase (4-6 weeks) is followed by a similar period of hypothyroidism, and finally by full recovery of thyroid function in 4-6 months. The diagnosis is confirmed by a raised white cell count and erythrocyte sedimentation rate, and low radioisotope uptake by the gland. Treatment is with aspirin or other non-steroidal anti-inflammatory drugs, but occasionally a short course (3-4 weeks) of steroids may be required. Hypothyroidism ensues in < 5% of cases.

Hyperthyroid crisis (thyroid storm)

This uncommon medical emergency is a life threatening exacerbation of thyrotoxicosis. It occurs in patients with untreated or inadequately treated hyperthyroidism, in response to stress factors such as infection, surgery, or trauma, or it may be precipitated by administration of radioiodine, iodinated contrast agents, or withdrawal of antithyroid drugs. The clinical features are those of severe thyrotoxicosis, followed by seizure, coma, hyperpyrexia, dehydration, multisystem failure, and death within a few hours or days. The diagnosis must be made before biochemical confirmation. Treatment is directed at counteracting this effect of excess activity of thyroid hormones: patients are rehydrated and given a broad spectrum antibiotic. Propanolol (80 mg given orally, or 1-5 mg intravenously) is also given, as well as sodium ipodate (500 mg intravenously), and carbimazole (15 mg). Intravenous hydrocortisone or dexamethasone may also be helpful.