Thyroid hormones, antithyroid drugs

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Chapter 37 Thyroid hormones, antithyroid drugs

• Thyroid hormones (thyroxine/levothyroxine T₄, liothyronine T₃).

• Use of thyroid hormone: treatment of hypothyroidism.

• Antithyroid drugs and hyperthyroidism: thionamides, drugs that block sympathetic autonomic activity, iodide and radio-iodine ¹³¹I, preparation of patients for surgery, thyroid storm (crisis), exophthalmos.

• Drugs that cause unwanted hypothyroidism.

• Calcitonin (see Ch. 39).

Thyroid hormones

L-Thyroxine (T₄ or tetra-iodo-l-thyronine) and lio-l-thyronine (T₃ or tri-iodo-l-thyronine) are the natural hormones of the thyroid gland. T₄ is a less active precursor of T₃, which is the major mediator of physiological effect. In this chapter, T₄ for therapeutic use is referred to as levothyroxine (the rINN; see p. 69).

For convenience, the term ‘thyroid hormone’ is used to comprise T₄ plus T₃. Both forms are available for oral use as therapy.

Calcitonin

Physiology and pharmacokinetics

Thyroid hormone synthesis requires oxidation of dietary iodine, followed by iodination of tyrosine to mono- and di-iodotyrosine; coupling of iodotyrosines leads to formation of the active molecules, tetra-iodothyronine (T₄ or L-thyroxine) and tri-iodothyronine (T₃ or l-thyronine).

These active thyroid hormones are stored in the gland within the molecule of thyroglobulin, a major component of the intrafollicular colloid. They are released into the circulation following reuptake of the colloid by the apical cells and proteolysis. The main circulating thyroid hormone is T₄. About 80% of the released T₄ is de-iodinated in the peripheral tissues to the biologically active T₃ (30–35%) and biologically inactive ‘reverse’ T₃ (45–50%); thus most circulating T₃ is derived from T₄. Further de-iodination, largely in the liver, leads to loss of activity.

In the blood both T₄ and T₃ are extensively (99.9%) bound to plasma proteins (thyroxine binding globulin (TBG) and transthyretin (TTR), albumin and lipoproteins). The concentration of TBG is raised by oestrogens (physiological or pharmacological) and prolonged use of neuroleptics. The concentration of TBG is lowered by adrenocortical and androgen (including anabolic steroid) therapy and by urinary protein loss in the nephrotic syndrome. Phenytoin and salicylates compete with thyroid hormone for TBG binding sites. Effects such as these would interfere with the assessment of the clinical significance of measurements of total thyroid hormone concentration but the availability of free thyroid hormone assay largely avoids such complicating factors. Normal values are: free T₄ 9–25 picomol/L, free T₃ 3–9 picomol/L.

T₄ and T₃ are well absorbed from the gut, except in myxoedema coma when parenteral therapy is required.

T₄ (levothyroxine)

A single dose reaches its maximum effect in about 10 days (its binding to plasma proteins is strong as well as extensive) and passes off in 2–3 weeks (t_½ 7 days in euthyroid, 14 days in hypothyroid and 3 days in hyperthyroid subjects).

T₃ (liothyronine)

is about five times as biologically potent as T₄; a single dose reaches its maximum effect in about 24 h (its binding to plasma proteins is weak) and passes off in 1 week (t_½ 2 days in euthyroid subjects).

Pharmacodynamics

Thyroid hormone passes into the cells of target organs. T₄ is de-iodinated to T₃, which combines with specific nuclear receptors and induces characteristic metabolic changes:

• Protein synthesis during growth.

• Increased metabolic rate with raised oxygen consumption.

• Increased sensitivity to catecholamines with proliferation of β-adrenoceptors (particularly important in the cardiovascular system).

Levothyroxine for hypothyroidism

The main indication for levothyroxine is treatment of thyroxine deficiency (cretinism, adult hypothyroidism) from any cause. The adult requirement of hormone is remarkably constant, and dosage does not usually have to be altered once the optimum has been found. Patients should be monitored annually. Monitoring needs to be more frequent in children, who may need more as they grow. Similarly, pregnant women should be monitored monthly, and require a 50–100% increase in their normal dose of levothyroxine.

Early treatment of neonatal hypothyroidism (cretinism) (1 in 5000 births) is important if permanent mental defect is to be avoided. It must be lifelong.

Hypothyroidism due to panhypopituitarism requires replacement with glucocorticoids as well as with thyroid hormone. Use of levothyroxine alone can cause acute adrenal insufficiency.

Small doses of levothyroxine in normal subjects merely depress pituitary thyroid-stimulating hormone (TSH) production and consequently reduce the output of thyroid hormone by an equivalent amount.

Levothyroxine is used in some countries for the treatment of non-toxic nodular goitre, on the assumption that nodular thyroid tissue growth is dependent on TSH. The treatment is not curative. Levothyroxine should not be used to treat obesity (see Obesity, p. 602).

Treatment of hypothyroidism

Levothyroxine tablets

contain pure L-thyroxine sodium and should be used.

The initial oral dose in healthy patients under the age of 60, without cardiac disease, is 50–100 micrograms/day. In the old and patients with heart disease or multiple coronary risk factors, this level should be achieved gradually (to minimise cardiovascular risk due to a sudden increase in metabolic demand), starting with 12.5–25 micrograms daily for the first 2–4 weeks, and then increasing by 12.5 micrograms monthly until normal TSH levels are achieved.

The usual replacement dose at steady state in patients with complete thyroid failure, is 1.6 micrograms/kg/day, 100–200 micrograms per day given as a single dose. This is usually sufficient to reduce plasma TSH to normal (0.3–3.5 mU/L), which is the best indicator of adequate treatment. Patients who appear to need increasing doses with fluctuating TSH levels, are probably not taking their tablets consistently; the possibility of malabsortion or other drug interaction should be excluded. The maximum effect of a dose is reached after about 10 days and passes off over about 2–3 weeks. Absorption is more complete and less variable if levothyroxine is taken at the same time every day, one hour before breakfast.

Tablets containing physiological mixtures of levothyroxine and liothyronine are not sufficiently evaluated to recommend in preference to levothyroxine alone.

Hypothyroid patients tend to be intolerant of drugs in general owing to slow metabolism.

Liothyronine tabs

Liothyronine is the most rapidly effective thyroid hormone, a single dose giving maximum effect within 24 h and passing off over 24–48 h. It is not routine treatment for hypothyroidism because its rapid onset of effect can induce heart failure. Its main uses are myxoedema coma and psychosis, both rare conditions. A specialised use is during the withdrawal of levothyroxine replacement (to permit diagnostic radioiodine scanning) in patients with thyroid carcinoma.

Myxoedema coma follows prolonged total hormone deficiency and constitutes an emergency. Liothyronine 5–20 micrograms is given intravenously every 12 h. Intravenous therapy is mandatory because drug absorption is impaired. Intravenous hydrocortisone should be given to cover the possibility of coexisting adrenocortical insufficiency.

Subclinical hypothyroidism

Subclinical hypothyroidism is defined as an elevated serum TSH concentration in the presence of normal free T₄ and free T₃. Although termed subclinical, 25% of patients have symptoms of hypothyroidism and cognitive disturbance. Meta-analyses of population based studies show a higher incidence of ischaemic heart disease and mortality in subjects younger than 65 years. Indications for treatment are pregnancy, ovarian dysfunction/infertility, symptoms of hypothyrodism, TSH ≥ 10 mU/L, TSH < 10 mU/L and positive thyroid antibodies and patients with high risk of cardiovascular disease.

Adverse effects

of thyroid hormone parallel the increase in metabolic rate. The symptoms and signs are those of hyperthyroidism. Symptoms of myocardial ischaemia, atrial fibrillation or heart failure are liable to be provoked by too vigorous therapy or in patients having serious ischaemic heart disease who may even be unable to tolerate optimal therapy. Should they occur, discontinue levothyroxine for at least a week, and recommence at lower dose. Only slight overdose may precipitate atrial fibrillation in patients aged over 60 years.

In pregnancy

a hypothyroid patient on thyroxine replacement should be assessed with a preconception TSH level measurement and free T₄ and TSH should be checked once pregnancy is confirmed. Monthly measurements of free T₄ and TSH are recommended. Optimal replacement therapy is essential in the first trimester when the athyroid fetus is dependent on maternal supply to ensure normal neuro-intellectual development. An average 50% increase in dose of levothyroxine is required and ideally patients should anticipate this increase. Some endocrinologists advise patients to increase their daily dose by 30% or 25–50 micrograms per day. Post delivery, patients revert to their preconception dose. Breast feeding is not contraindicated.

Antithyroid drugs and hyperthyroidism

Drugs used for the treatment of hyperthyroidism include:

• Thionamides, which block the synthesis of thyroid hormone.

• Iodine: radioiodine, which destroys the cells that make thyroid hormone; iodide, an excess of which reduces the production of thyroid hormone temporarily (it is also necessary for the formation of hormone, and both excess and deficiency can cause goitre).

Thionamides (thiourea derivatives) carbimazole, methimazole, propylthiouracil

Mode of action (Fig. 37.1)

The major action of thionamides is to reduce the formation of thyroid hormone by inhibiting oxidation and organification (incorporation into organic form) of iodine (iodotyrosines) and coupling of iodotyrosines. Maximum effect is delayed until existing hormone stores are exhausted (weeks, see below). With high dose, reduced hormone synthesis leads to hypothyroidism.

Fig. 37.1 Effects of antithyroid drugs. The multiple effects of antithyroid drugs include inhibition of thyroid hormone synthesis and a reduction in both intrathyroid immune dysregulation and (in the case of propylthiouracil) the peripheral conversion of thyroxine to tri-iodothyronine. Tyrosine-Tg, tyrosine residues in thyroglobulin; 1⁺, the iodinating intermediate; TPO, thyroid peroxidase.

(Adapted from Cooper D S 2005 Antithyroid drugs. New England Journal of Medicine 352:905–917.)

Carbimazole and methimazole

(the active metabolite of carbimazole) (t_½ 6 h) and propylthiouracil (t_½ 2 h) are commonly used, but the t_½ matters little because the drugs accumulate in the thyroid and act there for 30–40 h; thus a single daily dose suffices.

Propylthiouracil

(PTU) differs from other members of the group in that it also inhibits peripheral conversion of T₄ to T₃, but only at high doses used in treatment of thyroid storm (see p. 594). PTU differs from the other thionamides in its apparent radio-protective effect when used prior to radioiodine treatment.

Carbimazole is the drug of choice in the UK. PTU is used when a patient develops side-effects to carbimazole. PTU is not recommended in children because of the increased risk of severe hepatotoxicity and death.

Immunosuppression

In patients taking antithyroid drugs, serum concentrations of antithyrotropin receptor antibodies decrease with time, as do other immunologically important molecules, including intracellular adhesion molecule 1, and soluble interleukin-2 and interleukin-6 receptors. There is an increased number of circulating suppressor T cells and a decreased number of helper T cells. Antithyroid drugs may also induce apoptosis of intrathyroidal lymphocytes.

Doses

• Carbimazole 40 mg total/day is given orally (or methimazole 30 mg) until the patient is euthyroid (usually 4–6 weeks). Then either titrate (titration regimen) by decrements initially of 10 mg every 4–6 weeks to a maintenance dose of 5–10 mg/day, or continue (block–replace regimen) 40 mg once daily, and add levothyroxine 100 micrograms/day, with monitoring of free T₄ and TSH.

• Propylthiouracil 300–450 mg total/day is given orally until the patient is euthyroid: maintenance 50–100 mg total/day. Much higher doses (up to 2.4 g/day) with frequent administration are used for thyroid storm.

Use

It is probable that no patient is wholly refractory to these drugs. Failure to respond is likely to be due to the patient not taking the tablets or to wrong diagnosis. The drugs are used in hyperthyroidism:

• As principal therapy.

• As adjuvant to radioiodine, before and after administration, to control the disease until the radiation achieves its effect.¹

• To prepare patients for surgery.

Clinical improvement is noticeable in 2–4 weeks, and the patient should be euthyroid in 4–6 weeks.

The best guides to therapy are the patient’s symptoms (decreased nervousness and palpitations), increased strength and weight gain, and decreased pulse rate.

Symptoms and signs are, of course, less valuable as guides if the patient is also taking a β-adrenoceptor blocker, and reliance then rests on biochemical tests.

With optimal treatment the gland decreases in size, but over-treatment leading to low hormone concentrations in the blood activates the pituitary feedback system, inducing TSH secretion and goitre.

Adverse reactions

The thionamide drugs are all liable to cause adverse effects. Minor reactions include maculopapular or urticarial rash, pruritus, arthralgia, fever, anorexia, nausea, abnormalities of taste and smell. Major effects include agranulocytosis, aplastic anaemia, thrombocytopenia, acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome, vasculitis.

Blood disorders (< 3 per 10 000 patient-years) are most common in the first 2 months of treatment. Routine leucocyte counts to detect blood dyscrasia before symptoms develop are unlikely to protect, as agranulocytosis may be so acute that blood counts give no warning. Patients must be given written warning to stop the drug and have a leucocyte count performed if symptoms of a sore throat, fever, bruising or mouth ulcers develop. Any suggestion of anaemia should be investigated.

Cross-allergy between the drugs sometimes occurs, but is not to be assumed for agranulocytosis. Treatment of agranulocytosis consists of drug withdrawal, admission to hospital, and administration of broad-spectrum antibimicrobials plus granulocyte colony-stimulating factor.

Pregnancy

If a pregnant woman has hyperthyroidism (2 per 1000 pregnancies), she should be treated with the smallest possible amount of these drugs because they cross the placenta; over-treatment causes fetal goitre. Meticulous control is essential and thyroid test should be monitored monthly. Surgery in the second trimester may be preferred to continued drug therapy. Ideally, patients should be rendered euthyroid prior to pregnancy.

Both PTU and carbimazole are considered safe in nursing mothers but because of the risk of hepatotoxicity carbimazole is preferred.

Control of antithyroid drug therapy

The aim of drug therapy is to control the hyperthyroidism until a natural remission takes place. The recommended duration of therapy is 12–18 months. Longer treatment is usual for young patients with large, vascular goitres, because of the higher risk of recurrence (2–3 years). A shorter course (6–9 months) is recommended for the block–replace regimen. Most patients enter remission, but some will relapse – usually during the first 3 months after withdrawal from treatment. Approximately 30–40% of patients remain euthyroid 10 years later. If hyperthyroidism recurs, there is little chance of a second course of thionamide achieving long-term remission. In such patients, indefinite low-dose antithyroid treatment is an alternative option to radioiodine or surgery.

The use of levothyroxine concurrently with an antithyroid drug (‘block and replace regimen’) facilitates maintenance of a euthyroid state and reduces the frequency of clinic visits. There is a higher risk of the dose-related adverse effects of carbimazole, and no compensatory reduction in the incidence of relapse. Therefore, the ‘titration’ (see above) regimen is regarded as first-line treatment.

β-Adrenergic blockade

There is increased tissue sensitivity to catecholamines in hyperthyroidism with a rise in either the number of β-adrenoceptors or the second-messenger response (i.e. intracellular cyclic AMP synthesis) to their stimulation. Therefore, some of the unpleasant symptoms are adrenergic.

Quick relief can be obtained with a β-adrenoceptor blocking drug (judge the dose by heart rate), although these do not block all the metabolic effects of the hormone, e.g. on the myocardium, and the basal metabolic rate is unchanged. For this reason, β-blockade is not used as sole therapy except in mild thyrotoxicosis in preparation for radioiodine treatment, and in these patients it should be continued until the radioiodine has taken effect. β-Blockers do not alter the course of the disease, or affect biochemical tests of thyroid function. Any effect on thyroid hormonal action on peripheral tissues is clinically unimportant. Although atenolol is widely used, it is preferable to choose a drug that is non-selective for β₁ and β₂ receptors and lacks partial agonist effect (e.g. propranolol 20–80 mg 6–8-hourly, or timolol 5 mg once daily). The usual contraindications to β-blockade (see p. 403) apply, especially asthma.

Iodine (iodide and radioactive iodine)

Iodide is well absorbed from the intestine, distributed like chloride in the body, and rapidly excreted by the kidney. It is selectively taken up and concentrated (about × 25) by the thyroid gland, more in hyperthyroidism and less in hypothyroidism. A deficiency of iodide reduces the amount of thyroid hormone produced; this stimulates the pituitary to secrete TSH. The result is hyperplasia and increased vascularity of the gland, with eventual goitre formation.²

Effects

The effects of iodide are complex and related to the dose and thyroid status of the subject.

In hyperthyroid subjects, a moderate excess of iodide may enhance hormone production by providing ‘fuel’ for hormone synthesis. But a substantial excess inhibits hormone release and promotes storage of hormone and involution of the gland, making it firmer and less vascular so that surgery is easier. The effect is transient and its mechanism uncertain.

In euthyroid subjects with normal glands an excess of iodide from any source can cause goitre (with or without hyperthyroidism), e.g. use of iodide-containing cough medicines, iodine-containing radiocontrast media, amiodarone, seaweed eaters.

A euthyroid subject with an autonomous adenoma (hot nodule) becomes hyperthyroid if given iodide.

Uses

Iodide (large dose) is used for thyroid storm (crisis) and in preparation for thyroidectomy because it rapidly benefits the patient by reducing hormone release and renders surgery easier and safer (above).

Potassium iodate

in doses of 85 mg orally 8-hourly (longer intervals allow some escape from the iodide effect) produces some effect in 1–2 days, maximal after 10–14 days, after which the benefit declines as the thyroid adapts. A similar dose used for 3 days covers administration of some ¹³¹I- or ¹²³I-containing preparations, for instance meta-iodobenzylguanidine (¹²³I-MIBG) (see p. 409).

Iodine therapy maximises iodide stores in the thyroid, which delays response to thionamides. Prophylactic iodide (1 part in 100 000) may be added to the salt, water or bread where goitre is endemic.

In economically deprived communities, a method of prophylaxis is to inject iodised oil intramuscularly every 3–5 years; given early to women, this prevents endemic cretinism but occasional hyperthyroidism occurs (see autonomous adenoma, above).

As an antiseptic

for use on the skin, povidone–iodine (a complex of iodine with a sustained-release carrier, povidone or polyvinyl–pyrrolidone) can be applied repeatedly and used as a surgical scrub.

Bronchial secretions

Iodide is concentrated in bronchial and salivary secretions. It acts as an expectorant (see Cough, p. 467).

Organic compounds

containing iodine are used as contrast media in radio-imaging. It is essential to ask patients specifically whether they are allergic to iodine before such contrast media are used. Severe anaphylaxis, even deaths, occur every year in busy imaging departments; iodine-containing contrast media are being superseded by so-called non-ionic preparations.³

Adverse reactions

Patients vary enormously in their tolerance of iodine; some are intolerant or allergic to it both orally and when it is applied to the skin.

Symptoms of iodism

include: a metallic taste, excessive salivation with painful salivary glands, running eyes and nose, sore mouth and throat, a productive cough, diarrhoea, and various rashes that may mimic chickenpox. A saline diuresis enhances elimination.

Goitre can occur (see above) with prolonged use of iodide-containing expectorant by bronchitics and asthmatics. Such therapy should therefore be intermittent, if it is used at all.

Topical application of iodine-containing antiseptics to neonates has caused hypothyroidism. Iodide intake above that in a normal diet will depress thyroid uptake of administered radioiodine, because the two forms will compete.

In the case of diet, medication, and water-soluble radio-diagnostic agents, interference with thyroid function will cease 2–4 weeks after stopping the source, but with agents used for cholecystography it may last for 6 months or more (because of tissue binding).

Radioiodine (¹³¹I)

¹³¹I is treated by the body just like the ordinary non-radioactive isotope, so that when swallowed it is concentrated in the thyroid gland. It emits mainly β radiation (90%), which penetrates only 0.5 mm of tissue and thus allows therapeutic effects on the thyroid without damage to the surrounding structures, particularly the parathyroids. It also emits some γ-rays, which are more penetrating and are detectable with a radiation counter.⁴ ¹³¹I has a physical (radioactive) t_½ of 8 days.

¹³¹I is the preferred initial treatment for hyperthyroidism caused by Graves’ disease in North America. It is contraindicated in children and pregnant or breast-feeding women, and can induce or worsen ophthalmopathy. It is used in combination with surgery in thyroid carcinoma.

In hyperthyroidism, the beneficial effects of a single dose may be felt in 1 month, and patients should be reviewed at 6 weeks to monitor for onset of hypothyroidism. The maximal effect of radioiodine may take 3 months to achieve. β-Adrenoceptor blockade and, in severe cases, an antithyroid drug (but see footnote 1) will be needed to render the patient comfortable while waiting; this is more likely when radioiodine is used for patients with relapsing thyrotoxicosis. Very rarely radiation thyroiditis causes excessive release of hormone and thyroid storm. Repeated doses may be needed.

Adverse effects of radioiodine are as for iodism, above. In the event of inadvertent overdose, large doses of sodium or potassium iodate should be given to compete with the radioiodine for thyroid uptake and to hasten excretion by increasing iodide turnover (increased fluid intake and a diuretic are adjuvants).

Radioiodine offers the advantages that treatment is simple and carries no immediate mortality, but it is slow in acting and the dose that will render the patient euthyroid is difficult to judge. In the first year after treatment, 20% of patients will become hypothyroid. Thereafter, 5% of patients become hypothyroid annually, perhaps because the capacity of thyroid cells to divide is permanently abolished so that cell renewal ceases. There is therefore an obligation to monitor patients indefinitely after radioiodine treatment, for most are likely to need treatment for hypothyroidism eventually.

Risks

Experience had eliminated the fear that radioiodine causes carcinoma of the thyroid, and led to its use in patients of all ages. The Chernobyl disaster subsequently revived concern about exposure of children and it would be wise again to restrict radioiodine treatment to adults. Pregnant women should not be treated with radioiodine (¹³¹I) because it crosses the placenta.

There is a theoretical risk of teratogenic effect and women are advised to avoid pregnancy for an arbitrary 12 months after treatment.

Treatment of thyroid carcinoma requires larger doses of radioiodine than are used for hyperthyroidism, and there is an increased incidence of late leukaemia in these patients. The management of thyroid carcinoma is highly specialised, and extends beyond the scope of this textbook.

Radioisotope tests

Radioiodine uptake can be used to test thyroid function, although it has now been superseded by technetium-99m. Scanning the gland may be useful to identify solitary nodules and in the differential diagnosis of Graves’ disease from the less common thyroiditides, e.g. de Quervain’s thyroiditis. In thyroiditis, excessive thyroid hormone release caused by follicular cell damage can cause clinical and biochemical features of hyperthyroidism, but radionuclide uptake is reduced.

Choice of treatment of hyperthyroidism

• Antithyroid drugs.

• Radioiodine.

Antithyroid drugs are generally preferred provided the goitre is small and diffuse. They may be used in pregnancy.

Radioiodine is an alternative first-line treatment for adult patients, but not in pregnancy. It may be preferred to antithyroid drugs in patients with large or multinodular goitres, and in patients with a single hyperfunctioning adenoma (‘hot nodule’). Preparation with antithyroid drugs is recommended in severe thyrotoxicosis.

Surgery is generally a second choice for thyrotoxicosis. It may be indicated if the thyroid contains a nodule of uncertain nature, or in patients with large, multinodular goitre causing tracheal compression.

Preparation for surgery

Routine preparation of hyperthyroid patients for surgery can be achieved satisfactorily by making them euthyroid with one of the above drugs plus a β-adrenoceptor blocker for comfort (see below) and safety,⁵ and adding iodate for 7–10 days before operation (not sooner) to reduce the surgically inconvenient vascularity of the gland.

In an emergency, the patient is prepared with a β-adrenoceptor blocker (e.g. propranolol 6-hourly, with dose titration to eliminate tachycardia) for 4 days, continued through the operation and for 7–10 days afterwards. Iodide is also given (see p. 591). The important differences with this second technique are that the gland is smaller and less friable but the patient’s tissues are still hyperthyroid and, to avoid a hyperthyroid crisis or storm, it is essential that the adrenoceptor blocker continue as above without the omission of even a single 6-hourly dose of propranolol.

Thyroid storm

Thyroid crisis, or storm, is a life-threatening emergency owing to the liberation of large amounts of hormone into the circulation. Surgical storm is rare with modern methods of preparing hyperthyroid patients for surgery. Medical thyroid storm may occur in patients who are untreated or incompletely treated. It may be precipitated by infection, trauma, surgical emergencies or operations, radiation thyroiditis, toxaemia of pregnancy or parturition.

Treatment is urgently required to save life. Propranolol should be given immediately, 60–80 mg orally every 6 h or i.v. slowly, initially 0.5–1 mg over 10 min with continuous cardiac rhythm monitoring; the i.v. dose may be repeated every few hours until the oral dose takes effect. Large doses of an antithyroid agent, preferably propylthiouracil 300–400 mg 4-hourly are required, down a nasogastric tube or per rectum. Thereafter, iodide is used to inhibit further hormone release from the gland (potassium iodide/iodate 600 mg to 1.0 g orally in the first 24 h) (see above). Lithium carbonate may be used particularly in cases of iodide allergy. Large doses of adrenocorticoids, e.g. dexamethasone 4 mg 6-hourly, are given to inhibit both release of thyroid hormone from the gland and peripheral conversion of T₄ to T₃. Hyperthermia may be treated by cooling and aspirin; heart failure in the ordinary way; fluid deficit by a combination of normal saline and 5% dextrose.

Graves’ ophthalmopathy

Graves’ ophthalmopathy is characterized by inflammation of periorbital and retroorbital connective tissue, fat and muscle. It is associated with Graves’ thyrotoxicosis; it may also occur in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis.

It is an autoimmune disease which appears now to be due in part to the expression of the TSH receptor on orbital cells such as preadipocytes and fibrobalsts and probably myocytes.

Antithyroid drugs do not help directly. Nevertheless, it is important that any thyroid dysfunction is treated meticulously, and the TSH concentration held within the low normal range. Mild to moderate cases regress spontaneously. Artificial tears (hypromellose) are useful when natural tears and blinking are inadequate to maintain corneal lubrication. In severe cases, high doses of systemic prednisolone, alone or in combination with another immunosuppressive (azathioprine), may help. A course of low-dose orbital radiation achieves rapid regression of ophthalmopathy, and may avoid the need for prolonged immunosuppressive therapy. In severe cases with optic neuropathy decompressive surgery is indicated to relieve pressure of the optic nerve.

Treatment of subclinical hyperthyroidism

Subclinical hyperthyroidism is defined biochemically by normal serum free T₄ and free T₃ but suppressed TSH concentrations. Some 5% of patients per annum progress to frank hyperthyroidism, and there is an increased risk of atrial fibrillation, stroke and osteoporosis. The treatment of endogenous subclinical hyperthyroidism should be considered when the TSH level is less than 0.1 mU/L, especially in patients aged over 60 years, those with an increased risk for heart disease, osteopenia or osteoporosis, or with clinical symptoms suggestive of hyperthyroidism. Other patients should be monitored 6-monthly; eventually 50% become euthyroid.⁶

Drugs that cause hypothyroidism

In addition to drugs used for their antithyroid effects, the following substances can cause hypothyroidism: lithium (for mania, bipolar disorder, recurrent depression), amiodarone (see below), β-interferon (hepatitis and multiple sclerosis), iodide (see above), resorcinol (leg ulcers). Effects may be reversible on withdrawal.

Amiodarone

bears a significant structural resemblance to thyroxine. Each molecule of amiodarone contains two iodine atoms, constituting 37.5% of its mass. Hence, a patient taking a 200-mg/day dose ingests 75 mg organic iodine each day. Subsequent de-iodination through drug metabolism results in the daily release of approximately 6 mg free iodine into the circulation, which is 20 to 40 times higher than usual daily iodine intake of 0.15–0.30 mg. Amiodarone has a very long t_½ (54 days) on chronic dosing, mainly due to its storage in adipose tissue. Hence, the excess iodine clears slowly over months and the toxic effects of amiodarone can persist or can even occur well after its discontinuation.

Some 90% of patients receiving amiodarone remain euthyroid. Despite the exposure of the thyroid gland to an extraordinary load of iodine, important adjustments are made in thyroidal iodine handling and hormone metabolism; these are shown in Figure 37.2, and the consequences for thyroid function tests summarised in Table 37.1.

Fig. 37.2 Mechanisms by which amiodarone affects thyroid hormone metabolism. TSH, thyroid stimulating hormone.

(Adapted from Basaria S, Cooper D S 2005 Amiodarone and the thyroid. American Journal of Medicine 118:706–714.)

Table 37.1 Effects of amiodarone on thyroid function tests in euthyroid subjects

	Acute effects	Chronic effects
Thyroid hormone	(≤ 3 months)	(> 3 months)
Total and free T₄	↑ 50%	Remains ↑ 20–40% of baseline
T₃	↓ 15–20%, remains in low-normal range	Remains ↓ 20%, remains in low-normal range
Reverse T₃	↑ > 200%	Remains ↑ > 150%
TSH	↑ 20–50%, transient, generally remains < 20 mU/L	Normal

Amiodarone-induced hypothyroidism is more prevalent in iodine-sufficient areas of the world, whereas thyrotoxicosis is more prevalent in iodine-deficient regions. Amiodarone-induced hypothyroidism typically occurs between 6 and 12 months of treatment with amiodarone. The main risk factor is underlying Hashimoto’s disease. In other patients, hypothyroidism resolves within 2–4 months of discontinuing amiodarone.

Thyrotoxicosis induced by amiodarone is of two types. Type 1 develops in individuals with underlying thyroid disease (nodular goitre or latent Graves’disease) and is due to increased synthesis and release of thyroid hormone. Type 2 is a destructive thyroiditis in individuals with no underlying thyroid disease, and the thyrotoxicosis is due to release of preformed thyroid hormone from damaged thyroid follicular epithelium. Mixed forms also occur. The two types are difficult to distinguish. Measurement of interleukin-6 or C-reactive protein has marginal diagnostic role in differentiating the two forms because of poor specificity. Thyroid ultrasonography, colour flow Doppler sonography and thyroid radioactive iodine uptake may help in the diagnosis. In type 1, amiodarone treatment should be discontinued, if possible. Large doses of thionamides and longer periods of therapy are required, because high intrathyroidal iodine stores antagonise their inhibitory effect on thyroidal iodine utilisation. In patients who fail to respond after 4–6 weeks of treatment, potassium perchlorate 200–1000 mg daily can be a useful adjunct. Radioiodine is rarely used because uptake is blocked by the high concentration of circulating iodine. In type 2, prednisolone 40–60 mg leads to rapid improvement in thyroid function in most patients, often within 1 week, and amiodarone discontinuation may not be necessary. Iopanoic acid (an oral cholecystographic agent) has also been used to reduce T₄ to T₃ conversion, but is generally inferior to prednisolone and currently unavailable in the market. In resistant cases, other therapies have been recommended, including lithium, plasmapheresis and ultimately thyroidectomy in patients with severe thyrotoxicosis, whose amiodarone cannot be discontinued.

Miscellaneous

Treatment of thyroiditis

(Hashimoto’s thyroiditis, subacute thyroiditis or de Quervain) Where hyperthyroidism is a feature, treatment is by a β-adrenoceptor-blocking drug. Antithyroid drugs should not be used. Where there is permanent hypothyroidism, the treatment is thyroid hormone replacement.

Calcitonin

See Chapter 39.

• Autoimmune disease of the thyroid can cause over- or under-production of thyroid hormone.

• Hypothyroidism is readily treated with levothyroxine 50–200 micrograms daily orally, continued indefinitely.

• The treatment of hyperthyroidism due to Graves’ disease is either 12–18 months’ treatment with carbimazole or propylthiouracil, or a (usually) single dose of ¹³¹I.

• The natural history of Graves’ disease is of alternating remission and relapse. Progression to hypothyroidism can occur, especially after ¹³¹I treatment. All patients require long-term follow-up.

• Severe forms of thyroid eye disease require adrenal steroid and immunosuppressants, or low-dose radiotherapy. Urgent surgical decompression is required for optic nerve compression.

Guide to further reading

Bahn R.S. Graves’ ophthalmopathy. N. Engl. J. Med.. 2010;362:726–738.

Bartalena L., Tanda M.L. Clinical practice. Graves’ ophthalmopathy. N. Engl. J. Med.. 2009;360:994–1001.

Basaria S., Cooper D.S. Amiodarone and the thyroid. Am. J. Med.. 2005;118:706–714.

Biondi B., Palmieri E.A., Klain M., et al. Subclinical hyperthyroidism: clinical features and treatment options. Eur. J. Endocrinol.. 2005;152:1–9.

Chan G.W., Mandel S.J. Therapy insight: management of Graves’ disease during pregnancy. Nat. Clin. Pract. Endocrinol. Metab.. 2007;3:470–478.

Cooper D.S. Antithyroid drugs. N. Engl. J. Med.. 2005;352:905–917.

Mitchell A.L., Pearce S.H. How should we treat patients with low serum thyrotropin concentrations? Clin. Endocrinol. (Oxf.). 2010;72:292–296.

Pearce E.N., Farwell A.P., Bravermen L.E., et al. Thyroiditis. N. Engl. J. Med.. 2003;348:2646–2655.

Roberts C.G.P., Ladenson P.W. Hypothyroidism. Lancet. 2004;363:793–803.

Ross D.S. Radioiodine therapy for hyperthyroidism. N. Engl. J. Med.. 2011;364:542–550.

¹ Use of a thionamide during the week before and after radioiodine therapy may impair the response to radiation (Velkeniers B, Cytryn R, Vanhaelst L, Jonckheer M H 1988 Treatment of hyperthyroidism with radioiodine: adjunctive therapy with antithyroid drugs reconsidered. Lancet i: 1127–1129) (see Mode of action of thionamides, above).

² Apparently from the beginning of time: Michelangelo’s image of the separation of light from darkness on the ceiling of the Sistine Chapel in the Vatican depicts the creator with a multinodular goitre (Bondeson L, Bondeson A-G 2003 Michelangelo’s divine goitre. Journal of the Royal Society of Medicine 96:609–611).

³ The newer preparations approximately triple the cost of diagnostic investigations requiring contrast media. With a fatality rate of about 1 per 50 000 in patients receiving the older agents, hospitals are faced with an interesting cost–benefit equation.

⁴ And emissions can be sufficient to activate airport radiation alarms. One victim was detained, strip-searched and interrogated, but released on producing his radionucleotide card (Gangopadhyay K K, Sundram F, De P 2006 Triggering radiation alarms after radioiodine treatment. British Medical Journal 333:293–294).

⁵ No patient should be operated on with a resting pulse of 90 beats/min or above, and no dose of β-adrenoceptor blocker, including the important postoperative dose, should be omitted (Toft A D, Irvine W J, Sinclair I et al 1978 Thyroid function after surgical treatment of thyrotoxicosis. A report of 100 cases treated with propranolol before operation. New England Journal of Medicine 298:643–647).

⁶ Consensus statement: Surks M I, Ortiz E, Daniels G H et al 2004 Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Journal of the American Medical Association 291:228–238.

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