Hypothyroidism can affect multiple body systems, but symptoms are mainly non specific and gradual in onset (Box 43.2). Symptoms are frequently vague especially in the early stages. It is common for symptoms to be incorrectly attributed by patients and their relatives to increasing age. The reverse is also common in that patients who have read about, or have friends/family with, hypothyroidism will assume that it is responsible for symptoms of fatigue and weight gain. Thus, hypothyroidism is often confused with simple obesity and depression. Thyroid function tests give accurate diagnosis in all cases.

Box 43.2 Signs and symptoms of hypothyroidism

Skin and appendages	Dry, cool, flaking, thickened skin
	Reduced sweating
	Yellowish complexion. Puffy facies and eyes
	Sparse, coarse, dry hair
	Brittle nails
Neuromuscular system	Slow speech
	Poor memory and reduced cognitive function
	Somnolence
	Carpal tunnel syndrome
	Psychiatric disturbance
	Hearing loss
	Depression
	Muscle pain and weakness
	Delayed deep tendon reflexes
Metabolic abnormalities	Raised total and LDL cholesterol
Metabolic abnormalities	Macrocytic anaemia
Gastro-intestinal	Weight gain with decreased appetite
	Abdominal distension and ascites
	Constipation
Cardiovascular	Reduced cardiac output
	Bradycardia
	Cardiac enlargement

The most useful clinical signs are myotonic (slow-relaxing) tendon reflexes, bradycardia, hair loss and cool, dry skin. Effusions may occur into pericardial, pleural, peritoneal or joint spaces. Mild anaemia of a macrocytic type is quite common and responds to thyroxine replacement. Pernicious anaemia is a frequent concomitant finding in hypothyroidism. Other, organ-specific autoimmune diseases such as Addison’s disease may be associated.

Myxoedema coma

Myxoedema coma is a rare but potentially fatal complication of severe, untreated hypothyroidism. Coma can be precipitated by hypothermia, stress, infection, trauma and certain drugs, notably β-blockers and respiratory depressants, including anaesthetic agents, narcotics, phenothiazines and hypnotics. The condition is a medical emergency and should be treated rapidly and aggressively.

The term ‘myxoedema’ used to be synonymous with hypothyroidism. It is now reserved for advanced disease in which there is swelling of the skin and subcutaneous tissues.

Investigations

The laboratory investigation of hypothyroidism is extremely simple. Usually clinical assessment, combined with a single estimation of thyroid hormones and TSH, is sufficient to make the diagnosis. In primary disease, the levels of free T₄ and T₃ are low and the TSH level rises markedly. Some laboratories offer only TSH as a first-line test of thyroid function though this can result in delayed diagnosis of secondary or tertiary hypothyroidism, which should be suspected on the basis of a low free T₄ along with low TSH levels.

Elevation of the TSH level occurs early in the course of thyroid failure and may be present before overt clinical manifestations appear. It is important to appreciate that hypothyroidism is not one disease but a spectrum. Early hypothyroidism may be asymptomatic or the symptoms less obvious and non-specific, but a normal TSH with normal free T4 effectively excludes the diagnosis.

A chest radiograph may detect the presence of effusions, and an electrocardiogram (ECG) is useful, especially in patients with angina or coronary heart disease, in whom replacement therapy needs to be introduced gradually.

Testing thyroid function

As indicated earlier (and later in the section on thyrotoxicosis), a clinical assessment and measurement of free T₄ and TSH are usually all that are necessary to arrive at an accurate diagnosis of thyroid state. All modern TSH assays now employ double antibody immunometric techniques, which are robust and highly reliable. Moreover, these assays are now so sensitive that they are able to identify thyrotoxic patients with TSH levels below the normal euthyroid range. Commercial free T₄ and free T₃ assays, however, are all indirect methods and are subject to interference from drugs and other disease states. As such, both T₃ and T₄ can be decreased as a non-specific consequence of systemic illness (‘sick euthyroid’ syndrome) and depression along with a host of drugs (Surks and Sievert, 1995), which can interfere with thyroid hormone metabolism and free hormone assays (Table 43.2). Such patients require specialist assessment and collaboration with the local laboratory to rule out confounding disease and pituitary failure.

Table 43.2 Drug effects on thyroid function

	Clinical/biochemical effects
Decrease TSH secretion
Dopamine	Hypothyroidism (rarely clinically important)
Glucocorticoids
Octreotide
Alter thyroid hormone secretion
Iodide (amiodarone, contrast agents)	Both hyper- and hypothyroidism
Lithium	Hypothyroidism
Decrease T₄ absorption
Colestyramine/colestipol	Increased thyroxine dose requirement
Aluminium hydroxide
Ferrous sulphate
Calcium carbonate
Multivitamins
Sevelamer
Protein pump inhibitors
Sucralfate
Alter T₄ and T₃ metabolism
Increased hepatic metabolism
Phenobarbital	Low T₄ and T₃ levels
Phenytoin	Normal or increased TSH
Rifampicin
Carbamazepine
Reduce conversion of T₄ to T₃
B-blockers	Lower T₃ levels
Propylthiouracil	Normal or increased TSH
Amiodarone
Glucocorticoids
Reduce T₄ and T₃ binding
Furosemide	Increased measured free T₄ in some assays
Salicylates and NSAIDs
Heparin
Increase thyroglobulin levels
Oestrogen and tamoxifen	Increased total T₄
Opiates and methadone	Increased total T₄
Others
Cytokines – interferon and interleukin 2	Thyroiditis. Can produce hypothyroidism and thyrotoxicosis

Treatment

The aims of treatment with thyroxine are to ensure that patients receive a dose that will restore well-being and that usually returns the TSH level to the lower end of the normal range (Vanderpump et al., 1996). All patients with symptomatic hypothyroidism require replacement therapy. T₄ is usually the treatment of choice except in myxoedema coma where T₃ may be used in the first instance. Before commencing T₄ replacement, the diagnosis of glucocorticoid deficiency must be excluded to prevent precipitation of a hypoadrenal crisis. If in doubt, hydrocortisone replacement should be given concomitantly until cortisol deficiency is excluded.

The initial dose of T₄ will depend on the patient’s age, severity and duration of disease and the coexistence of cardiac disease. In young, healthy patients with disease of short duration, T₄ may be commenced in a dose of 50–100 μcg daily. As the drug has a long half-life, it should be given once daily. The most convenient time is usually in the morning. After 6 weeks on the same dose (not a shorter interval as TSH takes this time to stabilise after a dose change), thyroid function tests should be checked. The TSH concentration is the best indicator of the thyroid state, and this should be used for further dosage adjustment. A raised TSH concentration indicates inadequate treatment, poor adherence or both. The majority of patients will be controlled with doses of 100–200 μcg daily, with few patients requiring more than 200 μcg. In adults, the median dose required to suppress TSH to normal is 125 μcg daily. In the majority of patients, once the appropriate dose has been established, it remains constant. During pregnancy, an increase in the dose of thyroxine by 25–50% is needed to maintain normal TSH levels.

Exacerbation of myocardial ischaemia, infarction and sudden death are all well-recognised complications of T₄ replacement therapy. Patients with coronary heart disease may be unable to tolerate full replacement doses because of palpitations, angina or heart failure. Elderly patients may have undiagnosed ischemic heart disease. In these two groups of patients, treatment should therefore be started with 25 μcg daily and increased slowly by 25 μcg every 4–6 weeks. During this time, the patient’s clinical progress should be carefully monitored. In some patients, T₄ may be better tolerated if a β-blocker such as propranolol is given concomitantly. Some authorities recommend starting with 5 μcg of T_3, the rationale being that if adverse effects occur, these can be alleviated more rapidly with a dose reduction due to the shorter half-life of T₃.

It is important to avoid both under- and overtreatment. Hypothyroidism is very rarely life threatening, but adverse effects may result from prolonged overtreatment (which is indicated by a TSH level suppressed below the normal range). Though T₄ exerts an effect on many organs and tissues, it is the effect on bone and the heart that give the greatest cause for concern. There is evidence that bone density is reduced in patients taking excessive T₄ replacement therapy (Faber and Galloe, 1994; Uzzan et al., 1996), and that atrial fibrillation is more common if TSH is suppressed (Sawin et al., 1994). In order to minimise the risk of development of these complications, the dose of T₄ should be carefully tailored to the needs of each individual patient. Some patients will have undetectable serum TSH levels while taking thyroxine and may complain of recurrent fatigue if the dose is reduced to permit the TSH to rise. In these patients, it may be permissible to leave the dose unchanged if levels of free T₄ and T₃ are normal, after a discussion of the relative risks and benefits with the patient (Vanderpump et al., 1996).

Patient care

Hypothyroidism requires lifelong treatment with T₄. Patients on long-term drug therapy are recognised to have a low adherence with their medication regimen. Treatment with T₄ is often terminated because patients feel well and think that treatment is no longer required. Patients should understand the effects of drug holidays on their health and thyroid function tests and should know that a normal TSH indicates adequate dosage. Written advice should be provided and monitoring of dosage should continue annually. There are a series of excellent patient information leaflets available on the British Thyroid Association website at www.british-thyroid-association.org

Despite adequate counselling, some patients persistently forget to take their tablets reliably, leading to variable thyroid state and wildly fluctuating test results. Other patients lack capacity to self-medicate reliably. There is evidence to show that weekly dosing with T₄ is a safe and acceptable way to manage this type of patient, in whom family members or community staff can supervise treatment (Grebe et al., 1997; Rangan et al., 2007). There are no guidelines yet published, but in practice, patients are normally started on 500–700 μcg T₄ weekly. Dose changes are made in exactly the same way by assessing TSH levels after 6 weeks of stable dosing.

Rarely, patients are seen in whom TSH levels fluctuate or remain elevated despite high doses of thyroxine and in whom adherence seems to be very good. There are a number of possible causes for this, including malabsorption of thyroxine which can be due to coeliac or inflammatory bowel disease or a number of commonly prescribed drugs (Table 43.2). Such patients will need a careful sequential assessment by an endocrine service (Morris, 2009).

Prevention

At present, nothing can be done to prevent autoimmune thyroid failure from developing; however, much can be done to ensure early detection and treatment. Careful follow-up of patients who have undergone radioiodine treatment, subtotal thyroidectomy or completed a course of treatment for thyrotoxicosis is essential along with monitoring of those prescribed amiodarone and lithium. An increase in TSH with normal concentrations of T₃ and T₄ will indicate the onset of hypothyroidism before the patient becomes symptomatic. Box 43.3 shows the prevalence of hypothyroidism after treatment for thyrotoxicosis.

Hyperthyroidism/thyrotoxicosis

Hyperthyroidism is defined as the production by the thyroid gland of excessive amounts of thyroid hormones. Thyrotoxicosis refers to the clinical syndrome associated with prolonged exposure to elevated levels of thyroid hormone. This distinction is important when evaluating thyroid function tests (Table 43.3).

Table 43.3 Aetiology of hyperthyroidism

Epidemiology

Hyperthyroidism is a common condition. It has been estimated that there are 4.7/1000 women with active disease. When previously treated cases were included, the population prevalence rose to 20/1000 in women. As for hypothyroidism, it is much less common in men who have a lifetime prevalence of around 2/1000 (Tunbridge et al., 1977).

Aetiology

Hyperthyroidism is a disorder of various aetiologies. In clinical terms, thyrotoxicosis is the result of persistently elevated levels of thyroid hormones.

Clinical manifestations

Thyrotoxicosis is characterised by increases in metabolic rate and activity of many systems due to excessive circulating quantities of thyroid hormones. There is a wide spectrum of clinical disturbances. The signs and symptoms reflect increased adrenergic activity, especially in the cardiovascular and neurological systems (Box 43.4). Not all manifestations will be seen in every patient. Additional clinical features will depend on the underlying cause of the thyrotoxicosis (Table 43.3).

Box 43.4 Signs and symptoms of thyrotoxicosis

Skin and appendages	Warm, moist skin
	Thinning or loss of hair
	Increased sweating
	Heat intolerance
Nervous system	Insomnia
	Irritability, nervousness
	Lid retraction – staring eyes
	Symptoms of an anxiety state
	Psychosis
Musculoskeletal	Fine motor tremor
	Proximal muscle weakness
	Rapid deep tendon reflexes
	Osteoporosis
Gastro-intestinal	Weight loss despite increased appetite
	Thirst
	Diarrhoea
Cardiovascular	Palpitations, tachycardia
	Shortness of breath on exertion
	Atrial fibrillation
	Congestive cardiac failure
	Worsening angina

The clinical features of thyrotoxicosis in the elderly may not be so obvious. Signs and symptoms of cardiovascular disturbance tend to predominate, atrial fibrillation is frequent and the patient may develop congestive cardiac failure. Unexplained heart failure after middle age should always arouse suspicion of thyrotoxicosis.

The extrathyroidal manifestations of Graves’ disease deserve separate mention. Most frequent is ophthalmopathy due to inflammation and expansion of the contents of the orbit. The eye is pushed forward (proposed) such that white sclera appears between the iris and the lower lid. Congestive changes develop including peri-orbital oedema, conjunctival swelling and redness. The extraocular muscles are swollen and become tethered leading to failure of movement of the globe of the eye and thus diplopia. Severe disease causes pressure in the orbit, which can compress the optic nerve leading to blindness. The cutaneous features of Graves’ disease include thickening of the pretibial skin (myxoedema), onycholysis (separation of the nail from the nail bed) and acropachy (similar to finger clubbing).

Investigations

In those with suspected thyrotoxicosis, it is good practice to document the diagnosis with two sets of thyroid function tests. If the diagnosis is in doubt, treatment should be withheld because unless severe, thyrotoxicosis can usually be safely observed whilst awaiting the results of investigations. Plasma free T₄ (and/or T₃) levels are elevated. The TSH level is suppressed to subnormal levels in all causes of thyrotoxicosis, except the exceptionally rare cases of TSH secreting pituitary adenomas.

In the overwhelming majority of patients, the combination of the clinical findings and simple investigations is sufficient to make a firm diagnosis. Radioactive iodine uptake scans will differentiate those patients with thyroiditis. Measurement of TRABs will identify Graves’ disease patients. If the diagnosis is still equivocal, the clinical findings should be reassessed and particular attention paid to the patient’s drug history. There are a number of drugs that may modify the clinical features or interfere with the tests.

Treatment

A number of factors need to be considered when choosing the most appropriate form of therapy for an individual patient (Table 43.4). There are usually a number of therapeutic options available, and the patient should be involved in the deciding on treatment. The decision may also be influenced by physician preference, which in turn can depend on the facilities available. Three forms of therapy are available, including anti-thyroid drugs, surgery and radioactive iodine. There is no general agreement as to the specific indications for each form of therapy, and none of them is ideal, all being associated with both short- and long-term sequelae. Neither surgery nor radioactive iodine should be given until the patient has been rendered euthyroid due to the risk of inducing a thyroid crisis.

Table 43.4 Treatments available for thyrotoxicosis

In children, surgery may be difficult and the complication rate is higher. Also, radioiodine has been avoided due to concern about the potential development of thyroid malignancy, though there are no data which suggest this to be a problem. In pregnancy, radioiodine is not used due to the likelihood of producing a hypothyroid neonate. Thyroid surgery during pregnancy should be deferred until the second trimester if possible and most patients can be controlled with drugs. Thionamide doses should be kept as low as possible, especially in the last 2 months of pregnancy, as excessive treatment may produce goitre in the fetus. Aplasia cutis is said to occur after carbimazole therapy, so propylthiouracil (PTU) is usually used in pregnancy. Pregnant patients with thyrotoxicosis should be under the care of a specialist endocrine unit.

Immediate treatment of thyrotoxicosis

Patients need to have their symptoms addressed and their thyrotoxicosis controlled. β-Blockers in standard anti-hypertensive doses are effective within a matter of hours and should be offered to all non-asthmatics with severe thyrotoxicosis. Carbimazole (40 mg once a day) or PTU (150 mg twice daily) will render most patients euthyroid within 6 weeks. Adjunctive treatment of cardiac disease and anxiety/sleeplessness may be required.

Graves’ disease

A proportion (40–50%) of patients with Graves’ disease will achieve a long-lasting remission after a period of euthyroidism on thionamides. The optimal duration of anti-thyroid treatment is unknown and remains a controversial issue (Maugendre et al., 1999), but in most units, the length of the treatment course has fallen to between 6 and 12 months. It is not appropriate to discuss complex treatment decisions with a thyrotoxic patient, so most are well into this period when discussions of their options occur. Remission of Graves’ disease is much less likely in those with very large goitres, those who require high-dose thionamide treatment to maintain euthyroidism, those with high TRAB titres and patients who have relapsed once after a course of drug treatment. Such patients should therefore be rendered euthyroid and then have a discussion about either surgical or radioiodine thyroid ablation.

Nodular thyroid disease

As the nodules function autonomously and thyrotoxicosis will always recur when thionamides are stopped, there is no value in attempting to achieve a remission of nodular thyroid disease using prolonged medical treatment. Patients should be rendered euthyroid with drugs and then have a discussion about ablative therapy.

Anti-thyroid drugs

The thionamides, PTU, thiamazole (methimazole) and its precursor carbimazole are equally effective pharmacological therapies for thyrotoxicosis. In the UK, carbimazole is usually used. These drugs prevent thyroid hormone synthesis by inhibiting the oxidative binding of iodide and its coupling to tyrosine residues. PTU, but not carbimazole, inhibits the peripheral deiodination of T₄ to T₃. Thionamides may also have an immunosuppressive action.

Adverse effects

The most common adverse effect of anti-thyroid treatment is rash and arthropathy (5%) and less commonly agranulocytosis, hepatitis, aplastic anaemia and lupus-like syndromes (Table 43.5). Overall, serious effects such as these occur in approximately 0.3% of patients treated. These side effects usually occur during the first 6 weeks of treatment, but this is not invariable. Cross-sensitivity between carbimazole and PTU is around 10%, and the patient can often be safely changed to the alternative agent if an adverse event occurs.

Table 43.5 Adverse effects of thionamides

	Adverse effect	Comments
Skin	Pruritic, maculopapular rash	Most common in first 6 weeks
		May disappear spontaneously with continued treatment
		Can be treated with an antihistamine
		Change to alternative agent
		Occurs in 5% of patients
	Urticarial rash with systemic symptoms, that is fever, arthralgia	Discontinue drug
		Alternative treatment required
Haematological	Agranulocytosis	Most common in first 6 weeks
		Incidence increases with age
		Discontinue drug
		Reversible
		Consider alternative treatment
		Occurs in 0.3% of patients
	Leucopoenia	Transient
		Continue treatment
		Does not predispose to agranulocytosis
Other	Hepatitis	Rare
	Vasculitis	Discontinue drug
	Hypoprothrombinaemia
	Aplastic anaemia
	Thrombocytopenia

Regular monitoring of white cell counts has been advocated, but is not warranted. Agranulocytosis is a rare event, and even if it does occur, it happens rapidly such that routine monitoring of white cell counts may miss it. At the time of prescription, all patients should be counselled about the possible implication of sore throat, mouth ulcers and pyrexia, and instructed to seek an urgent (within hours) full blood count. This verbal information should be backed up by written advice which should specify where the patient should go for the blood test. An abnormal white cell count should prompt urgent admission under a specialist endocrine team.

Treatment regimen

Carbimazole is usually given initially at a dose up to 40–60 mg daily, depending on the severity of the condition. It can be given as a single daily dose in multiples of 20 mg tablets to aid adherence. Although the plasma half-life is short (4–6 h), the biological effect lasts longer (up to 40 h). T₄ concentrations are checked at 6-week intervals until the patient is clinically euthyroid and the T₄ and T₃ levels are normalised. (TSH remains suppressed for at least 4 weeks after resolution of significant thyrotoxicosis, so TSH levels are unhelpful in the early stages of treatment.)

At this point, a decision is made about ongoing treatment. It is simplest to continue a high dose of carbimazole to suppress endogenous thyroid hormone production and to give a standard replacement dose of thyroxine to maintain euthyroidism, the ‘block and replacement’ regimen. This combination results in a steadier thyroid state, reduces the need for blood monitoring and requires fewer hospital attendances. Since adverse drug effects are allergic and not dose related, it is no more risky than tailored dose regimens.

Pregnancy is a specific situation, however, in which tailored dose PTU should be used. Both the immunoglobulins which cause Graves’ disease and thionamide drugs cross the placenta and will affect the fetal thyroid, but maternal thyroxine is not able to reach the fetus. Thus, the lowest possible dose of PTU (preferred to carbimazole in pregnancy) should be used and the fetus closely monitored for heart rate and growth. Breast-feeding is considered to be safe when mothers are taking thionamides.

Patient counselling

Patients should be advised of the importance of regular clinic attendance. This is necessary to monitor both therapeutic outcome and the development of adverse effects. The development of skin rashes, mouth ulcers or a sore throat should be reported by the patient, immediately investigated and a full blood count performed (see Box 43.5). It may be dangerous to treat these symptoms with over-the-counter medication before carrying out further investigations.

Box 43.5 Counselling points for patients on anti-thyroid drugs

1. Carbimazole can be given as a single daily dose.

2. Identify anticipated duration of treatment.

3. Explain block and replacement regimens.

4. Explain use of adjuvant therapy, for example, β-blockers.

5. Encourage reporting of skin rashes, sore throat or mouth ulcers. Provide written guidance.

6. Ensure the patient understands the need for regular review.

7. Outline management of relapse.

It is important for the patient to understand the difference between specific anti-thyroid therapy and symptomatic treatment. The patient should also be advised about the timing of doses to aid adherence. Following completion of a course of treatment, the patient should understand relapse may occur, and medical help should be sought if the initial symptoms recur.

Thyroid ablative therapy

Thyroid ablation is required for all patients with toxic multinodular goitres, those who have relapsed or are likely to relapse after drug therapy for Graves’ disease and those who are allergic to thionamides. Thyroid ablation can be achieved by radioiodine or surgery.

Radioactive iodine

Radioiodine therapy is extremely easy to administer by mouth and is very effective for a large majority of patients. It is contraindicated in pregnancy and breastfeeding and is usually avoided in children. It is known to make ophthalmopathy worse in some patients with Graves’ disease, but giving prednisolone 0.5 mg/kg for 3 weeks and commencing thyroxine replacement early (3 weeks after radioiodine) can mitigate this. Despite public concern in relation to radioactivity, accumulated experience over more than 60 years has not demonstrated any discernible risk of genetic, leukaemic or lymphoma risk (Vanderpump et al., 1996).

The commonest complication is the development of hypothyroidism. Doses sufficient to cause thyrotoxicosis to remit will result in virtually 100% of patients given radioiodine for Graves’ disease becoming hypothyroid and around 50% of those treated for multinodular disease. Patients should be counselled to expect to require lifelong thyroxine treatment after radioiodine therapy.

Anti-thyroid drugs must be withdrawn before radioiodine is given and should not be restarted for at least 3 days afterwards (otherwise, the isotope will not be trapped by the thyroid). The author conventionally recommends they be stopped 7 days before radioiodine. Since the ablative effect of radioiodine usually commences within 2–3 months, many patients with mild or moderate disease will not need to restart their drug treatments, though close patient monitoring is required. Patients with severe thyrotoxicosis should restart their anti-thyroid drugs on day 3. Treatment is then withdrawn periodically to assess the effects of the radioiodine.

The patient receiving radioiodine treatment is effectively radioactive for 6 weeks without ill effect. Since the patients are not at risk from this radioactivity, it seems inherently unlikely that the public faces any risk at all to health. Nevertheless, there are regulations governing exposure to radiation, which must be followed. After a standard 555-MBq dose, a patient must for 14 days avoid close continuous contact (2 m) with other persons for periods of more than 1 h, undertake to be careful in disposing of urine, and must not work. For 24 days, they must avoid close contact with children and pregnant women. In practice, it is these regulations and the concerns they engender in the patient that result in a proportion of patients preferring a surgical approach.

Surgery

Surgery is required for those patients with very large goitres, patients who cannot be persuaded of the safety of radioiodine and those who have reacted adversely to both thionamides in pregnancy. The hyperthyroid patient to be treated surgically should first be rendered biochemically euthyroid whenever possible, but occasionally surgery needs to be performed as a semi-urgent procedure. This may require urgent patient preparation with a combination of anti-thyroid drugs and β-blockers, and iodide given as Lugols solution. Iodide exerts a (usually) transient inhibitory effect on the ability of the gland to trap iodide, and it may also reduce the vascularity of the gland. In doses of 800–1200 mg/day, lithium is an effective anti-thyroid drug for patients who have reacted to thionamides. Lithium levels should be monitored to minimise toxicity. β-Blockers should be introduced and the dose titrated to reduce the pulse rate to below 80 beats/min. They are usually continued for 1 week postoperatively. It is imperative that treatment is given right up to the time of operation and the operation deferred if the pulse rate is not adequately controlled. Inadequate pre-treatment can result in the occurrence of thyroid crisis.

Complications of surgery include the generic ones of anaesthetic risk, bleeding, thromboembolic disease and infection. Specific risks of thyroid surgery include damage to recurrent laryngeal nerves (which may be particularly important to actors, singers and teachers) and hypoparathyroidism as a result of interference of the blood supply to the parathyroids or their inadvertent removal during surgery. If this occurs, tetany will begin within 48 h of the operation, and treatment should be initiated with intravenous calcium gluconate. All patients who have undergone partial thyroidectomy should have serum calcium estimation 3 months after operation since the development of hypoparathyroidism can be delayed. Later complications of thyroidectomy include hypothyroidism and recurrent thyrotoxicosis.

Treatment of complications

Ophthalmopathy

In most patients with Graves’ disease, no specific treatment is required for the eyes. The commonest complaint is of ‘grittiness’, which can be treated with hypromellose eye drops or gel. If lid retraction is severe, inadequate lid closure can result in early morning soreness. This can be alleviated by the short-term use of 5% guanethidine eye drops instilled each night and morning. The eyes should be monitored for any signs of infection, and treated appropriately.

Fortunately, severe eye involvement occurs in less than 2% of patients with Graves’ disease. Progressive ophthalmopathy producing severe complications from proptosis, diplopia or visual failure should be treated with high-dose steroid therapy (prednisolone, 60 mg daily) until symptoms resolve. Failure to respond is an indication for orbital irradiation or surgical decompression, but such patients should be under the care of a highly specialised ophthalmic surgeon.

Treatment of localised myxoedema

Myxoedema is usually localised to small areas and is asymptomatic. More extensive disease causes difficulty in walking and considerable discomfort. Probably the most effective therapy is the nightly topical application of steroid creams, such as betamethasone, under occlusive polythene dressings.

Thyroid crisis

This condition can develop in any patient with significant untreated thyrotoxicosis but is most common in those with severe Graves’ disease. It is precipitated in such patients by infection, injury, trauma, anesthetics, surgery and radioiodine. There is rapidly progressive tachycardia, muscle weakness (including cardiomyopathy) hyperthermia, sweating and vomiting compounding hypotension with ensuing circulatory collapse. In addition, patients are extremely anxious and often psychotic. It should be managed as a medical emergency in a high-care area. In addition to supportive measures, specific anti-thyroid therapy is required along with drugs, which inhibit deiodination of T₄ to T₃. PTU (inhibits deiodinase) is given orally (or via NG tube) in high dose along with Lugols iodine. Glucocorticoids should be given i.v. as they also inhibit deiodinase. Effective β-blockade is required by i.v. infusion (propranolol preferred as it also inhibits deiodinase).

Drugs and the thyroid

From the previous pages, it will be evident that many commonly used drugs can affect the thyroid. This section draws together the most frequently encountered problems. In clinical practice, drug effects and interactions produce thyrotoxicosis, hypothyroidism or disturb thyroid function tests. It is worth specifically noting amiodarone, which contains large quantities of iodide which is released into the circulation during drug metabolism. The effects of amiodarone on the thyroid are extensive and complex.

Drugs and thyrotoxicosis

Table 43.2 indicates drug treatments associated with thyrotoxicosis. Amiodarone-induced thyrotoxicosis (AIT) is caused by two entirely different mechanisms. Type 1 AIT is similar to iodide-induced thyrotoxicosis and results from activation of nodular disease or of latent Graves’ disease in patients with thyroid autoimmunity. In this condition, the thyroid is actively synthesising hormone and treatment is with thionamides. Type 2 AIT has features similar to thyroiditis with leakage of pre-formed thyroid hormone, low uptake of radiolabel on scanning and is treated with glucocorticoids. AIT is an extremely challenging condition to manage for multiple reasons. These include difficulty in discrimination between type 1 and type 2 disease, each of which have different treatments, and the facts that most patients are taking amiodarone for serious cardiac dysrhythmias and amiodarone has a very long tissue half-life. These patients should be under the care of a specialist endocrinology team.

A recent observation has been the increased frequency of Graves’ disease in patients undergoing bone marrow transplantation, after administration of alemtuzumab (CAMPATH, a monoclonal antibody to CD52 cells), or alpha-interferon for multiple sclerosis and during Highly Active Anti-Retroviral Treatment (HAART) of HIV infection. It is thought that these cases all have immunological reconstitution as an underlying factor in their aetiology (Weetman, 2009).

Drugs and hypothyroidism

Amiodarone is frequently associated with the development of hypothyroidism, particularly in those patients with positive TPO antibodies, indicative of latent Hashimoto’s disease. Such patients seem particularly sensitive to the high levels of iodine liberated by drug metabolism, and it is thought that hypothyroidism occurs because of a failure of the patient’s thyroid to escape from the suppressive effect of iodine on thyroxine synthesis (the Wolff-Chaikoff effect). If amiodarone can be withdrawn, hypothyroidism will resolve over a period of months. More often, however, amiodarone is continued and thyroxine treatment is required.

Lithium inhibits T₄ and T₃ release from the thyroid (making it a useful adjunctive treatment for thyrotoxicosis in patients who react to thionamides) and causes a goitre in 40% of patients and hypothyroidism in 20%, again more commonly in those with positive TPO antibodies. Like amiodarone, lithium is usually continued and these patients are treated with thyroxine. Drug-related interference with absorption of thyroxine is one of the causes of hypothyroidism in patients treated with thyroxine. Table 43.2 indicates the agents which may be implicated.

Calcium and parathyroid hormone

Physiology

Most individuals possess four parathyroid glands situated posterior to the upper and lower lobes of the thyroid. These glands secrete parathyroid hormone (PTH). Calcium is approximately 50% ionically bound to albumin, and it is the unbound ionised plasma calcium levels which regulate the secretion of PTH, increased calcium concentration suppressing secretion and low levels stimulating it. PTH is an 84-amino acid straight-chain polypeptide which acts on hormone-specific receptors on target tissue cells. PTH acts on the renal tubular transport of calcium and phosphate and also stimulates the renal synthesis of 1,25-dihydroxycolecalciferol.

PTH and vitamin D act to maintain plasma calcium levels within the normal range. PTH increases distal tubular reabsorption of calcium and decreases proximal and distal tubular reabsorption of phosphate. The effects of PTH on bone are complex. The two major cell types in bone are osteoblasts and osteoclasts. Osteoblasts are responsible for the synthesis of extracellular bone matrix and priming of its subsequent mineralisation. Osteoclasts decalcify and digest the protein matrix of bone, liberating calcium. PTH stimulates osteoclast-mediated bone resorption but, in addition, has an anabolic effect on bone, with an increase in osteoblast number and function.

Hypoparathyroidism/hypocalcaemia

Hypoparathyroidism is the clinical state which may arise either from failure of the parathyroid glands to secrete PTH or from failure of its action at the tissue level.

Aetiology

Hypoparathyroidism most commonly occurs as a result of surgery for thyroid disease or after neck exploration and resection of adenoma causing hyperparathyroidism. In experienced hands, the incidence of permanent hypoparathyroidism is less than 1% for all thyroid and parathyroid surgery. Other causes include autoimmune parathyroid destruction either as an isolated idiopathic disorder or as part of a multiple endocrine deficiency characterised by hyposecretion of several endocrine glands. Transient hypoparathyroidism with symptomatic hypocalcaemia can occur in neonates. The condition pseudohypoparathyroidism occurs in patients with defects of the PTH receptor such that though PTH levels are normal (or raised), calcium is low. Increasingly, reports are identifying acute symptomatic hypocalcaemia and hypomagnesaemia complicating the use of omeprazole and other protein pump inhibitors. These patients are severely magnesium depleted and have an acquired hypoparathyroidism which is reversible on stopping the offending drug (Cundy and Dissanayake, 2008).

Investigations

Hypocalcaemia associated with undetectable or low plasma PTH levels is consistent with hypoparathyroidism. Total plasma calcium levels should always be corrected for any abnormality in the plasma albumin concentration using the following equation.

Hyperphosphataemia is often present. It should be noted that there are many other causes of hypocalcaemia (Box 43.7). Pseudohypoparathyroidism is easily distinguished as it is associated with excessive PTH secretion and reduced target organ responsiveness. Drugs that may produce hypocalcaemia include calcitonin, plicamycin (formerly mithramycin), phosphate, bisphosphonates, phenytoin, phenobarbital, colestyramine, cisplatin, 5-FU and high-dose i.v. citrate or lactate.

Treatment

Severe, acute hypocalcaemia with tetany should be treated with intravenous calcium gluconate. Initially, 10 mL of 10% calcium gluconate is given by slow intravenous injection, preferably with ECG monitoring. If the patient can swallow, oral therapy should then be commenced. If further parenteral therapy is required, 20 mL of 10% injection should be added to each 500 mL of intravenous fluid and given over 6 h. The plasma magnesium level should always be measured in patients with hypocalcaemia, and if low, magnesium therapy instituted.

For chronic treatment, PTH therapy is not currently a practical option as the hormone has to be administered parenterally, and the current high cost is prohibitive. Maintenance treatment for hypoparathyroidism is easily achieved with a vitamin D preparation to increase intestinal calcium absorption, often in conjunction with calcium supplementation. Details of the preparations available are given in Table 43.6. Ergocalciferol (vitamin D₂) is difficult to use and is not recommended. It has a long pharmacological and biological half-life, takes 4–8 weeks to restore normocalcaemia and its effects can persist for up to 4 months following withdrawal. In contrast, calcitriol and its synthetic analogue alfacalcidol are much easier to use. Alfacalcidol restores normocalcaemia within 1 week and its effects only persist for 1 week following withdrawal, permitting greater flexibility in dosage manipulation. The usual daily dose is 0.5–2 μcg. Patients need close monitoring initially until stable normocalcaemia is achieved and thereafter at a minimum of 6-month intervals indefinitely.

Table 43.6 Vitamin D preparations

Drug	Preparations	Activity
Ergocalciferol (calciferol, vitamin D₂)	Calciferol injection 7.5 mg (300,000 units/mL)	Requires renal and hepatic activation
	Calciferol tablets 250 μcg (10,000 units) and 1.25 mg (50,000 units)
	Calcium and ergocalciferol tablets (2.4 mmol of calcium + 400 units of ergocalciferol)
Colecalciferol (vitamin D₃)	A range of preparations containing calcium (500–600 mg) and colecalciferol (200–440 units)	Requires renal and hepatic activation
Alfacalcidol (1 α-hydroxycolecalciferol)	Alfacalcidol capsules, 250 ng, 500 ng and 1 μcg	Requires hepatic activation
Alfacalcidol (1 α-hydroxycolecalciferol)	Alfacalcidol injection, 2 μcg/mL	Requires hepatic activation
Calcitriol (1,25-dihydroxycholecalciferol)	Calcitriol capsules, 250 ng and 500 ng	Active
	Calcitriol injection, 1 μcg/mL
Dihydrotachysterol	Dihydrotachysterol oral solution, 250 mg/ml	Requires hepatic activation

Hyperparathyroidism

Hyperparathyroidism occurs when there is increased production of PTH by the parathyroid gland. Primary hyperparathyroidism causes hypercalcaemia. Secondary hyperparathyroidism reflects a physiological response to hypocalcaemia or hyperphosphataemia.

Epidemiology

Recent studies in the USA and Europe indicate an incidence rate for primary hyperparathyroidism of 25 cases per 100,000 of the population per year. The incidence is two to three times higher in women than in men, and the disease most commonly presents between the third and fifth decades.

Aetiology

Primary hyperparathyroidism is due to the development of either single parathyroid adenomas or rarely (<5%) hyperplasia of all four glands. It may occur as part of the dominantly inherited multiple endocrine neoplasia (MEN) syndromes.

There are several conditions associated with secondary hyperparathyroidism, including chronic renal failure and vitamin D deficiency. Chronic renal failure is the commonest cause. In the early stages of the disease, a rise in the plasma phosphate concentration causes stimulation of PTH release and, in more advanced renal impairment, reduced 1 α-hydroxylation of vitamin D results in reduced intestinal calcium absorption, hypocalcaemia and further stimulation of the parathyroid glands. Tertiary hyperparathyroidism occurs in a minority of patients with end-stage renal failure when hyperplastic parathyroid glands become autonomous and secrete PTH in levels that raise calcium levels above normal.

Clinical manifestations

The clinical features of primary hyperparathyroidism are shown in Box 43.8. These are related to the effects of hypercalcaemia itself, plus the effects of mobilisation of calcium from the skeleton and excretion in the urine. With increasingly early recognition of the biochemical abnormalities of primary hyperparathyroidism largely due to automated measurement of plasma calcium, most patients are identified at an early stage with mild or asymptomatic disease. The classical presenting features of bone disease and renal stones are now relatively uncommon. Although radiological evidence of bone disease is now rare in these patients, measurement of bone mineral content by densitometry (DEXA) scanning usually indicates that bone loss is accelerated and the risk of osteoporotic fractures later in life is increased.

Investigations

Hypercalcaemia is the primary biochemical abnormality in primary hyperparathyroidism. Phosphate levels are often decreased and PTH levels are either inappropriately normal in the face of hypercalcaemia or elevated. In a patient with borderline elevation of calcium and a normal or only marginally elevated PTH, the benign condition familial hypocalciuric hypercalcaemia (FHH) must be excluded. Urine calcium excretion is increased in primary hyperparathyroidism and low in FHH.

There are many other causes of hypercalcaemia, including malignancy (including myeloma), drugs (thiazides, excess vitamin D), thyrotoxicosis, immobilisation and sarcoidosis. In all these situations, PTH levels are undetectable as the normal parathyroid glands appropriately switch off production of PTH in the face of hypercalcaemia. The most common cause of symptomatic hypercalcaemia in clinical practice is that associated with malignancy and this diagnosis must always be excluded.

Localisation of parathyroid tumours is only required in those listed for neck exploration. Most parathyroid surgeons request a neck ultrasound prior to performing a neck exploration. Isotope scanning, CT, MRI and selective venous sampling are reserved for those patients (around 1% in experienced hands) in whom the adenoma cannot be located at the first operation.

Treatment

Surgical removal of the adenoma or removal of all hyperplastic tissue is the only curative treatment for primary hyperparathyroidism; however, the natural history of hyperparathyroidism is not fully documented. Some studies have indicated that over 50% of untreated patients with primary hyperparathyroidism show no deterioration over 5 years, but the longer-term effects on renal function and bone mass remain unknown. In practice, many patients are observed and their specific problems separately addressed. Thus, patients receive bisphosphonates for osteoporosis, anti-hypertensives, acid-lowering therapy and laxatives.

The main indications for surgical treatment are persistent hypercalcaemia > 2.85 mmol/L, symptomatic hypercalcaemia, renal impairment, renal stones and progression of osteoporosis. Postoperatively, temporary hypocalcaemia (hungry bones) is common. In patients with bone disease, treatment with alfacalcidol and calcium supplements should be started on the day before the operation. Approximately 10% of surgically treated patients develop permanent hyperparathyroidism.

Treatment of hypercalcaemia

Severe hypercalcaemia is a common medical emergency. It must be corrected whilst investigation continues to identify the cause. Table 43.7 shows the treatments available. In practice, rehydration and parenteral bisphosphonates, for example, pamidronate 60 mg in 250 mL normal saline over 30 min, will normalise calcium over 72 h in most patients.

Table 43.7 Treatment of hypercalcaemia

Mechanism	Treatment
Increase urinary calcium excretion	Normal saline plus loop diuretic
Reduce bone resorption	Bisphosphonates
	Calcitonin
	Gallium, mithramycin
Reduce gastro-intestinal absorption	Glucocorticoids in calcitriol dependent (vitamin D excess, sarcoid and some lymphoma patients)
Chelation	Intravenous EDTA or phosphate
Dialysis