Epidemiology

Accurate assessment of the prevalence and incidence of hypothyroidism is difficult due to variation in definitions and population samples. The prevalence of previously undiagnosed, spontaneous, overt hypothyroidism has been estimated to be between 2 and 4 per 1000 of the total population worldwide. However, if all cases of previously diagnosed hypothyroidism and the effects of previous thyroid surgery and radioiodine treatment are included, this prevalence rises to approximately 10 per 1000. In the UK, primary hypothyroidism is common with a prevalence of 14/1000 women (but <1/1000 men). Despite these data, population screening for autoimmune hypothyroidism is thought to be probably not cost-effective unless incorporated into a screening programme for other conditions. Although the disease may occur at any age, most patients present between 30 and 60 years of age.

Aetiology

Primary hypothyroidism accounts for more than 95% of adult cases. It is usually due to a failure of the thyroid gland itself as a result of autoimmune destruction, or the effects of treatment of thyrotoxicosis. Hypothyroidism may be drug induced. Amiodarone and lithium cause hypothyroidism in around 10% of patients treated (see later). Secondary disease is due to hypopituitarism, and tertiary disease due to failure of the hypothalamus. Peripheral hypothyroidism is due to tissue insensitivity to the action of thyroid hormones. A more extensive classification is shown in Box 43.1.

Iodides may produce hypothyroidism in patients who are particularly sensitive to their ability to block the active transport pump of the thyroid gland. Iodine absorption from topical iodine-containing antiseptics has been shown to cause hypothyroidism in neonates. This is potentially very dangerous at a critical time of neurological development in the newborn infant. Transient hypothyroidism may be seen in 25% of iodine-exposed infants.

Clinical manifestations

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.

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.

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.

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.

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.