10.1.5 Ageing and thyroid disease

The relationship between ageing and the thyroid has been the object of intensive investigation (1) for several pathophysiological, epidemiological, and clinical reasons. Symptoms of ageing can easily be confused with hypothyroidism, and decreased thyroid function was once believed to be a hallmark of senescence. Thyroid diseases are common in the elderly, but their clinical manifestations are different from those seen in younger patients, being more vague, subtle, and often hidden by concurrent diseases. The interpretation of thyroid function tests is often difficult in elderly individuals, due to age-associated changes of thyroid physiology, alterations of thyroid function tests secondary to nonthyroidal illness, and/or drug intake. Treatment of thyroid disease deserves special attention in elderly patients due to the increased risk of complications and/or drug interactions. If untreated, thyroid dysfunctions may lead to significant morbidity in elderly people, mostly through an aggravation of coexistent cardiovascular disease. A remarkable exception to this concept is represented by mild hypothyroidism, which in the oldest elderly population appears to be associated with no harm, and possibly increased survival.

Physiological ageing is associated with substantially normal hypothalamic–pituitary–thyroid activity (1). The mild abnormalities observed in elderly groups can be explained by the confounding effects of concomitant nonthyroidal illness (NTI) (Box 10.1.5.1). In early studies, a low metabolic rate suggestive of hypothyroidism was reported in the elderly, but this reduction can be explained by the age-associated fall in fat-free body mass (1). Ageing is associated with lower radioactive iodine uptake and reduced thyroxine (T₄) secretion and degradation rates (1). The net effect of these changes leads to unchanged serum total (TT₄) and free (FT₄) thyroxine concentrations, even in centenarians (2). In contrast, triiodothyronine (T₃) concentrations, both serum total (TT₃) and free (FT₃), decline with age, and this fall is maximal in those aged over 95–100 years. (2) The reduction of circulating T₃ is the consequence of reduced peripheral conversion of T₄ to T₃, due to decreased 5′-deiodination of T₄ secondary to concomitant NTI, and also due to age itself (1, 2).

Basal serum thyroid-stimulating hormone (TSH) concentrations do not change with ageing (1). However, mean serum TSH is significantly reduced in selected healthy euthyroid centenarians (2), and a small fraction of elderly subjects have consistently low serum TSH unrelated to subclinical hyperthyroidism (4). Other age-associated abnormalities of TSH secretion reported in humans include a reduction of the daily secretion rate and a blunting of the nocturnal peak (which also occurs 1–1.5 h earlier than in younger adults), while contrasting results have been reported in the analysis of TSH response to thyrotropin-releasing hormone (TRH) (1). The data above suggest that TSH secretion in healthy elderly humans is slightly decreased, but recent epidemiological data on unselected elderly populations, including centenarians with no clinical, biochemical and echographic evidence of thyroid diseases, provide clear evidence for higher median serum TSH values above 80 years of age (5, 6). The reasons for such a discrepancy are not immediately clear and deserve further investigation, although one possible explanation could be represented by the different prevalences of NTIs in selected and unselected elderly subjects.

Malnutrition, drugs, and several acute and chronic NTIs are associated with alterations in thyroid function tests, and may therefore confound the assessment of thyroid function in the elderly. Depending on severity, stage, and drug effects, NTIs are associated with low serum T₃, normal to low T₄, high reverse T₃ (rT₃), and normal to low or elevated TSH levels (7). The magnitude of changes correlates with the severity of illness and the prognosis for survival, which is particularly poor in the presence of low T₄. The low serum T₃ results from decreased extrathyroidal conversion of T₄ to T₃, due to reduced delivery of T₄ to tissue 5′-deiodinase and/or to a decreased activity of this enzyme (7). Impaired 5′-deiodination also accounts for increased serum rT₃ concentration. A low serum T₄ concentration may result from reduced TSH secretion. It may also arise from increased T₄ clearance, due to decreased production/affinity of thyroxine-binding globulin (TBG). Inhibitors of T₄ binding to TBG, such as free fatty acids, might contribute to the T₄-binding defect (7). Serum FT₄ concentrations are usually normal or even increased when measured by equilibrium dialysis or a two-step method, but in severe illness FT₄ may be low irrespective of the technique used (7). Serum TSH concentration may be reduced in acutely sick patients, particularly in those with low energy intake or concurrent glucocorticoid or dopamine treatment (4, 7, 8). The prevalence of patients with NTIs and undetectable serum TSH depends upon the sensitivity of the assay. With third generation TSH assays (sensitivity below 0.01 mU/l), most, but not all (8), patients with an NTI have low but detectable TSH levels. In the recovery phase, serum TSH may transiently rise to 15–20 mU/l (7); this condition should not be confused with subclinical hypothyroidism. Thyroid hormone abnormalities observed in ageing and in NTI are compared in Table 10.1.5.1. Confirmation of suspected intrinsic thyroid disease (discussed in more detail in the following paragraphs) may require deferment of thyroid testing until the NTI subsides. In emergency situations, the identification of thyroid dysfunctions in severely ill patients should be based on the combined measurements of serum free T₄ and TSH, rather than on the latter alone (3).

Ageing is associated with the appearance of several serum autoantibodies, including thyroid autoantibodies (9). The biological and clinical significance of this phenomenon is still unknown, since, with the exception of primary hypothyroidism, the prevalence of clinically overt thyroid autoimmune diseases is not increased in the elderly (9). The peculiar link between autoimmune thyroid failure and ageing is also underscored by the high prevalence of subclinical hypothyroidism in elderly subjects with positive serum thyroid autoantibodies (see below), and could be the consequence of preferential age-dependent expression of destructive effector mechanisms and/or increased target gland susceptibility (9). Thyroid autoimmunity and subclinical hypothyroidism have been implicated in the pathogenesis of other age-associated disorders, in particular coronary heart disease (9), but this hypothesis is not supported by recent epidemiological data (10). Thyroid autoantibodies are rare in healthy centenarians (11) and in other highly selected aged populations, while they are frequently observed in the hospitalized elderly (9). These data suggest that thyroid autoimmune phenomena are not the consequence of the ageing process itself, but rather an expression of age-associated disease (9).

A high percentage of elderly patients take medications which may interact with thyroid function, thyroid tests, and with l-thyroxine (LT₄) substitution therapy (3, 12). Several drugs (listed in Box 10.1.5.2) may alter the results of thyroid hormone and TSH measurements without altering thyroid status. Other compounds (listed in Box 10.1.5.3) may induce hypo- or hyperthyroidism: among those, amiodarone and other forms of iodine-induced hypothyroidism and thyrotoxicosis are frequently observed in the elderly. Up to 30% of subclinical and to 20% of overt hypothyroidism is observed in patients on long-term lithium therapy (12). Therapy with cytokines such as interferon-α or interleukin-2 may precipitate hypothyroidism, thyrotoxicosis, or the biphasic pattern of silent thyroiditis, especially in the presence of pre-existent thyroid autoimmunity (3, 12). Sulphonamides, sulphonylureas, ethionamide, p-aminosalicylic acid, phenylbutazone, and nicardipine may induce hypothyroidism, but the antithyroid potential of these drugs is so weak that an underlying thyroid abnormality should be suspected (3). In hypothyroid patients taking LT₄, the concomitant administration of other drugs may influence the optimal dose required by interfering with LT₄ absorption and metabolism (Box 10.1.5.4). Hypothyroidism and hyperthyroidism may also alter the metabolism and excretion of many drugs needed to treat concomitant diseases (3). The plasma half-life of digoxin, morphine, glucocorticoids, and insulin is increased in hypothyroidism, so that lower maintenance doses of these medications are required. Opposite metabolic changes occur in thyrotoxicosis, resulting in increased maintenance doses of these drugs. Hypothyroid patients have a slower clearance of vitamin K-dependent coagulation factors, and a resistance to the anticoagulant effect of warfarin, while an augmented response to warfarin is observed in hyperthyroidism (13).

The prevalence of hypothyroidism in the elderly is increased when compared to younger populations, ranging from 0.5 to 6% for overt hypothyroidism, and from 4 to 20% for subclinical hypothyroidism (14). Hypothyroidism is more frequent in elderly Caucasian women, and is more commonly observed in hospitalized as compared to independent subjects. The regional iodine intake appears to affect the prevalence of hypothyroidism, which is more common in iodine-rich than in iodine-deficient regions (15). An iodine-dependent exacerbation of thyroid autoimmunity might explain this finding (16).

Although autoimmune thyroiditis is the main cause of hypothyroidism in the elderly (14), other causes are more frequently found in old when compared to young patients. In a recent large, observational, cross-sectional study on 260 men with primary hypothyroidism aged 58.3±16.1 years, autoimmune thyroiditis was responsible for only 41.2% of cases (17). Iatrogenic hypothyroidism is also common as a consequence of radioiodine administration or thyroid surgery, head and neck radiation for non-thyroidal conditions, and antithyroid drugs (Box 10.1.5.3). Excess iodine derived from drugs (mostly represented by amiodarone) or iodinated radiographic contrast agents (16) is an important cause of hypothyroidism, especially in iodine-rich areas. This form of thyroid failure develops preferentially in glands with organification defects due to autoimmune thyroiditis or previous radioiodine administration.

Hypothyroidism in the elderly develops insidiously, and often lacks its classic clinical features (3). For example, loss rather than gain of weight may occur due to reduced appetite. Some manifestations (fatigue, cold intolerance, dry skin, constipation, poor appetite, cardiomegaly, pericardial effusions, mental deterioration, hearing loss) may be erroneously attributed to ageing or age-associated diseases. Indeed, when these symptoms are taken individually, they are unusual manifestations of thyroid failure in the elderly. The clue to the diagnosis of hypothyroidism in the elderly may be gleaned from a cluster of symptoms such as unexplained increases in serum cholesterol and creatine phosphokinase levels, macrocytic anaemia, severe constipation, and congestive heart failure with restrictive cardiomyopathy. Neurological signs (cerebellar ataxia, carpal tunnel syndrome, peripheral neuropathy) and arthritic complaints are common. Neuropsychiatric manifestations frequently include depression; lethargy, memory loss, and apathy, are sometime observed, while psychosis (myxoedema madness) is rare. Dementia may be present in some old hypothyroid patients, but this rarely improves after correction of hypothyroidism. Elderly patients are more susceptible to myxoedema coma (18), which may be precipitated by concurrent NTI or cold exposure. Localized neurologic signs, hypothermia, hyponatraemia, and hypoglycaemia are the hallmarks of myxoedema coma. The mortality in hypothermic patients is high, unless vigorous therapy is given immediately.

The single best diagnostic test for primary hypothyroidism is an increased serum TSH concentration, but transient nonspecific increases of TSH during the recovery phase of an NTI should be excluded. Glucocorticoids and dopamine may lower serum TSH concentrations in primary hypothyroidism (3). Decreased serum concentrations of TT₄ and free T₄ may be observed in both hypothyroidism and NTI, although decreased T₄ is observed more frequently in thyroid failure. Tests for antithyroid antibodies help to identify patients with autoimmune thyroiditis, but do not provide direct information on thyroid function. Obtaining a hypoechogenic pattern of the thyroid by ultrasonography helps in identifying autoimmune thyroiditis (3).

The average daily replacement dose of LT₄ in adults is 1.6 μg/kg body weight, but elderly hypothyroid patients require a dose 20–30% lower (19). Elderly hypothyroid patients also display a narrow therapeutic range and require close monitoring of serum TSH to avoid under- and overtreatment. Aoki et al. (20) performed an extensive analysis of the large epidemiological study NAHNES III, carried out between 1999 and 2002 in the USA. They found that up to 25.3% of patients aged over 70 years taking thyroid hormone medications were under-treated, and 5.8% were over-treated. In elderly hypothyroid patients LT₄ therapy should be initiated with a dose of 12.5–25 μg/day, followed by careful increments of 12.5–25 μg/day every 4–8 weeks, to reach the full replacement dose after several months (19). Particular attention should be paid in patients with coexistent or suspected cardiac disease, since LT₄ substitution may precipitate angina or myocardial infarction (21). On the other hand, LT₄ substitution ameliorates reversible hypothyroid heart dysfunction (22) and produces beneficial effects on hyperlipidaemia. Coronary bypass or angioplasty can be performed safely before starting LT₄ administration (21). Propranolol may not be effective in reducing the cardiac effects of LT₄ replacement therapy in coronary artery disease patients; calcium channels blockers may be more suitable to control angina in hypothyroid patients given LT₄(21). Long-term LT₄ substitution does not reduce bone mineral density, provided that serum TSH concentrations are maintained in the normal range (19).

Therapy of myxoedema coma requires rapid restoration of euthyroidism and correction of accompanying respiratory, cardiovascular, and fluid-electrolyte abnormalities. A combination of LT₄ and LT₃ or low doses of LT₃ alone have also been proposed, based on the rationale that LT₃ has a more rapid onset of action and that in critical illness the conversion of T₄ to T₃ is inhibited. This is obtained with a starting intravenous bolus dose of 4 μg/kg lean body weight (200–250 μg) of LT₄, followed by 100 μg 24 h later, and maintenance doses of 50–100 μg/day associated with 10 μg of LT₃ IV every 8 to 12 h until oral therapy can be instituted (18).

Subclinical hypothyroidism, defined as raised serum TSH with normal FT₄ concentration, is a common finding in old people. Like overt thyroid failure, most cases are due to autoimmune thyroiditis or to previous treatment of hyperthyroidism. Progression rates from subclinical to overt hypothyroidism range from 2 to 18% per year (14), the higher values being observed in subjects with higher basal serum TSH concentration and thyroid antibody titres (23). However, follow-up of subjects aged more than 55 years with marginal elevation of serum TSH shows that the proportion of subjects with normalization of circulating TSH concentrations (37.4%) is higher than that of those progressing to overt thyroid failure (26.8%) (24). Overt hypothyroidism is associated with hyperlipidaemia, which is a risk factor for coronary artery disease. The effect of subclinical hypothyroidism and its treatment upon circulating lipids is controversial. The most recent meta-analysis of the literature (25) favours a slight increase of total cholesterol in patients with subclinical hypothyroidism. Restoration of normal TSH levels with LT₄ is associated with a small but significant (6%) reduction in total cholesterol levels (25).

Indications for LT₄ substitution therapy in subclinical hypothyroidism remain controversial at all ages (26, 27). Mild complaints consistent with thyroid hormone deficiency, subtle alterations in myocardial contractility, cognitive dysfunction (mostly represented by impaired ‘working’ memory), and depression have been reported in patients with subclinical hypothyroidism (14). Restoration of normal cardiac contractility, improved psychometric tests, and reduced hypothyroid symptom ratings have been reported in some patients after LT₄ administration (14). Most authors (14, 26) advise replacement therapy in any patient with a serum TSH concentration above 10 mU/l, and in those with borderline high serum TSH (5–10 mU/l) and positive thyroid antibody. The presence of hypercholesterolaemia and symptoms consistent with thyroid hormone deficiency may favour active treatment (14, 26). However, these recommendations are adequate for young or middle-aged subjects, but may be misleading in the elderly. Indeed, recent reviews and meta-analyses (10, 28) provide evidence that subclinical hypothyroidism is a significant risk factor for ischaemic heart disease and cardiac mortality only in subject less than 65 years old. Moreover, hypothyroidism appears to be associated with higher survival in subjects more than 85 years old (29), suggesting protective effects of a lower metabolic status. It is therefore reasonable to speculate that mild subclinical hypothyroidism may produce different age-dependent effects on cardiovascular risk (30). As shown in figure 10.1.5.1, thyroid failure may contribute to the cardiovascular risk together with other genetic or environmental factors up to 60–65 years of age, while slightly decreased thyroid hormone levels may have opposite on the oldest elderly population (selected low-risk survivors). Finally, the decision to treat an elderly patient with any degree of hypothyroidism requires careful consideration of potential adverse reactions, such as aggravation of myocardial ischaemia. Taken together, the above considerations strongly argue against treating subclinical hypothyroidism in subjects older than 85 years. Moreover, the target of substitution therapy for patients aged more than 85 years with overt hypothyroidism should probably be targeted towards achieving serum TSH concentrations slightly above the normal adult range (e.g. 4–6 mU/l) (31).

The prevalence of endogenous and exogenous hyperthyroidism in the elderly ranges from 0.5 to 2.3% (1, 3). Graves’ disease, toxic nodular goitre, and solitary toxic adenoma account for most cases. In the elderly, the relative frequency of toxic nodular goitre as the cause of hyperthyroidism is higher than in younger age groups (3). This is particularly true in populations where nodular goitre is common (as in areas of iodine deficiency), while in the case of normal or high iodine intake the most common cause of hyperthyroidism is Graves’ disease (32). Hyperthyroidism in the elderly may frequently be the consequence of drug intake. Overt iatrogenic thyrotoxicosis due to excess thyroid hormone intake rarely occurs in patients on long-term LT₄ therapy, but subclinical hyperthyroidism may be very frequent in this group of patients if serum TSH is not carefully checked (4, 20). Quite rarely, thyrotoxicosis factitia (Münchausen’s syndrome), and thyrotoxicosis due to the ingestion of ‘natural’ desiccated thyroid as a ‘health food’ or weight-losing pills, may also occur (3). Hyperthyroidism in old patients with nodular goitre is often precipitated by excess iodine contained in medications or by radiographic contrast media (16). Among iodine-containing medications, amiodarone deserves particular attention. This drug contains 37.2 mg of iodine/100 mg of substance and is used in the treatment of ventricular arrhythmias and/or ischaemic heart disease (33). Amiodarone-induced thyrotoxicosis (AIT) occurs in about 10% of patients residing in iodine-deficient areas, but is less common in areas with normal or high iodine intake (33). AIT is more frequently observed in patients with pre-existing thyroid disorders such as nodular goitre or subclinical Graves’ disease (type I AIT), but may also induce destructive thyrotoxicosis by the release of preformed thyroid hormones (type II AIT). Distinction between the two types of AIT is not always possible, and both conditions may coexist in the same patient (33).

Elderly hyperthyroid patients typically display fewer signs and symptoms, hence the term ‘apathetic’ or ‘masked’ hyperthyroidism. Eye signs are often lacking, but Graves’ ophthalmopathy, when present, is usually worse (3). Tachycardia is less common, although it may be found in more than 50% of older patients (34). Presenting symptoms of thyrotoxicosis in the elderly are frequently related to heart complications, including refractory congestive heart failure and angina. A high prevalence (about 10–20%) of atrial fibrillation is found in thyrotoxic patients, but higher percentages (25–35%) may be observed in elderly male patients (34). Arterial embolism is observed in 10–40% of elderly hyperthyroid patients with atrial fibrillation (3, 13). Weight loss is often associated with anorexia; muscle wasting and weakness are also common. Depression and lethargy, agitation and anxiety, dementia, and confusion may be primary manifestations (3). The increased risk of osteoporosis and bone fracture typical of old age is markedly increased, due to accelerated bone loss (3).

Elevated levels of free T₄ and/or free T₃ and low levels of TSH by sensitive assay establish the diagnosis of primary hyperthyroidism. Serum T₃ (and, to a lesser degree, T₄) may show inappropriately low values in hyperthyroid severely ill patients with coexistent NTIs (7, 8). Serum TSH may be depressed independently from hyperthyroidism in old patients with an NTI or who are taking glucocorticoids or dopamine (7). With third generation assays, the majority of hyperthyroid patients have TSH values below 0.01 U/l, whereas critically ill patients have values between 0.01 and 0.1 mU/l, but complete discrimination between the two conditions may not be possible (8). Hence, a biochemical diagnosis of overt hyperthyroidism should always be based on the relation between free thyroid hormones and TSH. Thyroid scans, radioiodine uptake tests, and thyroid echography may help in confirming the diagnosis and in defining the type of hyperthyroidism. Radioiodine uptake is particularly useful in differentiating hyperthyroidism from destructive or exogenous thyrotoxicosis, but low radioiodine uptake values are also observed in iodine-induced hyperthyroidism (16, 33).

Long-term therapy with antithyroid drugs (methimazole or propylthiouracil) is not recommended in elderly patients because of the high relapse rate of hyperthyroidism after withdrawal and the increased incidence of adverse effects (35, 36). Radioiodine (¹³¹I) is the treatment of choice in aged hyperthyroid patients, since it results in a definitive cure and avoids the risks of surgery (35). Radioiodine takes time to control hyperthyroidism and may be followed by a transient worsening of thyrotoxicosis due to thyroid hormone release subsequent to radiation thyroiditis or from discontinuing antithyroid drugs (35). To limit the dangers associated with this event, euthyroidism should be restored with antithyroid drugs before ¹³¹I therapy. Control of heart rate with β-blockers (or calcium channel blockers) before and after radioiodine therapy is recommended, as long as the patient remains thyrotoxic. Hypothyroidism may develop within the first few months after radioiodine therapy or in subsequent years (35). Late-onset thyroid failure should be regarded as an expected endpoint rather than a complication of ¹³¹I therapy. Since persistent thyrotoxicosis is more deleterious than hypothyroidism, high doses of ¹³¹I are often recommended in old patients, especially in those with toxic nodular goitre (3). Treatment with thionamides after ¹³¹I is often required in the elderly, but these drugs should be reinstituted at least 1–2 weeks after radioiodine administration since thionamides may reduce the effectiveness of ¹³¹I treatment (35). Thyrotoxic atrial fibrillation (especially of recent onset) is likely to revert to sinus rhythm after euthyroidism is established, and patients should be treated with anticoagulants to prevent embolism (3, 13). Long-term follow-up of thyroid function is mandatory after radioiodine therapy, and eventual hypothyroidism must be corrected with the minimal dose of LT₄ sufficient to maintain normal serum TSH.

Treatment of iodine-induced thyrotoxicosis is difficult: low radio-iodine uptake prevents in most cases the use of ¹³¹I, thyroidectomy is hazardous in elderly patients with uncontrolled hyperthyroidism, and the response to antithyroid drugs is poor in the presence of iodine overload (33). The iodine-containing substance should be immediately withdrawn, since iodide-induced thyrotoxicosis is often self-limited, especially in patients with no underlying thyroid diseases. Several therapeutic strategies have been proposed for amiodarone-induced thyrotoxicosis. Combined treatment with high dose methimazole (40 mg/day) and potassium perchlorate (1.0 g/day) allows rapid control in most patients with type I AIT. In those with destructive AIT (type II), glucocorticoids (prednisone: 40 mg/day) may rapidly normalize thyroid function.

The prevalence of low serum TSH among elderly people is high (1.5–12.5%) (6, 14), but the proportion progressing to overt hyperthyroidism is generally lower (2–10%) (14). Subclinical hyperthyroidism in iodine-sufficient areas is due to ‘subclinical’ Graves’ disease or excessive/inappropriate thyroid hormone therapy (15, 32), while autonomously functioning thyroid nodules account for most cases observed in iodine-deficient areas (15, 32).

Although most patients lack specific symptoms, subclinical hyperthyroidism may be clinically relevant. Atrial fibrillation has frequently (4–17%) been reported in patients with this condition, and even higher figures (28%) were reported in patients with autonomously functioning nodular goitre (3). Persons aged about 60 years with a low serum TSH concentration have a significantly increased risk of atrial fibrillation in the subsequent decade (14, 37, 38). In keeping with these findings, there is a significant increase in 10-year mortality in subjects with subclinical hyperthyroidism as compared to the euthyroid population, which is particularly evident after 50–60 years of age (39). Other risks associated to subclinical hyperthyroidism are reduced bone density in post-menopausal women (3, 14), and cognitive impairment (40) or dementia (41). For the above reasons, subclinical hyperthyroidism in the elderly usually deserves active treatment (14, 26).

Thyroid hormone therapy is a frequent cause of low serum TSH in elderly patients (4, 20). In this case the LT₄ dose should be reduced until serum TSH returns to within the normal range (19).

An age-dependent increase in thyroid volume and nodularity has been documented by echography both in iodine-sufficient and iodine-deficient areas (1, 3). In nonendemic countries, the prevalence of clinically evident thyroid nodules is approximately 5% at 60 years of age, but pathological studies documented a nodular thyroid in up to 90% of women over 70 years and 60% of men over 80 years (1). In areas of iodine deficiency, the ultrasonographic prevalence of nodular goitre after 60 years of age is about 50% (1, 42).

The diagnostic evaluation of nodular goitre in the elderly is similar to that in younger patients. Relevant nodules require fine needle aspiration cytology, although, given the increased prevalence of nodular goitre in the elderly, a thyroid nodule is more likely to be benign than malignant (1).

Because surgical risks are higher in the elderly, most nontoxic nodular goitres are managed conservatively (3). Surgery is indicated in the presence of strong suspicion of malignancy or significant airway obstruction. In patients with contraindications to surgery, radioiodine has been successfully used with partial reduction in thyroid size and relief of pressure symptoms (43). The efficacy of radioiodine may be increased by previous administration of recombinant human TSH, but the intended positive effect on thyroid radioactive iodine uptake must be balanced against undesirable consequences such as thyrotoxicosis and goitre swelling (44). The initiation of TSH-suppressive therapy with LT₄ in old patients with nodular goitre is not justified, due to higher cardiovascular risks and to the possibility of precipitating thyrotoxicosis when areas of functional autonomy are present (19).

The overall annual age-specific incidence rate of clinical and occult differentiated thyroid carcinoma does not increase with age, but papillary carcinoma occurs more frequently during the third and the fifth decades, and follicular cancer peaks in the late fifth decade. (39) As a consequence, the ratio of papillary/follicular thyroid carcinoma is lower in the elderly (2:1) compared to the values (3–4:1) observed in younger patients (1, 3). Anaplastic thyroid carcinoma, the most lethal thyroid neoplasm, is almost exclusively observed in old patients over 65 years of age (45), as are other rare thyroid neoplasms such as sarcomas and primary thyroid lymphomas. Thus, differentiated thyroid carcinomas account for 50–60% of all thyroid cancers in patients over 60 years of age, with the remaining tumours mostly represented by anaplastic or undifferentiated types (1). According to recent epidemiological studies, however, the rate of anaplastic carcinoma decreased by 22% in the period 1973–2003, possibly as result of the successful early treatment of differentiated carcinomas in younger patients (46).

Age at the onset of disease is an important prognostic factor in differentiated thyroid carcinoma because these tumours are more aggressive in older patients, especially in males. Early preoperative diagnosis using fine needle aspiration cytology and urgent aggressive therapy are highly recommended (3, 45). The therapeutic approach of differentiated thyroid cancer is similar to that followed in younger persons. It includes total thyroidectomy and radioiodine ablation followed by LT₄ therapy. The use of TSH-suppressive doses in differentiated thyroid carcinoma has been recently questioned, and this schedule is presently advised only in patients with metastases (47). Given the increased cardiovascular risk associated with subclinical hyperthyroidism in the elderly, caution should be exercised in administering suppressive doses of thyroid hormone in old patients with thyroid carcinoma even in the presence of persistent disease. External radiation and chemotherapy are used in thyroid lymphoma and anaplastic carcinoma, although in the latter the outcome is in general rapidly fatal.