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Hyperthyroidism in Aging

, M.D.

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Last Update: March 21, 2018.

ABSTRACT

Hyperthyroidism in the elderly is a serious clinical condition that is associated with significant morbidity and excess mortality. It may be difficult to diagnose due to the confounding effects of drugs and acute or chronic illnesses on the interpretation of thyroid function tests. Hyperthyroidism is usually diagnosed when a suppressed TSH level is found, but this can also be due to comorbid illnesses or effects of medications, which need to be excluded before making a diagnosis of hyperthyroidism. In addition, there is a relative paucity of typical hyperadrenergic symptoms in older patients with hyperthyroidism, who instead may present with unexplained weight loss, neurocognitive changes, or cardiovascular effects. Of particular concern is the elevated risk of atrial fibrillation in this age group. Graves’ disease and toxic multinodular goiter are the most common etiologies of hyperthyroidism in the elderly, although other causes of hyperthyroidism also occur. The use of amiodarone or administration of iodinated contrast agents can also lead to hyperthyroidism. Radioiodine or thionamide therapy are typically used to treat hyperthyroidism in older patients with surgery reserved for rare cases. Treatment decisions must be individualized, taking into account projected lifespan, comorbidities, and side effects of therapy. Subclinical hyperthyroidism is a form of mild hyperthyroidism with an isolated low or suppressed TSH level. In the elderly, it also confers an excess risk of atrial fibrillation and may lead to other adverse consequences. Treatment of subclinical hyperthyroidism is indicated in the elderly to avoid cardiovascular and arrhythmia associated adverse events. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

PREVALENCE OF HYPERTHYROIDISM IN AGING

Hyperthyroidism in the elderly is a serious clinical problem both for the individual and for health services which must fund associated costs. Hyperthyroidism is known to be a common disorder (1); a population-based survey reported by Tunbridge et al (2) conducted 30 years ago revealed a prevalence in the general population in the UK of around 2.7% in females (10-fold less in males) and of undiagnosed disease in around 0.5% of women. A more recent population-based survey in the United States revealed a prevalence of hyperthyroidism of 1.3%, with no difference between men and women (3). This prevalence decreases to 0.4% if one excludes patients with known thyroid disease and those taking thyroid hormone preparations, indicating that many cases of hyperthyroidism are due to overtreatment with exogenous thyroid hormone. In fact, one recent study indicated that over 40% of older subjects taking thyroid hormone had low TSH levels, indicating excess thyroid hormone doses (4). Another recent study reported that iatrogenic thyrotoxicosis accounted for half of low TSH levels in a community-based cohort of older subjects (5).

A number of studies have reported on the prevalence of hyperthyroidism specifically in elderly populations. Prevalence rates vary depending on whether patients taking thyroid hormone are included, but most surveys report that approximately 1 – 3% of subjects over the age of 60-65 years have hyperthyroidism (2,3,6-9). If one excludes patients taking thyroid hormone, prevalence rates of hyperthyroidism appear similar in younger and older populations (3).

SYMPTOMS AND SIGNS OF HYPERTHYROIDISM

Classical symptoms and signs of thyrotoxicosis are shown in Table 1 (1). While some or all of these may be present in elderly subjects with thyrotoxicosis, the clinical picture is often significantly different in this age group (10,11). Problems such as weight loss and depression or agitation may predominate - so-called "apathetic" thyrotoxicosis, a condition in which more typical symptoms and signs reflecting sympathetic activation such as tremor and hyperactivity are absent (12-14). Instead, cardiovascular symptoms and signs often predominate in older patients, including atrial fibrillation. Other findings more common in older patients with hyperthyroidism include fatigue, anorexia, weight loss, apathy, agitation, or cognitive decline (13-16). Particularly in this age group, the diagnosis of thyrotoxicosis should also be considered in the presence of other symptoms and signs considered "non-specific" in nature, such as muscle weakness, persistent vomiting, hypercalcemia, and worsening osteoporosis.

Table 1. SYMPTOMS AND SIGNS IN HYPERTHYROIDISM

1. Weight loss
2. Sweating/heat intolerance
3. Nervousness/agitation
4. Tiredness
5. Muscle weakness
6. Tremor
7. Palpitation
8. Shortness of breath
1. Tremor
2. Hyperactivity
3. Proximal myopathy
4. Sinus tachycardia
5. Atrial fibrillation/atrial dysrhythmias
6. Systolic hypertension
7. Goiter
8. Lid lag/lid retraction
9. Ophthalmopathy*
10. Pretibial myxedema*
11. Thyroid acropachy*
*specific to Graves’ disease

Cardiovascular Symptoms and Signs

Cardiovascular complications of thyrotoxicosis are especially common in the elderly and may be a cause of significant morbidity and mortality (1,17). A study by Franklyn et al (18) in subjects with a past history of thyrotoxicosis treated with radioiodine revealed a striking excess mortality from both cardiovascular and cerebrovascular causes in those aged over 60 years at the time of treatment. Much of this excess mortality was observed early after therapy. Significant increases in deaths from ischemic heart disease, hypertensive heart disease, rheumatic heart disease, and deaths ascribed to dysrhythmias were found in this age group. More recent studies have confirmed that hyperthyroid patients have increased mortality rates and cardiovascular events at all ages, but this is particularly clinically relevant in older patients with higher underlying rates of cardiovascular disease (19-21). Cumulative periods of decreased TSH levels were associated with increased mortality, emphasizing the importance of adequate treatment of hyperthyroidism (20).

In addition to classical findings of sinus tachycardia and systolic hypertension, it is well recognized that atrial fibrillation complicates thyrotoxicosis in about 15% of cases; however, the incidence of this complication rises with age so it is observed more frequently in the elderly (21). It has been estimated that atrial fibrillation occurs at least three times more commonly in those with thyrotoxicosis than those without. Development of atrial fibrillation may itself lead to deteriorating cardiac status, especially in the presence of pre-existing heart disease, and it may also be associated with embolic complications, especially cerebral embolism (22). These influences of atrial fibrillation probably contribute significantly to the increased cardiovascular and cerebrovascular mortality described above. Furthermore, the likelihood of spontaneous restoration of sinus rhythm in those with atrial fibrillation complicating thyrotoxicosis lessens with age, probably reflecting the presence of underlying ischemic, hypertensive or valvular heart disease (23). There is an adverse influence of increasing age, as well as underlying heart disease, on the likelihood of restoration of sinus rhythm in those with AF complicating overt hyperthyroidism, while interestingly the likelihood of restoration of normal cardiac rhythm was increased in those initially hypothyroid following treatment of hyperthyroidism (21).

In view of these cardiovascular manifestations/complications, the diagnosis of thyrotoxicosis should be suspected in all subjects presenting with atrial fibrillation, as well as those with worsening heart failure, systolic hypertension and deteriorating ischemic heart disease. Nonetheless case-finding studies have shown that thyrotoxicosis accounts for less than 5% of newly diagnosed cases of atrial fibrillation (24).

Bone Metabolism and Hyperthyroidism

The other particularly significant consequence of thyrotoxicosis in terms of morbidity and mortality is its effect on bone metabolism. It is well recognized that overt hyperthyroidism is associated with increased bone turnover and reduction in bone mineral density, which is especially marked in estrogen deficient postmenopausal women (25-27). While effective anti-thyroid treatment results in an improvement in bone mineral density, recovery is incomplete so risks of osteoporosis associated with ageing, especially in women, are exacerbated and may not be completely reversed by treatment of hyperthyroidism (18,28,29).

DIAGNOSIS OF HYPERTHYROIDISM

There is no specific effect of ageing upon standard tests of thyroid function. Studies of healthy elderly subjects have shown that serum concentrations of thyroxine (T4) and tri-iodothyronine (T3) are unchanged compared with younger age groups (30). Recent analysis of large U.S. population-based normative data suggest that there may be a slight increase in the upper limit of normal TSH levels with aging, but most elderly euthyroid subjects have serum TSH levels within the standard laboratory reference range (31). Nonetheless, "non-thyroidal" illnesses and drug therapies that alter tests of thyroid function (see below) are more common with increasing age and typically lead to reduced peripheral conversion of T4 to T3 and therefore reduction in serum T3 concentrations. Serum TSH may be unaffected by illness, although reduction in TSH is commonly seen, as is modest elevation in TSH during the recovery phase of illness (32).

It is essential that a clinical suspicion of thyrotoxicosis is confirmed or refuted by biochemical testing before further investigation or treatment is contemplated (1). The single most important biochemical test is measurement of serum TSH. If the serum TSH concentration is within the normal range, then a diagnosis of thyrotoxicosis is effectively ruled out. Exceptions to this rule are rare TSH-dependent causes of hyperthyroidism, such as TSH-secreting tumors of the pituitary and syndromes of thyroid hormone resistance, although these diagnoses are more typically associated with a modest rise in TSH (with raised serum thyroid hormones, as opposed to the usual pattern of raised TSH in conjunction with low thyroid hormone levels).

The finding of a low serum TSH (through use of a sensitive TSH assay) is not, however, specific for a diagnosis of thyrotoxicosis. Low serum TSH, especially if below the normal range but nonetheless detectable, often reflects a "non-thyroidal" illness or therapy with a wide variety of drugs (33). Drugs such as dopamine agonists, glucocorticoids, and bexarotene directly suppress TSH levels, while other drugs may lower TSH levels by increasing thyroid hormone levels (ex. amiodarone, lithium, interferon alpha, interleukin 2, tyrosine kinase inhibitors). A diagnosis of thyrotoxicosis should therefore be confirmed biochemically by measurement of serum free thyroxine (T4) (and in some cases T3 if free T4 is in the high/normal range and T3-toxicosis is therefore suspected).

In the majority of cases of thyrotoxicosis, a typical biochemical picture of elevated free T4 and T3 with associated undetectable TSH will be observed. In some cases, a biochemical diagnosis of "T3-toxicosis" is evident; this is characterized by elevation of serum T3 in the absence of a rise in T4. This biochemistry is typically observed in mild cases of toxic nodular hyperthyroidism and early in the course of Graves' hyperthyroidism. In some instances, the converse is true in that a rise in T3 is absent despite elevation in free T4 and suppression of TSH in a patient thought clinically to have thyrotoxicosis. This lack of rise in T3 may reflect the presence of another "non-thyroidal" illness, the explanation becoming evident upon re-testing once the other morbidity is eliminated.

CAUSES OF THYROTOXICOSIS.

Graves' Disease and Toxic Nodular Hyperthyroidism

In iodine replete parts of the world, Graves' disease is the commonest cause of hyperthyroidism. In the elderly, however, toxic nodular hyperthyroidism becomes an important cause, being responsible for the majority of cases of thyrotoxicosis (1). In all age groups, toxic nodular hyperthyroidism is more common in those areas of the world that are relatively iodine deficient (34). The natural history of goiter is of progression from the presence of diffuse thyroid enlargement to development of one or more nodules and eventual autonomous function of one or more of these nodules resulting in thyrotoxicosis. This natural history is typically long so the elderly patient presenting with thyrotoxicosis often describes the presence of a goiter for many years. A relatively rare cause is the presence of a single toxic adenoma - a benign tumor exhibiting autonomous secretion of thyroid hormones (34). Biochemically, the development of autonomous function in a nodular goiter is first evidenced by suppression of serum TSH with normal serum concentrations of thyroid hormones ("subclinical" hyperthyroidism - see below), later followed by elevation of serum T3 and free T4.

In many cases, the cause of thyrotoxicosis is obvious from the clinical picture (1). The diagnosis of Graves' disease may be evident because of the presence of diffuse goiter and ophthalmopathy, whereas toxic nodular hyperthyroidism is characterized by the presence of a nodular goiter on examination of the neck. It should be noted, however, that the thyroid might be impalpable in about 30% of cases of both Graves' disease and toxic nodular hyperthyroidism. If the cause of thyrotoxicosis is not obvious, further investigation may be warranted. The presence of thyroid autoantibodies (to thyroid peroxidase - TPO and/or thyroglobulin) is suggestive (but not diagnostic of) Graves' disease; TSH receptor antibodies, although not measured routinely, are more specific for the diagnosis (35). Such antibodies are usually negative in cases of toxic nodular hyperthyroidism. If antibodies are positive, in the presence of a nodular goiter, both conditions may co-exist. Radioisotope scanning, using technetium-99m or iodine-123, typically shows a diffuse pattern of uptake in Graves' disease, in contrast to the presence of multiple "hot" nodules with surrounding thyroid tissue not demonstrating any uptake in cases of toxic nodular hyperthyroidism. Occasionally, a single "hot" nodule, with absent uptake elsewhere in the thyroid is observed. This finding suggests the presence of a toxic nodular adenoma.

Image hyperthyroidism-age_aging-figure-1.jpg

Figure 1. Radionuclide imaging of the thyroid illustrating hot nodules in toxic nodular hyperthyroidism (right) which contrasts with a diffuse uptake in Graves' Disease (left)

Other Causes of Thyrotoxicosis

It is not always essential to make a distinction between thyrotoxicosis due to Graves' disease and that due to toxic nodular goiter, since treatment is usually the same. It is important, however, to consider other diagnoses. As in other age groups, the elderly patient may develop transient thyroid hormone excess secondary to a temporary thyroiditis, i.e. destruction of the thyroid with release of pre-formed thyroid hormones (36). Sub-acute thyroiditis should be suspected if the patient complains of sore throat or neck tenderness, typically associated with symptoms of a viral illness or an upper respiratory tract infection. The diagnosis is confirmed by the finding of a raised erythrocyte sedimentation rate (ESR) and absent or very low uptake of iodine-123 or iodine-131. This is an important diagnosis to make since treatment with anti-thyroid drugs or radioiodine is inappropriate, both because it is ineffective and because the condition recovers spontaneously (usually after a self-limiting period of hypothyroidism). Silent thyroiditis has a similar clinical course as subacute thyroiditis, but the gland is not tender and there is no increased ESR. Both subacute and silent thyroiditis can occur in older patients, although the peak age range for these two conditions is among younger patients (36).

An iodine-induced thyroiditis should be considered in those who give a history of iodine ingestion (e.g. in the form of sea weed preparations, other over the counter iodine containing compounds, such as expectorants) or after administration of iodine containing radiographic contrast agents (37,38). The diagnosis can be confirmed by the finding of low iodine uptake and high urinary iodine concentrations. This condition also remits spontaneously and radioiodine therapy is contraindicated. This diagnosis is more common in older patients, who are more likely to receive iodinated contrast agents for diagnostic purposes and to have underlying multinodular goiters that predispose them to iodine-induced thyrotoxicosis.

Amiodarone and the Diagnosis of Thyrotoxicosis

The diagnosis of thyroid dysfunction should be considered in an elderly patient prescribed the anti-arrhythmic agent amiodarone. This drug is widely used in the older age group for control of dysrhythmias, particularly those associated with poor left ventricular function. The managing physician should be aware that amiodarone is an iodine-containing compound that affects the results of tests of thyroid function, even in those who are euthyroid (39). Typically, amiodarone, through its effect on the 5' deiodinase enzyme and hence upon the peripheral conversion of T4 to T3, results in modest reduction in serum concentrations of T3 (often to below the normal range) and modest elevation in serum T4 (often to above the normal range). Measurements of serum TSH may be unaffected; typically, TSH is slightly elevated early after commencement of treatment and normalizes later in euthyroid patients. Therefore, beginning about 2 months after amiodarone is started, the serum TSH level is an accurate indication of thyroid function.

Although amiodarone results in overt thyroid dysfunction in 5-10% of cases, it is important not to over-interpret mildly abnormal results of tests of thyroid function. Thyrotoxicosis should only be diagnosed in the presence of significant elevation of free T4, importantly together with elevation in serum T3 and suppression of TSH; sometimes serum T3 is at the upper range of normal rather than elevated, probably because of associated "non-thyroidal" illness in this age group, together with the block of T4 to T3 conversion seen with amiodarone.

TREATMENT OF THYROTOXICOSIS

Antithyroid Drugs

The thionamides - carbimazole (or its active metabolite methimazole) and propylthiouracil - represent the mainstay of drug treatment of thyrotoxicosis (1). These drugs inhibit the oxidation and organification of iodide and hence block the synthesis of T4 and T3 early in their biosynthetic pathway. They represent the most effective and rapid means of reducing circulating thyroid hormone concentrations. They can be used in several ways: short-term in preparation of the patient for definitive treatment with radioiodine or surgery, medium term in the hope of inducing remission in cases of thyrotoxicosis due to Graves' disease. and finally, long-term for control of clinical and biochemical thyroid hormone excess (35).

In many elderly patients, thionamides are used short-term in the preparation for curative treatment. A typical starting dose of methimazole is 20-30 mg per day as a single daily dose. In contrast, propylthiouracil is typically given in divided doses, the equivalent to methimazole 20 mg being 200mg. Doses higher than this are required only rarely and in clinical trials (of subjects with Graves' disease) high doses have not been shown to be more effective in terms of restoration of euthyroidism (40,41). Since compliance is better and side effects are less frequent, methimazole or carbimazole are considered the drugs of choice, in preference to propylthiouracil (35). Serum free T4 should be checked 4-6 weeks after beginning therapy and the thionamide dose adjusted accordingly. It is usually possible to render the patient euthyroid (or near euthyroid) after approximately 2-3 months, although further dose adjustments are sometimes required.

Drug side effects are relatively uncommon, but it is essential that all subjects (in whichever age group) be warned (preferably in writing) of the potential risk of agranulocytosis so that they present urgently for a full blood count if they develop a fever or sore throat. Agranulocytosis often, but not always, occurs in the first few weeks after beginning thionamide therapy and is probably more common in those taking higher doses (35,40). The latter observation represents a relative contraindication to doses of methimazole/carbimazole of greater than 20-30 mg per day; doses higher than this are rarely necessary in the elderly since toxic nodular hyperthyroidism is usually mild and therefore easy to control.

Other serious side effects can occur, notably antineutrophil cytoplasmic antibody-associated-vasculitis (typically associated with prescription of propylthiouracil) and hepatitis, although these are rare. These serious complications, together with agranulocytosis, represent absolute contraindications to further use of thionamides. Less serious side effects such as pruritic rash are more common and can usually be managed conservatively, although sometimes a change in drug therapy from one thionamide to another is required (35).

Anti-Thyroid Drugs and Graves' Disease

If the patient has an established diagnosis of Graves' thyrotoxicosis, then it may be appropriate to offer a full course of thionamide therapy in the hope of inducing long-term remission (1,35). In view of the potentially serious consequences of thyrotoxicosis (notably vascular and bone) in this age group, it is generally more appropriate to advise the patient to have definitive treatment early in the course of their disease. In general, remission rates in Graves' hyperthyroidism are less than 50%, nonetheless, there is some evidence that the remission rate in Graves’ may be higher in the elderly age group, probably reflecting the presence of milder disease. If the objective is to achieve remission or "cure" of thyrotoxicosis secondary to Graves' disease, then thionamide treatment should be prescribed for a course of 12-18 months, since shorter courses are associated with a lower rate of remission (35). Drug doses should be titrated according to serum concentrations of free T4 (serum TSH may remain suppressed for months in those with Graves' disease); for most of an 18-month course the majority of subjects will require a methimazole maintenance dose of 5-10 mg daily (propylthiouracil 50-100mg daily in divided doses). Larger dose requirements are suggestive of poor compliance. Poor prognostic features for achieving long-term remission reported by Allahabadia et al (42) (established in younger age groups) include male sex, the presence of a large goiter and biochemically severe disease at diagnosis. Most relapses of Graves' thyrotoxicosis occur 3-6 months after thionamide withdrawal. If relapse does occur, then the patient should be advised to proceed to definitive treatment.

Anti-Thyroid Drugs and Toxic Nodular Hyperthyroidism

It should be noted that thionamides virtually never result in remission or cure of thyrotoxicosis secondary to toxic nodular goiter, although some spontaneous fluctuation in the severity of the disease is seen. Thionamides may thus be used short-term (as above) to induce euthyroidism prior to definitive treatment but a "course" should not be prescribed in the hope of inducing cure. In subjects who decline definitive therapy or whose life expectancy is short (because of co-morbidity) it is appropriate to prescribe thionamides life-long to control clinical and biochemical disease (35). Typically, this scenario pertains in frail, elderly subjects. Once biochemical control has been achieved, biochemical monitoring every 3-6 months, to demonstrate euthyroidism and the absence of iatrogenic hypothyroidism, is desirable.

Beta-Adrenergic Blocking Agents and Other Drugs as Adjunctive Therapies

Beta adrenergic blockers often represent useful adjuncts to thionamides in the management of thyrotoxicosis. In cases of thyroiditis or mild cases of toxic nodular hyperthyroidism proceeding to radioiodine, they may be the only additional treatment required. Beta adrenergic blockers act promptly to reduce symptoms and signs of tremor and to improve tachycardia and associated palpitation (35). Such agents should be used cautiously in elderly subjects with heart failure (although if tolerated a beneficial effect often results because of amelioration of some of the cardiovascular effects of thyroid hormone excess) and in those with asthma or chronic obstructive pulmonary disease. Propranolol has been widely used in thyrotoxic subjects but it requires multiple daily dosing; longer acting beta adrenergic blockers such as atenolol (50-100mg daily) may therefore be preferred.

Other adjunctive therapies include salicylates for relief of local pain and tenderness in cases of subacute thyroiditis; occasionally glucocorticoids such as prednisolone are required short-term.

Anticoagulation with coumarin derivatives such as warfarin or newer oral anticoagulants should be considered in elderly subjects with thyrotoxicosis complicated by atrial fibrillation. This is driven by evidence for embolic complications. There have been no controlled trials of the use of anticoagulants in thyrotoxic atrial fibrillation but overwhelming evidence of their efficacy in other settings argues in favor of their use in this situation (43), unless clear contraindications exist. Specific therapy to restore sinus rhythm should be considered but not until the patient has been rendered permanently euthyroid. This therapy may comprise pharmacological cardioversion (with agents such as sotalol) or electrical cardioversion. Restoration of sinus rhythm is more likely in those whose atrial fibrillation is of short duration and in those without underlying heart disease (24), although rates of restoration of sinus rhythm may be relatively low, even with cardiological intervention, as Osman et al have described (22).

Treatment of Iodine-Induced Thyrotoxicosis

Treatment of iodine-induced thyrotoxicosis includes avoidance of additional iodine exposure and administration of beta-blockers alone or in combination with thionamides (35). The decision to use thionamides depends on the clinical status of the patient and the severity of the thyrotoxicosis. The duration of treatment depends on the clearance rate of iodine, and can be monitored with urine iodine measurements.

Treatment of Amiodarone-Induced Thyrotoxicosis (AIT)

This condition is widely recognized as being difficult to treat and a cause of significant morbidity/mortality in those with underlying cardiac disease (35,39). It is reported that AIT results either from induction of hyperthyroidism in an underlying abnormal thyroid gland due to Graves’ Disease or multinodular goiter (Type 1 AIT) (secondary to ingestion of a large iodine load since amiodarone is 37% iodine by weight) or from an amiodarone-induced destructive thyroiditis (Type 2 AIT). Some experts report that these two types can be distinguished by measurement of serum interleukin-6 (raised in destructive thyroiditis) (44) and by ultrasonographic definition of thyroid vascularity (39). These tests are not, however, routinely available, and it is increasingly recognized that these varieties may co-exist.

In general, thionamide therapy should be considered first line treatment of Type 1 AIT. High dose glucocorticoids are often considered first-line therapy for Type 2 AIT, although they can have significant side effects in elderly patients. In practice, it can be difficult to distinguish Type 1 from Type 2 AIT, and in severe acute cases, both thionamides and prednisone are sometimes started simultaneously. Perchlorate may be a helpful adjunct therapy, although it is not commercially available in the U.S. Withdrawal of amiodarone is often not possible because of the serious nature of underlying dysrhythmias leading to amiodarone treatment, although it should be carefully considered. In any case, the long half-life of the drug (around 50 days) determines that any effect of amiodarone withdrawal is slow. Because of the iodine content of the drug, radioiodine therapy is ineffective because the radioisotope is not taken up into the thyroid. Radioiodine treatment is typically not feasible until at least 6 months after amiodarone withdrawal. Several groups have described surgical treatment of AIT. Restoration of a euthyroid state with thionamides is preferable pre-operatively (see below).

Radioiodine Therapy

In many cases of thyrotoxicosis occurring in elderly subjects, radioiodine therapy represents the treatment of choice since thionamide treatment alone is unlikely to be curative (1). Iodine-131 may be administered by mouth in the outpatient setting and is associated with few side effects. Some patients notice sore throat or neck tenderness (reflecting a radiation thyroiditis) but this is usually mild and transient. Its long-term efficacy is well established, as is long-term safety in terms of cancer risk (35,45). There are few, if any, contraindications to radioiodine therapy apart from inability to comply with local radiation protection regulations. Such compliance may be difficult to achieve in hospital or nursing home residents, those with urinary incontinence, and those with significant mental impairment. In such cases, long-term thionamide therapy is often the best practical option (see above).

A relative contraindication to the use of radioiodine in cases of Graves' thyrotoxicosis is the presence of moderate or severe ophthalmopathy. This is based on evidence for a slightly increased risk of development or worsening of pre-existing thyroid eye disease in those treated with radioiodine compared with thionamides or surgery (35,46). Problematic eye disease is more likely in those with pre-existing ophthalmopathy, in smokers (smoking being an independent risk factor for development of ophthalmopathy in those with Graves’ disease) and those with severe biochemical disease. In view of evidence originally from Bartalena et al (47) that giving a course of glucocorticoid abolishes any increase in risk of ophthalmopathy in those receiving radioiodine, many experts prescribe a short course of prednisone/ prednisolone around the time of therapy. Typical doses of prednisone are 0.4-0.5 mg/kg/day starting 1-3 days following I-131 therapy and continued for one month, with gradual tapering over the next two months (35). However, recent data suggest that a lower dose of prednisone of 0.2 mg/kg/day for 6 weeks may be equally efficacious (reviewed in 48).

In those with severe clinical and biochemical thyrotoxicosis it is desirable to restore euthyroidism before proceeding to radioiodine therapy. This is because of the theoretical risk of exacerbating thyrotoxicosis or inducing "thyroid storm" due to thyroid destruction and release of pre-formed thyroid hormones following radioiodine administration, together with the need to stop thionamide therapy temporarily at the time of treatment. In mild cases (judged both clinically and biochemically), such pre-treatment with thionamides may be unnecessary and radioiodine may be given as initial therapy or after short-term preparation with beta-adrenergic blockers.

Radioiodine Dosing

Many studies have attempted to define optimal radioiodine doses in the hope of inducing euthyroidism and avoiding iatrogenic hypothyroidism in all (35). Such studies have examined attempts to titrate doses of radioiodine according to factors such as thyroid size (judged clinically or by imaging), isotope uptake, or isotope turnover in the thyroid. Older literature suggested that cases of toxic nodular hyperthyroidism require larger doses of radioiodine to induce euthyroidism than cases of Graves' disease. It is clear, however, that measures of thyroid size or isotope uptake/turnover generally do not allow effective "dose titration". Furthermore, the dose of radioiodine required to cure toxic nodular hyperthyroidism is not different from that required in Graves' disease in the majority of cases (49). Many thyroid centers intentionally aim for I-131 doses that cause hypothyroidism, since lower doses lead to higher treatment failure rates. In some subjects with large goiter, higher initial doses or multiple treatments are required.

Other thyroid centers avoid attempts at radioiodine "dose titration" and administer empirical doses. Such an approach avoids the necessity for extra hospital visits to document isotope uptake into the gland or the need for other imaging. The dose of radioiodine administered varies between centers, and is determined in part by radiation protection restrictions that vary considerably around the world. Typically, a dose of radioiodine is chosen which can be administered in the outpatient setting and which results in cure of thyrotoxicosis in the majority after a single dose, while not inducing hypothyroidism in all. In iodine-replete parts of the world such as the US and UK, a standard dose of radioiodine is 10-15 mCi or 400-600 MBq. In a UK series (50) a dose of this size resulted in cure of thyrotoxicosis in more than two thirds, at a cost of early hypothyroidism in 50%. Some centers administer larger doses to those with large goiter or to men, in view of some evidence of relative radioresistance in these groups. There is also evidence (some of it conflicting) that prescription of thionamides, especially use of propylthiouracil, before and/or after radioiodine treatment also induces relative radioresistance and hence the need for repeat dosing or a larger initial dose (35). It has been suggested that large doses should be administered routinely to elderly subjects, particularly those with cardiovascular disease or complications, to be certain of rapid restoration of euthyroidism. This view is tentatively reinforced by evidence that effective cure as indicated by the development of hypothyroidism requiring thyroxine replacement therapy is associated with a lessening of vascular mortality (compared with those not rendered hypothyroid) (20,21) and more likely conversion to sinus rhythm in those with AF associated with hyperthyroidism (22).

Follow-up After Radioiodine Therapy

Thionamide therapy should be withdrawn 3-7 days before radioiodine (to allow iodine uptake into the thyroid) and should be recommenced after a similar period post-treatment if the elderly subject has severe disease, incomplete biochemical control, significant complications e.g. atrial fibrillation, or has experienced return of symptoms in the short period of thionamide withdrawal before radioiodine therapy. After therapy, clinical and biochemical assessment should be carried out every 4-6 weeks for the first few months so that thionamide doses may be adjusted (according to free T4) and hypothyroidism identified. A transient rise in serum TSH may be seen in the first few months after radioiodine and does not necessarily indicate permanent hypothyroidism but more marked biochemical or symptomatic hypothyroidism usually indicates the need for life-long T4 therapy. Persistence of biochemical hyperthyroidism 6 months after radioiodine therapy usually indicates the need for re-dosing. Unless small empirical doses are administered, the vast majority of patients with either toxic nodular hyperthyroidism or Graves' disease are rendered euthyroid (off all treatment) or hypothyroid (on T4) with one, two or (uncommonly) three doses (50). Occasional cases of apparent resistance to radioiodine treatment are seen.

Long-term, all patients treated with radioiodine require biochemical follow-up for detection of hypothyroidism (35). Such follow-up is essential since the incidence of hypothyroidism is significant even many years after radioiodine and eventually up to 90% of those treated in this way become hypothyroid (35). Hypothyroidism rates may be slightly lower in those with toxic nodular hyperthyroidism (35,50) because of relative sparing of normal thyroid tissue through concentration of isotope in "hot" autonomous nodules.

Surgical Treatment of Thyrotoxicosis

Although surgery is a reasonable approach to treating thyrotoxicosis in selected patients (35), The relatively higher risk of complications of anesthetic and surgery in elderly subjects often limits its use in this population.

If surgery is contemplated, it is essential that clinical and biochemical euthyroidism are restored beforehand. This requires therapy with thionamides, typically for 2-3 months after diagnosis. Pre-operative preparation with beta-adrenergic blockers and/or Lugol's iodine is usually added to thionamides therapy, in the latter case to reduce thyroid blood flow (35). Thorough preparation is essential in order to avoid thyroid storm post-operatively, as well as other significant complications of thyroid hormone excess, especially cardiovascular complications.

There is on-going debate regarding the most appropriate surgical approach for treatment of thyrotoxicosis. Many large centers now advocate the use of total thyroidectomy for Graves' hyperthyroidism since partial thyroidectomy is associated with significant rates of short - and long-term recurrence, while in expert hands surgical complication rates should be similar (35). Such complications include bleeding into the neck, hypoparathyroidism, and damage to recurrent laryngeal nerves. Hypothyroidism is inevitable after total thyroidectomy (the patient leaves the hospital on T4 therapy) but is also common after partial thyroidectomy. Life-long follow-up (as with cases treated with radioiodine) is essential for detection of hypothyroidism (and recurrence of hyperthyroidism) after partial thyroidectomy.

Cases of toxic nodular hyperthyroidism may be treated by thyroid lobectomy or excision of a single hot nodule. Such an approach has the theoretical advantage of avoidance of hypothyroidism, as well as improvement in cosmetic appearance in those with large goiter. It should be noted, however, that reduction in nodule/goiter size is also evident after radioiodine therapy, albeit after several months. Surgery may be considered appropriate if toxic nodular goiter is associated with obstructive symptoms or if there is any specific concern about the presence of co-existent malignancy in the goiter/nodules.

SUBCLINICAL HYPERTHYROIDISM

"Subclinical" hyperthyroidism is a biochemical diagnosis characterized by a low serum TSH with normal serum thyroid hormone concentrations. Many of the subjects included in the studies quoted at the beginning of this chapter had subclinical, rather than overt, hyperthyroidism, as subclinical hyperthyroidism is more common than overt disease. There is significant variation in the reported prevalence of subclinical hyperthyroidism in the elderly, with typically quoted prevalence’s of 0.8 – 2% (3,7-9). As with overt hyperthyroidism, prevalence rates are lower if one excludes those subjects taking thyroid hormone preparations. The prevalence of endogenous subclinical hyperthyroidism in a population depends on age, gender and iodine intake (3,51,52).

The most common cause of suppression of TSH in the general population is exogenous thyroid hormone therapy, typically levothyroxine. Surveys have shown that 25-50% of those prescribed T4 long-term display reduction in TSH suggestive of mild over-treatment (4,5,53) (this is deliberate in the relatively small number of patients with a past history of thyroid cancer). Since T4 is prescribed to about 5% of the over 60's, this medication is a common cause of subclinical hyperthyroidism (5,54). In fact, a recent study showed that over 40% of patients over the age of 64 years treated with levothyroxine had low TSH levels, indicating overtreatment (4).

In patients not receiving exogenous thyroid hormone therapy, the differential diagnoses of a low or undetectable TSH includes nonthyroidal illness and medications (see above). Once these have been excluded, then nodular goiter is the next most common cause of low serum TSH in older patients. In subjects with a nodular goiter, either detectable clinically or evident on isotope imaging, suppression of serum TSH represents the earliest biochemical marker of thyroid autonomy and onset of hyperthyroidism. Other causes of a suppressed TSH in the elderly include Graves’ Disease, subacute thyroiditis, and silent thyroiditis, as in younger patients, although these are less common. Amiodarone and the other drugs that cause overt hyperthyroidism may also cause subclinical hyperthyroidism.

The natural history of endogenous subclinical hyperthyroidism is variable, and probably depends on the underlying cause. Most patients have stable subclinical hyperthyroidism over years, but a sizable minority either progress to overt hyperthyroidism or normalize their thyroid function (55-62). A low but detectable TSH probably has less pathophysiological significance than a completely suppressed TSH, in terms of clinical consequences as well as progression rates. In addition, endogenous subclinical hyperthyroidism, for example secondary to nodular goiter, is probably of greater significance than exogenous (due to levothyroxine therapy) since the former is associated with higher serum T3 concentrations.

There is little evidence to suggest that subclinical hyperthyroidism is associated with significant symptoms (63,64), but there is a growing body of evidence that low serum TSH is associated with adverse effects, particularly on heart and bone, as well as excess overall and cardiovascular mortality (35). A recent meta-analysis of individual-level data from 52,674 participants pooled from 10 cohort studies concluded that subclinical hyperthyroidism confers a 24% increased risk of overall mortality and 29% increased risk of cardiovascular mortality (65). A second meta-analysis of study-level data of 17 cohorts confirmed this finding (66), as did a recent large retrospective cohort study (67). In the individual-levels meta-analysis, relative risks did not differ based on age, but the risk was greater in subjects with TSH levels < 0.1 compared to those with TSH levels 0.1 – 0.4 mU/L. Having said that, it should be noted that baseline risks of cardiovascular death are much higher in older subjects, so the majority of excess cardiovascular mortality occurs in the elderly. Some studies, including the largest meta-analysis, have also examined non-fatal cardiovascular events in subclinical hyperthyroidism, with similar increased risks (65,68-70). The most recent data indicate that subclinical hyperthyroid subjects are at particular risk for the development of heart failure (65,71,72), especially older subjects and those with lower TSH levels.

Arrhythmias are another concern in subclinical hyperthyroidism. Sawin et al first reported a 3-fold increased incidence of atrial fibrillation in subjects over 60 years old with serum TSH of less than 0.1 mU/L compared with those with normal serum TSH in the Framingham study (73). The likelihood of developing atrial fibrillation was also increased, but less markedly, in those with low but detectable TSH. Similar findings have been reported in larger population-based studies since this initial observation (65,68,69,74,75). In the largest study to date (586,460 people followed for a median of 5.5 years), the highest relative risk for atrial fibrillation occurred in younger subjects and in subjects with lower TSH levels (75). However, as with cardiovascular mortality, absolute rates of atrial fibrillation were much higher in older subjects. A further study found that subclinical hyperthyroidism increased the risk for stroke in subjects over age 50 years (76), although a recent meta-analysis contained insufficient numbers of events to draw conclusions regarding stroke and subclinical hyperthyroidism (77). Currently, the risk of atrial fibrillation represents a major reason to consider therapy in older patients with subclinical hyperthyroidism.

Adverse effects of endogenous subclinical hyperthyroidism on bone also occur. Most cross-sectional studies show decreased bone mineral density in post-menopausal women but not in men or pre-menopausal women (reviewed in 78). A recent individual participant data analysis from six prospective cohorts confirmed increased femoral neck bone loss over time in older subjects with subclinical hyperthyroidism (79). There is also some evidence for improvement in bone metabolism or BMD after treatment of endogenous subclinical hyperthyroidism (80). A number of population-based studies have reported that different groups of subjects with subclinical hyperthyroidism have increased fracture rates (81-83), although other studies have not confirmed this (84-86). The most recent and largest study of 231,355 people reported increased fracture rates in subclinical hyperthyroidism (83). In this study, risk increased with duration of subclinical hyperthyroidism, such that after a median of 7.5 years, 13.5% of subjects with low TSH levels had experienced at least one major osteoporotic fracture, compared to 6.9% of subjects with normal TSH levels. Two recent meta-analyses also reported increased total fracture and hip fracture rates (87,88), although confidence intervals were not significant in one of the studies (87). The second meta-analysis (88) concluded that subclinical hyperthyroid subjects had elevated hazard rations of 1.36 for hip fractures and 1.28 for any fractures. Risks were further increased if TSH levels were < 0.1 mU/L, and if the subclinical hyperthyroidism was due to an endogenous etiology. Risks did not differ by age, although absolute fracture rates were higher in older subjects.

Mood and cognitive function have also been examined in older subjects with subclinical hyperthyroidism. To date, there has been little evidence of associations between subclinical hyperthyroidism and increased rates of depression or anxiety (8,89-93). Reported effects on cognitive decline and the development of dementia in subclinical hyperthyroidism have been variable (94-98). One recent study reported that subclinical hyperthyroidism with a TSH of less than 0.10 mU/L was associated with a higher risk of dementia and a larger cognitive decline (97), while a meta-analysis of eleven prospective cohorts that followed 16,805 subjects for a median of 4 years reported that subclinical hyperthyroidism might be associated with an elevated risk for dementia, but not with a faster decline in cognitive function (98).

Finally, a number of studies have investigated whether subclinical hyperthyroidism is associated with functional capacity and physical functioning in older subjects (96,99-102). Three found no correlation, while two found correlations between subclinical hyperthyroidism and lower physical performance in men (101,102). Another uncontrolled study showed an increase in muscle mass and strength in middle-aged women with subclinical hyperthyroidism after treatment (103).

The epidemiologic evidence summarized above regarding effects of mild thyroid hormone excess upon heart and bone have led to recommendations for treatment of this condition. In those taking exogenous thyroid hormone, management is relatively straightforward, namely reduction in prescribed dose and re-checking of serum TSH 6-8 weeks later. For those not taking thyroid hormone, the American Thyroid Association recommends treating all subjects over the age of 65 years with TSH levels less than 0.1 mU/L, and to consider treating subjects in the same age range with TSH levels between 0.1 mU/L and the lower limit of the assay normal range (35). Treatment is usually with either antithyroid drugs or radioiodine.

SCREENING FOR HYPERTHYROIDISM IN ELDERLY SUBJECTS

Several factors need to be considered before a decision should be made to institute either population or targeted screening in groups such as the elderly. Firstly, screening programs should be instituted only for those conditions in which the benefits of screening outweigh the costs. Whether benefits outweigh the costs depends on accurate quantification of these issues, then a judgment as to whether the costs of screening are justified. Although it is clear that hyperthyroidism is common, there are no data that demonstrate that such subjects when identified by screening benefit from being so diagnosed; it is not sufficient to demonstrate only that such subjects exist. Such benefits and costs should ideally be based upon the results of a randomized controlled trial in an appropriate sample of the relevant population. In considering costs, those incurred by those who do not themselves gain from the screening program should be considered. If, for example, the screening process uses a test such as serum TSH with occasional false positives, then some patients may be exposed to investigations which are unnecessary, with accompanying risk and potential morbidity.

While overt and subclinical hyperthyroidism are common in older subjects, and while there is evidence for adverse consequences of these diagnoses, the evidence that treatment in a screened population improves morbidity/mortality, and that the risks of such treatment outweigh the costs, is currently inconclusive (35). There should, nonetheless, be a high index of suspicion for hyperthyroidism in this age group and a low threshold for biochemical testing, especially in those with a previous personal or family history of thyroid disease or those with conditions such as atrial fibrillation that may reflect hyperthyroidism. Care must also be taken to recognize the atypical presentations of hyperthyroidism that occur in this age group, including unexplained weight loss and psychiatric symptoms.

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