- Email: [email protected]
Diagnosing and Managing Thyroid Disease in the Nursing Home
REVIEWS
Diagnosing and Managing Thyroid Disease in the Nursing Home Ligia J. Dominguez, MD, Maurizio Bevilacqua, MD, Giovanna DiBella, MD, and Mario Barbagallo, MD, PhD Thyroid disorders occur at any age, but hypothyroidism is more common in older than in younger adults. In fact, the prevalence of thyroid disorders increases with age, and it is higher in old-old frail residents in nursing homes. Since thyroid diseases in older age, both overt reduced and increased function, may manifest as disorders of other organs, physicians need a high index of suspicion to detect thyroid dysfunction in an older person with multiple comorbidities and chronic polypharmacy. This is particularly true for residents of longterm facilities, where multiple chronic diseases may make it less attractive to direct attention to thyroid function. Subclinical hyperthyroidism and hypothyroidism, more frequently seen in older populations, have been linked to increased total and cardiovascular mortality. Since chronic diseases are more prevalent in old age, nonthyroidal illness is also seen frequently in
this age group. Although, there is still debate on the decision to treat or not to treat subclinical thyroid disorders, current recommendations state the necessity of considering treatment on an individual basis according to symptomatology and to the possible benefit that the older person may obtain with treatment, discouraging extended screening and treatment in the community population of subjects older than 65. However, in the long-term setting, the possibility of thyroid dysfunction can be more often investigated, and the consideration of treatment and follow-up is needed to improve quality of life of affected older people. (J Am Med Dir Assoc 2008; 9: 9 –17)
Thyroid disorders are not infrequent in older populations and they are often undiagnosed.1–3 While some signs and symptoms of thyroid dysfunction may be similar to those in young patients, often hyperthyroidism and hypothyroidism have subtle clinical manifestations that may be misinterpreted as involvement of other organs or even as “normal” characteristics of aging (ie, constipation, arrhythmia, cognitive impairment, weight loss).1–5 The lack of overt clinical manifestations of thyroid disorders in older people increases the need for an attentive clinician to suspect their presence. That is particularly true in the long-term setting, where subtle changes may be interpreted as manifestations of the many other problems encountered in old residents with important
comorbidity and the use of multiple drugs. The main difficulty in diagnosing thyroid disease in older populations is that symptoms and signs may appear different from those described classically in textbooks, which usually describe the clinical characteristics frequently seen in younger populations. Older people may have these manifestations but more frequently the manifestations are variable and not easy to ascribe to the “typical” patient. For example, the same symptomatology may be the manifestation of either hypothyroidism or hyperthyroidism in an older patient. In both conditions there may be frailty, confusion, depression, falling, walking disturbances, incontinence from immobility, heart failure, bowel habits changes (either constipation or diarrhea), signs that make difficult the differentiation between hypothyroidism and hyperthyroidism. These signs also correspond to many other common illnesses of older people. A correct diagnosis is not simple but may be critical. Thus, the purpose of this review is to give some insight into approaches to thyroid disease in elderly persons, especially those living in long-term facilities, with emphasis of the most common thyroid problems in older people, including overt and subclinical hypothyroidism and hyperthyroidism, thyroid nodules, and nonthyroidal illness (NTI).
Geriatric Unit, Institute of Internal Medicine and Geriatrics, University of Palermo, Italy (L.J.D., G.B.D., M. Barbagallo); Endocrine and Diabetes Unit, Department of Internal Medicine, L. Sacco Hospital (Vialba)-University of Milan, Italy (M. Bevilacqua). None of the authors have any conflicts of interest, and there is no funding support pertaining to this study. Address correspondence to Ligia J Dominguez, MD, University of Palermo, Italy, Viale F. Scaduto 6/c 90144, Palermo, Italy. E-mail: [email protected]
Copyright ©2008 American Medical Directors Association DOI: 10.1016/j.jamda.2007.07.011 REVIEWS
Keywords: Thyroid disease; subclinical thyroid disease; nonthyroidal illness; thyroid nodule; nursing home
Dominquez, Bevilacqua, Barbagallo 9
PREVALENCE OF THYROID DISEASE IN NURSING HOMES In large epidemiological studies in older populations, hypothyroidism is reported in 1% to 20% of subjects, with women being more commonly affected than men, and subclinical hypothyroidism being more common than overt hypothyroidism. Hyperthyroidism is also quite common, occurring in 0.5% to 3% of all elderly patients.1–3 The difference between prevalence in men and women is less evident in hospitalized elderly patients.2 According to a recent survey of a community sample in the United Kingdom (n ⫽ 5960 subjects aged ⬎65 years), unidentified overt hyper- and hypothyroidism were uncommon (0.3% and 0.4%, respectively) and subclinical thyroid dysfunction was present in 5% of the population (hyperthyroidism in 2.1% and hypothyroidism in 2.9%).6 These numbers are higher when considering institutionalized older people, even if studies in long-term facilities are few and most include a limited number of patients.7–12 A study conducted in 658 institutionalized elderly patients recruited in 4 nursing homes in Cape Town disclosed abnormal thyroid stimulating hormone (TSH) in 15.6%, with 3 (0.5%) newly diagnosed cases of overt hyperthyroidism and 7 (1%) new cases of overt hypothyroidism. Conversely, subclinical disease was diagnosed in 40 subjects. In 22 subjects the thyroid dysfunction had been previously recognized, while in 50 the dysfunction was newly diagnosed by the survey.7 In a population of 242 healthy elderly subjects living in public nursing homes in Spain, there were 9 (3.7%) cases of previously undetected subclinical hypothyroidism, 4 (1.65%) cases of overt clinical hypothyroidism, 2 (0.82%) cases of subclinical hyperthyroidism, and 25 (10.3%) cases of autoimmune disease.8 Another study in Spain performing TSH assay on admission to a public nursing home in 201 elderly subjects disclosed 16 (7.9%) cases of primary hypothyroidism, of whom 7 received treatment with levothyroxine. Sick euthyroid syndrome was found in 28 (13.9%) cases, and no cases of hyperthyroidism were detected. These results suggest that routine TSH measurement in elders on admission to a nursing home may have a favorable cost-utility ratio.9 Similarly, a study performed in a skilled nursing facility in the United States among 434 male and 137 female residents older than 60 disclosed overt hypothyroidism in 3 men and 2 women. Subclinical hypothyroidism was diagnosed in 42 men (9.7%) and 20 women (14.6%). Tests for thyroid antibodies were positive in all patients with overt hypothyroidism and in 34% of men and 67% of women with subclinical hypothyroidism. The authors recommend the screening of institutionalized elderly for hypothyroidism since individuals with subclinical hypothyroidism are at risk for further decline in thyroid function.10 However, the progression to overt hypothyroidism has been estimated in only 5% of persons with subclinical hypothyroidism.5,13 An interesting study conducted in 2 nursing homes in Georgia aimed to determine the sensitivity of clinical determinants for hypothyroidism during withdrawal of thyroid hormone therapy. Studying 129 residents, the prevalence of true hypothyroidism ranged from 6.2% to 7.8% and identified unnecessary therapy 10 Dominquez, Bevilacqua, Barbagallo
in 2 of 13 patients (15.4%). Increased body weight was the most sensitive indicator of evolving hypothyroidism.11 Conversely, a study in nursing home residents from Connecticut reported that previously prescribed thyroid hormone therapy was unnecessary in one half of the nursing home residents studied, with important implications for health and health care costs.14 A survey in Eastern Europe compared groups from areas with different iodine intake investigating the relationship of iodine intake with the prevalence of thyroid dysfunction, autoimmunity, and goiter in nursing home residents with median age of 81 years. There was a higher prevalence of positive antithyroid antibodies in old age that was independent of iodine supply, but iodine supply seems to have a determining role in the development of autoimmune hypothyroidism in this age group.12 HYPOTHYROIDISM As mentioned above, hypothyroidism is not uncommon in subjects older than 60, particularly in women, and its prevalence increases progressively with age.1,2,5,10,11,15–17 It affects 5% to 20% of women and 3% to 8% of men.15 Undiagnosed hypothyroidism can be found as frequently as in 1 every 4 nursing home residents.11,17 A variety of medications, including amiodarone and lithium, may induce hypothyroidism (see Table 1). Symptoms of hypothyroidism are nonspecific, especially in old-old and frail elders, and may include memory loss, often attributed to old age or other causes, weight gain, constipation, lethargy, but lack of these symptoms does not rule out the presence of hypothyroidism. Hence, a high index of suspicion is needed to formulate the diagnosis. The presence of family history of thyroid disease may be helpful, as well as history of thyroidectomy or neck radiation therapy. In fact, the most common causes of hypothyroidism in older people are autoimmune destruction of the thyroid gland (Hashimoto’s thyroiditis) and previous thyroid surgery or radiation therapy.1,3,5 The finding of an elevated serum TSH level should be confirmed and supplemented with measurements of serum levels of thyroxine (T4) and eventually with thyroid antibodies to verify the abnormality (Figure 1). Although hypothyroidism is common in older persons, it may not be associated with adverse outcomes in the oldest individuals when detected by screening alone, as illustrated by a population-based, prospective study of 558 individuals in the Netherlands, who were screened for hypothyroidism during the month of their 85th birthday and again 3 years later.18 Annual evaluation included assessment of activities of daily living (ADLs), cognitive performance, and depressive mood. Twelve percent had hypothyroidism at baseline (7% overt and 5% subclinical). None of the patients with subclinical hypothyroidism had progressed to overt hypothyroidism when retested at age 88 years. There was no association of baseline TSH levels and cognitive function, depressive symptoms or ADLs disability. All these parameters declined over time, but the decline was not accelerated in those with subclinical or overt hypothyroidism. Conversely, increased TSH at baseline JAMDA – January 2008
Table 1. Drugs That May Alter Thyroid Function Tests Drug
TSH
T3
T4
Mechanism
Total
Free
Total
Free
Amiodarone
Increased or reduced
Reduced or increased
Reduced or increased
Reduced or increased
Reduced or increased
- Reduced T4 to T3 conversion - Reduced tyrosine synthesis - Increased iodine supply
Androgens
Normal
Reduced
Normal
Reduced
Normal
Reduced TBG synthesis
Aspirin
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Cholestyramine
Increased
Reduced
Reduced
Reduced
Reduced
Reduced T4 exogenous absorption (replacement therapy)
Estrogens
Normal
Increased
Normal
Increased
Normal
Increased TBG synthesis
Furosemide
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Glucocorticoids
Reduced (temporary)
Reduced
Normal
Reduced
Normal
- Reduced TBG synthesis - Reduced TSH synthesis (temporary)
Levodopa
Reduced (temporary)
Normal
Normal
Normal
Normal
Reduced TSH synthesis (temporary)
Lithium
Increased
Reduced
Reduced
Reduced
Reduced
T3 and T4 release inhibition
Neuroleptics
Normal
Increased
Normal
Increased
Normal
Increased TBG synthesis
Phenytoin
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Propranolol
Increased
Reduced
Reduced
Increased
Increased
- Reduced T4 to T3 conversion
TBG, thyroxine binding globulin; T3, triiodothyronine; T4, thyroxine.
was associated with a slower decline in instrumental ADL ability, as well as with lower all-cause and cardiovascular mortality despite higher serum cholesterol concentrations.18 Corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also incorrectly called Hashimoto’s encephalopathy) is a rare, life-threatening, treatable, and possibly autoimmune condition. This condition does not seem to be caused by thyroid dysfunction or antithyroid antibodies but may represent an association of an uncommon autoimmune encephalopathy with a common autoimmune thyroid disease. It has been described in both young and older patients, and even if infrequent, the awareness of its existence is important considering the possible association of hypothyroidism symptoms and encephalopathy in an older subject. The response of neurologic symptoms to high-dose corticosteroid treatment is very high (up to 83%), hence, this rare but important condition should be recognized.19,20 The decision to treat a patient with overt hypothyroidism is usually straightforward, in contrast with the decision to treat subclinical hypothyroidism (see below) that may depend on the individual presentation and an accurate evaluation of the possible benefit gained with therapy. Comorbidity, especially the presence of heart failure or alterations of heart REVIEWS
rhythm may determine the daily dose of oral levothyroxine sodium, which is the preferred replacement therapy. In older hypothyroid patients the full hormone replacement must be completed gradually, since heart and central nervous system problems may be seen if accomplished too quickly. The patient and caregiver must be advised of the possible increase in angina, dyspnea, confusion, insomnia, and notify these symptoms to the prescribing physician. The usual initial dose is 25 to 50 g/day, increasing the dose every 4 to 6 weeks until the laboratory results show normalization of thyroid hormone and TSH levels and amelioration of symptoms is achieved.1,2,15 The major risk of levothyroxine sodium therapy is overreplacement, with osteoporosis, anxiety, muscle wasting, and atrial fibrillation as adverse effects. In older patients on levothyroxine sodium replacement therapy, estimation of serum TSH level once or twice a year is recommended, with small dosage adjustments to keep serum TSH level within the normal range. Many older patients began taking thyroid hormone therapy when younger either for inappropriate reasons or for transient hypothyroidism and they may arrive into nursing homes with levothyroxine treatment that has not been evaluated for a long time. A study in nursing home residents reported that Dominquez, Bevilacqua, Barbagallo 11
TSH Normal
Reduced
Increased
Stop evaluation
FT4
FT4 Normal
Reduced
Low TSH syndrome or Subclinical hyperthyroi dism
Normal
Reduced
Increased
Primary Hyperthyroidism
Subclinical hypothyroidism
Primary hypothyroidism
Secondary hyperthyroidism
rT3
FT3 Normal
Increased
Increased
T3 toxicosis
Reduced
Secondary hypothyroidism Brain CT
treatment
Uptake TSH<0.1 mU/L and AF
Consider treatment
Increased
TSH>10 mU/L and positive ATAb
NTI
Thyroid radioisotope scan
“Hot” nodule
-Acute thyroiditis -Levothyroxin therapy Plummer disease or -Toxicosis factitia toxic goiter -Ectopic struma
Levothyroxine
Brain CT
Consider levothyroxine
Uptake
Graves disease
Fig 1. Algorithm for the diagnosis of thyroid disorders in the long-term setting.3–5 TSH, thyroid stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine; rT3, reverse triiodothyronine; AF, atrial fibrillation; NTI, nonthyroidal illness; ATAb, antithyroid antibodies.
thyroid hormone therapy was successfully withdrawn from one half of the residents studied.14 HYPERTHYROIDISM While in younger patients there are multiple symptoms related to an overactive thyroid, the older patient may have few symptoms and they are frequently atypical. Patients often lack the hyperdynamic symptomatology typical of the young hyperthyroid patient and instead have a more sedated, apathetic presentation. Weight loss and cardiac symptoms frequently predominate, and goiter is frequently absent, making the diagnosis less obvious than in a younger patient.1–3 The most common cause of hyperthyroidism in younger patients is Graves’ disease. In older patients, even if Graves’ disease may be found, the most common cause of hyperthyroidism is Plummer’s disease and multinodular toxic goiter, characterized by an enlarged thyroid with a nodule or nodules that are overactive.4,21 A typical patient in a nursing home could be an old-old woman with new-onset atrial fibrillation, unresponsive to usual treatment, that may be severely compromised in a short period of time, due to uncontrolled arrhythmia, heart failure, and weight loss, which can greatly affect 12 Dominquez, Bevilacqua, Barbagallo
her functional status. If in addition she has cognitive impairment, it is quite possible that her thyrotoxicosis may be overlooked. Treatment of older patients with hyperthyroidism includes antithyroid drugs and radioactive iodine. Surgery is rarely indicated because of high operative risk in older subjects with comorbidity.2,3,21 As mentioned, Graves’ disease may be seen in the elderly but toxic nodular goiter is seen more frequently in older patients as a cause of hyperthyroidism. The effects of therapy should be closely monitored, because of an increased likelihood of cardiac or central nervous system side effects. Antithyroid drugs (methimazole or propylthiouracil) may be the treatment of choice for controlling function, even if a definitive treatment with radioactive iodine may follow. Beta-adrenergic blockers (propranolol, metoprolol) may be used with prudence to handle a high heart rate but they should be avoid in patients with heart failure and, when needed, the dosage should be the lowest possible.3,21 A definitive treatment with radioactive iodine may be considered in the attempt to maintain a normal or low thyroid function in the elderly, since treatment of an underactive thyroid may be more simple than recurrence hyperthyroidism in an older patient. JAMDA – January 2008
SUBCLINICAL THYROID DISORDERS The current widespread availability of greatly sensitive assays and more frequent assessment of serum TSH concentrations have resulted in a more frequent finding of abnormal thyroid function tests, both in the community as well as in nursing homes, disclosing subclinical thyroid disorders, which are particularly frequent in older people.4,5,13 It is important to remember that subclinical thyroid disorders are, by definition, laboratory diagnoses, and that if considered as isolated findings unrelated to some symptomatology, may not be expression of a physiopathological condition. Subclinical Hypothyroidism Subclinical hypothyroidism is defined as an elevated serum TSH level in the face of normal or normal-low free thyroid hormone values. The overall prevalence of subclinical hypothyroidism is 4% to 10% in the general population and up to 20% in women older than 60.5,13,22 The rate of progression of subclinical hypothyroidism to overt hypothyroidism is around 5%, hence, patients with subclinical hypothyroidism should be followed and eventually treated13 (Figure 1). When TSH is over 4.5 mU/L a confirmation is recommended within 1 to 3 months. If the second test confirms the elevation of TSH, the possibility of past radioiodine administration, previous thyroid surgery, the presence of thyroid enlargement, and history of thyroid dysfunctions in the family should be considered. In addition, exploration of subtle clinical signs of hypothyroidism and evaluation of lipid profile evaluation are suggested. Antithyroid antibodies are useful to improve the prognosis of progression to overt hypothyroidism but they may not change the management of the patient. In asymptomatic patients, TSH measurement should be repeated every 6 to 12 months. If TSH increases over 10 mU/L the patient should be treated with levothyroxine. When TSH is between 4.5 and 10 mU/L, an ex adjuvantibus administration of levothyroxine may be considered in an individual basis to help improve subtle clinical symptoms. A consistent association of subclinical hypothyroidism with cardiovascular problems, increased LDL cholesterol, or other cardiovascular problems present in overt hypothyroidism (ie, hypertension, impaired diastolic relaxation) and to neuropsychiatric problems, is still a matter of debate.5,13 There is still no consensus on the potential benefits and risks of therapy for subclinical hypothyroidism. Early clinical and autopsy studies had suggested an association between subclinical hypothyroidism and coronary heart disease (CHD), which has been later confirmed by some,23–25 but not all26 –28 large cross-sectional and prospective studies. Alterations in lipid profiles, coagulation parameters, and low-grade chronic inflammation are claimed as possible mechanisms explaining a possible benefit. Indeed, there is evidence that restoration of euthyroidism with levothyroxine can improve LDL cholesterol levels in most patients with subclinical hypothyroidism,25,29,30 but the reduction of cardiovascular events remains to be elucidated. It is probable that the decision to treat a patient might depend on the presence of risk factors, rather than on a TSH threshold. Even if levothyroxREVIEWS
ine replacement therapy is usually safe with adequate monitoring of serum TSH levels, the possibility that restoring euthyroidism from subclinical hypothyroidism may be harmful in the oldest old (⬎85 years) should be considered, since there are no controlled data on the benefits of treatment in this population. A recent cross-sectional study from Western Australia examined the prevalence of CHD in 2108 subjects with and without subclinical thyroid dysfunction, and the risk of cardiovascular mortality and CHD events in 20 years of followup, excluding subjects with CHD at baseline. Subjects with subclinical hypothyroidism (5.1%) had a significantly higher prevalence of CHD than euthyroid subjects (odds ratio [OR] ⫽ 1.8). In the longitudinal analysis, there were 21 cardiovascular deaths observed compared with 9.5 expected, and 33 CHD events observed compared with 14.7 expected, that remained significant after further adjustment for standard cardiovascular risk factors, suggesting that subclinical hypothyroidism may be an independent risk factor for CHD.31 There is still a great deal of debate concerning the possible impact of mild or subclinical thyroid disorders on cognitive function, performance and survival in older people. A prospective, observational study conducted in individuals older than 85 in Leiden with mean follow-up of 3.7 ⫾ 1.4 years reported that neither TSH nor free thyroxine were associated with disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Surprisingly, elevated TSH levels were associated with a lower mortality rate that remained significant after adjustment for baseline disability and health status, favoring no treatment for subclinical hypothyroidism.18 However, 2 recent studies reported an association of subclinical hypothyroidism with depression in older subjects.32,33 Another recent cross-sectional survey, conducted in 5865 patients older than 65, of whom 295 patients with subclinical thyroid dysfunction, reported the association of mild thyroid dysfunction and cognition, depression, and anxiety in elderly persons in primary care setting in England, after adjustment for comorbid conditions and use of medications.34 Subclinical Hyperthyroidism The finding of TSH levels below 0.45 mU/L in the presence of thyroid hormones in the normal or high borderline range is indicative of subclinical hyperthyroidism, which may be found in older institutionalized subjects. In most cases the cause is recognized: initial Graves’ disease, initial nodular toxic goiter, excessive TSH suppressive therapy with levothyroxine for benign thyroid nodular disease, differentiated thyroid cancer, or hormone overreplacement in patients with hypothyroidism. Consistent data indicates that subclinical hyperthyroidism may be associated to relevant signs and symptoms of excessive thyroid hormone action, hence, reducing the quality of life.4,16,35 Subclinical hyperthyroidism is usually associated with a higher heart rate and a higher risk of supraventricular arrhythmias, especially atrial fibrillation, and with an increased left ventricular mass, often associated with impaired diastolic function. The risk of atrial fibrillation is 3 times that of controls.36 It is as well becoming increasingly Dominquez, Bevilacqua, Barbagallo 13
apparent that subclinical hyperthyroidism may decrease bone mineral mass and accelerate the development of osteoporosis, hence, increasing bone vulnerability to fractures, particularly in postmenopausal women with a preexisting predisposition.16,37,38 Therefore, patients with subclinical hyperthyroidism should be carefully evaluated. TSH measurement should be repeated and if the low value is confirmed in a patient with atrial fibrillation or cardiovascular or other medical problems, a thyroid scintigraphy may help to consider the presence of thyroiditis (in the destructive phase), Graves’ disease, or toxic goiter (Figure 1). A retrospective study investigating nursing home residents with low TSH and normal total T4 levels showed that only 3 subjects became overt hyperthyroid among 40 subjects with subclinical hyperthyroidism. However, 7 subjects with subclinical hyperthyroidism died during the first 4 months of follow-up compared with 3 in a control group, and 9 of the 40 subjects with subclinical hyperthyroidism had a history of or current atrial fibrillation, confirming the importance of identification and follow-up of subjects at risk.39 Analyses of data from the Cardiovascular Health Study in a total of 3233 US community-dwelling individuals older than 65 enrolled in 1989 –1990 and reassessed through June 2002, reported an incidence of subclinical hyperthyroidism of 1.5%. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function, with no differences for incident CHD, cerebrovascular disease, cardiovascular death, or allcause death. Similarly, there were no differences between the subclinical hypothyroidism compared to euthyroidism group for cardiovascular outcomes or mortality.27 A population-based study by Parle et al40 in a cohort of 1191 individuals older than 60 evaluated after 10 years in England and Wales disclosed a significantly increased cardiovascular and total mortality in the first 5 years after first measurement in those with low TSH, concluding that a single measurement of low serum TSH in older individuals is associated with increased mortality from all causes, and in particular mortality due to circulatory and cardiovascular diseases. Thus, since subclinical hyperthyroidism and its related clinical manifestations are reversible and may be prevented by timely treatment,16 it is important to consider the possible benefit of treatment on an individual basis. NONTHYROIDAL ILLNESS (NTI) In the evaluation of thyroid disorders in the long-term setting, where most of the patients have important comorbidity, it is pertinent to consider the possible presence of NTI. This entity is also called “euthyroid-sick syndrome”; however, in some sick patients it is possible that an acquired transient central hypothyroidism is present,41 hence, they may not be “euthyroid,” but this is still a controversial area.42,43 However, it is important to differentiate changes in serum thyroid hormone levels due to NTI from those due to concurrent hypothyroidism or hyperthyroidism. Systemic illnesses have multiple effects on thyroid hormone metabolism and on serum thyroid hormone concentrations, even in the absence of spe14 Dominquez, Bevilacqua, Barbagallo
Table 2. Possible Mechanism of Nonthyroidal Illness (NTI)46 –52
Albumin TBPA TBG TRH Dopamine Glucocorticoids NEFA INF Leptin IL1 IL6 TNF␣
Low T3
Low T4
Low TSH
Reduced Reduced Reduced — — — Increased — — Increased Increased Increased
— — Reduced — — — — Increased Reduced Increased Increased Increased
— — — Reduced Increased Increased — Increased — Increased Increased Increased
TBPA, thyroxin binding pre-albumin; TBG, thyronine-binding globulin; TRH, thyrotropin releasing hormone; NEFA, nonesterified fatty acids; INF, interferons; IL, interleukin; TNF, tumor necrosis factor.
cific hypothalamic, pituitary or thyroid diseases. These changes seem to be primarily related to the severity, and to the chronicity of illnesses,44 rather than to the specific disease states. Changes related to chronicity may be secondary to malnutrition and/or increased catabolism, which result in progressive declines in thyroid-binding protein concentrations. In addition, the aging process itself has been implicated in a tendency to decrease serum levels of T3 and TSH concentrations that are to some extent independent of NTI.2 Despite these abnormalities, treatment of NTI patients with thyroid hormone, while controversial, appears to be of little benefit, and it may even be harmful.45 It is possible that the changes in thyroid function during severe illness are protective to prevent excessive tissue catabolism. Proposed mechanisms mediating NTI are listed in Table 2.46 –52 The most common finding related to NTI is a low total T3, but low T4 and low TSH may as well be found in an ill patient. Most of circulating T3 (⬃80%) is produced by the peripheral deiodination of T4 to T3. Measurement of serum reverse T3 (rT3), the product of 5-monodeiodination of T4, may be occasionally helpful to distinguish between NTI and central hypothyroidism, since rT3 concentrations are usually high in patients with NTI and low in patients with hypothyroidism.43,45 The concentrations of thyroid hormones are low mainly because of reductions in serum concentrations of thyroid hormone– binding proteins. More rarely, free thyroid hormone fractions are decreased because circulating substances may inhibit binding to thyroid hormone-binding proteins, ie, free fatty acids and cytokines.46 Low TSH may be found in ill patients as well. Almost all patients with subnormal but detectable TSH levels (⬍0.3 mU/L and ⬎0.05 mU/L) will be euthyroid when reassessed after recovery of the acute illness. Conversely, most of patients with undetectable serum TSH levels (⬍0.01 mU/L) have hyperthyroidism.21 Numerous drugs may have important effects on thyroid function and/or on thyroid function tests (Table 1) and nursing home residents often have multiple drugs prescribed. Amberson and Drinka53 reviewed 1153 T4 determinations in nursJAMDA – January 2008
Thyroid Nodule TSH Reduced
Increased Normal US Not suspicious
FNA
Suspicious
Radioisotope scan
Cold
ATAb
Malignant
Follicular neoplasia
Benign
Non diagnostic
Levothyroxine
Radioisotope scan
Surgery
Cold
Repeat FNA or US-FNA
Hot
Observation
Hot Suspicious US
MNG
Single
Not suspicious US
Treatment of overt hyperthyroidism and selected cases of subclinical hyperthyroidism
Fig 2. Algorithm for the diagnosis and management of thyroid nodule (data from references 54 and 55). FNA, fine-needle aspiration; MNG, multinodular goiter; TSH, thyroid-stimulating hormone; US, ultrasound; ATAb, antithyroid antibodies.
ing homes and identified 22 individuals with low T4 and normal TSH, of which 36% were treated with high-dose salicylates, 18% with phenytoin, 14% with carbamazepine, and 9% with prednisone. Six of the 22 were placed on levothyroxine replacement with no documentation of hypothyroidism, even if in 5 of them, low T4 level could be attributed to a medication effect. There is no evidence that thyroid hormone replacement is beneficial for patients with critical illness who have low serum T4 or T3 concentrations. If, however, there is evidence to support a diagnosis of hypothyroidism (such as a TSH ⬎20 mU/L with low free T4 and/or history, symptoms, and signs of hypothyroidism), cautious administration of thyroid hormone is appropriate.21 THYROID NODULE AND NODULAR GOITER Thyroid nodules may occur with increasing frequency in the elderly, but most of them are benign. The American Association of Clinical Endocrinologists (AACE) reports a prevalence of palpable thyroid nodules in 3% to 7% in North America; however, the prevalence increases to approximately 50% based on ultrasound (US) or autopsy data.54 Fine-needle aspiration (FNA) for cytology is very helpful in determining REVIEWS
which patients should be referred for surgery. Well-differentiated cancers predominate in older persons, but their course is frequently less predictable than in younger patients. Lymphoma of the thyroid and undifferentiated cancers occur with increasing frequency in the elderly. Multinodular goiter, usually longstanding, is frequently seen in elderly patients, and thyroid hormone suppressive therapy not only is not indicated but may contribute to exogenous hyperthyroidism.1 The clinical examination of women with goiter may be complicated by the changes in posture frequently associated to dorsal hyperkyphosis due to osteoporosis. Indeed, if the thyroid gland can be palpated in an older woman, it is probably enlarged. Occasionally enlargements of the thyroid gland are calcified thyroid nodules that can cause compression of near structures with consequent dyspnea, dysphagia, or dysphonia. They can be misdiagnosed as cancer metastases to lymphoid nodes. Even if most of them are benign, some thyroid cancers tend to calcify and also nodular goiter in older women tends to produce calcified nodules; hence, FNA is recommended to determine the nature of calcified lesions.55 According to AACE guidelines, thyroid US should not be performed as a screening test; however, patients with a palpable thyroid Dominquez, Bevilacqua, Barbagallo 15
nodule should undergo US examination. FNA (with or without US guidance) is recommended for nodules 10 mm or larger in diameter; US-FNA is suggested for nodules smaller than 10 mm only if clinical information or US features are suspicious. Benign thyroid nodules by FNA should undergo follow-up, and malignant or suspicious nodules should be treated surgically. Thyroid radioisotope scan is useful if TSH level is low or suppressed. Large, symptomatic goiters may be treated surgically or with radioiodine. Routine measurement of serum calcitonin is not recommended.54 Figure 2 illustrates a suggested algorithm for the diagnosis and management of thyroid nodule.54,55 CONCLUSIONS Thyroid problems in older people are especially important to understand because they occur with rather high frequency, and their mode of presentation is frequently different from those seen in younger patients. Indeed, there is often considerable delay and difficulty in the formulation of the diagnosis because symptoms are subtle and attributed to normal aging, and because atypical presentations are not uncommon. Routine screening of asymptomatic, healthy adults is not recommended; however, physicians should maintain a high index of suspicion for testing thyroid function. The interpretation of thyroid function tests is difficult in old individuals because of age-associated changes in thyroid function and also because of frequent alterations secondary to nonthyroidal illnesses and/or drugs. Subclinical abnormalities of thyroid function are more prevalent than overt disease. The benefits of treatment of subclinical disease are not completely clear. Hence, the decision to treat subclinical conditions should be individualized and restricted to high-risk patients to avoid side effects of unnecessary thyroid replacement and antithyroid medications in vulnerable elderly, in whom appropriate caution and careful dose adjustments are needed. Treatment of thyroid disease deserves special attention in old-old patients because of the increased risk of complications. REFERENCES 1. Levy EG. Thyroid disease in the elderly. Med Clin North Am 1991;75: 151–167. 2. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thyroid. Endocr Rev 1995;16:686 –715. 3. Mohandas R, Gupta KL. Managing thyroid dysfunction in the elderly. Answers to seven common questions. Postgrad Med 2003;113:54 –56, 65– 68, 100. 4. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512–516. 5. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260 –265. 6. Wilson S, Parle JV, Roberts LM, et al. Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey. J Clin Endocrinol Metab 2006;91:4809 – 4816. 7. Muller GM, Levitt NS, Louw SJ. Thyroid dysfunction in the elderly. S Afr Med J 1997;87:1119 –1123. 8. Ayala C, Cozar MV, Rodriguez JR, et al. Subclinical thyroid disease in institutionalised healthy geriatric population. Med Clin 2001;117:534 – 535. 9. Ania Lafuente BJ, Suarez Almenara JL, Fernandez-Burriel Tercero M, et al. Thyroid function in the aged admitted to a nursing home. An Med Interna 2000;17:5– 8. 16 Dominquez, Bevilacqua, Barbagallo
10. Drinka PJ, Nolten WE. Prevalence of previously undiagnosed hypothyroidism in residents of a midwestern nursing home. South Med J 1990; 83:1259 –1261, 1265. 11. Thong H, Rahimi AR. Prevalence of hypothyroidism in a southeastern nursing home. J Am Med Dir Assoc 2000;1:25–28. 12. Szabolcs I, Podoba J, Feldkamp J, et al. Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol 1997;47:87– 92. 13. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004; 291:228 –238. 14. Coll PP, Abourizk NN. Successful withdrawal of thyroid hormone therapy in nursing home patients. J Am Board Fam Pract 2000;13:403– 407. 15. Laurberg P, Andersen S, Bulow Pedersen I, Carle A. Hypothyroidism in the elderly: Pathophysiology, diagnosis and treatment. Drugs Aging 2005;22:23–38. 16. Biondi B, Palmieri EA, Klain M, et al. Subclinical hyperthyroidism: Clinical features and treatment options. Eur J Endocrinol 2005;152:1–9. 17. Drinka PJ, Nolten WE, Voeks SK, Langer EH. Follow-up of mild hypothyroidism in a nursing home. J Am Geriatr Soc 1991;39:264 –266. 18. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292:2591–2599. 19. Sawka AM, Fatourechi V, Boeve BF, Mokri B. Rarity of encephalopathy associated with autoimmune thyroiditis: A case series from Mayo Clinic from 1950 to 1996. Thyroid 2002;12:393–398. 20. Fatourechi V. Hashimoto’s encephalopathy: Myth or reality? An endocrinologist’s perspective. Best Pract Res Clin Endocrinol Metab 2005;19: 53– 66. 21. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996;42:188 –192. 22. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489 – 499. 23. Singh S, Duggal J, Molnar J, et al. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: A meta-analysis. Int J Cardiol 2007 [Epub ahead of print]. 24. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: A meta-analysis. Am J Med 2006;119:541–551. 25. Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002;137:904 –914. 26. Yun KH, Jeong MH, Oh SK, et al. Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients. Int J Cardiol 2007 [Epub ahead of print]. 27. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033–1041. 28. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;165:2460 –2466. 29. Arem R, Patsch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med 1990; 150:2097–2100. 30. Kung AW, Pang RW, Janus ED. Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin Endocrinol 1995;43:445– 449. 31. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005; 165:2467–2472. 32. Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr 2007;44:21–28. 33. Fountoulakis KN, Kantartzis S, Siamouli M, et al. Peripheral thyroid dysfunction in depression. World J Biol Psychiatry 2006;7:131–137. 34. Roberts LM, Pattison H, Roalfe A, et al. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 2006;145:573–581. 35. Auer J, Eber B. Subclinical hyperthyroidism and atrial fibrillation. Acta Med Austria 2003;30:98 –99. JAMDA – January 2008
36. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249 –1252. 37. Foldes J, Tarjan G, Szathmari M, et al. Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis? Clin Endocrinol 1993;39:521–527. 38. Kumeda Y, Inaba M, Tahara H, et al. Persistent increase in bone turnover in Graves’ patients with subclinical hyperthyroidism. J Clin Endocrinol Metab 2000;85:4157– 4161. 39. Drinka PJ, Amberson J, Voeks SK, et al. Low TSH levels in nursing home residents not taking thyroid hormone. J Am Geriatr Soc 1996;44: 573–577. 40. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study. Lancet 2001;358: 861– 865. 41. Chopra IJ. Clinical review 86: Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82:329 –334. 42. DeGroot LJ. ”Non-thyroidal illness syndrome” is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge. J Endocrinol Invest 2003;26:1163–1170. 43. Fliers E, Alkemade A, Wiersinga WM. The hypothalamic-pituitarythyroid axis in critical illness. Best Pract Res Clin Endocrinol Metab 2001;15:453– 464. 44. Van den Berghe GH. Acute and prolonged critical illness are two distinct neuroendocrine paradigms. Verh K Acad Geneeskd Belg 1998;60:487– 520. 45. Utiger RD. Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? N Engl J Med 1995;333:1562–1563.
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46. Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol 1995;146:475– 483. 47. Davies PH, Black EG, Sheppard MC, Franklyn JA. Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness. Clin Endocrinol 1996;44:199 – 205. 48. Heinen E, Herrmann J, Konigshausen T, Kruskemper HL. Secondary hypothyroidism in severe non thyroidal illness? Horm Metab Res 1981; 13:284 –288. 49. Kabadi UM. Thyrotropin dysregulation during a non-thyroidal illness: Transient hypothalamic hypothyroidism? J Endocrinol Invest 2001;24: 178 –182. 50. Karga H, Papaioannou P, Venetsanou K, et al. The role of cytokines and cortisol in the non-thyroidal illness syndrome following acute myocardial infarction. Eur J Endocrinol 2000;142:236 –242. 51. Lim CF, Docter R, Krenning EP, et al. Transport of thyroxine into cultured hepatocytes: Effects of mild non-thyroidal illness and calorie restriction in obese subjects. Clin Endocrinol 1994;40:79 – 85. 52. Young R, Worthley LI. Diagnosis and management of thyroid disease and the critically ill patient. Crit Care Resusc 2004;6:295–305. 53. Amberson J, Drinka PJ. Medication and low serum thyroxine values in nursing home residents. South Med J 1998;91:437– 440. 54. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi. Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006;12:63– 102. 55. Castro MR, Gharib H. Thyroid fine-needle aspiration biopsy: Progress, practice, and pitfalls. Endocr Pract 2003;9:128 –136.
Dominquez, Bevilacqua, Barbagallo 17
Diagnosing and Managing Thyroid Disease in the Nursing Home Ligia J. Dominguez, MD, Maurizio Bevilacqua, MD, Giovanna DiBella, MD, and Mario Barbagallo, MD, PhD Thyroid disorders occur at any age, but hypothyroidism is more common in older than in younger adults. In fact, the prevalence of thyroid disorders increases with age, and it is higher in old-old frail residents in nursing homes. Since thyroid diseases in older age, both overt reduced and increased function, may manifest as disorders of other organs, physicians need a high index of suspicion to detect thyroid dysfunction in an older person with multiple comorbidities and chronic polypharmacy. This is particularly true for residents of longterm facilities, where multiple chronic diseases may make it less attractive to direct attention to thyroid function. Subclinical hyperthyroidism and hypothyroidism, more frequently seen in older populations, have been linked to increased total and cardiovascular mortality. Since chronic diseases are more prevalent in old age, nonthyroidal illness is also seen frequently in
this age group. Although, there is still debate on the decision to treat or not to treat subclinical thyroid disorders, current recommendations state the necessity of considering treatment on an individual basis according to symptomatology and to the possible benefit that the older person may obtain with treatment, discouraging extended screening and treatment in the community population of subjects older than 65. However, in the long-term setting, the possibility of thyroid dysfunction can be more often investigated, and the consideration of treatment and follow-up is needed to improve quality of life of affected older people. (J Am Med Dir Assoc 2008; 9: 9 –17)
Thyroid disorders are not infrequent in older populations and they are often undiagnosed.1–3 While some signs and symptoms of thyroid dysfunction may be similar to those in young patients, often hyperthyroidism and hypothyroidism have subtle clinical manifestations that may be misinterpreted as involvement of other organs or even as “normal” characteristics of aging (ie, constipation, arrhythmia, cognitive impairment, weight loss).1–5 The lack of overt clinical manifestations of thyroid disorders in older people increases the need for an attentive clinician to suspect their presence. That is particularly true in the long-term setting, where subtle changes may be interpreted as manifestations of the many other problems encountered in old residents with important
comorbidity and the use of multiple drugs. The main difficulty in diagnosing thyroid disease in older populations is that symptoms and signs may appear different from those described classically in textbooks, which usually describe the clinical characteristics frequently seen in younger populations. Older people may have these manifestations but more frequently the manifestations are variable and not easy to ascribe to the “typical” patient. For example, the same symptomatology may be the manifestation of either hypothyroidism or hyperthyroidism in an older patient. In both conditions there may be frailty, confusion, depression, falling, walking disturbances, incontinence from immobility, heart failure, bowel habits changes (either constipation or diarrhea), signs that make difficult the differentiation between hypothyroidism and hyperthyroidism. These signs also correspond to many other common illnesses of older people. A correct diagnosis is not simple but may be critical. Thus, the purpose of this review is to give some insight into approaches to thyroid disease in elderly persons, especially those living in long-term facilities, with emphasis of the most common thyroid problems in older people, including overt and subclinical hypothyroidism and hyperthyroidism, thyroid nodules, and nonthyroidal illness (NTI).
Geriatric Unit, Institute of Internal Medicine and Geriatrics, University of Palermo, Italy (L.J.D., G.B.D., M. Barbagallo); Endocrine and Diabetes Unit, Department of Internal Medicine, L. Sacco Hospital (Vialba)-University of Milan, Italy (M. Bevilacqua). None of the authors have any conflicts of interest, and there is no funding support pertaining to this study. Address correspondence to Ligia J Dominguez, MD, University of Palermo, Italy, Viale F. Scaduto 6/c 90144, Palermo, Italy. E-mail: [email protected]
Copyright ©2008 American Medical Directors Association DOI: 10.1016/j.jamda.2007.07.011 REVIEWS
Keywords: Thyroid disease; subclinical thyroid disease; nonthyroidal illness; thyroid nodule; nursing home
Dominquez, Bevilacqua, Barbagallo 9
PREVALENCE OF THYROID DISEASE IN NURSING HOMES In large epidemiological studies in older populations, hypothyroidism is reported in 1% to 20% of subjects, with women being more commonly affected than men, and subclinical hypothyroidism being more common than overt hypothyroidism. Hyperthyroidism is also quite common, occurring in 0.5% to 3% of all elderly patients.1–3 The difference between prevalence in men and women is less evident in hospitalized elderly patients.2 According to a recent survey of a community sample in the United Kingdom (n ⫽ 5960 subjects aged ⬎65 years), unidentified overt hyper- and hypothyroidism were uncommon (0.3% and 0.4%, respectively) and subclinical thyroid dysfunction was present in 5% of the population (hyperthyroidism in 2.1% and hypothyroidism in 2.9%).6 These numbers are higher when considering institutionalized older people, even if studies in long-term facilities are few and most include a limited number of patients.7–12 A study conducted in 658 institutionalized elderly patients recruited in 4 nursing homes in Cape Town disclosed abnormal thyroid stimulating hormone (TSH) in 15.6%, with 3 (0.5%) newly diagnosed cases of overt hyperthyroidism and 7 (1%) new cases of overt hypothyroidism. Conversely, subclinical disease was diagnosed in 40 subjects. In 22 subjects the thyroid dysfunction had been previously recognized, while in 50 the dysfunction was newly diagnosed by the survey.7 In a population of 242 healthy elderly subjects living in public nursing homes in Spain, there were 9 (3.7%) cases of previously undetected subclinical hypothyroidism, 4 (1.65%) cases of overt clinical hypothyroidism, 2 (0.82%) cases of subclinical hyperthyroidism, and 25 (10.3%) cases of autoimmune disease.8 Another study in Spain performing TSH assay on admission to a public nursing home in 201 elderly subjects disclosed 16 (7.9%) cases of primary hypothyroidism, of whom 7 received treatment with levothyroxine. Sick euthyroid syndrome was found in 28 (13.9%) cases, and no cases of hyperthyroidism were detected. These results suggest that routine TSH measurement in elders on admission to a nursing home may have a favorable cost-utility ratio.9 Similarly, a study performed in a skilled nursing facility in the United States among 434 male and 137 female residents older than 60 disclosed overt hypothyroidism in 3 men and 2 women. Subclinical hypothyroidism was diagnosed in 42 men (9.7%) and 20 women (14.6%). Tests for thyroid antibodies were positive in all patients with overt hypothyroidism and in 34% of men and 67% of women with subclinical hypothyroidism. The authors recommend the screening of institutionalized elderly for hypothyroidism since individuals with subclinical hypothyroidism are at risk for further decline in thyroid function.10 However, the progression to overt hypothyroidism has been estimated in only 5% of persons with subclinical hypothyroidism.5,13 An interesting study conducted in 2 nursing homes in Georgia aimed to determine the sensitivity of clinical determinants for hypothyroidism during withdrawal of thyroid hormone therapy. Studying 129 residents, the prevalence of true hypothyroidism ranged from 6.2% to 7.8% and identified unnecessary therapy 10 Dominquez, Bevilacqua, Barbagallo
in 2 of 13 patients (15.4%). Increased body weight was the most sensitive indicator of evolving hypothyroidism.11 Conversely, a study in nursing home residents from Connecticut reported that previously prescribed thyroid hormone therapy was unnecessary in one half of the nursing home residents studied, with important implications for health and health care costs.14 A survey in Eastern Europe compared groups from areas with different iodine intake investigating the relationship of iodine intake with the prevalence of thyroid dysfunction, autoimmunity, and goiter in nursing home residents with median age of 81 years. There was a higher prevalence of positive antithyroid antibodies in old age that was independent of iodine supply, but iodine supply seems to have a determining role in the development of autoimmune hypothyroidism in this age group.12 HYPOTHYROIDISM As mentioned above, hypothyroidism is not uncommon in subjects older than 60, particularly in women, and its prevalence increases progressively with age.1,2,5,10,11,15–17 It affects 5% to 20% of women and 3% to 8% of men.15 Undiagnosed hypothyroidism can be found as frequently as in 1 every 4 nursing home residents.11,17 A variety of medications, including amiodarone and lithium, may induce hypothyroidism (see Table 1). Symptoms of hypothyroidism are nonspecific, especially in old-old and frail elders, and may include memory loss, often attributed to old age or other causes, weight gain, constipation, lethargy, but lack of these symptoms does not rule out the presence of hypothyroidism. Hence, a high index of suspicion is needed to formulate the diagnosis. The presence of family history of thyroid disease may be helpful, as well as history of thyroidectomy or neck radiation therapy. In fact, the most common causes of hypothyroidism in older people are autoimmune destruction of the thyroid gland (Hashimoto’s thyroiditis) and previous thyroid surgery or radiation therapy.1,3,5 The finding of an elevated serum TSH level should be confirmed and supplemented with measurements of serum levels of thyroxine (T4) and eventually with thyroid antibodies to verify the abnormality (Figure 1). Although hypothyroidism is common in older persons, it may not be associated with adverse outcomes in the oldest individuals when detected by screening alone, as illustrated by a population-based, prospective study of 558 individuals in the Netherlands, who were screened for hypothyroidism during the month of their 85th birthday and again 3 years later.18 Annual evaluation included assessment of activities of daily living (ADLs), cognitive performance, and depressive mood. Twelve percent had hypothyroidism at baseline (7% overt and 5% subclinical). None of the patients with subclinical hypothyroidism had progressed to overt hypothyroidism when retested at age 88 years. There was no association of baseline TSH levels and cognitive function, depressive symptoms or ADLs disability. All these parameters declined over time, but the decline was not accelerated in those with subclinical or overt hypothyroidism. Conversely, increased TSH at baseline JAMDA – January 2008
Table 1. Drugs That May Alter Thyroid Function Tests Drug
TSH
T3
T4
Mechanism
Total
Free
Total
Free
Amiodarone
Increased or reduced
Reduced or increased
Reduced or increased
Reduced or increased
Reduced or increased
- Reduced T4 to T3 conversion - Reduced tyrosine synthesis - Increased iodine supply
Androgens
Normal
Reduced
Normal
Reduced
Normal
Reduced TBG synthesis
Aspirin
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Cholestyramine
Increased
Reduced
Reduced
Reduced
Reduced
Reduced T4 exogenous absorption (replacement therapy)
Estrogens
Normal
Increased
Normal
Increased
Normal
Increased TBG synthesis
Furosemide
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Glucocorticoids
Reduced (temporary)
Reduced
Normal
Reduced
Normal
- Reduced TBG synthesis - Reduced TSH synthesis (temporary)
Levodopa
Reduced (temporary)
Normal
Normal
Normal
Normal
Reduced TSH synthesis (temporary)
Lithium
Increased
Reduced
Reduced
Reduced
Reduced
T3 and T4 release inhibition
Neuroleptics
Normal
Increased
Normal
Increased
Normal
Increased TBG synthesis
Phenytoin
Normal
Increased
Normal
Increased
Normal
Reduced TBG binding
Propranolol
Increased
Reduced
Reduced
Increased
Increased
- Reduced T4 to T3 conversion
TBG, thyroxine binding globulin; T3, triiodothyronine; T4, thyroxine.
was associated with a slower decline in instrumental ADL ability, as well as with lower all-cause and cardiovascular mortality despite higher serum cholesterol concentrations.18 Corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also incorrectly called Hashimoto’s encephalopathy) is a rare, life-threatening, treatable, and possibly autoimmune condition. This condition does not seem to be caused by thyroid dysfunction or antithyroid antibodies but may represent an association of an uncommon autoimmune encephalopathy with a common autoimmune thyroid disease. It has been described in both young and older patients, and even if infrequent, the awareness of its existence is important considering the possible association of hypothyroidism symptoms and encephalopathy in an older subject. The response of neurologic symptoms to high-dose corticosteroid treatment is very high (up to 83%), hence, this rare but important condition should be recognized.19,20 The decision to treat a patient with overt hypothyroidism is usually straightforward, in contrast with the decision to treat subclinical hypothyroidism (see below) that may depend on the individual presentation and an accurate evaluation of the possible benefit gained with therapy. Comorbidity, especially the presence of heart failure or alterations of heart REVIEWS
rhythm may determine the daily dose of oral levothyroxine sodium, which is the preferred replacement therapy. In older hypothyroid patients the full hormone replacement must be completed gradually, since heart and central nervous system problems may be seen if accomplished too quickly. The patient and caregiver must be advised of the possible increase in angina, dyspnea, confusion, insomnia, and notify these symptoms to the prescribing physician. The usual initial dose is 25 to 50 g/day, increasing the dose every 4 to 6 weeks until the laboratory results show normalization of thyroid hormone and TSH levels and amelioration of symptoms is achieved.1,2,15 The major risk of levothyroxine sodium therapy is overreplacement, with osteoporosis, anxiety, muscle wasting, and atrial fibrillation as adverse effects. In older patients on levothyroxine sodium replacement therapy, estimation of serum TSH level once or twice a year is recommended, with small dosage adjustments to keep serum TSH level within the normal range. Many older patients began taking thyroid hormone therapy when younger either for inappropriate reasons or for transient hypothyroidism and they may arrive into nursing homes with levothyroxine treatment that has not been evaluated for a long time. A study in nursing home residents reported that Dominquez, Bevilacqua, Barbagallo 11
TSH Normal
Reduced
Increased
Stop evaluation
FT4
FT4 Normal
Reduced
Low TSH syndrome or Subclinical hyperthyroi dism
Normal
Reduced
Increased
Primary Hyperthyroidism
Subclinical hypothyroidism
Primary hypothyroidism
Secondary hyperthyroidism
rT3
FT3 Normal
Increased
Increased
T3 toxicosis
Reduced
Secondary hypothyroidism Brain CT
treatment
Uptake TSH<0.1 mU/L and AF
Consider treatment
Increased
TSH>10 mU/L and positive ATAb
NTI
Thyroid radioisotope scan
“Hot” nodule
-Acute thyroiditis -Levothyroxin therapy Plummer disease or -Toxicosis factitia toxic goiter -Ectopic struma
Levothyroxine
Brain CT
Consider levothyroxine
Uptake
Graves disease
Fig 1. Algorithm for the diagnosis of thyroid disorders in the long-term setting.3–5 TSH, thyroid stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine; rT3, reverse triiodothyronine; AF, atrial fibrillation; NTI, nonthyroidal illness; ATAb, antithyroid antibodies.
thyroid hormone therapy was successfully withdrawn from one half of the residents studied.14 HYPERTHYROIDISM While in younger patients there are multiple symptoms related to an overactive thyroid, the older patient may have few symptoms and they are frequently atypical. Patients often lack the hyperdynamic symptomatology typical of the young hyperthyroid patient and instead have a more sedated, apathetic presentation. Weight loss and cardiac symptoms frequently predominate, and goiter is frequently absent, making the diagnosis less obvious than in a younger patient.1–3 The most common cause of hyperthyroidism in younger patients is Graves’ disease. In older patients, even if Graves’ disease may be found, the most common cause of hyperthyroidism is Plummer’s disease and multinodular toxic goiter, characterized by an enlarged thyroid with a nodule or nodules that are overactive.4,21 A typical patient in a nursing home could be an old-old woman with new-onset atrial fibrillation, unresponsive to usual treatment, that may be severely compromised in a short period of time, due to uncontrolled arrhythmia, heart failure, and weight loss, which can greatly affect 12 Dominquez, Bevilacqua, Barbagallo
her functional status. If in addition she has cognitive impairment, it is quite possible that her thyrotoxicosis may be overlooked. Treatment of older patients with hyperthyroidism includes antithyroid drugs and radioactive iodine. Surgery is rarely indicated because of high operative risk in older subjects with comorbidity.2,3,21 As mentioned, Graves’ disease may be seen in the elderly but toxic nodular goiter is seen more frequently in older patients as a cause of hyperthyroidism. The effects of therapy should be closely monitored, because of an increased likelihood of cardiac or central nervous system side effects. Antithyroid drugs (methimazole or propylthiouracil) may be the treatment of choice for controlling function, even if a definitive treatment with radioactive iodine may follow. Beta-adrenergic blockers (propranolol, metoprolol) may be used with prudence to handle a high heart rate but they should be avoid in patients with heart failure and, when needed, the dosage should be the lowest possible.3,21 A definitive treatment with radioactive iodine may be considered in the attempt to maintain a normal or low thyroid function in the elderly, since treatment of an underactive thyroid may be more simple than recurrence hyperthyroidism in an older patient. JAMDA – January 2008
SUBCLINICAL THYROID DISORDERS The current widespread availability of greatly sensitive assays and more frequent assessment of serum TSH concentrations have resulted in a more frequent finding of abnormal thyroid function tests, both in the community as well as in nursing homes, disclosing subclinical thyroid disorders, which are particularly frequent in older people.4,5,13 It is important to remember that subclinical thyroid disorders are, by definition, laboratory diagnoses, and that if considered as isolated findings unrelated to some symptomatology, may not be expression of a physiopathological condition. Subclinical Hypothyroidism Subclinical hypothyroidism is defined as an elevated serum TSH level in the face of normal or normal-low free thyroid hormone values. The overall prevalence of subclinical hypothyroidism is 4% to 10% in the general population and up to 20% in women older than 60.5,13,22 The rate of progression of subclinical hypothyroidism to overt hypothyroidism is around 5%, hence, patients with subclinical hypothyroidism should be followed and eventually treated13 (Figure 1). When TSH is over 4.5 mU/L a confirmation is recommended within 1 to 3 months. If the second test confirms the elevation of TSH, the possibility of past radioiodine administration, previous thyroid surgery, the presence of thyroid enlargement, and history of thyroid dysfunctions in the family should be considered. In addition, exploration of subtle clinical signs of hypothyroidism and evaluation of lipid profile evaluation are suggested. Antithyroid antibodies are useful to improve the prognosis of progression to overt hypothyroidism but they may not change the management of the patient. In asymptomatic patients, TSH measurement should be repeated every 6 to 12 months. If TSH increases over 10 mU/L the patient should be treated with levothyroxine. When TSH is between 4.5 and 10 mU/L, an ex adjuvantibus administration of levothyroxine may be considered in an individual basis to help improve subtle clinical symptoms. A consistent association of subclinical hypothyroidism with cardiovascular problems, increased LDL cholesterol, or other cardiovascular problems present in overt hypothyroidism (ie, hypertension, impaired diastolic relaxation) and to neuropsychiatric problems, is still a matter of debate.5,13 There is still no consensus on the potential benefits and risks of therapy for subclinical hypothyroidism. Early clinical and autopsy studies had suggested an association between subclinical hypothyroidism and coronary heart disease (CHD), which has been later confirmed by some,23–25 but not all26 –28 large cross-sectional and prospective studies. Alterations in lipid profiles, coagulation parameters, and low-grade chronic inflammation are claimed as possible mechanisms explaining a possible benefit. Indeed, there is evidence that restoration of euthyroidism with levothyroxine can improve LDL cholesterol levels in most patients with subclinical hypothyroidism,25,29,30 but the reduction of cardiovascular events remains to be elucidated. It is probable that the decision to treat a patient might depend on the presence of risk factors, rather than on a TSH threshold. Even if levothyroxREVIEWS
ine replacement therapy is usually safe with adequate monitoring of serum TSH levels, the possibility that restoring euthyroidism from subclinical hypothyroidism may be harmful in the oldest old (⬎85 years) should be considered, since there are no controlled data on the benefits of treatment in this population. A recent cross-sectional study from Western Australia examined the prevalence of CHD in 2108 subjects with and without subclinical thyroid dysfunction, and the risk of cardiovascular mortality and CHD events in 20 years of followup, excluding subjects with CHD at baseline. Subjects with subclinical hypothyroidism (5.1%) had a significantly higher prevalence of CHD than euthyroid subjects (odds ratio [OR] ⫽ 1.8). In the longitudinal analysis, there were 21 cardiovascular deaths observed compared with 9.5 expected, and 33 CHD events observed compared with 14.7 expected, that remained significant after further adjustment for standard cardiovascular risk factors, suggesting that subclinical hypothyroidism may be an independent risk factor for CHD.31 There is still a great deal of debate concerning the possible impact of mild or subclinical thyroid disorders on cognitive function, performance and survival in older people. A prospective, observational study conducted in individuals older than 85 in Leiden with mean follow-up of 3.7 ⫾ 1.4 years reported that neither TSH nor free thyroxine were associated with disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Surprisingly, elevated TSH levels were associated with a lower mortality rate that remained significant after adjustment for baseline disability and health status, favoring no treatment for subclinical hypothyroidism.18 However, 2 recent studies reported an association of subclinical hypothyroidism with depression in older subjects.32,33 Another recent cross-sectional survey, conducted in 5865 patients older than 65, of whom 295 patients with subclinical thyroid dysfunction, reported the association of mild thyroid dysfunction and cognition, depression, and anxiety in elderly persons in primary care setting in England, after adjustment for comorbid conditions and use of medications.34 Subclinical Hyperthyroidism The finding of TSH levels below 0.45 mU/L in the presence of thyroid hormones in the normal or high borderline range is indicative of subclinical hyperthyroidism, which may be found in older institutionalized subjects. In most cases the cause is recognized: initial Graves’ disease, initial nodular toxic goiter, excessive TSH suppressive therapy with levothyroxine for benign thyroid nodular disease, differentiated thyroid cancer, or hormone overreplacement in patients with hypothyroidism. Consistent data indicates that subclinical hyperthyroidism may be associated to relevant signs and symptoms of excessive thyroid hormone action, hence, reducing the quality of life.4,16,35 Subclinical hyperthyroidism is usually associated with a higher heart rate and a higher risk of supraventricular arrhythmias, especially atrial fibrillation, and with an increased left ventricular mass, often associated with impaired diastolic function. The risk of atrial fibrillation is 3 times that of controls.36 It is as well becoming increasingly Dominquez, Bevilacqua, Barbagallo 13
apparent that subclinical hyperthyroidism may decrease bone mineral mass and accelerate the development of osteoporosis, hence, increasing bone vulnerability to fractures, particularly in postmenopausal women with a preexisting predisposition.16,37,38 Therefore, patients with subclinical hyperthyroidism should be carefully evaluated. TSH measurement should be repeated and if the low value is confirmed in a patient with atrial fibrillation or cardiovascular or other medical problems, a thyroid scintigraphy may help to consider the presence of thyroiditis (in the destructive phase), Graves’ disease, or toxic goiter (Figure 1). A retrospective study investigating nursing home residents with low TSH and normal total T4 levels showed that only 3 subjects became overt hyperthyroid among 40 subjects with subclinical hyperthyroidism. However, 7 subjects with subclinical hyperthyroidism died during the first 4 months of follow-up compared with 3 in a control group, and 9 of the 40 subjects with subclinical hyperthyroidism had a history of or current atrial fibrillation, confirming the importance of identification and follow-up of subjects at risk.39 Analyses of data from the Cardiovascular Health Study in a total of 3233 US community-dwelling individuals older than 65 enrolled in 1989 –1990 and reassessed through June 2002, reported an incidence of subclinical hyperthyroidism of 1.5%. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function, with no differences for incident CHD, cerebrovascular disease, cardiovascular death, or allcause death. Similarly, there were no differences between the subclinical hypothyroidism compared to euthyroidism group for cardiovascular outcomes or mortality.27 A population-based study by Parle et al40 in a cohort of 1191 individuals older than 60 evaluated after 10 years in England and Wales disclosed a significantly increased cardiovascular and total mortality in the first 5 years after first measurement in those with low TSH, concluding that a single measurement of low serum TSH in older individuals is associated with increased mortality from all causes, and in particular mortality due to circulatory and cardiovascular diseases. Thus, since subclinical hyperthyroidism and its related clinical manifestations are reversible and may be prevented by timely treatment,16 it is important to consider the possible benefit of treatment on an individual basis. NONTHYROIDAL ILLNESS (NTI) In the evaluation of thyroid disorders in the long-term setting, where most of the patients have important comorbidity, it is pertinent to consider the possible presence of NTI. This entity is also called “euthyroid-sick syndrome”; however, in some sick patients it is possible that an acquired transient central hypothyroidism is present,41 hence, they may not be “euthyroid,” but this is still a controversial area.42,43 However, it is important to differentiate changes in serum thyroid hormone levels due to NTI from those due to concurrent hypothyroidism or hyperthyroidism. Systemic illnesses have multiple effects on thyroid hormone metabolism and on serum thyroid hormone concentrations, even in the absence of spe14 Dominquez, Bevilacqua, Barbagallo
Table 2. Possible Mechanism of Nonthyroidal Illness (NTI)46 –52
Albumin TBPA TBG TRH Dopamine Glucocorticoids NEFA INF Leptin IL1 IL6 TNF␣
Low T3
Low T4
Low TSH
Reduced Reduced Reduced — — — Increased — — Increased Increased Increased
— — Reduced — — — — Increased Reduced Increased Increased Increased
— — — Reduced Increased Increased — Increased — Increased Increased Increased
TBPA, thyroxin binding pre-albumin; TBG, thyronine-binding globulin; TRH, thyrotropin releasing hormone; NEFA, nonesterified fatty acids; INF, interferons; IL, interleukin; TNF, tumor necrosis factor.
cific hypothalamic, pituitary or thyroid diseases. These changes seem to be primarily related to the severity, and to the chronicity of illnesses,44 rather than to the specific disease states. Changes related to chronicity may be secondary to malnutrition and/or increased catabolism, which result in progressive declines in thyroid-binding protein concentrations. In addition, the aging process itself has been implicated in a tendency to decrease serum levels of T3 and TSH concentrations that are to some extent independent of NTI.2 Despite these abnormalities, treatment of NTI patients with thyroid hormone, while controversial, appears to be of little benefit, and it may even be harmful.45 It is possible that the changes in thyroid function during severe illness are protective to prevent excessive tissue catabolism. Proposed mechanisms mediating NTI are listed in Table 2.46 –52 The most common finding related to NTI is a low total T3, but low T4 and low TSH may as well be found in an ill patient. Most of circulating T3 (⬃80%) is produced by the peripheral deiodination of T4 to T3. Measurement of serum reverse T3 (rT3), the product of 5-monodeiodination of T4, may be occasionally helpful to distinguish between NTI and central hypothyroidism, since rT3 concentrations are usually high in patients with NTI and low in patients with hypothyroidism.43,45 The concentrations of thyroid hormones are low mainly because of reductions in serum concentrations of thyroid hormone– binding proteins. More rarely, free thyroid hormone fractions are decreased because circulating substances may inhibit binding to thyroid hormone-binding proteins, ie, free fatty acids and cytokines.46 Low TSH may be found in ill patients as well. Almost all patients with subnormal but detectable TSH levels (⬍0.3 mU/L and ⬎0.05 mU/L) will be euthyroid when reassessed after recovery of the acute illness. Conversely, most of patients with undetectable serum TSH levels (⬍0.01 mU/L) have hyperthyroidism.21 Numerous drugs may have important effects on thyroid function and/or on thyroid function tests (Table 1) and nursing home residents often have multiple drugs prescribed. Amberson and Drinka53 reviewed 1153 T4 determinations in nursJAMDA – January 2008
Thyroid Nodule TSH Reduced
Increased Normal US Not suspicious
FNA
Suspicious
Radioisotope scan
Cold
ATAb
Malignant
Follicular neoplasia
Benign
Non diagnostic
Levothyroxine
Radioisotope scan
Surgery
Cold
Repeat FNA or US-FNA
Hot
Observation
Hot Suspicious US
MNG
Single
Not suspicious US
Treatment of overt hyperthyroidism and selected cases of subclinical hyperthyroidism
Fig 2. Algorithm for the diagnosis and management of thyroid nodule (data from references 54 and 55). FNA, fine-needle aspiration; MNG, multinodular goiter; TSH, thyroid-stimulating hormone; US, ultrasound; ATAb, antithyroid antibodies.
ing homes and identified 22 individuals with low T4 and normal TSH, of which 36% were treated with high-dose salicylates, 18% with phenytoin, 14% with carbamazepine, and 9% with prednisone. Six of the 22 were placed on levothyroxine replacement with no documentation of hypothyroidism, even if in 5 of them, low T4 level could be attributed to a medication effect. There is no evidence that thyroid hormone replacement is beneficial for patients with critical illness who have low serum T4 or T3 concentrations. If, however, there is evidence to support a diagnosis of hypothyroidism (such as a TSH ⬎20 mU/L with low free T4 and/or history, symptoms, and signs of hypothyroidism), cautious administration of thyroid hormone is appropriate.21 THYROID NODULE AND NODULAR GOITER Thyroid nodules may occur with increasing frequency in the elderly, but most of them are benign. The American Association of Clinical Endocrinologists (AACE) reports a prevalence of palpable thyroid nodules in 3% to 7% in North America; however, the prevalence increases to approximately 50% based on ultrasound (US) or autopsy data.54 Fine-needle aspiration (FNA) for cytology is very helpful in determining REVIEWS
which patients should be referred for surgery. Well-differentiated cancers predominate in older persons, but their course is frequently less predictable than in younger patients. Lymphoma of the thyroid and undifferentiated cancers occur with increasing frequency in the elderly. Multinodular goiter, usually longstanding, is frequently seen in elderly patients, and thyroid hormone suppressive therapy not only is not indicated but may contribute to exogenous hyperthyroidism.1 The clinical examination of women with goiter may be complicated by the changes in posture frequently associated to dorsal hyperkyphosis due to osteoporosis. Indeed, if the thyroid gland can be palpated in an older woman, it is probably enlarged. Occasionally enlargements of the thyroid gland are calcified thyroid nodules that can cause compression of near structures with consequent dyspnea, dysphagia, or dysphonia. They can be misdiagnosed as cancer metastases to lymphoid nodes. Even if most of them are benign, some thyroid cancers tend to calcify and also nodular goiter in older women tends to produce calcified nodules; hence, FNA is recommended to determine the nature of calcified lesions.55 According to AACE guidelines, thyroid US should not be performed as a screening test; however, patients with a palpable thyroid Dominquez, Bevilacqua, Barbagallo 15
nodule should undergo US examination. FNA (with or without US guidance) is recommended for nodules 10 mm or larger in diameter; US-FNA is suggested for nodules smaller than 10 mm only if clinical information or US features are suspicious. Benign thyroid nodules by FNA should undergo follow-up, and malignant or suspicious nodules should be treated surgically. Thyroid radioisotope scan is useful if TSH level is low or suppressed. Large, symptomatic goiters may be treated surgically or with radioiodine. Routine measurement of serum calcitonin is not recommended.54 Figure 2 illustrates a suggested algorithm for the diagnosis and management of thyroid nodule.54,55 CONCLUSIONS Thyroid problems in older people are especially important to understand because they occur with rather high frequency, and their mode of presentation is frequently different from those seen in younger patients. Indeed, there is often considerable delay and difficulty in the formulation of the diagnosis because symptoms are subtle and attributed to normal aging, and because atypical presentations are not uncommon. Routine screening of asymptomatic, healthy adults is not recommended; however, physicians should maintain a high index of suspicion for testing thyroid function. The interpretation of thyroid function tests is difficult in old individuals because of age-associated changes in thyroid function and also because of frequent alterations secondary to nonthyroidal illnesses and/or drugs. Subclinical abnormalities of thyroid function are more prevalent than overt disease. The benefits of treatment of subclinical disease are not completely clear. Hence, the decision to treat subclinical conditions should be individualized and restricted to high-risk patients to avoid side effects of unnecessary thyroid replacement and antithyroid medications in vulnerable elderly, in whom appropriate caution and careful dose adjustments are needed. Treatment of thyroid disease deserves special attention in old-old patients because of the increased risk of complications. REFERENCES 1. Levy EG. Thyroid disease in the elderly. Med Clin North Am 1991;75: 151–167. 2. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thyroid. Endocr Rev 1995;16:686 –715. 3. Mohandas R, Gupta KL. Managing thyroid dysfunction in the elderly. Answers to seven common questions. Postgrad Med 2003;113:54 –56, 65– 68, 100. 4. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512–516. 5. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260 –265. 6. Wilson S, Parle JV, Roberts LM, et al. Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey. J Clin Endocrinol Metab 2006;91:4809 – 4816. 7. Muller GM, Levitt NS, Louw SJ. Thyroid dysfunction in the elderly. S Afr Med J 1997;87:1119 –1123. 8. Ayala C, Cozar MV, Rodriguez JR, et al. Subclinical thyroid disease in institutionalised healthy geriatric population. Med Clin 2001;117:534 – 535. 9. Ania Lafuente BJ, Suarez Almenara JL, Fernandez-Burriel Tercero M, et al. Thyroid function in the aged admitted to a nursing home. An Med Interna 2000;17:5– 8. 16 Dominquez, Bevilacqua, Barbagallo
10. Drinka PJ, Nolten WE. Prevalence of previously undiagnosed hypothyroidism in residents of a midwestern nursing home. South Med J 1990; 83:1259 –1261, 1265. 11. Thong H, Rahimi AR. Prevalence of hypothyroidism in a southeastern nursing home. J Am Med Dir Assoc 2000;1:25–28. 12. Szabolcs I, Podoba J, Feldkamp J, et al. Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol 1997;47:87– 92. 13. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004; 291:228 –238. 14. Coll PP, Abourizk NN. Successful withdrawal of thyroid hormone therapy in nursing home patients. J Am Board Fam Pract 2000;13:403– 407. 15. Laurberg P, Andersen S, Bulow Pedersen I, Carle A. Hypothyroidism in the elderly: Pathophysiology, diagnosis and treatment. Drugs Aging 2005;22:23–38. 16. Biondi B, Palmieri EA, Klain M, et al. Subclinical hyperthyroidism: Clinical features and treatment options. Eur J Endocrinol 2005;152:1–9. 17. Drinka PJ, Nolten WE, Voeks SK, Langer EH. Follow-up of mild hypothyroidism in a nursing home. J Am Geriatr Soc 1991;39:264 –266. 18. Gussekloo J, van Exel E, de Craen AJ, et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292:2591–2599. 19. Sawka AM, Fatourechi V, Boeve BF, Mokri B. Rarity of encephalopathy associated with autoimmune thyroiditis: A case series from Mayo Clinic from 1950 to 1996. Thyroid 2002;12:393–398. 20. Fatourechi V. Hashimoto’s encephalopathy: Myth or reality? An endocrinologist’s perspective. Best Pract Res Clin Endocrinol Metab 2005;19: 53– 66. 21. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996;42:188 –192. 22. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489 – 499. 23. Singh S, Duggal J, Molnar J, et al. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: A meta-analysis. Int J Cardiol 2007 [Epub ahead of print]. 24. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: A meta-analysis. Am J Med 2006;119:541–551. 25. Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002;137:904 –914. 26. Yun KH, Jeong MH, Oh SK, et al. Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients. Int J Cardiol 2007 [Epub ahead of print]. 27. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033–1041. 28. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;165:2460 –2466. 29. Arem R, Patsch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med 1990; 150:2097–2100. 30. Kung AW, Pang RW, Janus ED. Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin Endocrinol 1995;43:445– 449. 31. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005; 165:2467–2472. 32. Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr 2007;44:21–28. 33. Fountoulakis KN, Kantartzis S, Siamouli M, et al. Peripheral thyroid dysfunction in depression. World J Biol Psychiatry 2006;7:131–137. 34. Roberts LM, Pattison H, Roalfe A, et al. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 2006;145:573–581. 35. Auer J, Eber B. Subclinical hyperthyroidism and atrial fibrillation. Acta Med Austria 2003;30:98 –99. JAMDA – January 2008
36. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249 –1252. 37. Foldes J, Tarjan G, Szathmari M, et al. Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis? Clin Endocrinol 1993;39:521–527. 38. Kumeda Y, Inaba M, Tahara H, et al. Persistent increase in bone turnover in Graves’ patients with subclinical hyperthyroidism. J Clin Endocrinol Metab 2000;85:4157– 4161. 39. Drinka PJ, Amberson J, Voeks SK, et al. Low TSH levels in nursing home residents not taking thyroid hormone. J Am Geriatr Soc 1996;44: 573–577. 40. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study. Lancet 2001;358: 861– 865. 41. Chopra IJ. Clinical review 86: Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82:329 –334. 42. DeGroot LJ. ”Non-thyroidal illness syndrome” is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge. J Endocrinol Invest 2003;26:1163–1170. 43. Fliers E, Alkemade A, Wiersinga WM. The hypothalamic-pituitarythyroid axis in critical illness. Best Pract Res Clin Endocrinol Metab 2001;15:453– 464. 44. Van den Berghe GH. Acute and prolonged critical illness are two distinct neuroendocrine paradigms. Verh K Acad Geneeskd Belg 1998;60:487– 520. 45. Utiger RD. Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? N Engl J Med 1995;333:1562–1563.
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46. Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol 1995;146:475– 483. 47. Davies PH, Black EG, Sheppard MC, Franklyn JA. Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness. Clin Endocrinol 1996;44:199 – 205. 48. Heinen E, Herrmann J, Konigshausen T, Kruskemper HL. Secondary hypothyroidism in severe non thyroidal illness? Horm Metab Res 1981; 13:284 –288. 49. Kabadi UM. Thyrotropin dysregulation during a non-thyroidal illness: Transient hypothalamic hypothyroidism? J Endocrinol Invest 2001;24: 178 –182. 50. Karga H, Papaioannou P, Venetsanou K, et al. The role of cytokines and cortisol in the non-thyroidal illness syndrome following acute myocardial infarction. Eur J Endocrinol 2000;142:236 –242. 51. Lim CF, Docter R, Krenning EP, et al. Transport of thyroxine into cultured hepatocytes: Effects of mild non-thyroidal illness and calorie restriction in obese subjects. Clin Endocrinol 1994;40:79 – 85. 52. Young R, Worthley LI. Diagnosis and management of thyroid disease and the critically ill patient. Crit Care Resusc 2004;6:295–305. 53. Amberson J, Drinka PJ. Medication and low serum thyroxine values in nursing home residents. South Med J 1998;91:437– 440. 54. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi. Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006;12:63– 102. 55. Castro MR, Gharib H. Thyroid fine-needle aspiration biopsy: Progress, practice, and pitfalls. Endocr Pract 2003;9:128 –136.
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