Age-Related Changes in Thyroid Function

Are you sure the patient has age-related changes in thyroid function?

The thyroid gland plays an important role in the readjustment of the hormonal milieu that occurs with aging. Although aging euthyroid patients have thyrotropin and thyroid hormone parameters which are substantially within the normal ranges of adults, changes in thyroid hormone production, metabolism and action occur during the aging processes. Thyroid disorders (especially subclinical thyroid dysfunction) are common in the elderly. However, the clinical manifestations may be different from those observed in younger patients. Moreover, aging patients are frequently characterized by comorbidities that may represent confounding factors in the correct diagnosis of thyroid disease, the estimation of their clinical consequences, and the approach to their treatment.

Potential confounders of thyroid function tests in the elderly

Acute and chronic illnesses, as well as malnutrition, may be associated with decreased levels of serum triiodothyronine (T3) and free T3 (and sometimes thyroid stimulating hormone, TSH) without concomitant thyroid disease.

Also, use of certain medications common to the elderly may interfere with thyroid function tests. Some drugs may induce hyperthyroidism or hypothyroidism (i.e. amiodarone, lithium). Others may cause abnormal thyroid function tests by interfering with T4 to T3 conversion ( i.e. glucocorticoids, beta-blockers, amiodarone), decreasing TSH secretion (i.e. glucocorticoids, dopamine), inducing changes in circulating concentrations of thyroxine binding globulin (i.e. estrogens, glucocorticoids) or with the binding of T4 to thyroxine binding globulin (i.e. heparin).

Hypothyroidism in the elderly

The prevalence of overt hypothyroidism increases in the elderly and approximates 5% in those older than 60 years of age. Autoimmune thyroiditis and the overtreatment of pre-existing hyperthyroidism are the main causes of hypothyroidism in the elderly. The presentation of hypothyroidism in aging patients may be atypical and different than the classic clinical picture observed in younger adults, in part due to the more gradual decline in thyroid function that may occur in older individuals.

Subclinical hypothyroidism in the elderly

Subclinical hypothyroidism is characterized by an elevated serum TSH level with normal free thyroid hormone concentrations. The prevalence of subclinical hypothyroidism is higher in the elderly and may reach 20% in people over age 60. The prevalence is lower in blacks than in whites and in populations living in iodine-insufficient areas. The causes of subclinical hypothyroidism in the elderly are similar to those of overt hypothyroidism. In a large proportion of people aged 55 years or older, progression of subclinical hypothyroidism to overt hypothyroidism may occur at a rate of approximately 8% per year. The magnitude of TSH elevation at the initial evaluation is the most powerful predictor of progression, in addition to symptoms of hypothyroidism, positive anti-thyroperoxidase (TPO) antibodies, goiter, and perhaps a low-normal serum FT4 concentration. Subclinical hypothyroidism may be unrecognized because of the lack of signs and symptoms. Various studies have suggested the possible adverse clinical outcomes of subclinical hypothryoidism, including cardiac dysfunction, dyslipidemia leading to an increased risk of atherosclerosis, and neuropsychiatric symptoms.

Signs and symptoms of hypothyroidism in the elderly

Normal aging may sometimes resemble hypothyroidism in elderly patients. Edema (often due to concomitant heart failure), anemia, subtle neuropsychiatric problems, and moderate weight gain are among the signs more frequently observed in elderly patients with hypothyroidism. Subclinical hypothyroidism is asymptomatic in the vast majority of elderly patients, although signs of hypothyroidism may be present in those with TSH values >10 mIU/L.

Laboratory tests to assess for hypothyroidism in the elderly

Since the most frequent cause of thyroid failure in the elderly is primary hypothyroidism, the most important diagnostic test is the measurement of circulating concentrations of TSH. If further evaluation is indicated, serum free thyroxine (FT4) and free triiodothyronie (FT3) are decreased in overt hypothyroidism and normal in subclinical hypothyroidism, although serum TSH and FT4 levels alone are usually sufficient to make the diagnosis of either overt or subclinical hypothyroidism. Anti-thyroperoxidase (TPO) antibodies are helpful in the diagnosis of autoimmune thyroiditis, the major cause of hypothyroidism in the elderly, especially women, although serum concentrations of these antibodies may also be elevated in euthyroid individuals. Hypercholesterolemia may also be seen in untreated hypothyroidism.

Hyperthyroidism in the elderly

The prevalence of hyperthyroidism in the elderly is higher than in younger adults, with frequencies of about 3% in individuals older than 60 years of age. The most frequent causes of hyperthyroidism in the elderly are toxic multinodular goiter (in areas with low iodine intake) and Graves’ disease (in iodine-sufficient areas, such as the United States). Hyperthyroidism may also be induced by excess iodine intake (from iodine-rich medications or radiographic contrast agents), especially in patients with a multinodular goiter.

Studies have suggested that an anabolic-catabolic imbalance, resulting in an increased catabolic rate, may characterize the aging process. This imbalance has been mostly related to abnormalities in anabolic endocrine systems, such as those of the gonadal, adrenal, and somatotropic axes, with a decline in testosterone, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 (IGF-1) levels. Concomitantly, however, some catabolic endocrine systems, such as that which regulates cortisol secretion, may be overactive in aging subjects. Hyperthyroidism (even subclinical hyperthyroidism) may result in a further increase in the catabolic state and exacerbate reduced muscle mass, increased fat mass, and impairment of physical function, all resulting in increased frailty of the elderly patient.

Subclinical hyperthyroidism in the elderly

Subclinical hyperthyroidism is defined by low circulating levels of TSH with normal free thyroid hormone concentrations. The causes of subclinical hyperthyroidism are primarily the same as those for overt hyperthyroidism in the elderly. However, other causes of low TSH, such as non-thyroidal illness and the use of certain medications more commonly used by the elderly (e.g. glucocorticoids, dopamine), should be excluded. The prevalence of subclinical hyperthyroidism is around 2% in iodine-sufficient areas and up to 8% or higher in iodine-deficient areas. Approximately 2% of elderly subclinically hyperthyroid individuals progress to overt hyperthyroidism. This progression is mainly observed for TSH values below 0.1 mIU/L.

Signs and symptoms of hyperthyroidism in the elderly

In aging patients, hyperthyroidism may be characterized by fewer signs and symptoms in comparison to younger adults and is therefore sometimes termed “masked hyperthyroidism” or “apathetic hyperthyroidism”. Tremors, nervousness, tachycardia, and heat intolerance may be absent in elderly patients with hyperthyroidism. Palpitations may represent an important symptom in elderly hyperthyroid patients and may suggest the onset of new atrial fibrillation. Symptoms of heart failure, due to thyrotoxicosis, may be present. Contrary to younger patients, elderly patients with hyperthyroidism may complain of a loss of appetite and unexplained weight loss.

Psychiatric symptoms, such as those seen in mania and panic disorder, have been reported. Osteoporosis may represent an adverse clinical outcome in elderly women with hyperthyroidism, and bone pain and fractures may occur in some patients. Certain signs of hyperthyroidism, such as smooth skin and ocular changes, are less frequently observed in elderly patients with hyperthyroidism as compared to younger adult individuals. Weight loss and signs potentially related to an underlying psychiatric disorders may represent important clinical clues. Although signs and symptoms may be absent in elderly patients with subclinical hyperthyroidism, heart failure, atrial fibrillation or other arrhythmias, impaired bone metabolism, and neuropsychiatric symptoms can be observed.

Laboratory tests to assess for hyperthyroidism in the elderly

A suppressed serum TSH concentration is the main diagnostic laboratory test. Serum TT3, FT3, TT4, and FT4 concentrations are increased in overt hyperthyroidism and normal in subclinical hyperthyroidism. In toxic multinodular goiter, TT3 and FT3 may be increased with normal or high normal values for TT4 and FT4, consistent with the diagnosis of “T3 toxicosis”. TSH receptor-antibodies are usually positive in patients with Graves’ disease.

What else could the patient have?

Differential diagnoses for suspected hypothyroidism in the elderly

Several signs and symptoms of hypothyroidism may be attributed to and confused with the aging process. In the elderly, hypothyroidism may be accompanied by congestive heart failure or a worsening of already present heart failure. Dyspnea has been reported in about 50% of elderly hypothyroid patients. Also, loss of appetite, reduced cognitive performances, and worsening of carpal tunnel syndrome and constipation may occur. Other elderly individuals may complain of fatigue (which may however be due to a concomitant macrocytic anemia as a consequence of folate deficiency and/or coexistence of autoimmune gastritis), cold intolerance, and hearing loss.

  • Congestive heart failure: Although hypothyroidism may cause or worsen the clinical outcomes in elderly patients with congestive heart failure, it is very important to obtain a careful medical history. A serum TSH measurement is indicated if hypothyroidism is suspected.

  • Fatigue and weakness: Other causes of weakness, including anemia and heart failure, should be ruled out. In some patients, neuropsychiatric disorders should be excluded. Importantly, patients may have adrenal insufficiency, which may be associated with autoimmune hypothyroidism, and electrolyte levels should be assessed.

  • A transient TSH increase may be encountered in the recovery phase of non-thyroidal illness.

  • The aging-associated decreases in testosterone may also result in many of the changes suggestive of hypothyroidism commonly observed in the elderly male.

Differential diagnoses for suspected hyperthyroidism in the elderly

Several signs and symptoms of hyperthyroidism may be attributed to and confused with the common comorbidities seen in the elderly.

  • Cardiovascular diseases: Arrhythmias, especially atrial fibrillation, are often observed in elderly patients and may be independent of thyroid disease.

  • Neuropsychiatric disorders: Although some reports have demonstrated that thyrotoxicosis may be accompanied by an impairment in cognitive performance, mania, and panic disorders, neuropsychiatric symptoms are often independent of thyrotoxicosis in elderly patients.

Key laboratory and imaging tests

Thyroid dysfunction is best evaluated by the measurement of circulating TSH concentrations. In general, normal thyroid function is characterized by normal circulating TSH concentrations unless specific causes of thyroid disorders are present. Recent data has suggested that the very elderly patients may have serum TSH concentrations slightly higher than the normal listed ranges in various laboratories, and values up to 7 mIU/L in the absence of TPO antibodies may be the norm in these patients.

Related to this concept are several studies that have demonstrated that TSH distribution and reference limits shift to higher concentrations with age and which vary by ethnicity ( i.e., higher TSH concentrations have been reported in Caucasians as compared to either Blacks or American Hispanics, such as those from Puerto Rico or Dominican Republic). Slightly elevated TSH concentrations may be normal or even protective in elderly subjects, as has been reported in Ashkenazi Jewish centenarians whose heritable phenotype, characterized by a slightly higher serum TSH, is associated with longevity.

Imaging may be helpful in the diagnosis. However, physical examination remains the first step in the diagnostic approach to elderly patients for suspected thyroid disorders. If a goiter is suspected, thyroid ultrasound is helpful in the evaluation of goiter size, the number of nodules, and suspicion for malignancy based on imaging characteristics. Thyroid ultrasound also evaluates thyroid blood flow to assess for thyroid hypervascularization and nodules in suspected Graves’ disease and toxic multinodular goiter.

In toxic multinodular goiter, a thyroid nuclear scan with either technetium or 123I may be useful to characterize nodules as hot or cold. Fine needle aspiration biopsy to rule out malignancy should be carried out if cold nodules are demonstrated on a thyroid scan. The thyroid scan is also important in defining any hyperfunctioning nodules which might be ablated with radioactive iodine (131I).

Other tests that may prove helpful diagnostically

In patients with a goiter thought to extend into the mediastinum, chest X-ray or computed tomography (CT) may be useful in order to define the goiter and to identify compressive changes on the trachea. These data are particularly useful if thyroid surgery is considered.

Management and treatment of the disease

Treatment of hypothyroidism in elderly patients

Levothyroxine (LT4) should be administered at a low starting dose (25 mcg or less daily) to avoid potential harmful cardiovascular effects, especially in patients with coronary disease or multiple cardiovascular risk factors. Doses should be adjusted every 6-12 weeks. In elderly patients, there is a narrow range between TSH suppressive and replacement doses, and close monitoring is required.

Whether subclinical hypothyroidism should be treated in elderly subjects is still a matter of debate. Advantages of thyroid hormone replacement therapy in elderly patients with subclinical hypothyroidism (at least for TSH values less than 10 mIU/L) have not been demonstrated. Circulating concentrations of TSH between 4 and 6 mIU/L represent a reasonable goal of LT4 therapy in elderly patients treated for hypothyroidism.

Treatment of hyperthyroidism in elderly patients

Before considering treatment, other causes of a low serum TSH should be excluded. It is important to note that non-thyroidal illness and the effects of certain drugs will rarely result in serum TSH concentrations lower than 0.1 mIU/L. Thus, endogenous subclinical hyperthyroidism in elderly patients, with serum TSH values lower than 0.1 mIU/L, usually requires treatment. Treatment should also be considered for elderly patients with serum TSH values between 0.1 and 0.5 mIU/L when cardiovascular risks or osteoporosis are present.

Radioactive iodine (131I) may be the treatment of choice in most cases of hyperthyroidism in elderly patients. This option is indicated in patients with a toxic multinodular goiter and confers definitive cure and the avoidance of surgery. Radioactive iodine treatment may require weeks to months to control the hyperthyroidism and may be associated with a transient worsening of thyrotoxicosis. To prevent this, which may be particularly dangerous in elderly patients with underlying cardiovascular disorders, methimazole should be given before radioiodine administration and discontinued approximately five days prior to therapy. Short term treatment with methimazole is also suggested after the administration of radioiodine, especially in patients with increased cardiovascular risk. Methimazole should be given for 1 or 2 weeks after radioiodine administration in order to avoid interference with radioiodine recycling and a possible reduction in the efficacy of the radioiodine.

Long-term treatment with methimazole may be alternatively considered in elderly patients with Graves’ disease, although a high rate of relapse has been demonstrated after drug withdrawal and poor patient compliance. It is a reasonable treatment option in very elderly patients with multiple comorbidities, especially when a low dose of methimazole is sufficient to maintain euthyroidism and side effects are absent.

Beta blockers may be useful, either in combination with methimazole or after radioiodine administration to prevent cardiac side effects associated with potential and transient radioiodine-associated worsening of thyrotoxicosis.

Iodine-induced hyperthyroidism may represent an important problem in aging patients who, more frequently than younger adult patients, are treated with iodine-rich medications, such as amiodarone for arrhythmias, or exposed to iodine-rich radiological contrast agents. In some cases, the disease may be self-limiting, especially in patients without underlying thyroid disease, and spontaneous remission may be observed in a few weeks. When amiodarone-induced (type 2) destructive thyroiditis is suspected, corticosteroids are effective in normalizing thyroid function. In cases of iodine-induced hyperthyroidism, including amiodarone-induced (type 1) thyroiditis, the treatment may be more difficult. Radioiodine cannot be administered due to the low radioiodine uptake associated with the iodine load. The concomitant administration of methimazole (usually up to 40 mg/day) and potassium perchlorate (KClO4) (1 g/day), which is a competitive inhibitor of the sodium iodide symporter (NIS), has been proposed as a potential therapy.

Special considerations of thyroid dysfunction treatment in elderly patients with coexisting diseases and/or other medication use

In treating hypothyroidism, attention should be paid to the concomitant use of drugs and coffee, which are known to decrease LT4 absorption. Among these, calcium and iron are the most frequently used by elderly patients. An interval of at least one hour is recommended between the ingestion of LT4 and other medications.

Reasons for failure of LT4 treatment:

  • Poor compliance

  • Interference of LT4 absorption by other drugs (i.e. the time interval between the ingestion of LT4 and other drugs is too short)

  • Malabsorption (i.e. celiac disease, intestinal parasitosis)

  • Chronic gastritis

When treatment for hyperthyroidism fails

If methimazole is ineffective, radioiodine (131I) treatment is an appropriate alternative. If methimazole use is associated with side effects, switching to propylthiouracil (PTU) may be considered, but the occurrence of the same (or other) side effects remains a possibility. Thyroid surgery should be reserved in the elderly for those with large goiters with compressive symptoms in whom the surgical risks have been considered.

Emerging potential therapeutic options

Novel therapeutic options for some patients with a compressive goiter, especially some elderly patients who may not be good surgical candidates, include laser treatments and radiofrequency ablation.

What’s the Evidence?/References

Ceresini, G, Lauretani, F, Maggio, M, Ceda, GP, Morganti, S, Usberti, E, Chezzi, C, Valcavi, R, Bandinelli, S, Guralnik, JM, Cappola, AR, Valenti, G, Ferrucci, L. “Thyroid function anbormalities and cognitive impairment in elderly people: results of the Invecchiare in Chianti Study”. J Am Geriatr Soc.. vol. 57. 2009. pp. 89-93. (This paper describes the changes in serum FT3, FT4 and TSH in community-dwelling euthyroid individuals in an area of mild iodine deficiency. In addition, the prevalence of thyroid diseases and the association of thyroid disease with cognitive status are discussed.)

Mariotti, S, Franceschi, C, Cossarizza, A, Pinchera, A. “The aging thyroid”. Endocr Rev. vol. 16. 1995. pp. 686-715. (This is an important review on the relationship between aging and changes in thyroid function.)

Van Coevorden, A, Laurent, E, Decoster, C, Kerkhofs, M, Neve, P, van Cauter, E, Mockel, J. “Decreased basal and stimulated thyrotropin secretion in elderly men”. J Clin Endcorinol Metab. vol. 69. 1989. pp. 177-185. (This paper demonstrates the aging-associated abnormalities of the pituitary regulation of thyrotropin secretion.)

Peeter, RP, Wouters, PJ, van Toor, H, Kaptein, E, Visser, TJ, Van den Berghe, G. “Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities”. J Clin Endocroinol Metab. vol. 90. 2005. pp. 4559-4565. (This paper explores the issue of nonthyroidal illness, which is particularly frequent in aging patients, and gives a comprehensive description of the relationships between peripheral thyroid hormone metabolism and various clinical outcomes.)

Van den Beld, AW, Visser, TJ, Feelders, RA, Grobbe, DE, Lamberts, SW. “Thyroid hormone concentrations, disease, physical function, and mortality in elderly men”. J Clin Endocrinol Metab. vol. 90. 2005. pp. 6403-6409. (In this paper describing a population of independently living elderly men, higher serum FT4 and rT3 levels are associated with lower physical function, and low serum FT4 levels are associated with an increased 4-year survival rate, suggesting an adaptive mechanism to minimize excessive catabolism in the elderly.)

Biondi, B, Cooper, D. “The clinical significance of subclinical thyroid dysfunctions”. End Rev. vol. 29. 2008. pp. 76-131. (In this comprehensive review, the clinical consequences and epidemiology of subclinical thyroid disorders are described.)

Sawin, CT, Geller, A, Wolf, PA, Belanger, AJ, Baker, E, Bacharach, P, Wilson, PWF, Benjamin, EJ, D’Agostino, RB. “Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons”. N Engl J Med. vol. 331. 1994. pp. 1249-1252. (This paper describes that a low serum thyrotropin level is associated with a threefold higher risk of atrial fibrillation in the subsequent decade among individuals greater than 60 years of age.)

Cappola, AR, Fried, P, Arnold, AM, Danese, MD, Kuller, LH, Burke, GL, Tracy, RP, Ladenson, PW. “Thyroid status, cardiovascular risk, and mortality in older adults”. JAMA. vol. 295. 2006. pp. 1033-1041. (This paper demonstrates an association between subclinical hyperthyroidism and the development of atrial fibrillation. However, the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyrpidism is associated with other cardiovascular disorders or mortality is unsupported.)

Biondi, B. “Invited Commentary: Cardiovascular mortality in subclinical hyperthyroidism: an ongoing dilemma”. Eur J Endocrinol. vol. 162. 2010. pp. 587-589. (This article describes the controversies in the studies evaluating the relationship between subclinical hyperthyroidism and cardiovascular mortality among the elderly.)

Ceresini, G, Ceda, GP, Lauretani F, MD, Maggio, M, Usberti, E, Marina, M, Bandinelli, S, Guralnik, JM, Valenti, G, Ferrucci, L. “Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: the aging in the Chianti area study”. J Am Geriatr Soc. vol. 61. 2013. pp. 868-874. (This study represents a 6-year survey which demonstrates an association between subclinical hyperthyroidism and all-cause mortality in elderly subjects)

Bahn, RS, Burch, HB, Cooper, DS, Garber, JR, Greenlee, MC, Klein, I, Laurberg, P, McDougall, IR, Montori, VM, Rivkees, SA, Ross, DS, Sosa, JA, Stan, MN. “Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists”. Thyroid. vol. 21. 2011. pp. 593-646. (These are guidelines on the management of thyrotoxicosis and include the treatment of overt and subclinical hyperthyroidism in aging patients.)

Surks, MI, Boucai, L. “Age-and race-based serum thyrotropin reference limits”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 496-502. (This paper describes the normal ranges of TSH adjusted for age and race.)

Atzmon, G, Barzilai, N, Surks, MI, Gabriely, I. “Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity”. J Clin Endocrinol Metab. vol. 94. 2009. pp. 4768-4775. (Higher serum TSH levels among Ashkenazi Jewish centenarians may be associated with increased longevity.)