Abnormal thyroid function tests consistent with either subclinical hypothyroidism or subclinical hyperthyroidism are not uncommon in the elderly. The question remains: do these changes represent authentic subclinical disease or are they simply a reflection of physiologic changes associated with aging? Interpretation of thyroid function in the elderly is further confounded by alterations secondary to chronic illnesses that may manifest as the nonthyroidal illness syndrome and by medication-induced changes in thyroid function parameters.
There are, however, predictable changes of thyroid function with aging¹. T4 secretion by the thyroid decreases with age, but since T4 degradation is also decreased with aging, the net result is an unchanged serum free T4. Both total and free T3 undergo age-related reductions likely due to decreased peripheral conversion of T4 to T3. It is hypothesized that the activity of 5’-monodeiodinase decreases with consequences of decreased outer ring deiodination of T4 similar to that seen in the nonthyroidal illness syndrome: (1) reduced T4 clearance, (2) reduced conversion of T4 to T3, and (3) increased T4 substrate available for conversion of T4 to rT3 and hence increased rT3 (Table 1).
Alterations in TSH associated with aging are complex. It is believed that increased TSH levels observed in the elderly are primarily identified in elderly women with antithyroid antibodies or in those with primary hypothyroidism, which is known to increase in prevalence with age². However, when those subjects with subclinical hypothyroidism are excluded, TSH levels are low or towards the lower end of the normal reference range reflecting the age-related decrease in TSH secretion by the pituitary. This may in part be due to reduced hypothalamic TRH secretion. However, pituitary thyrotrophs may also develop an increased sensitivity to thyroid-hormone induced negative feedback such that there is less TSH released for a given level of thyroid hormone sensed in the circulation or at the pituitary level. In addition to decreased TSH release, there are alterations in the circadian rhythm of TSH secretion with a 1-1.5 hour earlier shift in diurnal variation compared with young, healthy controls, and a blunted nocturnal peak in TSH in the elderly³.

Subclinical hyperthyroidism
Subclinical hyperthyroidism is defined as a low level of TSH in the setting of free T4 and T3 levels within the normal reference range. NHANES III found the prevalence of subclinical hyperthyroidism with a TSH < 0.1 mIU/L in the U.S. adult population to be 0.7% and to increase in those aged 80 or older⁴. The most common etiology of subclincal hyperthyroidism is multinodular goiter followed by Graves’ disease and iatrogenic causes, namely thyroid hormone suppressive therapy (usually unintentional), in older individuals⁵. The natural history of subclinical hyperthyroidism in those aged 60 and older is the progression to overt hyperthyroidism in approximately 1 to 2% per year⁶,⁷. Exposure to excess iodine (e.g., radiocontrast agent) may precipitate more overt thyroid abnormalities in individuals with subclinical thyroid disease.
Subclinical hyperthyroidism predominately exerts physiological effects on the bone and cardiovascular system⁸. Effects on the bone may consist of decreased bone density and increased bone turnover markers. In one study, there was no statistically significant difference in fracture rate between women over age 65 with normal TSH (0.9%) and those with TSH < 0.05 mIU/L (2.5%)⁹. However, more recently, a threefold increased risk for hip fracture and fourfold increased risk for vertebral fracture were reported in women 65 years or older with TSH < 0.1 mIU/L compared to normal TSH levels 0.5-5.5 mIU/L¹⁰. Cardiovascular effects include increased heart rate, increased cardiac contractility, increased left ventricular mass, delayed diastolic relaxation, and increased risk of atrial fibrillation¹¹. One prospective study of individuals 60 years or older found a threefold risk of the development of atrial fibrillation over 10 years in those with a low TSH (< 0.1 mIU/L) compared to those with a normal TSH¹², and another study found a greater than fivefold increased risk of atrial fibrillation, which was determined to be no different from that of overt hyperthyroidism¹³. However, in the recent prospective cohort study of individuals 65 years or older conducted by Cappola, et al, although there was an increased risk of atrial fibrillation associated with subclinical hyperthyroidism, there was no increased risk of stroke, coronary artery disease, cardiovascular death, or all-cause mortality¹⁴.
Recent guidelines following a consensus conference on sublinical thyroid disease¹⁵ stratified those with subclinical hyperthyroidism into two groups based on TSH level (Table 2). For those with TSH levels 0.1-0.45 mIU/L, the panel recommended against routine treatment for all patients, but stated that treatment should be considered in the elderly population for both bone and cardiac adverse effects. However, treatment apart from beta-blockers for cardiac protection and bisphosphonates for bone density protection is not typically necessary. For the elderly with TSH lower than 0.1 mIU/L not ingesting levothyroxine, treatment is indicated for bone and cardiac protection on an individualized basis. Certainly, close monitoring for the development of atrial arrhythmia and for loss of bone mineral density are warranted in all elderly with subclinical hyperthyroidism.

Subclinical hypothyroidism
Subclinical hypothyroidism is defined as an elevated level of TSH in the setting of free T4 and T3 levels within the normal reference range. NHANES III found the prevalence of subclinical hypothyroidism with a TSH > 4.5 mIU/L in the U.S. adult population to be 4.3%, six times more prevalent than subclinical hyperthyroidism, and to increase precipitously in those age 70 or older⁴. The most common causes in individuals older than 55 years are autoimmune thyroiditis and prior therapy for previous thyrotoxicosis¹⁶; inadequately dosed thyroid hormone replacement is another cause. The natural history of subclinical hypothyroidism in this age group is the progression to overt hypothyroidism in approximately 8% per year. However in one study, 37% of patients were found to normalize their TSH levels without intervention over an average follow-up period of 31.7 months. In this same study, the presence of thyroid antibodies reduced the likelihood of spontaneous TSH normalization since 61.5% of those without antibodies compared to only 30% of those with positive antibodies were found to normalize their TSH levels¹⁷.
The possible physiologic effects of subclinical hypothyroidism include dyslipidemia and hence adverse cardiovascular risk, neurocognitive effects, and non-specific symptoms of overt hypothyroidism such as fatigue. A review of multiple studies found that thyroid hormone administration to individuals with subclinical hypothyroidism lowers total and LDL cholesterol but has no effect on HDL or triglycerides¹⁸. A recent randomized, double-blind, crossover study confirmed decreases in LDL and total cholesterol after 12 weeks of levothyroxine therapy as compared to placebo and found improvements in endothelial function, a known early marker of atherosclerosis¹⁹. However, the prospective cohort study of individuals 65 years or older by Cappola, et al found no increased risk of cardiovascular death or all-cause mortality in the subclinical hypothyroid group compared to the euthyroid group¹⁴. The effects on neurocognitive function are also inconclusive. Roberts, et al found that subclinical hypothyroidism was not associated with depression, anxiety, or cognition in a clinically meaningful way in individuals 65 years or older. In terms of hypothyroid symptoms, data suggest that there are no difference in the clinical signs and symptoms in elderly individuals with subclinical hypothyroidism compared to symptoms in those with either overt hypothyroidism or euthyroid individuals²⁰,²¹.
One prospective trial found that increasing levels of TSH were associated with a lower mortality rate in a cohort of octogenerians even after adjustment for baseline disability and health status²². Therefore, initiation of levothyroxine therapy in elderly individuals with subclinical hypothyroidism should be individualized to the specific patient. Current guidelines do not suggest routine levothyroxine therapy for those with normal free T4 and T3 but with slightly elevated TSH levels between 4.5-10 mIU/L¹⁵ (Table 3). Rather, asymptomatic individuals should be followed closely with repeat thyroid function testing every 6-12 months. In those patients with hypothyroid symptoms despite normal free T4 and T3, a several month trial of thyroid hormone therapy may be considered with careful monitoring.. In those elderly patients with TSH >10 mIU/L, treatment is usually considered. Although evidence suggests that starting levothyroxine at full replacement doses is likely safe even in elderly individuals without a history of cardiac disease²³, it is prudent to initiate lower starting dose of 25-50 mcg daily in this group and in those with pre-existing cardiac disease.
In conclusion, there are predictable changes in thyroid function parameters in the elderly including mild decreases in TSH and T3 levels, but free and total T4 levels are typically unchanged. As the current available data do not lead to definitive conclusions, therapy in the elderly with either subclinical hypothyroidism or hyperthyroidism should be individualized by the clinician to the specific patient until more definitive clinical studies are performed.

Table 1: Changes in thyroid function parameters in the healthy elderly

(KEY: FT4: free T4; FT3: free T3; rT3: reverse T3; TBG: thyroid binding globulin; TSH: thyrotropin stimulating hormone. *Parameters may also remain within the normal range.)

Table 2: Treatment recommendations in the elderly with subclinical hyperthyroidism

Table 3: Treatment recommendations in the elderly with subclinical hypothyroidism