March/April 2020

Subclinical Hypothyroidism in Older Adults
By Jamie Santa Cruz
Today’s Geriatric Medicine
Vol. 13 No. 2 P. 10

How should this condition be diagnosed, and when should it be treated?

For patients with overt hypothyroidism, the preferred course of action is well established: thyroid hormone replacement therapy (levothyroxine). But for patients with subclinical hypothyroidism, which is far more common, it’s a trickier matter.

There’s debate about how subclinical hypothyroidism should be defined and diagnosed, especially in older adults, and as a result, there’s concern that many older adults are being overdiagnosed, leading to unnecessary—and potentially harmful—treatment.

What Is Subclinical Hypothyroidism?
Overt hypothyroidism is characterized by elevated values of thyroid-stimulating hormone (TSH) in the presence of reduced circulating free thyroxine (FT4). By contrast, subclinical hypothyroidism is characterized by elevated TSH values in the presence of normal levels of circulating FT4.

However, a key question arises around the issue of diagnosis: What counts as a normal circulating TSH level?

In the general population, the upper limit of a normal TSH level is typically said to be about 4.5 mIU/L, based on the distribution of TSH levels in a disease-free population with normal thyroid function. Using this definition, hypothyroidism is a common condition, with a prevalence in the United States of approximately 4.6% (0.3% overt hypothyroidism and 4.3% subclinical hypothyroidism), according to the National Health and Nutrition Examination Survey.1

However, it’s well established that TSH levels tend to be lower in younger individuals and higher in older adults.1-3

“If you look at a breakdown of TSH values by decade, you’ll find, for example, that those between 20 and 29 years will have an upper limit of normal at about 3.56. But those who are 70 to 79, it’s more or less 6. And if you’re over 80, it’s about 7.5,” says James V. Hennessey, MD, director of clinical endocrinology in the division of endocrinology at Beth Israel Deaconess Medical Center.

The fact that older adults have higher average circulating TSH levels means that they are far more likely to be diagnosed with subclinical hypothyroidism than are younger patients. The question, however, is whether mildly elevated circulating TSH is actually harmful in older adults. While it’s possible that a mild elevation indicates subclinical thyroid malfunction, it could also be that it is a normal part of aging.

To tease out whether mild TSH elevations are cause for concern in older adults, it is useful to look at two sets of data: the clinical trial data on whether treatment improves clinical symptoms or provides other health benefits, and observational data on whether not treating is associated with harms.

Examining Clinical Benefits
Several studies in the last few years have suggested that treating subclinical hypothyroidism in older adults does not actually affect thyroid-related symptoms or quality of life.

The most significant study in this regard is the TRUST trial (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism — A Randomized Placebo Controlled Trial). Published in the New England Journal of Medicine in 2017, this trial set out to test whether levothyroxine provided clinical benefits to older adults with subclinical hypothyroidism.

The study enrolled 737 adults aged 65 and older, all of whom had persistent subclinical hypothyroidism (their TSH levels ranged from 4.6 up to 19.99 mIU/L at baseline). All participants were randomized to either levothyroxine treatment or placebo and were then followed for 18 months. At the conclusion of the trial, the study authors found levothyroxine therapy successfully lowered participants’ TSH levels, but it had no effect on thyroid-related symptoms, quality of life, or functional outcomes.4

Importantly, the average TSH level of participants in the TRUST study was relatively low. The mean TSH was just 6.4, and only 5% of subjects had TSH levels greater than 10 mIU/L. Other research has found that levothyroxine substitution might indeed improve symptoms when participants have TSH levels higher than 10 to 12 mIU/L.5 But the TRUST trial provides important evidence that there’s no clinical benefit to treating older adults if their TSH levels are only mildly elevated.

Two additional studies provide further evidence that treating subclinical hypothyroidism in older adults doesn’t affect clinical symptoms. In 2018, Feller et al published a meta-analysis of 21 different randomized clinical trials of patients who had been diagnosed with subclinical hypothyroidism. The meta-analysis was not restricted to studies of older adults, but, according to Hennessey, the subjects who were enrolled in the studies included in Feller’s meta-analysis were disproportionately older adults. As in the TRUST trial, the Feller meta-analysis found that the therapy successfully lowered the TSH levels of study participants but didn’t improve either quality of life or thyroid-related symptoms.6

Finally, a 2019 study examined the impact of levothyroxine treatment on subclinical hypothyroidism specifically among adults aged 80 and older. Based on their analysis of data from the TRUST trial as well as an ancillary study to TRUST, the authors found, once again, that treatment produced no improvement in thyroid-related symptoms or fatigue compared with placebo.7

According to Hennessey, such findings are unsurprising. In his view, the reason older adults with slightly elevated TSH don’t see improvement in symptoms with levothyroxine is that these symptoms are probably not actually related to thyroid function. As he observes, older adults with elevated TSH often do not experience the classic symptoms of hypothyroidism, even in the case of overt hypothyroidism.8-10 When they do report symptoms, the symptoms are often nonspecific, including such complaints as fatigue, constipation, feeling of coldness, and lack of energy. These could easily be due to another condition, or could simply be a result of aging, in which case it is predictable that levothyroxine treatment would not result in improvement.

“Most of those symptoms are not related to hypothyroidism,” Hennessey says. “So if I treat somebody with a specific treatment for hypothyroidism but they’re not hypothyroid, what would I expect to happen? The answer is, nothing.”

Subclinical Hypothyroidism and Morbidity
Subclinical hypothyroidism has clear negative impacts on cardiovascular function and mortality, but these negative impacts are most obvious in adults under 65 and are not as clear-cut in older adults, especially in those over the age of 80.11,12

More than one meta-analysis suggests that subclinical hypothyroidism is associated with an increased risk of ischemic heart disease in younger individuals but not in older adults.13,14 Furthermore, while higher TSH levels are associated with metabolic syndrome and heart failure in older adults, several studies suggest the association holds only when TSH is above 10 mIU/L.11,15-17 A large meta-analysis similarly showed an increased risk of coronary heart disease events and mortality in adults with elevated TSH levels, but again, this association was strongest when the levels were above 10 mIU/L and was absent in the case of only minimal elevation.18

As for cognition, there is a clear association between subclinical hypothyroidism and reduced cognitive function in younger adults, but this connection is not as obvious in older adults.19 In the Framingham study, women at the lowest (<1 mIU/L) and highest (>2.1 mIU/L) tertiles of TSH concentration had an increased risk of developing Alzheimer's disease.20 But other research has pointed in a different direction.

A longitudinal study of cognitively normal adults between the ages of 60 and 90 found no relationship between TSH levels and risk of developing Alzheimer’s.21 Meanwhile, the Health, Aging and Body Composition study, which included adults aged 70 to 79, found that the risk of dementia was higher in individuals with subclinical hyperthyroidism, but not in those with subclinical hypothyroidism;22 these results are consistent with an earlier meta-analysis that produced similar findings.23 A separate meta-analysis found that subclinical hypothyroidism was associated with impaired cognitive performance, but this association was evident only in adults under age 75 and in those with higher TSH levels.24

Regarding mortality, the general picture suggested by current research is that subclinical hypothyroidism does not increase risk of death in older adults. One study did find that subclinical hypothyroidism was associated with increased all-cause mortality in older adults, and treating the condition with levothyroxine therapy was associated with reduced risk.25 However, another study of older men (aged 65 or older) came to the opposite conclusion—that subclinical hypothyroidism was not associated with either cardiovascular mortality or all-cause mortality.26 And several other studies have found that increased TSH levels in older adults are associated with longevity, suggesting that TSH elevation could actually confer benefit in older adults as long as that elevation remains slight.27,28

None of these studies on mortality distinguished between degrees of elevation, and thus there is still concern that an elevation over 7 to 10 mIU/L could increase mortality risk, but the mild elevations that are most prevalent in older adults do not appear to be problematic.

Considering all the evidence, there seems to be little harm in not treating older adults with only mildly elevated TSH (in the 4.5 to 7 mIU/L range), says Anne Cappola, MD, ScM, a professor of medicine in the division of endocrinology, diabetes, and metabolism at the University of Pennsylvania.

“If you follow those people over time, and they’re older people, do they have more problems than people whose tests are in our usual reference range? The answer is no—they don’t have more cardiovascular disease, they don’t have more cardiovascular mortality, they don’t have more fractures, they don’t have more cognitive problems. There’s nothing different about them,” Cappola says. “It doesn’t seem to hurt them if you leave their mildly elevated TSH untreated.”

The Need for Age-Specific Reference Ranges
Based on the above considerations, an increasing number of researchers are arguing that older adults are being overdiagnosed with subclinical hypothyroidism and that there’s usually no need to treat mildly elevated TSH levels in adults older than 65.

“What we may be calling subclinical hypothyroidism may in fact be normal aging,” Cappola says.

At present, standard laboratory tests will flag a TSH greater than 4.5 mIU/L as being “abnormal” regardless of the patient’s age, but Cappola and other experts in the field believe that the single reference range for TSH that’s currently in use for all age groups should be replaced by age-specific reference ranges.29 The European Thyroid Association (ETA) supports this idea, having spoken out in favor of age-specific reference ranges in the association’s 2013 guideline on management of subclinical hypothyroidism.30

Although the field is moving toward agreement that reference ranges should be age specific, there’s not yet enough evidence to determine exactly what those reference ranges should be, leaving some room for disagreement among experts as to when to prescribe levothyroxine for older adults.

Some guidelines, such as that of the ETA, recommend refraining from treatment unless the patient’s TSH is 10 mIU/L or above.30 However, one recent guideline published in the British Medical Journal recommended refraining from treatment unless the patient’s TSH reaches 20 mIU/L.31 The 20 mIU/L threshold is relatively high, and it may be too high, according to Angela M. Leung, an associate professor of medicine at the UCLA David Geffen School of Medicine.

“They are the first group that has come out with such a high number. If you take into account that the normal set point for older adults would be already starting at 6, 7, or 8, then 10 and above isn’t that far from 6, 7, 8, but 20 certainly is,” Leung says. Thus, according to Leung, most now agree that mild elevations shouldn’t be treated, but there is still controversy about exactly how high TSH should be allowed to go.

When — and How — to Treat Elevated TSH in Older Adults
When considering how to manage elevated TSH in an older patient, physicians should consider the following factors:

• Is the elevation persistent? TSH elevations are often transient, and patients who show an elevated TSH level on an initial test frequently revert to a normal TSH level at follow-up even without treatment.4,32,33

A variety of factors can cause temporary elevations in TSH levels. To begin with, there are circadian fluctuations in TSH levels that can cause variations of 30% over the course of a day. In addition, TSH levels can be temporarily affected by subacute or painless thyroiditis, withdrawal of levothyroxine treatment, significant nonthyroidal illness, and treatment with various drugs (such as lithium and amiodarone). They can also be impacted by nightshift work, irregular sleep patterns, vigorous exercise, and mood disorders/depression. Thus, a proper diagnosis of subclinical hypothyroidism requires a confirmation of sustained elevations in TSH levels through repeat testing two to three months after the initial finding of elevated TSH.30

• Is there a possibility that the TSH elevation is caused by some factor other than a primary thyroid disorder? Other factors that could cause an elevation in TSH include recovery from a nonthyroidal illness, drug interference, and a number of general medical conditions.34 Additionally, many symptoms that could be attributed to hypothyroidism could also have other etiologies besides thyroid malfunction.

• Does the patient have thyroid autoantibodies? Hashimoto’s disease, which is the leading cause of hypothyroidism (whether overt or subclinical) in adults of all age groups in the United States, is marked by the presence of thyroid autoantibodies in the blood. If a patient’s circulating TSH level is only mildly elevated but testing reveals thyroid autoantibodies, he or she is at slightly greater risk of progressing to overt hypothyroidism, according to Leung.

“If a person has antibodies in the blood and they are older, then one might want to check their thyroid function more frequently just to see if they progress to subclinical hypothyroidism—which doesn’t necessarily require treatment—[or] overt hypothyroidism, which would require treatment,” Leung says.

Cappola agrees: “I wouldn’t necessarily treat them if their TSH level is less than 7, but I might watch them more frequently. I would get follow-up tests to make sure they’re not progressing to overt hypothyroidism.”

• What is the degree of elevation? According to all the experts quoted in this article, patients older than 65 with circulating TSH below 7 mIU/L generally should not be treated. But for those with levels higher than 7 mIU/L, there’s room for clinical judgment.

Additional Considerations
The 2013 ETA guideline recommends a watch-and-wait approach for older adults as long as their TSH levels remain below 10 mIU/L (the association recommends repeat measurements of both TSH and FT4 levels after two to three months).30 Leung tends to agree with this guideline and favors avoiding treatment if the patient’s TSH is below 10 mIU/L.

However, others in the field favor a threshold that’s either lower or higher. As noted above, a few experts now advocate waiting until TSH reaches 20 mIU/L.31 By contrast, Cappola believes there’s a case for starting levothyroxine at 7 mIU/L instead of waiting until 10 mIU/L based on the fact that patients who reach a TSH higher than 7 mIU/L are at greater likelihood of progressing to overt hypothyroidism.

“Observational data will show that if you have a TSH in that 4.5 to 7 range, very few people progress to overt hypothyroidism, and a great number revert to euthyroidism. But once you start to get higher levels, particularly 10 or higher, then many do progress to overt hypothyroidism within a year,” Cappola says.

In addition, a large meta-analysis showed that adults with subclinical hypothyroidism who had a TSH of 7 to 9.9 mIU/L had an increased risk of cardiovascular mortality.18

The older a patient is, the more hesitancy there should be in prescribing levothyroxine. The ETA recommends that patients older than 80 shouldn’t be treated for subclinical hypothyroidism even if their TSH levels are over 10 mIU/L.30

If a physician opts to start levothyroxine therapy on an older patient, it’s acceptable to aim for a higher treatment target. The American Thyroid Association suggests a target of 4 to 6 mIU/L in patients older than 70 to 80 years of age.35 In keeping with the recommendation to aim for a higher treatment target, physicians should also be cautious about overdosing. Levothyroxine has stronger effects on TSH levels in older adults than in younger adults, meaning the odds of overdosage are higher in older adults, which puts them at increased risk of both atrial fibrillation and osteoporotic fractures.36-38

“I don’t want to say thyroid hormone is a dangerous drug. In my opinion it’s not. But if it’s overutilized, we can cause more harm than good,” Hennessey says.

Finally, it may be worth stressing that the movement toward a watch-and-wait approach for mild TSH elevations applies specifically to older adults. In younger adults, the harms of even mild elevations are clearer, and treatment should be started sooner. This is particularly true for any woman of child-bearing age who is pregnant or lactating or who could become pregnant, Leung says. “Any sort of hypothyroidism in that group, even if it’s subclinical, could have adverse outcomes for sure,” she explains. “These issues we’ve been talking about do not pertain to that population.”

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

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