Subclinical Hypothyroidism May be Linked to Cognitive Impairment in Patients Younger Than Age 75

pituitary-thyroidal axisCommentary by James V. Hennessey, MD

Conflicting data have led to uncertainly regarding the association between mild thyroid failure and cognitive function. In the first-ever systematic review and meta-analysis on this topic, researchers found a possible link between subclinical hypothyroidism and cognitive impairment in individuals younger than 75 years of age and in those with higher thyroid stimulating hormone levels (TSH). The findings were published in the August 25 issue of the Journal of Clinical Endocrinology and Metabolism.

“We selected 13 studies that met the following criteria: cross-sectional, case control or longitudinal analysis enrolling at least 15 patients with subclinical hypothyroidism and well defined normal upper limit of serum TSH value,” explained senior author Fabio Monzani, MD, Associate Professor in the Geriatrics Unit of the Department of Clinical & Experimental Medicine, University of Pisa, Italy. “The primary outcome of cognitive function was assessed as composite endpoint of incidence or prevalence of dementia or difference of Mini-Mental State Examination (MMSE), Wechsler Adult Intelligence Scale, and Wechsler Memory Scale-Revised scores,” he said.

A significant risk for the composite endpoint (odds ratio [OR]=1.56) and dementia (OR=1.81) was observed only in patients younger than 75 years, Dr. Monzani said. “Moreover, a positive association was found between the composite endpoint and the degree of TSH elevation. No correlation was obtained while considering all the studies as a whole,” he explained.

“Thus, our systematic review and meta-analysis demonstrates a relationship between mild thyroid function impairment and cognitive function only documented in individuals younger than 75 years and those with higher TSH concentrations,” Dr. Monzani told

“The lack of utilization of age-related TSH reference ranges and consequent potential overdiagnosis of subclinical hypothyroidism in older people is likely to account for [these findings],” Dr. Monzani said. “Accordingly, physicians should be particularly cautious in treating subclinical hypothyroidism in older people (>75-80 years) with serum TSH levels lower than 10 mU/L, and also for the risk of iatrogenic hyperthyroidism,” he said.


James V. Hennessey, MD
Director, Clinical Endocrinology
Division of Endocrinology
Beth Israel Deaconess Medical Center
Boston, Massachusetts 

For years now, we have considered the presence of symptoms of hypothyroidism found in those with subclinical hypothyroidism (SCHypo) an indication for treatment but have not had good proof that the intervention with levothyroxine was effective. As we age, non-specific symptoms potentially consistent with the presence of hypothyroidism seem to increase in frequency. At the same time, perfectly healthy, older persons with no symptoms experience a gradual increase in their thyroid stimulating hormone (TSH) levels while their circulating thyroxine (T4) levels remain unchanged.

This change in thyroid function tests is not consistent with the presence of hypothyroidism in the elderly, but rather of a yet not well-understood change in the function of the pituitary-thyroidal axis, which has been associated with increased longevity and overall better survival in several studies.

Because of this expected increase in TSH levels, many studies have included older individuals who do not have hypothyroidism into study groups labeled as SCHypo because an arbitrary threshold of 4.1 or 4.5 mIu/L for TSH has been exceeded. Because many of those included are not hypothyroid, it is difficult to identify specific symptoms as being associated with true mild hypothyroidism. Worse yet, when some studies have looked at randomly treating (usually asymptomatic) older people thought to have SCHypo with LT4, no effect of therapy was evident as so many in the study group were not actually hypothyroid and so would not be expected to have their non-specific symptoms “respond” to hypothyroid treatment.

This study seems to indicate that the presence of hypothyroid like symptoms found in those with SCHypo are more likely related to hypothyroidism in younger patients (where the upper limits of TSH ARE closer to 4.1-4.5); thus, using this criteria to identify SCHypo in younger individuals is likely to be proven to be an indication for treatment as LT4 intervention may result in improvement in their clinical state.

These findings reinforce the need to use age-adjusted TSH values when assigning the diagnosis of SCHypo and add some support to using the presence of symptoms consistent with hypothyroidism as a potentially legitimate indication for the initiation of LT4 therapy.

We have seen this same pattern of SCHypo and its impact on cardiovascular disease where younger individuals seem to be affected (when included as SCHypo with a TSH of 4.1-4.5) while an impact of SCHypo on cardiovascular disease is not clearly evident when older individuals are included in these studies using non-age adjusted TSH values.

Two problems arise in making the diagnosis of true SCHypo, the first is the use of a single TSH value to make the diagnosis. It turns out that the lower the TSH elevation above “normal," the more likely that the TSH value will return to normal during follow up leaving open the question of whether SCHypo is actually present. In addition, using the lower TSH values (4.1-4.5) to define SCHypo in the elderly includes many individuals who are not hypothyroid, making it difficult to identify a hypothyroidism connection to disease and then the use of LT4 has not clearly been shown to be of benefit. Most clearly, using the recommended TSH cutoff of >10 mIu/L as a sure indication for LT4 intervention is prudent, especially when dealing with elderly patients.

Continue Reading:
Ultrasound Criteria May Reduce the Unnecessary Thyroid Biopsies
close X