Cognitive impairment associated with low but still ‘normal’ TSH

Journal of Clinical Endocrinology & MetabolismCognitive impairment can occur at any age with suboptimal thyroid function—neurons require thyroid stimulus as much as any other cells. A study just published JCEM (The Journal of Clinical Endocrinology & Metabolism) offers evidence that TSH (thyroid stimulating hormone) levels when low but still ‘normal’ are associated with cognitive impairment and dementia. The authors state:

“The association between subclinical hyperthyroidism and the risk of dementia has been validated in several studies. However, the effect of thyroid function within reference range on the risk of cognitive dysfunction including mild cognitive impairment (MCI) and dementia is still unclear…Our aim was to investigate the association between thyroid function and the risk of MCI and dementia in euthyroid elderly subjects.”

313 participants who were euthyroid (normal thyroid) and not demented at the beginning of their study were followed for 5 years and evaluated for baseline thyroid function and cognitive impairment or dementia during the study period. They found a significant association between low-normal TSH levels and cognitive impairment:

“At baseline evaluation, 237 subjects were cognitively normal, and 76 subjects were MCI. Diagnoses of cognitive function in 259 subjects remained unchanged or improved during the study period (non-progression group), whereas 54 subjects showed progression of cognitive impairment to MCI or dementia (progression group). In the progression group, baseline serum TSH levels were lower than those in non-progression group. Baseline serum free-T4 levels were not significantly different between these two groups. The association between lower baseline serum TSH levels and the development of MCI or dementia was maintained after adjustment for conventional baseline risk factors.”

Clinical note: Practitioners should bear in mind the various possible factors besides subclinical hyperthyroidism that can suppress TSH to low ‘normal’ levels that on their own contribute to cognitive impairment including chronic inflammation.

The authors conclude:

Lower serum TSH level within reference range was independently associated with the risk of cognitive impairment including MCI and dementia in elderly subjects.”

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Borderline TSH can strongly predict future hypothyroidism

Summary: Borderline levels of TSH (thyroid stimulating hormone) still within the reference ranges typically printed in laboratory reports can indicate low thyroid function (and predict hyperthyroid on the other end of the scale). A thorough assessment of the more than two dozen patterns of thyroid dysfunction is necessary for an accurate diagnosis.

Clinicians and patients may often be misled by TSH levels that appear normal, but experienced practitioners know that they can mask the presence thyroid disorders. Because hypothyroidism affects function globally, a study just published in the Journal of Clinical Endocrinology & Metabolism that practitioners in all specialties should be vigilant. The authors state:

Serum TSH in the upper part of the reference range may sometimes be a response to autoimmune thyroiditis in early stage and may therefore predict future hypothyroidism. Conversely, relatively low serum TSH could predict future hyperthyroidism…The objective of the study was to assess TSH within the reference range and subsequent risk of hypothyroidism and hyperthyroidism.”

The authors examined 10,083 women and 5,023 men without previous thyroid disease who had a baseline TSH of 0.20–4.5 mU/liter for the predictive probabilities of developing hypothyroidism or hyperthyroidism according to categories of baseline TSH during follow-up 11 years later. Their data drew a strong result:

“During 11 yr of follow-up, 3.5% of women and 1.3% of men developed hypothyroidism, and 1.1% of women and 0.6% of men developed hyperthyroidism. In both sexes, the baseline TSH was positively associated with the risk of subsequent hypothyroidism. The risk increased gradually from TSH of 0.50–1.4 mU/liter [women, 1.1%; men, 0.3%] to a TSH of 4.0–4.5 mU/liter (women, 31.5%; men, 14.7%). The risk of hyperthyroidism was higher in women with a baseline TSH of 0.20–0.49 mU/liter (3.9%) than in women with a TSH of 0.50–0.99 mU/liter (1.4%) or higher (∼1.0%).”

Too many patients with thyroid dysfunction fall between the cracks of routine care. This evidence strongly supports the importance of a complete assessment of thyroid function when these disorders, especially autoimmune thyroid disease, are suspected. The authors conclude:

TSH within the reference range is positively and strongly associated with the risk of future hypothyroidism. TSH at the lower limit of the reference range may be associated with an increased risk of hyperthyroidism.”

Thyroid dysfunction in pediatric disorders of learning, behavior and development

Thyroid dysfunction is not to be overlooked as a possible contributing cause to problems with learning, behavior and brain development. It can be expressed in a variety of ways, often requiring a nuanced functional analysis to detect and solve the problem. A study published in the journal Brain Research discusses an often overlooked type of thyroid dysregulation that can contribute to ADHD. The authors state:

Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor β gene.”

They used PET scans to measure cerebral glucose metabolism in regions of the brain involved in attention, comparing normal subjects to those with RTH. A clear-cut difference was observed:

“Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.

In other words, resistance to thyroid hormone was associated with impaired function in the parts of the brain that are active in paying attention to and processing what we are trying to listen to. Other parts of the brain went into ‘hyperdrive’ in an attempt to compensate. Remember that this type of thyroid dysfunction, peripheral resistance to thyroid hormone, will appear normal on the usual lab tests.

A paper published in Pediatric Neurology directs our attention to the disruption of learning and behavior caused by subclinical hyperthyroidism—’subclinical’ meaning that no other overt signs of hyperthyroid are clinically apparent. The authors…

“…report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism.”

Though it may not be the most sustainable long-term therapy from a functional perspective, they treated with medication to suppress thyroid hormone synthesis and reported that it…

“…resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy.”

Although only a subset of children with learning and behavioral disorders will be found to found to have subclinical hyperthyroidism, it is a possibility that should be borne in mind and ‘crossed off the list’. The authors state:

“Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.”

Another study published in the journal Psychoneuroendocrinology draws our attention to functional disturbances in thyroid hormone regulation from a different perspective. The authors state:

Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children.”

They examined 338 children referred to a clinic for learning and behavior problems, measuring their thyroid stimulating hormone (TSH) levels and free thyroxine index (FT4I) and correlating them with diagnostic and descriptive information. Not surprisingly, the data showed that it was the more subtle functional abnormalities rather than gross pathologic ones that discriminated different types of ADHD:

“Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD–Predominantly Inattentive type, but not for ADHD–Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD–Combined Type compared to ADHD–Predominantly Inattentive, mood disorders, and pervasive developmental disorders.”

The authors sum up their findings for this group of children with subtle disturbances in thyroxine regulation:

Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.”

We can gain additional insight into the issue of thyroid hormone resistance and ADHD from a case report published in the journal Deutsche Medizinische Wochenschrift (German Medical Weekly). The authors state:

“Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children.”

Review for lay readers: as in the first paper cited, elevation of thyroid hormones in hyperthyroidism is accompanied by low levels of TSH (thyroid stimulating hormone ‘aka’ thyrotropin, which is  produced in the pituitary; it stimulates thyroid hormone production in the thyroid gland on a feedback loop). Resistance to thyroid hormone by its receptors in the rest of the body can cause TSH to be high even when thyroid hormones are elevated. Peripheral resistance can also cause a low thyroid state with labs that look normal. The doctors in this case did what was necessary to rule out hyperthyroid disease:

“Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH).”

This spared the children inappropriate aggressive thyrostatic treatment (thyroid suppression or destruction). Moreover, there are functional therapies for RTH. I certainly concur with the authors’ conclusion:

“Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.”

A paper recently published in the Journal of Affective Disorders sheds more light on how profound thyroid dysregulation evidenced by an increase TSH can be. The authors begin by observing:

“The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of psychiatric children and adolescents with and without the CBCL-DP.”

They correlated the CBCL-DP scores according to each behavioral phenotype with serum levels of TSH, fT3 (free T3) and fT4 (free T4). What did their data show?

“In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels.

Here again we see the manifestation of resistance to thyroid hormone, this time with elevated TSH and normal fT3 and fT4. It is likely, in our experience, that the chronic microinflammation resulting in peripheral resistance to thyroid hormone (RTH) is due to autoimmune/allergic phenomena that are simultaneously activating microglial cells (immune cells in the brain) to produce neuroinflammation. In this case the brain gets a ‘double whammy’—RTH and brain inflammation.

Bringing the matter even more up to date, an excellent and important paper recently published in the journal Clinical Endocrinology clearly articulates why it is mandatory for clinicians to be alert to functional changes in thyroid hormone measurements that are usually within the ‘normal’ laboratory reference range.The authors stated their initial objective:

Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.”

They assessed mental and motor development with McCarthy’s scales for neuropsychological outcomes and ADHD-DSM-IV for ADHD symptoms, correlating them with thyroid hormones TSH, free T4 and T3. What did the data show?

Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy’s scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 and 6·9 points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms…No associations were observed with T3.”

Bottom line: when there are symptoms of learning, behavioral or developmental disorders, the astute parent or clinician must ask “Is there any indication that thyroid function needs to be investigated in this case?” If so, it must be borne in mind that there are types of thyroid dysfunction that occur in the presence of ‘normal’ values for TSH, T3 and T4. The authors emphasize this in their conclusion:

Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.