Thyroid Status, Disability and Cognitive Function, and Survival in Old Age
Abstract
CONTEXT: Despite the equivocal outcomes of randomized controlled trials, general clinical opinion favors screening and treatment of elderly individuals with subclinical thyroid disorders. OBJECTIVES: To determine whether subclinical thyroid dysfunction should be treated in old age and the long-term impact of thyroid dysfunction on performance and survival in old age. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, population-based follow-up study within the Leiden 85-Plus Study of 87% of a 2-year birth cohort (1912-1914) in the municipality of Leiden, the Netherlands. A total of 599 participants were followed up from age 85 years through age 89 years (mean [SD] follow-up, 3.7 [1.4] years). MAIN OUTCOME MEASURES: Complete thyroid status at baseline; disability in daily life, depressive symptoms, cognitive function, and mortality from age 85 years through 89 years. RESULTS: Plasma levels of thyrotropin and free thyroxine were not associated with disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Increasing levels of thyrotropin were associated with a lower mortality rate that remained after adjustments were made for baseline disability and health status. The hazard ratio (HR) for mortality per SD increase of 2.71 mIU/L of thyrotropin was 0.77 (95% confidence interval [CI], 0.63-0.94; P = .009). The HR for mortality per SD increase of 0.21 ng/dL (2.67 pmol/L) of free thyroxine increased 1.16-fold (95% CI, 1.04-1.30; P = .009). CONCLUSIONS: In the general population of the oldest old, elderly individuals with abnormally high levels of thyrotropin do not experience adverse effects and may have a prolonged life span. However, evidence for not treating elderly individuals can only come from a well-designed, randomized placebo-controlled clinical trial.
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Epidemiological studies suggest survival advantages both for low thyroid hormones and high TSH concentrations within the normal reference range in older individuals.
“epidemiological studies suggest survival advantages both for low thyroid hormones and high TSH concentrations within the normal reference range in older individuals.34,132”
From Hypothyroidism (2024) · cites this paper as [34]
The distribution of serum TSH reference interval is right-shifted with age, giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people.
“the distribution of serum TSH reference interval is right -shifted with age, 24 -26 giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people. 2,3”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [26]
In older individuals the prevalence of hypothyroidism is as high as 7% in individuals aged 85-89 years when age-related reference ranges are not used.
“and in older individuals the prevalence is as high as 7% in individuals aged 85-89 years 34 when age-related reference ranges are not used.”
From Hypothyroidism (2024) · cites this paper as [34]
Longevity was associated with higher TSH concentrations in the Ashkenazi population and confirmed by two Dutch studies.
“Longevity was associated with higher TSH concentrations in the Ashkenazi population (19) and confirmed by two Dutch studies (the Leiden 85-Plus Study and the Leiden Longevity Study) (33–35).”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [33]
Men and women aged 85 years with abnormally high TSH concentrations according to the general reference range for younger people and abnormally low concentrations of fT4 had the lowest mortality rate during the 3.7-year follow-up.
“Men and women aged 85 years with abnormally high TSH concentrations according to the general reference range for younger people and abnormally low concentrations of fT4 had the lowest mortality rate during the 3.7-yr follow-up (33).”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [33]
Epidemiological studies confirm survival advantages, both for low thyroid hormones and high TSH levels within the normal reference range.
“Epidemiological studies confirm survival advantages, both for low thyroid hormones and high TSH levels within the normal reference range [103, 104].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [103]
Several studies of older patients have shown subclinical hypothyroidism to have either a protective or no impact on cardiovascular disease risk.
“In addition, several studies of older patients have shown SCH to have either a protective or no impact on CV disease risk (103-105).”
From Thyroid Hormones and Cardiovascular Function and Diseases (2018) · cites this paper as [103]
One study of individuals age 85 years showed that a high serum TSH at baseline was associated with a favorable outcome compared with euthyroid contemporaries.
“although one study of individuals age 85 years showed that a high serum TSH at baseline was associated with a favorable outcome compared with that of euthyroid contemporaries (29).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
The Leiden 85+ study found that subclinical hypothyroidism was associated with reduced all-cause mortality and cardiovascular mortality.
“Notably, the Leiden 85+ study, a cohort study of 85-year-olds with a similar design to our study, found that subclinical hypothyroidism was associated with reduced all-cause mortality and cardiovascular mortality (29).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
Repeating analyses using the same confounding factors as Gussekloo et al and restricting survival to 4 years left results unchanged, with only rT3 showing a significant relationship with mortality.
“To examine whether our results were dependent upon the choice of confounders, we repeated analyses using the same confounding factors as Gussekloo et al (29), (age, sex, albumin, CRP, disease count, MMSE score, disability score, subjective health) and restricting survival to 4 years. Results were unchanged with only rT3 showing a significant relationship with mortality.”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
Many previous studies have shown that low serum TSH is associated with poor outcomes, including increased all-cause or vascular mortality, or atrial fibrillation.
“In contrast with subclinical hypothyroidism, many previous studies have shown that low serum TSH is associated with poor outcomes, either increased all-cause or vascular mortality, or AF (12–14, 17, 29, 36, 37).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
Subclinical hypothyroidism is a benign state in advanced older age.
“These findings, therefore, provide further reassurance that subclinical hypothyroidism is a benign state in advanced older age (2, 29).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
Some studies suggest an adverse effect of subclinical hypothyroidism on outcome, whereas others show a neutral or even protective effect.
“some studies suggest an adverse effect of this state (8, 10, 22, 24) whereas others show a neutral or even protective effect on outcome (2, 17, 25, 29, 36, 37).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
It has widely been assumed that these associations are caused by subclinical hyperthyroidism with detrimental effects of excess thyroid hormone, despite serum thyroid hormones being within reference range.
“It has widely been assumed that these associations are caused by subclinical hyperthyroidism with detrimental effects of excess thyroid hormone, for instance its proarrhythmic effect on the heart leading to AF, despite the fact that serum thyroid hormones are within reference range (1, 13–15, 29, 41, 42).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [29]
Some studies report increased overall mortality rates in SH subjects, especially older subjects, while others indicate no relation.
“Some studies report increased overall mortality rates in SH subjects (374,379-383), especially older subjects, while others indicate no relation (384)(385)(386)(387).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [379]
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- Authors
- Gussekloo, J.
- Affiliations
- Leiden University Medical Center (NL)
- Corresponding author
- Gussekloo, Jacobijn
- ORCID
- Gussekloo, Jacobijn
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2004-12-01
- Volume
- 292
- Issue
- 21
- Pages
- 2591
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2087194312
- Cited by
- 899
- References
- 44
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 28 · 2023: 30 · 2022: 70 · 2021: 50 · 2020: 32 · 2019: 39 · 2018: 52 · 2017: 49 · 2016: 49 · 2015: 55 · 2014: 53 · 2013: 67 · 2012: 56
- FWCI
- 17.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- subclinical thyroid dysfunction, older adults, oldest old, thyroid-stimulating hormone, free thyroxine, mortality, disability, cognitive function, depressive symptoms, thyroid screening, Leiden 85-plus Study
- MeSH terms
- Activities of Daily Living, Aged, Aged, 80 and over, Cognition Disorders, Depression, Female, Disabled Persons, Persons with Disabilities, Humans, Hypothyroidism, Male, Mortality, Prospective Studies, Thyroid Diseases, Thyrotropin, Thyroxine, Triiodothyronine, Proportional Hazards Models, Survival Analysis
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