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Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study

Open access
Pearce, Simon H. S., Razvi, Salman, Yadegarfar, Mohammad E., Martin-Ruiz, Carmen, Kingston, Andrew, Collerton, Joanna, Visser, Theo J., Kirkwood, Tom B. +1 more·2016·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2016-1935PMC PMC5095241
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Abstract

Perturbations in thyroid function are common in older individuals but their significance in the very old is not fully understood. This study sought to determine whether thyroid hormone status and variation of thyroid hormones within the reference range correlated with mortality and disability in a cohort of 85-year-olds. A cohort of 85-year-old individuals were assessed in their own homes (community or institutional care) for health status and thyroid function, and followed for mortality and disability for up to 9 years. Six hundred and forty-three 85-year-olds registered with participating general practices in Newcastle and North Tyneside, United Kingdom. All-cause mortality, cardiovascular mortality, and disability according to thyroid disease status and baseline thyroid hormone parameters (serum TSH, FT4, FT3, and rT3). Models were adjusted for age, sex, education, body mass index, smoking, and disease count. After adjustment for age and sex, all-cause mortality was associated with baseline serum rT3 and FT3 (both P < .001), but not FT4 or TSH. After additional adjustment for potential confounders, only rT3 remained significantly associated with mortality (P = .001). Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively. Our study is reassuring that individuals age 85 y with both subclinical hypothyroidism and subclinical hyperthyroidism do not have a significantly worse survival over 9 years than their euthyroid peers. However, thyroid function tests did predict disability, with higher serum TSH levels predicting better outcomes. These data strengthen the argument for routine use of age-specific thyroid function reference ranges.

AI snapshot

Written from the paper’s full text.

TL;DR

In 643 85-year-olds followed for up to 9 years, baseline thyroid status (subclinical hypothyroidism or hyperthyroidism) was not significantly associated with all-cause or cardiovascular mortality. However, serum rT3 predicted all-cause mortality and disability, and higher TSH predicted better disability outcomes, especially in men.

Key findings

  • Among 643 participants, 83.1% (n=534) were euthyroid, 12.5% (n=79) had subclinical hypothyroidism, 2.9% (n=19) had subclinical hyperthyroidism, 0.9% (n=6) were overtly hypothyroid, and 0.8% (n=5) were overtly hyperthyroid; thyroid status was not significantly associated with all-cause mortality (male P=.32; female P=.54) or cardiovascular mortality (male P=.94; female P=.18).
  • After age/sex adjustment, all-cause mortality was associated with FT3 (HR 0.81 per SD; 95% CI, 0.73–0.91; P<.001) and rT3 (HR 1.23 per SD; 95% CI, 1.12–1.34; P<.001); after full adjustment only rT3 remained significant (HR 1.18; 95% CI, 1.07–1.31; P=.001). In euthyroid participants, both FT3 (HR 0.84; 95% CI, 0.74–0.96; P=.008) and rT3 (HR 1.17; 95% CI, 1.05–1.31; P=.006) remained associated with all-cause mortality after adjustment.
  • For disability trajectories, after adjustment higher rT3 in women predicted increased disability (OR 1.28 per SD; 95% CI, 1.01–1.62; P=.04), while lower TSH in men predicted increased disability (OR 0.62 per SD; 95% CI, 0.40–0.97; P=.038); FT4 was not associated with disability in either sex.

Methods

  • Longitudinal cohort study: Newcastle 85+ Study, a single-year birth cohort (1921) recruited at age 85 from general practices in Newcastle and North Tyneside; 643 participants with complete baseline TSH, FT3, FT4, and rT3 data and not on thyroid-affecting medication were followed for mortality and disability for up to 9 years (mortality documented until January 1, 2015).
  • Baseline assessments included home health assessment, general practice record review, and fasting blood sampling; serum TSH, FT4, FT3, rT3, and thyroid peroxidase antibodies were measured, and thyroid status was categorized using defined reference ranges. Disability was assessed from 17 activities of daily living at baseline, 18, 36, and 60 months and modeled as disability trajectories separately for men and women.
  • Analyses used Kaplan-Meier plots, Cox proportional hazards models for all-cause and cardiovascular mortality (Model 1 adjusted for age and sex; Model 2 additionally adjusted for education, BMI, smoking, and disease count), restricted cubic splines for nonlinearity, and ordinal logistic regression for disability trajectories with similar adjustment.

Limitations

  • Stated in the paper: relatively low number of individuals studied, with less power to detect differences in cardiovascular deaths; adjustment for only 17 common comorbid conditions, leaving possible unmeasured conditions; possible bias toward healthier participants, with likely under-representation of individuals with sensory impairments; however, the cohort included frail individuals in care homes and those with dementia, so results should be representative for age-matched populations.
  • Evident from the text: the number of participants with subclinical or overt hyperthyroidism was small (24 in total), making mortality findings related to low TSH less robust; the observational design cannot establish causality; thyroid function was measured at baseline only, and residual confounding remains possible.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/jc.2016-1935

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 74 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Baseline rT3 predicted future disability in the Newcastle 85+ cohort.

    “Our analysis showed that baseline serum TSH, FT3, and rT3 each predicted future disability with the strongest effects seen in women.”
    Quote in the paperSubstantial claim
  • Findingown data

    Baseline FT3 predicted future disability in the Newcastle 85+ cohort.

    “Our analysis showed that baseline serum TSH, FT3, and rT3 each predicted future disability with the strongest effects seen in women.”
    Quote in the paperSubstantial claim
  • Findingown data

    FT3 was the exception, where both low and high values were predictive of mortality in the very old.

    “The exception was FT3 where both low and high values were predictive of mortality in the very old.”
    Quote in the paperSubstantial claim
  • Findingown data

    Baseline serum TSH predicted future disability in the Newcastle 85+ cohort.

    “Our analysis showed that baseline serum TSH, FT3, and rT3 each predicted future disability with the strongest effects seen in women.”
    Quote in the paperSubstantial claim
  • Findingown data

    After adjustment for potential confounders, only rT3 remained significantly associated with increased disability in women.

    “although after adjustment for potential confounders only rT3 remained significantly associated with increased disability (Table 3).”
    • Also stated in: § Results: · plain
      “Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 27
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingown data

    In the cohort of 643 85-year-olds, 83.1% were euthyroid at baseline, 12.5% had subclinical hypothyroidism, 2.9% had subclinical hyperthyroidism, and less than 1% were overtly hypothyroid or hyperthyroid.

    “In this population of 643 85-year-olds, 83.1% (n = 534) were euthyroid at baseline, 12.5% (n = 79) had subclinical hypothyroidism, 2.9% (n = 19) had subclinical hyperthyroidism, and less than 1% were overtly hypothyroid (0.9%, n = 6) or hyperthyroid (0.8%, n = 5) (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    None of the participants classified as euthyroid from biochemical analysis had thyroid disease recorded in the general practice records.

    “None of the participants classified as euthyroid from biochemical analysis had thyroid disease recorded in the general practice records.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no significant difference between thyroid status categories for all-cause mortality or cardiovascular mortality.

    “No significant difference was found between the categories for all-cause mortality (male: P = .32; female: P = .54) or cardiovascular mortality (male: P = .94; female: P = .18).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.
    • Rests on an assumption: Cause of death recorded from national registration accurately reflects cardiovascular death.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    After adjustment for age and sex, all-cause mortality was negatively associated with FT3 and positively associated with rT3.

    “Analysis of each of the serum thyroid hormones individually showed that all-cause mortality was negatively associated with FT3 concentrations (HR = 0.81; 95% CI, 0.73–0.91; P < .001) and positively associated with levels of rT3 (HR = 1.23; 95% CI, 1.12–1.34; P < .001)”
    • Also stated in: § Results: · plain
      “After adjustment for age and sex, all-cause mortality was associated with baseline serum rT3 and FT3 (both P < .001), but not FT4 or TSH.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • May combine two claims.

    Findingown data

    No association was found between thyroid status and either all-cause mortality or cardiovascular mortality after adjustment for age and sex, or after further adjustment for potential confounding factors.

    “Nor was association found between thyroid status and either all-cause mortality or cardiovascular mortality after adjustment for age and sex, or after further adjustment for potential confounding factors (Supplemental Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.
    • Rests on an assumption: Cause of death recorded from national registration accurately reflects cardiovascular death.

  • May combine two claims.

    Findingown data

    For cardiovascular mortality, similar trends were found, but the association of rT3 with cardiovascular mortality was no longer significant after adjustment for baseline factors.

    “Similar trends were found for cardiovascular mortality although, due to smaller number of deaths, the association of rT3 with cardiovascular mortality was no longer significant after adjustment for baseline factors (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.
    • Rests on an assumption: Cause of death recorded from national registration accurately reflects cardiovascular death.

  • May combine two claims.

    Findingown data

    In the euthyroid subset, the same associations were found, and all-cause mortality associations for both FT3 and rT3 remained significant after adjustment for baseline factors.

    “When analyses were repeated for the subset of euthyroid participants (n = 534), the same associations were found although all-cause mortality associations for both FT3 and rT3 remained significant after adjustment for baseline factors (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • May combine two claims.

    Findingown data

    In euthyroid participants, higher serum TSH had a hint of a protective effect on all-cause mortality, but this did not persist after adjustment for comorbidities.

    “when only euthyroid participants were considered there is a hint of a protective effect of higher serum TSH on all-cause mortality, although this did not persist after adjustment for comorbidities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For men, trends were in a similar direction to women, but after adjustment only decreasing levels of TSH were predictive of increased disability.

    “Trends for men were in a similar direction to women although after adjustment, only decreasing levels of TSH were predictive of increased disability.”
    • Also stated in: § Results: · plain
      “Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • May combine two claims.

    Findingown data

    Lower FT3 was associated with both all-cause and cardiovascular mortality, but these associations were lost after full correction for disease burden.

    “In contrast, lower FT3 was also associated with both all-cause and cardiovascular mortality but following full correction for disease burden, these associations were lost.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In men, lower serum TSH was associated with future disability (fully adjusted OR per sd increase 0.62, 95% CI 0.40-0.97, P=.038), with a nonsignificant similar trend in women.

    “In addition, lower serum TSH was associated with disability in men, with a nonsignificant though similar trend in women.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In women, higher rT3 predicted disability (fully adjusted OR per sd increase 1.28, 95% CI 1.01-1.62, P=.04).

    “in women higher rT3 predicted disability.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Up to 3% of older individuals have a serum TSH concentration below the healthy reference interval for younger people (subclinical hyperthyroidism), and approximately 10% have an elevated serum TSH level (subclinical hypothyroidism).

    “However, this topic has taken on increasing significance, given that it has been recognized that up to 3% of older individuals have a serum TSH concentration that is below the healthy reference interval for younger people (subclinical hyperthyroidism), and approximately 10% have an elevated serum TSH level (subclinical hypothyroidism) (4–7).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Vanderpump, 2011, The epidemiology of thyroid disease, Br Med Bull source

      Not checked in the free run.

    • cites [5] Somwaru, 2012, The natural history of subclinical hypothyroidism in the elderly: The cardiovascular health study, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [6] Hollowell, 2002, Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III), J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [7] Atzmon, 2009, Extreme longevity is associated with increased serum thyrotropin, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Elevated serum TSH is associated with adverse cardiac outcomes, including myocardial infarction, heart failure, and mortality.

    “Similarly, several studies have found an association of elevated serum TSH with adverse cardiac outcomes, including myocardial infarction (MI), heart failure, and mortality (8, 10, 21–24).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [8] Hak, 2000, Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study, Ann Intern Med source

      Not checked in the free run.

    • cites [10] Razvi, 2010, The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: Reanalysis of the Whickham Survey cohort, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [21] Walsh, 2005, Subclinical thyroid dysfunction as a risk factor for cardiovascular disease, Arch Intern Med source

      Not checked in the free run.

    • cites [22] Imaizumi, 2004, Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [23] Gencer, 2012, Subclinical thyroid dysfunction and the risk of heart failure events: An individual participant data analysis from 6 prospective cohorts, Circulation source

      Not checked in the free run.

    • cites [24] Rodondi, 2010, Subclinical hypothyroidism and the risk of coronary heart disease and mortality, JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A low serum TSH level was first associated with an increased risk of atrial fibrillation.

    “Twenty years ago, a low serum TSH level was first associated with an increased risk of atrial fibrillation (AF) (12)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Sawin, 1994, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Serum reverse T3 was assayed in duplicate by RIA using antiserum 3684 at a final dilution of 1:600 000 and sample volumes of 25 μL.

    “Serum reverse T3 (rT3) was assayed in duplicate by RIA, using antiserum 3684 at a final dilution of 1:600 000 and sample volumes of 25 μL, as described (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Visser, 1977, Radioimmunoassay of reverse tri-iodothyronine, J. Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Mild biochemical abnormalities of thyroid function are common with increasing age but their significance remains unclear, particularly in the very old.

    “Thus, mild biochemical abnormalities of thyroid function are common with increasing age but their significance remains unclear, particularly in the very old.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from subjects in advanced old age is scarce and the finding of a favorable outcome with high serum TSH has not been confirmed.

    “However, data from subjects in advanced old age is scarce and this finding has not been confirmed (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Waring, 2012, Longitudinal changes in thyroid function in the oldest old and survival: The cardiovascular health study all-stars study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A low serum TSH concentration is associated with a higher rate of cardiovascular events, osteoporotic fracture, dementia, and death.

    “Similarly, longitudinal studies have shown that a low serum TSH concentration is associated with a higher rate of cardiovascular events, osteoporotic fracture, dementia, and death (14, 17–20).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [14] Vadiveloo, 2011, The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in patients with endogenous subclinical hyperthyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [17] Parle, 2001, Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study, Lancet source

      Not checked in the free run.

    • cites [18] Blum, 2015, Subclinical thyroid dysfunction and fracture risk: A meta-analysis, JAMA source

      Not checked in the free run.

    • cites [19] Collet, 2012, Subclinical hyperthyroidism and the risk of coronary heart disease and mortality, Arch Intern Med source

      Not checked in the free run.

    • cites [20] Gan, 2012, Clinical review: The thyroid in mind: Cognitive function and low thyrotropin in older people, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    After excluding participants on thyroid medication or medication interfering with thyroid function and one participant with hypopituitarism, 643 participants remained with mortality outcome documented until January 1, 2015.

    “An additional 116 were excluded as they were on thyroid medication or medication interfering with thyroid function (levothyroxine, antithyroid drugs, amiodarone, lithium, corticosteroids). One additional participant was excluded because she was diagnosed with hypopituitarism as part of the study assessments, leaving 643 participants whose mortality outcome was documented until January 1, 2015.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The heterogeneity in findings on elevated serum TSH and adverse cardiac outcomes may be due to differences between populations or confounding by comorbidities, medications, methodology, or other unknown factors.

    “suggesting that there may be heterogeneity between the populations studied, or confounding by comorbidities, medications, methodology or other unknown factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The recruited cohort was sociodemographically representative of the general United Kingdom population and included institutionalized older adults.

    “The recruited cohort was sociodemographically representative of the general United Kingdom population and included institutionalized older adults (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Collerton, 2009, Health and disease in 85 year olds: Baseline findings from the Newcastle 85+ cohort study, BMJ source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Measurement of TSH, FT4, and FT3 was performed using a Centaur platform with intra-assay coefficients of variation of 3.8% for TSH, 7.9% for FT4, and 3.1% for FT3.

    “Measurement of TSH, FT4, and FT3 was performed using a Centaur platform (Seimens). Intra-assay coefficients of variation were serum TSH, 3.8% (at 5.3 mU/L); FT4, 7.9% (at 13.5 pmol/L) and FT3, 3.1% (at 10.5 pmol/L).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The proportional hazards assumption was tested by examining the Schoenfeld residuals.

    “The proportional hazards assumption was tested by examining the Schoenfeld residuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    These data strengthen the argument for routine use of age-specific thyroid function reference ranges.

    “These data strengthen the argument for routine use of age-specific thyroid function reference ranges.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In cohort studies, subclinical hyperthyroidism or lower serum TSH have been associated with many involutional disease states including dementia, osteoporosis, AF, muscle weakness, low bone density, and fracture.

    “in cohort studies, subclinical hyperthyroidism or lower serum TSH have been associated with many involutional disease states including dementia, osteoporosis, AF, muscle weakness, low bone density, and fracture (12–14, 18, 20, 48, 49).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [12] Sawin, 1994, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons, N Engl J Med source

      Not checked in the free run.

    • cites [13] Cappola, 2006, Thyroid status, cardiovascular risk, and mortality in older adults, JAMA source

      Not checked in the free run.

    • cites [14] Vadiveloo, 2011, The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in patients with endogenous subclinical hyperthyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [18] Blum, 2015, Subclinical thyroid dysfunction and fracture risk: A meta-analysis, JAMA source

      Not checked in the free run.

    • cites [20] Gan, 2012, Clinical review: The thyroid in mind: Cognitive function and low thyrotropin in older people, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [48] Kalmijn, 2000, Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [49] Brennan, 2006, The impact of overt and subclinical hyperthyroidism on skeletal muscle, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An elevated serum TSH may be positively associated with longevity and favorable outcomes in the very old.

    “This finding, along with the results of familial studies of the oldest old (7, 38), suggests that an elevated serum TSH may be positively associated with longevity and favorable outcomes in the very old.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Atzmon, 2009, Extreme longevity is associated with increased serum thyrotropin, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [38] Jansen, 2015, Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fasting, cold exposure, and even minor infective or inflammatory disease are sufficient to reduce serum FT3 and elevate rT3 in otherwise-healthy individuals.

    “Indeed, fasting, cold exposure, and even minor infective or inflammatory disease are sufficient to reduce serum FT3 and elevate rT3 in otherwise-healthy individuals (44, 45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Spencer, 1983, Dynamics of serum thyrotropin and thyroid hormone changes in fasting, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [45] de Vries, 2015, The molecular basis of the non-thyroidal illness syndrome, J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    There are a relatively low number of participants with subclinical or overt hyperthyroidism in this study (24 in total), so this result is less robust than that for individuals with higher serum TSH concentrations or subclinical hypothyroidism.

    “there are a relatively low number of participants with subclinical or overt hyperthyroidism in this study (24 in total), so this result is less robust than that for individuals with higher serum TSH concentrations or subclinical hypothyroidism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reduced circulating concentration of free T3 is a sensitive marker of ill health.

    “Reduced circulating concentration of free T3 is a sensitive marker of ill health (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] van den Beld, 2005, Thyroid hormone concentrations, disease, physical function, and mortality in elderly men, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [12] Sawin, 1994, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons, N Engl J Med source

      Not checked in the free run.

    • cites [13] Cappola, 2006, Thyroid status, cardiovascular risk, and mortality in older adults, JAMA source

      Not checked in the free run.

    • cites [14] Vadiveloo, 2011, The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in patients with endogenous subclinical hyperthyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [17] Parle, 2001, Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study, Lancet source

      Not checked in the free run.

    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

    • cites [36] Ceresini, 2013, Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: The Aging in the Chianti Area Study, J Am Geriatr Soc source

      Not checked in the free run.

    • cites [37] Ceresini, 2016, Relationship between circulating thyroid-stimulating hormone, free thyroxine, and free triiodothyronine concentrations and 9-year mortality in euthyroid elderly adults, J Am Geriatr Soc source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A longitudinal study of 403 Dutch males age 73-94 years found that a group with higher rT3 but normal FT3 had better performance status than those with lower FT3.

    “This finding is consistent with a longitudinal study of 403 Dutch males age 73–94 years in which a group with higher rT3 but normal FT3 had better performance status than those with lower FT3 (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] van den Beld, 2005, Thyroid hormone concentrations, disease, physical function, and mortality in elderly men, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Our disease count incorporating 17 common conditions is incomplete and serum rT3 is sensitive to uncounted conditions not included in the adjustment.

    “the alternative being that our disease count incorporating 17 common conditions is incomplete and that serum rT3 is sensitive to uncounted conditions not included in the adjustment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [8] Hak, 2000, Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study, Ann Intern Med source

      Not checked in the free run.

    • cites [10] Razvi, 2010, The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: Reanalysis of the Whickham Survey cohort, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [22] Imaizumi, 2004, Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [24] Rodondi, 2010, Subclinical hypothyroidism and the risk of coronary heart disease and mortality, JAMA source

      Not checked in the free run.

    • cites [2] Waring, 2012, Longitudinal changes in thyroid function in the oldest old and survival: The cardiovascular health study all-stars study, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [17] Parle, 2001, Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study, Lancet source

      Not checked in the free run.

    • cites [25] Hyland, 2013, Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: The cardiovascular health study, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

    • cites [36] Ceresini, 2013, Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: The Aging in the Chianti Area Study, J Am Geriatr Soc source

      Not checked in the free run.

    • cites [37] Ceresini, 2016, Relationship between circulating thyroid-stimulating hormone, free thyroxine, and free triiodothyronine concentrations and 9-year mortality in euthyroid elderly adults, J Am Geriatr Soc source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Thyroid function tests predicted disability, with higher serum TSH levels predicting better outcomes.

    “However, thyroid function tests did predict disability, with higher serum TSH levels predicting better outcomes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.
    • Rests on an assumption: A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Models were adjusted for age, sex, education, body mass index, smoking, and disease count.

    “Models were adjusted for age, sex, education, body mass index, smoking, and disease count.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    There may be a bias toward healthier people participating in the cohort.

    “similar to most other longitudinal observational cohort studies, there may be a bias toward healthier people participating.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    We did include participants with advanced frailty living in supervised care and nursing homes as well as those with dementia, so our results should be representative for age-matched populations.

    “Nevertheless, in contrast with most studies of this age group, we did include participants with advanced frailty living in supervised care and nursing homes as well as those with dementia, so our results should be representative for age-matched populations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductreasoning

    These potential limitations, as well as other unknown confounders, may also have influenced the results of our study.

    “Thus, these self-evident potential limitations, as well as other unknown confounders, may also have influenced the results of our study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In advanced old age, lower TSH (and in the unadjusted analysis, lower FT3/higher rT3) correlates with an increasing burden of nonthyroidal disease.

    “suggests that in advanced old age, lower TSH (and in the unadjusted analysis, lower FT3/higher rT3) correlates with an increasing burden of nonthyroidal disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We assessed 17 common comorbid conditions for which we adjusted in our multivariate analyses.

    “In addition, we assessed 17 common comorbid conditions for which we adjusted in our multivariate analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Individuals with sensory impairments may have been under-represented in the cohort.

    “In particular, it seems probable that individuals with sensory impairments may have been under-represented in the cohort.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    This is still the largest study of this kind in this age group, as far as we are aware.

    “However, this is still the largest study of this kind in this age group, as far as we are aware.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [1] Cooper, 2012, Subclinical thyroid disease, Lancet source

      Not checked in the free run.

    • cites [13] Cappola, 2006, Thyroid status, cardiovascular risk, and mortality in older adults, JAMA source

      Not checked in the free run.

    • cites [14] Vadiveloo, 2011, The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in patients with endogenous subclinical hyperthyroidism, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [15] Selmer, 2012, The spectrum of thyroid disease and risk of new onset atrial fibrillation: A large population cohort study, BMJ source

      Not checked in the free run.

    • cites [29] Gussekloo, 2004, Thyroid status, disability and cognitive function, and survival in old age, JAMA source

      Not checked in the free run.

    • cites [41] Biondi, 2015, The 2015 European Thyroid Association Guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism, Eur Thyroid J source

      Not checked in the free run.

    • cites [42] Bahn, 2011, Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists, Endocr Pract source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    There may be other less common yet influential conditions that have not been taken into account.

    “It is possible that there may be other less common yet influential conditions that have not been taken into account.”
    Quote in the paperNot a substantial claim
48 of 48

  • The paper relies on this without support.

    The covariates included in the adjusted models are sufficient to control for confounding of the associations between thyroid hormones and mortality or disability.

    “Models were adjusted for age, sex, education, body mass index, smoking, and disease count.”

  • The paper relies on this without support.

    A single baseline measurement of serum thyroid hormones reflects participants' usual thyroid status.

    “Blood sampling took place between June 2006 and August 2007.”

  • The paper relies on this without support.

    Cause of death recorded from national registration accurately reflects cardiovascular death.

    “Information on date and cause of death (to ICD-10) were provided from linkage with the national registration system.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [132]

    The Discussion (Mortality; page unavailable) notes a hint that higher TSH within the reference range was protective in euthyroid 85-year-olds, but says the association did not persist after adjustment for comorbidities. The Results (Individual serum thyroid parameters; page unavailable) do not support a general survival advantage for low thyroid hormones: lower FT3 was associated with higher mortality, while FT4 had no significant association. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • 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 [104]

  • 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 [104]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Subclinical hypothyroidism percentage does not match the count

    Minor

    Of 643 participants, 79 is 12.29%, or 12.3% to one decimal place, not 12.5%. Table 1 also reports 12.3% for this group.

    Reported 12.5 · recomputed 12.286159

  • Table 2 gives conflicting units for its hazard ratios

    Minor

    The table title describes hazard ratios per unit increase, while its note specifies that they are per standard-deviation increase. Those are different increments for the listed thyroid measures.

2 of 2

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Related

Authors
Pearce, S. H. S., Razvi, S., Yadegarfar, M. E., Martin-Ruiz, C., Kingston, A., Collerton, J., Visser, T. J., Kirkwood, T. B., & Jagger, C.
Affiliations
  • Newcastle University (GB)
  • Erasmus MC (NL)
  • Institute of Health and Society (M.E.Y., C.M.-R., A.K., J.C., T.B.K., C.J.), Newcastle University, Newcastle upon Tyne NE2 4AX, United Kingdom;
Corresponding author
Pearce, Simon H. S.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2016-08-23
Volume
101
Issue
11
Pages
4385-4394
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2016-1935
PMC
PMC5095241
OpenAlex
W2511103514
Semantic Scholar
5bcda42386492b3dfef0f6850be521298e101d61
Cited by
91
References
49
Citations by year
2026: 4 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 13 · 2020: 8 · 2019: 11 · 2018: 13 · 2017: 12 · 2016: 1
FWCI
12.39
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Newcastle University
  • Medical Research Council (G0500997, MR/J50001X/1)
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
thyroid function, oldest old, mortality, disability, reverse T3, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, subclinical hypothyroidism, subclinical hyperthyroidism, all-cause mortality, cardiovascular mortality, disability trajectories
MeSH terms
Aged, 80 and over, Cardiovascular Diseases, Dextrothyroxine, England, Female, Persons with Disabilities, Humans, Longitudinal Studies, Male, Mortality, Reference Values, Thyroid Diseases, Thyroid Function Tests, Thyrotropin, Triiodothyronine, Triiodothyronine, Reverse

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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