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Cited by 73Thyroid Disorders and TreatmentsClinical Laboratory Practices and Quality ControlHormonal and reproductive studies

Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice

Open access
Taylor, Peter N., Lansdown, Andrew, Witczak, Justyna, Khan, Rahim, Rees, Aled, Dayan, Colin M., Okosieme, Onyebuchi·2023·Thyroid Research
DOI 10.1186/s13044-023-00149-5PMC PMC10069079
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Abstract

Background: Thyroid hormones are key determinants of health and well-being. Normal thyroid function is defined according to the standard 95% confidence interval of the disease-free population. Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age. However, thyroid hormones vary with age and current reference intervals may not be appropriate across all age groups. In this review, we summarize the recent literature on age-related variation in thyroid function and discuss important implications of such variation for research and clinical practice. Main text: There is now substantial evidence that normal thyroid status changes with age throughout the course of life. Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations. Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass. Furthermore, the aging process exerts differential effects on the health consequences of thyroid hormone variations. Older individuals with declining thyroid function appear to have survival advantages compared to individuals with normal or high-normal thyroid function. In contrast younger or middle-aged individuals with low-normal thyroid function suffer an increased risk of adverse cardiovascular and metabolic outcomes while those with high-normal function have adverse bone outcomes including osteoporosis and fractures. Conclusion: Thyroid hormone reference intervals have differential effects across age groups. Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups. Further studies are now needed to determine the validity of age-appropriate reference intervals and to understand the impact of thyroid hormone variations in younger individuals.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes evidence that thyroid function varies substantially across life, with higher TSH at the extremes of age, falling FT3 with age, and differential health consequences of thyroid hormone variation in younger versus older individuals. It argues that current adult reference intervals may misclassify children and older adults and calls for age-appropriate reference intervals and further research.

Key findings

  • In iodine-sufficient Caucasian populations, TSH shows a U-shaped longitudinal trend, being higher at the extremes of life; FT3 falls with age and appears to play a role in pubertal development.
  • Applying adult reference ranges to children misclassified TSH as abnormal or normal in 3–6% of the population in two longitudinal studies; adult FT3 reference ranges would have misclassified 35% of 12-year-old girls and 58% of 14-year-old boys as high.
  • In older individuals, the TSH distribution shifts right, with NHANES III reporting a 97.5th centile exceeding 7.0 mIU/L in those aged over 80 years; one analysis estimated that 70% of older patients with TSH above the laboratory reference interval had values within their age-specific reference brackets.
  • Declining thyroid function in older individuals appears associated with survival advantages, whereas younger or middle-aged individuals with low-normal thyroid function have increased adverse cardiovascular and metabolic outcomes and those with high-normal function have adverse bone outcomes including osteoporosis and fractures.

Methods

  • Narrative review of the literature, searching PubMed with keywords including thyroid function, TSH, FT4, FT3, TT4, TT3 reference range, reference interval, children, adolescents, aging, and elderly.
  • Included relevant English-language articles published between January 2000 and February 2021, preferring original studies, observational studies, clinical trials, and meta-analyses that shaped knowledge on age-related variation in thyroid function.
  • Pregnancy-related thyroid status and ideal population/trimester reference ranges were excluded as beyond scope.

Limitations

  • The paper states that changes to thyroid status and ideal population and trimester reference ranges are beyond its scope and are covered elsewhere.
  • The paper notes that discrepancies among studies may relate to cohort selection, analytical factors, iodine nutrition, and genetic characteristics, and that observational associations are prone to unmeasured or residual confounding and reverse causation.
  • Evident from the text: as a narrative review, it does not report a systematic search, formal quality appraisal, or meta-analysis, and many cited studies are cross-sectional or observational with heterogeneous assays and populations.

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

Integrity signals

Registry

Crossref · 10.1186/s13044-023-00149-5

Cites

120 of 120 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 162 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Applying adult reference ranges to children in both longitudinal studies would have misclassified TSH as either abnormal or normal in 3-6% of the population.

    “Applying the adult reference ranges to children in both studies would have misclassified TSH as either abnormal or normal in 3-6% of the population [32, 42].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

    • cites [42] Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020;105(4). source

      Not checked in the free run.

  • Findingcitation

    In the ALSPAC study, TSH levels rose from age 7 to 15 years in 884 participants.

    “In the first of these studies, we reported a rise in TSH levels from age 7 to 15 years in 884 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • Findingcitation

    In the Brisbane Longitudinal Twin study, FT4 increased from age 14 to 16 years in both sexes.

    “FT4 on the other hand increased from age 14 to 16 years in both sexes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020;105(4). source

      Not checked in the free run.

  • Findingcitation

    A Mendelian Randomization study in the ALSPAC cohort identified that higher levels of fat mass appeared to result in higher levels of FT3, particularly in younger children.

    “Intriguingly, a Mendelian Randomization study in our cohort identified that higher levels of fat mass appeared to result in higher levels of FT3 particularly in younger children [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Taylor PN, Richmond R, Davies N, Sayers A, Stevenson K, Woltersdorf W, et al. Paradoxical relationship between body mass index and thyroid hormone levels: a study using Mendelian randomization. J Clin Endocrinol Metab. 2016;101(2):730–8. source

      Not checked in the free run.

  • Interpretationreasoning

    Current reference ranges could potentially lead to inappropriate treatment in older individuals.

    “Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups.”
    Quote in the paperSubstantial claim
  • May combine two claims. 50
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingcitation

    In the Brisbane Longitudinal Twin study, there was no change in TSH concentration from age 12 to 14 years but a subsequent increase from 14 to 16 years.

    “The study reported no change in TSH concentration from age 12 to 14 years but with a subsequent increase from 14 to 16 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020;105(4). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the ALSPAC study, TSH level was higher in boys than in girls, but there was no difference in the slope of increase between the sexes.

    “In addition, we found a higher TSH level in boys than in girls but with no difference in the slope of increase between the sexes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Application of the adult FT3 reference range would have misclassified 35% of 12-year-old girls and 58% of 14-year-old boys as high.

    “Application of the adult FT3 reference range would have misclassified 35% of 12-year-old girls and 58% of 14-year-old boys as high [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020;105(4). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the ALSPAC cohort, at age 7 children had a higher FT3 than children at age 15, and 23% of children at age 7 had FT3 above the adult reference-range.

    “At age 7 children had a higher FT3 than children at age 15, and 23% of children at age 7 had FT3 above the adult reference-range.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the ALSPAC cohort, girls had a higher baseline FT3 than boys and a greater slope of decline.

    “Girls had a higher baseline FT3 than boys and a greater slope of decline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the ALSPAC cohort, both FT3 and FT4 had greater variability at age 7 compared to age 15 years, with convergence towards the adult reference ranges with age.

    “In both hormones there was greater variability at age 7 compared to age 15 years with convergence towards the adult reference ranges with age [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the ALSPAC data, higher FT3 levels at age 7 in boys and girls were associated with attainment of a more advanced pubertal stage at age 13, but no clear effect was seen with TSH and FT4.

    “In our data, higher FT3 levels at age 7 in boys and girls were associated with attainment of a more advanced pubertal stage at age 13, but no clear effect was seen with TSH and FT4 [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the Brisbane Longitudinal Twin study, FT3 in girls showed minimal change from 12 to 14 years and then declined sharply from 14 to 16 years, whereas in boys it increased from age 12 to 14 and decreased by age 16 years.

    “In the study by Campbell et al, FT3 in girls showed minimal change from 12 to 14 years and then declined sharply from 14 to 16 years whereas in boys it increased from age 12 to 14 and decreased by age 16 years [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Campbell PJ, Brown SJ, Kendrew P, Lewer M, Lim EM, Joseph J, et al. Changes in thyroid function across adolescence: a longitudinal study. J Clin Endocrinol Metab. 2020;105(4). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the ALSPAC cohort, FT4 at age 7 years was slightly higher than at 15 years and was higher in girls compared to boys.

    “FT4 at age 7 years was slightly higher than at 15 years and was higher in girls compared to boys.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSH concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations.

    “Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. 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. 2002;87(2):489–99. source

      Not checked in the free run.

    • cites [16] Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575–82. source

      Not checked in the free run.

    • cites [17] Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). J Clin Endocrinol Metab. 2013;98(3):1147–53. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyroid hormone levels are largely genetically determined, with similar genetic effects observed in children and adults.

    “Furthermore, thyroid hormone levels are largely genetically determined [6–8] with similar genetic effects observed in children and adults [8].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol. 2008;68(4):652–9. source

      Not checked in the free run.

    • cites [7] Teumer A, Chaker L, Groeneweg S, Li Y, Di Munno C, Barbieri C, et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat Commun. 2018;9(1):4455. source

      Not checked in the free run.

    • cites [8] Taylor PN, Porcu E, Chew S, Campbell PJ, Traglia M, Brown SJ, et al. Whole-genome sequence-based analysis of thyroid function. Nat Commun. 2015;6:5681. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Indian children of a similar age group, FT3 and FT4 showed an inverse association with age, although this relationship was only significant in girls.

    “In Indian children of a similar age group FT3 and FT4 also showed an inverse association with age, although this relationship was only significant in girls [47, 48].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Marwaha RK, Tandon N, Desai A, Kanwar R, Grewal K, Aggarwal R, et al. Reference range of thyroid hormones in normal Indian school-age children. Clin Endocrinol. 2008;68(3):369–74. source

      Not checked in the free run.

    • cites [48] Marwaha RK, Tandon N, Desai AK, Kanwar R, Aggarwal R, Sastry A, et al. Reference range of thyroid hormones in healthy school-age children: country-wide data from India. Clin Biochem. 2010;43(1-2):51–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous cross-sectional studies have indicated that FT3 falls and FT4 rises from age 4 years.

    “Previous cross-sectional studies have indicated that free triiodothyronine (FT3) falls and FT4 rises from age 4 years [43–45].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Kulasingam V, Jung BP, Blasutig IM, Baradaran S, Chan MK, Aytekin M, et al. Pediatric reference intervals for 28 chemistries and immunoassays on the Roche cobas 6000 analyzer--a CALIPER pilot study. Clin Biochem. 2010;43(13-14):1045–50. source

      Not checked in the free run.

    • cites [44] Marwaha RK, Tandon N, Desai AK, Kanwar R, Sastry A, Narang A, et al. The evolution of thyroid function with puberty. Clin Endocrinol. 2012;76(6):899–904. source

      Not checked in the free run.

    • cites [45] Strich D, Edri S, Gillis D. Current normal values for TSH and FT3 in children are too low: evidence from over 11,000 samples. J Pediatr Endocrinol Metab. 2012;25(3-4):245–8. source

      Not checked in the free run.

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

    Premisecitation

    The prevalence of hypothyroidism in the UK increased 50% from 2.3 to 3.5% between 2005 and 2014.

    “the prevalence of hypothyroidism in the UK increased 50% from 2.3 to 3.5% between 2005 and 2014 [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Razvi S, Korevaar TIM, Taylor P. Trends, determinants, and associations of treated hypothyroidism in the United Kingdom, 2005-2014. Thyroid. 2019;29(2):174–82. source

      Not checked in the free run.

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

    Premisecitation

    In some studies, TSH concentration was higher in boys than in girls.

    “In some studies, TSH concentration was higher in boys than in girls [38]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Tozzoli R, D'Aurizio F, Metus P, Steffan A, Mazzon C, Bagnasco M. Reference intervals for thyrotropin in an area of northern Italy: the Pordenone thyroid study (TRIPP). J Endocrinol Investig. 2018;41(8):985–94. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cross-sectional studies generally show higher TSH upper limits in younger children (<5 years) compared to older children, with a gradual decline in TSH concentration as adult age is approached.

    “Cross-sectional studies generally show higher TSH upper limits in younger children (< 5 years) compared to older children, with a gradual decline in TSH concentration as the adult age is approached [33, 36–39].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [33] Kapelari K, Kirchlechner C, Hogler W, Schweitzer K, Virgolini I, Moncayo R. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord. 2008;8:15. source

      Not checked in the free run.

    • cites [36] Önsesveren I, Barjaktarovic M, Chaker L, de Rijke YB, Jaddoe VWV, van Santen HM, et al. Childhood thyroid function reference ranges and determinants: a literature overview and a prospective cohort study. Thyroid. 2017;27(11):1360–9. source

      Not checked in the free run.

    • cites [37] Argente Del Castillo P, Pastor García MI, Morell-Garcia D, Martinez-Gomez L, Ballesteros MA, Barcelo A. Thyroid panel reference intervals in healthy children and adolescents: a Spanish cohort. Clin Biochem. 2021. source

      Not checked in the free run.

    • cites [38] Tozzoli R, D'Aurizio F, Metus P, Steffan A, Mazzon C, Bagnasco M. Reference intervals for thyrotropin in an area of northern Italy: the Pordenone thyroid study (TRIPP). J Endocrinol Investig. 2018;41(8):985–94. source

      Not checked in the free run.

    • cites [39] Lim HH. Korean pediatric reference intervals for FT4, TSH, and TPO Ab and the prevalence of thyroid dysfunction: a population-based study. Clin Biochem. 2017;50(18):1256–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TSH threshold for levothyroxine initiation has been falling in recent years, with many older individuals increasingly started on Levothyroxine at borderline TSH levels.

    “the TSH threshold for levothyroxine initiation has been falling in recent years with many older individuals increasingly started on Levothyroxine at borderline TSH levels [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med. 2014;174(1):32–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A systematic review of reference range studies in children showed TSH upper limit ranges as wide as 2.36-6.45 mIU/L in 11-20-year-olds, with FT4 lower and upper limits of 7.0-14.2 and 15.5-31.5 pmol/L, respectively.

    “A systematic review of reference range studies in children showed TSH upper limit ranges as wide as 2.36–6.45 mIU/L in 11–20-year-olds with free thyroxine (FT4) lower and upper limits of 7.0–14.2 and 15.5–31.5 pmol/L, respectively [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Önsesveren I, Barjaktarovic M, Chaker L, de Rijke YB, Jaddoe VWV, van Santen HM, et al. Childhood thyroid function reference ranges and determinants: a literature overview and a prospective cohort study. Thyroid. 2017;27(11):1360–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSH showed ethnic-related variation, being higher in Caucasian children compared to children of African descent or in Jewish versus non-Jewish children.

    “showed ethnic-related variation. For example, TSH was higher in Caucasian children compared to children of African descent [36] or in Jewish versus non-Jewish children [41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Önsesveren I, Barjaktarovic M, Chaker L, de Rijke YB, Jaddoe VWV, van Santen HM, et al. Childhood thyroid function reference ranges and determinants: a literature overview and a prospective cohort study. Thyroid. 2017;27(11):1360–9. source

      Not checked in the free run.

    • cites [41] Oron T, Lazar L, Feldhamer I, Manor M, Koren-Morag N, Tenenbaum A, et al. Pediatric reference values of TSH should be personalized according to BMI and ethnicity. Eur J Endocrinol. 2020;183(4):419–26. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypothyroidism is common globally and increases in prevalence with age.

    “hypothyroidism is common globally and increases in prevalence with age [22, 23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14(5):301–16. source

      Not checked in the free run.

    • cites [23] Chaker L, Cappola AR, Mooijaart SP, Peeters RP. Clinical aspects of thyroid function during ageing. Lancet Diab Endocrinol. 2018;6(9):733–42. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Variation in thyroid function within the normal population reference range in children is associated with negative effects on blood pressure, lipid metabolism, and pubertal development.

    “variation in thyroid function within the normal population reference range in children is associated with negative effects on important outcomes such as blood pressure [30] lipid metabolism [31], and pubertal development [32].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Ittermann T, Thamm M, Wallaschofski H, Rettig R, Volzke H. Serum thyroid-stimulating hormone levels are associated with blood pressure in children and adolescents. J Clin Endocrinol Metab. 2012;97(3):828–34. source

      Not checked in the free run.

    • cites [31] Witte T, Ittermann T, Thamm M, Riblet NB, Volzke H. Association between serum thyroid-stimulating hormone levels and serum lipids in children and adolescents: a population-based study of german youth. J Clin Endocrinol Metab. 2015;100(5):2090–7. source

      Not checked in the free run.

    • cites [32] Taylor PN, Sayers A, Okosieme O, Das G, Draman MS, Tabasum A, et al. Maturation in serum thyroid function parameters over childhood and puberty: results of a longitudinal study. J Clin Endocrinol Metab. 2017;102(7):2508–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a population-based Danish cohort of 2411 healthy 6-19-year-old children, median values of FT4 and FT3 fell with increasing age for both sexes, with the decline most pronounced around puberty, age 11-15 years.

    “In a population-based Danish cohort of 2411 healthy 6–19-year-old children, median values of FT4 and FT3 fell with increasing age for both sexes with the decline most pronounced around the time of puberty, age 11-15 years [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Gunapalasingham G, Frithioff-Bøjsøe C, Lund MAV, Hedley PL, Fonvig CE, Dahl M, et al. Reference values for fasting serum concentrations of thyroid-stimulating hormone and thyroid hormones in healthy Danish/north-European white children and adolescents. Scand J Clin Lab Invest. 2019;79(1-2):129–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher TSH levels within the reference-range were associated with higher all cause and cardiovascular mortality.

    “In addition, higher TSH levels within the reference-range were associated with higher all cause [63] and cardiovascular mortality [63, 64].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Inoue K, Tsujimoto T, Saito J, Sugiyama T. Association between serum Thyrotropin levels and mortality among Euthyroid adults in the United States. Thyroid. 2016;26(10):1457–65. source

      Not checked in the free run.

    • cites [64] Asvold BO, Bjoro T, Nilsen TI, Gunnell D, Vatten LJ. Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. Arch Intern Med. 2008;168(8):855–60. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These studies were undertaken in samples with predominantly middle-aged participants and so will not be applicable to older individuals for whom a differential impact of thyroid function on health outcomes has been observed in the euthyroid population.

    “Also, these studies were undertaken in samples with predominantly middle-aged participants and so will not be applicable to older individuals for whom a differential impact of thyroid function on health outcomes has been observed in the euthyroid population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Lowering the TSH upper limit would classify 15-20% of the elderly population as subclinical hypothyroidism, a condition for which treatment benefits are unproven.

    “Thus, lowering the TSH upper limit would classify 15–20% of the elderly population as subclinical hypothyroidism, a condition for which treatment benefits are unproven [55].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005;90(9):5489–96. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The effect of fat mass on FT3 is less apparent in older children and may be diminished in adults.

    “This effect was less apparent in older children and may be diminished in adults.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Taylor PN, Richmond R, Davies N, Sayers A, Stevenson K, Woltersdorf W, et al. Paradoxical relationship between body mass index and thyroid hormone levels: a study using Mendelian randomization. J Clin Endocrinol Metab. 2016;101(2):730–8. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The meta-analysis included a significant proportion of elderly participants (mean age > 65 years) with mild TSH elevations which may reflect the aging process rather than intrinsic thyroid disease.

    “However, the meta-analysis included a significant proportion of elderly participants (mean age > 65 years) with mild TSH elevations which may reflect the aging process rather than intrinsic thyroid disease [18, 57].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RG, Mooijaart SP, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534–44. https://doi.org/10.1056/NEJMoa1603825. Epub 2017 Apr 3. source

      Not checked in the free run.

    • cites [57] Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham elderly thyroid study. J Clin Endocrinol Metab. 2010;95(8):3623–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obese adults often have higher FT3 levels and a higher FT3:FT4 ratio than the general population.

    “a similar effect is still observed in obese adults who often have higher FT3 levels and a higher FT3:FT4 ratio than the general population [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Xu R, Huang F, Zhang S, Lv Y, Liu Q. Thyroid function, body mass index, and metabolic risk markers in euthyroid adults: a cohort study. BMC Endocr Disord. 2019;19(1):58. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher TSH levels were associated with increased BMI, and in longitudinal studies, individuals with rising TSH levels over time exhibited greater weight gain.

    “Higher TSH levels were associated with increased BMI [65, 66], and in longitudinal studies, individuals with rising TSH levels over time exhibited greater weight gain [67, 68].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [65] Knudsen N, Laurberg P, Rasmussen LB, Bulow I, Perrild H, Ovesen L, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab. 2005;90(7):4019–24. source

      Not checked in the free run.

    • cites [66] Asvold BO, Bjoro T, Vatten LJ. Association of serum TSH with high body mass differs between smokers and never-smokers. J Clin Endocrinol Metab. 2009;94(12):5023–7. source

      Not checked in the free run.

    • cites [67] Fox CS, Pencina MJ, D'Agostino RB, Murabito JM, Seely EW, Pearce EN, et al. Relations of thyroid function to body weight: cross-sectional and longitudinal observations in a community-based sample. Arch Intern Med. 2008;168(6):587–92. source

      Not checked in the free run.

    • cites [68] Svare A, Nilsen TI, Bjoro T, Asvold BO, Langhammer A. Serum TSH related to measures of body mass: longitudinal data from the HUNT study, Norway. Clin Endocrinol. 2011;74(6):769–75. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-normal TSH was associated with adverse cardiovascular and metabolic outcomes, whereas low-normal TSH was associated with adverse bone outcomes.

    “In essence, high-normal TSH, was associated with adverse cardiovascular and metabolic outcomes whereas low-normal TSH was associated with adverse bone outcomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Taylor PN, Razvi S, Pearce SH, Dayan CM. A review of the clinical consequences of variation in thyroid function within the reference range. J Clin Endocrinol Metab. 2013;98(9):3562–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher levels of TSH were associated with worsening of both blood pressure and lipid levels, although these effects were modest.

    “In particular higher levels of TSH were associated with worsening of both blood pressure [58–60] and lipid levels [61, 62] although these effects were modest.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [58] Iqbal A, Figenschau Y, Jorde R. Blood pressure in relation to serum thyrotropin: the Tromso study. J Hum Hypertens. 2006;20(12):932–6. source

      Not checked in the free run.

    • cites [59] Asvold BO, Bjoro T, Nilsen TI, Vatten LJ. Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range: a population-based study. J Clin Endocrinol Metab. 2007;92(3):841–5. source

      Not checked in the free run.

    • cites [60] He W, Li S, Wang B, Mu K, Shao X, Yao Q, et al. Dose-response relationship between thyroid stimulating hormone and hypertension risk in euthyroid individuals. J Hypertens. 2019;37(1):144–53. source

      Not checked in the free run.

    • cites [61] Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT study. Eur J Endocrinol. 2007;156(2):181–6. source

      Not checked in the free run.

    • cites [62] Lee YK, Kim JE, Oh HJ, Park KS, Kim SK, Park SW, et al. Serum TSH level in healthy Koreans and the association of TSH with serum lipid concentration and metabolic syndrome. Kor J Intern Med. 2011;26(4):432–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lower TSH levels and higher levels of FT4 within the population reference-range are associated with increased risk of developing osteoporosis and suffering subsequent fractures in post-menopausal women.

    “Similar cross-sectional analyses have identified that lower TSH levels and higher levels of FT4 within the population reference-range are associated with increased risk of developing osteoporosis [70–73] and suffering subsequent fractures [71, 74] in post-menopausal women.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [70] Morris MS. The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal American women. Bone. 2007;40(4):1128–34. source

      Not checked in the free run.

    • cites [71] Murphy E, Gluer CC, Reid DM, Felsenberg D, Roux C, Eastell R, et al. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab. 2010;95(7):3173–81. source

      Not checked in the free run.

    • cites [72] Kim BJ, Lee SH, Bae SJ, Kim HK, Choe JW, Kim HY, et al. The association between serum thyrotropin (TSH) levels and bone mineral density in healthy euthyroid men. Clin Endocrinol. 2010;73(3):396–403. source

      Not checked in the free run.

    • cites [73] Kim DJ, Khang YH, Koh JM, Shong YK, Kim GS. Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin Endocrinol. 2006;64(1):86–90. source

      Not checked in the free run.

    • cites [74] Mazziotti G, Porcelli T, Patelli I, Vescovi PP, Giustina A. Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral density. Bone. 2010;46(3):747–51. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    These associations are based on observational cross-sectional data and therefore prone to the limitations of unmeasured or residual confounding as well as the possibility of reverse causation.

    “However, it is important to note that these associations are based on observational cross-sectional data and therefore prone to the limitations of unmeasured or residual confounding as well as the possibility of reverse causation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Not all studies have confirmed age-related TSH elevations; studies from Holland, India, Germany, China, Italy, and the UK Whickham community survey failed to show TSH elevations with age.

    “However, not all studies have confirmed these changes. Studies from Holland [89], India [90], Germany [91], China [92] as well as older data from Italy [93] and the UK Whickham community survey failed to show TSH elevations with age.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [89] van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403–9. source

      Not checked in the free run.

    • cites [90] Marwaha RK, Tandon N, Ganie MA, Mehan N, Sastry A, Garg MK, et al. Reference range of thyroid function (FT3, FT4 and TSH) among Indian adults. Clin Biochem. 2013;46(4-5):341–5. source

      Not checked in the free run.

    • cites [91] Volzke H, Alte D, Kohlmann T, Ludemann J, Nauck M, John U, et al. Reference intervals of serum thyroid function tests in a previously iodine-deficient area. Thyroid. 2005;15(3):279–85. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. Jama. 2004;292(21):2591–9. source

      Not checked in the free run.

    • cites [104] Pearce SH, Razvi S, Yadegarfar ME, Martin-Ruiz C, Kingston A, Collerton J, et al. Serum thyroid function, mortality and disability in advanced old age: the Newcastle 85+ study. J Clin Endocrinol Metab. 2016;101(11):4385–94. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These studies show that the reference range becomes wider as age increases, with lower 2.5 centiles in the older age groups.

    “These studies also show that the reference range becomes wider as age increases, with lower 2.5 centiles in the older age groups (Fig. 3).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [15] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. 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. 2002;87(2):489–99. source

      Not checked in the free run.

    • cites [17] Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). J Clin Endocrinol Metab. 2013;98(3):1147–53. source

      Not checked in the free run.

    • cites [87] Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010;95(2):496–502. source

      Not checked in the free run.

    • cites [88] Boucai L, Surks MI. Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin Endocrinol. 2009;70(5):788–93. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Busselton health survey, TSH levels increased after a 13-year period but with no significant change in FT4.

    “The first, a study of 908 individuals in the Busselton health survey, showed that TSH levels increased after a 13-year period but with no significant change in FT4 [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Bremner AP, Feddema P, Leedman PJ, Brown SJ, Beilby JP, Lim EM, et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012;97(5):1554–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Cardiovascular Health Study All-Stars Study, there was a TSH increase of 13%, FT4 increase of 1.7%, and a 13% fall in total T3 concentrations over a 13-year period.

    “The second study was an analysis of thyroid function in the Cardiovascular Health Study All-Stars Study which showed a TSH increase of 13%, FT4 increase of 1.7%, and a 13% fall in total T3 concentrations over a 13-year period [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab. 2012;97(11):3944–50. source

      Not checked in the free run.

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

    Premisecitation

    A study from Western Australia suggested that age-specific TSH reference intervals exerted only a negligible impact on the diagnosis of thyroid dysfunction in the elderly population.

    “A study from Western Australia suggested that age-specific TSH reference intervals exerted only a negligible impact on the diagnosis of thyroid dysfunction in the elderly population [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Kahapola-Arachchige KM, Hadlow N, Wardrop R, Lim EM, Walsh JP. Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. Clin Endocrinol. 2012;77(5):773–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the UK Birmingham Elderly Thyroid Study, TSH was stable over time with 96% of euthyroid individuals (TSH < 4.5 mIU/L) remaining euthyroid at follow up.

    “In a 5-year follow up study of 2936 participants from the UK Birmingham Elderly Thyroid Study, TSH was shown to be stable over time with 96% of euthyroid individuals (TSH < 4.5 mIU/L) remaining euthyroid at follow up [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Roberts L, McCahon D, Johnson O, Haque MS, Parle J, Hobbs FR. Stability of thyroid function in older adults: the Birmingham elderly thyroid study. Br J Gen Pract. 2018;68(675):e718–26. source

      Not checked in the free run.

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

    Premisecitation

    Up to 67% of the circulating TSH and thyroid hormone concentrations are genetically determined, and several candidate genes have been implicated including the genes for phosphodiesterase 8B, DIO1, and the TSH receptor.

    “Regarding genetic factors, up to 67% of the circulating TSH and thyroid hormone concentrations are genetically determined [6] and several candidate genes have been implicated including the genes for phosphodiesterase 8B, DIO1, and the TSH receptor [96].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol. 2008;68(4):652–9. source

      Not checked in the free run.

    • cites [96] Panicker V. Genetics of thyroid function and disease. Clin Biochem Rev. 2011;32(4):165–75.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Rotterdam study, there was no change in TSH but an increase was observed for FT4 concentrations after 6.5 years of follow up.

    “A longitudinal analysis of 9402 participants from the Rotterdam study showed no change in TSH but an increase was observed for FT4 concentrations after 6.5 years of follow up [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Chaker L, Korevaar TI, Medici M, Uitterlinden AG, Hofman A, Dehghan A, et al. Thyroid function characteristics and determinants: the Rotterdam study. Thyroid. 2016;26(9):1195–204. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal studies show negative correlations between thyroid hormone levels and longevity, with the longest survival observed in mice with lower thyroid hormone levels.

    “Animal studies show negative correlations between thyroid hormone levels and longevity, with the longest survival observed in mice with lower thyroid hormone levels [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Bowers J, Terrien J, Clerget-Froidevaux MS, Gothie JD, Rozing MP, Westendorp RG, et al. Thyroid hormone signaling and homeostasis during aging. Endocr Rev. 2013;34(4):556–89. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the absence of age-stratified reference intervals, individuals with age-related changes in TSH could be misdiagnosed as thyroid dysfunction and exposed to potentially harmful treatments.

    “In the absence of age-stratified reference intervals, individuals with age-related changes in TSH could be misdiagnosed as thyroid dysfunction and exposed to potentially harmful treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The hypothalamic pituitary thyroid axis is altered with age and older individuals have been shown to exhibit a blunted TSH response to thyroid hormone deficiency.

    “The hypothalamic pituitary thyroid axis is altered with age and older individuals have been shown to exhibit a blunted TSH response to thyroid hormone deficiency [4, 23].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T(4) in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab. 2013;98(7):2936–43. source

      Not checked in the free run.

    • cites [23] Chaker L, Cappola AR, Mooijaart SP, Peeters RP. Clinical aspects of thyroid function during ageing. Lancet Diab Endocrinol. 2018;6(9):733–42. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Baltimore Longitudinal Study of Aging, mean TSH was higher in older individuals at baseline, but TSH remained stable in the majority of participants.

    “Although mean TSH was higher in older individuals at baseline, the TSH remained stable in the majority of participants.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Mammen JS, McGready J, Ladenson PW, Simonsick EM. Unstable thyroid function in older adults is caused by alterations in both thyroid and pituitary physiology and is associated with increased mortality. Thyroid. 2017;27(11):1370–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Time-related changes in TSH were more common in older individuals, associated with decreased survival, and showed a heterogeneous pattern including progression to primary thyroid disease as well as non-pathological TSH elevations.

    “Time-related changes were more common in older individuals, associated with decreased survival and showed a heterogeneous pattern of change that included progression to primary thyroid disease as well as non-pathological TSH elevations [100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Mammen JS, McGready J, Ladenson PW, Simonsick EM. Unstable thyroid function in older adults is caused by alterations in both thyroid and pituitary physiology and is associated with increased mortality. Thyroid. 2017;27(11):1370–7. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TPO antibody positivity is unlikely to be the sole explanation for higher TSH levels in the elderly, as the NHANES study identified that only 40% of the elderly with a TSH above 4.5 mU/L were TPO antibody positive.

    “TPO antibody positivity is unlikely to tbe the sole explanation for higher TSH levels in the elderly as the NHANES study identified that only 40% of the elderly with a TSH above 4.5 mU/L were TPO antibody positive [16]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575–82. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A study in elderly Dutch men showed no age-related changes in TSH and FT4 but reported lower FT3 levels together with an increase in reverse T3 (rT3) with age.

    “A study in elderly Dutch men showed no age-related changes in TSH and FT4 but reported lower FT3 levels together with an increase in reverse T3 (rT3) with age [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly persons with the lowest TSH tertile at baseline had more concurrent depressive symptoms and were at two-fold increased risk of subsequent depression than those with the highest tertile.

    “In addition, elderly persons with the lowest TSH tertile at baseline had more concurrent depressive symptoms and were at two-fold increased risk of subsequent depression than those with the highest tertile [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Medici M, Direk N, Visser WE, Korevaar TI, Hofman A, Visser TJ, et al. Thyroid function within the normal range and the risk of depression: a population-based cohort study. J Clin Endocrinol Metab. 2014;99(4):1213–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Variation in DIO1 is associated with the FT3:FT4 ratio but not TSH.

    “Genetic association studies using variation in DIO1 which is associated with FT3:FT4 ratio but not TSH [111, 112] may also provide insights.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JR, et al. A common variation in Deiodinase 1 gene DIO1 is associated with the relative levels of free Thyroxine and Triiodothyronine. J Clin Endocrinol Metab. 2008;93(8):3075–81. source

      Not checked in the free run.

    • cites [112] Taylor PN, Panicker V, Sayers A, Shields B, Iqbal A, Bremner AP, et al. A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement. Eur J Endocrinol. 2011;164(5):773–80. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    If the TSH increase in the elderly is beneficial, older individuals may be over-treated by aiming for lower reference range TSH values.

    “If the TSH increase in the elderly is indeed beneficial, then it is plausible that older individuals are over-treated by aiming for lower reference range TSH values.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The TSH increase in the elderly is beneficial.

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

    Interpretationreasoning

    These findings support the need for age-appropriate thyroid hormone reference intervals.

    “These findings support the need for age-appropriate thyroid hormone reference intervals.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Immunoassay platforms are currently the method of choice for the measurement of thyroid function tests.

    “It is worth highlighting that whilst immunoassay platforms are currently the method of choice for the measurement of thyroid function tests [116], there are limitations; as well as macro-TSH, interference from biotin, thyroid hormone autoantibodies, heterophilic antibodies, antistreptavidin antibodies, anti-ruthenium antibodies, and heterophilic antibodies can occur [116].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Favresse J, Burlacu M-C, Maiter D, Gruson D. Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocr Rev. 2018;39(5):830–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunoassay platforms have limitations; interference from biotin, thyroid hormone autoantibodies, heterophilic antibodies, antistreptavidin antibodies, anti-ruthenium antibodies, and heterophilic antibodies can occur.

    “It is worth highlighting that whilst immunoassay platforms are currently the method of choice for the measurement of thyroid function tests [116], there are limitations; as well as macro-TSH, interference from biotin, thyroid hormone autoantibodies, heterophilic antibodies, antistreptavidin antibodies, anti-ruthenium antibodies, and heterophilic antibodies can occur [116].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Favresse J, Burlacu M-C, Maiter D, Gruson D. Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocr Rev. 2018;39(5):830–50. source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    Standard laboratory reference intervals for thyroid function are widely applied in research and clinical practice irrespective of age.

    “Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age.”

  • The paper relies on this without support.

    Most laboratories report a TSH interval between 0.4 and 4.5 mIU/L in the disease-free adult population.

    “Most laboratories report a TSH interval between 0.4 and 4.5 mIU/L in the disease-free adult population.”

  • The authors state this as an assumption.

    The TSH increase in the elderly is beneficial.

    “If the TSH increase in the elderly is indeed beneficial, then it is plausible that older individuals are over-treated by aiming for lower reference range TSH values.”
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?

  • Serum TSH increases at high age.

    “Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”

    From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [11]

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.

  • Rotterdam longitudinal study has two participant counts

    Minor

    The text says the longitudinal analysis included 9402 participants, while Table 2 lists 1225 for the same study.

1 of 1

Cites

Flagged first, then by citations

7 of the 127 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. United Nations. World population prospects. New York: United Nations; 2019.
  2. Taylor PN, Iqbal A, Minassian C, et al. Falling threshold for treatment of borderline elevated thyrotropin levels—balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med. 2013. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Taylor, P. N., Lansdown, A., Witczak, J., Khan, R., Rees, A., Dayan, C. M., & Okosieme, O.
Affiliations
University Hospital of Wales (GB)
Corresponding author
Taylor, Peter N.
ORCID
Venue
Thyroid Research
Publisher
Springer Science and Business Media LLC
Published
2023-04-03
Volume
16
Issue
1
Pages
7-7
ISSN
1756-6614 (ISSN-L)
DOI
10.1186/s13044-023-00149-5
PMC
PMC10069079
OpenAlex
W4362505814
Semantic Scholar
2521c0bd6107d1137075ff17743f46e53a3f14f5
Cited by
72
References
127
Citations by year
2026: 23 · 2025: 25 · 2024: 18 · 2023: 6
FWCI
2.60
Type
journal article
Language
en
Update notices
correction (2023-05-30)
Open access
Licence
Locations
  • Thyroid Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
age-related variation, thyroid function, thyroid-stimulating hormone, free triiodothyronine, aging, pubertal development, fat mass, cardiovascular risk, bone health, osteoporosis, fracture, thyroid hormone replacement

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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