Thyroid in older people

 

Thyroid pipeline

In the past two decades researchers of the Theme have performed bench-to-bedside research in the aging thyroid.

Observational clinical data

  • In the Leiden 85-plus Study, a prospective follow-up study in the oldest old, we showed that in the general population older individuals with abnormally high levels of thyrotropin do not experience adverse effects and may have a prolonged life span.
  • In several meta-analyses of the Thyroid Studies Collaboration, initiated by researchers of the Theme, we showed that subclinical hypothyroidism in older persons gives higher risks of negative outcomes (like cardiovascular disease, cognitive decline) only in patients with the highest thyrotropin levels (> 10 µg/l). Since this is a rare laboratory finding in the general population, most older patients with subclinical hypothyroidism do not have increased risks.

Intervention studies

  • In TRUST and IEMO 80-plus RCT’s, both double-blind, randomized, placebo-controlled, parallel-group trials involving persons aged 65 years and over with persisting subclinical hypothyroidism, levothyroxine treatment provided no apparent patient benefits compared to placebo. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older.

Biological studies:

  • In Thyrage, we addressed the hypothesis that inappropriate thyroid hormone action in target cells is a common mechanism underlying age-related degenerative diseases and co-morbidities. Human studies assessed the effect of short-term manipulation of thyroid status on markers of tissue maintenance and repair. We performed challenge studies with a low doses of TSH and T3 in participants from the Leiden Longevity Study. The results from the TSH challenge study indicate that members from long-lived families have a lower thyroidal response to TSH. The results from the T3 challenge study point to similar T3 turnover and similar negative T3 feedback control of TSH secretion in members from long-lived families and controls. After the TSH and T3 challenges, transient increases in markers of bone turnover were observed, as well as a transient increase in IGF-1 and a decrease in cortisol, with similar effects in members of long-lived families and controls. In Mendelian Randomization studies, we found no evidence that genetically determined TSH was associated with Bone Mineral Density, Diabetes or anemia. In a mixed-methods project utilizing both Mendelian randomization and metabolomics data, we found a potentially causal association between TSH and risk of coronary disease and robust associations between thyroid status and an unfavorable lipid profile.

Ongoing projects

Release: This self-controlled trial aims to determine the effects of discontinuation of levothyroxine treatment in older adults. Participants are community-dwelling subjects aged ≥60 years using levothyroxine continuously at a stable dosage of ≤150 µg and a level of thyroid-stimulating hormone (TSH) <10 mU/L. After a control period of 12 weeks, levothyroxine treatment is discontinued gradually guided by their GP. The primary outcome is the proportion of participants withdrawn from levothyroxine while maintaining a free T4 level within the reference range and a TSH level <10 mU/L, 52 weeks after the start of discontinuation.

Restore: Since the clinical relevance of subclinical thyroid disorders in older GP patients is limited, abnormal laboratory tests results may do unnecessarily alarm patients, could lead to unnecessary lab analyses, unnecessary treatment for selected patients and unnecessary use of resources. This highlights the need for a new diagnostic strategy. RESTORE aims to assess the diagnostic value of two new diagnostic testing strategies to identify the least clinically irrelevant abnormal thyroid function test results without missing clinically relevant thyroid disorders that require clinical action (treatment, additional diagnostic tests or follow-up measurements) in GP patients aged 60 years and over.

 

 

Most important references

 

Observational data

  • Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RGJ. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292:2591-9. doi: 10.1001/jama.292.21.2591. (https://jamanetwork.com/journals/jama/fullarticle/199904)
  • Rodondi N, den Elzen WPJ, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MPJ, Newman AB, Cornuz J, Franklyn JA, Westendorp RGJ, Vittinghoff E, Gussekloo J. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304:1365-74. doi: 10.1001/jama.2010.1361. https://jamanetwork.com/journals/jama/fullarticle/186630
  • van Vliet NA, van Heemst D, Almeida OP, Åsvold BO, Aubert CE, Bae JB, Barnes LE, Bauer DC, Blauw GJ, Brayne C, Cappola AR, Ceresini G, Comijs HC, Dartigues JF, Degryse JM, Dullaart RPF, van Eersel MEA, den Elzen WPJ, Ferrucci L, Fink HA, Flicker L, Grabe HJ, Han JW, Helmer C, Huisman M, Ikram MA, Imaizumi M, de Jongh RT, Jukema JW, Kim KW, Kuller LH, Lopez OL, Mooijaart SP, Moon JH, Moutzouri E, Nauck M, Parle J, Peeters RP, Samuels MH, Schmidt CO, Schminke U, Slagboom PE, Stordal E, Vaes B, Völzke H, Westendorp RGJ, Yamada M, Yeap BB, Rodondi N, Gussekloo J, Trompet S. Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis. JAMA Intern Med. 2021;181:1440-1450. doi: 10.1001/jamainternmed.2021.5078. PMID: 34491268 Free PMC article. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2783799
  • Incidence and Determinants of Spontaneous Normalization of Subclinical Hypothyroidism in Older Adults. van der Spoel E, van Vliet NA, Poortvliet RKE, Du Puy RS, den Elzen WPJ, Quinn TJ, Stott DJ, Sattar N, Kearney PM, Blum MR, Alwan H, Rodondi N, Collet TH, Westendorp RGJ, Ballieux BE, Jukema JW, Dekkers OM, Gussekloo J, Mooijaart SP, van Heemst D. J Clin Endocrinol Metab 2024;109:e1167-e1174. doi: 10.1210/clinem/dgad623. https://academic.oup.com/jcem/article/109/3/e1167/7325863

Intervention data

  • Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, Kean S, Kelly M, Krebs D, Langhorne P, McCarthy G, McCarthy V, McConnachie A, McDade M, Messow M, O’Flynn A, O’Riordan D, Poortvliet RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland A, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3. https://www.nejm.org/doi/10.1056/NEJMoa1603825?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
  • Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RGJ, den Elzen WPJ, Postmus I, Poortvliet RKE, van Heemst D, van Munster DC, Peeters RP, Ford I, Kean S, Messow C, Blum MR, Collet TH, Watt T, Dekkers OM, Jukema JW, Smit JWA, Langhorne P, Gussekloo J. Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. 2019;322:1977-1986. doi: 10.1001/jama.2019.17274. (https://jamanetwork.com/journals/jama/fullarticle/2753909)
  • Ravensberg J, Poortvliet RKE, Du Puy R, Rodondi N, Blum M, Kearney P, McCarthy VJC, Quinn T, Dekkers O, Jukema JW, Mooijaart SM, Gussekloo J. Patient-Reported Satisfaction with Thyroid Hormone Replacement Therapy for Subclinical Hypothyroidism in Older Adults: A Pooled Analysis of Individual Participant Data from Two Randomized Controlled Trials. Thyroid 2024;34:702-712. doi: 10.1089/thy.2023.0624. Epub 2024 May 3. https://www.liebertpub.com/doi/10.1089/thy.2023.0624?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Biological data

  • Van Heemst, D. The ageing thyroid: implications for longevity and patient care. Nat Rev Endocrinol. 2024;20:5-15. doi: 10.1038/s41574-023-00911-7. Epub 2023 Nov 3. https://www.nature.com/articles/s41574-023-00911-7
  • van Vliet NA, Bos MM, Thesing CS, Chaker L, Pietzner M, Houtman E, Neville MJ, Li-Gao R, Trompet S, Mustafa R, Ahmadizar F, Beekman M, Bot M, Budde K, Christodoulides C, Dehghan A, Delles C, Elliott P, Evangelou M, Gao H, Ghanbari M, van Herwaarden AE, Ikram MA, Jaeger M, Jukema JW, Karaman I, Karpe F, Kloppenburg M, Meessen JMTA, Meulenbelt I, Milaneschi Y, Mooijaart SP, Mook-Kanamori DO, Netea MG, Netea-Maier RT, Peeters RP, Penninx BWJH, Sattar N, Slagboom PE, Suchiman HED, Völzke H, Willems van Dijk K, Noordam R, van Heemst D; BBMRI Metabolomics Consortium. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling. BMC Med. 2021 Nov 3;19(1):266
  • Zutinic A, Pijl H, Ballieux BE, Roelfsema F, Westendorp RGJ, Blauw GJ, van Heemst D. Familial Longevity is Associated with an Attenuated Thyroidal Response to Recombinant Human Thyroid Stimulating Hormone. J Clin Endocrinol Metab. 2020 Jul 1;105(7):e2572-80