Incidence and Determinants of Spontaneous Normalization of Subclinical Hypothyroidism in Older Adults.
Evie van der Spoel, Nicolien A van Vliet, Rosalinde K E Poortvliet, Robert S Du Puy, Wendy P J den Elzen, Terence J Quinn, David J Stott, Naveed Sattar, Patricia M Kearney, Manuel R Blum, Heba Alwan, Nicolas Rodondi, Tinh-Hai Collet, Rudi G J Westendorp, Bart E Ballieux, J Wouter Jukema, Olaf M Dekkers, Jacobijn Gussekloo, Simon P Mooijaart, Diana van Heemst
Journal: The Journal of clinical endocrinology and metabolism
2024;109(3):e1167-e1174
PMID: 37862463
With increasing age, circulating levels of thyroid stimulating hormone (TSH) generally rise, accompanied by a higher prevalence of subclinical hypothyroidism. Subclinical hypothyroidism is defined as an elevated TSH level while the serum free T4 (fT4) concentration is within the normal range.
The aim of this study was to investigate the incidence of spontaneous normalisation of TSH levels and identify determinants of normalisation in a large group of adults aged 65 years and older with (persistent) subclinical hypothyroidism.
This study was a longitudinal study that pooled data from 2 randomised, double-blind, placebo-controlled parallel-group clinical trials.
Results showed that 60.8% of the older adults with biochemical subclinical hypothyroidism based on at least 1 elevated TSH measurement, TSH levels had returned to the normal range without intervention after a median follow-up of 1 year. Subsequently, TSH levels had still normalised after 1 year in 39.9% of older adults with persistent subclinical hypothyroidism. Younger age, female sex, lower initial TSH level, higher normal initial fT4 level, the absence of thyroid peroxidase antibodies, and a second measurement in summer were independent determinants for TSH normalisation.
Authors concluded that since TSH levels spontaneously normalised in a large proportion of older adults with subclinical hypothyroidism, a third measurement is recommended before considering treatment.
Expert Review
Reviewer: Nicky Ester
25th Feb 2025
Conflict of interest
Take home message
- The paper demonstrates that subclinical hypothyroidism in older adults can resolve naturally and that this should be taken into consideration in their treatment plan.
Evidence category
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
Summary review
Introduction
- As we age the incidence of subclinical hypothyroidism, defined in this study as elevated TSH 4.60-19.99mIU/L with fT4 within normal range, increases.
- The paper aims to pool data from 2 randomised clinical controlled trials to investigate incidence and determinants of spontaneous normalisation of TSH levels in older adults with subclinical hypothyroidism.
Methods
- The paper analyses 2 randomised, double blind, placebo-controlled parallel-group trials on the effect of levothyroxine treatment for subclinical hypothyroidism in older adults.
- One trial by TRUST recruited adults (n=2647) ≥65 years (April 2013- May 2015) from the Netherlands, Switzerland, Ireland and the United Kingdom.
- The second trial, IEMO recruited adults (n=342) ≥80 years (May 2014-May 2017) from the Netherlands and Switzerland.
- Data was pooled from 1) pretrial population and 2) in-trail placebo group.
- The pretrial cohort (baseline) (N=2335) had 2 readings of TSH taken to assess subclinical hypothyroidism, one 3 months to 3 years before trial and one at trial baseline.
- The in-trial cohort (N=361, placebo) had persistently elevated TSH confirmed pre-baseline and baseline, with a follow up TSH measurement taken 300-400 days later to assess if normalisation had occurred.
Results
- In the pretrial, subclinical hypothyroidism (based on at least 1 elevated TSH measure) normalised without intervention, after a median follow-up of 1 year in 1419 of the 2335 participants (60.8%).
- In the in-trial cohort, persistent subclinical hypothyroidism normalised in 144 of 361 participants (39.9%).
- Normalisation was linked to lower age (OR 0.98, P=0.007 and OR 0.96, P=0.05), female sex (OR 1.39, P<0.01 and OR 1.80, P=0.05), lower trial baseline TSH (OR 1.22, P=0.01), lower screening TSH (OR 0.57, P<0.001), higher normal fT4 (OR 1.06, P=0.03) a second measurement in summer (OR 0.59, P<0.001) and absence of TPO antibodies (OR 0.36, P=0.007).
Conclusion
- Subclinical hypothyroidism in older adults can normalise without medical intervention.
- Parameters like lower age, female sex, lower initial TSH, higher initial fT4, and summer follow-up measurements are independently associated with a higher chance of spontaneous TSH normalisation.
Clinical practice applications
- Supporting older adults with nutritional intervention aimed to optimise thyroid function could support spontaneous TSH normalisation.
- Older adults may benefit from 2 or 3 measures of TSH to assess if spontaneous normalisation is achievable before treatment is considered.
Considerations for future research
- Identify if the findings can be replicated and therefore support a review of reference ranges in TSH for older adults.
- Explore why certain parameters e.g. testing in summer are associated with TSH normalisation and how these findings can be applied to improve clinical outcome.
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Abstract
CONTEXT
With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.
OBJECTIVE
To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism.
DESIGN
Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial).
SETTING
Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom.
PARTICIPANTS
The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included.
MAIN OUTCOME MEASURES
Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization.
RESULTS
In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization.
CONCLUSION
Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851.
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
Address:
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department of Public Health and Primary Care, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Public Health Research Institute, 1081 HV Amsterdam, The Netherlands.; Department of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G4 0SF, UK.; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.; School of Public Health, University College Cork, Cork T12 K8AF, Ireland.; Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland.; Institute of Primary Health Care (BIHAM), University of Bern, 3012 Bern, Switzerland.; Institute of Primary Health Care (BIHAM), University of Bern, 3012 Bern, Switzerland.; Graduate School for Health Sciences, University of Bern, Mittelstrasse 43, 3012 Bern, Switzerland.; Service of Endocrinology, Diabetes, Nutrition and Therapeutic Education, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.; Diabetes Centre, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland.; Department of Public Health, University of Copenhagen, 1353 Copenhagen, Denmark.; Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.; Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department of Cardiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Netherlands Heart Institute, 3511 EP Utrecht, The Netherlands.; Department of Internal Medicine, Section of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department of Public Health and Primary Care, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
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