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A Review of the Clinical Consequences of Variation in Thyroid Function Within the Reference Range
Abstract
CONTEXT: Overt thyroid disease is associated with profound adverse health outcomes; however, data are conflicting for studies of borderline/subclinical thyroid dysfunction. Many studies of subclinical thyroid disease have had low power and were prone to selection bias. In contrast, large datasets are available from community studies in healthy individuals. Studies of the effects of variation of thyroid function across the reference range on health outcomes in these populations may provide useful information regarding thresholds for treatment of abnormal thyroid function. EVIDENCE ACQUISITION: MEDLINE and the Cochrane Database of Systematic Reviews and Controlled Trials Register were searched for articles studying the effect of variation in thyroid hormone parameters within the reference range on cardiovascular, bone, metabolic, pregnancy, neurological, and psychological outcomes. EVIDENCE SYNTHESIS: Higher TSH/lower thyroid hormone levels are associated with more cardiovascular risk factors and cardiovascular events and worse metabolic parameters and pregnancy outcomes, whereas lower TSH/higher thyroid hormone levels are associated with reduced bone mineral density and increased fracture risk. The evidence base was good for cardiovascular, metabolic, bone, and pregnancy outcomes; however, high-quality data remained lacking for neurological and psychological outcomes. CONCLUSIONS: Common variation in persons with thyroid function in the normal range are associated with adverse health outcomes. These data suggest, by extrapolation, that carefully monitored treatment of even modest elevations of TSH may have substantial health benefits. Appropriately powered large-scale clinical trials analyzing the risks vs benefits of treating subclinical thyroid disease are required to determine whether these benefits can be achieved with levothyroxine therapy.
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“There is increasing evidence that variation in thyroid status within the reference range is a risk factor for disease burden.[115][116][117][118]”
From Hypothyroidism (2024) · cites this paper as [116]
In the citing paper
“A 2013 meta-analysis of observational studies revealed that even within the population reference range, variations in thyroid hormone levels were associated with a range of adverse cardiovascular, metabolic, and bone outcomes [10].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [10]
In the citing paper
“In essence, high-normal TSH, was associated with adverse cardiovascular and metabolic outcomes whereas low-normal TSH was associated with adverse bone outcomes.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [10]
In the citing paper
“Variation in thyrotropin (TSH) levels within the normal reference range generally shows an inverse relationship with fracture risk so that low-normal TSH values are associated with modest increases in the risk of fractures.(13)(14)(15) and with decreases in BMD.(13,16)”
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Metadata
- Authors
- Taylor, P. N., Razvi, S., Pearce, S. H., & Dayan, C. M.
- Affiliations
- Cardiff University (GB)
- Gateshead Health NHS Foundation Trust (GB)
- Royal Victoria Infirmary (GB)
- Corresponding author
- Dayan, Colin M.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2013-09
- Volume
- 98
- Issue
- 9
- Pages
- 3562-3571
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2136343353
- Cited by
- 274
- References
- 101
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 18 · 2023: 19 · 2022: 25 · 2021: 24 · 2020: 17 · 2019: 29 · 2018: 18 · 2017: 20 · 2016: 33 · 2015: 26 · 2014: 17 · 2013: 5
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cardiff University
- 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 › Thyroid Cancer Diagnosis and Treatment
- Keywords
- subclinical thyroid dysfunction, thyroid-stimulating hormone, thyroid hormones, cardiovascular risk, bone mineral density, fracture risk, pregnancy outcomes, metabolic outcomes, levothyroxine therapy, treatment thresholds, healthy individuals
- MeSH terms
- Cardiovascular Diseases, Female, Humans, Male, Pregnancy, Pregnancy Outcome, Reference Values, Risk Factors, Thyroid Diseases, Thyroid Gland, Thyroid Hormones
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