Subclinical and Overt Thyroid Dysfunction and Risk of All-Cause Mortality and Cardiovascular Events: A Large Population Study
Open accessAbstract
CONTEXT: Thyroid dysfunction has been associated with both increased all-cause and cardiovascular mortality, but limited data are available on mild thyroid dysfunction and cause-specific mortality. OBJECTIVE: The objective of the study was to examine the risk of all-cause mortality, major adverse cardiovascular events (MACEs), and cause-specific events in subjects with overt and subclinical thyroid dysfunction. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: Participants in the study were subjects who underwent thyroid blood tests, without prior thyroid disease, consulting their general practitioner in 2000-2009 in Copenhagen, Denmark. MAIN OUTCOME MEASURE: All-cause mortality, MACEs, and cause-specific events identified in nationwide registries were measured. RESULTS: A total of 47 327 (8.4%) deaths occurred among 563 700 included subjects [mean age 48.6 (SD ± 18.2) y; 39% males]. All-cause mortality was increased in overt and subclinical hyperthyroidism [age adjusted incidence rates of 16 and 15 per 1000 person-years, respectively; incidence rate ratios (IRRs) 1.25 [95% confidence interval (CI) 1.15-1.36] and 1.23 (95% CI 1.16-1.30)] compared with euthyroid (incidence rate of 12 per 1000 person-years). Risk of MACEs was elevated in overt and subclinical hyperthyroidism [IRRs 1.16 (95% CI 1.05-1.27) and 1.09 (95% CI 1.02-1.16)] driven by heart failure [IRRs 1.14 (95% CI 0.99-1.32) and 1.20 (95% CI 1.10-1.31)]. A reduction of all-cause mortality was observed in subclinical hypothyroidism with TSH of 5-10 mIU/L [IRR 0.92 (95% CI 0.86-0.98)]. CONCLUSIONS: Heart failure is the leading cause of an increased cardiovascular mortality in both overt and subclinical hyperthyroidism. Subclinical hypothyroidism with TSH 5-10 mIU/L might be associated with a lower risk of all-cause mortality.
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A recent retrospective Danish cohort study reported a trend for increased risk for major adverse cardiac events and heart failure with increasing degree of hyperthyroidism.
“A recent retrospective Danish cohort study, which was not included in the meta-analysis by Gencer et al. [75] , reported a trend for increased risk for major adverse cardiac events and HF with increasing degree of hyperthyroidism [77] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [77]
The Hyperthyroid states results report a trend with increasing hyperthyroidism for all-cause mortality, not for MACE or heart failure. They describe MACE risk as elevated in both subclinical and overt hyperthyroidism, while the discussion says the study could not demonstrate a clear dose-dependent relationship with decreasing TSH. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCardiovascular morbidity and mortality are particularly increased in men, in elderly patients with high-normal FT4 levels and in patients with underlying heart disease.
“Cardiovascular morbidity and mortality are particularly increased in men, in elderly patients with high-normal FT 4 levels and in patients with underlying heart disease [71-73, 76, 77, 87, 91, 92, 94] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [77]
In “Hyperthyroid states” (page not available), the paper says increased all-cause mortality and major adverse cardiovascular events were mainly found in people older than 65. It does not link that finding to high-normal FT4 or report a particular increase in men. It also says its results did not agree with a comorbidity-restricted finding: excluding people with known comorbidity did not change its results. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn age-stratified sensitivity analyses, the risk of major adverse cardiac events was mainly found in individuals older than 65 years.
“In the age-stratified sensitivity analyses, the risk of major adverse cardiac events was mainly found in individuals older than 65 years [77] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [77]
Heart failure was the leading specific cause of increased cardiovascular mortality in patients with subclinical hyperthyroidism.
“HF was the leading specific cause of increased cardiovascular mortality in patients with SHyper [77] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [77]
A Danish population study did not find a link between stroke risk and overt, mild, or severe hyperthyroidism after stratifying by thyroid-stimulating hormone levels.
“Similarly, a Danish population study did not find any link between the risk of stroke and overt, mild, and severe hyperthyroidism after stratifying the analysis according to TSH levels (74).”
From Thyroid Hormones and Cardiovascular Function and Diseases (2018) · cites this paper as [74]
Some other, smaller studies have reached similar conclusions, although other smaller studies have failed to find a correlation.
“Some other, smaller studies have reached similar conclusions (374,383), although other smaller studies have failed to find a correlation (380,381,384,386).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [381]
Some studies report increased overall mortality rates in SH subjects, especially older subjects, while others indicate no relation.
“Some studies report increased overall mortality rates in SH subjects (374,379-383), especially older subjects, while others indicate no relation (384)(385)(386)(387).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [381]
The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure, especially older subjects and those with lower TSH levels.
“The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure (381,388,392), especially older subjects (381,392) and those with lower TSH levels (392).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [381]
Subsequent studies have confirmed that the risk of arrhythmias, particularly atrial fibrillation, is increased in SH.
“Sawin et al. (399) first reported a 2.8-fold increased risk of atrial fibrillation in SH subjects over age 60 years in 1994, and subsequent studies have confirmed that the risk of arrhythmias, particularly atrial fibrillation, is increased in SH (381,384,388,391,400,401).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [381]
Subclinical hyperthyroidism is associated with increased heart failure.
“Some of these studies re-ported increased risks of overall mortality in older subjects (380,429), cardiovascular events (391), heart failure (381), and atrial fibrillation in all subjects (401) or in older subjects (384), and vertebral fractures in older women (408).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [381]
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References 59 · Cited by 288
Research works printed but not linked: 1
- Asvold BO, Bjoro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway. Clin Endocrinol (Oxf). 2012;77:911-917.
- Authors
- Selmer, C., Olesen, J. B., Hansen, M. L., von Kappelgaard, L. M., Madsen, J. C., Hansen, P. R., Pedersen, O. D., Faber, J., Torp-Pedersen, C., & Gislason, G. H.
- Affiliations
- Herlev Hospital (DK)
- Gentofte Hospital (DK)
- National Institute of Public Health (L.M.v.K., G.H.G.), University of Southern Denmark, DK-1353 Copenhagen, Denmark
- Copenhagen General Practitioners Laboratory (J.C.M.), DK-2100 Copenhagen, Denmark
- Roskilde Sygehus (DK)
- University of Copenhagen (DK)
- Aalborg University (DK)
- Corresponding author
- Selmer, Christian
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-07-01
- Volume
- 99
- Issue
- 7
- Pages
- 2372-2382
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2168406714
- Cited by
- 288
- References
- 59
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 30 · 2023: 25 · 2022: 32 · 2021: 31 · 2020: 23 · 2019: 24 · 2018: 20 · 2017: 27 · 2016: 24 · 2015: 16 · 2014: 11
- FWCI
- 20.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- 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 hypothyroidism, subclinical hyperthyroidism, overt hyperthyroidism, all-cause mortality, major adverse cardiovascular events, heart failure, thyroid-stimulating hormone, thyroid dysfunction
- MeSH terms
- Adult, Cardiovascular Diseases, Cause of Death, Denmark, Female, Humans, Male, Middle Aged, Registries, Retrospective Studies, Risk Factors, Thyroid Diseases, Incidence, Asymptomatic Diseases
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