Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a Danish nationwide register-based cohort study of twins and singletons

Brandt, Frans; Almind, Dorthe; Christensen, Kaare; Green, Anders; Brix, Thomas Heiberg; Hegedüs, Laszlo

doi:10.1210/jc.2012-2268

Cited by 83Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a Danish nationwide register-based cohort study of twins and singletons

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Brandt, Frans, Almind, Dorthe, Christensen, Kaare, Green, Anders, Brix, Thomas Heiberg, Hegedüs, Laszlo·2012·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2012-2268PMC PMC3485592

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Abstract

CONTEXT: Hyperthyroidism is associated with severe comorbidity, such as stroke, and seems to confer increased mortality. However, it is unknown whether this increased mortality is explained by hyperthyroidism per se, comorbidity, and/or genetic confounding. OBJECTIVE: The objective of the study was to investigate whether hyperthyroidism is associated with an increased mortality and, if so, whether the association is influenced by comorbidity and/or genetic confounding. METHODS: This was an observational cohort study using record-linkage data from nationwide Danish health registers. We identified 4850 singletons and 926 twins from same-sex pairs diagnosed with hyperthyroidism. Each case was matched with four controls for age and gender. The Charlson score was calculated from discharge diagnoses on an individual level to measure comorbidity. Cases and controls were followed up for a mean of 10 yr (range 0-31 yr), and the hazard ratio (HR) for mortality was calculated using Cox regression analyses. RESULTS: In singletons there was a significantly higher mortality in individuals diagnosed with hyperthyroidism than in controls [HR 1.37; 95% confidence interval (CI) 1.30-1.46]. This persisted after adjustment for preexisting comorbidity (HR 1,28; 95% CI 1.21-1.36). In twin pairs discordant for hyperthyroidism (625 pairs), the twin with hyperthyroidism had an increased mortality compared with the corresponding cotwin (HR 1.43; 95% CI 1.09-1.88). However, this was found only in dizygotic pairs (HR 1.80; 95% CI 1.27-2.55) but not in monozygotic pairs (HR 0.95; 95% CI 0.60-1.50). CONCLUSIONS: Hyperthyroidism is associated with an increased mortality independent of preexisting comorbidity. The study of twin pairs discordant for hyperthyroidism suggests that genetic confounding influences the association between hyperthyroidism and mortality.

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Overtreatment of hypothyroidism most likely carries a similar risk of increased morbidity and mortality as shown for hyperthyroidism.
“Thus, overtreatment of hypothyroidism most likely carries a similar risk of increased morbidity (39,40) and mortality, (41) as shown for hyperthyroidism.”
From The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis (2015) · cites this paper as [41]

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Additional file 1 of Use of thyroid hormones in hypothyroid and euthyroid patients: a THESIS* survey of Belgian specialists *THESIS: treatment of hypothyroidism in Europe by specialists: an international survey
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Additional file 3 of Clinical evaluation of an automated TSI bridge immunoassay in the diagnosis of Graves’ disease and its relationship to the degree of hyperthyroidism
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Additional file 2 of Clinical evaluation of an automated TSI bridge immunoassay in the diagnosis of Graves’ disease and its relationship to the degree of hyperthyroidism
Liu, T., Zhang, X., Long, L., Zhou, L., Chen, J., Li, M., Gao, Y., Zhou, X., Han, X., & Ji, L. (2022) · Figshare · doi:10.6084/m9.figshare.20762897
Additional file 2 of Psychometric properties of the thyroid-specific quality of life questionnaire ThyPRO in Singaporean patients with Graves’ disease
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Additional file 1 of Clinical evaluation of an automated TSI bridge immunoassay in the diagnosis of Graves’ disease and its relationship to the degree of hyperthyroidism
Liu, T., Zhang, X., Long, L., Zhou, L., Chen, J., Li, M., Gao, Y., Zhou, X., Han, X., & Ji, L. (2022) · Figshare · doi:10.6084/m9.figshare.20762894
Additional file 4 of Clinical evaluation of an automated TSI bridge immunoassay in the diagnosis of Graves’ disease and its relationship to the degree of hyperthyroidism
Liu, T., Zhang, X., Long, L., Zhou, L., Chen, J., Li, M., Gao, Y., Zhou, X., Han, X., & Ji, L. (2022) · Figshare · doi:10.6084/m9.figshare.20762903
Additional file 1 of Psychometric properties of the thyroid-specific quality of life questionnaire ThyPRO in Singaporean patients with Graves’ disease
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Additional file 2 of Use of thyroid hormones in hypothyroid and euthyroid patients: a THESIS* survey of Belgian specialists *THESIS: treatment of hypothyroidism in Europe by specialists: an international survey
Burlacu, M.-C., Attanasio, R., Hegedüs, L., Nagy, E. V., Papini, E., Perros, P., Sawadogo, K. A., Bex, M., Corvilain, B., Daumerie, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19313717
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Excess Mortality in Patients Diagnosed With Hypothyroidism: A Nationwide Cohort Study of Singletons and Twins
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Increased Risk of Multisystem Comorbidities and Disease Trajectories Following Hyperthyroidism: Evidence from 0.5 Million UK Biobank PopulationPreprint
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Authors: Brandt, F., Almind, D., Christensen, K., Green, A., Brix, T. H., & Hegedüs, L.
Affiliations: Odense University Hospital (DK)
The Danish Aging Research Center and The Danish Twin Registry (D.A., K.C.), 5000 Odense C, Denmark
University of Southern Denmark (DK)
Departments of Endocrinology and Metabolism (F.B., T.H.B., L.H.), Odense University Hospital
ORCID: Brandt, Frans
Christensen, Kaare
Green, Anders
Brix, Thomas Heiberg
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2012-11-01
Volume: 97
Issue: 11
Pages: 4123-4129
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2012-2268
PMC: PMC3485592
OpenAlex: W2086018880
Cited by: 83
References: 40
Citations by year: 2025: 3 · 2024: 3 · 2023: 1 · 2022: 14 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 7 · 2014: 14 · 2013: 5 · 2012: 1
FWCI: 6.93
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
Funders: National Institute on Aging (P01AG008761, P01-AG08761)
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: hyperthyroidism, excess mortality, genetic confounding, pre-existing comorbidities, twin discordance, dizygotic twins, monozygotic twins, Charlson Comorbidity Index, stroke
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Denmark, Diseases in Twins, Female, Humans, Hyperthyroidism, Male, Middle Aged, Registries, Twins, Cohort Studies, Comorbidity, Incidence, Prevalence, Genetic Predisposition to Disease

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Excess mortality in hyperthyroidism: the influence of preexisting comorbidity and genetic confounding: a Danish nationwide register-based cohort study of twins and singletons

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