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Comment
. 2023 Dec 1;183(12):1324-1331.
doi: 10.1001/jamainternmed.2023.5619.

Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults

Roy Adams  1 , Esther S Oh  1   2 , Sevil Yasar  2 , Constantine G Lyketsos  1 , Jennifer S Mammen  3
Affiliations
Comment

Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults

Roy Adams et al. JAMA Intern Med. .

Abstract

Importance: Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis.

Objective: To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders.

Design, setting, and participants: This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023.

Exposure: The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications.

Main outcomes and measures: The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care.

Results: A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response.

Conclusions and relevance: In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lyketsos reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA GmbH, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer disease outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Thyrotropin (TSH) Measurement Waterfall Diagram
Waterfall diagram showing the inclusion criteria for low TSH measurements and their categorization by type (endogenous, exogenous, and unknown cause) and severity. ED indicates emergency department.
Figure 2.
Figure 2.. Cumulative Incidence of Thyrotoxicosis and Cognitive Disorder Diagnoses
Kaplan-Meier estimates of cumulative incidence for thyrotoxicosis stratified by sex (A), cognitive disorder (dementia plus mild cognitive impairment [MCI]) stratified by sex (B), and cognitive disorder stratified by thyrotoxicosis exposure (C). Cumulative incidences are calculated relative to patient age, not time on study. Patients were considered left-truncated until the age of their first visit and right censored after their most recent visit.
Figure 3.
Figure 3.. Adjusted Hazard Ratios (aHRs) for Cognitive Disorder Following Thyrotoxicosis
aHRs for cognitive disorder following exposure to different types and severities of thyrotoxicosis estimated using a time-varying Cox model. Bars indicate 95% CIs.
See this image and copyright information in PMC

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References

    1. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia: the Rotterdam study. Clin Endocrinol (Oxf). 2000;53(6):733-737. doi:10.1046/j.1365-2265.2000.01146.x - DOI - PubMed
    1. Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab. 2011;96(5):1344-1351. doi:10.1210/jc.2010-2693 - DOI - PubMed
    1. Chaker L, Wolters FJ, Bos D, et al. . Thyroid function and the risk of dementia: the Rotterdam Study. Neurology. 2016;87(16):1688-1695. doi:10.1212/WNL.0000000000003227 - DOI - PubMed
    1. Aubert CE, Bauer DC, da Costa BR, et al. ; Health ABC Study . The association between subclinical thyroid dysfunction and dementia: the Health, Aging and Body Composition (Health ABC) Study. Clin Endocrinol (Oxf). 2017;87(5):617-626. doi:10.1111/cen.13458 - DOI - PMC - PubMed
    1. Folkestad L, Brandt F, Lillevang-Johansen M, Brix TH, Hegedüs L. Graves’ disease and toxic nodular goiter, aggravated by duration of hyperthyroidism, are associated with Alzheimer’s and vascular dementia: a registry-based long-term follow-up of two large cohorts. Thyroid. 2020;30(5):672-680. doi:10.1089/thy.2019.0672 - DOI - PubMed