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Low Serum Thyrotropin Concentrations as a Risk Factor for Atrial Fibrillation in Older Persons
Open accessAbstract
BACKGROUND: Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation. METHODS: We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (< or = 0.1 mU per liter; 61 subjects); those with slightly low values (> 0.1 to 0.4 mU per liter; 187 subjects); those with normal values (> 0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (> 5.0 mU per liter; 183 subjects). RESULTS: During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (< or = 0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among those with low values and 10 per 1000 person-years among those with normal values (P = 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P < 0.001). The 10-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values. CONCLUSIONS: Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade.
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In the citing paper
“Cardiovascular symptoms are the most frequent indicators of mild thyroid hormone excess in the elderly, similar to overt hyperthyroidism [52,53] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“An increased incidence of AF has also been observed in elderly persons with low serum TSH (0.1-0.5 mIU/l) with an HR of 1.6 (95% CI: 1.0-2.5)[52] and 1.85 (95% CI: 1.14-3.00)[53] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [52]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A 2-to 3-fold increased risk of atrial fibrillation (AF) was associated with SHyper in elderly subjects in two large prospective studies [52,53] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“Excess thyroid hormone can also increase the risk of arrhythmias24 25 and muscle weakness23 in older people, which can contribute to a greater risk of falls.”
From Levothyroxine dose and risk of fractures in older adults: nested case-control study (2011) · cites this paper as [24]
The cited source says what the claim attributes to it.
In the citing paper
“lower serum TSH levels are associated with increased risk of atrial fibrillation (AF) (60)”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [60]
In the citing paper
“Older patients with low TSH and higher fT4 have a higher prevalence and incidence of atrial fibrillation compared with euthyroid subjects (94–98)”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [97]
In the citing paper
“Twenty years ago, a low serum TSH level was first associated with an increased risk of atrial fibrillation (AF) (12)”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [12]
In the citing paper
“in cohort studies, subclinical hyperthyroidism or lower serum TSH have been associated with many involutional disease states including dementia, osteoporosis, AF, muscle weakness, low bone density, and fracture (12–14, 18, 20, 48, 49).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [12]
In the citing paper
“In contrast with subclinical hypothyroidism, many previous studies have shown that low serum TSH is associated with poor outcomes, either increased all-cause or vascular mortality, or AF (12–14, 17, 29, 36, 37).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [12]
In the citing paper
“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 [399]
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Management of Subclinical Hyperthyroidism
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Song, Y. S., Kim, M. J., Sun, H. J., Kim, H. H., Shin, H. S., Kim, Y. A., Oh, B., Cho, S. W., & Park, Y. J. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0663 · Cited by 43
“However, T4 suppression therapy should be considered after weighing the potential risks and benefits of TSH suppression (4–7), because long-term, aggressive suppression of TSH could be related to systemic adverse events, such as the exacerbation of ischemic heart disease, as well as an increased risk of atrial fibrill…”
BackgroundGorenek, B., Boriani, G., Dan, G.-A., Fauchier, L., Fenelon, G., Huang, H., Kudaiberdieva, G., Lip, G. Y. H., Mahajan, R., Potpara, T., et al. (2018) · EP Europace · doi:10.1093/europace/euy051 · Cited by 43
Papillary thyroid cancer: Medical management and follow-up
Kloos, R. T. (2005) · Current Treatment Options in Oncology · doi:10.1007/s11864-005-0036-8 · Cited by 42
“Sawin et al. [ 69 ] studied 2007 persons greater than or equal to 60 years of age who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period.”
BackgroundResultBhagat, M. C., Dhaliwal, S. S., Bonnema, S. J., Hegedüs, L., & Walsh, J. P. (2003) · British journal of surgery · doi:10.1002/bjs.4171 · Cited by 42
Frank, N., Buchanan, B. R., & Elliott, S. B. (2008) · American Journal of Veterinary Research · doi:10.2460/ajvr.69.1.68 · Cited by 42
“Electrocardiographic abnormalities including atrial premature beats and atrial fibrillation have also been associated with L-T 4 administration in humans receiving the drug at thyrotropin-suppressive dosages.(3,6) Detection of these arrhythmias has been facilitated by 24hour Holter monitoring.”
BackgroundThyroid Hormone Therapy and Incident Stroke
Papaleontiou, M., Levine, D. A., Reyes-Gastelum, D., Hawley, S. T., Banerjee, M., & Haymart, M. R. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab444 · Cited by 43
Evaluation of the thyroid nodule
McIver, B. (2013) · Oral Oncology · doi:10.1016/j.oraloncology.2013.03.435 · Cited by 41
Zaborek, N. A., Cheng, A., Imbus, J. R., Long, K. L., Pitt, S. C., Sippel, R. S., & Schneider, D. F. (2018) · Surgery · doi:10.1016/j.surg.2018.04.097 · Cited by 41
New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation
Aguilar, M., Rose, R. A., Takawale, A. R., Nattel, S., & Reilly, S. N. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab080 · Cited by 42
Hypothyroidism following Hemithyroidectomy for Benign Nontoxic Thyroid Disease
Seiberling, K. A., Dutra, J., & Bajaramovic, S. (2007) · Ear Nose & Throat Journal · doi:10.1177/014556130708600517 · Cited by 41
Parsa, A. A., & Bhangoo, A. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9248-6 · Cited by 41
“8 fold risk of atrial fibrillation [49, 50] and thus it is recommended that these patients be treated.”
BackgroundThe Effect of Famotidine, Esomeprazole, and Ezetimibe on Levothyroxine Absorption
Ananthakrishnan, S., Braverman, L. E., Levin, R. M., Magnani, B., & Pearce, E. N. (2008) · Thyroid · doi:10.1089/thy.2007.0381 · Cited by 38
Nonthyroidal illness and the cardiorenal syndrome
Meuwese, C. L., Dekkers, O. M., Stenvinkel, P., Dekker, F. W., & Carrero, J. J. (2013) · Nature Reviews Nephrology · doi:10.1038/nrneph.2013.170 · Cited by 39
Prognosis of papillary thyroid carcinoma in elderly patients after thyroid resection
Chéreau, N., Trésallet, C., Noullet, S., Godiris-Petit, G., Tissier, F., Leenhardt, L., & Ménégaux, F. (2016) · Medicine · doi:10.1097/md.0000000000005450 · Cited by 40
Gluvic, Z. M., Obradovic, M. M., Stewart, A. J., Essack, M., Pitt, S. J., Samardzic, V. S., Šoškić, S., Gojobori, T., & Isenović, E. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.758043 · Cited by 42
“Also, subclinical hyperthyroidism is associated with an almost 3-fold increase in the risk of developing AF (103).”
BackgroundInfluentialEvaluation of thyroid status in patients with thyrotoxicosis
Braverman, L. E. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.1.174 · Cited by 39
“fibrillation over the next decade than do people with normal values for serum TSH [4].”
BackgroundSerum free thyroxine levels are positively associated with arterial stiffness in the Sardi NIA study
Delitala, A., Orrù, M., Filigheddu, F., Pilia, M. G., Delitala, G., Ganau, A., Saba, P. S., Decandia, F., Scuteri, A., Marongiu, M., et al. (2014) · Clinical Endocrinology · doi:10.1111/cen.12532 · Cited by 39
Competing Causes of Death in Older Adults with Thyroid Cancer
Papaleontiou, M., Norton, E. C., Reyes‐Gastelum, D., Banerjee, M., & Haymart, M. R. (2021) · Thyroid · doi:10.1089/thy.2020.0929 · Cited by 39
Bonnema, S. J., Knudsen, D. U., Bertelsen, H. C., Mortensen, J., Andersen, P. B., Bastholt, L., & Hegedűs, L. D. (2002) · Thyroid · doi:10.1089/10507250252949441 · Cited by 38
“In addition, the troublesome adverse effects after long-term use must also be taken into account (21,22).”
Thyroid disease and its treatment: short-term and long-term cardiovascular consequences
Osman, F. (2001) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(01)00107-2 · Cited by 38
Kreuzberg, U., THEISSEN, P., Schicha, H., Schröder, F., Mehlhorn, U., de Vivie, E. R., Boknı́k, P., Neumann, J., Grohé, C., & Herzig, S. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.278.3.h723 · Cited by 38
“, serum levels of thyroid-stimulating hormone (TSH) are decreased, but the circulating hormones thyroxine and triiodothyronine are within the normal range (26, 31).”
BackgroundMariotti, S. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2214 · Cited by 38
“1 mU/liter) serum TSH concentrations (14).”
O’Neal, W. T., Judd, S. E., Limdi, N. A., McIntyre, W. F., Kleindorfer, D., Cushman, M., Howard, V. J., Howard, G., & Soliman, E. Z. (2016) · Journal of Racial and Ethnic Health Disparities · doi:10.1007/s40615-016-0275-3 · Cited by 37
“Additionally, lower levels of thyrotropin, a sensitive indicator of thyroid function, are associated with an increased risk for AF [28], and smoking has been associated with lower concentrations of thyrotropin [29].”
Ling, S. M., Bhatt, A. D., Brown, N. V., Nguyen, P. A. H., Sipos, J. A., Chakravarti, A., & Rong, Y. (2016) · Head & Neck · doi:10.1002/hed.24643 · Cited by 37
“Likewise, supratherapeutic doses of levothyroxine pose a danger to patients, particularly in the elderly, in which those patients over age 60 years have a 3-fold greater risk of developing atrial fibrillation with low serum TSH.(30) Posttherapy hyperthyroidism was not observed in our study.”
BackgroundOlmos, R. D., Nogueira, A.-C., Penalva, D. Q. F., Lotufo, P. A., & Benseñor, I. M. (2010) · Sao Paulo Medical Journal · doi:10.1590/s1516-31802010000100005 · Cited by 36
Takawale, A. R., Aguilar, M., Bouchrit, Y., & Hiram, R. (2022) · Cells · doi:10.3390/cells11244047 · Cited by 36
“It increases the risk of AF up to 3-fold [12,16], but is relatively uncommon [17].”
BackgroundMetabolic Syndrome, Thyroid Dysfunction, and Cardiovascular Risk: The Triptych of Evil
Pingitore, A., Gaggini, M., Mastorci, F., Sabatino, L., Cordiviola, L., & Vassalle, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910628 · Cited by 39
“…(SHyper), characterized by subnormal serum TSH levels and T4 and T3 within normal range, in the long term, leads to changes in cardiac function, consisting of impairment in diastolic function due to reduced myocardial relaxation, and occurrence of arrhythmias such as atrial fibrillation [89].”
BackgroundHigher Serum Free Thyroxine Levels Are Associated with Coronary Artery Disease
Jung, C., Rhee, E., Shin, H. S., Jo, S.-K., Won, J. C., Park, C. ‐., Kim, B. J., Sung, K., Bum-Soo, K. I. M., Lee, W., et al. (2008) · Endocrine Journal · doi:10.1507/endocrj.k08e-010 · Cited by 36
Update on Thyroid Cancer Treatment
Regalbuto, C., Frasca, F., Pellegriti, G., Malandrino, P., Marturano, I., Carlo, I. D., & PEZZINO, V. (2012) · Future Oncology · doi:10.2217/fon.12.123 · Cited by 36
“However, TSH suppression is obtained by a subclinical thyrotoxicosis with several adverse effects that may be critical in older patients, including angina in patients with ischemic heart disease, atrial fibrillation and osteoporosis in p ostmenopausal women [52,53].”
BackgroundEndothelial dysfunction in subjects with subclinical hyperthyroidism
Çoban, E., Aydemir, M., Yazicioglu, G., & Özdoğan, M. (2006) · Journal of Endocrinological Investigation · doi:10.1007/bf03345539 · Cited by 36
Subclinical hypothyroidism: the case against treatment
Vanderpump, M. P. J. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(03)00103-6 · Cited by 36
Papoian, V., Ylli, D., Felger, E. A., Wartofsky, L., & Rosen, J. E. (2019) · Thyroid · doi:10.1089/thy.2019.0251 · Cited by 35
“Overdosing can lead to metabolic abnormalities, cardiac dysfunction, bone loss, and fractures (8–12).”
Buscemi, S., Verga, S., Cottone, S., Andronico, G., D’Orio, L., Mannino, V., Panzavecchia, D., Vitale, F., & Cerasola, G. (2007) · Journal of Endocrinological Investigation · doi:10.1007/bf03347430 · Cited by 35
McDermott, M. T. (2020) · Annals of Internal Medicine · doi:10.7326/aitc202004070 · Cited by 35
Metadata
- Authors
- Sawin, C. T., Geller, A., Wolf, P. A., Belanger, A. J., Baker, E., Bacharach, P., Wilson, P., Benjamin, E. J., & D'Agostino, R. B.
- Affiliations
- Boston University (US)
- Veterans Health Administration (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1994-11-10
- Volume
- 331
- Issue
- 19
- Pages
- 1249-1252
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2335515807
- Cited by
- 1,259
- References
- 31
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 27 · 2023: 25 · 2022: 46 · 2021: 37 · 2020: 27 · 2019: 38 · 2018: 41 · 2017: 44 · 2016: 48 · 2015: 45 · 2014: 44 · 2013: 63 · 2012: 65
- FWCI
- 16.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hc038038-022, 5r01hl040423-06)
- National Heart, Lung, and Blood Institute (R01-HL-40423-04, N01-HC-38038)
- National Institute of Neurological Disorders and Stroke (2-R01-NS-17950-12, R01NS017950)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- thyroid-stimulating hormone, subclinical hyperthyroidism, older adults, hyperthyroidism, arrhythmia risk, thyroid function, incidence, risk factors, euthyroid patients, parathyroid hormone, parathyroidectomy, parathyroid hormone replacement, hypoparathyroidism
- MeSH terms
- Age Factors, Aged, Atrial Fibrillation, Female, Follow-Up Studies, Humans, Hyperthyroidism, Male, Middle Aged, Risk Factors, Thyrotropin, Thyroxine, Incidence, Confidence Intervals
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