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Association Between Serum Thyrotropin Levels and Mortality Among Euthyroid Adults in the United States

Inoue, Kosuke, Tsujimoto, Tetsuro, Saito, Jun, Sugiyama, Takehiro·2016·Thyroid
DOI 10.1089/thy.2016.0156
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Abstract

BACKGROUND: Low thyroid function within the euthyroid range, as well as overt and subclinical hypothyroidism, reportedly increases the risk of cardiovascular disease and mortality. However, the association between low normal thyroid function and mortality remains controversial. This study was performed to elucidate the association between low normal thyroid function and all-cause and/or cause-specific mortalities among U.S. adults. METHODS: A prospective cohort study was conducted using a nationally representative sample of 12,584 U.S. adults aged ≥20 years with thyrotropin (TSH) levels within the reference range from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Associations between TSH tertiles (high, medium, and low normal TSH groups) and mortalities (all-cause, cardiovascular, and cancer) were investigated using multivariable Cox models. Stratum-specific analyses were estimated within subgroups defined according to sex (male or female) and baseline age (age <60 years or age ≥60 years). Further, the same analysis was conducted using continuous NHANES 2001-2002, 2007-2008, and 2009-2010 cohorts, which included data on free thyroxine levels. RESULTS: The median follow-up period was 19.1 years, with 3395 all-cause deaths. A significantly higher risk of all-cause mortality (adjusted hazard ratio [HR] 1.27; [confidence interval (CI) 1.10-1.47]), and cardiovascular mortality (HR 1.30 [CI 1.02-1.67]), and cancer mortality (HR 1.43 [CI 1.01-2.01]) was observed in the high normal TSH group than in the medium normal TSH group. Additionally, the low normal TSH group had an increased risk of all-cause mortality. In stratum-specific analyses, a significant association was found between high normal TSH levels and all-cause mortality among males, females, and participants <60 years. Continuous NHANES cohorts demonstrated a non-significant increase in the HR for all-cause mortality in the high normal TSH group. CONCLUSIONS: High normal TSH levels compared with medium normal TSH levels were associated with increased risk of all-cause, cardiovascular, and cancer mortalities over a long-term follow-up period among U.S. adults. This study indicates that the reference range for TSH levels may require re-evaluation.

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  • In 12,584 adults with normal TSH levels, the frequency of diabetes, hypertension, and hypercholesterolemia increased significantly across TSH tertiles (diabetes = 6.3, 7.7, and 9.1%; hypertension = 20.9, 24.8, and 29.8%; hypercholesterolemia = 13.2, 15.2, and 19.4%).

    “In 12,584 adults with normal TSH levels, the frequency of diabetes, hypertension, and hypercholesterolemia, increased significantly across TSH tertiles (diabetes = 6.3, 7.7, and 9.1%; hypertension = 20.9, 24.8, and 29.8%; hypercholesterolemia = 13.2, 15.2, and 19.4%) (102).”

    From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [102]

  • Higher TSH levels within the reference-range were associated with higher all cause and cardiovascular mortality.

    “In addition, higher TSH levels within the reference-range were associated with higher all cause [63] and cardiovascular mortality [63, 64].”

    From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [63]

  • Subclinical hypothyroidism or high-normal TSH concentrations are associated with dyslipidemia, increased insulin resistance, and hypertension.

    “Other epidemiological studies4,5,6,7 have also found an association between subclinical hypothyroidism or high-normal TSH concentrations (ie, serum TSH concentrations at the upper end of the normal range) and dyslipidemia, increased insulin resistance, and hypertension—components of metabolic syndrome.”

    From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [5]

  • Results from previous studies that examined associations of serum thyroid function within the normal range and various long-term adverse outcomes have been inconsistent across different populations.

    “Results from previous studies5,33,34,35,36 that examined associations of serum thyroid function within the normal range and various long-term adverse outcomes have been inconsistent across different populations.”

    From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [5]

  • Some recent studies have suggested that high-normal TSH concentrations are associated with increased risk of cardiovascular disease and mortality among the US general population or adults with chronic kidney disease.

    “Meanwhile, some recent studies5,15,16 have suggested that even high-normal TSH concentrations are associated with increased risk of CVD and mortality among the US general population or adults with chronic kidney disease”

    From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [5]

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Authors
Inoue, K., Tsujimoto, T., Saito, J., & Sugiyama, T.
Affiliations
  • Yokohama Rosai Hospital (JP)
  • National Center for Global Health and Medicine (JP)
Corresponding author
Inoue, Kosuke
ORCID
Venue
Thyroid
Publisher
SAGE Publications
Published
2016-10
Volume
26
Issue
10
Pages
1457-1465
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/thy.2016.0156
OpenAlex
W2521501166
Cited by
63
References
33
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 4 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 10 · 2016: 1
FWCI
8.35
Type
journal article
Language
en
Open access
closed
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Thyroid (publishedVersion)
  • PubMed (publishedVersion)
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
thyroid-stimulating hormone, euthyroid adults, all-cause mortality, cardiovascular mortality, cancer mortality, subclinical hypothyroidism, free thyroxine, sex differences, age differences, NHANES cohort, cardiovascular risk, cancer risk, long-term follow-up, United States adults, NHANES III
MeSH terms
Adult, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Hyperthyroidism, Hypothyroidism, Male, Mortality, Neoplasms, Nutrition Surveys, Prospective Studies, Risk, Severity of Illness Index, Thyroid Gland, Thyrotropin, United States, Cohort Studies, Biomarkers, Comorbidity, Survival Analysis, Metabolic Syndrome, Asymptomatic Diseases

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