Serum TSH, T 4 , and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)
Abstract
NHANES III measured serum TSH, total serum T4, antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17,353 people aged ≥12 yr representing the geographic and ethnic distribution of the U.S. population. These data provide a reference for other studies of these analytes in the U.S. For the 16,533 people who did not report thyroid disease, goiter, or taking thyroid medications (disease-free population), we determined mean concentrations of TSH, T4, TgAb, and TPOAb. A reference population of 13,344 people was selected from the disease-free population by excluding, in addition, those who were pregnant, taking androgens or estrogens, who had thyroid antibodies, or biochemical hypothyroidism or hyperthyroidism. The influence of demographics on TSH, T4, and antibodies was examined. Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). (Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.) For the disease-free population, mean serum TSH was 1.50 (95% confidence interval, 1.46–1.54) mIU/liter, was higher in females than males, and higher in white non-Hispanics (whites) [1.57 (1.52–1.62) mIU/liter] than black non-Hispanics (blacks) [1.18 (1.14–1.21) mIU/liter] (P < 0.001) or Mexican Americans [1.43 (1.40–1.46) mIU/liter] (P < 0.001). TgAb were positive in 10.4 ± 0.5% and TPOAb, in 11.3 ± 0.4%; positive antibodies were more prevalent in women than men, increased with age, and TPOAb were less prevalent in blacks (4.5 ± 0.3%) than in whites (12.3 ± 0.5%) (P < 0.001). TPOAb were significantly associated with hypo or hyperthyroidism, but TgAb were not. Using the reference population, geometric mean TSH was 1.40 ± 0.02 mIU/liter and increased with age, and was significantly lower in blacks (1.18 ± 0.02 mIU/liter) than whites (1.45 ± 0.02 mIU/liter) (P < 0.001) and Mexican Americans (1.37 ± 0.02 mIU/liter) (P < 0.001). Arithmetic mean total T4 was 112.3 ± 0.7 nmol/liter in the disease-free population and was consistently higher among Mexican Americans in all populations. In the reference population, mean total T4 in Mexican Americans was (116.3 ± 0.7 nmol/liter), significantly higher than whites (110.0 ± 0.8 nmol/liter) or blacks (109.4 ± 0.8 nmol/liter) (P < 0.0001). The difference persisted in all age groups. In summary, TSH and the prevalence of antithyroid antibodies are greater in females, increase with age, and are greater in whites and Mexican Americans than in blacks. TgAb alone in the absence of TPOAb is not significantly associated with thyroid disease. The lower prevalence of thyroid antibodies and lower TSH concentrations in blacks need more research to relate these findings to clinical status. A large proportion of the U.S. population unknowingly have laboratory evidence of thyroid disease, which supports the usefulness of screening for early detection.
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Higher serum TSH values might occur naturally as part of the ageing process.
“Although higher serum TSH values might occur naturally, as part of the ageing process, [15][16][17]”
From Hypothyroidism (2024) · cites this paper as [15]
The NHANES III study identified that the overall prevalence of hypothyroidism was 4.6%.
“although the NHANES III study identified that the overall prevalence of hypothyroidism was 4•6%.15”
From Hypothyroidism (2024) · cites this paper as [15]
The prevalence of hypothyroidism was markedly lower in individuals of African Caribbean descent (1.7%).
“The prevalence was markedly lower in individuals of African Caribbean descent (1•7%).15”
From Hypothyroidism (2024) · cites this paper as [15]
The distribution of serum TSH reference interval is right-shifted with age, giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people.
“the distribution of serum TSH reference interval is right -shifted with age, 24 -26 giving an upper 97.5% confidence interval of around 7.5 mU/L in healthy elderly people. 2,3”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [24]
The shift in the normal TSH distribution to a higher range in older individuals might represent a normal part of ageing.
“This shift in the normal TSH distribution to a higher range in older individuals might represent a normal part of ageing,15-17,131”
From Hypothyroidism (2024) · cites this paper as [15]
NHANES III reported that the 97.5th percentile for TSH exceeded 7.0 mIU/L in individuals older than 80 years, even after exclusion of TPO-Ab-positive individuals.
“NHANES III reported the 97•5th percentile for TSH exceeded 7•0 mIU/L in individuals older than 80 years, 15,16 even after exclusion of TPO-Ab-positive individuals”
From Hypothyroidism (2024) · cites this paper as [15]
Studies in iodine-replete populations without thyroid disease have reported higher TSH concentrations in older individuals.
“studies in iodine-replete populations without thyroid disease have reported higher TSH concentrations in older individuals.15,17,19,20”
From Hypothyroidism (2024) · cites this paper as [15]
In NHANES, the prevalence of subclinical hyperthyroidism was 0.7% with a TSH cutoff of <0.1 mIU/l and 1.8% with a cutoff of <0.4 mIU/l.
“The prevalence of SHyper was 0.7% with a cutoff TSH value of <0.1 mIU/l, and 1.8% with a cutoff TSH value of <0.4 mIU/l [10] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [10]
Studies in several populations have shown progressively increasing TSH concentrations with age.
“Studies in several populations (Americans, Scottish, Ashkenazi Jews, Chinese) have shown progressively increasing TSH concentrations with age.”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [32]
The 97.5th percentiles of the reference population are considerably higher in the elderly (older than 70 years old) than in younger adults.
“The 97.5th percentiles of the reference population are considerably higher in the elderly (older than 70 years old) than in younger adults [32–35], which is not explained only by higher prevalence of thyroid autoimmunity [36, 37].”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [32]
Non-optimal thyroxine therapy, as evidenced by TSH levels above or below the reference range, is common in hypothyroid patients.
“Even though its prevalence has not been precisely documented, non-optimal thyroxine therapy, as evidenced by TSH levels above (or below) the reference range, is common (Table 2)”
From Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report (2017) · cites this paper as [14]
In NHANES III, median TSH concentrations progressively increased with age and the 97.5th percentiles were higher in the >70 years old reference population without thyroid antibodies.
“In the NHANES III study, median TSH concentrations progressively increased with age and the 97.5th percentiles were considerably higher in the >70 years old reference population without thyroid antibodies (97.5th percentile TSH in the reference population: total 4.1 mU/l; 70–79 yo 5.9 mIU/l; >80 yo 7.5 mU/l) (11).”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [11]
There is an age-dependent shift in TSH distribution towards higher concentrations with increasing age.
“Convincing evidence during the last decades has shown an age-dependent shift in TSH distribution towards higher concentrations with increasing age.”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [11]
Five to 24 percent of all patients taking L-T4 develop iatrogenic thyrotoxicosis, a proportion that is even higher in the elderly (up to 41%).
“Five to 24 percent of all patients taking L-T4 develop iatrogenic thyrotoxicosis (9, 11, 78, 81–83), a proportion that is even higher in the elderly [up to 41% (79)].”
From Levothyroxine therapy in elderly patients with hypothyroidism (2021) · cites this paper as [11]
The normal TSH distribution curve is shifted to the right in the elderly.
“the normal TSH distribution curve is shifted to the right in the elderly (Fig. 1) and it is increasingly recognised that higher TSH levels may represent a normal part of ageing [15–17].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
TSH concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations.
“Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
Higher TSH levels may represent a normal part of ageing.
“it is increasingly recognised that higher TSH levels may represent a normal part of ageing [15–17].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
The positively skewed TSH distribution means that most individuals have a TSH between 0.4 and 3.0 mIU/L.
“In reality the positively skewed TSH distribution means that most individuals have a TSH between 0.4 and 3.0 mIU/L (Fig. 1) [15].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
In older individuals, the TSH distribution curve shifts to the right such that the upper TSH reference limit is as high as 7.0 mIU/L.
“In older individuals on the other hand, the TSH distribution curve shifts to the right such that the upper TSH reference limit is as high as 7.0 mIU/L.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
Several large cross-sectional studies in iodine-replete thyroid disease-free populations have reported higher TSH concentrations in older individuals.
“Several large cross-sectional studies in iodine-replete thyroid disease-free populations have reported higher TSH concentrations in older individuals (Fig. 3), [15, 17, 87, 88].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
These studies show that the reference range becomes wider as age increases, with lower 2.5 centiles in the older age groups.
“These studies also show that the reference range becomes wider as age increases, with lower 2.5 centiles in the older age groups (Fig. 3).”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
NHANES III reported an age-related increase in TSH with the 97.5 centile exceeding 7.0 mIU/L in individuals aged over 80 years.
“The National Health and Nutrition Examination Survey (NHANES) III reported an age-related increase in TSH with the 97.5 centile exceeding 7.0 mIU/L in individuals aged over 80 years [15, 87].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [15]
The study used both serum TSH and FT4 to define subclinical hypothyroidism, which has not been implemented in previous studies using NHANES III owing to the lack of FT4 data.
“Moreover, we used both serum TSH and FT4 to define subclinical hypothyroidism, which has not been implemented in previous studies using NHANES III owing to the lack of FT4 data (ie, only total thyroxine data are available in NHANES III).5,29,44”
From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [44]
Up to 3% of older individuals have a serum TSH concentration below the healthy reference interval for younger people (subclinical hyperthyroidism), and approximately 10% have an elevated serum TSH level (subclinical hypothyroidism).
“However, this topic has taken on increasing significance, given that it has been recognized that up to 3% of older individuals have a serum TSH concentration that is below the healthy reference interval for younger people (subclinical hyperthyroidism), and approximately 10% have an elevated serum TSH level (subclinical hypothyroidism) (4–7).”
From Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study (2016) · cites this paper as [6]
Evidence from the US National Health and Nutrition Examination Survey (NHANES) found that about 4% of a population of community-dwelling subjects who were nominally free of thyroid dysfunction had evidence of occult autoimmune thyroid disease that increased the median TSH level and the upper reference limit for TSH.
“Evidence from the US National Health and Nutrition Examination Survey (NHANES) found that about 4% of a population of community-dwelling subjects who were nominally free of thyroid dysfunction had evidence of occult autoimmune thyroid disease that increased the median TSH level and the upper reference limit for TSH [24, 51].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [24]
Higher levels of TSH are observed in women than in men.
“Increasing TSH with age was observed for both men and women in this study, while this and other studies have demonstrated higher levels of TSH in women than in men [14, 20, 23, 24].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [24]
A study from a large, nationally representative, population-based cohort in the USA found higher levels of TSH in non-Hispanic white vs. non-Hispanic black or Mexican American subjects.
“A study from a large, nationally representative, population-based cohort in the USA found higher levels of TSH in non-Hispanic white vs. non-Hispanic black or Mexican American subjects [24].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [24]
Undiagnosed thyroid disease may be common among the general population.
“There is less of a consensus regarding screening of the population for undiagnosed thyroid disease, which may be common among the general population.”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [24]
About 6% of subjects in the NHANES III cohort in the USA had evidence of undiagnosed thyroid disease.
“For example, about 6% of subjects in the NHANES III cohort in the USA had evidence of undiagnosed thyroid disease [24].”
From Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction (2019) · cites this paper as [24]
Mild subclinical thyroid disease progresses slowly, at roughly 1% over five years, which suggests a need for long-term screening.
“Mild subclinical thyroid disease can progress at a low rate, suggesting a long-term screening program.”
From Thyroid dysfunction and diabetes mellitus: two closely associated disorders (2019) · cites this paper as [3]
Interrupting PD-1/PD-L1 signaling causes diabetes in the non-obese diabetic mouse model.
“disruption of PD-1/PD-L1 signaling induces diabetes in the non-obese diabetic (NOD) mouse model 71”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [71]
Immune checkpoint inhibitor-associated diabetes mellitus is presumably caused by immune destruction of pancreatic beta cells, as in classic type 1 diabetes.
“Similar to classic type 1 diabetes (T1D), ICI-DM is presumably caused by immune destruction of pancreatic beta cells.”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [71]
In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), and 1.8% had low TSH levels (<0.4 mU/L).
“In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), and 1.8% had low TSH levels (<0.4 mU/L) (365).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [365]
Mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease.
“In addition, mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease (365).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [365]
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“In addition, mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease (365).”
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“LT3-only therapy should be monitored with measurements of fasting serum TSH levels before the administration of the dose, aiming to target serum TSH within the lower tertile of the reference range, if aiming for TSH values seen in a normal population (54).”
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The Thyrotropin Reference Range Should Remain Unchanged
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Casey, B. M., & Leveno, K. J. (2006) · Obstetrics and Gynecology · doi:10.1097/01.aog.0000244103.91597.c5 · Cited by 289 · see citing works
- Authors
- Hollowell, J. G., Staehling, N. W., Flanders, W. D., Hannon, W. H., Gunter, E. W., Spencer, C. A., & Braverman, L. E.
- Affiliations
- National Center for Environmental Health (US)
- Emory University (US)
- University of Southern California (US)
- Boston Medical Center (US)
- Corresponding author
- Hollowell, Joseph G.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2002-02
- Volume
- 87
- Issue
- 2
- Pages
- 489-499
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1984273763
- Cited by
- 4,279
- References
- 41
- Citations by year
- 2026: 114 · 2025: 159 · 2024: 207 · 2023: 257 · 2022: 267 · 2021: 237 · 2020: 246 · 2019: 224 · 2018: 235 · 2017: 264 · 2016: 245 · 2015: 211 · 2014: 191 · 2013: 224 · 2012: 188
- FWCI
- 38.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- thyroid-stimulating hormone, serum thyroxine, thyroid peroxidase antibodies, thyroglobulin antibodies, thyroid autoantibodies, subclinical hypothyroidism, subclinical hyperthyroidism, reference values, sex differences, age differences, racial and ethnic differences, NHANES III, United States
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Autoantibodies, Black or African American, Demography, Female, Humans, Iodide Peroxidase, Iodine, Male, Middle Aged, Nutrition Surveys, Thyroglobulin, Thyrotropin, Thyroxine, Mexican Americans, White People
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