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Subclinical Hypothyroidism: A Review

Biondi, Bernadette, Cappola, Anne R., Cooper, David S.·2019·JAMA
DOI 10.1001/jama.2019.9052
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Abstract

IMPORTANCE: Subclinical hypothyroidism, defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT4) affects up to 10% of the adult population. OBSERVATIONS: Subclinical hypothyroidism is most often caused by autoimmune (Hashimoto) thyroiditis. However, serum thyrotropin levels rise as people without thyroid disease age; serum thyrotropin concentrations may surpass the upper limit of the traditional reference range of 4 to 5 mU/L among elderly patients. This phenomenon has likely led to an overestimation of the true prevalence of subclinical hypothyroidism in persons older than 70 years. In patients who have circulating thyroid peroxidase antibodies, there is a greater risk of progression from subclinical to overt hypothyroidism. Subclinical hypothyroidism may be associated with an increased risk of heart failure, coronary artery disease events, and mortality from coronary heart disease. In addition, middle-aged patients with subclinical hypothyroidism may have cognitive impairment, nonspecific symptoms such as fatigue, and altered mood. In the absence of large randomized trials showing benefit from levothyroxine therapy, the rationale for treatment is based on the potential for decreasing the risk of adverse cardiovascular events and the possibility of preventing progression to overt hypothyroidism. However, levothyroxine therapy may be associated with iatrogenic thyrotoxicosis, especially in elderly patients, and there is no evidence that it is beneficial in persons aged 65 years or older. CONCLUSIONS AND RELEVANCE: Subclinical hypothyroidism is common and most individuals can be observed without treatment. Treatment might be indicated for patients with subclinical hypothyroidism and serum thyrotropin levels of 10 mU/L or higher or for young and middle-aged individuals with subclinical hypothyroidism and symptoms consistent with mild hypothyroidism.

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  • At present, there is insufficient evidence that treatment of younger individuals (<65 years) with subclinical hypothyroidism improves symptoms or quality of life.

    “At present, there is insufficient evidence that treatment of younger individuals (<65 years) with subclinical hypothyroidism improves symptoms or quality of life.51”

    From Hypothyroidism (2024) · cites this paper as [51]

  • Hypothyroidism may affect up to 12% of the population, primarily as subclinical hypothyroidism, with higher prevalence in areas with inadequate nutritional iodine levels.

    “The prevalence in North America and Europe ranges from 0.3%to2%, 3-5 but may affect up to 12% of the population, primarily as subclinical hypothyroidism,withhigherprevalenceinareaswith inadequate nutritional iodine levels. 2,6”

    From Hypothyroidism: A Review (2025) · cites this paper as [2]

  • This recommendation has been followed by 2 recent comprehensive reviews that summarized the evidence arguing against clinical benefits of thyroid hormone replacement therapy toward quality of life or hypothyroid symptoms among adults, especially elderly individuals, with subclinical hypothyroidism.

    “This recommendation has been followed by 2 recent comprehensive reviews1,12 that summarized the evidence arguing against clinical benefits of thyroid hormone replacement therapy toward quality of life or hypothyroid symptoms among adults, especially elderly individuals, with subclinical hypothyroidism.”

    From Association of subclinical hypothyroidism and cardiovascular disease with mortality (2020) · cites this paper as [1]

  • For individuals aged <65 years, LT4 therapy is recommended when TSH is persistently >7.0 mIU/L.

    “LT4 therapy is recommended in this age group when TSH is persistently >7.0 mIU/L”

    From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [132]

  • LT4 may be considered for reduced risk of progression to overt hypothyroidism and adverse cardiovascular outcomes for patients aged >65 years with TSH >7 mIU/L, and offered when TSH is persistently over 10 mIU/L.

    “LT4 may be considered for reduced risk of progression to overt hypothyroidism and adverse cardiovascular outcomes for patients aged >65 years with TSH >7 mIU/L, and offered when TSH is persistently over 10 mIU/L”

    From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [132]

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Authors
Biondi, B., Cappola, A. R., & Cooper, D. S.
Affiliations
  • Federico II University Hospital (IT)
  • University of Pennsylvania (US)
  • Johns Hopkins University (US)
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2019-07-09
Volume
322
Issue
2
Pages
153
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2019.9052
OpenAlex
W2958558042
Cited by
604
References
80
Citations by year
2026: 70 · 2025: 82 · 2024: 88 · 2023: 106 · 2022: 95 · 2021: 86 · 2020: 62 · 2019: 14
FWCI
9.87
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (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
subclinical hypothyroidism, thyroid-stimulating hormone, Hashimoto's thyroiditis, thyroid peroxidase antibodies, cardiovascular risk, heart failure, coronary artery disease, mortality, cognitive impairment, levothyroxine therapy, thyrotoxicosis, elderly patients
MeSH terms
Age Factors, Female, Humans, Hypothyroidism, Thyrotropin, Thyroxine, Disease Progression, Hormone Replacement Therapy, Hashimoto Disease

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