Hypothyroidism

Chaker, Layal; Bianco, Antonio C; Jonklaas, Jacqueline; Peeters, Robin P

doi:10.1016/s0140-6736(17)30703-1

Cited by 1,159Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Hypothyroidism

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Chaker, Layal, Bianco, Antonio C, Jonklaas, Jacqueline, Peeters, Robin P·2017·The Lancet

DOI 10.1016/s0140-6736(17)30703-1PMC PMC6619426

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Abstract

Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.

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Crossref · 10.1016/s0140-6736(17)30703-1

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Typical persistent hypothyroid symptoms include lethargy, sleepiness, memory problems, depression, and weight gain.
“Typical persistent hypothyroid symptoms include lethargy, sleepiness, memory problems, depression, and weight gain.6”
From Hypothyroidism (2024) · cites this paper as [6]
The Signs and symptoms section lists lethargy and weight gain as common hypothyroid symptoms and discusses cognitive impairment. The Treatment section identifies depression as a possible persistent symptom despite biochemical control, but does not establish that the full list—including sleepiness and memory problems—is typical of persistent symptoms. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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 [2]
The Diagnosis section (“Reference ranges of thyroid function tests”; page not provided) says the upper limit of TSH reference ranges typically increases with age. It defines the upper reference limit as the 97.5th percentile, but does not give a value of around 7.5 mU/L for healthy elderly people. The claim also calls that percentile a confidence interval. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Free T4 measurement is often disturbed in the presence of high circulating thyroid hormone-binding proteins because the methods do not correct the total T4 measured by the platforms in the extreme ends of the correction curve.
“free T4 measurement is often disturbed in the presence of high circulating thyroid hormone-binding proteins, because the methods do not correct the total T4 measured by the platforms in the extreme ends of the correction curve”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [87]
In “Diagnosis > Conditions that interfere with diagnosis” (page not available), the paper says the accuracy of free thyroxine immunoassays has been questioned when binding-protein concentrations change. It does not specify high concentrations, say measurement is often disturbed, or attribute the problem to failure to correct total T4 at the ends of a correction curve; it also says the assays generally perform well in clinical practice. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Due to high and increasing distribution proteins, a TSH-like effect from HCG, an unstable hypothalamus-pituitary-thyroid balance, and the long physiological half-life of T4, it can be challenging to correctly interpret TSH and FT4.
“Due to the very high and increasing distribution proteins, a TSH-like effect from HCG, an unstable hypothalamus–pituitary–thyroid balance, and the long physiological half-life of T4, it can be challenging to correctly interpret the most commonly used thyroid function tests TSH and FT4 (87, 88).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [87]
The Diagnosis section ('Conditions that interfere with diagnosis'; page unavailable) says that pregnancy-related changes in binding-protein concentrations can complicate free-thyroxine immunoassays. It does not attribute difficulty interpreting TSH and FT4 to an hCG-mediated TSH-like effect, an unstable hypothalamic–pituitary–thyroid balance, or T4’s long half-life; searches for those terms did not establish those mechanisms in this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measured
TSH is the most sensitive and earliest biochemical marker of hypothyroidism.
“The pituitary -derived TSH, due to its complex inverse association with the thyroid hormones (thyroxine and triiodothyronine), is the most sensitive and earliest biochemical marker of hypothyroidism. 2,3”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [2]
The Introduction (page not available) describes elevated TSH with normal free thyroxine as a sign of early thyroid failure, supporting TSH as an early biochemical indicator. The Diagnosis section uses TSH to define primary hypothyroidism, but the paper does not establish that it is the most sensitive or earliest marker compared with all others. (LLM, conf=0.82)
Experimental — accuracy not yet measured

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TSH Reference Limits: New Concepts and Implications for Diagnosis of Subclinical Hypothyroidism
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New Thyroxine Treatment in Older Adults Beginning Lithium Therapy: Implications for Clinical Practice
Shulman, K. (2005) · American Journal of Geriatric Psychiatry · doi:10.1176/appi.ajgp.13.4.299 · Cited by 11 · see citing works

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Global epidemiology of hyperthyroidism and hypothyroidism
Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.18 · Cited by 1,552 · see citing works
Congenital Hypothyroidism: A 2020–2021 Consensus Guidelines Update—An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology
van Trotsenburg, P., Stoupa, A., Léger, J., Rohrer, T., Peters, C., Fugazzola, L., Cassio, A., Heinrichs, C., Beauloye, V., Pohlenz, J., et al. (2021) · Thyroid® · doi:10.1089/thy.2020.0333 · Cited by 469 · see citing works
Hypothyroidism
Chaker, L., Razvi, S., Bensenor, I. M., Azizi, F., Pearce, E. N., & Peeters, R. P. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00357-7 · Cited by 330 · see citing works
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Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
Teumer, A., Chaker, L., Groeneweg, S., Li, Y., Di Munno, C., Barbieri, C., Schultheiss, U. T., Traglia, M., Ahluwalia, T. S., Akiyama, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06356-1 · Cited by 280 · see citing works
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An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction
Peterson, S. J., Cappola, A. R., Castro, M. R., Dayan, C. M., Farwell, A. P., Hennessey, J. V., Kopp, P. A., Ross, D. S., Samuels, M. H., Sawka, A. M., et al. (2018) · Thyroid · doi:10.1089/thy.2017.0681 · Cited by 231 · see citing works
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Association of subclinical hypothyroidism and cardiovascular disease with mortality
Inoue, K., Ritz, B., Brent, G. A., Ebrahimi, R., Rhee, C. M., & Leung, A. M. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.20745 · Cited by 191 · see citing works
Primary hypothyroidism and quality of life
Hegedüs, L., Bianco, A. C., Jonklaas, J., Pearce, S. H., Weetman, A. P., & Perros, P. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00625-8 · Cited by 144 · see citing works
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Hypothyroidism
Taylor, P. N., Medici, M. M., Hubalewska-Dydejczyk, A., & Boelaert, K. (2024) · The Lancet · doi:10.1016/s0140-6736(24)01614-3 · Cited by 128 · see citing works
Prevalence of undiagnosed hypothyroidism in Europe: a systematic review and meta-analysis.
Mendes, D., Alves, C., Silverio, N., & Batel Marques, F. (2019) · European Thyroid Journal · doi:10.1159/000499751 · Cited by 113 · see citing works
Hypothyroidism prevalence in the United States: a retrospective study combining National Health and Nutrition Examination Survey and claims data, 2009-2019.
Wyne, K. L., Nair, L., Schneiderman, C. P., Pinsky, B., Antunez Flores, O., Guo, D., Barger, B., & Tessnow, A. H. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac172 · Cited by 111 · see citing works
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
Jo, S., Fonseca, T. L., Bocco, B. M. L. C., Fernandes, G. W., McAninch, E. A., Bolin, A. P., Da Conceição, R. R., Werneck-de-Castro, J. P., Ignacio, D. L., Egri, P., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci123176 · Cited by 107 · see citing works
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Clinical aspects of thyroid function during ageing
Chaker, L., Cappola, A. R., Mooijaart, S. P., & Peeters, R. P. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30028-7 · Cited by 94 · see citing works
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Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism
Shakir, M. K. M., Brooks, D. I., McAninch, E. A., Fonseca, T. L., Mai, V. Q., Bianco, A. C., & Hoang, T. D. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab478 · Cited by 92 · see citing works
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Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice
Taylor, P. N., Lansdown, A., Witczak, J., Khan, R., Rees, A., Dayan, C. M., & Okosieme, O. (2023) · Thyroid Research · doi:10.1186/s13044-023-00149-5 · Cited by 72 · see citing works
Recent advances in thyroid hormone regulation: toward a new paradigm for optimal diagnosis and treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00364 · Cited by 69 · see citing works
The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review
Perros, P., Van Der Feltz‐Cornelis, C., Papini, E., Nagy, E. V., Weetman, A. P., & Hegedüs, L. (2023) · Clinical Endocrinology · doi:10.1111/cen.14473 · Cited by 65 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Relationship between thyroid hormones and central nervous system metabolism in physiological and pathological conditions
Sawicka-Gutaj, N., Zawalna, N., Gut, P., & Ruchała, M. (2022) · Pharmacological Reports · doi:10.1007/s43440-022-00377-w · Cited by 57 · see citing works
Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism
Idrees, T., Palmer, S., Maciel, R. M. B., & Bianco, A. C. (2020) · Thyroid® · doi:10.1089/thy.2020.0153 · Cited by 58 · see citing works
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Persisting symptoms in patients with Hashimoto’s disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review
Groenewegen, K. L., Mooij, C. F., & van Trotsenburg, A. S. P. (2021) · Journal of Translational Autoimmunity · doi:10.1016/j.jtauto.2021.100101 · Cited by 49 · see citing works
Association between rheumatoid arthritis and thyroid dysfunction: a meta-analysis and systematic review.
Liu, Y.-J., Miao, H.-B., Lin, S., & Chen, Z. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1015516 · Cited by 49 · see citing works
Trends, Determinants, and Associations of Treated Hypothyroidism in the United Kingdom, 2005–2014
Razvi, S., Korevaar, T. I. M., & Taylor, P. (2019) · Thyroid · doi:10.1089/thy.2018.0251 · Cited by 45 · see citing works
Prevalence of gastrointestinal disorders having an impact on tablet levothyroxine absorption: should this formulation still be considered as the first-line therapy?
Castellana, M., Castellana, C., Giovanella, L., & Trimboli, P. (2020) · Endocrine · doi:10.1007/s12020-019-02185-4 · Cited by 41 · see citing works
Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: a propensity score-matched analysis
Yi, W., Kim, B. H., Kim, M., Kim, J., Im, M., Ryang, S., Kim, E. H., Jeon, Y. K., Kim, S. S., & Kim, I. J. (2022) · Thyroid · doi:10.1089/thy.2021.0634 · Cited by 36 · see citing works
Emerging Therapies in Hypothyroidism
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Self-citation
Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality
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Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement
Ahluwalia, R., Baldeweg, S. E., Boelaert, K., Chatterjee, K., Dayan, C., Okosieme, O., Priestley, J., Taylor, P., Vaidya, B., Zammitt, N., et al. (2023) · Clinical Endocrinology · doi:10.1111/cen.14935 · Cited by 34 · see citing works
ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism
Centanni, M., Duntas, L., Feldt-Rasmussen, U., Koehrle, J., Peeters, R. P., Razvi, S., Trimboli, P., & Virili, C. (2025) · European Thyroid Journal · doi:10.1530/etj-25-0123 · Cited by 38 · see citing works
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Sustained release T3 therapy: animal models and translational applications
Idrees, T., Price, J. D., Piccariello, T., & Bianco, A. C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00544 · Cited by 30 · see citing works
Self-citation
Attitudes and perceptions of health professionals towards management of hypothyroidism in general practice: a qualitative interview study
Dew, R., King, K., Okosieme, O. E., Pearce, S. H., Donovan, G., Taylor, P. N., Hickey, J., Dayan, C. M., Leese, G., Razvi, S., et al. (2018) · BMJ Open · doi:10.1136/bmjopen-2017-019970 · Cited by 31 · see citing works
Serum thyrotropin and triiodothyronine levels in levothyroxine-treated patients
Ettleson, M. D., Prieto, W. H., Russo, P. S. T., de Sa, J., Wan, W., Laiteerapong, N., Maciel, R. M. B., & Bianco, A. C. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac725 · Cited by 25 · see citing works
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Impact of a forced dose-equivalent levothyroxine brand switch on plasma thyrotropin: a cohort study.
Flinterman, L. E., Kuiper, J. G., Korevaar, J. C., van Dijk, L., Hek, K., Houben, E., Herings, R., Franken, A. A. M., de Graaf, J. P., Horikx, A., et al. (2020) · Thyroid · doi:10.1089/thy.2019.0414 · Cited by 23 · see citing works
Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats
Da Conceição, R. R., Fernandes, G. W., Fonseca, T. L., Bocco, B. M. L. C., & Bianco, A. C. (2018) · Thyroid · doi:10.1089/thy.2018.0205 · Cited by 23 · see citing works
Self-citation
Effect of Antipsychotic Treatment on Neutrophil-to-Lymphocyte Ratio during Hospitalization for Acute Psychosis in the Course of Schizophrenia—A Cross-Sectional Retrospective Study
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Extended absorption of liothyronine from poly-zinc-liothyronine: results from a phase 1, double-blind, randomized, and controlled study in humans
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Alternative routes of levothyroxine administration for hypothyroidism
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Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss: Scientific Impact Paper No. 70 June 2022
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A novel levothyroxine solution results in similar bioavailability whether taken 30 or just 15 minutes before a high-fat high-calorie meal
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Real Practice Assessment of Persistent Symptoms After Initiation of Levothyroxine
Hidalgo, J., Vallejo, B. A., Soto Jacome, C., Ayala, I. N., Cordova, S., Duran, M., Golembiewski, E., Toro-Tobon, D., & Brito, J. P. (2024) · Endocrine Practice · doi:10.1016/j.eprac.2023.10.132 · Cited by 12 · see citing works
Risk of Death and Adverse Effects in Patients on Liothyronine: A Multisource Systematic Review and Meta-analysis
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Hypothyroid Symptoms in Levothyroxine-Treated Patients
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Pituitary Hyperplasia Due to Longstanding Primary Hypothyroidism: A Case Report and Comprehensive Review of the Literature
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Thyroid function and opium use disorder: a cross-sectional study on the Fasa adults cohort study (FACS), 2017
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Authors: Chaker, L., Bianco, A. C., Jonklaas, J., & Peeters, R. P.
Affiliations: Erasmus MC (NL)
Rush University Medical Center (US)
Georgetown University (US)
Corresponding author: Peeters, Robin P
ORCID: Chaker, Layal
Bianco, Antonio C
Jonklaas, Jacqueline
Peeters, Robin P
Venue: The Lancet
Publisher: Elsevier BV
Published: 2017-09
Volume: 390
Issue: 10101
Pages: 1550-1562
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(17)30703-1
PMC: PMC6619426
OpenAlex: W4211084027
Cited by: 1,159
References: 141
Citations by year: 2026: 111 · 2025: 165 · 2024: 193 · 2023: 154 · 2022: 157 · 2021: 139 · 2020: 110 · 2019: 68 · 2018: 51 · 2017: 9 · 2016: 1
FWCI: 9.49
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Newcastle University ePrints (Newcastle Univesity)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065055)
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: hypothyroidism, thyroid hormone deficiency, levothyroxine, thyroid hormone replacement, hypothyroidism diagnosis, hypothyroidism symptoms, long-term risk, treatment goals
MeSH terms: Hypothyroidism, Thyroxine, Disease Management, Hormone Replacement Therapy

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