Risks of suboptimal and excessive thyroid hormone replacement across ages
Open accessAbstract
Background: Hypothyroidism is prevalent at all ages and represents a non-communicable disease with preventable consequences. Method: Narrative review. Review: In children and adolescents, the most devastating consequences of undertreatment with levothyroxine (LT4) are poor growth and development. Delayed treatment in congenital hypothyroidism can lead to permanent brain damage. In young to middle-aged adults, symptoms are often overlooked, and treatment delayed by many years. The resulting consequences are also at this age group compromised brain and physical function but less severe and partly reversible with treatment. The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life. Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life. In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development. On the other hand, excessive LT4 treatment has been related to gestational hypertension, preeclampsia and preterm birth. In the elderly, care must be given to avoid confusing a slightly high age-related serum TSH with requirement for LT4 treatment in a truly hypothyroid patient. Excessive LT4 treatment in patients of high age is associated with an increased mortality. Conclusion: Suboptimal and excessive LT4 replacement of the preventable non-communicable disease hypothyroidism requires more focus from the healthcare system and from the global political systems to prevent the personally devastating and socioeconomically challenging consequences.
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Written from the paper’s full text.
TL;DR
This narrative review argues that both suboptimal and excessive levothyroxine replacement in hypothyroidism carry age-specific risks, from permanent neurodevelopmental damage in congenital hypothyroidism to increased mortality and cardiovascular events in older adults. It calls for greater healthcare and political focus on preventing under- and overtreatment across the lifespan.
Key findings
- In a Danish population study cited, the most common hypothyroidism subtype was spontaneous/autoimmune at 84.4%, followed by postpartum 4.7%, amiodarone-induced 4.0%, subacute thyroiditis 1.8%, prior radiation/surgery 1.8%, congenital 1.6%, and lithium-associated 1.6%.
- Approximately 70% of the world’s population lacks access to neonatal dried blood spot screening; untreated congenital hypothyroidism can cause permanent neurological damage, and later childhood/adolescent hypothyroidism impairs growth, behavior/ADHD, education, and independence.
- In adults, undertreatment is linked to poor mental function, reduced cardiac output, hypertension, obesity, increased cardiovascular disease burden, and poor quality of life; excessive LT4 is linked to cardiac death, osteoporosis, muscle loss, psychological instability, and poor quality of life. In pregnancy, undertreatment is linked to subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development, while excessive LT4 is linked to gestational hypertension, preeclampsia, and preterm birth.
- Meta-analyses cited report overt hypothyroidism associated with increased myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%), and overall mortality (25%) across 55 studies and 1,898,314 subjects; overt hyperthyroidism increased overall mortality by 13% and cardiovascular mortality by 21% across 7 studies and 31,138 subjects, with another meta-analysis of 37 studies and 113,393 hyperthyroid subjects confirming increased ischemic heart disease, stroke, and cardiovascular mortality. In the elderly, excessive LT4 is associated with increased mortality, and about 1/3 of older hypothyroid patients on LT4 had taken at least one medication that interferes with thyroid hormones.
Methods
- Narrative review; no systematic review protocol, search strategy, or formal meta-analysis is described.
- Synthesizes evidence across age groups and special situations: intrauterine/neonatal, children/adolescents, adults, reproductive-age women, elderly/cardiac disease, central hypothyroidism, and ICU patients, with an overview table of consequences and risks.
- Main analysis is a narrative synthesis of cited cohort studies, meta-analyses, guidelines, and physiological/measurement considerations.
Limitations
- Stated: consequences of excessive LT4 replacement are “not well explored” in children and adolescents.
- Stated: studies of undertreatment in older patients used different criteria and different numbers of TSH measurements, and further studies are needed on the optimal TSH target in older hypothyroid patients.
- Evident: as a narrative review, it lacks a systematic search, formal quality appraisal, and quantitative pooling, so conclusions rely on selected cited literature; the paper also states there is no evidence to support general use of age-appropriate reference intervals, nor to understand the impact of thyroid hormone variations in younger individuals.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 73 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Delayed treatment in congenital hypothyroidism can lead to permanent brain damage.
“Delayed treatment in congenital hypothyroidism can lead to permanent brain damage.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Ford G, LaFranchi SH (2014) Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 28:175–187. https://doi.org/10.1016/j.beem.2013.05.008 source
Not checked in the free run.
- Premisecitation
In young fertile women, undertreatment with levothyroxine is associated with compromised fetal growth.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Korevaar TIM, Derakhshan A, Taylor PN et al (2019) Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. JAMA 322:632–641. https://doi.org/10.1001/jama.2019.10931 source
Not checked in the free run.
- cites [24] Bliddal S, Feldt-Rasmussen U, Rasmussen ÅK et al (2019) Thyroid peroxidase antibodies and prospective live birth rate: a cohort study of women with recurrent pregnancy loss. Thyroid 29:1465–1474. https://doi.org/10.1089/thy.2019.0077 source
Not checked in the free run.
- Premisenone given
Excessive levothyroxine replacement in all adult age groups is associated with poor quality of life.
“Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life.”
Quote in the paperSubstantial claim - Premisecitation
Undertreated hypothyroidism in young to middle-aged adults is associated with increased cardiovascular disease burden.
“The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisecitation
In young fertile women, undertreatment with levothyroxine is associated with compromised neurocognitive development.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Korevaar TIM, Derakhshan A, Taylor PN et al (2019) Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. JAMA 322:632–641. https://doi.org/10.1001/jama.2019.10931 source
Not checked in the free run.
- cites [24] Bliddal S, Feldt-Rasmussen U, Rasmussen ÅK et al (2019) Thyroid peroxidase antibodies and prospective live birth rate: a cohort study of women with recurrent pregnancy loss. Thyroid 29:1465–1474. https://doi.org/10.1089/thy.2019.0077 source
Not checked in the free run.
- Premisecitation
Excessive levothyroxine treatment in young fertile women is related to preeclampsia.
“On the other hand, excessive LT4 treatment has been related to gestational hypertension, preeclampsia and preterm birth.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Maraka S, Mwangi R, McCoy RG et al (2017) Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 356:i6865. https://doi.org/10.1136/bmj.i6865 source
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- Premisecitation
Serum TSH is very high in neonates.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Naafs JC, Heinen CA, Zwaveling-Soonawala N et al (2020) Age-specific reference intervals for plasma free thyroxine and thyrotropin in term neonates during the first two weeks of life. Thyroid 30:1106–1111. https://doi.org/10.1089/thy.2019.0779 source
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- Premisenone given
Excessive levothyroxine replacement in all adult age groups is associated with increased risk of cardiac death.
“Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life.”
Quote in the paperNot a substantial claim - Premisecitation
In young fertile women, undertreatment with levothyroxine is associated with recurrent pregnancy loss.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Korevaar TIM, Derakhshan A, Taylor PN et al (2019) Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. JAMA 322:632–641. https://doi.org/10.1001/jama.2019.10931 source
Not checked in the free run.
- cites [24] Bliddal S, Feldt-Rasmussen U, Rasmussen ÅK et al (2019) Thyroid peroxidase antibodies and prospective live birth rate: a cohort study of women with recurrent pregnancy loss. Thyroid 29:1465–1474. https://doi.org/10.1089/thy.2019.0077 source
Not checked in the free run.
- Premisecitation
Undertreated hypothyroidism in young to middle-aged adults is associated with poor quality of life.
“The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
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- Premisecitation
Serum TSH is variable during pregnancy according to gestation.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Boas M, Forman JL, Juul A et al (2009) Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women. Eur J Endocrinol 161:903–910. https://doi.org/10.1530/EJE-09-0579 source
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- Premisecitation
Excessive levothyroxine treatment in young fertile women is related to preterm birth.
“On the other hand, excessive LT4 treatment has been related to gestational hypertension, preeclampsia and preterm birth.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Maraka S, Mwangi R, McCoy RG et al (2017) Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 356:i6865. https://doi.org/10.1136/bmj.i6865 source
Not checked in the free run.
- Premisecitation
Excessive levothyroxine treatment in young fertile women is related to gestational hypertension.
“On the other hand, excessive LT4 treatment has been related to gestational hypertension, preeclampsia and preterm birth.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Maraka S, Mwangi R, McCoy RG et al (2017) Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 356:i6865. https://doi.org/10.1136/bmj.i6865 source
Not checked in the free run.
- Premisecitation
In young fertile women, undertreatment with levothyroxine is associated with subnormal fertility.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [25] Alexander EK, Pearce EN, Brent GA et al (2017) 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27:315–389. https://doi.org/10.1089/thy.2016.0457 source
Not checked in the free run.
- cites [26] Krassas GE, Poppe K, Glinoer D (2010) Thyroid function and human reproductive health. Endocr Rev 31:702–755. https://doi.org/10.1210/er.2009-0041 source
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- Premisecitation
Serum TSH is higher in some genetic population groups such as Ashkenazy Jews.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Atzmon G, Barzilai N, Surks MI, Gabriely I (2009) Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab 94:4768–4775. https://doi.org/10.1210/jc.2009-0808 source
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- Premisecitation
In children and adolescents, the most devastating consequences of undertreatment with levothyroxine are poor growth and development.
“In children and adolescents, the most devastating consequences of undertreatment with levothyroxine (LT4) are poor growth and development.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Maria S (2017) Disorders of the thyroid gland in infancy, childhood and adolescence. https://www.endotext.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence-3/. Accessed 5 Oct 2023
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- Premisecitation
Undertreated hypothyroidism in young to middle-aged adults is associated with hypertension.
“The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisenone given
Excessive levothyroxine replacement in all adult age groups is associated with loss of muscle function.
“Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life.”
Quote in the paperSubstantial claim - Premisenone given
Excessive levothyroxine replacement in all adult age groups is associated with psychological instability.
“Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life.”
Quote in the paperSubstantial claim - Interpretationcitation
Undertreatment of hypothyroidism in young to middle-aged adults results in compromised brain and physical function that is less severe and partly reversible with treatment.
“The resulting consequences are also at this age group compromised brain and physical function but less severe and partly reversible with treatment.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisecitation
Undertreated hypothyroidism in young to middle-aged adults is associated with obesity.
“The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisecitation
Serum TSH is higher in areas of both overt and partial iodine deficiency.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Zimmermann MB, Boelaert K (2015) Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol 3:286–295. https://doi.org/10.1016/S2213-8587(14)70225-6 source
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- Premisecitation
Serum TSH increases at high age.
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Taylor PN, Lansdown A, Witczak J et al (2023) Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice. Thyroid Res 16:7. https://doi.org/10.1186/s13044-023-00149-5 source
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- Premisecitation
Excessive levothyroxine treatment in patients of high age is associated with increased mortality.
“Excessive LT4 treatment in patients of high age is associated with an increased mortality.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [41] Akirov A, Shochat T, Shechvitz A et al (2017) Pre-admission TSH levels predict long-term mortality in adults treated for hypothyroidism. Endocrine 58:481–487. https://doi.org/10.1007/s12020-017-1453-8 source
Not checked in the free run.
- cites [42] Akirov A, Gimbel H, Grossman A et al (2017) Elevated TSH in adults treated for hypothyroidism is associated with increased mortality. Eur J Endocrinol 176:57–66. https://doi.org/10.1530/EJE-16-0708 source
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- cites [43] Thayakaran R, Adderley NJ, Sainsbury C et al (2019) Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:l4892. https://doi.org/10.1136/bmj.l4892 source
Not checked in the free run.
- cites [44] Lillevang-Johansen M, Abrahamsen B, Jørgensen HL et al (2018) Over- and under-treatment of hypothyroidism is associated with excess mortality: a register-based cohort study. Thyroid 28:566–574. https://doi.org/10.1089/thy.2017.0517 source
Not checked in the free run.
- Premisenone given
Excessive levothyroxine replacement in all adult age groups is associated with increased risk of osteoporosis.
“Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life.”
Quote in the paperSubstantial claim - Premisenone given
Consequences of excessive levothyroxine replacement are not well explored in children and adolescents.
“Consequences of excessive LT4 replacement are unfortunately not well explored in this age group (Table 1).”
Quote in the paperSubstantial claim - Premisecitation
A recent large cohort study found that approximately one third of older hypothyroid patients on levothyroxine treatment had taken at least one medication that interferes with thyroid hormones.
“A recent large cohort study found that approximately 1/3 of older hypothyroid patients on LT4 treatment had taken at least one medication that interferes with thyroid hormones [39].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Livecchi R, Coe AB, Reyes-Gastelum D et al (2022) Concurrent use of thyroid hormone therapy and interfering medications in older US veterans. J Clin Endocrinol Metab 107:e2738–e2742. https://doi.org/10.1210/clinem/dgac216 source
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- Premisecitation
There is no evidence to support a benefit to offspring IQ by levothyroxine treatment of subclinical hypothyroidism or hypothyroxinemia.
“Noteworthy, there is no evidence to support a benefit to offspring IQ by LT4 treatment of subclinical hypothyroidism or hypothyroxinemia [29, 30].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29] Lazarus JH, Bestwick JP, Channon S et al (2012) Antenatal thyroid screening and childhood cognitive function. N Engl J Med 366:493–501. https://doi.org/10.1056/NEJMoa1106104 source
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- cites [30] Casey BM, Thom EA, Peaceman AM et al (2017) Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 376:815–825. https://doi.org/10.1056/NEJMoa1606205 source
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- Premisenone given
Women with higher estrogen concentrations, e.g., by use of oral contraceptives or during pregnancy, have increased thyroid hormone binding proteins, causing an increase in total T4 concentration.
“Women with a higher concentration of estrogen, e.g., by use of oral contraceptives or during pregnancy, will have an increased concentration of thyroid hormone binding proteins, which will cause an increase in the total T4 concentration.”
Quote in the paperSubstantial claim - Premisecitation
Approximately 70% of the world's population does not have access to neonatal TSH screening.
“However, despite the available dried blood spots technology since the early 1970s, approximately 70% of the world’s population does not have access to it.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Ford G, LaFranchi SH (2014) Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 28:175–187. https://doi.org/10.1016/j.beem.2013.05.008 source
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- Premisecitation
In the same cohort, risk of stroke or transient ischemic attack was not increased in any patients.
“The risk of stroke/transient ischemic attack was not increased in any patients.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Thayakaran R, Adderley NJ, Sainsbury C et al (2019) Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:l4892. https://doi.org/10.1136/bmj.l4892 source
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- Premisecitation
Several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients are associated with increased early mortality risk in older patients.
“However, several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients associated with increased early mortality risk in older patients [41–44].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [41] Akirov A, Shochat T, Shechvitz A et al (2017) Pre-admission TSH levels predict long-term mortality in adults treated for hypothyroidism. Endocrine 58:481–487. https://doi.org/10.1007/s12020-017-1453-8 source
Not checked in the free run.
- cites [42] Akirov A, Gimbel H, Grossman A et al (2017) Elevated TSH in adults treated for hypothyroidism is associated with increased mortality. Eur J Endocrinol 176:57–66. https://doi.org/10.1530/EJE-16-0708 source
Not checked in the free run.
- cites [43] Thayakaran R, Adderley NJ, Sainsbury C et al (2019) Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:l4892. https://doi.org/10.1136/bmj.l4892 source
Not checked in the free run.
- cites [44] Lillevang-Johansen M, Abrahamsen B, Jørgensen HL et al (2018) Over- and under-treatment of hypothyroidism is associated with excess mortality: a register-based cohort study. Thyroid 28:566–574. https://doi.org/10.1089/thy.2017.0517 source
Not checked in the free run.
- Premisecitation
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.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [32] Hollowell JG, Staehling NW, Flanders WD et al (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489–499. https://doi.org/10.1210/jcem.87.2.8182 source
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- cites [33] Vadiveloo T, Donnan PT, Murphy MJ, Leese GP (2013) Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). J Clin Endocrinol Metab 98:1147–1153. https://doi.org/10.1210/jc.2012-3191 source
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- cites [34] Atzmon G, Barzilai N, Hollowell JG et al (2009) Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 94:1251–1254. https://doi.org/10.1210/jc.2008-2325 source
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- cites [35] Boucai L, Surks MI (2009) Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin Endocrinol 70:788–793. https://doi.org/10.1111/j.1365-2265.2008.03390.x source
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- Premisenone given
There is no evidence to support the general use of age-appropriate reference intervals.
“There is no evidence to support the general use of age-appropriate reference intervals, nor”
Quote in the paperNot a substantial claim - Premisenone given
Congenital hypothyroidism usually cannot be diagnosed on clinical grounds until the child is several months old.
“Congenital hypothyroidism usually cannot be diagnosed on clinical grounds until the child is several months old.”
Quote in the paperSubstantial claim - Premisecitation
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].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [32] Hollowell JG, Staehling NW, Flanders WD et al (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489–499. https://doi.org/10.1210/jcem.87.2.8182 source
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- cites [33] Vadiveloo T, Donnan PT, Murphy MJ, Leese GP (2013) Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). J Clin Endocrinol Metab 98:1147–1153. https://doi.org/10.1210/jc.2012-3191 source
Not checked in the free run.
- cites [34] Atzmon G, Barzilai N, Hollowell JG et al (2009) Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 94:1251–1254. https://doi.org/10.1210/jc.2008-2325 source
Not checked in the free run.
- cites [35] Boucai L, Surks MI (2009) Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin Endocrinol 70:788–793. https://doi.org/10.1111/j.1365-2265.2008.03390.x source
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- Premisecitation
Undertreatment of hypothyroid women often leads to irregular menstrual periods and infertility.
“Furthermore, undertreatment of hypothyroid women will often lead to irregular menstrual periods and infertility, which is also the reason for the internationally recommended screening for thyroid dysfunction of all women referred to fertility treatment [25, 26].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [25] Alexander EK, Pearce EN, Brent GA et al (2017) 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27:315–389. https://doi.org/10.1089/thy.2016.0457 source
Not checked in the free run.
- cites [26] Krassas GE, Poppe K, Glinoer D (2010) Thyroid function and human reproductive health. Endocr Rev 31:702–755. https://doi.org/10.1210/er.2009-0041 source
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- Premisecitation
In the same cohort, increased risk of ischemic heart disease remained significant only in patients aged 65 years or younger.
“whereas, the increased risk of ischemic heart disease remained significant only in patients ≤ 65 years [43].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Thayakaran R, Adderley NJ, Sainsbury C et al (2019) Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:l4892. https://doi.org/10.1136/bmj.l4892 source
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- Premisecitation
A recent study found that cardiovascular mortality risk increased progressively with higher TSH, especially in older adults.
“Furthermore, a recent study found that the cardiovascular mortality risk increased progressively with higher TSH, especially in the older adults [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Evron JM, Hummel SL, Reyes-Gastelum D et al (2022) Association of thyroid hormone treatment intensity with cardiovascular mortality among US veterans. JAMA Netw Open 5:e2211863. https://doi.org/10.1001/jamanetworkopen.2022.11863 source
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- Premisecitation
All symptoms and signs of under-treated hypothyroidism result in poor quality of life and general work-functioning.
“All of these symptoms and signs result in a poor quality of life and general work-functioning [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisecitation
All patients in intensive care units have non-thyroidal illness with uninterpretable thyroid function tests.
“In the monitoring of the biochemical thyroid function, it is important to realize that all patients in ICU have non-thyroidal illness (NTI) [55] with uninterpretable thyroid function tests.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Peeters RP, Boelen A (2021) Non-thyroidal Illness (NTI). In: Wass JAH, Stewart PM, Amiel SA, Davies M (eds) Oxford textbook of endocrinology and diabetes, 3rd edn. Oxford University Press, Oxford
Not checked in the free run.
- Interpretationreasoning
Current reference ranges could also result in inappropriate treatment at all ages.
“However, they could also result in inappropriate treatment at all ages.”
Quote in the paperSubstantial claim - Premisecitation
Total and free T4 measurements are the only useful tools for diagnosis and monitoring in central hypothyroidism by current methodology.
“Total and free T4 measurements (free T4 estimates) are thus the only useful tools by current methodology [51].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Persani L, Brabant G, Dattani M et al (2018) 2018 European Thyroid Association (ETA) Guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J 7:225–237. https://doi.org/10.1159/000491388 source
Not checked in the free run.
- Premisereasoning
Treatment delay in congenital hypothyroidism leaves children with permanent neurological damage.
“The consequent treatment delay therefore leaves these children with permanent neurological damage.”
Quote in the paperSubstantial claim - Premisecitation
A recent retrospective cohort study of more than 150,000 patients with incident hypothyroidism showed an association between the highest TSH concentration and increased risk of heart failure both in patients younger and older than 65 years.
“A recent retrospective cohort study of more than 150,000 patients with incident hypothyroidism of whom 97% received LT4 therapy during the follow-up period, showed that there was an association between the highest TSH concentration and increased risk of heart failure both in patients younger and older than 65 years; whereas, the increased risk of ischemic heart disease remained significant only in”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Thayakaran R, Adderley NJ, Sainsbury C et al (2019) Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:l4892. https://doi.org/10.1136/bmj.l4892 source
Not checked in the free run.
- Premisecitation
The higher TSH in the elderly is not explained only by higher prevalence of thyroid autoimmunity.
“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].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [36] Effraimidis G, Watt T, Feldt-Rasmussen U (2021) Levothyroxine therapy in elderly patients with hypothyroidism. Front Endocrinol 12:641560. https://doi.org/10.3389/fendo.2021.641560 source
Not checked in the free run.
- cites [37] Surks MI, Hollowell JG (2007) Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 92:4575–4582. https://doi.org/10.1210/jc.2007-1499 source
Not checked in the free run.
- Premisecitation
Young or middle-aged adults are at risk of underdiagnosis and undertreatment for hypothyroidism mostly due to very non-specific symptomatology and few typical features.
“Young or middle-aged adults are also at risk of underdiagnosis and undertreatment for hypothyroidism mostly due to very non-specific symptomatology and few typical features [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Premisenone given
Patients with under-treated hypothyroidism have a low glomerular filtration rate.
“Furthermore, patients with under-treated hypothyroidism have a low glomerular filtration rate.”
Quote in the paperNot a substantial claim
- May combine two claims. 16
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 3
May combine two claims.
PremisecitationIn young to middle-aged adults, symptoms of hypothyroidism are often overlooked, and treatment is delayed by many years.
“In young to middle-aged adults, symptoms are often overlooked, and treatment delayed by many years.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
May combine two claims.
InterpretationreasoningCurrent reference ranges could potentially lead to inappropriate commencement of treatment in older individuals and in certain populations with other genetic traits.
“Consequently, current reference ranges could potentially lead to inappropriate commencement of treatment in older individuals and in certain populations with other genetic traits.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationHypothyroidism is prevalent at all ages and represents a non-communicable disease.
“Hypothyroidism is prevalent at all ages and represents a non-communicable disease with preventable consequences.”
- Also stated in: § Conclusions · plain
“Hypothyroidism is very prevalent at all age groups and represents a non-communicable disease in which the risks and consequences are preventable.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
- Rests on an assumption: The risks and consequences of hypothyroidism are preventable.
- Also stated in: § Conclusions · plain
The quote only partly states this claim.
PremisecitationUndertreated hypothyroidism in young to middle-aged adults is associated with poor physical capacity.
“The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
May combine two claims.
PremisecitationA more recent meta-analysis including 37 studies and 113,393 hyperthyroid subjects confirmed that overt hyperthyroidism increased the risk of ischemic heart disease, stroke, and cardiovascular mortality.
“Another more recent meta-analysis including 37 studies and enrolling 113,393 hyperthyroid subjects confirmed that overt hyperthyroidism increased the risk of ischemic heart disease, stroke, and cardiovascular mortality [49].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Sohn SY, Lee E, Lee MK, Lee JH (2020) The association of overt and subclinical hyperthyroidism with the risk of cardiovascular events and cardiovascular mortality: meta-analysis and systematic review of cohort studies. Endocrinol Metab 35:786–800. https://doi.org/10.3803/EnM.2020.728 source
Not checked in the free run.
May combine two claims.
PremisecitationUndertreatment of a diagnosed hypothyroid state is associated with poor mental function, ADHD or other behavioral conditions, reduced cardiac output, and decreased physical capacity.
“The risks of undertreatment of a diagnosed hypothyroid state are related to poor mental function, ADHD or other behavioral conditions, reduced cardiac output, and decreased physical capacity due to low cardiac output combined with muscle weakness and reduced lung function (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wiersinga WM (2000) Adult hypothyroidism. In: Feingold KR, Anawalt B, Blackman MR et al (eds) Endotext [Internet]. MDText.com, Inc. South Dartmouth, MA
Not checked in the free run.
May combine two claims.
Interpretationnone givenReflex overstimulation of catecholamines leads to hypertension, which together with obesity subsequently leads to an increased cardiovascular disease burden.
“A reflex overstimulation of catecholamines leads to hypertension, which together with obesity subsequently leads to an increased cardiovascular disease burden.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA comprehensive meta-analysis including 55 studies and 1,898,314 subjects concluded that overt hypothyroidism is associated with increased risk of myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%) and overall mortality (25%) compared to euthyroidism.
“Recently, a comprehensive meta-analysis including 55 studies and a total of 1,898,314 subjects, concluded that the presence of overt hypothyroidism is associated with an increased risk of myocardial ischemia (13%), myocardial infarction (15%), arrhythmias (96%) and overall mortality (25%) when compared to euthyroidism [47].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] Corona G, Croce L, Sparano C et al (2021) Thyroid and heart, a clinically relevant relationship. J Endocrinol Invest 44:2535–2544. https://doi.org/10.1007/s40618-021-01590-9 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe best approach in intensive care is to continue the regular replacement dose independent of the false thyroid function measurements to avoid both suboptimal and excessive replacement.
“The best is to continue the regular replacement dose independent of the false thyroid function measurements to avoid both suboptimal and excessive replacement [56].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Feldt-Rasmussen U (2020) Laboratory measurement of thyroid-related hormones, proteins, and autoantibodies in serum. In: Braverman LE, Cooper DS, Kopp P (eds) Werner and Ingbar"s the thyroid: a fundamental and clinical text, 11th edn. Williams & Wilkins, Lippincott, pp 868–907
Not checked in the free run.
May combine two claims.
PremisecitationLater-occurring hypothyroidism in childhood and adolescence results in impaired growth, behavioral problems, ADHD, failure of education, and failure to become independent adults.
“Later occurrence is usually associated with milder symptoms, but also results in impaired growth, behavioral problems and symptoms of attention-deficit/hyperactivity disorder (ADHD), failure of obtaining a proper education and, thus, very often failure to become independent adults.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Maria S (2017) Disorders of the thyroid gland in infancy, childhood and adolescence. https://www.endotext.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence-3/. Accessed 5 Oct 2023
Not checked in the free run.
May combine two claims.
Premisenone givenSevere untreated congenital hypothyroidism results in cretinism with blunted growth, very low IQ, failed neurological development and psychological disturbances.
“Severe untreated congenital hypothyroidism will result in cretinism with blunted growth, very low IQ, generally failed neurological development and psychological disturbances.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA meta-analysis of 7 studies and 31,138 subjects concluded that overt hyperthyroidism increased overall mortality by 13% and cardiovascular mortality by 21%.
“In another paper, a meta-analysis involved 7 studies and 31,138 subjects concluded that the presence of overt hyperthyroidism increased overall mortality by 13% and the mortality for cardiovascular causes by 21% [48].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Brandt F, Green A, Hegedüs L, Brix TH (2011) A critical review and meta-analysis of the association between overt hyperthyroidism and mortality. Eur J Endocrinol 165:491–497. https://doi.org/10.1530/EJE-11-0299 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationTo avoid undertreatment, levothyroxine dosage should be increased to mimic the physiological increase in T4 in pregnancy.
“To avoid undertreatment, the LT4 dosage should be increased to mimic the physiological increase in T4 in pregnancy [7, 25].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Feldt-Rasmussen U, Klose M (2000) Clinical strategies in the testing of Thyroid Function. In: Feingold KR, Anawalt B, Boyce A et al (eds) Endotext [Internet]. MDText.com Inc., South Dartmouth, MA
Not checked in the free run.
- cites [25] Alexander EK, Pearce EN, Brent GA et al (2017) 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27:315–389. https://doi.org/10.1089/thy.2016.0457 source
Not checked in the free run.
May combine two claims.
PremisecitationLater-occurring hypothyroidism in childhood and adolescence has high socioeconomic consequences for the individual and society, which might be prevented or reversed if treated early with levothyroxine.
“This disorder, therefore, also has high socioeconomic consequences for the individual and society, which might be prevented or reversed if treated early with LT4 [22].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Maria S (2017) Disorders of the thyroid gland in infancy, childhood and adolescence. https://www.endotext.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence-3/. Accessed 5 Oct 2023
Not checked in the free run.
May combine two claims.
PremisecitationWomen with multiple pituitary hormone deficiencies on estrogen replacement or oral contraceptives are at high risk of suboptimal replacement with a consequent worse metabolic profile.
“In case of multiple pituitary hormone deficiencies, the situation becomes more complex, e.g., in women on estrogen replacement therapy (or on oral contraceptive drugs), except worse, since TSH cannot be used [52]. These women are, therefore, at high risk of suboptimal replacement with a consequent worse metabolic profile [53].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [52] Feldt-Rasmussen U, Effraimidis G, Klose M (2021) The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions. Mol Cell Endocrinol 525:111173. https://doi.org/10.1016/j.mce.2021.111173 source
Not checked in the free run.
- cites [53] Feldt-Rasmussen U, Klose M (2016) Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients. Endocrine 54:15–23. https://doi.org/10.1007/s12020-016-1047-x source
Not checked in the free run.
May combine two claims.
PremisecitationIn pregnancy, levothyroxine treatment is important to secure sufficient placental transfer of T4, needed for fetal development and to reduce adverse pregnancy outcomes such as pregnancy loss and preterm birth.
“Specifically in pregnancy, the LT4 treatment is not only important to the woman, but also to secure a sufficient placental transfer of T4, which is needed for fetal development and to reduce adverse pregnancy outcomes such as pregnancy loss and preterm birth [23, 24].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Korevaar TIM, Derakhshan A, Taylor PN et al (2019) Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. JAMA 322:632–641. https://doi.org/10.1001/jama.2019.10931 source
Not checked in the free run.
- cites [24] Bliddal S, Feldt-Rasmussen U, Rasmussen ÅK et al (2019) Thyroid peroxidase antibodies and prospective live birth rate: a cohort study of women with recurrent pregnancy loss. Thyroid 29:1465–1474. https://doi.org/10.1089/thy.2019.0077 source
Not checked in the free run.
The quote only partly states this claim.
PremisereasoningChildren still develop cretinism because of lack of access to neonatal TSH screening.
“Therefore, children still develop cretinism [19].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Ford G, LaFranchi SH (2014) Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 28:175–187. https://doi.org/10.1016/j.beem.2013.05.008 source
Not checked in the free run.
May combine two claims.
PremisecitationIn central or secondary hypothyroidism, biologically inactive TSH is measurable by TSH immunoassays and is useless in diagnosis and monitoring of replacement.
“Unfortunately, the biologically inactive TSH molecule is measurable by the TSH immunoassays and therefore useless in the diagnosis of hypothyroidism as well as monitoring of replacement [50].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Persani L (2012) Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 97:3068–3078. https://doi.org/10.1210/jc.2012-1616 source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenExcessive levothyroxine overdosing infers serious risks such as osteoporosis, cardiac arrhythmias and heart failure, muscle wasting, poor quality of life, and cognitive disturbances.
“Excessive LT4 overdosing also infers serious risks such as osteoporosis, cardiac arrythmias and heart failure, muscle wasting, poor quality of life, and cognitive disturbances.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningIncreased thyroid hormone binding proteins interfere with most immunoassays measuring free T4, causing risk of misinterpreting free T4 and under- or overtreating women.
“This will interfere with most immunoassays measuring free T4 as they are unable to sufficiently correct for the extremes found in the high end of the correction curves. Thus, there is a risk of misinterpreting the free T4 concentrations and thereby under- or overtreating the women and correct management will require additional measures of thyroid function.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The risks and consequences of hypothyroidism are preventable.
“Hypothyroidism is prevalent at all ages and represents a non-communicable disease with preventable consequences.”
“Hypothyroidism is very prevalent at all age groups and represents a non-communicable disease in which the risks and consequences are preventable.”
The paper relies on this without support.
Hypothyroidism as a non-communicable disease is not part of any governmental focus.
“Hypothyroidism as a non-communicable disease is not part of any governmental focus.”
The paper relies on this without support.
The diagnosis of hypothyroidism is often delayed for long periods.
“However, the diagnosis is often delayed for long periods with resulting consequences for the individual and the society.”
The paper relies on this without support.
The consequences of suboptimal and excessive levothyroxine replacement are personally devastating and socioeconomically challenging.
“Suboptimal and excessive LT4 replacement of the preventable non-communicable disease hypothyroidism requires more focus from the healthcare system and from the global political systems to prevent the personally devastating and socioeconomically challenging consequences.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Undertreated patients may experience subtle and nonspecific symptoms difficult to distinguish from other clinical situations.
“while undertreated patients may experience subtle and nonspecific symptoms that are difficult to distinguish from those in many other clinical situations (6).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [6]
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“To avoid undertreatment, the LT4 dosage should be increased to mimic the physiological increase in T4 in pregnancy [7, 25].”
BackgroundThyroid Function and Human Reproductive Health
Krassas, G. E., Poppe, K., & Glinoer, D. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0041 · Cited by 1,223 · cited 1× · see citing works
“Furthermore, undertreatment of hypothyroid women will often lead to irregular menstrual periods and infertility, which is also the reason for the internationally recommended screening for thyroid dysfunction of all women referred to fertility treatment [25, 26].”
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“…increasing age and an observed relationship between longevity and lower thyroid function prompted experts to recommend a higher TSH level target of, e.g., 6 mIU/L in a 70-year-old patient treated with LT4 [40] considering other factors (drugs, comorbidities) affecting the thyroid function tests.”
BackgroundIodine deficiency and thyroid disorders
Zimmermann, M. B., & Boelaert, K. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(14)70225-6 · Cited by 930 · cited 1× · see citing works
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
BackgroundSurks, M. I., & Hollowell, J. G. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1499 · Cited by 750 · see citing works
Antenatal Thyroid Screening and Childhood Cognitive Function
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“Noteworthy, there is no evidence to support a benefit to offspring IQ by LT4 treatment of subclinical hypothyroidism or hypothyroxinemia [29, 30].”
BackgroundHypothyroidism in Context: Where We’ve Been and Where We’re Going
Chiovato, L., Magri, F., & Carlé, A. (2019) · Advances in Therapy · doi:10.1007/s12325-019-01080-8 · Cited by 491 · cited 5× · see citing works
“Other drug intakes can also influence the thyroid-related hormone measurements as well [6].”
BackgroundInfluentialTreatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy
Casey, B. M., Thom, E. A., Peaceman, A. M., Varner, M. W., Sorokin, Y., Hirtz, D. G., Reddy, U. M., Wapner, R. J., Thorp, J. M., Saade, G., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1606205 · Cited by 462 · cited 1× · see citing works
“Noteworthy, there is no evidence to support a benefit to offspring IQ by LT4 treatment of subclinical hypothyroidism or hypothyroxinemia [29, 30].”
BackgroundThe Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar, T. I. M., Derakhshan, A., Taylor, P. N., Meima, M., Chen, L., Bliddal, S., Carty, D. M., Meems, M., Vaidya, B., et al. (2019) · JAMA · doi:10.1001/jama.2019.10931 · Cited by 378 · see citing works
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THE IDENTIFICATION OF 3:5:3'-L-TRIIODOTHYRONINE IN HUMAN PLASMA
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Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges
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Screening for congenital hypothyroidism: A worldwide view of strategies
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Extreme Longevity Is Associated with Increased Serum Thyrotropin
Atzmon, G., Barzilai, N., Hollowell, J. G., Surks, M. I., & Gabriely, I. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2325 · Cited by 260 · see citing works
Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm
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“Women in fertility treatment with untreated subclinical hypothyroidism may need LT4 substitution prior to fertility treatment to support the critical phase of implantation and early pregnancy [27, 28].”
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“Total and free T4 measurements (free T4 estimates) are thus the only useful tools by current methodology [51].”
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Self-citationA critical review and meta-analysis of the association between overt hyperthyroidism and mortality
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“In another paper, a meta-analysis involved 7 studies and 31,138 subjects concluded that the presence of overt hyperthyroidism increased overall mortality by 13% and the mortality for cardiovascular causes by 21% [48].”
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“However, several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients associated with increased early mortality risk in older patients [41–44].”
Genetic Predisposition to Elevated Serum Thyrotropin Is Associated with Exceptional Longevity
Atzmon, G., Barzilai, N., Surks, M. I., & Gabriely, I. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0808 · Cited by 145 · cited 1× · see citing works
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
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“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].”
BackgroundThayakaran, R., Adderley, N. J., Sainsbury, C., Torlinska, B., Boelaert, K., Šumilo, D., Price, M., Thomas, G. N., Toulis, K. A., & Nirantharakumar, K. (2019) · BMJ · doi:10.1136/bmj.l4892 · Cited by 138 · cited 1× · see citing works
“…during the follow-up period, showed that there was an association between the highest TSH concentration and increased risk of heart failure both in patients younger and older than 65 years; whereas, the increased risk of ischemic heart disease remained significant only in patients ≤ 65 years [43].”
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Association of thyroid hormone treatment intensity with cardiovascular mortality among US veterans.
Evron, J. M., Hummel, S. L., Reyes-Gastelum, D., Haymart, M. R., Banerjee, M., & Papaleontiou, M. (2022) · JAMA Network Open · doi:10.1001/jamanetworkopen.2022.11863 · Cited by 75 · see citing works
Boas, M., Forman, J. L., Juul, A., Feldt-Rasmussen, U., Skakkebæk, N. E., Hilsted, L., Chellakooty, M., Larsen, T., Larsen, J. F., Petersen, J. H., et al. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0579 · Cited by 74 · cited 1× · see citing works
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
BackgroundSelf-citationTaylor, 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
Gut microbiome and thyroid autoimmunity
Virili, C., Stramazzo, I., & Centanni, M. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101506 · Cited by 69 · cited 1× · see citing works
“Finally, a number of concomitant drug intakes can compromise the absorption of levothyroxine [6, 17] as can gastrointestinal diseases such as coeliac disease, pernicious anemia, ulcerative colitis [18], and many more.”
BackgroundRao, M., Zeng, Z., Zhao, S., et al. (2018) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-018-0410-6 · Cited by 67 · see citing works
Bliddal, S., Feldt-Rasmussen, U., Rasmussen, Å. K., Kolte, A. M., Hilsted, L. M., Christiansen, O. B., Nielsen, C. H., & Nielsen, H. S. (2019) · Thyroid® · doi:10.1089/thy.2019.0077 · Cited by 63 · cited 1× · see citing works
“Specifically in pregnancy, the LT4 treatment is not only important to the woman, but also to secure a sufficient placental transfer of T4, which is needed for fetal development and to reduce adverse pregnancy outcomes such as pregnancy loss and preterm birth [23, 24].”
BackgroundSelf-citationLevothyroxine therapy in elderly patients with hypothyroidism
Effraimidis, G., Watt, T., & Feldt-Rasmussen, U. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.641560 · Cited by 60 · cited 4× · see citing works
“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].”
BackgroundInfluentialSelf-citationSohn, S. Y., Lee, E., Lee, M. K., & Lee, J. H. (2020) · Endocrinology and Metabolism · doi:10.3803/enm.2020.728 · Cited by 60 · see citing works
Thyroid and heart, a clinically relevant relationship
Corona, G., Croce, L., Sparano, C., Petrone, L., Sforza, A., Maggi, M., Chiovato, L., & Rotondi, M. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-021-01590-9 · Cited by 60 · cited 1× · see citing works
“%) when compared to euthyroidism [47].”
An update on thyroid disorders in the postpartum period
Peng, C. C., & Pearce, E. N. (2022) · Journal of Endocrinological Investigation · doi:10.1007/s40618-022-01762-1 · Cited by 46 · see citing works
Hattori, N., Ishihara, T., Matsuoka, N., Saito, T., & Shimatsu, A. (2016) · Thyroid · doi:10.1089/thy.2016.0442 · Cited by 44 · cited 1× · see citing works
“Although most of them are rare, it is important to know of their existence since they may otherwise result in wrong diagnoses and treatment [6, 15, 16].”
BackgroundCentral hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients
Feldt-Rasmussen, U., & Klose, M. (2016) · Endocrine · doi:10.1007/s12020-016-1047-x · Cited by 43 · cited 1× · see citing works
“These women are, therefore, at high risk of suboptimal replacement with a consequent worse metabolic profile [53].”
BackgroundSelf-citationFamilial longevity is associated with higher tsh secretion and strong TSH-fT3 relationship
Jansen, S. W., Roelfsema, F., van der Spoel, E., Akintola, A. A., Postmus, I., Ballieux, B. E., Slagboom, P. E., Cobbaert, C. M., van der Grond, J., Westendorp, R. G., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2624 · Cited by 41 · cited 1× · see citing works
“Although an association between increased serum TSH and/or lower levels of thyroid hormones and extended life span have been observed, it is still unclear if it is a positive adaptation or a progressive, negative deterioration [38].”
BackgroundRiis, K. R., Frølich, J. S., Hegedüs, L., Negro, R., Attanasio, R., Nagy, E. V., Papini, E., Perros, P., & Bonnema, S. J. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-021-01555-y · Cited by 37 · see citing works
Oral Thyroxine in the Treatment of Myxoedema
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“L-thyroxine (LT4) has been commercially available since the 1950ies and remains the cornerstone in treatment of hypothyroidism [4, 5], despite several challenges mainly including that of patients and patient organizations wishing to shift to combination therapy with T3 [1] or to revert to…”
BackgroundElevated TSH in adults treated for hypothyroidism is associated with increased mortality
Akirov, A., Gimbel, H., Grossman, A., Shochat, T., & Shimon, I. (2017) · European Journal of Endocrinology · doi:10.1530/eje-16-0708 · Cited by 24 · see citing works
Treatment of Hypothyroidism in Elderly Patients and in Patients with Cardiac Disease
Feldt-Rasmussen, U. (2007) · Thyroid · doi:10.1089/thy.2007.0033 · Cited by 24 · cited 1× · see citing works
“The profound negative effect of hypothyroidism, and the beneficial effect of LT4 therapy on cardiac function should be taken into consideration when planning thyroid hormone therapy [36, 45, 46].”
BackgroundSelf-citationL-T4 Therapy in Enteric Malabsorptive Disorders
Fallahi, P., Ferrari, S. M., Elia, G., Ragusa, F., Paparo, S. R., & Antonelli, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.626371 · Cited by 23 · cited 1× · see citing works
“Finally, a number of concomitant drug intakes can compromise the absorption of levothyroxine [6, 17] as can gastrointestinal diseases such as coeliac disease, pernicious anemia, ulcerative colitis [18], and many more.”
BackgroundNaafs, J. C., Heinen, C. A., Zwaveling-Soonawala, N., van der Schoor, S. R. D., van Tellingen, V., Heijboer, A. C., Fliers, E., Boelen, A., & van Trotsenburg, A. S. P. (2020) · Thyroid® · doi:10.1089/thy.2019.0779 · Cited by 21 · cited 1× · see citing works
“Serum TSH is, thus, higher in areas of both overt and partial iodine deficiency [8], very high in neonates [9], variable during pregnancy according to gestation [10], increasing at high age [11] and higher in some genetic population groups such as Ashkenazy Jews [12].”
BackgroundThe Management of Thyroid Abnormalities in Chronic Heart Failure
Biondi, B. (2019) · Heart Failure Clinics · doi:10.1016/j.hfc.2019.02.008 · Cited by 20 · cited 1× · see citing works
“The profound negative effect of hypothyroidism, and the beneficial effect of LT4 therapy on cardiac function should be taken into consideration when planning thyroid hormone therapy [36, 45, 46].”
BackgroundOutcomes of lowered newborn screening thresholds for congenital hypothyroidism
Yu, A., Alder, N., Lain, S. J., Wiley, V. C., Nassar, N., & Jack, M. (2023) · Journal of Paediatrics and Child Health · doi:10.1111/jpc.16425 · Cited by 13 · see citing works
Liquid levothyroxine formulations in patients taking drugs interfering with L-T4 absorption
Gatta, E., Bambini, F., Buoso, C., Gava, M., Maltese, V., Anelli, V., Delbarba, A., Pirola, I., & Cappelli, C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1080108 · Cited by 13 · see citing works
Omuse, G., Kawalya, D. E., Mugaine, P., Chege, A., & Maina, D. (2023) · BMC Endocrine Disorders · doi:10.1186/s12902-023-01367-6 · Cited by 11 · see citing works
Concurrent Use of Thyroid Hormone Therapy and Interfering Medications in Older US Veterans
Livecchi, R., Coe, A. B., Reyes-Gastelum, D., Banerjee, M., Haymart, M. R., & Papaleontiou, M. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac216 · Cited by 10 · see citing works
Pre-admission TSH levels predict long-term mortality in adults treated for hypothyroidism
Akirov, A., Shochat, T., Shechvitz, A., Shimon, I., Diker-Cohen, T., & Robenshtok, E. (2017) · Endocrine · doi:10.1007/s12020-017-1453-8 · Cited by 10 · cited 1× · see citing works
“However, several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients associated with increased early mortality risk in older patients [41–44].”
Unexplained Hyperthyrotropinemia: A Biochemical and Clinical Challenge
Croce, L., Chytiris, S., Coperchini, F., Ferraro, G., Minelli, L., Navarra, A., Magri, F., Chiovato, L., Trimboli, P., & Rotondi, M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082934 · Cited by 8 · see citing works
Flagged first, then by citations
1 of the 55 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
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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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Self-citationEnvironmental pollutants as emerging disruptors of thyroid function: Mechanisms and early-life risks
Li, Z., Deng, L., & Zhang, Y. (2026) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.119581 · Cited by 11 · see citing works
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- Authors
- Feldt-Rasmussen, U., Effraimidis, G., Bliddal, S., & Klose, M.
- Affiliations
- University of Thessaly (GR)
- Copenhagen University Hospital (DK)
- Venue
- Journal of Endocrinological Investigation
- Published
- 2023-11-28
- Volume
- 47
- Issue
- 5
- Pages
- 1083-1090
- ISSN
- 0391-4097 (ISSN-L)
- 1720-8386
- PMC
- PMC11035408
- OpenAlex
- W4389091454
- Semantic Scholar
- 70f42098cc3095ac9d08eb8afe45d32a3911121d
- Cited by
- 23
- References
- 55
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 5 · 2023: 1
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Endocrinological Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Funders
- Kirsten og Freddy Johansens Fond
- Novo Nordisk Fonden (ID 0077221)
- 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 › Hormonal and reproductive studies
- Keywords
- hypothyroidism, levothyroxine, thyroid hormone replacement, undertreatment, overtreatment, congenital hypothyroidism, growth and development, brain damage, cardiovascular disease, obesity, quality of life, fertility, miscarriage, fetal growth, gestational hypertension, preeclampsia, preterm birth, older adults, mortality, non-communicable diseases
- MeSH terms
- Female, Humans, Hypothyroidism, Quality of Life, Thyroid Hormones, Thyroxine, Hormone Replacement Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
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