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Cited by 4Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Pharmacodynamic and Therapeutic Actions of Levothyroxine

Open access
Hennessey, James V.·2021·70 Years of Levothyroxine
DOI 10.1007/978-3-030-63277-9_3
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Abstract

The opening chapters of this book outlined the historical development of levothyroxine (LT4) as a treatment for hypothyroidism and described the pharmacokinetic properties of exogenously applied levothyroxine. The purpose of this chapter is to summarise the therapeutic actions of LT4 in key organs of the body. Exogenous LT4 is indistinguishable from endogenous T4, and so I have sought to summarise the biological actions of T4 per se , in terms of the regulation of secretion and action of thyroid hormones and the therapeutic effects of LT4 supplementation in people with hypothyroidism in key areas of the body (Fig. 1 ). This chapter will not include detailed descriptions of the effects of LT4 on the heart or the skeleton: these aspects are covered in chapters, “Levothyroxine and the Heart” and “Levothyroxine and Bone” of this book, respectively. Finally, I have considered the evolution and current status of guidelines for the management of hypothyroidism, and the current evidence base for the therapeutic use of LT4 monotherapy, the current mainstay of treatment for hypothyroidism.

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Written from the paper’s full text.

TL;DR

This book chapter reviews the pharmacodynamics and therapeutic actions of levothyroxine (LT4), emphasizing that LT4 acts largely as a prodrug of T3 and reverses many metabolic, lipid, glucose, inflammatory, coagulation, renal, and mood-related consequences of hypothyroidism. LT4 monotherapy titrated to a normal TSH remains the guideline-recommended mainstay, while evidence for LT4–LT3 combination therapy remains inconsistent.

Key findings

  • LT4 replacement reverses many hypothyroidism-associated disturbances, including reduced resting energy expenditure and metabolic rate, dyslipidaemia, insulin resistance/glucose intolerance, pro-inflammatory and procoagulant states, and some mood symptoms; however, mood and non-specific symptoms are often less completely resolved.
  • T4 is the primary thyroid secretory product, accounting for about 60–80% of circulating thyroid hormones; about 80% of circulating T3 is derived from peripheral activation of T4, while the remaining 20% is produced in the thyroid.
  • TSH is highly sensitive to T4: reducing FT4 by half would typically increase TSH up to 100-fold, whereas a five-fold TSH increase may be seen when FT4 is reduced by only about 10%.
  • In subclinical hypothyroidism, evidence for LT4 benefit on subjective outcomes is weak: a meta-analysis of 21 randomized placebo-controlled trials (N = 2,192 subclinically hypothyroid adults) confirmed lack of improvement in quality of life and thyroid-related symptoms, and the TRUST trial in 737 patients aged >65 years found no significant change in thyroid symptoms or tiredness scores at 12 months.
  • LT4–LT3 combination therapy has not shown convincing or consistent benefit over LT4 monotherapy, and current guidelines do not support routine LT3 use.

Methods

  • Narrative review/book chapter summarizing the pharmacodynamics and therapeutic actions of LT4 across key organ systems, based on selected literature, clinical trials, meta-analyses, and guidelines.
  • The chapter includes a table overview of LT4 effects in hypothyroidism and a table summarizing strong American Thyroid Association recommendations for overt hypothyroidism management.
  • No primary data collection or systematic search strategy is reported; the work synthesizes existing evidence and expert interpretation.

Limitations

  • The chapter does not state its own limitations. It does note limitations of the TRUST trial, including use of non-age-adjusted TSH at entry, likely inclusion of many functionally euthyroid subjects, one-quarter of subjects being asymptomatic, and normalization of TSH in an unknown but significant portion of the placebo group.
  • Evident from the text: this is a narrative review rather than a systematic review, with no described search strategy, inclusion criteria, or formal risk-of-bias assessment.
  • Evident from the text: many conclusions rely on heterogeneous, sometimes conflicting, observational studies and randomized trials, and the chapter explicitly excludes detailed coverage of LT4 effects on the heart and bone, referring readers to other chapters.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/978-3-030-63277-9_3

Cites

141 of 141 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 92 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In hypothyroid patients rendered surgically athyroid who were titrated to a normal TSH with LT4, 49% had higher T3 levels on LT4 than in their native preoperative state in one study.

    “49% of those titrated to a normal TSH had higher T3 levels on LT4 than in their native preoperative state in one study”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008;299:769–77. source

      Not checked in the free run.

  • Interpretationnone given

    Monotherapy with LT4 remains the mainstay of treatment for hypothyroidism due to a lack of clinical evidence for superior treatment outcomes with combinations of LT4 and triiodothyronine.

    “Monotherapy with LT4 remains the mainstay of treatment for hypothyroidism, due to a lack of clinical evidence for superior treatment outcomes with combinations of LT4 and triiodothyronine.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    LT4 replacement corrects dyslipidaemia in hypothyroidism.

    “correction of dyslipidaemia”
    Quote in the paperNot a substantial claim
  • Premisecitation

    LT4 acts essentially as a prodrug of T3 in target tissues, via the actions of the deiodinase enzymes.

    “LT4 acts essentially as a prodrug of T3 in target tissues, via the actions of the deiodinase enzymes, described above”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Bianco AC, da Conceição RR. The deiodinase trio and thyroid hormone signaling. Methods Mol Biol. 2018;1801:67–83. source

      Not checked in the free run.

  • Premisecitation

    Loss-of-function mutations in THRs produce elevated circulating T4 and T3 levels simultaneously with signs of a functional peripheral hypothyroidism.

    “Loss-offunction mutations in THRs have been shown to produce elevated circulating T4 and T3 levels simultaneously with signs of a functional peripheral hypothyroidism”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Singh BK, Yen PM. A clinician’s guide to understanding resistance to thyroid hormone due to receptor mutations in the TRα and TRβ isoforms. Clin Diab Endocrinol. 2017;3:8. source

      Not checked in the free run.

  • May combine two claims. 29
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Interpretationnone given

    LT4 replacement eventually corrects mood disturbances in hypothyroidism, although mood disturbances appear more refractory to LT4 treatment than other consequences of hypothyroidism.

    “and the eventual correction of mood disturbances (although on the surface these appear more refractory to LT4 treatment than other consequences of hypothyroidism)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    LT4 replacement improves insulin sensitivity and glycaemic control in hypothyroidism.

    “improvement in insulin sensitivity and glycaemic control”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TSH release is highly sensitive to the prevailing level of T4: reducing FT4 by half would typically increase the TSH level by up to 100-fold; conversely, a five-fold increase in the TSH level might be seen when FT4 is reduced by only about 10%.

    “reducing FT4 by half would typically increase the TSH level by up to 100-fold; conversely, a five-fold increase in the TSH level might be seen when FT4 is reduced by only about 10%”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Sheehan MT. Biochemical testing of the thyroid: TSH is the best and, oftentimes, only test needed—a review for primary care. Clin Med Res. 2016;14:83–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Production of TRH by the hypothalamus is an absolute requirement for the production of TSH, and thus thyroidal T4.

    “Production of TRH by the hypothalamus is an absolute requirement for the production of TSH, and thus thyroidal T4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Nikrodhanond AA, Ortiga-Carvalho TM, Shibusawa N, et al. Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis. J Biol Chem. 2006;281:5000–7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    LT4 replacement reverses a pro-inflammatory and procoagulant state in hypothyroidism.

    “reversal of a pro-inflammatory and procoagulant state”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The relationship of TSH levels to FT4 levels has been described as inverse log-linear although more complex non-linear associations have been described.

    “The relationship of TSH levels to FT4 levels has been described as inverse log-linear although more complex non-linear associations have been described”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22][23][24][25]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ubiquitination of Deiodinase 2 in some tissues reduces its activity, and this occurs to a lesser extent in the hypothalamus than in some other tissues, which may increase sensitivity to feedback inhibition of TRH release by (L)T4.

    “ubiquitination of Deiodinase 2 in some tissues reduces its activity; this occurs to a lesser extent in the hypothalamus than in some other tissues, which may increase sensitivity to feedback inhibition of TRH release by (L)T4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Werneck de Castro JP, Fonseca TL, Ueta CB, et al. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest. 2015;125:769–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excess thyroid hormone activity results in a procoagulant state, with increased VWF, FVIII, fibrinogen, and D-dimer in subclinical hyperthyroidism and elevations in fibrinogen, fibronectin, VWF, thrombomodulin, and PAI-1, with decreased t-PA in overt endogenous hyperthyroidism.

    “Excess thyroid hormone activity results in a procoagulant state, with increased VWF, FVIII, fibrinogen, and D-dimer in subclinical hyperthyroidism and elevations in fibrinogen, fibronectin, VWF, thrombomodulin, and PAI-1, with decreased t-PA in overt, endogenous hyperthyroidism”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [103] Elbers LPB, Fliers E, Cannegieter SC. The influence of thyroid function on the coagulation system and its clinical consequences. J Thromb Haemost. 2018;16:634–45. source

      Not checked in the free run.

    • cites [112] Lippi G, Salvagno GL, Rugolotto S, et al. Routine coagulation tests in newborn and young infants. J Thromb Thrombolysis. 2007;24:153–5. source

      Not checked in the free run.

    • cites [113] Li Y, Chen H, Tan J, Wang X, Liang H, Sun X. Impaired release of tissue plasminogen activator from the endothelium in Graves’ disease—indicator of endothelial dysfunction and reduced fibrinolytic capacity. Eur J Clin Investig. 1998;28:1050–4. source

      Not checked in the free run.

    • cites [114] Liu L, Wang X, Lin Z, Wu H. Elevated plasma levels of VWF: Ag in hyperthyroidism are mediated through beta-adrenergic receptors. Endocr Res. 1993;19:123–33. source

      Not checked in the free run.

    • cites [115] Myrup B, Bregengård C, Faber J. Primary haemostasis in thyroid disease. J Intern Med. 1995;238:59–63. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a randomised, placebo-controlled study, LT4 treatment reduced serum uric acid and excretion of albumin in patients with diabetic nephropathy and subclinical hypothyroidism, consistent with a renoprotective effect.

    “In another randomised, placebocontrolled study, LT4 treatment reduced serum uric acid and excretion of albumin in a trial in patients with diabetic nephropathy and subclinical hypothyroidism, an effect consistent with a renoprotective effect”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Liu P, Liu R, Chen X, et al. Can levothyroxine treatment reduce urinary albumin excretion rate in patients with early type 2 diabetic nephropathy and subclinical hypothyroidism? A randomized double-blind and placebo-controlled study. Curr Med Res Opin. 2015;31:2233–40. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most recent ATA guideline for the management of hypothyroidism (2014) considered 64 questions relating to the care of these patients, grouped under 24 topics.

    “The most recent ATA guideline for the management of hypothyroidism (2014) considered 64 questions relating to the care of these patients, grouped under 24 topics”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that trial, the effect in the LT4 group was driven strongly by improvements in the somatic subscale of the BDI, with no significant improvement in the affect scale.

    “The effect in the LT4 group was driven strongly by improvements in the somatic subscale of the BDI, with no significant improvement in the affect scale”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Najafi L, Malek M, Hadian A, Ebrahim Valojerdi A, Khamseh ME, Aghili R. Depressive symptoms in patients with subclinical hypothyroidism—the effect of treatment with levothyroxine: a double-blind randomized clinical trial. Endocr Res. 2015;40:121–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyrotoxicosis induced by administration of LT4 to healthy volunteers and those with thyroid nodules induces a procoagulant state, associated with increased levels of FVIII, FIX, FX, VWF, fibrinogen D-dimer, and PAI-1 with delayed fibrin clot lysis and a shortening of the APTT, but with an inconsistent impact on clot structure parameters.

    “Thyrotoxicosis induced by administration of LT4 to healthy volunteers and those with thyroid nodules also induces a procoagulant state, associated with increased levels of FVIII, FIX, FX, VWF, fibrinogen D-dimer, and PAI-1 with delayed fibrin clot lysis and a shortening of the APTT, but with an inconsistent impact on clot structure parameters”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [118] Akinci B, Demir T, Comlekci A, et al. Effect of levothyroxine suppression therapy on plasma thrombin activatable fibrinolysis inhibitor antigen levels in benign thyroid nodules. Med Princ Pract. 2011;20:23–8. source

      Not checked in the free run.

    • cites [119] Demir T, Akinci B, Comlekci A, et al. Levothyroxine (LT4) suppression treatment for benign thyroid nodules alters coagulation. Clin Endocrinol (Oxf). 2009;71:446–50. source

      Not checked in the free run.

    • cites [120] Hooper JM, Stuijver DJ, Orme SM, et al. Thyroid dysfunction and fibrin network structure: a mechanism for increased thrombotic risk in hyperthyroid individuals. J Clin Endocrinol Metab. 2012;97:1463–73. source

      Not checked in the free run.

    • cites [121] Van Zaane B, Squizzato A, Debeij J, et al. Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study. J Thromb Haemost. 2011;9:1816–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism is paradoxically associated with a shift to a procoagulant state, with higher FVII, PAI-1, and tissue plasminogen activator, which seem to normalise with 6 months of LT4.

    “Subclinical hypothyroidism is paradoxically associated with a shift to a procoagulant state, with higher FVII, PAI-1, and tissue plasminogen activator (t-PA), which seem to normalise with 6 months of LT4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Lupoli R, Di Minno MN, Tortora A, et al. Primary and secondary hemostasis in patients with subclinical hypothyroidism: effect of levothyroxine treatment. J Clin Endocrinol Metab. 2015;100:2659–65. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt hypothyroidism is associated with modest weight gain, which reverses with LT4 treatment; however, this weight loss may be associated more with loss of excess fluid than loss of fat mass.

    “overt hypothyroidism is associated with modest weight gain, which reverses with LT4 treatment; however, this weight loss may be associated more with loss of excess fluid than loss of fat mass”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Santini F, Marzullo P, Rotondi M, et al. Mechanisms in endocrinology: the crosstalk between thyroid gland and adipose tissue: signal integration in health and disease. Eur J Endocrinol. 2014;171:R137–52. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low levels of circulating thyroid hormone shift the haemostatic system to a hypocoagulable hyper-fibrinolytic state, with reduced Factors VIII, IX, and XI and von Willebrand factor that are normalised on LT4.

    “low levels of circulating thyroid hormone shift the haemostatic system to a hypocoagulable hyper-fibrinolytic state, with reduced Factors VIII, IX, and XI and von Willebrand factor (VWF) that are normalised on LT4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] Gullo S, Sav H, Kamel N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism. Eur J Endocrinol. 2005;152:355–61. source

      Not checked in the free run.

    • cites [103] Elbers LPB, Fliers E, Cannegieter SC. The influence of thyroid function on the coagulation system and its clinical consequences. J Thromb Haemost. 2018;16:634–45. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Correction of subclinical hypothyroidism with LT4 improves insulin resistance and/or control of blood glucose.

    “Correction of subclinical hypothyroidism with LT4 has been shown to improve insulin resistance and/or control of blood glucose”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42,[64][65][66]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Symptoms consistent with hypothyroidism in euthyroid individuals do not respond to LT4 and should not be treated with LT4.

    “It seems clear that symptoms consistent with hypothyroidism in euthyroid individuals do not respond to (nor should they be treated with) LT4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001;323:891–5. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The therapeutic use of LT4 for other conditions, such as obesity, psychiatric conditions, and dyslipidaemia, is not supported and such uses remain an area for research.

    “The therapeutic use of LT4 for other conditions, such as obesity, psychiatric conditions, and dyslipidaemia, is not supported and such uses remain an area for research”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of LT4 has been observed to improve renal function, in one study improving odds of progression and lowering the incidence of end-stage kidney disease by limiting the rate of decline in glomerular filtration rate.

    “Administration of LT4 has been observed to improve renal function, in one study improving odds of progression and lowering the incidence of end-stage kidney disease by limiting the rate of decline in glomerular filtration rate”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97:2732–40. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A randomised, placebo-controlled trial in 60 patients with subclinical hypothyroidism demonstrated a significant improvement in Beck Depression Inventory scores in those randomised to LT4 therapy, while improvement was not observed in the placebo group.

    “a randomised, placebo-controlled trial in 60 patients with subclinical hypothyroidism did demonstrate a significant improvement in Beck Depression Inventory (BDI) scores in those randomised to LT4 therapy, while improvement was not observed in the placebo group”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Najafi L, Malek M, Hadian A, Ebrahim Valojerdi A, Khamseh ME, Aghili R. Depressive symptoms in patients with subclinical hypothyroidism—the effect of treatment with levothyroxine: a double-blind randomized clinical trial. Endocr Res. 2015;40:121–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circulating levels of inflammatory cytokines were increased in hypothyroidism and reduced after treatment with LT4 in a randomised, placebo-controlled trial and in an observational study.

    “Circulating levels of inflammatory cytokines were increased in hypothyroidism and reduced after treatment with LT4 in a randomised, placebo-controlled trial [100] and in an observational study [101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Krysiak R, Okopien B. The effect of levothyroxine and selenomethionine on lymphocyte and monocyte cytokine release in women with Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2011;96:2206–15. source

      Not checked in the free run.

    • cites [101] Bilgir O, Bilgir F, Calan M, Calan OG, Yuksel A. Comparison of pre- and post-levothyroxine high-sensitivity c-reactive protein and fetuin-a levels in subclinical hypothyroidism. Clinics (Sao Paulo). 2015;70:97–101. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ATA guidelines emphasise the key role of monotherapy with LT4 (the use of thyroid extracts is not supported) in the management of hypothyroidism, due mainly to its proven efficacy and safety profile, long half-life and low cost.

    “These guidelines emphasise the key role of monotherapy with LT4 (the use of thyroid extracts is not supported) in the management of hypothyroidism, due mainly to its proven efficacy and safety profile, long half-life and low cost.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Confirmation of the elevated TSH is considered essential in establishing the diagnosis of subclinical hypothyroidism although this is not a guarantee of persistent thyroid failure.

    “Confirmation of the elevated TSH is considered essential in establishing the diagnosis of subclinical hypothyroidism although this is not a guarantee of persistent thyroid failure”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534–44. source

      Not checked in the free run.

    • cites [133] Somwaru LL, Rariy CM, Arnold AM, Cappola AR. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. J Clin Endocrinol Metab. 2012;97:1962–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A guideline from the UK National Institute for Health and Care Excellence (2019) provided similar recommendations to the ATA guideline.

    “A guideline from the UK National Institute for Health and Care Excellence (2019) provided similar recommendations”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Thyroid disease: assessment and management. NICE guideline [NG145]. Nov 2019. Available at https://www.nice.org.uk/guidance/ng145/chapter/Recommendations. Accessed Jul 2020.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Another international expert group concluded that few patients with subclinical hypothyroidism would be likely to benefit from treatment with LT4.

    “Another international expert group concluded that few patients with subclinical hypothyroidism would be likely to benefit from treatment with LT4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365:l2006. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LT4 can be withdrawn if symptoms have not resolved after normalisation of the thyrotropin level.

    “LT4 can be withdrawn if symptoms have not resolved after normalisation of the thyrotropin level.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2:215–28. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An ETA guideline based on this meta-analysis recommended that a trial of LT4 should be considered in younger (<65 years) subjects with symptoms reminiscent of hypothyroidism with TSH that is elevated, but <10 mIU/L.

    “A guideline from the European Thyroid Association (ETA) based on this meta-analysis recommended that a trial of LT4 should be considered in younger (<65 years) subjects with symptoms reminiscent of hypothyroidism with TSH that is elevated, but <10 mIU/L”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2:215–28. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TSH and FT4 should be re-measured in 1-3 months when TSH is 4.5-14.9 mIU/L, and in 1-2 weeks when TSH is ≥15 mIU/L.

    “TSH and FT4 should be re-measured in 1-3 months when TSH is 4.5-14.9mIU/L, and in 1-2 weeks when TSH is ≥15 mIU/L”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322:153–60. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In TRUST, the TSH levels of the placebo group had also normalised in an unknown but significant portion with no intervention, further reducing the potential for demonstrating a therapeutic impact of LT4.

    “the TSH levels of the placebo group had also normalised in an unknown but significant portion with no intervention, further reducing the potential for demonstrating a therapeutic impact of LT4”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

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

    “LT4 may be considered for reduced risk of progression to overt hypothyroidism and adverse cardiovascular outcomes for patients aged >65 years with TSH >7 mIU/L, and offered when TSH is persistently over 10 mIU/L”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322:153–60. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most (at least 75%) of the general population and subjects unaware of their thyroid dysfunction reported their health as good; however, only half of those aware of a diagnosis of thyroid dysfunction reported good health.

    “Most (at least 75%) of the general population and subjects unaware of their thyroid dysfunction reported their health as good; however, only half of those aware of a diagnosis of thyroid dysfunction reported good health”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Jørgensen P, Langhammer A, Krokstad S, Forsmo S. Diagnostic labelling influences self-rated health. A prospective cohort study: the HUNT Study, Norway. Fam Pract. 2015;32:492–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “LT4 therapy is recommended in this age group when TSH is persistently >7.0 mIU/L”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322:153–60. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 2014 ATA guidance did not address the issue of managing subclinical hypothyroidism.

    “The 2014 ATA guidance did not address the issue of managing subclinical hypothyroidism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing age, lower education, smoking, low self-esteem, underweight, overweight, or obese and long-term illness/injury-but not thyroid function-predicted lower self-reported health.

    “Increasing age, lower education, smoking, low self-esteem, underweight, overweight, or obese and long-term illness/injury-but not thyroid function-predicted lower self-reported health”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Jørgensen P, Langhammer A, Krokstad S, Forsmo S. Diagnostic labelling influences self-rated health. A prospective cohort study: the HUNT Study, Norway. Fam Pract. 2015;32:492–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In TRUST, a total of 737 patients aged >65 years were recruited and the primary outcome parameter was QoL (Thyroid-Related Quality of Life Patient Reported Outcome [ThyPro] subscales for hypothyroid symptoms score and tiredness score).

    “A total of 737 patients aged >65 years were recruited and the primary outcome parameter was QoL (Thyroid-Related Quality of Life Patient Reported Outcome [ThyPro] subscales for hypothyroid symptoms score and tiredness score).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534–44. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Younger subjects with thyrotropin >10 mIU/L should receive LT4 whether or not they have symptoms.

    “Younger subjects with thyrotropin >10 mIU/L should receive LT4 whether or not they have symptoms”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2:215–28. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Differences in initial residual thyroid function between patients may have introduced variability into the results of trials of LT4-LT3 combination therapy.

    “differences in initial residual thyroid function between patients may have introduced variability into the results of these trials”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] DiStefano J 3rd, Jonklaas J. Predicting optimal combination LT4 + LT3 therapy for hypothyroidism based on residual thyroid function. Front Endocrinol (Lausanne). 2019;10:746. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In TRUST, although the TSH levels in those on LT4 were reduced impressively, one-quarter of subjects were asymptomatic.

    “Although the TSH levels in those on LT4 were reduced impressively, one-quarter of subjects were asymptomatic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534–44. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss-of-function polymorphisms in deiodinases have been proposed to contribute to failure of thyrotropin-guided LT4 therapy to completely abolish symptoms of hypothyroidism in some patients, due to insufficient provision of T3.

    “Loss-of-function polymorphisms in deiodinases have been proposed to contribute to failure of thyrotropin-guided LT4 therapy to completely abolish symptoms of hypothyroidism in some patients, due to insufficient provision of T3”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Paragliola RM, Corsello A, Concolino P, et al. Iodothyronine deiodinases and reduced sensitivity to thyroid hormones. Front Biosci (Landmark Ed). 2020;25:201–28. source

      Not checked in the free run.

    • cites [135] Hennessey JV, Espaillat R. Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy. Int J Clin Pract. 2018;72:e13062. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Monotherapy with LT4, optimised according to a normalised serum TSH level, remains the preferred treatment for hypothyroidism recommended by current major guidelines.

    “Monotherapy with LT4, optimised according to a normalised serum TSH level, remains the preferred treatment for hypothyroidism recommended by current major guidelines in this area.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670–751. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Hypothyroidism disturbs multiple functions within the body.

    “Accordingly, hypothyroidism disturbs multiple functions within the body.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Thyroid hormones are tightly integrated within the development, homeostasis, and repair of numerous tissues in the body, including the regulation of the HPT axis itself.

  • May combine two claims.

    Interpretationnone given

    Hormone replacement with LT4 can reverse many symptoms of hypothyroidism, including reduced energy expenditure, dyslipidaemia, and disturbances of diverse functions, including haemostasis and mood.

    “Hormone replacement with LT4 can reverse many symptoms of hypothyroidism, including reduced energy expenditure, dyslipidaemia, and disturbances of diverse functions, including haemostasis and mood.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Exogenous LT4 is indistinguishable from endogenous T4.

    “Exogenous LT4 is indistinguishable from endogenous T4, and so I have sought to summarise the biological actions of T4 per se”

  • The paper relies on this without support.

    Many patients with hypothyroidism will have residual thyroid activity.

    “as many patients will have residual thyroid activity”

  • The paper relies on this without support.

    Thyroid hormones are tightly integrated within the development, homeostasis, and repair of numerous tissues in the body, including the regulation of the HPT axis itself.

    “Thyroid hormones are tightly integrated within the development, homeostasis, and repair of numerous tissues in the body, including the regulation of the HPT axis itself.”

  • The paper relies on this without support.

    Further attempts to satisfy subjects treated with LT4 who continue to report symptoms consistent with hypothyroidism have led to the practice of finely titrating the TSH into specific tertiles of the expected range with small LT4 dose adjustments.

    “Once confidence in a diagnosis of hypothyroidism is established, further attempts to satisfy subjects treated with LT4 who continue to report symptoms consistent with hypothyroidism has led to the practice of finely titrating the TSH into specific tertiles of the expected range with small LT4 dose adjustments.”
4 of 4

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?

  • The designs of these trials attracted criticism because they recruited relatively unselected populations with hypothyroidism, with no reason to believe that they might have benefitted specifically from T3 supplementation, such as those with polymorphisms of deiodinases that would predict low fT3.

    “The designs of these trials attracted criticism, however, in that they recruited relatively unselected populations with hypothyroidism, with no reason to believe that they might have benefitted specifically from T3 supplementation, such as those with polymorphisms of deiodinases that would predict low fT3 3,5,23,27 .”

    From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [23]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • 2013 guideline described as based on a 2018 meta-analysis

    Minor

    The text says the European Thyroid Association guideline was based on the 2018 meta-analysis, but its cited reference is dated 2013. A 2013 guideline could not have been based on a 2018 publication.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Pirahanchi Y, Jialal I. Physiology, thyroid stimulating hormone (TSH). StatPearls [Internet]. Available at https://www.ncbi.nlm.nih.gov/books/NBK499850/. Accessed Jul 2020.
  2. Mariotti S, Beck-Peccoz P. Physiology of the hypothalamic-pituitary-thyroid axis. Endotext [Internet]. Available at https://www.ncbi.nlm.nih.gov/books/NBK278958/. Accessed Jul 2020.

Cited by

Sorted by citations

Related

Authors
Hennessey, J. V.
Affiliations
Beth Israel Deaconess Medical Center (US)
Corresponding author
Hennessey, James V.
ORCID
Hennessey, James V.
Venue
70 Years of Levothyroxine
Publisher
Springer International Publishing
Published
2021
Pages
23-45
DOI
10.1007/978-3-030-63277-9_3
OpenAlex
W3136055647
Cited by
4
References
141
Citations by year
2026: 2 · 2024: 1 · 2021: 1
FWCI
2.35
Type
book chapter
Language
en
Open access
Licence
Locations
Springer eBooks (publishedVersion, cc-by)
Funders
Merck KGaA
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
levothyroxine, thyroxine, hypothyroidism, thyroid hormone regulation, pharmacodynamics, thyroid hormone action, levothyroxine monotherapy

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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