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Cited by 58Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism

Open access
Idrees, Thaer, Palmer, Scott, Maciel, Rui M.B., Bianco, Antonio C.·2020·Thyroid®
DOI 10.1089/thy.2020.0153PMC PMC7640752
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Abstract

Background: The basis for the treatment of hypothyroidism with levothyroxine (LT4) is that humans activate T4 to triiodothyronine (T3). Thus, while normalizing serum thyrotropin (TSH), LT4 doses should also restore the body's reservoir of T3. However, there is evidence that T3 is not fully restored in LT4-treated patients. Summary: For patients who remain symptomatic on LT4 therapy, clinical guidelines recommend, on a trial basis, therapy with LT4+LT3. Reducing the LT4 dose by 25 mcg/day and adding 2.5–7.5 mcg liothyronine (LT3) once or twice a day is an appropriate starting point. Transient episodes of hypertriiodothyroninemia with these doses of LT4 and LT3 are unlikely to go above the reference range and have not been associated with adverse drug reactions. Trials following almost a 1000 patients for almost 1 year indicate that similar to LT4, therapy with LT4+LT3 can restore euthyroidism while maintaining a normal serum TSH. An observational study of 400 patients with a mean follow-up of ∼9 years did not indicate increased mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures after adjusting for age when compared with patients taking only LT4. Desiccated thyroid extract (DTE) is a form of combination therapy in which the LT4/LT3 ratio is ∼4:1; the mean daily dose of DTE needed to normalize serum TSH contains ∼11 mcg T3, but some patients may require higher doses. The DTE remains outside formal FDA oversight, and consistency of T4 and T3 contents is monitored by the manufacturers only. Conclusions: Newly diagnosed hypothyroid patients should be treated with LT4. A trial of combination therapy with LT4+LT3 can be considered for those patients who have unambiguously not benefited from LT4.

AI snapshot

Written from the paper’s full text.

TL;DR

This review concludes that newly diagnosed hypothyroid patients should be treated with levothyroxine (LT4), while a trial of LT4+liothyronine (LT3) can be considered for patients who have unambiguously not benefited from LT4. It finds that LT4+LT3 and desiccated thyroid extract (DTE) can restore euthyroidism with normal serum TSH, but long-term safety data remain limited.

Key findings

  • Clinical guidelines universally recommend LT4 for newly diagnosed hypothyroidism; a trial of LT4+LT3 can be considered for patients who have unambiguously not benefited from LT4. A reasonable starting point is reducing LT4 by 25 mcg/day and adding 2.5–7.5 mcg LT3 once or twice daily, with transient hypertriiodothyroninemia unlikely to exceed the reference range and not associated with increased adverse drug reactions versus LT4 alone.
  • Trials following almost 1000 patients for almost 1 year indicate that LT4+LT3 can maintain normal serum TSH and clinical/biochemical euthyroidism; an observational study of 400 patients with mean follow-up of ∼9 years did not indicate increased mortality or morbidity from cardiovascular disease, atrial fibrillation, or fractures after adjusting for age compared with LT4-only patients.
  • DTE is a combination therapy with an LT4/LT3 ratio of ∼4:1; the mean daily dose needed to normalize serum TSH contains ∼11 mcg T3, though some patients may require higher doses bringing daily T3 to ∼24 mcg. DTE produces a daily serum T3 peak 2–3 hours after dosing that can be 40–80% above baseline and may exceed the reference range at higher doses, but no adverse drug reactions were reported in trials where serum TSH was maintained within normal range.
  • In the Tayside observational study (280,334 person-years; mean follow-up 9.3 years), LT4+LT3 (n = 327) or LT3 alone (n = 73) versus nearly 34,000 LT4-only patients showed no increased mortality or morbidity from cardiovascular disease, atrial fibrillation, or fractures after age adjustment, but there was increased risk of new antipsychotic prescriptions (HR 2.26 [CI 1.64–3.11], p < 0.0001).

Methods

  • Narrative review; searched PubMed, Google Scholar, and ClinicalTrials.gov for clinical trials using keywords “liothyronine” or “desiccated thyroid extract,” completed December 2019.
  • Also reviewed the topic “treatment of hypothyroidism” in 115 textbooks published between 1883 and 1980 on medical and surgical aspects of goiter and/or the thyroid gland.
  • The search yielded 832 publications, of which 55 contained pharmacokinetic or pharmacodynamic data on LT3 or DTE and/or their use in hypothyroidism, psychiatric disorders, or metabolic disorders.

Limitations

  • The paper states that available LT3 and combination therapy trials are few, enrolled limited numbers of patients, and lasted only weeks to about 1 year; no data are available on long-term bone density or turnover markers.
  • The paper notes that most clinical trials recruited only uncomplicated hypothyroid patients—excluding pregnant or breast-feeding patients, those with cardiovascular preconditions, and those receiving concomitant drugs such as sympathomimetics—and that the Tayside safety study was retrospective, with the antipsychotic prescription finding needing assessment in other series.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, relying on heterogeneous trials and observational data; DTE remains outside formal FDA oversight, with T4/T3 content consistency monitored by manufacturers only and no independent surveillance.

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

Integrity signals

Registry

Crossref · 10.1089/thy.2020.0153

Cites

138 of 138 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

47 of 162 cited sources checked · 22 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning
    § Abstract

    T3 signaling and homeostasis in LT4-treated patients may not be fully restored in all tissues using LT4 alone.

    “This suggests that T3 signaling and homeostasis in LT4-treated patients may not be fully restored in all tissues using LT4 alone (22).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] 22. Taylor P, Bianco AC. 2019. Urgent need for further research in subclinical hypothyroidism. Nat Rev Endocrinol 15:503–504 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Abstract calls for biomarkers of tissue hypothyroidism and research into combining liothyronine with levothyroxine, which is consistent with uncertainty about LT4 replacement. It does not state that T3 signaling or homeostasis remains unrestored in any tissue of LT4-treated patients. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    In 14 hypothyroid patients taking 113 mcg/day LT4, mathematical modeling predicted that reducing LT4 by 25 mcg/day and adding 5 mcg LT3 twice daily (10 mcg daily) would increase integrated serum T3 levels without reaching the upper limit of normal.

    “In 14 hypothyroid patients (∼49 years old, 72 kg, and body mass index 26) taking 113 mcg/day LT4, the model predicted that reducing the dose of LT4 by 25 mcg/day and adding 5 mcg LT3 given twice daily (to an LT3 dose of 10 mcg daily) would increase integrated serum T3 levels, without reaching the upper limit of normal (45).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] 45. Van Tassell B, Wohlford GFt, Linderman JD, Smith S, Yavuz S, Pucino F, Celi FS. 2019. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid 29:1371–1379 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    The increase in fT3:fT4 ratio associated with this polymorphism is driven by decreased circulating fT4 and not an elevation in fT3 levels.

    “the increase in fT3:fT4 ratio associated with this polymorphism is driven by the strong association with decreased circulating fT4 and not an elevation in fT3 levels; indeed, fT3 levels were not associated with the DIO1 polymorphism (64).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] 64. Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JR, Weedon MN, Singleton A, Hernandez D, Evans J, Durant C, Ferrucci L, Melzer D, Saravanan P, Visser TJ, Ceresini G, Hattersley AT, Vaidya B, Dayan CM, Frayling TM. 2008. A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J Clin Endocrinol Metab 93:3075–3081 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Discussion (page unavailable) says the increased fT3/fT4 ratio is mainly driven by decreased fT4, supporting that part of the claim. But it also describes increased fT3 with the C allele, and the Results report an association between the polymorphism and fT3 in the WATTS cohort. The claim that fT3 levels were not associated is therefore not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Abstract

    In the same model, substituting 50 mcg LT4 for 10 mcg LT3 twice daily (20 mcg daily) would elevate serum T3 levels above the reference range only 14% of the time.

    “the substitution of 50 mcg LT4 for 10 mcg LT3 twice daily (to an LT3 dose of 20 mcg daily) would elevate serum T3 levels above the reference range only 14% of the time (45).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] 45. Van Tassell B, Wohlford GFt, Linderman JD, Smith S, Yavuz S, Pucino F, Celi FS. 2019. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid 29:1371–1379 [DOI] [PMC free article] [PubMed] [Google Scholar] source
  • Premisecitation
    § Abstract

    Lower serum TSH levels are associated with increased risk of atrial fibrillation.

    “lower serum TSH levels are associated with increased risk of atrial fibrillation (AF) (60)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [60] 60. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D'Agostino RB. 1994. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 331:1249–1252 [DOI] [PubMed] [Google Scholar] source
  • Classified as probably not a substantial claim. 27
  • May combine two claims. 59
  • The quote only partly states this claim. 3

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

    Premisecitation
    § Abstract

    ATA and NICE guidelines tolerate therapy with LT4+LT3 provided it is not used as a routine approach to hypothyroid patients.

    “the American Thyroid Association (ATA) (10) and the U.K. National Institute for Health and Care Excellence (NICE) guidelines (30) tolerate therapy with LT4+LT3, provided that it is not used as a routine approach to hypothyroid patients”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] 10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The paper’s Conclusions state that LT4 should remain the standard of care and that there is no consistently strong evidence that LT4+LT3 improves outcomes over LT4 alone. This supports the claim that combination therapy is not a routine approach, but the available copy does not establish that the ATA guidelines tolerate its nonroutine use. The NICE portion is attached to a different citation and is not assessed here. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [30] 30. NIfHaCaE 2019 Thyroid Disease: assessment and Management. Available at www.nice.org.uk/guidance/ng145 (accessed January31, 2020)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    After the T3 spike, T3 rapidly subsides after two distinct phases of linear elimination: a fast distribution phase with a half-life of about 2 hours and a slow elimination phase with a half-life of about 23 hours.

    “rapidly subsides after two distinct phases of linear elimination: a fast distribution phase with a half-life of ∼2 hours and a slow elimination phase with a half-life of ∼23 hours, supporting a two-compartment model”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [45] 45. Van Tassell B, Wohlford GFt, Linderman JD, Smith S, Yavuz S, Pucino F, Celi FS. 2019. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid 29:1371–1379 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [46] 46. Jonklaas J, Burman KD, Wang H, Latham KR. 2015. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther Drug Monit 37:110–118 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results report a 22-hour half-life calculated across the decline from 2.5 to 94 hours, broadly consistent with the claimed approximately 23-hour value. The Discussion acknowledges distribution into other compartments, but does not report a distinct 2-hour distribution half-life or two linear elimination phases. It instead says multiple release rates from the gut best explain the observed T3 profile; the two-compartment gut model it mentions is a model from another study. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    BTA and ETA guidelines recognize that a trial with LT4+LT3 can be attempted in patients who have unambiguously not benefited from LT4.

    “the most recent clinical guidelines prepared by the British Thyroid Association (BTA) (29) and the European Thyroid Association (ETA) (9) explicitly recognize that a trial with LT4+LT3 can be attempted in patients who have unambiguously not benefited from LT4”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [29] 29. Okosieme O, Gilbert J, Abraham P, Boelaert K, Dayan C, Gurnell M, Leese G, McCabe C, Perros P, Smith V, Williams G, Vanderpump M. 2016. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol 84:799–808 [DOI] [PubMed] [Google Scholar] source
    • cites [9] 9. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 1:55–71 [DOI] [PMC free article] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    T3 acts by interacting with nuclear TH receptors, changing the rate at which genes are transcribed.

    “The T3 acts by interacting with nuclear TH receptors (TRs), changing the rate at which genes are transcribed.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [54] 54. Brent GA. 2012. Mechanisms of thyroid hormone action. J Clin Invest 122:3035–3043 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § Abstract

    LT3 is recognized in the treatment of myxedema coma and briefly suppresses serum TSH levels in a number of diagnostic and treatment conditions.

    “Currently, LT3 is recognized in the treatment of myxedema coma and it briefly suppresses serum TSH levels in a number of diagnostic and treatment conditions (10,106).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] 10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Section III contents listing (p. 1721) asks whether liothyronine should be initiated for myxedema coma, but does not give the guideline’s answer. Searches for short-term LT3 suppression of serum TSH in diagnostic or treatment settings found no supporting passage. Our copy is truncated, so the relevant discussion may be missing. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [106]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation
    § Abstract

    The AACE, ATA, BTA, ETA, and NICE guidelines do not recommend the use of desiccated thyroid extract (DTE).

    “The American Association of Clinical Endocrinologist (AACE), ATA, BTA, ETA, and NICE guidelines do not recommend the use of DTE (Table 1) (9,10,11,29,30).”
    Quote in the paperNot a substantial claim3 of 5 sources checked
    • cites [9] 9. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 1:55–71 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [10] 10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751 [DOI] [PMC free article] [PubMed] [Google Scholar] source
    • cites [11] 11. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. 2012. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Practice 18:988–1028 [DOI] [PubMed] [Google Scholar]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29] 29. Okosieme O, Gilbert J, Abraham P, Boelaert K, Dayan C, Gurnell M, Leese G, McCabe C, Perros P, Smith V, Williams G, Vanderpump M. 2016. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol 84:799–808 [DOI] [PubMed] [Google Scholar] source

      The Summary of ETA and ATA guidelines (page unavailable) says routine use of thyroid extracts is not recommended, supporting the claim for the guidance this paper summarizes. The Background (page unavailable) also reports that an earlier UK statement did not support thyroid extracts. Our copy does not establish a DTE recommendation from AACE or NICE, and it does not separately identify an ETA recommendation specifically about DTE. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [30] 30. NIfHaCaE 2019 Thyroid Disease: assessment and Management. Available at www.nice.org.uk/guidance/ng145 (accessed January31, 2020)

      Not checked in the free run.

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

    Premisecitation
    § Abstract

    The AACE and Latin American Thyroid Society guidelines do not support the use of combination therapy as a form of thyroid hormone replacement in patients with primary hypothyroidism, while the ATA, BTA, ETA, and NICE guidelines recommend against routine use but recognize that a trial of LT4+LT3 can be attempted on a case-by-case basis for patients who remain symptomatic on LT4 alone.

    “At this time, the AACE and Latin American Thyroid Society guidelines do not support the use of combination therapy as a form of TH replacement in patients with primary hypothyroidism (105,130). At the same time, the ATA, BTA, ETA, and NICE guidelines take a more permissive stance. They recommend against the routine use of combination therapy but recognize that a trial of LT4+LT3 can be attempted”
    Quote in the paperNot a substantial claim3 of 6 sources checked
    • cites [105]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [130]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9] 9. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 1:55–71 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [10] 10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [29] 29. Okosieme O, Gilbert J, Abraham P, Boelaert K, Dayan C, Gurnell M, Leese G, McCabe C, Perros P, Smith V, Williams G, Vanderpump M. 2016. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol 84:799–808 [DOI] [PubMed] [Google Scholar] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [30] 30. NIfHaCaE 2019 Thyroid Disease: assessment and Management. Available at www.nice.org.uk/guidance/ng145 (accessed January31, 2020)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    In 18 hypothyroid patients with normal serum TSH, switching from LT4 to 15 mcg/day LT3 for 2 weeks and then to 30 or 45 mcg/day for 6 weeks resulted in serum TSH remaining slightly elevated throughout, with no changes in heart rate, temperature, blood pressure, or respiratory rate.

    “In the study of 18 hypothyroid patients (aged 24–56 years; 16 females) with normal serum TSH levels, their regular LT4 regimen was switched to 15 mcg/day LT3 for 2 weeks and then to 30 or 45 mcg/day for 6 weeks (51). Although serum TSH remained slightly elevated throughout treatment with LT3, no changes in heart rate, temperature, blood pressure, or respiratory rate were observed throughout the”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] 51. Jonklaas J, Burman KD. 2016. Daily administration of short-acting liothyronine is associated with significant triiodothyronine excursions and fails to alter thyroid-responsive parameters. Thyroid 26:770–778 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Abstract

    Treatment of hypothyroidism with LT3 alone resulted in a pronounced T3 peak in the circulation, the magnitude of which is proportionally less if LT3 is given twice or three times daily.

    “As expected, the treatment of hypothyroidism with LT3 alone resulted in pronounced T3 peak in the circulation, the magnitude of which is proportionally less if LT3 is given twice or trice daily (Fig. 1A–C) (45).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] 45. Van Tassell B, Wohlford GFt, Linderman JD, Smith S, Yavuz S, Pucino F, Celi FS. 2019. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid 29:1371–1379 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Results (page not provided) model the same total LT3 dose given once, twice, or three times daily and report progressively less variation in serum T3 with more frequent dosing, supporting the direction of the peak comparison. But this comparison is a pharmacokinetic prediction, not an observed treatment result; the study involved patients undergoing thyroid-hormone withdrawal for thyroid cancer, rather than a general hypothyroidism-treatment population. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation
    § Abstract

    The ATA and AACE guidelines recommend against the use of thyroid hormone therapy for conditions other than hypothyroidism.

    “The ATA and AACE guidelines recommend against the use of TH therapy for conditions other than hypothyroidism (10,11).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [10] 10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM, American Thyroid Association Task Force on Thyroid Hormone Replacement. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      The Background, Objectives, and Rationale section identifies this as an ATA guideline and mentions separate AACE/ATA guidelines. Its table of contents lists questions about thyroid hormone use in euthyroid patients (pp. 1702–1703), but the retrieved passages do not give the recommendations. Our copy is truncated, so it cannot establish the claimed recommendation against therapy for conditions other than hypothyroidism. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [11] 11. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. 2012. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Practice 18:988–1028 [DOI] [PubMed] [Google Scholar]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Adverse drug reactions in combination therapy trials included atrial fibrillation in one patient, premature atrial beats in one patient, tachycardia/nervousness/heat intolerance in two patients, and vague symptoms 10% more likely; in all other instances, the frequency of adverse drug reactions was similar in the LT4+LT3 and LT4 groups.

    “The ADRs included (i) AF in one patient (LT3 6.5 mcg/day and LT4 123 mcg/day for 24 weeks) with suppressed serum TSH (113); (ii) premature atrial beats in one patient (116); (iii) tachycardia, nervousness, and heat intolerance in two patients (124); and vague symptoms 10% more likely (115). In all other instances, the frequency of ADRs was similar in the LT4+LT3 and LT4 groups.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [113]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [124]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Sixteen clinical trials studied hypothyroid patients on combination therapy given as a single daily dose, including a total of 888 patients (23-79 years old; 763 females) who received LT4 (75-228 mcg/day) and LT3 (3-21.4 mcg/day) for 10-48 weeks.

    “With the benefit of measuring serum TSH and TH levels to define euthyroidism, 16 clinical trials studied hypothyroid patients placed on combination therapy given as a single daily dose (Supplementary Table S1) (109–124). Overall, the studies include a total of 888 patients (23–79 years old; 763 females) who received LT4 (75–228 mcg/day) and LT3 (3–21.4 mcg/day) for 10–48 weeks.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [109]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [110]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [111]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [112]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [113]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [114]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [115]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [117]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [118]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Findingcitation
    § Abstract

    In the Tayside observational study, total follow-up was 280,334 person-years with a mean follow-up of 9.3 years (SD 5.6) and a maximum follow-up of 17.3 years.

    “The total follow-up was 280,334 person-years with a mean follow-up of 9.3 years (SD 5.6) and a maximum follow-up of 17.3 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Findingcitation
    § Abstract

    Four trials comparing mono and combined therapy evaluated similar parameters except that LT3 was given twice daily; overall, 88 patients (25-75 years old, 74 females) received LT4 (117.5-224 mcg/day) and LT3 (6.25-12.5 mcg B.I.D.) for 15-36 weeks.

    “Another group of four trials (125–128) comparing mono and combined therapy for hypothyroidism evaluated similar parameters except that LT3 was given twice daily (Supplementary Table S2). Overall, 88 patients (25–75 years old, 74 females) were studied while receiving LT4 (117.5–224 mcg/day) and LT3 (6.25–12.5 mcg B.I.D.) for 15–36 weeks (125–128).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [125]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [126]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [127]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [128]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Urinary deoxypyridinoline levels and serum osteocalcin levels were higher in patients on combination therapy, but they were well within normal reference ranges.

    “Urinary deoxypyridinoline levels (121) and serum osteocalcin levels (116,118) were higher in patients on combination therapy, but they were well within normal reference ranges.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [121]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [118]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Heart rate remained largely unaffected by combination therapy, while systolic blood pressure increased by 4-12 mmHg in two studies.

    “Heart rate and blood pressure were reported in 12 trials (109,110,112–118,123): Heart rate remained largely unaffected by combination therapy, while systolic blood pressure increased by 4–12 mmHg in two studies (113,116).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [113]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Compared with nearly 34,000 patients taking only LT4, those using LT4+LT3 (n = 327) or LT3 alone (n = 73) had no increased mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures after adjusting for age; the number of prescriptions for bisphosphonates or statins were similar.

    “Compared with the nearly 34,000 patients taking only LT4, those using LT4+LT3 (n = 327) or LT3 alone (n = 73) had no increased mortality or morbidity risk due to cardiovascular disease, AF, or fractures after adjusting for age; the number of prescriptions for bisphosphonates or statins were similar.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data
    § Abstract

    In the twice-daily trials, serum TSH was 7-90% lower in three studies and 3% higher in one study; serum T4 was 18-38% lower and serum T3 was 15-74% higher compared with the LT4 arm.

    “At the end, serum TSH was 7–90% lower in three studies and 3% higher in one study. Serum T4 was 18–38% lower when compared with the LT4 arm; serum T3 was 15–74% higher.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Abstract

    In the Tayside study, there was an increased risk of new prescriptions for antipsychotic medication (HR 2.26 [CI 1.64-3.11], p < 0.0001), proportional to the number of LT3 prescriptions.

    “Remarkably, there was an increased risk of new prescriptions for antipsychotic medication (HR 2.26 [CI 1.64–3.11], p < 0.0001), proportional to the number of LT3 prescriptions (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingreasoning
    § Abstract

    In these trials, patients on combination therapy exhibited 5-40% lower fasting serum T4 levels and 3-161% higher serum T3 levels, with the magnitude depending on the LT3:LT4 molar ratio used.

    “As expected, patients on combination therapy exhibited 5–40% lower fasting serum T4 levels and 3–161% higher serum T3 levels; the magnitude of these differences depended on the LT3:LT4 molar ratio used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Abstract

    In the twice-daily trials, no adverse drug reactions were reported except for one patient who dropped out due to tremulousness, fatigue, and poor performance and four patients due to palpitation; body weight, heart rate, lipid levels, and blood pressure were not different compared with LT4 therapy.

    “No ADRs were reported except for one patient who dropped out due to tremulousness, fatigue, and poor performance (125) and four patients due to palpitation (127). Body weight, heart rate, lipid levels, and blood pressure were not different when compared with LT4 therapy (125,127).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [125]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [127]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given
    § Conclusions

    The doses of LT3 that restore clinical euthyroidism and normalize serum TSH range between 30 and 45 mcg/day; these doses bring serum T3 levels well above the upper limit of the normal reference range for several hours.

    “The doses that restore clinical euthyroidism and normalize serum TSH range between 30 and 45 mcg/day; these doses will bring serum T3 levels well above the upper limit of the normal reference range for several hours.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingcitation
    § Abstract

    In eight euthyroid morbidly obese patients taking LT3 25 mcg three times daily for 30 weeks, with a mean of 11 tablets per day, they lost ∼25 lbs and serum total cholesterol dropped by ∼80 mg/dL; two individuals dropped out due to nervousness and increased heart rate, hyperglycemia was detected in one patient with a family history of diabetes, and all others developed tachycardia (+18 bpm), milde

    “We identified a clinical trial that included eight euthyroid, morbidly obese patients who were instructed to take one LT3 tablet (25 mcg/tablet) three times daily for 30 weeks, increasing the dose by one tablet daily each week to maintain weight loss for as long as they did not develop ADRs (147). Overall, patients received a mean of 11 tablets per day (range 6–20). They lost ∼25 lbs, and serum”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Findingown data
    § Abstract

    A PubMed search reveals that thyroid hormone, including LT3, has been used in a variety of conditions other than hypothyroidism.

    “A search in PubMed reveals that TH, including LT3, has been used in a variety of conditions other than hypothyroidism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Abstract

    In nine adult individuals after a period of caloric restriction and weight loss, LT3 25 mcg/day given fasting in the morning or 12.5 mcg/day B.I.D. for 5 weeks increased serum T3 by ∼20% and decreased serum TSH by ∼75%, with minimal accelerated epinephrine and norepinephrine urinary excretion and no adverse drug reactions.

    “Patients were treated with 25 mcg/day LT3 given either fasting in the morning or 12.5 mcg/day B.I.D. during 5 weeks. Doses were titrated to maintain T3 serum levels within 80–220 ng/dL (blood collected at 8 AM fasting). Treatment with LT3 increased serum T3 levels by ∼20% (102 ± 14 to 121 ± 13 ng/dL), whereas serum TSH levels dropped by ∼75% (1.95 ± 0.65 to 0.51 ± 0.20 μU/L). The LT3 treatment”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    Twelve prospective clinical trials conducted between the 1970s and 2018 used LT3 in patients with major depressive disorder as an adjuvant to antidepressants; overall, 364 adult patients (<65 years old; 200 females) were treated with 25-50 mcg/day LT3 for 2-16 weeks, and in none of these 12 studies did the association of LT3 result in adverse drug reactions.

    “We identified 12 prospective clinical trials conducted between 1970s and 2018 (Supplementary Table S2) in which a regimen with LT3 was used. Overall, 364 adult (<65 years old) patients (200 females) were treated with 25–50 mcg/day LT3 for 2–16 weeks.”
    • Also stated in: § Abstract · plain
      “Remarkably, in none of these 12 studies did the association of LT3 result in ADRs (131–140,143,144).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [131]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [132]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [133]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [134]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [135]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [136]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [137]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [138]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [139]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [140]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    A meta-analysis of eight studies failed to identify differences in adverse drug reactions in LT3 versus control patients, and a second meta-analysis of six trials confirmed that daily administration of 25 mcg LT3 during 3-4 weeks was well tolerated with no specific adverse drug reactions reported.

    “A subsequent meta-analysis that included eight studies (five clinical trials described earlier plus three observational studies) failed to identify differences in ADRs in LT3 versus control patients (145). Along these lines, a second meta-analysis of six trials confirmed that daily administration of 25 mcg LT3 during 3–4 weeks was well tolerated by patients, with no specific ADRs reported (142).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [145]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [142]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation
    § Abstract

    In 60 patients receiving LT3 at 25 or 50 mcg/day for 8 weeks, serum T3 increased by ∼25% and ∼50% respectively; in the 25 mcg group, adverse drug reactions were not different than placebo (18%), while in the 50 mcg group about 30% exhibited adverse drug reactions (palpitation, sweating, and/or nervousness) that interfered with normal functioning or outweighed therapeutic benefit.

    “In a separate study, 60 patients (46 ± 11 years old; 36 females) received LT3 at 25 or 50 mcg/day for 8 weeks (141). As a result, serum T3 levels increased by ∼25 and ∼50% in the 25- and 50 mcg-patient groups, respectively. In the 25 mcg-patients, ADRs were not different than in patients who received placebo (18%). Only in the 50 mcg-patient group, about 30% of the patients exhibited ADRs (palp”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given
    § Conclusions

    The mean daily dose of DTE needed to restore euthyroidism and bring serum TSH back to the reference range contains ∼11 mcg T3; some patients may require higher DTE doses, which can bring the daily T3 dose to ∼24 mcg.

    “The mean daily dose needed to restore euthyroidism and bring serum TSH back to the reference range contains ∼11 mcg T3; some patients may require higher DTE doses, which can bring the daily T3 dose to ∼24 mcg.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingcitation
    § Abstract

    In six randomized trials of 60 obese individuals given LT3 25-225 mcg/day with caloric restriction for 3 days to 12 weeks, LT3 accelerated weight loss, associated with a rise in urinary nitrogen indicating lean body mass loss; adverse drug reactions prompted four patients to drop out, and in patients taking 225 mcg/day LT3, 21 had accelerated heart rate, 1 developed atrial fibrillation, 6 reported

    “A group of 6 similar randomized trials analyzed weight loss and other metabolic parameters in 60 obese individuals (17–68 years old; 40% females) who were given LT3 (25–225 mcg/day) in combination with caloric restriction for 3 days to 12 weeks (148–153). Treatment with LT3 accelerated weight loss, which was associated with a rise in urinary nitrogen, an indication that lean body mass was being”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [148]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [149]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [150]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [151]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [152]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [153]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation
    § Abstract

    An additional about 25 mcg T3 is produced daily outside the thyroid parenchyma via T4 deiodination.

    “an additional ∼25 mcg T3 is produced daily outside of the thyroid parenchyma via T4 deiodination (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 32. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. 2002. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89 [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    The thyroid produces only about 5 mcg T3 daily.

    “with the thyroid producing only ∼5 mcg T3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 32. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. 2002. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89 [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    Daily T3 production in a 70-kg healthy adult is about 30 mcg.

    “The daily T3 production in a 70-kg healthy adult is ∼30 mcg”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] 32. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. 2002. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89 [DOI] [PubMed] [Google Scholar] source

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

    Premisecitation
    § Abstract

    In 2017, DTE was the 130th most prescribed medication in the United States with about 5.5 million prescriptions per year.

    “In 2017, DTE was the 130th most prescribed medication in the United States with ∼5.5 million prescriptions per year (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] 31. ClinCalc.com The top 300 of 2019. Available at https://clincalc.com/DrugStats/Top300Drugs.aspx (accessed January31, 2020).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    DTE was occasionally found to be clinically inactive, or of variable potency between batches.

    “DTE was occasionally found to be clinically inactive, or of variable potency between batches (81–83).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [82]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [83]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § Abstract

    DTE remains outside formal FDA oversight, and consistency of T4 and T3 contents is monitored by the manufacturers only.

    “The DTE remains outside formal FDA oversight, and consistency of T4 and T3 contents is monitored by the manufacturers only.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Abstract

    The deiodination pathway is predominantly via type 2 deiodinase (D2), which is accelerated during hypothyroidism and suppressed during hyperthyroidism.

    “The deiodination pathway is predominantly via the type 2 deiodinase (D2), which tends to play a homeostatic role, that is it is accelerated during hypothyroidism and is suppressed during hyperthyroidism (33,34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] 33. Zavacki AM, Harney JW, Li J, Gereben B, Fekete C, Bianco AC. 2007. TEB4 Is an Endoplasmic Reticulum Ubiquitin Ligase That Mediates Type 2 Iodothyronine Deiodinase (D2) Degradation 89th Annual Meeting of the Endocrine Society. Vol OR7-1, Toronto, Canada [Google Scholar]

      Not checked in the free run.

    • cites [34] 34. Bianco AC, Dumitrescu A, Gereben B, Ribeiro MO, Fonseca TL, Fernandes GW, Bocco B. 2019. Paradigms of dynamic control of thyroid hormone signaling. Endocr Rev 40:1000–1047 [DOI] [PMC free article] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § Abstract

    DTE preparations could not be standardized from lot to lot to provide uniform hormonal activity because standardization was based on iodine levels and not on T4 and T3 content.

    “they could not be standardized from lot to lot to provide uniform hormonal activity (67,78,79) given that standardization was based on iodine levels and not on T4 and T3 content (80,81).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [67] 67. Hartsock CL 1932 Clinical Aspects of Hypothyroidism. In: Crile G (ed) Diagnosis and Treatment of Diseases of the Thyroid Gland. W. B. Saundres Co., Philadelphia, pp 86–100 [Google Scholar]

      Not checked in the free run.

    • cites [78] 78. Wool MS, Selenkow HA. 1965. Physiologic combinations of synthetic thyroid hormones in myxedema. Clin Pharmacol Ther 6:710–715 [DOI] [PubMed] [Google Scholar] source
    • cites [79]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisenone given
    § Abstract

    The rationale for LT4 therapy is that multiple tissues can deiodinate T4 to T3, restoring the body's T3 reservoir.

    “The rationale for LT4 therapy resides on the fact that multiple tissues are capable of T4 deiodination to triiodothyronine (T3), the active form of TH, “restoring” the body's T3 reservoir.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In that study, 23 of the 40 patients were not being treated for hypothyroidism; they were on DTE as medical therapy for gland suppression.

    “However, 23 of these patients were not being treated for hypothyroidism; they were on DTE “as medical therapy for gland suppression.””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Abstract

    Dampened enthusiasm for DTE over standardization concerns led physicians to progressively turn to synthetic LT4 and/or LT3 preparations that eventually became the standard of care.

    “Dampened enthusiasm for DTE to treat hypothyroidism over-standardization concerns (78) led physicians to progressively turn to synthetic LT4 and/or LT3 preparations that eventually became the standard of care (78,79,86).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [78] 78. Wool MS, Selenkow HA. 1965. Physiologic combinations of synthetic thyroid hormones in myxedema. Clin Pharmacol Ther 6:710–715 [DOI] [PubMed] [Google Scholar] source
    • cites [79]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [86]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Clinical euthyroidism and absence of cardiovascular ADRs in all reported patients indicate that, at the doses used and during a mean observational period of 27 months, a daily transient elevation in serum T3 levels was not associated with cardiovascular ADRs.

    “the clinical euthyroidism and absence of cardiovascular ADRs in all reported patients indicate that, at the doses used and during a mean observational period of 27 months, a daily transient elevation in serum T3 levels was not associated with cardiovascular ADRs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In that study, DTE use did not result in additional risk of AF, cardiovascular disease, or mortality in patients of any ages.

    “DTE use did not result in additional risk of AF, cardiovascular disease, or mortality in patients of any ages (98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Abstract

    In a 6-year observational retrospective chart review of 100 patients receiving combination therapy compared with 2400 patients receiving LT4 monotherapy, analysis of 60 patients on DTE indicated about 97% had therapeutic TSH levels, with <5% exhibiting supra-therapeutic levels of fT3.

    “The second study is a 6-year observational retrospective chart review that identified 100 patients (20–81 years old; 95 females) receiving combination therapy and compared them with 2400 patients receiving LT4 monotherapy (98). The analysis of 60 patients on DTE indicated that ∼97% patients had therapeutic TSH levels, with <5% exhibiting supra-therapeutic levels of fT3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • The quote only partly states this claim.

    Premisecitation
    § Abstract

    A study of 40 patients taking DTE after being switched to LT4 associated DTE usage with hypertriiodothyroninemia and thyrotoxic symptoms.

    “In this study, DTE usage was associated with hypertriiodothyroninemia and thyrotoxic symptoms (93).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductnone given
    § Abstract

    The available trials of LT3 alone are few, enrolled a limited number of patients, and lasted a few weeks; no data are available about bone density or turnover markers.

    “However, the available trials are few, only enrolled a limited number of patients, and lasted a few weeks; no data are available about bone density or turnover markers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    Treatment of hypothyroidism with LT3 alone is not practical and loss of clinical effect occurs rapidly if therapy were to lapse.

    “The treatment of hypothyroidism with LT3 alone is not practical and loss of clinical effect occurs rapidly if therapy were to lapse.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Typically, DTE at mean doses of 80 mg/day (containing 11 mcg T3/day) restores clinical and biochemical euthyroidism with no reports of ADRs, as long as fasting serum TSH levels are used to adjust the replacement dose.

    “Typically, DTE at mean doses of 80 mg/day (containing 11 mcg T3/day) restores clinical and biochemical euthyroidism with no reports of ADRs, as long as fasting serum TSH levels are used to adjust the replacement dose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In that study, serum TSH was not reported; it was only used to exclude hypothyroidism and not to adjust the replacement doses.

    “In addition, serum TSH was not reported; it was only used to exclude hypothyroidism and not to adjust the replacement doses (93).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given
    § Abstract

    LT3 administration rapidly restores euthyroidism and normalizes serum TSH in hypothyroid patients.

    “While LT3 administration rapidly restores euthyroidism and normalizes serum TSH in hypothyroid patients, there is no reason as to why a hypothyroid patient should be treated with LT3 alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In another similar trial that did not use serum TSH to guide replacement doses, patients on combination therapy had a higher number of adverse drug reactions, with higher thyroid hormone replacement doses of 160-240 mcg/day LT4 and 40-60 mcg/day LT3.

    “In another similar trial that also did not use serum TSH to guide replacement doses, patients on combination therapy were found to have a higher number of ADRs. However, in this case, TH replacement doses were higher, 160–240 mcg/day LT4 and 40–60 mcg/day LT3 (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Abstract

    Switching from LT4 to LT3 can be accomplished without major changes in thyroid-responsive parameters or the occurrence of adverse drug reactions.

    “More recent studies indicate that switching from LT4 to LT3 can be accomplished without major changes in thyroid-responsive parameters or the occurrence of ADRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    A comparative study of 12 hypothyroid patients receiving progressively larger doses of LT4 and 9 hypothyroid patients receiving progressively larger doses of DTE revealed that both treatments can normalize plasma TSH levels and similarly eliminate signs and symptoms of hypothyroidism, with no ADRs.

    “a comparative study of 12 hypothyroid patients receiving progressively larger doses of LT4 and 9 hypothyroid patients receiving progressively larger doses of DTE (monthly increments of 30 mg/day; mean 138 ± 27; range 114–180 mg/day) revealed that both treatments can normalize plasma TSH levels and similarly eliminate signs and symptoms of hypothyroidism, with no ADRs”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Abstract

    In 10 hypothyroid patients treated with increasing LT3 doses, 20-25 mcg/day normalized cardiac systolic time intervals and serum creatine phosphokinase activity but not BMR, total cholesterol, or serum TSH; increasing to 50 mcg/day decreased mean basal serum TSH from 55 to 16 μU/mL and brought all parameters within normal reference range except total cholesterol, which remained above 200 mg/dL.

    “On LT3, 20–25 mcg/day, cardiac systolic time intervals and serum creatine phosphokinase activity had normalized, but BMR, total cholesterol concentration, and serum TSH levels had not. As the dose of LT3 was increased to 50 mcg/day, mean basal serum TSH levels decreased from 55 to 16 μU/mL, bringing all parameters to within normal reference range, except for total cholesterol that remained above 2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] 18. Ridgway EC, Cooper DS, Walker H, Daniels GH, Chin WW, Myers G, Maloof F. 1980. Therapy of primary hypothyroidism with L-triiodothyronine: discordant cardiac and pituitary responses. Clin Endocrinol 13:479–488 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Premisecitation
    § Abstract

    In a crossover study of 10 adult hypothyroid patients, LT3 40 ± 11 mcg/day for 4 weeks resulted in fasting serum total T3 of 185 ± 100 ng/dL and serum TSH of 1.48 ± 0.78 μU/L, with no differences in heart rate or blood pressure versus the LT4 arm and no reported adverse drug reactions.

    “At the end of the LT3 arm, fasting serum total T3 was 185 ± 100 ng/dL and serum TSH was 1.48 ± 0.78 μU/L. Monitoring heart rate and blood pressure revealed no differences versus the LT4 arm; none of the patients reported ADRs (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given
    § Abstract

    The T3 peak caused by LT3 doses of 30-45 mcg/day does not acutely affect thyroid-responsive parameters or result in cardiovascular adverse drug reactions.

    “This does not acutely affect thyroid-responsive parameters or results in cardiovascular ADRs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Only 50 mcg/day LT3 normalized the 24-hour-integrated serum concentration of T3, and no adverse drug reactions were reported.

    “Notably, only 50 mcg/day LT3 normalized the 24-hour-integrated serum concentration of T3; no ADRs were reported (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] 18. Ridgway EC, Cooper DS, Walker H, Daniels GH, Chin WW, Myers G, Maloof F. 1980. Therapy of primary hypothyroidism with L-triiodothyronine: discordant cardiac and pituitary responses. Clin Endocrinol 13:479–488 [DOI] [PubMed] [Google Scholar] source

  • May combine two claims.

    Interpretationnone given
    § Abstract

    The peaks of serum T3 observed after LT3 tablets only minimally affected serum TSH, heart rate, and blood pressure; the frequency of adverse drug reactions was similar to patients taking LT4.

    “The peaks of serum T3 observed after the LT3 tablets only minimally affected serum TSH, heart rate, and blood pressure; the frequency of ADRs was similar to patients taking LT4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    The daily peak in serum T3 after DTE depends on the dose taken, but it could reach 40-80% above baseline values and last for several hours.

    “The peak depends on the dose taken, but it could reach 40–80% above the baseline values, and last for several hours”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Abstract

    In the 1960s, T4 and T3 were seen as two independent hormones produced by the thyroid gland.

    “It is fascinating that, in the 1960s, T4 and T3 were seen as two independent hormones produced by the thyroid gland.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    The main differences between therapies that normalize serum TSH with DTE versus LT4 alone are that DTE treatment results in a much higher serum T3/T4 ratio and DTE patients exhibit a daily peak in serum T3 levels two to three hours after taking a DTE tablet.

    “The main differences between therapies that normalize serum TSH with DTE versus LT4 alone are that DTE treatment results in a much higher serum T3/T4 ratio and DTE patients exhibit a daily peak in serum T3 levels two to three hours after taking a DTE tablet.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Abstract

    The Tayside antipsychotic prescription finding needs to be assessed in other series but adds to the idea that treatment with thyroid hormone may unpredictably interfere with psychiatric outcomes.

    “This, of course, needs to be assessed in other series but it adds to the idea that treatment with TH may unpredictably interfere with psychiatric outcomes (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § Abstract

    During 1968-1978, hypothyroid patients in Brazil were routinely treated with LT3 alone, with doses up to 75 mcg/day adjusted clinically and given two to three times a day, rapidly reversing symptoms of hypothyroidism.

    “For example, during 1968–1978, hypothyroid patients in Brazil were routinely treated with LT3 alone, given that LT4 was not commercially available and DTE was considered unreliable at the time. The LT3 doses of up to 75 mcg/day were adjusted clinically and given two to three times a day, rapidly reversing symptoms of hypothyroidism (102).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Abstract

    There is no reason why a hypothyroid patient should be treated with LT3 alone.

    “While LT3 administration rapidly restores euthyroidism and normalizes serum TSH in hypothyroid patients, there is no reason as to why a hypothyroid patient should be treated with LT3 alone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In that study, there were no differences in heart rate, blood pressure, serum lipids, or symptoms and neurocognitive parameter measurements between DTE and LT4, although patients on DTE lost about 3 lbs.

    “there were no differences in heart rate, blood pressure, serum lipids, or symptoms and neurocognitive parameter measurements between the two therapies, although patients on DTE lost ∼3 lbs. of weight; no ADRs were reported (97).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisereasoning
    § Abstract

    Liotrix, a combination of LT4 and LT3, was formulated with the intention of circumventing the disconnect between metabolic state and circulating thyroid hormone levels.

    “Indeed, liotrix, a combination of LT4 and LT3, was formulated with the intention of circumventing this disconnect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    In a randomized, double-blind, crossover study of 70 hypothyroid patients, DTE (mean 80 ± 30 mg/day) versus LT4 for 16 weeks resulted in serum T3 about 55% higher and fT4 about 40% lower in patients taking DTE while serum TSH remained within normal range in all patients.

    “The first study is a randomized, double-blind, crossover study of 70 hypothyroid patients (age 23–65 years old; 53 females) that compared treatment with DTE (mean 80 ± 30 mg/day; range 43–172 mg/day) versus LT4 for 16 weeks (97). The study used an equivalency conversion formula: 1 mg DTE = 1.667 mcg LT4, and revealed that while serum TSH remained within normal range in all patients, serum T3 was ∼”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning
    § Conclusions

    We are not aware of any conceptual or practical reason that justifies long-term treatment of hypothyroid patients with LT3 alone.

    “We are not aware of any conceptual or practical reason that justifies long-term treatment of hypothyroid patients with LT3 alone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    Higher doses of LT3 were clearly associated with cardiovascular and metabolic adverse drug reactions, even as they achieved the desired outcome in some cases.

    “However, higher doses of LT3 were clearly associated with cardiovascular and metabolic ADRs, even as they achieved the desired outcome in some cases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given
    § Conclusions

    Various LT3/LT4 ratios were tested in clinical trials.

    “Various LT3/LT4 ratios were tested in clinical trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Conclusions

    Transient episodes of hypertriiodothyroninemia with LT3 doses of 2.5-7.5 mcg once or twice a day are unlikely to reach outside the normal reference range and have not been associated with increased incidence of adverse drug reactions when compared with LT4 alone.

    “Transient episodes of hypertriiodothyroninemia with these doses of LT3 are unlikely to reach outside the normal reference range and have not been associated with increased incidence of ADRs when compared with LT4 alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Conclusions

    DTE doses are more likely to transiently elevate serum T3 above the normal reference range, but adverse drug reactions have not been reported in clinical trials in which serum TSH was maintained within the normal range.

    “Whereas these doses are more likely to transiently elevate serum T3 above the normal reference range, ADRs have not been reported in clinical trials in which serum TSH was maintained within the normal range.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Conclusions

    DTE is a non-FDA approved form of combination therapy in which the LT3/LT4 ratio is relatively higher.

    “The DTE is a non-FDA approved form of combination therapy in which the LT3/LT4 ratio is relatively higher.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given
    § Conclusions

    Even though LT3 monotherapy has not been associated with adverse drug reactions, the trials are few, lasted only a few weeks, and include a relatively small number of patients.

    “Even though LT3 monotherapy has not been associated with ADRs, the trials are few, lasted only a few weeks, and include a relatively small number of patients.”
    Quote in the paperSubstantial claim

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

    Premisenone given
    § Conclusions

    Persistent symptoms by some hypothyroid patients on LT4 monotherapy are not uncommon.

    “Persistent symptoms by some hypothyroid patients on LT4 monotherapy are not uncommon and should prompt an investigation of other conditions that may present with similar symptoms.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given
    § Conclusions

    Clinical guidelines alert for potential safety concerns of combination therapy, such as the presence of supraphysiologic serum T3 levels and a paucity of long-term safety outcome data.

    “Clinical guidelines alert for potential safety concerns of combination therapy, such as the presence of supraphysiologic serum T3 levels and a paucity of long-term safety outcome data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data
    § Conclusions

    Mathematical modeling and observations in clinical trials indicate that reducing the LT4 dose by 25 mcg/day and adding 2.5-7.5 mcg LT3 once or twice a day is a reasonable starting point, provided that serum TSH is kept within normal range.

    “Mathematical modeling and observations in these trials indicate that reducing the LT4 dose by 25 mcg/day and adding 2.5–7.5 mcg LT3 once or twice a day is a reasonable starting point (nota bene, the thyroid only secretes ∼5 mcg T3/day), provided that serum TSH is kept within normal range.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The thyroid gland secretes approximately 5 mcg of T3 per day.

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

    Premisenone given
    § Conclusions

    There is universal consensus among all clinical guidelines that newly diagnosed hypothyroid patients should be treated with LT4.

    “There is universal consensus among all clinical guidelines that newly diagnosed hypothyroid patients should be treated with LT4.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § Conclusions

    LT3 alone has been used in the treatment of hypothyroidism, but it is rarely seen these days.

    “The LT3 alone has been used in the treatment of hypothyroidism, but it is rarely seen these days.”
    Quote in the paperNot a substantial claim
79 of 79

  • The paper relies on this without support.

    For 50 years, providers have been steered away from using anything other than LT4, resulting in two generations of physicians with limited clinical experience prescribing LT3 or DTE and with the taught perception that these drugs were unsafe.

    “For 50 years now, providers have been steered away from using anything other than LT4 in the treatment of hypothyroidism. This has resulted in two generations of physicians with limited clinical experience prescribing LT3 or DTE, and with the taught perception that these drugs were unsafe.”

  • The paper relies on this without support.

    The sympathetic, cardiovascular, and musculoskeletal systems, as well as mood and behavior, are particularly sensitive to minimal excess thyroid hormone.

    “there is general agreement that the sympathetic, cardiovascular, and musculoskeletal systems, as well as mood and behavior, are particularly sensitive to minimal excess of TH.”

  • The paper relies on this without support.

    The thyroid gland secretes approximately 5 mcg of T3 per day.

    “nota bene, the thyroid only secretes ∼5 mcg T3/day”
3 of 3

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?

  • During the last 50 years, scores of clinical trials have compared the effectiveness and safety of LT4 monotherapy versus LT4+LT3 combination therapy in the treatment of hypothyroidism.

    “During the last 50 years, scores of clinical trials have compared the effectiveness and safety of LT4 monotherapy versus LT4+LT3 combination therapy in the treatment of hypothyroidism (48).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [48]

    The trial summaries in our copy (labelled Abstract; page unavailable) describe 16 once-daily and four twice-daily trials comparing LT4+LT3 with LT4 alone, including effectiveness and safety measures. They support the substance of the comparison, but document about 20 trials—not clearly “scores”—and do not establish the claimed 50-year span. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Serum T3 drops rapidly after the peak level has been reached and returns to baseline values immediately before a new tablet is administered.

    “As a result, serum T3 will drop rapidly after the peak level has been reached and return to baseline values (immediately before a new tablet is administered) (48).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [48]

    The passage on LT3-containing tablets (labelled Abstract in our copy; no page supplied) says serum T3 peaks about 2–3 hours after a dose and rapidly subsides. The DTE passage says T3 returns to within the normal range 12–24 hours after a dose, but neither passage establishes that it returns to its pre-dose baseline immediately before the next tablet. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • T3 is rapidly metabolized through inner ring deiodination to 3,3′-T2, with a half-life of 12-24 hours.

    “T3 is also rapidly metabolized through inner ring deiodination to 3,3′-T2, with a half-life of 12–24 h.”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [48]

    The Pharmacokinetics of LT3 passage (labeled Abstract in our copy; page unavailable) reports rapid changes in circulating T3 after oral dosing and a slow elimination-phase half-life of approximately 23 hours, within the claimed 12–24-hour range. The Pharmacodynamics passage says T3 is rapidly metabolized, but our copy does not identify inner-ring deiodination to 3,3′-T2 as the pathway. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Observational studies lasting 9 to 17 years found no increased risk of cardiovascular disease, atrial fibrillation, or fractures in patients using T3 compared to patients using T4.

    “Observational studies lasting 9 to 17 years found no increased risk of cardiovascular disease, atrial fibrillation, or fractures in patients using T3 compared to patients using T4 [87,88].”

    From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [88]

  • Two to three hours after administering a T3-containing tablet, serum T3 reaches a peak level that depends on baseline fasting values and the dose of T3 administered.

    “Two to three hours after administering a T3-containing tablet, serum T3 will reach a peak level that depends on the baseline (fasting) values and the dose of T3 administered.”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [48]

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.

  • Three bone-turnover trials are listed, but the summary says two

    Minor

    The earlier passage identifies bone-turnover measurements in three distinct trials, cited as 121, 116, and 118; the summary says they were studied in two trials.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 11

  1. Zavacki AM, , Harney JW, , Li J, , Gereben B, , Fekete C, , Bianco AC. 2007. TEB4 Is an Endoplasmic Reticulum Ubiquitin Ligase That Mediates Type 2 Iodothyronine Deiodinase (D2) Degradation 89th Annual Meeting of the Endocrine Society. Vol OR7-1, Toronto, Canada.
  2. Jackson AS. 1926. Diagnosis and Treatment of Myxedema and Cretinism Goiter and Other Disease of the Thyroid Gland. Paul B. Hoeber, Inc., New York.
  3. Means JH 1948 Myxedema: diagnosis treatment special features and complications. In: Means JH (ed) The Thyroid and Its Diseases. J.B. Lippincott Co. Philadelphia pp 241–273.
  4. McGavack TH 1951 Hypothyroidism: II. After maturity. Adult myxedema. In: McGavack TH (ed) The Thyroid. The C. V. Mosby Co St Louis pp 374–417.
  5. Williams RH 1955 The thyroid. In: Williams RH (ed) Textbook of Endocrinology. W. B. Saunders Co. Philadelphia pp 99–230.
  6. Means JH 1937 Mixedema. In: Means JH (ed) The Thyroid and Its Diseases. J. B. Lippincott Co. Philadelphia pp 228–261.
  7. Wolf W 1939 The thyroid gland. In: Wolf W (ed) Endocrinology in Modern Practice. W. B. Saunders Co. Philadelphia pp 238–335.
  8. Means JH DeGroot LJ Stanbury JB. 1963. Adult Hypothyroid States: The Thyroid and Its Diseases. McGraw-Hill Book Co. New York.
  9. Maciel RMB 1977 Development of a thyroglobulin radioimmunoassay and its application on the follow-up of patients with differentiated thyroid cancer. [PhD Thesis]. Sao Paulo SP: Department of Medicine Federal University of Sao Paulo.
  10. Ingbar SH Woeber KA. 1974. The thyroid gland. In: Williams RH (ed) Textbook of Endocrinology. W. B. Saunders Philadelphia pp 95–232.
  11. Steiner M RM, , Elizur A, , Blum I, , Atsmon A, , Davidson S. 1978. Failure of L-triiodothyronine to potentiate tricyclic antidepressant response. Curr Ther Res, 23:655–659.

Cited by

Sorted by citations

Related

Authors
Idrees, T., Palmer, S., Maciel, R. M. B., & Bianco, A. C.
Affiliations
  • University of Chicago (US)
  • Rush University Medical Center (US)
  • Universidade Federal de São Paulo (BR)
Corresponding author
Bianco, Antonio C.
ORCID
Venue
Thyroid®
Publisher
SAGE Publications
Published
2020-10
Volume
30
Issue
10
Pages
1399-1413
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/thy.2020.0153
PMC
PMC7640752
OpenAlex
W3015249763
Cited by
58
References
137
Citations by year
2026: 3 · 2025: 11 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 8
FWCI
1.38
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Thyroid (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065055)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
hypothyroidism, liothyronine, desiccated thyroid extract, levothyroxine, triiodothyronine, combination thyroid hormone therapy, T4 to T3 conversion, serum thyrotropin, cardiovascular risk, atrial fibrillation, fracture
MeSH terms
Drug Therapy, Combination, Female, Humans, Hypothyroidism, Male, Models, Theoretical, Reference Values, Thyroid Gland, Thyroid Hormones, Thyrotropin, Triiodothyronine, United States, Practice Guidelines as Topic, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-03.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-03.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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