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2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism

Open access
Wiersinga, Wilmar M., Duntas, Leonidas, Fadeyev, Valentin, Nygaard, Birte, Vanderpump, Mark P.J.·2012·European Thyroid Journal
DOI 10.1159/000339444PMC PMC3821467
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Abstract

Background: Data suggest symptoms of hypothyroidism persist in 5–10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. Methods: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. Results: Suggested explanations for persisting symptoms include: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. Conclusion: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

Integrity signals

Registry

Crossref · 10.1159/000339444

Cites

90 of 90 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

36 of 168 cited sources checked · 26 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    A formal sample size calculation is reported in seven of the reviewed RCTs.

    “A formal sample size calculation is reported in seven studies [5,39,41,42,[45][46][47] .”
    Quote in the paperNot a substantial claim1 of 7 sources checked
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source
    • cites [39] Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM: Partial substitution of thyroxine (T4) with triiodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab 2005;90:805–812.10.1210/jc.2004-167215585551 source
    • cites [41] Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543–4550.10.1210/jc.2003-03024914557419 source
    • cites [42] Clyde PW, Harari AE, Getka EJ, Shakir KM: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952–2958.10.1001/jama.290.22.295214665656 source
    • cites [45] Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF: Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with thyroxine alone. Endocrine Pract 2005;11:223–233. source

      The Methods section (‘Sample Size and Power’) says sample size was not predetermined. The authors selected 30 participants after an exploratory variance estimate from 11 participants and performed the reported power analysis only after the study; they do not report a formal sample size calculation. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [46] Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J: Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine withL-thyroxine alone. Ann Intern Med 2005;142:412–424.15767619 source
    • cites [47] Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, Kirsche G, Sanger E, Engel G, Hamm AO, Nauck M, Meng W: Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14:1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol 2004;60:750–757.10.1111/j.1365-2265.2004.02050.x15163340 source
  • Premisecitation

    Administration of L-T4 alone to thyroidectomised rats does not, at any dose tested, result in normal T4 and T3 concentrations simultaneously in all tissues.

    “Administration of L-T4 alone to thyroidectomised rats does not, at any dose tested, result in normal T4 and T3 concentrations simultaneously in all tissues (which can be taken as one criterion for defining euthyroidism) [32] .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [32] Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G: Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. Endocrinology 1995;28:2828–2838. source
  • Premisecitation

    Serum thyroid hormone concentrations are related to T3-dependent gene expression only to a certain extent, as bioavailability of T3 to its nuclear receptors is modified by specific thyroid hormone transporters in the plasma membrane and cellular deiodinases which locally may activate or inactivate thyroid hormone.

    “Serum thyroid hormone concentrations are related to T3-dependent gene expression only to a certain extent, as bioavailability of T3 to its nuclear receptors is modified by specific thyroid hormone transporters in the plasma membrane and cellular deiodinases which locally may activate or inactivate thyroid hormone [30] .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] Bianco AC, Kim BW: Deiodinase: implications of the local control of thyroid hormone action. J Clin Invest 2006;116:2571–2579.10.1172/JCI2981217016550 source
  • Premisecitation

    A significant carry-over effect was not observed in the studies which tested specifically for its presence.

    “A significant carry-over effect was not observed in the studies which tested specifically for its presence [5,41,45,46] .”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source
    • cites [41] Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543–4550.10.1210/jc.2003-03024914557419 source
    • cites [45] Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF: Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with thyroxine alone. Endocrine Pract 2005;11:223–233. source
    • cites [46] Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J: Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine withL-thyroxine alone. Ann Intern Med 2005;142:412–424.15767619 source
  • Premisecitation

    Polymorphisms in DIO2 and DIO3 are not associated with serum TSH or thyroid hormone concentrations according to the most recent and largest studies.

    “Polymorphisms in DIO2 and DIO3 are not associated with serum TSH or thyroid hormone concentrations according to the most recent and largest studies [54,55,57] .”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [54] Medici M, van der Deure WM, Verbiest M, Vermeulen SH, Hansen PS, Kiemeney LA, Hermus ARMM, Breteler MM, Hofman A, Hegedus L, Kyvik KO, den Heijer M, Uitterlinden AG, Visser TJ, Peeters RP: A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol 2011;164:781–788.10.1530/EJE-10-1130 source

      The available passages have no section or page labels and do not report results for DIO2 or DIO3. Searches for both genes and for their association with TSH and FT4 returned no gene-specific findings; the listed significant associations alone cannot establish that DIO2 and DIO3 were not associated. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [55] Taylor PN, Panicker V, Sayers A, Shields B, Iqbal A, Bremner AP, Beilby JP, Leedman PJ, Hattersley AT, Vaidya B, Frayling T, Evans J, Tobias JH, Timpson NJ, Walsh JP, Dayan CM: A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement. Eur J Endocrinol 2011;164:773–780.10.1530/EJE-10-0938 source

      The Results section reports associations for PDE8B and DIO1, including no association between a DIO1 variant and TSH; it does not report findings for DIO2 or DIO3. Searches for DIO2, DIO3, and the claimed lack of association found no passage addressing either gene, so this copy cannot verify the claim. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [57] Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JRB, Weedon MN, Singleton A, Hernandez D, Evans J, Durant C, Ferucci L, Meltzer D, Saravanan P, Visser TJ, Ceresini G, Hattersley AT, Vaidya B, Dayan CM, Frayling TM: A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and free triiodothyronine. J Clin Endocrinol Metab 2008;93:3075–3081.10.1210/jc.2008-039718492748 source
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 66
  • The quote only partly states this claim. 2

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

    Premisecitation

    Autoimmune thyroid disease is associated with other autoimmune diseases.

    “It is well known that autoimmune thyroid disease is associated with other autoimmune diseases [20,21] .”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [20] Somers EC, Thomas SL, Smeeth L, Hall AJ: Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009;169:749–755.10.1093/aje/kwn408 source
    • cites [21] Weetman AP: Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol 2011;74:411–418.10.1111/j.1365-2265.2010.03855.x source

  • May combine two claims.

    Findingcitation

    The earliest study from 1970 and the most recent one from 2009 are not included in the meta-analysis, but all other studies performed between 1999 and 2005 are included.

    “The earliest study from 1970 [37] and the most recent one from 2009 [5] are not included in the meta-analysis, but all other studies (performed between 1999 and 2005) are included in the meta-analysis [34] .”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [37] Smith RN, Taylor SA, Massey JC: Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 1970;iv:145–148.10.1136/bmj.4.5728.145 source
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source
    • cites [34] Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L: Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006;91:2592–2599.10.1210/jc.2006-0448 source

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

    Premisecitation

    The daily L-T3 dose was administered as a single dose in all trials except four, in which it was divided in two doses.

    “The daily L-T3 dose was administered as a single dose in all trials except four, in which it was divided in two doses [37,40,42,43] .”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [37] Smith RN, Taylor SA, Massey JC: Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 1970;iv:145–148.10.1136/bmj.4.5728.145 source

      The Dosage passage supports identifying this as a trial in which the daily L-T3 dose was divided rather than given once daily. But patients taking two tablets spaced them 12 hours apart, while those taking three spaced them eight hours apart; the dose was not divided into two administrations for everyone in this trial. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [40] Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, Weert HCPM van, Wiersinga WM: Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90:2666–2674.10.1210/jc.2004-211115705921 source
    • cites [42] Clyde PW, Harari AE, Getka EJ, Shakir KM: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952–2958.10.1001/jama.290.22.295214665656 source
    • cites [43] Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT: Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551–4555.10.1210/jc.2003-03013914557420 source

  • May combine two claims.

    Premisecitation

    The L-T3 dose administered during combination therapy varied between 5 and 25 g daily, with the exception of the oldest study in which 40-60 g L-T3 was given.

    “The L-T3 dose administered during combination therapy varied between 5 and 25 g daily, with the exception of the oldest study in which 40-60 g L-T3 was given [37] .”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Smith RN, Taylor SA, Massey JC: Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 1970;iv:145–148.10.1136/bmj.4.5728.145 source

  • May combine two claims.

    Premisecitation

    In five studies, baseline dissatisfaction or mood state was not associated with outcomes; in one study, patients preferring combination therapy had worse baseline scores for depression and social functioning than patients without preference.

    “This has been done in five studies: results were not different in patients with or without depression [44] , in patients in the highest tertile of the psychiatric Symptoms Checklist [40] , in patients with high or low fatigue levels [45] , or in dissatisfied patients at baseline [41] .In one study, patients preferring combination therapy had worse baseline scores for depression and social function”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [44] Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424–429.10.1056/NEJM1999021134006039971866 source
    • cites [40] Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, Weert HCPM van, Wiersinga WM: Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90:2666–2674.10.1210/jc.2004-211115705921 source
    • cites [45] Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF: Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with thyroxine alone. Endocrine Pract 2005;11:223–233. source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Three further studies assessed body weight, but none reported significant changes.

    “Three further studies assessed body weight, but none reported significant changes [39,42,45] .”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [39] Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM: Partial substitution of thyroxine (T4) with triiodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab 2005;90:805–812.10.1210/jc.2004-167215585551 source
    • cites [42] Clyde PW, Harari AE, Getka EJ, Shakir KM: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA 2003;290:2952–2958.10.1001/jama.290.22.295214665656 source
    • cites [45] Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF: Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with thyroxine alone. Endocrine Pract 2005;11:223–233. source

  • May combine two claims.

    Premisecitation

    A meta-analysis of 1,512 studied polymorphisms in 68 thyroid hormone pathway genes in four populations showed a significant association of 30 SNPs in 10 genes with TSH; only 8 SNPs in PDE8B remained significant with p values below the threshold of 0.0022.

    “A meta-analysis of 1,512 studied polymorphisms in 68 thyroid hormone pathway genes in four populations showed a significant association of 30 SNPs in 10 genes with TSH; only 8 SNPs in PDE8B remained significant with p values below the threshold of 0.0022 [54] .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [54] Medici M, van der Deure WM, Verbiest M, Vermeulen SH, Hansen PS, Kiemeney LA, Hermus ARMM, Breteler MM, Hofman A, Hegedus L, Kyvik KO, den Heijer M, Uitterlinden AG, Visser TJ, Peeters RP: A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol 2011;164:781–788.10.1530/EJE-10-1130 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A recent meta-analysis confirmed that genetic variation in PDE8B is associated with serum TSH (+0.20 SD/allele), and identified a possible new association with free T4 (-0.07 SD/allele).

    “A recent meta-analysis confirmed that genetic variation in PDE8B is associated with serum TSH (+0.20 SD/allele), and identified a possible new association with free T4 (-0.07 SD/allele) [55] .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Taylor PN, Panicker V, Sayers A, Shields B, Iqbal A, Bremner AP, Beilby JP, Leedman PJ, Hattersley AT, Vaidya B, Frayling T, Evans J, Tobias JH, Timpson NJ, Walsh JP, Dayan CM: A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement. Eur J Endocrinol 2011;164:773–780.10.1530/EJE-10-0938 source

  • May combine two claims.

    Premisecitation

    The C-allele of SNP rs2235544 in DIO1 is associated with increased D1 activity with resulting increase in serum free T3, decrease in serum free T4 and reverse T3 (rT3), and thereby in a decreased serum free T4 to free T3 concentration ratio.

    “The C-allele of SNP rs2235544 in DIO1 is associated with increased D1 activity with resulting increase in serum free T3, decrease in serum free T4 and reverse T3 (rT3), and thereby in a decreased serum free T4 to free T3 concentration ratio.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [57] Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JRB, Weedon MN, Singleton A, Hernandez D, Evans J, Durant C, Ferucci L, Meltzer D, Saravanan P, Visser TJ, Ceresini G, Hattersley AT, Vaidya B, Dayan CM, Frayling TM: A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and free triiodothyronine. J Clin Endocrinol Metab 2008;93:3075–3081.10.1210/jc.2008-039718492748 source

  • May combine two claims.

    Premisecitation

    Subsequent studies also reported the association between PDE8B and higher serum TSH, but not between PDE8B and serum free T4 which would have expected to be lower.

    “Subsequent studies also reported the association between PDE8B and higher serum TSH, but not between PDE8B and serum free T4 which would have expected to be lower [53,54] .”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [53] Shields BM, Freathy RM, Knight BA, Hill A, Weedon MN, Frayling TM, Hattersley AT, Vaidya B: Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy. J Clin Endocrinol Metab 2009;94:4608–4612.10.1210/jc.2009-1298 source
    • cites [54] Medici M, van der Deure WM, Verbiest M, Vermeulen SH, Hansen PS, Kiemeney LA, Hermus ARMM, Breteler MM, Hofman A, Hegedus L, Kyvik KO, den Heijer M, Uitterlinden AG, Visser TJ, Peeters RP: A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol 2011;164:781–788.10.1530/EJE-10-1130 source

      The indexed copy returned only a bibliographic abstract (no section or page), ending mid-sentence, rather than a full-text passage. Searches for PDE8B’s association with TSH and its lack of association with FT4 found no Results or Discussion passage in our copy that could verify the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The linear regression line of the negative log-linear relationship between serum TSH and free T4 was much steeper in L-T4-treated patients than in controls; thus, a greater change in serum free T4 is required in L-T4-treated patients to obtain the same feedback on pituitary TSH secretion.

    “Whereas the familiar negative log-linear relationship between serum TSH and free T4 was observed in both groups, the linear regression line in L-T4-treated patients was much steeper than in controls: thus, a greater change in serum free T4 is required in L-T4-treated patients in order to obtain the same feedback on pituitary TSH secretion [67] .”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [67] Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R: Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 2011;6:e22552.10.1371/journal.pone.0022552 source

  • May combine two claims.

    Premisecitation

    In L-T4-treated patients, despite a serum TSH value within the normal range of 0.4-4.0 mU/l, 7.2% had serum free T4 levels above the upper normal limit, 15.2% had serum free T3 levels below the lower normal limit, and 29.6% had free T4/free T3 ratios higher than the normal range.

    “In the L-T4-treated patients, despite a serum TSH value within the normal range of 0.4-4.0mU/l, 7.2% had serum free T4 levels above the upper normal limit, 15.2% had serum free T3 levels below the lower normal limit, and 29.6% had free T4/free T3 ratios higher than the normal range.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [67] Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R: Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 2011;6:e22552.10.1371/journal.pone.0022552 source

  • May combine two claims.

    Interpretationreasoning

    Because of tissue heterogeneity, pituitary TSH secretion may not reflect what happens in other target tissues, and therefore serum TSH alone may not be a good marker for the adequacy of thyroid hormone replacement.

    “Because of tissue heterogeneity, pituitary TSH secretion may not reflect what happens in other target tissues, and therefore serum TSH alone may not be a good marker for the adequacy of thyroid hormone replacement [67,68,70] .”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [67] Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R: Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 2011;6:e22552.10.1371/journal.pone.0022552 source
    • cites [68] Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA: TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wien Klin Wochenschr 2005;117:636–640.10.1007/s00508-005-0421-0 source
    • cites [70] Toft AD, Beckett GJ: Thyroid function tests and hypothyroidism. Measurement of serum TSH alone may not always reflect thyroid status. Br Med J 2003;326:295–296.10.1136/bmj.326.7384.29512574021 source

  • May combine two claims.

    Findingown data

    Five of the reviewed RCTs have a parallel study design and eight have a crossover study design.

    “Five studies have a parallel study design and eight a crossover study design.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    One study is available only in abstract form.

    “One study is available only in abstract form [38] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Levitt JA, Silverberg J: T4 plus T3 for hypothyroidism: a double-blind comparison with usual T4. Abstract, Proc 74th Ann Meet American Thyroid Association, Los Angeles, 2002.

      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). The quote only partly states this claim.

    Findingnone given

    All reviewed RCTs are double-blind in nature.

    “All RCTs are double-blind in nature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    L-T4 monotherapy is preferred by 28% of participants, although their L-T4 dose in the study period was exactly the same as prior to randomization.

    “L-T4 monotherapy is preferred by 28% of participants, although their L-T4 dose in the study period was exactly the same as prior to randomization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    52% of participants expressed no preference or a preference for L-T4 monotherapy, and 48% preferred L-T4 + L-T3 combination therapy.

    “Whereas 52% of participants expressed no preference or a preference for L-T4 monotherapy, it is striking that 48% preferred L-T4 + L-T3 combination therapy.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    Assuming 70% absorption of oral L-T4 does not significantly change the final dose of L-T3 and L-T4.

    “Assuming 70% absorption of oral L-T4 does not significantly change the final dose of L-T3 and L-T4 ( table 6 , method B2).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: 70% absorption of oral L-T4.

  • May combine two claims.

    Findingreasoning

    The calculated L-T4/L-T3 dose ratio for method A is 14:1, and 13:1 to 14:1 after rounding off dosages to the nearest available strength.

    “From the examples given in table 6, it can be seen that the calculated L-T4/L-T3 dose ratio for method A is 14: 1, and 13: 1 to 14: 1 after rounding off dosages to the nearest available strength.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among patients in RCTs comparing T4 monotherapy with T4+T3 combination therapy, 48% preferred T4+T3 therapy, 27% preferred T4 monotherapy, and 25% had no preference.

    “Total | 228 (100%) | 61 (27%) | 58 (25%) | 109 (48%) |”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543–4550.10.1210/jc.2003-03024914557419 source
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source
    • cites [44] Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424–429.10.1056/NEJM1999021134006039971866 source

  • May combine two claims.

    Findingown data

    The mean serum FT4:FT3 ratio in L-T4-treated hypothyroid patients is 4.3 at baseline, 4.5 after T4 monotherapy, and 3.4 after T4+T3 combination therapy.

    “Mean FT4:FT3 ratio | 4.3 | 4.5 | 3.4”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM: Partial substitution of thyroxine (T4) with triiodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab 2005;90:805–812.10.1210/jc.2004-167215585551 source
    • cites [41] Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543–4550.10.1210/jc.2003-03024914557419 source
    • cites [43] Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT: Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551–4555.10.1210/jc.2003-03013914557420 source

  • May combine two claims.

    Findingreasoning

    The L-T4/L-T3 dose ratio calculated with method B1 is 16:1 before correction for absorption and 14:1 to 20:1 after rounding off to the nearest strength available.

    “The L-T4/L-T3 dose ratio calculated with method B1 is 16: 1 before correction for absorption and 14: 1 to 20: 1 after rounding off to the nearest strength available.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: 80% absorption of L-T4 and 100% absorption of L-T3.

  • May combine two claims.

    Premisecitation

    In humans, daily triiodothyronine (T3) production is about 29 μg at a body surface area of 1.79 m2; about 20% is secreted by the thyroid gland and about 80% is generated extrathyroidally by 5-deiodination of T4.

    “Daily production rate of triiodothyronine (T3) for a body surface area of 1.79 m 2 is about 29 g (16 g/day/m 2 ): 20% ( ϳ 6 g, or 3.3 g/day/m 2 ) is secreted by the thyroid gland, and 80% ( ϳ 23 g, or 12.7 g/day/m 2 ) is generated in extrathyroidal tissues by 5 -deiodination of T4 [1] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990;258:E715–E726.2333963 source

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

    Premisecitation

    In humans, thyroxine (T4) is produced exclusively by the thyroid gland, with a daily production rate of about 100 μg at an average body surface area of 1.79 m2.

    “Thyroxine (T4) is produced exclusively by the thyroid gland; its daily production rate is about 100 g at an average body surface area of 1.79 m 2 (56.2 g/day/m 2 ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990;258:E715–E726.2333963 source

  • May combine two claims.

    Premisecitation

    In an Austrian study of 426 euthyroid women undergoing thyroid surgery, patients with TPO-Ab >121 kU/l had higher rates of chronic fatigue, dry hair, chronic irritability, chronic nervousness and lower quality of life than those with TPO-Ab <121 kU/l, with no difference in serum TSH levels or thyroid hormone replacement use.

    “Patients with TPO-Ab 1 121 kU/l had higher rates for several symptoms including chronic fatigue, dry hair, chronic irritability, chronic nervousness and lower quality of life (SF-36 questionnaire) than those patients with TPO-Ab !121 kU/l; there was no difference in serum TSH levels or the use of thyroid hormone replacement therapy (29%) between both groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Ott J, Promberger R, Kober F, Neuhold N, Tea M, Huber JC, Hermann M: Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid 2011;21:161–167.10.1089/thy.2010.0191 source

  • May combine two claims.

    Premisecitation

    In a study comparing thyroid function before and after total thyroidectomy, pre- and postoperative serum TSH and T3 concentrations were not different.

    “Pre-and postoperative serum TSH (1.18 8 0.58 vs. 1.30 8 1.89 mU/l) and serum T3 (1.99 8 0.41 vs. 1.96 8 0.43 nmol/l) concentrations were not different.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Jonklaas J, Davidson B, Bhagat S, Soldin SJ: Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA 2008;299:769–777.10.1001/jama.299.7.76918285588 source

  • May combine two claims.

    Premisecitation

    In a double-blind RCT with a crossover design, small changes in L-T4 dosage did not produce measurable changes in hypothyroid symptoms, well-being, quality of life, or cognition, and no significant treatment preference was observed.

    “These small changes in L-T4 dosage did not produce measurable changes in hypothyroid symptoms, well-being, quality of life, or cognition, and no significant treatment preference was observed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Walsh JP, Ward LC, Burke V, Bhagat CI, Shiels L, Henley D, Gillett MJ, Gilbert R, Tanner M, Stuckey BGA: Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab 2006;91:2624–2630.10.1210/jc.2006-0099 source

  • May combine two claims.

    Premisecitation

    In a Norwegian community-based study, more women on L-T4 had high HADS scores for depression (18.4% vs 12.8%, p < 0.001) and anxiety (23.4% vs 18.6%, p < 0.001) than women not on L-T4.

    “More women on L-T4 had high scores (HADS 6 8) for depression and anxiety than women not on L-T4: depression 18.4 versus 12.8% (p !0.001), anxiety 23.4 versus 18.6% (p !0.001), respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Panicker V, Evans J, Bjoro T, Asvold BO, Dayan CM, Bjerkeset O: A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the HUNT study. Clin Endocrinol 2009;71:574–580.10.1111/j.1365-2265.2008.03521.x source

  • May combine two claims.

    Premisecitation

    In the Dutch study, neither serum TSH nor anti-thyroid antibodies were determinants of neurocognitive functioning or well-being.

    “Neither serum TSH nor anti-thyroid antibodies were determinants of neurocognitive functioning or well-being.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JGP, Wiersinga WM: Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005;153:747–753.10.1530/eje.1.02025 source

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

    Premisecitation

    Combination therapy ensuring euthyroidism in all tissues at the same time was only obtained at a dose of 0.90 μg T4 and 0.15 μg T3 per 100 g body weight per day; the molar ratio of the T4 and T3 dose is 5:1, similar to that present in the normal thyroidal secretion of the rat.

    “Combination therapy ensuring euthyroidism in all tissues at the same time was only obtained at a dose of 0.90 g T4 and 0.15 g T3 per 100 g body weight per day; the molar ratio of the T4 and T3 dose is 5: 1, similar to that present in the normal thyroidal secretion of the rat.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Escobar-Morreale HF, Escobar del Rey F, Obregon MJ, Morreale de Escobar G: Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomised rat. Endocrinology 1996;137:2490–2502.10.1210/en.137.6.24908641203 source

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

    Study design and conductcitation

    Recommendations are rated according to the GRADE system.

    “Recommendations are rated according to the GRADE system [7,8] .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schunemann H: Grading strength of recommendations and quality of evidence in clinical guidelines. Report from an American College of Chest Physicians Task Force. Chest 2006;129:174–181.10.1378/chest.129.1.17416424429 source
    • cites [8] Swiglo BA, Murad MH, Schunemann HJ, Kunz R, Vigersky RA, Guyatt GH, Montori VM: A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 2008;93:666–673.10.1210/jc.2007-190718171699 source

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

    Study design and conductnone given

    The recommendations are based on unanimous consensus of task force members.

    “The recommendations are based on consensus of task force members which was unanimous.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The dimension and causality of the problem of persistent complaints in L-T4-treated hypothyroid patients is not clear.

    “The dimension and causality of the problem is not clear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The molar ratio of T4 to T3 in thyroidal secretion is about 5.7:1 in rats and about 14:1 in humans.

    “The molar ratio of T4 to T3 in thyroidal secretion is ϳ 5.7: 1 in rats and ϳ 14: 1 in humans [1] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R: Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990;258:E715–E726.2333963 source

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

    Study design and conductnone given

    The task force excluded papers on L-T4 + L-T3 combination therapy in central hypothyroidism, children, and hepatic hemangioma, and restricted investigations to adults with a definite diagnosis of primary hypothyroidism, preferentially randomized clinical trials rather than observational studies.

    “The task force excluded from the present analysis papers on L-T4 + L-T3 combination therapy in central hypothyroidism, in children, and in hepatic hemangioma; investigations were restricted to papers on adults with a definite diagnosis of primary hypothyroidism, evaluating preferentially randomized clinical trials rather than observational studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A Dutch community-based study of 583 randomly selected perimenopausal women reported an association between TPO-Ab >100 kU/l and depression (OR 3.0, 95% CI 1.3-6.8); neither thyroid dysfunction nor menopausal status was related to depression.

    “In contrast, a Dutch community-based study of 583 randomly selected perimenopausal women reports an association between TPO-Ab 1 100 kU/l and depression (OR 3.0, 95% CI 1.3-6.8);neither thyroid dysfunction nor menopausal status was related to depression [24] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Pop VJ, Maartens LH, Leusink G, van Son MJ, Knottnerus AA, Ward AM, Metcalfe R, Weetman AP: Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab 1998;83:3194–3197.10.1210/jc.83.9.3194 source

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

    Study design and conductnone given

    The literature search used a systematic PubMed, Embase and Medline search for primary references and reviews published until September 2011.

    “using a systematic PubMed, Embase and Medline search for primary references and reviews published until September 2011.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a large UK study, the frequency of other autoimmune disorders was 9.67% in 2,791 patients with Graves' disease and 14.3% in 495 patients with Hashimoto's disease.

    “In a large UK study the frequency of other autoimmune disorders was 9.67% in 2,791 patients with Graves' disease, and 14.3% in 495 patients with Hashimoto's disease [22] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA: Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 2010;123:183.e1–183.e9.10.1016/j.amjmed.2009.06.030 source

  • May combine two claims.

    Premisecitation

    In a Dutch community-based study, 141 L-T4-treated patients with autoimmune hypothyroidism and serum TSH 0.11-4.0 mU/l showed poor performance on various domains of neurocognitive functioning compared with Dutch general population reference values (p = 0.001), especially on a complex attention task and verbal memory tests.

    “Patients showed poor performance on various domains of neurocognitive functioning compared with standard reference values (p = 0.001), especially on a complex attention task and on verbal memory tests.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JGP, Wiersinga WM: Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005;153:747–753.10.1530/eje.1.02025 source

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

    Study design and conductreasoning

    Funding was derived solely from the general funds of the ETA, and the task force functioned without commercial support.

    “Funding was derived solely from the general funds of the ETA and thus the task force functioned without commercial support.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Based on frequency differences between patients and controls, about 10% of L-T4-treated hypothyroid patients have impaired psychological well-being and about 5% have depression or anxiety which can be related to the disease and L-T4 therapy.

    “Based on the frequency differences between patients and controls, about 10% of L-T4-treated hypothyroid patients have impaired psychological well-being and about 5% depression or anxiety which can be related to the disease and L-T4 therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that UK study, rheumatoid arthritis was the most common coexisting autoimmune disorder (3.15% in Graves' disease and 4.24% in Hashimoto's disease), and relative risks of almost all other autoimmune diseases were significantly increased (RR >10 for pernicious anaemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo).

    “Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves' disease and 4.24% of Hashimoto's disease).Relative risks of almost all other autoimmune diseases were significantly increased (RR 1 10 for pernicious anaemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA: Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 2010;123:183.e1–183.e9.10.1016/j.amjmed.2009.06.030 source

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

    Study design and conductnone given

    The draft guidelines were posted on the ETA website for 1 month for comments, and the final document was approved by the Guidelines Board and the Executive Committee of the ETA.

    “The draft guidelines were put on the 'Members-only' section of the ETA website for 1 month, in order to receive comments of ETA members.The final document was approved by the Guidelines Board and the Executive Committee of the ETA.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Task force members declared whether they had any potential conflict of interest.

    “Task force members declared whether they had any potential conflict of interest.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a US study, 34 L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to 22 euthyroid controls, with no correlations between serum TSH levels and outcomes.

    “In a study from the USA recruiting women mostly by advertisement, 34 L-T4treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to 22 euthyroid controls.There were no correlations between serum TSH levels and outcomes [16] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS: Health status, psychological symptoms, mood, and cognition in L-thyroxine treated hypothyroid subjects. Thyroid 2007;17:249–258.10.1089/thy.2006.0252 source

  • May combine two claims.

    Premisecitation

    In women on L-T4, serum TSH was positively associated with depression and anxiety; each 1 mU/l increase in serum TSH was associated with 3% more depression cases (p = 0.04) and 3% more anxiety cases (p = 0.046).

    “In women on L-T4, serum TSH was positively associated with depression and anxiety.For each 1 mU/l increase in serum TSH there was 3% more depression cases (p = 0.04) and 3% more anxiety cases (p = 0.046).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Panicker V, Evans J, Bjoro T, Asvold BO, Dayan CM, Bjerkeset O: A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the HUNT study. Clin Endocrinol 2009;71:574–580.10.1111/j.1365-2265.2008.03521.x source

  • May combine two claims.

    Premisenone given

    Serum TSH values at the end of combination therapy were higher than at the end of L-T4 monotherapy in two trials, similar in seven trials, and lower in two trials.

    “Serum TSH values at the end of combination therapy were higher than serum TSH values at the end of L-T4 monotherapy in two trials, similar in seven trials, and lower in two trials.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Serum TSH was not determined in two trials.

    “Serum TSH was not determined in two trials.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Exposure to study medication varied between 15 and 52 weeks (median 16 weeks) in parallel studies, and between 5 and 12 weeks (median 8 weeks) in crossover studies.

    “Exposure to study medication varied between 15 and 52 weeks (median 16 weeks) in parallel studies, and between 5 and 12 weeks (median 8 weeks) in crossover studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recruitment by advertisement carries the risk of including a disproportionate number of patients dissatisfied with the outcome of L-T4 treatment; participants responding to advertisements were dissatisfied in 55% in one study and had depressive symptoms in 100% in another study.

    “Recruitment by advertisement carries the risk to include a disproportionate number of patients dissatisfied with the outcome of L-T4 treatment.Indeed, participants responding to advertisements were dissatisfied in 55% in one study [41] and had depressive symptoms in 100% in another study [43] .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 2003;88:4543–4550.10.1210/jc.2003-03024914557419 source
    • cites [43] Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT: Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4551–4555.10.1210/jc.2003-03013914557420 source

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent RCT observed that combination therapy was superior to monotherapy.

    “However, a recent RCT observed combination therapy was superior to monotherapy [5] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source

  • May combine two claims.

    Premisenone given

    Combination therapy was not better than L-T4 monotherapy in nine but better in three of the 12 RCTs.

    “Combination therapy was not better than L-T4 monotherapy in nine but better in three of the 12 RCTs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In one trial, the benefit of combination therapy was observed only in thyroid cancer patients and not in patients with autoimmune thyroiditis.

    “This may constitute a bias, as the benefit of combination therapy in one trial was observed only in the thyroid cancer patients and not in patients with autoimmune thyroiditis [48,49] .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Bunevicius R, Jakubonien N, Jurkevicius R, Cernicat J, Lasas L, Prange AJ Jr: Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine 2002;18:129–133.10.1385/ENDO:18:2:12912374459 source
    • cites [49] Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G: Review: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90:4946–4954.10.1210/jc.2005-018415928247 source

  • May combine two claims.

    Premisecitation

    Serum free T4 to free T3 ratios in patients randomized to receive L-T4 monotherapy range from 4.0 to 5.5, higher than the value of 3.3 observed in healthy controls.

    “Indeed, serum free T4 to free T3 ratios in patients randomized to receive L-T4 monotherapy range from 4.0 to 5.5 ( table 3 ), higher than the value of 3.3 observed in healthy controls [49] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G: Review: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90:4946–4954.10.1210/jc.2005-018415928247 source

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

    Interpretationnone given

    Polymorphisms in genes involved in thyroid hormone pathways may change the set-point of the hypothalamus-pituitary-thyroid axis, and such small but common genetic variations may also modulate the effect of exogenous T4 in particular target tissues of hypothyroid patients.

    “Polymorphisms in genes involved in thyroid hormone pathways may change the set-point of the hypothalamus-pituitary-thyroid axis, and such small but common genetic variations may also modulate the effect of exogenous T4 in particular target tissues of hypothyroid patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SNPs in DIO1 are not related to psychological well-being or response to L-T4 + L-T3 combination therapy.

    “However, SNPs in DIO1 are not related to psychological well-being or response to L-T4 + L-T3 combination therapy [59] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM: Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab 2009;94:1623–1629.10.1210/jc.2008-1301 source

  • May combine two claims.

    Premisecitation

    PDE8B variants are associated with serum TSH; each additional copy of the minor allele of rs4704397 is associated with an increase of 0.13 mU/l in serum TSH.

    “Phosphodiesterase 8B gene (PDE8B) variants are associated with serum TSH (e.g. each additional copy of the minor allele of rs4704397 is associated with an increase of 0.13 mU/l in serum TSH [52] ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Arnaud-Lopez L, Usala G, Ceresini G, Mitchell BD, Pilia MG, Piras MG, Sestu N, Maschio A, Busonero F, Albai G, Dei M, Lai S, Mulas A, Crisponi L, Tanaka T, Bandinelli S, Guralnik JM, Loi A, Balaci L, Sole G, Prinzis A, Mariotti S, Shuldiner AR, Cao A, Schlessinger D, Uda M, Abecasis GR, Nagaraja R, Sanna S, Naitza S: Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet 2008;82:1270–1280.10.1016/j.ajhg.2008.04.019 source

  • May combine two claims.

    Premisecitation

    D2 catalyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signalling.

    “D2 cata lyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signal-ling [63] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Kim BW, Bianco AC: For some, L-thyroxine replacement might not be enough: a genetic rationale. J Clin Endocrinol Metab 2009;94:1521–1523.10.1210/jc.2009-0410 source

  • May combine two claims.

    Premisecitation

    Both the OATP1C1-intron 3C 1 T and the OATP1C1-C3035T polymorphisms (but not the OATP1C1-Pro143Thr polymorphism) were associated with symptoms of fatigue and depression.

    “Both the OATP1C1-intron 3C 1 T and the OATP1C1-C3035T polymorphisms (but not the OATP1C1-Pro143Thr polymorphism) were associated with symptoms of fatigue and depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] van der Deure WM, Appelhof BC, Peeters RP, Wiersinga WM, Wekking EM, Huyser J, Schene AH, Tijssen JGP, Hoogendijk WJG, Visser TJ, Fliers E: Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol 2008;69:804–811.10.1111/j.1365-2265.2008.03267.x source

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

    Premisecitation

    The meta-analysis did not perform a quantitative analysis of patient's preference.

    “The meta-analysis did not perform a quantitative analysis of patient's preference [34] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L: Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006;91:2592–2599.10.1210/jc.2006-0448 source

  • May combine two claims.

    Premisecitation

    Patient preference for combination therapy was associated with improvement in QoL, cognition, mood and symptoms in three trials but absent in two trials.

    “Patient preference for combination therapy was associated with improvement in QoL, cognition, mood and symptoms in three trials [5,44,48] but absent in two trials [40,46] .”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source
    • cites [44] Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999;340:424–429.10.1056/NEJM1999021134006039971866 source
    • cites [48] Bunevicius R, Jakubonien N, Jurkevicius R, Cernicat J, Lasas L, Prange AJ Jr: Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine 2002;18:129–133.10.1385/ENDO:18:2:12912374459 source
    • cites [40] Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, Weert HCPM van, Wiersinga WM: Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90:2666–2674.10.1210/jc.2004-211115705921 source
    • cites [46] Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J: Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine withL-thyroxine alone. Ann Intern Med 2005;142:412–424.15767619 source

  • May combine two claims.

    Premisecitation

    Polymorphisms in DIO1 are associated with serum FT4 but not with serum TSH.

    “Polymorphisms in DIO1 are associated with serum FT4 but not with serum TSH [56][57][58] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56][57][58]

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

  • May combine two claims.

    Premisecitation

    In the 2009 study, depression scores and seven out of 11 QoL scores were significantly better during combination therapy than during L-T4 monotherapy.

    “In that study, depression scores and seven out of 11 QoL scores were significantly better during combination therapy than during L-T4 monotherapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J: Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine (T3) versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol 2009;161:895–902.10.1530/EJE-09-0542 source

  • May combine two claims.

    Premiseown data

    The rarer phenotype rs225014 of DIO2 was present in 16% of the subjects on L-T4 therapy, and associated with worse scores on the General Health Questionnaire (GHQ) (scores 14.1 vs. 12.8, p = 0.03).

    “The rarer phenotype rs225014 of DIO2 was present in 16% of the subjects on L-T4 therapy, and associated with worse scores on the General Health Questionnaire (GHQ) (scores 14.1 vs. 12.8, p = 0.03).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The significance of the finding that about half preferred combination therapy is limited by relevant data being available in only six trials and due to preference resulting from overtreatment with thyroid hormones in one trial.

    “The significance of this finding is limited by relevant data being available in only six trials and due to preference resulting from overtreatment with thyroid hormones in one trial [40] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, Weert HCPM van, Wiersinga WM: Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90:2666–2674.10.1210/jc.2004-211115705921 source

  • May combine two claims.

    Interpretationown data

    The results require replication but suggest that DIO2 polymorphisms are associated with impaired psychological well-being in patients on L-T4 replacement and enhanced response to L-T4 + L-T3 combination therapy.

    “The results require replication but suggest that DIO2 poly-morphisms are associated with impaired psychological well-being in patients on L-T4 replacement and enhanced response to L-T4 + L-T3 combination therapy.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    These negative results are possibly due to the still limited sample size of 141 patients in this study, because a larger study among 552 patients on L-T4 replacement reported positive results.

    “These negative results are possibly due to the still limited sample size of 141 patients in this study, because a larger study among 552 patients on L-T4 replacement reported positive results [59] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM: Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab 2009;94:1623–1629.10.1210/jc.2008-1301 source

  • May combine two claims.

    Premisecitation

    Whereas serum free T4 remains constant over 24 h, there is a circadian free T3 rhythm with its acrophase occurring around 3 a.m., approximately 90 min after TSH acrophase.

    “Whereas serum free T4 remains constant over 24 h, there is a circadian free T3 rhythm with its acrophase occurring around 3 a.m., approximately 90 min after TSH acrophase [77] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Russell W, Harrison RF, Smith N, Darzy K, Shalet S, Weetman AP, Ross RJ: Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels. J Clin Endocrinol Metab 2008;93:2300–2306.10.1210/jc.2007-2674 source

  • May combine two claims.

    Premisecitation

    During L-T4 monotherapy no change in serum free T3 is seen in the first four hours post-dose, whereas during L-T4 + L-T3 combination therapy a marked rise of 42% in serum free T3 has been observed within the first 4 h after ingestion of L-T3.

    “Whereas during L-T4 monotherapy no change in serum free T3 is seen in the first four hours post-dose, during L-T4 + L-T3 combination therapy a marked rise of 42% in serum free T3 has been observed within the first 4 h after ingestion of L-T3 [66] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM: Twenty-four hour hormone profiles of TSH, free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Exp Clin Endocrinol Diabetes 2007;115:261–267.10.1055/s-2007-973071 source

  • May combine two claims.

    Premisenone given

    Armour Thyroid contains about 38 g L-T4 and 9 g L-T3 per one grain (60 mg of desiccated thyroid extract), that is a L-T4/L-T3 dose ratio of 4.2:1.

    “For example, Armour Thyroid (a mixture of T4 and T3, made from porcine thyroid glands) contains about 38 g L-T4 and 9 g L-T3 per one grain (60 mg of desiccated thyroid extract), that is a L-T4/L-T3 dose ratio of 4.2: 1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a recent study, the serum free T4/free T3 ratio was lower during L-T4 + slow-release L-T3 therapy than during L-T4 monotherapy, although still higher than in controls.

    “Proof of principle of such preparations has been obtained in a recent study, in which the serum free T4/free T3 ratio was lower during L-T4 + slow-release L-T3 therapy than during L-T4 monotherapy, although still higher than in controls [76] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Henneman G, Docter R, Visser TJ, Postema PT, Krenning EP: Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism. Thyroid 2004;14:271–275.10.1089/105072504323030924 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The consequences of prolonged L-T4 + L-T3 combination therapy for bone and cardiovascular health are unknown.

    “The consequences, if any, of prolonged L-T4 + L-T3 combination therapy for bone and cardiovascular health are unknown [50] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Fadeyev VV, Morgunova TB, Melnichenko GA, Dedov II: Combined therapy with L-thyroxine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Hormones 2010;9:245–252. source

  • May combine two claims.

    Premisenone given

    The L-T4/L-T3 dose ratio in combination tablets is lower than the recommended ratio of 13:1 to 20:1, and may be variable from batch to batch.

    “The L-T4/L-T3 dose ratio in combination tablets is lower than the recommended ratio of 13: 1 to 20: 1, and may be variable from batch to batch.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    If serum free T3 is too low, an increase of L-T3 dose is logical, as a higher L-T4 dose is likely to increase serum free T4.

    “If serum free T3 is too low, an increase of L-T3 dose is logical, as a higher L-T4 dose is likely to increase serum free T4.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    If serum free T4 is too high, an increase of L-T3 dose will lower serum free T4.

    “If serum free T4 is too high, an increase of L-T3 dose will lower serum free T4.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for T4+T3 combination therapy.

    “OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for T4+T3 combination therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] van der Deure WM, Appelhof BC, Peeters RP, Wiersinga WM, Wekking EM, Huyser J, Schene AH, Tijssen JGP, Hoogendijk WJG, Visser TJ, Fliers E: Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol 2008;69:804–811.10.1111/j.1365-2265.2008.03267.x source

  • May combine two claims.

    Premisecitation

    65-75% of oral L-T4 and 69-99% of oral L-T3 is absorbed.

    “It has been reported that 65-75% of oral L-T4 and 69-99% of oral L-T3 is absorbed [72][73][74][75] .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72][73][74][75]

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

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

    Interpretationnone given

    A positive outcome at 3 months might be caused by a placebo effect, and it may not be uncommon that the positive outcome is not sustained with longer duration of L-T4 + L-T3 combination treatment.

    “A positive outcome at 3 months might be caused by a placebo effect, and it may not be uncommon that the positive outcome is not sustained with longer duration of L-T4 + L-T3 combination treatment.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Dose ratios of other combination tablets are 10:1 (Prothyrid, 100 + 10), 5:1 (Novothyral, 100 + 20, 75 + 15, 25 + 5) and 4:1 (Thyreotom, 120 + 30, 40 + 10 g L-T4 + g L-T3, respectively).

    “Dose ratios of other combination tablets are 10: 1 (Prothyrid, 100 + 10), 5: 1 (Novothyral, 100 + 20, 75 + 15, 25 + 5) and 4: 1 (Thyreotom, 120 + 30, 40 + 10 g L-T4 + g L-T3, respectively).”
    Quote in the paperNot a substantial claim
80 of 80

  • The authors state this as an assumption.

    A general work-up has already excluded well-known causes of nonspecific symptoms and unwellness unrelated to thyroid disease, such as anaemia, hypercalcemia, and occult infections.

    “It is assumed that a general work-up has already excluded well-known causes of nonspecific symptoms and 'unwellness' that have nothing to do with thyroid diseases such as anaemia, hypercalcemia, occult infections, etc.”

  • The paper relies on this without support.

    Most if not all hypothyroid patients on L-T4 treatment require lifelong replacement therapy with thyroid hormones, and transient thyroid hormone deficiency is rare.

    “Most if not all hypothyroid patients on L-T4 treatment will require lifelong replacement therapy with thyroid hormones.Transient thyroid hormone deficiency is rare.”

  • The authors state this as an assumption.

    An adequate L-T4 dose will eventually normalize serum TSH values in all patients with primary hypothyroidism, assuming compliance with the medication.

    “an adequate L-T4 dose will eventually normalize serum TSH values in all patients with primary hypothyroidism (assuming compliance with the medication).”

  • The paper relies on this without support.

    Hypothyroidism is most frequently caused by chronic autoimmune thyroiditis and by thyroid ablation in Graves' disease, so most hypothyroid patients have autoimmune thyroid disease.

    “Hypothyroidism is most frequently caused by chronic autoimmune thyroiditis (Hashimoto's disease) and by thyroid ablation in Graves' disease.Most hypothyroid patients thus have autoimmune thyroid disease.”

  • The paper relies on this without support.

    Thyroid peroxidase antibodies (TPO-Abs) are very prevalent in the general population and also in subjects with normal TSH values.

    “TPO-Abs are very prevalent in the general population and also in subjects with normal TSH values.”

  • The paper relies on this without support.

    A low sample size limits the power to detect differences between treatment arms.

    “It is obvious that a low sample size limits the power to detect differences between treatment arms.”

  • The paper relies on this without support.

    Currently available combined L-T4 + L-T3 preparations all have an L-T4/L-T3 dose ratio of less than 13:1.

    “Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13: 1, and are not recommended.”

  • The authors state this as an assumption.

    Persistent complaints in L-T4-treated hypothyroid patients with normal serum TSH are related to findings in rats that T4 monotherapy does not ensure euthyroidism simultaneously in all tissues.

    “-persistent complaints in this context are related to findings in rats that T4 monotherapy does not ensure euthyroidism simultaneously in all tissues [32] ;”

  • The authors state this as an assumption.

    A euthyroid state simultaneously in all tissues of hypothyroid patients can be reached by L-T4 + L-T3 in a dose ratio that mimics the physiological T4 to T3 secretion ratio by the human thyroid gland.

    “-a euthyroid state simultaneously in all tissues of hypothyroid patients can be reached by L-T4 + L-T3 in a dose ratio that mimics the physiological T4 to T3 secretion ratio by the human thyroid gland [33] ;”

  • The authors state this as an assumption.

    A euthyroid state simultaneously in all tissues of hypothyroid patients is present if serum TSH, free T4, free T3 and free T4:free T3 ratio are all within the reference range.

    “-a euthyroid state simultaneously in all tissues of hypothyroid patients is present if serum TSH, free T4, free T3 and free T4:free T3 ratio are all within the reference range.”

  • The authors state this as an assumption.

    80% absorption of L-T4 and 100% absorption of L-T3.

    “Assuming 80% absorption of L-T4 and 100% absorption of L-T3 the dose of L-T4 and L-T3 in L-T4 + L-T3 combination therapy is calculated as follows ( table 6 , method B1):”

  • The authors state this as an assumption.

    70% absorption of oral L-T4.

    “Assuming 70% absorption of oral L-T4 does not significantly change the final dose of L-T3 and L-T4 ( table 6 , method B2).”

  • The authors state this as an assumption.

    Persistent symptoms in L-T4-treated hypothyroid patients are due to higher than normal serum free T4 to free T3 ratios.

    “For, if one assumes persistent symptoms in L-T4-treated hypothyroid patients are due to higher than normal serum free T4 to free T3 ratios, the T4 to T3 dose ratio during combination therapy should mimic the physiological ratio of T4 to T3 secretion by the thyroid gland in order to secure normal serum free T4 to free T3 ratios: this is not accomplished in most trials.”

  • The authors state this as an assumption.

    Serum TSH concentrations have been normalized to within the reference range and patients are compliant with the prescribed medication.

    “Table 1 lists a number of possibilities to explain persistent complaints in L-T4-treated hypothyroid patients, assuming serum TSH concentrations have been normalized to within the reference range and patients are compliant with the prescribed medication.”

  • The paper relies on this without support.

    Persisting symptoms occur in patients on T4 monotherapy despite a serum TSH within the reference range.

    “There is an urgent need for further research in order to understand the nature of persisting symptoms in patients on T4 monotherapy despite a serum TSH within the reference range.”

  • The paper relies on this without support.

    The safety of L-T4 + L-T3 combination therapy is unclear in patients with cardiovascular diseases other than cardiac arrhythmias.

    “Likewise, the safety of L-T4 + L-T3 combination therapy is unclear in patients with cardiovascular diseases other than cardiac arrhythmias.”

  • The paper relies on this without support.

    The L-T4/L-T3 dose ratio that best approximates the serum free T4/free T3 concentration ratios in healthy subjects is not precisely known.

    “Other studies may investigate more precisely the L-T4/L-T3 dose ratio that best approximates the serum free T4/free T3 concentration ratios in healthy subjects.”
17 of 17

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?

  • An earlier meta-analysis of cross-over studies suggested that 27% of patients preferred monotherapy, 25% had no preference, and 48% preferred combination therapy.

    “An earlier meta-analysis of the cross-over studies suggested that 27% of patients preferred monotherapy, 25% had no preference, and 48% preferred combination therapy (55).”

    From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [55]

    Table 4 reports the stated percentages for 228 patients in crossover studies: 27% preferred monotherapy, 25% had no preference, and 48% preferred combination therapy. But the Synopsis of RCTs says the earlier meta-analysis did not quantitatively analyze patient preference; the percentages come from the guidelines’ own analysis of the trials, not that meta-analysis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The 2013 ETA guidelines advise considering combination therapy for patients with persistent symptoms despite adequate doses of LT4, after all other relevant comorbidities have been excluded.

    “The 2013 ETA guidelines advise considering combination therapy for patients with persistent symptoms despite adequate doses of LT4, after all other relevant comorbidities have been excluded (55).”

    From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [55]

    The “Which Patients Would Qualify” section says combination therapy might be considered for patients with persistent symptoms despite normalized TSH after associated autoimmune disease has been excluded. The “Biologic Rationale” section also assumes a general work-up has excluded other causes of symptoms. However, the cited guidelines are from 2012, not 2013, and describe combination therapy as experimental rather than a routine treatment option; page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The notable inaccuracy of FT3 assays requires precaution when interpreting serial laboratory results.

    “Yet the notable inaccuracy of FT3 assays requires precaution when interpreting serial laboratory results (19, 20).”

    From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [20]

    The monitoring section (page unavailable) says there is substantial variation between free T4 and free T3 assays and recommends laboratory-specific reference ranges. This supports caution when interpreting results, but it does not establish that FT3 assays are inaccurate or specifically discuss interpreting serial results. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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”

    From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [9]

    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

  • The ETA guidelines recommend a starting ratio of 13:1 to 20:1 (LT4:LT3), which represents a dose of 5 or 10 μg LT3 for patients taking 100 to 200 μg LT4.

    “The ETA guidelines recommend a starting ratio of 13:1 to 20:1 (LT4:LT3), which represents a dose of 5 or 10 μg LT3 for patients taking 100 to 200 μg LT4 (55).”

    From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [55]

Cites

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Related

Authors
Wiersinga, W. M., Duntas, L., Fadeyev, V., Nygaard, B., & Vanderpump, M. P. J.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • National and Kapodistrian University of Athens (GR)
  • Endocrinology Research Center (RU)
  • Herlev Hospital (DK)
  • Royal Free London NHS Foundation Trust (GB)
ORCID
Venue
European Thyroid Journal
Publisher
Bioscientifica
Published
2012-06-13
Volume
1
Issue
2
Pages
55-71
ISSN
  • 2235-0640 (ISSN-L)
  • 2235-0802
DOI
10.1159/000339444
PMC
PMC3821467
OpenAlex
W2120985321
Semantic Scholar
a4b9c60c3a6d5342a83f711bf1bfd022fd43b413
Cited by
427
References
89
Citations by year
2026: 14 · 2025: 39 · 2024: 29 · 2023: 36 · 2022: 45 · 2021: 54 · 2020: 39 · 2019: 38 · 2018: 32 · 2017: 26 · 2016: 24 · 2015: 25 · 2014: 11 · 2013: 7 · 2012: 3
FWCI
10.58
Type
journal article
Language
en
Open access
Licence
www.karger.com/Services/SiteLicenses (vor, 4997 d)
Locations
  • European Thyroid Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
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, levothyroxine, liothyronine, combination thyroid hormone therapy, autoimmune thyroid disease, dose ratio, treatment monitoring, 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 2026-10-14.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-14.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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