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

In the paper

“It is well known that autoimmune thyroid disease is associated with other autoimmune diseases [20,21] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The section “Autoimmune disease associations with AITD” says that other autoimmune diseases cluster in the same individuals and families. The “Rheumatological conditions” section gives specific examples, including rheumatoid arthritis and systemic lupus erythematosus. The claim is a general association, not an assertion that every autoimmune disease is associated with AITD. (LLM, conf=0.94)

  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

In the paper

“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] .”

What the sources say

• Supported

  The Discussion identifies this work as a trial comparing combined triiodothyronine and thyroxine with thyroxine alone, and the Method passage carries its 1970 publication date. Citation [37] identifies the 1970 study; the statement about which studies the meta-analysis included is attached to citation [34], not this source. (LLM, conf=0.90)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• Supported

  The Dosage passage (page not supplied) says each combination tablet contained 20 µg of L-triiodothyronine and patients took two or three tablets daily. That gives 40–60 µg daily in this study, supporting the exception for which this source is cited. (LLM, conf=0.92)

  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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Partly supported

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

  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. sourceExperimental — accuracy not yet measured

In the paper

“Three further studies assessed body weight, but none reported significant changes [39,42,45] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  The Methods list weight as an outcome, and Table 4 in the Results reports no significant difference in weight between treatments (p = 0.27). The Discussion also states that weight did not differ significantly. This confirms the claim for this cited study, not the other two studies cited alongside it. (LLM, conf=0.94)

  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

In the paper

“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] .”

What the sources say

• Partly supported

  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.

  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 sourceExperimental — accuracy not yet measured

In the paper

“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] .”

What the sources say

• Supported

  The Results passage in our copy’s Abstract reports the same effect estimates: +0.20 SD per allele for TSH and −0.07 SD per allele for free T4, describing the latter as a possible new association. The main Results and Discussion likewise confirm the TSH association and describe the free T4 finding as requiring further validation. Page numbers are unavailable in our copy. (LLM, conf=0.95)

  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

In the paper

“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.”

What the sources say

• Supported

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

  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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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] .”

What the sources say

• Supported

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

  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

In the paper

“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.”

What the sources say

• Supported

  The Methods (Subjects; page not provided) specify that the levothyroxine-treated patients had TSH levels of 0.4–4.0 mU/L. The Results report 7.2% with FT4 above normal, 15.2% with FT3 below normal, and 29.6% with an FT3/FT4 ratio below normal. Because FT4/FT3 is the reciprocal, the last finding supports the citing sentence’s description of an above-normal FT4/FT3 ratio. (LLM, conf=0.94)

  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

In the paper

“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] .”

What the sources say

• Supported

  The Introduction states that differences among tissues may make pituitary-secreted TSH an inappropriate indicator of euthyroidism in peripheral tissues. The Discussion likewise says that normal serum TSH cannot always be taken as a marker of euthyroidism in levothyroxine-treated patients. (LLM, conf=0.95)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Five studies have a parallel study design and eight a crossover study design.”

In the paper

“One study is available only in abstract form [38] .”

What the sources say

• ?Not matched

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

In the paper

“All RCTs are double-blind in nature.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“Total | 228 (100%) | 61 (27%) | 58 (25%) | 109 (48%) |”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Mean FT4:FT3 ratio | 4.3 | 4.5 | 3.4”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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 ).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Neither serum TSH nor anti-thyroid antibodies were determinants of neurocognitive functioning or well-being.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Recommendations are rated according to the GRADE system [7,8] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“The recommendations are based on consensus of task force members which was unanimous.”

In the paper

“The dimension and causality of the problem is not clear.”

In the paper

“The molar ratio of T4 to T3 in thyroidal secretion is ϳ 5.7: 1 in rats and ϳ 14: 1 in humans [1] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“using a systematic PubMed, Embase and Medline search for primary references and reviews published until September 2011.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“Serum TSH was not determined in two trials.”

In the paper

“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.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“However, a recent RCT observed combination therapy was superior to monotherapy [5] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“However, SNPs in DIO1 are not related to psychological well-being or response to L-T4 + L-T3 combination therapy [59] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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] ).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“D2 cata lyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signal-ling [63] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“The meta-analysis did not perform a quantitative analysis of patient's preference [34] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Polymorphisms in DIO1 are associated with serum FT4 but not with serum TSH [56][57][58] .”

What the sources say

• ?Not matched

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

  cites [56][57][58]

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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).”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“The consequences, if any, of prolonged L-T4 + L-T3 combination therapy for bone and cardiovascular health are unknown [50] .”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“It has been reported that 65-75% of oral L-T4 and 69-99% of oral L-T3 is absorbed [72][73][74][75] .”

What the sources say

• ?Not matched

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

  cites [72][73][74][75]

In the paper

“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.”

In the paper

“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).”