Is the Combination of Thyroxine and Triiodothyronine Better than T4 alone for Hypothyroidism? ESEO Alexandria 2017

Transcription

1 Is the Combination of Thyroxine and Triiodothyronine Better than T4 alone for Hypothyroidism? ESEO Alexandria 2017 James V. Hennessey M. D. Associate Professor Harvard Medical School

2 Case 53 year old woman with a 3 year history of 1 hypothyroidism returns for follow up on LT4. TSH values have been miu/ml. ROS includes increasing fatigue, hair loss, and a new worry of some brain fog. She asks if her LT4 mono therapy is the problem and shares an article on bioidentical hormone replacement therapies.

3 Thyroid Extract: First Combination Rx 1890 Bettencourt and Serrano report subcutaneous injection of patients with extract of animal thyroids Bettencourt-Rodrigues AM. J Soc Sci Med Lisbon. 1890;15: Murray presents his initial idea to treat a case of myxedema with an extract of sheep thyroid subcutaneously. His idea was ridiculed at a medical meeting Murray GR Northumberland & Durham Med Soc minutes U Newcastle Archives 1891; Feb 12:91-93 Slater S. J R Soc Med. 2011; 104:

4 Before After Murray GR. BMJ p. 796 Oct. 10, 1891

5 Alternative for Extract Evaluated 1961 fixed combinations of T4 and T3 available in Britain and later in the United States. Introduced to address the inconsistent hormonal content of desiccated and extract preparations. Peripheral conversion of T4 to T3 had not been demonstrated, replacement therapy assumed to require ingestion of both hormones. Combination LT4/LT3 was NOT introduced as an adjunct to inadequate LT4 mono Rx.

6 Conversion of T4 to T3 Established 11 Hypothyroid patients 7/11 S/P thyroidectomy 3/11 S/P 131-I ablation All receiving LT4 Rx mcg/day T3 found in the sera of ALL 243 to 680 ng/100ml (normal ) FAR in excess of any LT3 contamination of LT4 125 I labeled LT4 administered 125 I labeled T3 found in the circulation thereafter!! Braverman LE et al JCI 49(5):855-64

7 L-Thyroxine Seen as Alternative 1462 middle-aged women enrolled in women treated with LT4 (1 to 28 years) 12-year follow-up in end-points MI, DM, CVA, CA, and death Status of 99.7% of participants was established The women treated with LT4 showed no increase in morbidity or mortality. 24 (83%) women still on LT4 at follow up Petersen K et al. Arch Intern Med. 1990;150:

8 22/24 (92%) of LT4 Rxd had TSH and TT3 wnl. When C/W the 968 having no thyroid disease LT4 Rxd identical by lab and clinical data BUT: Higher BMI, taller stature, lower cholesterol. LT4 treated life quality estimate C/W controls NS Based on 19 question satisfaction and sensory survey Concluded LT4-treated woman have: Equal life quality Suffer no side effects from her life-long therapy Petersen K et al. Arch Intern Med. 1990;150:

9 Satisfaction While Euthyroid on LT4 More recently there appears to be increasing numbers of patients who express dissatisfaction with thyroxine mono therapy. 597 LT-4 Rxd Hypothyroid patients (T4-P) 397 Nl TSH in previous 12 mo. ( mu/l) 551 Non-Hypothyroid controls Evaluation: General Health Questionnaire-12 Thyroid Symptom Questionnaire-12 Saravanan P et al Clin Endo 57:577-85

10 GHQ-12 Score GHQ-12 Scores Max Score *p < * Max score Score Min Score * Caseness 5 Caseness 0 GHQ Control LT4 (nl) LT4 Saravanan P et al Clin Endo 57:577-85

11 Control LT4 Rxd Saravanan P et al Clin Endo 57:577-85

12 TSQ-12 Score TSQ-12 Scores Higher scores c/w Hypothyroidism Max Score *p < * * Max score Score Caseness 0 GHQ Control LT4 (nl) LT4 Saravanan P et al Clin Endo 57:577-85

13 Reemergence of Combination LT4/LT3 Therapy

14 Meta-Analysis of Studies When every trial is a little different and one says LT3/LT4 is superior but most do not, WHAT should I do???

15 Meta-Analysis 1 Systematic review, all published controlled studies comparing LT4 vs. LT4/LT3 in primary hypothyroidism. Nine, controlled clinical trials, sufficient adult hypothyroid subjects to yield meaningful results. One study favored LT4/LT3, results not confirmed. Some studies LT4/LT3 was preferred (subjective). Until clear advantages of LT4/LT3 demonstrated, LT4 should remain treatment of choice. Escobar-Morreale HF et al JCEM 90:

16 Meta-Analysis 2 PubMed, EMBASE, LILACS and Cochrane Searched September 2005 All randomized trials comparing effectiveness of LT4/LT3 vs. LT4 monotherapy Included 11 studies, 1216 patients 7/11 Crossover studies: LT4/LT3 X LT4 4/11 parallel groups: LT4/LT3 or LT4 Grozinsky-Glasberg et al JCEM 91(7):

17 Results: Bodily Pain NS Grozinsky-Glasberg et al JCEM 91(7):

18 Results: Quality of Life NS Grozinsky-Glasberg et al JCEM 91(7):

19 Results: Depression NS Grozinsky-Glasberg et al JCEM 91(7):

20 Results: Fatigue NS Grozinsky-Glasberg et al JCEM 91(7):

21 Meta-Analysis 3 9 double blind parallel or crossover studies 33 to 679 subjects treated 5 to 52 weeks Evaluated mood, depression, QOL, GHQ NS difference in treatment effect Preferences for LT4, LT4/LT3, either Rx LT4/LT % LT % No Preference 22.9% % Joffe RT et al Psychosomatics 48(5):

22 Conclusions Meta-Analysis 4 Combined LT4/LT3 does NOT improve well-being, cognitive function nor Quality of life compared to LT4 alone. LT4 was most beneficial in improving psychological or physical well-being. LT4 monotherapy may remain the drug of choice for hypothyroid patients. Ma C et al Nuc Med Commun 30(8):586-93

23 International Evidence Based Practice Guidance

24 European Thyroid Association (4) There is insufficient evidence that L-T4 + L-T3 combination therapy serves the hypothyroid patient better than T4 monotherapy (1/++0). (5) It is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism (1/+++). Wiersinga WM et al Eur Thyroid J 1:55-71

25 British Thyroid Association 5. There is insufficient evidence that combination therapy with L- T4 and L-T3 therapy is superior to L-T4 monotherapy 6. L-T4/L-T3 therapy may be considered as an experimental approach in compliant LT4-treated hypothyroid patients who have persistent complaints despite reference range serum TSH values, provided they have received adequate chronic disease support and associated autoimmune diseases have been ruled out There is currently insufficient evidence to support the routine use of such a trial of L-T4 and L-T3 outside a formal clinical trial or N of 1 trial (ATA) Okosieme O et al Clin Endo. 84(6):

26 Okosieme O et al Clin Endo. 84(6):

27 Conclusions 1. 25% of controls and 30% of LT4 treated hypothyroid patients with normal TSH have symptoms consistent with hypothyroidism. 2. LT4 treated hypothyroid patients also have: A chronic disease, higher BMIs, are older, more comorbidities and medications other than LT4. 3. Combination LT4/LT3 therapy is no more effective in treating hypothyroidism than LT4.

28 Final Thoughts 4. Symptomatic hypothyroid individuals adequately treated with LT4 deserve aggressive consideration of other causes. 5. Currently recognized polymorphisms of deiodinases have no role in the evaluation of those dissatisfied while on LT4. 6. Levothyroxine mono therapy remains the treatment of choice for hypothyroidism.

29 Thank You For Your Attention Questions?