docT3 plus T4 Combination Therapy: Yes or No?
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T3 plus T4 Combination Therapy: Yes or No?
T3 plus T4 Combination Therapy: Yes or No? Antonio C. Bianco, MD, PhD Division of Endocrinology and Metabolism Rush University Medical Center Chicago, IL Contact: www.BiancoLab.org Disclosures: Chief, Division of Endocrinology and Metabolism; Executive Vice‐Chair, Department of Internal Medicine, Rush University Medical Center, President‐ Elect American Thyroid Association, Board of Scientific Counselors of the NIDDK‐NIH, Bethesda MD, USA A Patient’s Email Dear Dr. Bianco, I know my body well enough to know when the thyroid is out of sorts. I had a sense of being unwell this entire season. Before my college classes start in the fall, I must get regulated. I am the type of person, who never misses a day of work. I believe this crisis is the result of a doctor taking me off of XXX and not giving me liothyronine. He just gave me levothyroxine.....I cannot walk a straight line and am in a constant state of dizziness. My vision is blurry and I feel like I have vertigo. I have chronic insomnia and am extremely jumpy. I cannot focus and worse of all cannot focus on reading. My thyroid problems all started when XXX went off the market. Since then I have had a 30 pound weight gain. I cannot understand why all these new med cannot do the job of XXX. I think this drug was taken off the market several times.....each time when I go back on it, I feel healthy and have the energy and alertness of a 20 year old. Would you please give me both levothyroxine and T3? Sincerely, KB © 2013 BLab KB 2/12 - KB is a 65 y.o. female that in 1973 was diagnosed with hypothyroidism. Treated with XXX (desiccated porcine thyroid). However, ever since XXX came out of the market she was placed on levothyroxine and does not feel well. She is gaining weight and has difficulty in focusing (she is a high school teacher). Currently on 100mcg/day levothyroxine; TSH = 2.75; FT4 = 1.6; T3 = 71 Recommendation: Increase levothyroxine by ½ tablet/week or add to 5-10 mcg/day of liothyronine to the levothyroxine regimen? © 2013 BLab AACE and ATA ‐ 2012 Clinical Practice Guidelines for Hypothyroidism in Adults: Jeffrey R. Garber, Rhoda H. Cobin, Hossein Gharib, James V. Hennessey, Irwin Klein, Jeffrey I. Mechanick, Rachel Pessah-Pollack, Peter A. Singer, and Kenneth A. Woeber How should patients with hypothyroidism be treated and monitored? RECOMMENDATION 22.1 Patients with hypothyroidism should be treated with L-thyroxine monotherapy. Grade A RECOMMENDATION 22.2 The evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism. Grade B Recommendation 22.2 was downgraded to Grade B because of still-unresolved issues raised by studies that report that some patients prefer and some patient subgroups may benefit from a combination of L-thyroxine and L-triiodothyronine.. © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TRH PITUITARY TSH © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES TRH PITUITARY TSH Development WT Growth Metabolism Cognition D2KO © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS 12 consecutive monthly measurements of serum T3 in 15 healthy subjects. TRH PITUITARY TSH Andersen et al. Thyroid, 2003 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS 12 consecutive monthly measurements of serum T3 in 15 healthy subjects. TRH PITUITARY TSH Andersen et al. Thyroid, 2003 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH 12 consecutive monthly measurements of serum T3 in 15 healthy subjects. D2 PITUITARY D2 TSH CELLS TSH Andersen et al. Thyroid, 2003 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 12 consecutive monthly measurements of serum T3 in 15 healthy subjects. PITUITARY D2 TSH CELLS TSH Andersen et al. Thyroid, 2003 ACCE&ATA Guidelines: …serum T3 measurement, whether total or free, has limited utility in hypothyroidism because levels are often normal due to hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of type 2 iodothyronine deiodinase. © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 PITUITARY D2 TSH CELLS TSH 30 g/day WHAT ARE THE SOURCES OF SERUM T3? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 PITUITARY D2 TSH CELLS TSH 30 g/day 5 WHAT ARE THE SOURCES OF SERUM T3? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS Brain, BAT, SKM, Skin TANYCYTES TRH D2 D2 Nucleus PITUITARY D2 Liver Kidney TSH CELLS TSH D1 30 g/day 5 WHAT ARE THE SOURCES OF SERUM T3? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS Brain, BAT, SKM, Skin TANYCYTES TRH D2 D2 Nucleus PITUITARY D2 Liver Kidney TSH CELLS TSH 20 D1 5 30 g/day 5 WHAT ARE THE SOURCES OF SERUM T3? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 WT D2KO D1def D1def D2KO nl PITUITARY D2 TSH 30 g/day 5 Christoffolete et al, Endocrinology 2007 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 WT D2KO D1def D1def D2KO nl PITUITARY D2 TSH 30 g/day 5 Christoffolete et al, Endocrinology 2007 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 WT D2KO D1def D1def D2KO nl PITUITARY D2 TSH 30 g/day 5 Christoffolete et al, Endocrinology 2007 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 WT D2KO D1def D1def D2KO nl PITUITARY D2 TSH 30 g/day 5 Christoffolete et al, Endocrinology 2007 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 WT D2KO D1def D1def D2KO nl PITUITARY D2 TSH 30 g/day 5 RESETTING OF HPT AND SERUM T3 IS PRESERVED Christoffolete et al, Endocrinology 2007 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 PITUITARY D2 TSH 30 g/day 5 TRH-TSH-THYROID UNIT IS WIRED TO DEFEND SERUM T3 (MAJOR ROLE PLAYED BY THYROID GLAND) Fonseca et al, JCI 2013 HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES TANYCYTES TRH D2 Brain, BAT, SKM, Skin PITUITARY D2 Nucleus D2 TSH Liver Kidney 20 D1 30 g/day 5 5 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES TANYCYTES TRH D2 Brain, BAT, SKM, Skin PITUITARY D2 Nucleus D2 TSH Liver Kidney 20 D1 30 g/day 5 5 HOW WELL IS SERUM T3 DEFENDED IN THE ABSENCE OF A FULLY FUNCTIONAL THYROID GLAND? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES TANYCYTES TRH D2 Brain, BAT, SKM, Skin PITUITARY D2 Nucleus D2 TSH Liver Kidney 20 D1 30 g/day 5 5 IS SERUM T3 EVEN A THERAPEUTIC TARGET IN HYPOTHYROID PATIENTS? © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES TANYCYTES TRH D2 Brain, BAT, SKM, Skin PITUITARY D2 Nucleus D2 TSH Liver Kidney 20 D1 30 g/day 5 5 CAN SERUM T3 BE MAINTAINED IN L-T4-TREATED HYPOTHYROID PATIENTS? © 2013 BLab Gullo et al ; 2011 HYPOTHALAMUS-PITUITARY THYROID AXIS FT4 TANYCYTES TRH D2 PITUITARY D2 TSH FT3 30 g/day 5 CAN SERUM T3 BE MAINTAINED IN L-T4-TREATED HYPOTHYROID PATIENTS? © 2013 BLab Gullo et al ; 2011 HYPOTHALAMUS-PITUITARY THYROID AXIS FT4 TANYCYTES TRH D2 PITUITARY D2 TSH FT3 30 g/day 5 Euthyroid controls (3875) Athyrotic on l-thyroxine (1811) 5.0 FT3 (pmol/L) CAN SERUM T3 BE MAINTAINED IN L-T4-TREATED HYPOTHYROID PATIENTS? - TSH 4.5 4.0 3.5 3.0 12 data normalized for serum TSH 13 14 15 16 17 FT4 (pmol/L) © 2013 BLab American Thyroid Association Guidelines (2014) Guidelines for Treatment of Hypothyroidism Jonklaas, J. & Bianco, A.C., Bauer, A.J., Burman, K.D., Cappola, A.R., Celi, F.S., Cooper, D.S., Kim, B.W., Peeters, R.P., Rosenthal, M.S., Sawka, A.M. 7b. Does levothyroxine therapy that returns the TSH levels of hypothyroid patients to the reference range also result in normalization of their T3 levels? Summary statement Patients with hypothyroidism treated with levothyroxine to achieve normal TSH values often have T3 concentrations that are at the lower end of the reference range, or even below the reference range. The clinical significance of this is unknown. © 2013 BLab What is the mechanism? Werneck & Fonseca et al, JCI 2015 © 2013 BLab What is the mechanism? Hippocampus Cerebral Cortex Hypothalamus ubiquitin GST-WSB-1 GST + + + + + + - + + + + + + + + + + Ub-D2 35S-D2 Werneck & Fonseca et al, JCI 2015 © 2013 BLab What is the mechanism? Werneck & Fonseca et al, JCI 2015 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH IS SUCH A SMALL DECREASE IN SERUM T3 CLINICALLY RELEVANT? D2 PITUITARY D2 TSH © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH IS SUCH A SMALL DECREASE IN SERUM T3 CLINICALLY RELEVANT? D2 PITUITARY D2 TSH Geffner et al, JCI 1975 © 2013 BLab HYPOTHALAMUS-PITUITARY THYROID AXIS TANYCYTES TRH D2 PITUITARY D2 TSH IS SUCH A SMALL DECREASE IN SERUM T3 CLINICALLY RELEVANT? Methods -Surgically Tx rats -Implanted with LT4 or LT4+LT3 pellets -Killed 7 weeks later Results and Conclusions 1-Monotherapy results in normal serum TSH, higher serum T4 and lower serum T3 2-Monotherapy results in brain, liver and skeletal muscle hypothyroidism Werneck & Fonseca et al, JCI 2015 © 2013 BLab Rationale for combination therapy with levothyroxine and liothyronine 1. Thyroidectomized patients on monotherapy with levothyroxine normalize serum FT4 and TSH but do not seem to normalize serum T3, maintaining a high serum T4/T3 ratio and in some cases serum T3 levels that are below the normal range. However, with very few exceptions, most clinical trials failed to show any significant advantage/benefit of combination therapy vs. monotherapy. © 2013 BLab American Thyroid Association Guidelines (2014) Guidelines for Treatment of Hypothyroidism Jonklaas, J. & Bianco, A.C., Bauer, A.J., Burman, K.D., Cappola, A.R., Celi, F.S., Cooper, D.S., Kim, B.W., Peeters, R.P., Rosenthal, M.S., Sawka, A.M. 13a. In adults requiring thyroid hormone replacement treatment for primary hypothyroidism, is the combination treatment including synthetic triiodothyronine and levothyroxine superior to the use of levothyroxine alone? Recommendation: There is no consistently strong evidence of superiority of combination therapy over monotherapy with levothyroxine. Therefore, we recommend against the routine use of combination treatment with levothyroxine and liothyronine as a form of thyroid replacement therapy in patients with primary hypothyroidism, based on conflicting results of benefits from randomized controlled trials comparing this therapy to levothyroxine therapy alone and a paucity of long-term outcome data. © 2013 BLab How good are the clinical trials? Q: Does combination therapy with tablets of levothyroxine and liothyroinine normalize plasma T3? 12 consecutive monthly measurements of serum T3 in 15 healthy subjects. Andersen et al. Thyroid, 2003 © 2013 BLab How good are the clinical trials? Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM. Exp Clin Endocrinol Diabetes. 2007 Apr;115(4):261-7. Methods In this study, we have compared 24-hour profiles of thyroid stimulating hormone (TSH), free T4 (fT4) and free T3 (fT3) and cardiovascular parameters in 10 hypothyroid patients who had been on once daily combined T3/T4 therapy for more than 3 months with 10 patients on T4 alone. Results and Conclusions On T4 alone, a modest 16% rise in fT4 with no change in fT3 was seen in the first 4-hours post-dose. In contrast, on combined treatment, fT3 levels showed a marked rise of 42% within the first 4-hours post-dose (T3/T4:T4=6.24: 4.63 mU/L, p<0.001). Mean exposure to fT3 calculated by area under the curve (AUC) was higher (T3/T4:T4=1148:1062, p<0.0001) on T3. Our data suggests that despite chronic combined T3/T4 therapy, wide peak-to-trough variation in fT3 levels persists. © 2013 BLab L-T3 administration modeling 1 day Francesco Celi, NIH © 2013 BLab Neuron‐Astrocyte Crosstalk Cognition Figure 7 Juan Bernal, Ronald Lechan & Theo Visser © 2013 BLab D2 KO MOUSE HAS BRAIN-SPECIFIC HYPOTHYROIDISM Galton et al, Endocrinology, 2007 © 2013 BLab Thr92AlaD2 polymorphism Thr92Ala DIO2 Association Between a Novel Variant of the Human Type 2 Deiodinase Gene Thr92Ala and Insulin Resistance: Evidence of Interaction With the Trp64Arg Variant of the β-3-Adrenergic Receptor Daniela Mentuccia, Laura Proietti-Pannunzi, Keith Tanner, Vincenzo Bacci, Toni I. Pollin, Eric T. Poehlman, Alan R. Shuldiner and Francesco S. Celi; Diabetes 2002 vol. 51 no. 3 880-883 Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Dora, J.M., et al., Eur J Endocrinol, 2010 Case-control study with 1057 type II diabetes patients and 516 non-diabetic subjects indicated that the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for type II diabetes, a conclusion that was supported by a meta-analysis including 11,033 individuals. © 2013 BLab Thr92AlaD2 polymorphism Bianco & Casula, ETJ 2012 © 2013 BLab Rationale for combination therapy with levothyroxine and liothyronine 1. Thyroidectomized patients on monotherapy with levothyroxine normalize serum FT4 and TSH but do not seem to normalize serum T3, maintaining a high serum T4/T3 ratio and in some cases serum T3 levels that are below the normal range. 2. Possible defects (e.g. genetic polymorphism) in the type 2 deiodinase, which contributes with half of the total T3 in the brain and brown adipose tissue, could result in tissue-specific hypothyroidism, explaining impaired cognition, body weight gain, etc. However, with very few exceptions, most clinical trials failed to show any significant advantage/benefit of combination therapy vs. monotherapy. © 2013 BLab Thr92AlaD2 polymorphism Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM J Clin Endocrinol Metab 2009;94:1623-1629 Methods: Response to T4/T3 in 552 subjects on T4 from the Weston Area T4 T3 Study (WATTS) Original dose of levothyroxine minus 50ug and added 10ug of lithyronine Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12), Thyroid Specific Questionnaire (TSQ). Results and Conclusions: There was a statistically significant association between the DIO2 gene polymorphism and an improved outcome of the combination therapy vs. monotherapy for (i) general health, (ii) thyroid specific and (iii) satisfaction questioners. © 2013 BLab Ala92-D2 Homozygotes Thr92-D2 Homozygotes 3 4 C 2 1 -Log10(p-value) A p= 0.05 -4 -2 1 2 4 Ala92-D2 vs. Thr92-D2 Fold Change Ala92-D2 Homozygotes Thr92-D2 Homozygotes RNU6-51 MIR4694 RNA5SP215 MIR4679-2 ACSL5 FCGR1C RNU6-81P ZNF705B LINC00969 RNU7-9P ANXA2P3 ASAH2 MIR495 YME1L1 OTTHUMG00000165902 C5orf60 HLA-A DPCR1 OTTHUMG00000153650 HCP5 MIR1179 OTTHUMG00000014802 LOC100652931 METTL7B MUC20 SNORA34 FSTL5 SNORD18A OTTHUMG00000176917 PTPN20A TERC SNAR-F SNORD91B OTTHUMG00000030769 SCARNA21 ZNF813 HIST2H4B IRF8 HIST1H4B MIR4497 SNORD60 SNORA71D CCL3L3 TTC9B SNORD114-28 HNRNPA1L2 SNORA64 SNORD16 RNU5B-1 SNORA76 B Thr92AlaD2 polymorphism CNS diseases Growth Factor Signaling mTOR Signaling EGF Signaling PDGF Signaling EIF2 Signaling Insulin Receptor Signaling NGF Signaling VEGF Signaling Huntington’s Disease Signaling CREB Signaling in Neurons Amyloid Processing Neuregulin Signaling ALS Signaling Parkinson’s Signaling CDK5 Signaling Apoptosis/DNA repair P53 Signaling DNA Break Repair PTEN Signaling Mechanisms of Cancer NOTCH Signaling Brain Pathway Analysis p < 0.05 Genes > 60% Ubiquitin & ER Stress Inflammation Protein Ubiquitin Pathway ER Stress Pathway CXCR4 Signaling Thrombin Signaling IL-1 Signaling Chemokine Signaling Mitochondria Mitochondrial Dysfunction Oxidative Phosphorylation NRF2-mediated Oxidative Stress nNOS Signaling in Neurons PKA Signaling © 2013 BLab Thr92AlaD2 polymorphism Thr92‐D2HY C B Ala92‐D2HY D Thr92‐D2HY E F Ala92‐D2HY Thr92-D2HY G Ala92-D2HY H Thr92-D2HY CHX CHX D2HY/Actin A Ala92-D2HY J I Nucleus Rough Endoplasmic Reticulum © 2013 BLab Thr92AlaD2 polymorphism D Thr92-D2HY Thr92-D2HY Ala92-D2HY B D2HY GM-130 E C Ala92D2HY Ala92-D2HY D2HY GM-130 1.0 Circularity of Golgi A F p<0.0001 0.8 0.6 0.4 0.2 0.0 Thr92-D2HY Ala92-D2HY © 2013 BLab Thr92AlaD2 polymorphism A B D Ala92 Thr92 5 4 3 1 2 -Log10(p-value) 6 7 Thr92 Ala92 p= 0.05 -2 C 2 1 Ala92-D2 vs. Thr92-D2 Fold Change MIR1244-1 PTMA PTMA SNORA16B SNORD59B LOC441081 MIR573 BST2 RNU6-83P MIR4295 RNA5SP259 TSIX MIR4774 RNU7-52P OTTHUMG00000158558 SCN3A MIR4677 HNRNPU-AS1 LOC100130976 LOC100996511 MIR3685 TMEM236 DKFZP434L187 LRLE1 LOC101060147 LOC349160 NXT2 OTTHUMG00000162672 TDP2 ATF1 COQ3 LINC00500 OTTHUMG00000163517 ADAT3 DNLZ GREB1 MIR892A SNAP25 RNU6-78P ZNF284 HIST1H2BC DDIT3 TRNAI2 GMNN MIR4530 FAM206A RNU5F-6P OTTHUMG00000039859 NEAT1 SNORA42 © 2013 BLab Relative Expression CD24/cycloA Relative Expression CDK2/cycloA Thr92AlaD2 polymorphism p = 0.02 2.0 1.5 1.0 0.5 0.0 Thr92-D2 Het Ala92-D2 p = 0.05 1.5 GENES IN GENE SETS 1.0 G 0.5 0.0 Thr92-D2 Het Ala92-D2 Thr92-D2 Ala92-D2 (Het + Hmz) p-values 0.03 0.04 0.04 0.04 0.04 0.04 0.02 0.04 0.05 GALK1 SEMA4F CALD1 FADS1 SLC27A2 HAO1 RPL7A RIT1 SLIT2 COL4A3 APOL1 APOD CELA3A PIGZ PIGT PIGH RTN4RL1 NUDT4 NFE2 OPHN1 BMPR1B APOA2 ARAP3 ATP8B1 CARTPT CADM1 PPARD FOXO4 GLI2 MAP3K12 ABCG1 BNIP3 BCL2L10 MAP1S MRPL41 MBL2 GAB1 PYDC1 NBN AKR1C1 ENOX2 POLD1 DMC1 DDB2 GPX4 CD24 NMUR2 LDLR MFN2 NRXN1 NPR1 GLTP ROBO1 CYFIP1 ATP11B IQGAP1 DAPK2 HTATIP2 AGPS TRAF6 TYR SOD2 TP53 AKR1C3 PRDX3 COX7B SLC25A1 UQCRH TOMM22 SPINK5 UQCRC1 CYP11B2 MRPL23 MRPS12 RPS6KA4 ERBB2IP EPS8 EREG TDGF1 1. 0 0. 5 MIR573 LINC005 HNRNPU GLA CCL4 DDIT3 SNORA42 SNORD61 SNORD59B 0. 0 1149 79 303 Brains Cells Fold © 2013 BLab Conclusions • The hypothalamus‐pituitary‐thyroid axis is wired to maintain serum T3. The thyroid gland plays a major role in this process. • Limited data available indicate that serum T3 cannot be maintained/defended in the absence of a fully functional thyroid gland. More studies are needed to define whether normalization of serum T3 and/or serum T3/T4 ratio in hypothyroid patients is clinically relevant. • There is a need to develop a new long‐acting T3 delivery system in order to execute clinical trials testing combination vs. monotherapy; current L‐T3 tablets are not suitable. • Defects in the D2 pathway compromising T3 production could explain residual symptoms in hypothyroid patients that have normal serum TSH. The commonly observed Dio2 gene polymorphism Thr92Ala seems to have effects that are independent of T3 production; more studies are needed to define its clinical role. © 2013 BLab Acknowledgements • Undergrad. Students: Jessica Freitas, Cristina Andrade • Graduate Students: Lattoya Lartey • Post‐Docs: Tatiana Fonseca PhD, Sungro Jo PhD Joao Pedro Werneck PhD, Melany Castillo MD, Elizabeth McAninch MD, Sherine Abdalla MD • Research Assistants: Liping Dong • Collaborators: Balazs Gereben PhD, Ronald M. Lechan, MD PhD Valerie Galton PhD, Donald St. Germain MD Arturo Hernandez PhD • Funding Agencies: NIDDK, ATA © 2013 BLab
