Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study

Betty Ann Bjerkreim, Sara Salehi Hammerstad, Hanne Løvdal Gulseth, Tore Julsrud Berg, Sindre Lee-Ødegård, Anbjørg Rangberg, Christine Monceyron Jonassen, Helen Budge, David Morris, James Law, Michael Symonds, Erik Fink Eriksen, Betty Ann Bjerkreim, Sara Salehi Hammerstad, Hanne Løvdal Gulseth, Tore Julsrud Berg, Sindre Lee-Ødegård, Anbjørg Rangberg, Christine Monceyron Jonassen, Helen Budge, David Morris, James Law, Michael Symonds, Erik Fink Eriksen

Abstract

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution.

Materials and methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome.

Results: Cold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P<0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P<0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups.

Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation.

Clinical trial registration: ClinicalTrials.gov, identifier NCT03627611.

Keywords: brown adipose tissue (BAT); cold-induced thermogenesis; hypothyroidism; infrared thermography; levothyroxine; liothyronine.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Bjerkreim, Hammerstad, Gulseth, Berg, Lee-Ødegård, Rangberg, Jonassen, Budge, Morris, Law, Symonds and Eriksen.

Figures

Figure 1
Figure 1
Flow chart describing recruitment, randomization and analysis of patients in the study.
Figure 2
Figure 2
Thermal imaging. (A) Representative example of thermal images of the skin area overlying neck and upper chest during cold stimulation after 12 weeks of LT4 treatment with corresponding images of the contour of ROI (blue) and hottest 10% of pixels (red) identified in the SCV fossa and sternal reference region (turquoise). (B) Same as for (A), but after 12 weeks of LT3 treatment.
Figure 3
Figure 3
Body weight, energy expenditure and core temperature. Box plots showing treatment effects after 12 weeks treatment with LT4 (grey) and LT3 (white) in terms of: (A) body weight (BW) in kilograms, (B) energy expenditure relative to body weight (EE/BW), and (C) rectal temperature in degrees Celsius.
Figure 4
Figure 4
Infrared thermography. (A) Response in sternal reference region temperature to cold stimuli on LT4 (grey) and LT3 (white) treatment. Minutes -5 to 0 depicts the response to room air and minutes 0 to 5 the response to hand immersion of both hands into cold water. (B) Same as for (A), but for supraclavicular (SCV) temperature. Data are means ± 95% confidence intervals. (C) A box & whiskers plot for resting SCV temperature minus sternal reference temperature within each of the two treatment periods.

References

    1. Cannon B, Nedergaard J. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev (2004) 84(1):277–359. doi: 10.1152/physrev.00015.2003
    1. Aquila H, Link TA, Klingenberg M. The Uncoupling Protein From Brown Fat Mitochondria Is Related to the Mitochondrial ADP/ATP Carrier. Analysis of Sequence Homologies and of Folding of the Protein in the Membrane. EMBO J (1985) 4(9):2369–76. doi: 10.1002/j.1460-2075.1985.tb03941.x
    1. Krauss S, Zhang CY, Lowell BB. The Mitochondrial Uncoupling-Protein Homologues. Nat Rev Mol Cell Biol (2005) 6(3):248–61. doi: 10.1038/nrm1592
    1. Ricquier D. UCP1, the Mitochondrial Uncoupling Protein of Brown Adipocyte: A Personal Contribution and a Historical Perspective. Biochimie (2017) 134:3–8. doi: 10.1016/j.biochi.2016.10.018
    1. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. . Hypothalamic AMPK and Fatty Acid Metabolism Mediate Thyroid Regulation of Energy Balance. Nat Med (2010) 16(9):1001–8. doi: 10.1038/nm.2207
    1. Branco M, Ribeiro M, Negrão N, Bianco AC. 3,5,3'-Triiodothyronine Actively Stimulates UCP in Brown Fat Under Minimal Sympathetic Activity. Am J Physiol (1999) 276(1):E179–87. doi: 10.1152/ajpendo.1999.276.1.E179
    1. Bianco AC, Silva JE. Intracellular Conversion of Thyroxine to Triiodothyronine Is Required for the Optimal Thermogenic Function of Brown Adipose Tissue. J Clin Invest (1987) 79(1):295–300. doi: 10.1172/JCI112798
    1. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur Thyroid J (2012) 1(2):55–71. doi: 10.1159/000339444
    1. Wartofsky L. Combination L-T3 and L-T4 Therapy for Hypothyroidism. Curr Opin Endocrinol Diabetes Obes (2013) 20(5):460–6. doi: 10.1097/01.med.0000432611.03732.49
    1. Mentuccia D, Proietti-Pannunzi L, Tanner K, Bacci V, Pollin TI, Poehlman ET, et al. . 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 Beta-3-Adrenergic Receptor. Diabetes (2002) 51(3):880–3. doi: 10.2337/diabetes.51.3.880
    1. Bianco AC, Silva JE. Nuclear 3,5,3'-Triiodothyronine (T3) in Brown Adipose Tissue: Receptor Occupancy and Sources of T3 as Determined by In Vivo Techniques. Endocrinology (1987) 120(1):55–62. doi: 10.1210/endo-120-1-55
    1. Bunevicius R, Prange AJ. Mental Improvement After Replacement Therapy With Thyroxine Plus Triiodothyronine: Relationship to Cause of Hypothyroidism. Int J Neuropsychopharmacol (2000) 3(2):167–74. doi: 10.1017/S1461145700001826
    1. 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(6):424–9. doi: 10.1056/NEJM199902113400603
    1. Bunevicius R, Jakuboniene 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(2):129–33. doi: 10.1385/ENDO:18:2:129
    1. Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J. Effect of Combination Therapy With Thyroxine (T4) and 3,5,3'-Triiodothyronine Versus T4 Monotherapy in Patients With Hypothyroidism, a Double-Blind, Randomised Cross-Over Study. Eur J Endocrinol (2009) 161(6):895–902. doi: 10.1530/EJE-09-0542
    1. 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(10):4551–5. doi: 10.1210/jc.2003-030139
    1. Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, et al. . 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(5):2666–74. doi: 10.1210/jc.2004-2111
    1. Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, et al. . 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(10):4543–50. doi: 10.1210/jc.2003-030249
    1. 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(22):2952–8. doi: 10.1001/jama.290.22.2952
    1. 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 Levothyroxine Alone. Endocr Pract (2005) 11(4):223–33. doi: 10.4158/EP.11.4.223
    1. 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 With L-Thyroxine Alone. Ann Internal Med (2005) 142(6):412–24. doi: 10.7326/0003-4819-142-6-200503150-00007
    1. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. . Functional Brown Adipose Tissue in Healthy Adults. N Engl J Med (2009) 360(15):1518–25. doi: 10.1056/NEJMoa0808949
    1. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. . Identification and Importance of Brown Adipose Tissue in Adult Humans. N Engl J Med (2009) 360(15):1509–17. doi: 10.1056/NEJMoa0810780
    1. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. . High Incidence of Metabolically Active Brown Adipose Tissue in Healthy Adult Humans: Effects of Cold Exposure and Adiposity. Diabetes (2009) 58(7):1526–31. doi: 10.2337/db09-0530
    1. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. . Cold-Activated Brown Adipose Tissue in Healthy Men. N Engl J Med (2009) 360(15):1500–8. doi: 10.1056/NEJMoa0808718
    1. Yeung HW, Grewal RK, Gonen M, Schöder H, Larson SM. Patterns of (18)F-FDG Uptake in Adipose Tissue and Muscle: A Potential Source of False-Positives for PET. J Nucl Med (2003) 44(11):1789–96.
    1. Law J, Morris DE, Izzi-Engbeaya C, Salem V, Coello C, Robinson L, et al. . Thermal Imaging Is a Noninvasive Alternative to PET/CT for Measurement of Brown Adipose Tissue Activity in Humans. J Nucl Med (2018) 59(3):516–22. doi: 10.2967/jnumed.117.190546
    1. Jang C, Jalapu S, Thuzar M, Law PW, Jeavons S, Barclay JL, et al. . Infrared Thermography in the Detection of Brown Adipose Tissue in Humans. Physiol Rep (2014) 2(11):e12167. doi: 10.14814/phy2.12167
    1. Chen Y, Buyel JJ, Hanssen MJ, Siegel F, Pan R, Naumann J, et al. . Exosomal microRNA miR-92a Concentration in Serum Reflects Human Brown Fat Activity. Nat Commun (2016) 7:11420. doi: 10.1038/ncomms11420
    1. Silva JE. The Thermogenic Effect of Thyroid Hormone and Its Clinical Implications. Ann Internal Med (2003) 139(3):205–13. doi: 10.7326/0003-4819-139-3-200308050-00010
    1. Silva JE. The Multiple Contributions of Thyroid Hormone to Heat Production. J Clin Invest (2001) 108(1):35–7. doi: 10.1172/JCI200113397
    1. Warner A, Mittag J. Brown Fat and Vascular Heat Dissipation: The New Cautionary Tail. Adipocyte (2014) 3(3):221–3. doi: 10.4161/adip.28815
    1. Warner A, Rahman A, Solsjo P, Gottschling K, Davis B, Vennstrom B, et al. . Inappropriate Heat Dissipation Ignites Brown Fat Thermogenesis in Mice With a Mutant Thyroid Hormone Receptor Alpha1. Proc Natl Acad Sci U S A (2013) 110(40):16241–6. doi: 10.1073/pnas.1310300110
    1. Celi FS, Zemskova M, Linderman JD, Babar NI, Skarulis MC, Csako G, et al. . The Pharmacodynamic Equivalence of Levothyroxine and Liothyronine: A Randomized, Double Blind, Cross-Over Study in Thyroidectomized Patients. Clin Endocrinol (2010) 72(5):709–15. doi: 10.1111/j.1365-2265.2009.03700.x
    1. Law JM, Morris DE, Astle V, Finn E, Muros JJ, Robinson LJ, et al. . Brown Adipose Tissue Response to Cold Stimulation Is Reduced in Girls With Autoimmune Hypothyroidism. J Endocr Soc (2019) 3(12):2411–26. doi: 10.1210/js.2019-00342
    1. Hartwig V, Guiducci L, Marinelli M, Pistoia L, Tegrimi TM, Iervasi G, et al. . Multimodal Imaging for the Detection of Brown Adipose Tissue Activation in Women: A Pilot Study Using NIRS and Infrared Thermography. J Healthc Eng (2017) 2017:5986452. doi: 10.1155/2017/5986452
    1. Sun L, Verma S, Michael N, Chan SP, Yan J, Sadananthan SA, et al. . Brown Adipose Tissue: Multimodality Evaluation by PET, MRI, Infrared Thermography, and Whole-Body Calorimetry (TACTICAL-II). Obesity (Silver Spring Md) (2019) 27(9):1434–42. doi: 10.1002/oby.22560
    1. Nirengi S, Wakabayashi H, Matsushita M, Domichi M, Suzuki S, Sukino S, et al. . An Optimal Condition for the Evaluation of Human Brown Adipose Tissue by Infrared Thermography. PloS One (2019) 14(8):e0220574. doi: 10.1371/journal.pone.0220574
    1. Symonds ME, Henderson K, Elvidge L, Bosman C, Sharkey D, Perkins AC, et al. . Thermal Imaging to Assess Age-Related Changes of Skin Temperature Within the Supraclavicular Region Co-Locating With Brown Adipose Tissue in Healthy Children. J Pediatr (2012) 161(5):892–8. doi: 10.1016/j.jpeds.2012.04.056
    1. Ang QY, Goh HJ, Cao Y, Li Y, Chan SP, Swain JL, et al. . A New Method of Infrared Thermography for Quantification of Brown Adipose Tissue Activation in Healthy Adults (TACTICAL): A Randomized Trial. J Physiol Sci (2017) 67(3):395–406. doi: 10.1007/s12576-016-0472-1
    1. Andersson J, Lundström E, Engström M, Lubberink M, Ahlström H, Kullberg J. Estimating the Cold-Induced Brown Adipose Tissue Glucose Uptake Rate Measured by (18)F-FDG PET Using Infrared Thermography and Water-Fat Separated MRI. Sci Rep (2019) 9(1):12358. doi: 10.1038/s41598-019-48879-7
    1. Law J, Chalmers J, Morris DE, Robinson L, Budge H, Symonds ME. The Use of Infrared Thermography in the Measurement and Characterization of Brown Adipose Tissue Activation. Temperature (Austin) (2018) 5(2):147–61. doi: 10.1080/23328940.2017.1397085
    1. Law JM, Morris DE, Robinson L, Randell T, Denvir L, Symonds ME, et al. . Reduced Brown Adipose Tissue-Associated Skin Temperature Following Cold Stimulation in Children and Adolescents With Type 1 Diabetes. Pediatr Diabetes (2020) 22(3):407–16. doi: 10.1111/pedi.13163
    1. Leibel RL, Rosenbaum M, Hirsch J. Changes in Energy Expenditure Resulting From Altered Body Weight. N Engl J Med (1995) 332(10):621–8. doi: 10.1056/NEJM199503093321001
    1. Barker SB, Klitgaard HM. Metabolism of Tissues Excised From Thyroxine-Injected Rats. Am J Physiol (1952) 170(1):81–6. doi: 10.1152/ajplegacy.1952.170.1.81
    1. Lean ME, James WP, Jennings G, Trayhurn P. Brown Adipose Tissue Uncoupling Protein Content in Human Infants, Children and Adults. Clin Sci (London Engl 1979) (1986) 71(3):291–7. doi: 10.1042/cs0710291
    1. World Health Organization (WHO) . Fifty-seventh World Health Assembly, Geneva In: Resolutions and Decisions, Annexes, Geneva: World Health Organization; (2004).

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe