TSH
La verità sul TSH e gli esami di laboratorio
Il dosaggio nel sangue del TSH (Thyroid Stimulating Hormone) è lo standard di riferimento su cui pressochè tutti i medici e gli specialisti endocrinologi oggi si basano per diagnosticare (od escludere) un eventuale ipotiroidismo. Se il TSH supera i valori massimi del laboratorio (in genere da 4 a 5 mU/l) il paziente è considerato ipotiroideo, ma in realtà se il valore è appena al di sopra del limite molti medici non lo considerano ancora un “vero” ipotiroidismo e consigliano di aspettare un ulteriore peggioramento prima di prendere una qualche iniziativa terapeutica. Se il TSH è invece nel range di normalità (generalmente da 0,5 a 4,5-5 mU/I) il paziente è considerato eutiroideo (cioè con una tiroide che funziona normalmente). Se il TSH è inferiore al minimo, il paziente viene giudicati ipertiroideo. E quello che è paradossale è che se il TSH è nel range, non vengono nemmeno più dosati FT3 ed FT4 (cioè le frazioni libere dei due ormoni tiroidei), quindi un TSH normale è tutto quello che oggi serve per escludere un ipotiroidismo.
Perchè il TSH è spesso inaffidabile
Per decenni gli endocrinologi avevano cercato un esame di laboratorio che potesse individuare i casi di alterato funzionamento tiroideo in maniera semplice ed affidabile ma nessuno dei test proposti negli anni aveva mantenuto le aspettative ed era quindi stato rapidamente abbandonato. Nel 1973 un consesso di endocrinologi decise che si era finalmente trovato il test definitivo per diagnosticare l’ipotiroidismo, il TSH. Va notato che per stabilire il range di normalità gli autori si erano basati sul valore del TSH in soli 200 volontari (apparentemente) sani. Inoltre all’inizio il range era assai più ampio che oggi arrivando come limite superiore fino a 15 mU/l, poi col passare degli anni questo limite fu ridotto a 10, poi a 5 e ora a 4-4,5mU/l.
Ma vediamo quali sono in sintesi i motivi per cui il TSH non può essere considerato un test sicuro ed affidabile per la diagnosi di ipotiroidismo:
- Il TSH non è un ormone tiroideo ma ipofisario, non misura la funzione della tiroide, ma solo la risposta dell’ipofisi ai livelli di ormoni tiroidei presenti nel sangue
- il range di normalità dell’esame del TSH è troppo ampio (è accettata come normale una variazione del suo valore di ben 10 volte!)
- il TSH ha una vita media di poche ore e la sua produzione varia durante la giornata (per esempio nel pomeriggio è in genere più basso che al mattino)
- il TSH può risultare normale o addirittura basso se è l’ipofisi ad avere problemi e quindi non riesce a rispondere al livello di ormoni circolanti (ipotiroidismo secondario), stessa cosa se il problema fosse nell’ipotalamo (ipotiroidismo terziario)
- poichè il TSH risponde solo al livello di ormoni tiroidei circolanti esso sarà normale in caso di mancata conversione da T4 a T3, oppure di resistenza periferica agli ormoni, oppure di problemi nei recettori cellulari o nel trasporto degli ormoni all’interno della cellula. Cioè il fatto che T3 e T4 siano presenti nel sangue non significa necessariamente che poi questi svolgano la loro azione nei tessuti.
Naturalmente in quest’ultimo caso anche la misurazione di FT3 e FT4 sarà inaffidabile per lo stesso motivo del TSH, gli ormoni in circolo ci sono (e quindi sono misurabili) ma per vari motivi essi non possono svolgere adeguatamente la loro funzione. E nei rari casi in cui oltre al TSH il medico prescriva un altro esame questo è quasi sempre solo l’ FT4. Ma il T4 come sappiamo è in realtà solo un precursore dell’ormone attivo T3 per cui misurare solo il T4 senza il T3 non ci consente di capire se abbiamo una buona conversione di un ormone nell’altro e se abbiamo quindi livelli accettabili di ormone attivo.
Infine c’è l’esperienza clinica, non solo nostra, che negli anni ci ha insegnato che ci sono molti, troppi casi di pazienti col TSH perfettamente nei limiti ma con tutta una serie di sintomi che indicano chiaramente che siamo di fronte ad un caso di ipotiroidismo, e la controprova ce l’abbiamo quando questi sintomi poi migliorano o scompaiono una volta che il paziente è sottoposto ad una adeguata terapia tiroidea.
E allora?
Quindi se il laboratorio non è sempre attendibile come può il medico fare una corretta diagnosi di ipotiroidismo? Semplicemente come facevano i medici fino a 40 anni fa quando questi test praticamente non esistevano, cioè basandosi essenzialmente sulla clinica (sintomi e segni del paziente) e magari aiutandosi con mezzi “empirici” come il test della temperatura basale di Barnes. E gli esami del sangue? Naturalmente è bene che vengano comunque prescritti e considerati ma i risultati andrebbero valutati in modo un pò più “elastico” basandosi sulla propria esperienza e capacità clinica e ricordando sempre che non siamo di fronte alle Tavole della Legge ma ad un semplice test che molte volte, purtroppo, non ci può dire tutta la verità.
N.B. Gli esami degli anticorpi tiroidei anti-TPO-perossidasi (TPOAb) e anti-tireoglobulina (TgAb) sono invece piuttosto affidabili e ci consentono di sapere se siamo di fronte ad un problema autoimmunitario che interessa la tiroide (generalmente la tiroidite di Hashimoto che oggi è la più importante causa di ipotiroidismo).
Referenze
1a. O’Reilly DS. Thyroid hormone replacement: an iatrogenic problem. Int J Clin Pract. 2010 Jun;64(7):991-4
1b. 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 Sep;117(18):636-40.
1c. Peeters RP, Geyten SV, Wouters PJ, et al. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;12:6498–507.
2. Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499–518.
3. Fliers E, Alkemade A, Wiersinga WM. The hypothalamic-pituitary-thyroid axis in critical illness. Best Practice & Research Clinical Endocrinology & Metabolism 2001;15(4):453–64.
4. Chopra IJ. Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34.
5. Van der Poll T, Romijn JA, Wiersinga WM, et al. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71(6):1567–72.
6. Stouthard JM, van der Poll T, Endert E, et al. Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 1994;79(5):1342–6.
7. Corssmit EP, Heyligenberg R, Endert E, et al. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. Clin Endocrinol Metab 1995;80(11):3140–4.
8. Nagaya T, Fujieda M, Otsuka G, et al. A potential role of activated NF-Kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106(3):393–402.
9. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodieidinases. Endocr Rev 2002;23:38–89.
10. Chopra IJ, Huang TS, Beredo A, et al. Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3,5,3’-triiodothyronine in sera of patients with nonthyroidal illnesses. J Clin Endocrinol Metab 1985;60:666–72.
11. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:3202–11.
12. Chopra IJ, Chopra U, Smith SR, et al. Reciprocal changes in serum concentrations of 3,3’,5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 1975;41:1043–9.
13. Iervasi G, Pinitore A, Landi P, et al. Low-T3 syndrome a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107(5): 708–13.
14. Peeters RP, Wouters PJ, van Toor H, et al. Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90(8):4559–65.
15. Wartofsky L, Burman K. Alterations in thyroid function in patients with systemic illness; the ‘‘euthyroid sick syndrome’’. Endocr Rev 1982;3(2):164–217.
16. Hennemann G, Everts ME, de Jong, et al. The significance of plasma membrane transport in the bioavailability of thyroid hormone. Clin Endocrinol 1998;48:1–8.
17. Vos RA, de Jong M, Bernard HF, et al. Impaired thyroxine and 3,5,3’-triodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthryoidal illness. J Clin Endocrinology met 1995;80:2364–70.
18. Chopra IJ, Solomon DH, Hepner GW, et al. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann Intern Med 1979;90(6):905–12. Usefulness of rT3 in NTI
19. De Jong M, Docter R, Van Der Hoek HJ, et al. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131:463–70.
20. Mooradian AD, Reed RL, Osterweil D, et al. Decreased serum triiodothyronine is associated with increased concentrations of tumor necrosis factor. J Clin Endocrinol Metab 1990;71(5):1239–42.
21. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007;262:690–701.
22. 234. Zoccali C, Tripepi G, Cutrupi S, et al. Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J Am Soc Nephrol 2005;16:2789–95.
23. Zoccali C, Mallamaci F, Tripepi G, et al. Low triiodothyronine and survival in endstage renal disease. Kidney Int 2006;70:523–8.
24. Pingitore A, Landi P, Taddei MC, et al. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118(2):132–6.
25. Kozdag G, Ural D, Vural A, et al. Relation between free triiodothyronine/free thyroxine ratio, echocardiographic parameters and mortality in dilated cardiomyopathy.
Eur J Heart Fail 2005;7(1):113–8.
26. Karadag F, Ozcan H, Karul AB, et al. Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med 2007;101:1439–46.
27. Kok P, Roelfsema F, Langendonk JG, et al. High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction.. J Clin Endocrinol Metab 2005;90:4659–63.
28. Parr JH. The effect of long-term metabolic control on free thyroid hormone levels in diabetics during insulin treatment. Ann Clin Biochem 1987;24(5):466–9.
29. Dimopoulou I, Ilias I, Mastorakos G, et al. Effects of severity of chronic obstructive pulmonary disease on thyroid function. Metabolism 2001;50(12):1397–401.
30. Mariotti S, Barbesino G, Caturegli P, et al. Complex alterations of thyroid function in healthy centenarians. J Clin Endocrinol Met 1993;77(5):1130–4.
31. Nomura S, Pittman CS, Chambers JB, et al. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest 1975;
56:643–8.
32. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine replacement therapy in patients with chronic heart failure and low T3 syndrome: a randomized placebo-controlled study. J Clin Endocrinol Met 2008;93:1351–8.
33. 268. Premachandra BN, Kabir MA, Williams IK, Low T3 syndrome in psychiatric depression. J Endocrinol Invest 2006;29:568-572.
34. Jackson I. The thyroid axis and depression. Thyroid 1998;8(10):952-956.
35. Linnoila M, Lamberg BA, Potter WZ, Gold PW, Goodwin FK. High reverse T3 levels in manic and unipolar depressed women. Psychiatry Research 1982;6:271-276.
36. Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L. Reverse T3 levels in affective disorders. Psychiatry Research 1983;10:1-9.
37. 272. Stipcevic T, Pivax N, Kozaric-Kovacic D, Muck-Seler D. Thyroid activity in patients with major depression. Coll Antropol 2008;32(3):973-6.
38. Gold MS, Pottash LC, Extein I. Hypothyroidism and depression. JAMA 1981;245(19):1919-1922.
39. Islam S, Yesmine S, Khan SA, Alam NH, Islam S. A comparative study of thyroid hormone levels in diabetic and non-diabetic patients. SE Asian J Trop Med Public Health 2008;39(5):913-916. 50% reduction in free t3 in diabetics.
40. Carle A, Laurberg P, Pedersen IB, et al. Thyrotropin secretion decreases with age in patients with hypothyroidism. Clinical Thyroidology 2007;17:139–44.
41. Annewieke W, van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab 2005;90(12):6403–9.
42. Van Coevorden A, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989;69:
177–85.
43. Rubenstein HA, Butler VPJ, Werner SC. Progressive decrease in serum triiodothyronine concentrations with human aging: radioimmunoassay following extraction of serum. J Clin Endocrinol Metab 1973;37:247–53.
44. Chakraborti S, Chakraborti T, Mandal M, et al. Hypothalamic–pituitary–thyroid axis status of humans during development of ageing process. Clin Chim Acta 1999;288(1-2):137–45.
45. Piers LS, Soars MJ, McCormack LM, et al. Is there evidence for an age-related reduction in metabolic rate? J Appl Phys 1998;85:2196–204.
46. Poehlman ET, Berke EM, Joseph JR, et al. Influence of aerobic capacity, body composition, and thyroid hormones on the age-related decline in resting metabolic rate. Metabolism 1992;41:915–21.
47. Magri F, Fioravanti CM, vignati G, et al. Thyroid function in old and very old healthy subjects. J Endocrinol Invest 2002;25(10):60–3.
48. Goichot B, Schlienger JL, Grunenberger F, et al. Thyroid hormone status and nutrient intake in the free-living elderly. Interest of reverse triiodothyronine assessment. Eur J Endocrinol 1994;130:244–52.
49. Cizza G, Brady LS, Calogero AE, et al. Central hypothyroidism is associated with advanced age in male Fischer 344/n rats: in vivo and in vitro studies. Endocrinology 1992;131:2672–80.
50. Cheron RG, Kaplan MM, Larsen PR. Physiological and pharmacological influences on thyroxine to 3,5,3’-triiodothyronine conversion and nuclear 3,5,3’-triiodthyroidne binding in rat anterior pituitary. J clin Invest 1979;64:1402-1414.
51. Kaplan MM, Utiger RD. Iodothyronine metabolism in rate liver homogenates. J Clin Invest 1978;61:459-471.
52. Kaplan MM. Subcellular alterations causing reduced hepatic thyroxine 5’-monodeiodinase activity in fasted rats. Endocrinology 1979:104:58-64.
53. Portnay GI, O’Brien JT, Bush J, et al. The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J. Clin Endocrinol Metab 1974;39:191-194.
54. Croxson MS, Hall TD, Kletzky OA, Jaramillo JE, et al. Decreased serum thyrotropin induced by fasting. J. Clin Endocrinol Metab 1977; 45:560-568.
55. Carlson HE, Drenick EJ, Chopra IJ, Hershman JM. Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin and thyroid hormones in starved obese men. J Clin Endocrinol Metab 1977;45:707-713.
56. Vinik AI, Kalk W, McLaren JH, Paul M. Fasting blunts the TSH response to synthetic thyrotropinreleasing hormone (TRH). J Clin Endocrinol Metab 1975;40:509-511.
57. Azizi F. Effect of dietary composition of fasting induced changes in serum thyroid hormones and thyrotropin. Metab. Clin. Exp 1978;27:935-942.
58. Brayshaw ND, Brayshaw DD. Thyroid hypofunction in premenstrual syndrome. NEJM 1986;315(23):1486-7.
59. Girdler SS, Pedersen CA, Light CK. Thyroid axis function during the menstrual cycle in women with premenstrual syndrome. Psychoneuroendocrinology 1995;20(4):395-403.
60. Neek G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheum 1992;19(7):1120-1122.
61. Wikland B, Lowhagen T, Sandberg PO. Fine needle aspiration cytology of the thyroid in chronic fatigue. Lancet 2001:357:956-57.
62. Chopra IJ. A study of extrathyroidial conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro. Endocrinology 1977;101:453-463. Blocks T4 to T3 conversion
63. Kaplan MM. Thyroxine 5’-monodeiodination in rat anterior pituitary homogenates. Endocrinology 1980;106(2):567-76
64. Wartofsky L, BurmanKD. Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 1982;3:164–217.
65. Rothwell PM, Lawler PG 1995 Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med 23:78–83.
66. De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of the current evidence, should be treated with appropriate replacement therapies. Crit Care Clin 2006;22:57-86.
67. Schilling JU, Zimmermann T, Albrecht S, et al. Low T3 syndrome in multiple trauma patients – a phenomenon or important pathogenetic factor? Medizinische Klinik 1999;3:
66– 9.
68. Girvent M, Maestro S, Hernandez R, et al. Euthyroid sick syndrome, associated endocrine abnormalities, and outcome in elderly patients undergoing emergency operation. Surgery 1998;123:560–7.
69. Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite effects of dexamethasone on serum concentrations of 3,3′,5′- triiodothyronine (reverse T3) and 3,3’5-triiodothyronine (T3). JCEM 1975;41:911-920. increased rt3 decrease t3 with steroids.
70. Danforth EJ, Desilets EJ, Jorton ES, Sims EAH, et al. Reiprocal serum triiodothryronine (T3) and reverse (rT3) induced by altering the carbohydrate content of the diet. Clin Res 1975;23:573. increased reverse T3 with carbohydrate diet.
71. Palmbald J, Levi J, Burger AG, Melade H, Westgren U, et al. Effects of total energy withdrawal (fasting) on the levels of growth hormone, thryrotropin, cortisol, noradrenaline, T4, T3 and rT3 in healthy males. Acta Med Scand 1977;201:150.
72. Islam S, Yesmine S, Khan SA, Alam NH, Islam S. A comparative study of thyroid hormone levels in diabetic and non-diabetic patients. SE Asian J Trop Med Public Health 2008;39(5):913-916. 50% reduction in free t3 in diabetics.
73. De Jong F, den Heijer T, Visser TJ, et al. Thyroid hormones, dementia, and atrophy of the medical temporal lobe. J Clin Endocrinol Met 2006;91(7):2569–73. high reverese t3 with brain atrophy.
74. Goichot B, Schlienger JL, Grunenberger F, et al. Thyroid hormone status and nutrient intake in the free-living elderly. Interest of reverse triiodothyronine assessment. Eur J Endocrinol 1994;130:244–52.
75. Robin P. Peeters, Pieter J. Wouters, Hans van Toor, Ellen Kaptein, Theo J. Visser, and Greet Van den Berghe. Serum 3,3_,5_-Triiodothyronine (rT3) and 3,5,3_-Triiodothyronine/rT3 Are Prognostic Markers in Critically Ill Patients and Are Associated with Postmortem Tissue Deiodinase Activities. The Journal of Clinical Endocrinology & Metabolism 90(8):4559–4565.
76. Everts ME, De Jong M, Lim CF, Docter R, et al. Different regulation of thyroid hormone transport in liver and pituitary: Is possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man. Thyroid 1996;6(4):359-368. —increased T4 with NTI
77. Lim CF, Docter R, Visser, Drenning. Inhibition of thyroxine transport into cultured rathepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty. JCEM 1993;76(5):1165-1172.
78. Hennemann G, Vos R A, de Jong M, Krenning E P, Docter R. Decreased peripheral 3,5,3′-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues. JCEM 1993;77(5):1431-5.
79. De Jong M, Docter R, Bernard BF, van der Heijden JT, van Toor H. T4 uptake into the perfused rat liver and liver T4 uptake in humans are inhibited by fructose. Am J Physiol Endocrinol Metab 1994;266:E768-E775.
80. De Jong M, Docter R, Van Der Hoek HJ, et al. Transport of 3,5,3’-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting. Endocrinology 1992;131:463–70.
81. Hennemann G, Krenning EP. The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation. Best Practice & Research Clinical Endo& Metab 2007;21(2); 323–338.
82. Krenning EP, Docter R, Bernard B, Visser T, Hennemann G. Decreased transport of thyroxine (T4), 3,3′,5-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett. 1982 Apr 19;140(2):229-33.
83. Hennemann G, Krenning EP, Bernard B, Huvers F, Mol J, et al. Regulation of influx and efflux of thyroid hormones in rat hepatocytes: possible physiologic significance of the plasma membrane in the regulation of thyroid hormone activity. Horm Metab Res Suppl 1984;14:1-6.
84. FW Wassen, EP Moerings, H van Toor, G Hennemann, and ME Everts. Thyroid hormone uptake in cultured rat anterior pituitary cells: effects of energy status and bilirubin. J Endocrinology 2000;165:599-606. pituitary different transport not suppressed with decrease energy
85. Visser TJ, Lamberts WJ, Wilson JHP, Docter WR, Hennemann G. Serum thyroid hormone concentrations during prolonged reduction of dietary intake. Metabolism 1978;1978;27(4):405-409.
86. Lowe J, Garrison R, Reichman A, MD, Yellin J, Thompson BA, Kaufman D. Effectiveness and safety of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double-blind placebo-controlled response-driven crossover study.: Clinical Bulletin of Myofascial Therapy, 2(2/3):31-58, 1997.
87. Lowe JC ,Reichman AJ, Yellin J. The process of change during T3 treatment for euthyroid fibromyalgia: a double-blind placebo-controlled crossover study.: Clinical Bulletin of Myofascial Therapy, 2(2/3):91-124, 1997.
88. Lowe JC ,Reichman AJ, Garrison R, Yellin J.. Triiodothyronine (T3) treatment of euthyroid fibromyalgia: a small-n replication of a double-blind placebo-controlled crossover study. Clinical Bulletin of Myofascial Therapy, 2(4):71-88, 1997.
89. Yellin BA, Reichman AJ, Lowe JC ,The process of Change During T3 Treatment for Euthyroid Fibomyalgia: A Doulbe-Blind Palcebo-Controlled Crossover Study. The Metabolic Treatment of Fibromyalgia. McDowell Publishing 2000.
90. Wikland B, Lowhagen T, Sandberg PO. Fine needle aspiration cytology of the thyroid in chronic fatigue. Lancet 2001:357:956-57.
91. Teitelbaum J, Bird B, Greenfield R, Weiss A, Muenz L, Gould L. Effective Treatment of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) – A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study. Journal of Chronic Fatigue Syndrome Volume 8, Issue 2 – 2001.
92. Gitlin M, Altshuler LL, Frye MA, Suri R, et al. Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors. J Psychiatry Neurosci 2004;29(5):383-386.
93. Krotkiewski M, Holm G, Shono N. Small doses of triiodothyronine can change some risk factors associated with abdominal obesity. International J Obesity 1997;21:922-929.
94. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: A STAR*D Report. Am J Psychiatry 2006; 163:1519–153.
95. Brayshaw ND, Brayshaw DD. Thyroid hypofunction in premenstrual syndrome NEJM 1986;315(23):1486-1487.
96. Abraham G, Milev R, Lawson JS. T3 augmentation of SSRI resistant depression. Journal of Affective Disorders 2006;91:211–215
97. Posternak M, Novak S, Stern R, Hennessey J, Joffe R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. International Journal of Neuropsychopharmacology (2008), 11, 15–25.
98. Klein I, Danzi S. Thyroid Hormone Treatment to Mend a Broken Heart. J Clin Endocrinol Metab. April 2008;93(4):1172–1174.
99. Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, et al. Acute effects of triiodothyronine replacement therapy in patients with chronic heart failure and low-T3 syndrome: A randomized, placebo-controlled study. J Clin Endocrinol Metab 2008;93(4):1351-8.
100. Okamoto R et al. Adverse effects of reverse triiodothyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy. Res Exp Med (Berl) 1997;197(4):211-7. blocks T3 lower metabolism
101. Tien ES, Matsui K, Moore R, Negishi M. The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J Pharmacol Exp Ther. 2007;320(1):307-13. Blocks thryoid receptor and suppresses D1
102. Benvenga S, Cahnmann HJ, and Robbins J. Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain. Endocrinology 1993;133:1300–1305.reduced thyroid binding and activity
103. Sechman A, Niezgoda J, Sobocinski R. The relationship between basal metabolic rate (BMR) and concentrations of plasma thyroid hormones in fasting cockerels. Follu Biol 1989;37(1-2):83-90. decreased BMR with fasting and increased rT3 (decreased T4 to T3 coversion and metabolim
104. Pittman JA, Tingley JO, Nickerson JF, Hill SR. Antimetabolic activity of 3,3’,5’-triiodo-dl-thyronine in man 1960; Metabolism;9:293-5. reduced metabolism
105. Mitchell AM, Manley SW, Rowan KA, and Mortimer RH. Uptake of reverse T3 in the human choriocarcinoma cell line, JAr. Placenta 20: 65–70. Placenta 1999, 20, 65–70 inhibits uptake of T3 and T4 into the cell
106. Demers LM, Spencer CA. NACB: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease–Thyrotropin/Thyroid Stimulating Hormone (TSH). Academy of the American Association for Clinical Chemistry 2003.
107. Lecomte P, Lecureuil N, Lecureuil M, Salazar CO, Valat C. Age modulates effects of thyroid dysfunction on sex hormone binding globulin (SHBG) levels. Exp Clin Endocrinol 1995;103:339-342.
108. Chopra IJ, Sakane S, Teco GNC. A study of the serum concentration of tumor necrosis factor-_ in thyroidal and nonthyroidal illnesses. J Clin Endocrinol Metab 1991;72:1113–1116.
109. Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM 1993 Association between serum interleukin-6 and serum 3,5,3_-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 77:1695–
1699.
110. Hashimoto H, Igarashi N, Yachie A, Miyawaki T, et al. The relationship between serum levels of interleukin-6 and thyroid hormone in children with acute respiratory infection. J Clin Endocrinol Metab 78: 288-291.
111. van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endo Metab;71:1567-1572.
112. Coiro V, Passeri M, Capretti L, Speroni G. Serotonergic control of TSH and PRL secretion in obese men. Psychoneuroendocrinology 1990;15(4):261-268.
113. Donders S H; Pieters G F; Heevel J G; Ross H A; Smals A G; Kloppenborg P W. Disparity of thyrotropin (TSH) and prolactin responses to TSH-releasing hormone in obesity. JCEM;1985;61(1):56-9.
114. Ford M, Cameron E, Ratcliffe W, Horn DB, Toft AD, et al. TSH response to TRH in substantial obesity. Int J Obes 1980(4):121–125.
115. Meier C, Trittibach P, Guglielmetti M, Staub JJ, et al. Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey. BMJ 2003;326(8):311-312.
116. Pittman CS, Suda AK, Chambers JB, McDaniel HG, Ray GY. Abnormalities of thyroid hormone turnover in patients with diabetes mellitus before and after insulin therapy. JCEM 1979;48(5):854-60.
117 Saunders J, Hall SHE, Sonksen PH. Thyroid hormones in insulin requiring diabetes before and after treatment. Diabetologia 1978;15:29-32.
118. Zulewski H, Muller B, Exer P, Miserez AR Staub JJ. Estimation of tissue hypothyroid by a new clinical score: Evaluaton of patients with various grades of hypothyroidism and controls. JCEM 1997;82:771-776.