Thyroid Hormone Indices During Illness in Six Hypothyroid Subjects Rendered Euthyroid with Levothyroxine Therapy

Abstract

Purpose: We wanted to evaluate changes in the natural course of serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3), and thyroid stimulating hormone (TSH) concentrations during hospitalization for an acute illness, in subjects rendered euthyroid with Levothyroxine (LT4) replacement therapy.

Methods: Six male subjects ranging in age 30 - 65 years with a history of primary hypothyroidism were included. They were euthyroid prior to hospitalization. LT4 continued to be administered orally in the same pre-admission daily dose. Serum, T4, T3, rT3, and TSH concentrations were determined on day of admission to the intensive care unit (ICU) for an acute illness. These were repeated during the first week on alternate days and again during a follow-up visit 1 week after discharge. Student's t-test, analysis of variance, and linear regression were used to analyze the data.

Results: Serum T4, T3 declined to a nadir and serum rT3 rose to its peak by day 3 of hospitalization before returning to pre admission euthyroid levels. Serum TSH declined initially but rose to supernormal levels on day 7 before normalization. Significant correlations were noted between TSH on one hand and T3/T4 (r = 0.76, p < 0.001) and rT3/T4 (r= - 0.64, p < 0.001) ratios.

Conclusions: Alterations ensuing during a short stay in the hospital due to an acute illness in subjects with primary hypothyroidism rendered euthyroid with appropriate replacement therapy with Levothyroxine (LT4) are almost identical to those in normal subjects. These changes are probably secondary to altered thyroid hormone metabolism. The altered levels of thyroid hormones and TSH noted in these subjects are transient and therefore providers should refrain from initiating frequent changes in daily LT4 replacement dose during the acute illness in these subjects.

Euthyroid sick syndrome - non thyroidal illness syndrome - hypothyroid - thyroxine replacement - thyroid hormone indices

References

• 1 Adriaanse R, Romijn J A, Brabant G, Endert E, Wiersinga W M. Pulsatile thyrotropin secretion in nonthyroidal illness.  J Clin Endocrinol Metab. 1993;  77 1313-1317
• 2 Afandi B, Schussler G C, Arafeh A H, Boutros A, Yap M G, Finkelstein A. Selective consumption of thyroxine-binding globulin during cardiac bypass surgery.  Metabolism. 2000;  49 270-274
• 3 Bacci V, Schussler G C, Kaplan T B. The relationship between serum triiodothyronine and thyrotropin during systemic illness.  J Clin Endocrinol Metab. 1982;  54 1229-1235
• 4 Berry M J, Banu L, Larsen P R. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme.  Nature. 1991;  349 438-440
• 5 Bianchi R, Mariani G, Molea N, Vitek F, Cazzuola F, Carpi A, Mazzuca N, Toni M G. Peripheral metabolism of thyroid hormones in man. I. Direct measurement of the conversion rate of thyroxine to 3,5,3′-triiodothyronine (T3) and determination of the peripheral and thyroidal production of T3.  J Clin Endocrinol Metab. 1983;  56 1152-1163
• 6 Bianco A C, Nunes M T, Hell N S, Maciel R M. The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3,5,3′-triiodothyronine generation in rats.  Endocrinology. 1987;  120 1033-1038
• 7 Boelen A, Platvoet-ter Schiphorst M C, Wiersinga W M. Immunoneutralization of interleukin-1, tumor necrosis factor, interleukin-6 or interferon does not prevent the LPS-induced sick euthyroid syndrome in mice.  J Endocrinol. 1997;  153 115-122
• 8 Brent G A, Hershman J M. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration.  J Clin Endocrinol Metab. 1986;  63 1-8
• 9 Brent G A, Hershman J M, Braunstein G D. Patients with severe nonthyroidal illness and serum thyrotropin concentrations in the hypothyroid range.  Am J Med. 1986;  81 463-466
• 10 Chopra I J, Chopra U, Smith S R, Reza M, Solomon D H. Reciprocal changes in serum concentrations of 3,3′,5-triiodothyronine (T3) in systemic illnesses.  J Clin Endocrinol Metab. 1975;  41 1043-1049
• 11 Chopra I J, Huang T S, Beredo A, Solomon D H, Chua Teco G N, Mead J F. 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;  60 666-672
• 12 Chopra I J, Huang T S, Solomon D H, Chaudhuri G, Teco G N. The role of thyroxine (T4)-binding serum proteins in oleic acid-induced increase in free T4 in nonthyroidal illnesses.  J Clin Endocrinol Metab. 1986;  63 776-779
• 13 Chopra I J, Smith S R. Circulating thyroid hormones and thyrotropin in adult patients with protein-calorie malnutrition.  J Clin Endocrinol Metab. 1975;  40 221-227
• 14 Chopra I J, Teco G N, Nguyen A H, Solomon D H. In search of an inhibitor of thyroid hormone binding to serum proteins in nonthyroid illnesses.  J Clin Endocrinol Metab. 1979;  49 63-69
• 15 Davis F B, Spector D A, Davis P J, Hirsch B R, Walshe J J, Yoshida K. Comparison of pituitary-thyroid function in patients with end stage renal disease and in age- and sex-matched controls.  Kid Inter. 1982;  21 362-364
• 16 Duntas L H, Nguyen T T, Keck F S, Nelson D K, Iii J J. Changes in metabolism of TRH in euthyroid sick syndrome.  Euro J Endocrinol. 1999;  141 337-341
• 17 Faber J, Kirkegaard C, Rasmussen B, Westh H, Busch-Sorensen M, Jensen I W. Pituitary-thyroid axis in critical illness.  J Clin Endocrinol Metab. 1987;  65 315-320
• 18 Feelders R A, Swaak A J, Romijn J A, Eggermont A M, Tielens E T, Vreugdenhil G, Endert E, van Eijk H G, Berghout A. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients.  Metabolism. 1999;  48 324-329
• 19 Hamblin P S, Dyer S A, Mohr V S, Le Grand B A, Lim C F, Tuxen D V, Topliss D J, Stockigt J R. Relationship between thyrotropin and thyroxine changes during recovery from severe hypothyroxinemia of critical illness.  J Clin Endocrinol Metab. 1986;  62 717-722
• 20 Hidal J T, Kaplan M M. Inhibition of thyroxine 5′-deiodination type II in cultured human placental cells by cortisol, insulin, 3′,5′-cyclic adenosine monophosphate, and butyrate.  Metabolism. 1988;  37 664-668
• 21 Jennings A S, Ferguson D C, Utiger R D. Regulation of the conversion of thyroxine to triiodothyronine in the perfused rat liver.  J Clin Invest. 1979;  64 1614-1623
• 22 Kabadi U, Fragstedt 2nd L. Impaired TSH secretion during sustained hyperglucagonemia in anesthetized dogs.  Thyroid. 1995;  5 389-393
• 23 Kabadi U M. Impaired pituitary thyrotroph function in uncontrolled type II diabetes mellitus: normalization on recovery.  J Clin Endocrinol Metab. 1984;  59 521-525
• 24 Kabadi U M. Thyrotropin dysregulation during a non-thyroidal illness: transient hypothalamic hypothyroidism?.  J Endocrinol Invest. 2001;  24 178-182
• 25 Kabadi U M, Kabadi M U. Serum Thyrotropin in primary hypothyroidism: a reliable and accurate predictor of optimal daily levothyroxine dose.  Endocr Pract. 2001;  7 16-18
• 26 Kabadi U M, Kabadi M U, Premachandra B N. Low serum T3 and raised reverse T3 levels in hepatic cirrhosis: role of glucagon.  Am J Gastroenterol. 1991;  86 1504-1507
• 27 Kabadi U M, Premachandra B N. Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who have type II diabetes mellitus: influence of metabolic control, not age.  J Am Ger Soc. 1984;  32 375-379
• 28 Kabadi U M, Premachandra B N. Glucagon administration induces lowering of serum T3 and rise in reverse T3 in euthyroid healthy subjects.  Horm Metab Res. 1985;  17 667-670
• 29 Kabadi U M, Premachandra B N. Lowering of T3 and rise in reverse T3 induced by hyperglucagonemia: altered thyroid hormone metabolism, not altered release of thyroid hormones.  Horm Metab Res. 1987;  19 486-489
• 30 Kabadi U M, Premachandra B N. Decline of T3 and elevation in reverse T3 induced by hyperglucagonemia: changes in thyroid hormone metabolism, not altered release of thyroid hormones.  Horm Metab Res. 1988;  20 513-516
• 31 Kabadi U M, Premachandra B N, Maayan M. Low serum 3,5,3′-triiodothyronine (T3) and raised 3,3′,5′-triidothyronine (reverse T3 or RT3) in diabetes mellitus: normalization on improvement in hyperglycemia.  Acta Diab Lat. 1982;  19 233-242
• 32 Kayima J K, Otieno L S, Gitau W, Mwai S. Thyroid hormone profiles in patients with chronic renal failure on conservative management and regular haemodialysis.  E Afr Med J. 1992;  69 333-336
• 33 Kimura T, Kanda T, Kotajima N, Kuwabara A, Fukumura Y, Kobayashi I. Involvement of circulating interleukin-6 and its receptor in the development of euthyroid sick syndrome in patients with acute myocardial infarction.  Eur J Endocrinol. 2000;  143 179-184
• 34 Langer P, Balazova E, Vician M, Martino E, Jezova D, Michalikova S, Moravec R. Acute development of low T3 syndrome and changes in pituitary-adrenocortical function after elective cholecystectomy in women: some differences between young and elderly patients.  Scand J Clin Lab Invest. 1992;  52 215-220
• 35 Langer P, Foldes O. Effect of adrenaline on biliary excretion of triiodothyronines in rats mediated by alpha 1-adrenoceptors and related to the inhibition of 5′-monodeiodination in liver.  J Endocrinol Invest. 1988;  11 471-476
• 36 Langer P, Foldes O, Gschwendtova K. Effect of the glycogenolytic gluconeogenetic hormones, glucagon, vasopressin and angiotensin II, on biliary excretion of iodothyronines in rats is possibly related to the inhibition of 5′-monodeiodination in the liver.  J Endocrinol. 1989;  121 299-302
• 37 Langer P, Suzuki M, Kakegawa T, Foldes O, Gschwendtova K. Acute changes of iodothyronine excretion by bile after a single and repeated administration of dexamethasone in rats.  Endocrinol Exp. 1985;  19 253-260
• 38 Michalaki M, Vagenakis A G, Makri M, Kalfarentzos F, Kyriazopoulou V. Dissociation of the early decline in serum T(3) concentration and serum IL-6 rise and TNFalpha in nonthyroidal illness syndrome induced by abdominal surgery.  J Clin Endocrinol Metab. 2001;  86 4198-4205
• 39 Oppenheimer J H, Schwartz H L, Mariash C N, Kaiser F E. Evidence for a factor in the sera of patients with nonthyroidal disease which inhibits iodothyronine binding by solid matrices, serum proteins, and rat hepatocytes.  J Clin Endocrinol Metab. 1982;  54 757-766
• 40 Pittman C S, Suda A K, Chambers Jr J B, McDaniel H G, Ray G Y, Preston B K. Abnormalities of thyroid hormone turnover in patients with diabetes mellitus before and after insulin therapy.  J Clin Endocrinol Metab. 1979;  48 854-860
• 41 Premachandra B N. A simple and rapid radioimmunoassay of triiodothyronine in unextracted serum.  J Nucl Med. 1976;  17 411-416
• 42 Premachandra B N. Radioimmunoassay of reverse triiodothyronine.  J Clin Endocrinol Metab. 1978;  47 746-750
• 43 Premachandra B N, Ibrahim I I. A simple and rapid thyroxine radioimmunoassy (T4-RIA) in unextracted human serum; a comparison of T4-RIA and T4 displacement assay, T4(D), in normal and pathologic sera.  Clinica Chimica Acta. 1976;  70 43-60
• 44 Ramirez G, O'Neill Jr W, Jubiz W, Bloomer H A. Thyroid dysfunction in uremia: evidence for thyroid and hypophyseal abnormalities.  Ann Inter Med. 1976;  84 672-676
• 45 Silva J E, Dick T E, Larsen P R. The contribution of local tissue thyroxine monodeiodination to the nuclear 3,5,3′-triiodothyronine in pituitary, liver, and kidney of euthyroid rats.  Endocrinol. 1978;  103 1196-1207
• 46 Silva J E, Larsen P R. Hormonal regulation of iodothyronine 5′-deiodinase in rat brown adipose tissue.  Am J Physiol. 1986;  251 E639-643
• 47 Silva J E, Leonard J L, Crantz F R, Larsen P R. Evidence for two tissue-specific pathways for in vivo thyroxine 5′-deiodination in the rat.  J Clin Invest. 1982;  69 1176-1184
• 48 Spencer C A, Lum S M, Wilber J F, Kaptein E M, Nicoloff J T. Dynamics of serum thyrotropin and thyroid hormone changes in fasting.  J Clin Endocrinol Metab. 1983;  6 883-888
• 49 Van den Berghe G, de Zegher F, Veldhuis J D, Wouters P, Gouwy S, Stockman W, Weekers F, Schetz M, Lauwers P, Bouillon R, Bowers C Y. Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues.  Clin Endocrinol. 1997;  47 599-612
• 50 Wu S Y. Thyrotropin-mediated induction of thyroidal iodothyronine monodeiodinases in the dog.  Endocrinology. 1983;  112 417-424