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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4278-4279
Copyright © 1997 by The Endocrine Society

Letters to the Editor

Leptin Levels Are Elevated Despite Low Thyroid Hormone Levels in the "Euthyroid Sick" Syndromei

S.R. Bornstein, D.J. Torpy and G.P. Chrousos

National Institute of Child Health and Development National Institutes of Health Bethesda, Maryland

J. Licinio

National Institute of Mental Health National Institutes of Health Bethesda, Maryland

L. Engelmann

Department of Internal Medicine III University of Leipzig, Germany

Valcavi et al. (1) recently reported that leptin levels in patients with hypothyroidism are decreased. They suggested that physiological thyroid hormone levels are needed to ensure normal circulating leptin levels.

We recently examined the effects of critical illness, a catabolic state associated with low plasma T3 and TSH levels [termed "euthyroid sick" syndrome (2) or "nonthyroidal illness" syndrome (3)]. Nine patients from the intensive care unit of the University of Leipzig, fulfilling the criteria of acute sepsis (4), had leptin, free T4 (n = 8), T3 (n = 8), T4 (n = 9), and TSH (n = 7) levels measured on day 1 of admission at 0800 in the morning. Nine healthy controls, matched for body mass index (BMI) and gender, had leptin levels measured. Mean BMI of critically ill patients (5 females, 4 males) was 24.1 ± 0.9, similar to that of controls (5 females, 4 males, 23.6 ± 1.2). All patients had decreased T3 levels (0.50 ± 0.06, normal range 1.2–2.8) (Fig. 1AGo).TSH levels in critically ill patients were low (0.3 ± 0.2, normal range: 0.25–4), while mean free T4 levels were normal (17.3 ± 3.0, reference range: 10–24 pmol/L) (Fig. 1BGo). Mean plasma leptin levels were increased in critically ill patients with acute sepsis as compared with controls (18.1 ± 5.8 vs. 4.1 ± 1.0, df = 16, P < 0.03, Student’s t test) (Fig. 1CGo). Thus, while low thyroid hormone levels may mitigate the catabolic effects of critical illness by decreasing energy expenditure, our preliminary data suggest that this is not accompanied by a decrease of leptin levels that would accentuate this phenomenon.



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  		Figure 1. Plasma T3 (A), free T4 (B), and leptin (C) levels in critically ill patients (n = 9) and controls, matched for gender, age, and BMI. Low plasma T3 levels (0.5 ± 0.06), but generally normal free T4 levels (4.13 ± 1.03), were noted. Despite low T3 concentrations, leptin levels were increased in patients compared with controls (18.1 ± 5.8 vs. 11.1 ± 1.0, P = 0.029).

 
We suggest two potential mechanisms for the increase of leptin levels observed in patients with sepsis. First, the stress of critical illness results in the activation of the hypothalamic-pituitary-adrenal (HPA) axis and a resultant rise of circulating glucocorticoids (5). Glucocorticoids acutely increase leptin expression and leptin levels (6, 7). Second, acute sepsis is associated with elevations of plasma inflammatory cytokines such as tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin 1 (IL-1), and interleukin 6 (IL-6), which increase leptin levels in rodents (8, 9). Thus, glucocorticoids and the inflammatory cytokines, which are the primary mediators of the "euthyroid sick" syndrome (10), may also increase plasma leptin in acute critical illness.

Prolonged fasting, which has been associated with increased HPA axis and decreased sympathetic nervous system activity, has profound effects on the hypothalamic-pituitary-thyroid axis manifested by low plasma T3 and low or normal levels of TSH, identical to the thyroid function profile of patients with critical illness (10). Interestingly, the fasting-induced reduction in pre-pro TRH messenger RNA in the rat hypothalamus can be prevented by the systemic administration of leptin (11). The same hormone inhibits the HPA axis and stimulates the sympathetic system (12, 13, 14), hence contributing to the correction of the thyroid dysfunction of starved individuals.

Elevated leptin levels may also account for the increase of TSH levels frequently observed in patients recovering from critical illness (10). In our patients, there was a further elevation of leptin concentrations in the recovery phase, while leptin levels were low in the patients who did not survive the acute sepsis. These results suggest that leptin is a stress-related peptide, which is elevated during the acute phase of critical illness. The positive action of leptin on the hypothalamic-pituitary-thyroid axis, however, appears to be overcome by the activation of the HPA axis and the increased secretion of cytokines that accompany acute critical illness.

Footnotes

Received July 31, 1997.

Address correspondence to: Dr. Stefan R. Bornstein, Developmental Endocrinology Branch, NIH-NICHD, Bldg. 10 Rm. 10N-26Z, 9000 Rockville Pike, Bethesda, Maryland 20892.

References

  1. Valcavi R, Zini M, Peino R, Casanueva FF, Dieguez C. 1997 Influence of thyroid status on serum immunoreactive leptin levels. J Clin Endocrinol Metab. 82:1632–1634.[Abstract/Free Full Text]
  2. Wartofsky L, Burman KD. 1982 Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome." Endocr Rev. 3:164–217.[Abstract/Free Full Text]
  3. Chopra IJ. 1997 Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 82:329–334.[Free Full Text]
  4. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA. 1987 The methylprednisolone severe sepsis study group: a controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 317:653–658.[Abstract]
  5. Torpy DJ, Chrousos GP. 1997 General adaptation syndrome (an overview). In: Ober KP, ed. Contemporary endocrinology: endocrinology of critical illness. Totowa, New Jersey: Humana Press; p 1–24.
  6. De Vos P, Saladin R, Auwerx J, Staels B. 1995 Induction of ob gene expression by corticosteroids is accomplished by body weight loss and reduced food intake. J Biol Chem. 270:15958–15961.[Abstract/Free Full Text]
  7. Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK. 1997 Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab. 82:1635–1637.[Abstract/Free Full Text]
  8. Grunfeld C, Zhao C, Fuller J, et al. 1996 Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. 97:2151–2157.
  9. Sarraf P, Frederich RC, Turner EM, et al. 1997 Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med. 185:171–175.[Abstract/Free Full Text]
  10. LoPresti JS, Nicoloff JT. 1997 Thyroid response to critical illness. In: Ober KP, ed. Contemporary endocrinology: endocrinology of critical illness. Totowa, New Jersey: Humana Press; p 155–173.
  11. Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. 1997 Leptin prevents fasting-induced suppression of prothrombin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology. 138:2569–2576.[Abstract/Free Full Text]
  12. Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 382:250–252.
  13. Licinio J, Mantzoros C, Negrao AB, et al. 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Med. 3:575–579.[CrossRef][Medline]
  14. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. 1997 Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland; leptin inhibits cortisol release directly. Diabetes. 46:1235–1238.[Abstract]



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