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 1.22.8) (Fig. 1A
).TSH levels in critically ill patients were low (0.3 ± 0.2, normal
range: 0.254), while mean free T4 levels were normal (17.3 ±
3.0, reference range: 1024 pmol/L) (Fig. 1B
). 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, Students t test) (Fig. 1C
).
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).
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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-
(TNF-
),
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.
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