Mechanisms behind the non-thyroidal illness syndrome: an update

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   Figure 1

   Schema showing the general changes that occur in serum thyroid-related hormones following illness of varying severity. The yellow area represents the reference range. The changes for free T₄ and free T₃ represent those found using either ultrafiltration or equilibrium dialysis of serum with low sample dilution. Publications that use methods for free hormone measurement that are unreliable in situations of low serum hormone binding capacity tend to follow the same profile as for total T₃ and total T₄ (see text for full explanation).
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   Figure 2

   Proposed mechanisms behind the central hypothyroidism (low hypothalamic TRH) induced by the NTIS and fasting. (Left panel) The neurons of the paraventricular nucleus (PVN) that secrete TRH are innervated by neurons from the arcuate nucleus (ARC) that contain melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), agouti-related protein (AGRP), and the inhibitory neurotransmitter GABA. Both NPY and AGRP inhibit TRH gene expression, an action prevented by leptin. During fasting, when leptin decreases, the inhibitory actions of NPY of AGRP can prevail leading to diminished TRH. The expression of TRH in the PVN is stimulated by MSH, and this effect is enhanced by leptin. Thus, in fasting (low leptin), the stimulatory action of MSH on TRH expression in the PVN is diminished. (Right panel) T₃ produced by iodothyroinine deiodinase D2 in tanycytes has important feedback inhibitory actions on TRH production in the PVN. During sepsis and trauma, there is an increase in tanycyte D2, which is postulated to lead to an increased generation of T₃ from T₄. Tanycyte processes may extract T₄ from portal capillaries, blood vessels in the arcuate nucleus or the CSF (in the third ventricle). The T₃ can then be released back into the CSF or the blood stream. TRH neurons may take up T₃ via diffusion from the CSF, by axonal terminals of the TRH neurons present in the median eminence, or the release of T₃ into the arcuate nucleus may influence the activity of arcuate neurons that project into the PVN (Lechan & Fekete 2005).
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   Figure 3

   Deiodination reactions catalyzed by the iodothyronine deiodinase isoenzymes D1, D2 and D3.
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   Figure 4

   The percentage of patients admitted to an intensive care unit who had serum thyroid hormone and TSH concentrations below the lower reference limit. Data for the first 3 days of admission are shown in both survivors and non-survivors, and significant differences between these two groups are shown by (*). Free T₄ and Free T₃ were measured by Amerlite MAB methodology (Ortho Clinical Diagnostics, Amersham), which show good correlation with equilibrium dialysis and ultrafiltration respectively (see text for details). Data taken from Table 4, Ray D C, Macduff A, Drummond G B, Wilkinson E, Adams B & Beckett GJ 2002 Endocrine measurements in survivors and non-survivors from critical illness. Intensive Care Medicine 28 1301–1308 with kind permission from Springer Science & Business Media.
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   Figure 5

   Summary of the mechanisms that give rise to the serum thyroid hormone changes in the non-thyroidal illness syndrome.

• © 2010 Society for Endocrinology