The reduced TSH release seems to be secondary selleck chemicals to the diminished drive by TRH [1]. It remains unclear which mechanism is responsible for the reduced hypothalamic TRH expression during prolonged critical illness.Several mechanisms have been proposed for the suppression of the hypothalamus-pituitary-thyroid (HPT) axis during critical illness, among which is a local thyrotoxicosis in the hypothalamus. Increased hypothalamic T3 availability could indeed explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3 syndrome. A first mechanism for increasing the local concentration of T3 in the hypothalamus is increased local conversion of T4 to T3. More than 80% of T3 in the brain originates from local T4 to T3conversion by the type II iodothyronine deiodinase (D2) [5].

Therefore, an upregulation of D2 in the mediobasal hypothalamus could lead to a local hyperthyroid state which in turn would suppress TRH in hypophysiotropic neurons. Injection of lipopolysacharide in rats and mice has been shown to upregulate hypothalamic D2 expression and activity [6-9]. Alternatively, decreased inactivation of T3 and T4 by the type III iodothyronine deiodinase (D3) could also lead to higher hypothalamic thyroid hormone levels suppressing TRH. In line with this, a mouse model for chronic inflammation showed decreased D3 mRNA expression in the region of the hypothalamic PVN [10].A second possible mechanism by which local iodothyronine levels in the hypothalamus could be increased is elevated transport of iodothyronines into the hypothalamus.

The entry of thyroid hormone from the circulation into the hypothalamus is mediated by specific thyroid hormone transporters of which two categories have been identified, organic anion transporters and amino acid transporters. Na+-independent organic anion co-transporting polypeptides (OATPs) represent a large family of homologous proteins of which OATP1C1 (SLCO1C1) shows a high specificity and affinity towards iodothyronines, in particular T4 and reverse T3 (rT3) [11,12]. OATP1C1 is mainly expressed in brain capillaries and is considered to be important for the uptake of T4 across the blood-brain barrier [11-13]. The human monocarboxylate transporter 8 (MCT8), a specific thyroid hormone transporter, is also expressed in the hypothalamus and transports T4 and T3 in a Na+-independent manner [14].

Study of MCT8 null-mice suggests that its expression is necessary for normal feedback regulation of TRH neurons in the hypothalamus [15,16]. MCT10 was identified as a T-type amino-acid transporter [17,18] and was recently shown to be at least as active for thyroid hormone transport as MCT8 [19]. Brefeldin_A The role of these transporters in hypothalamic feedback regulation in critically ill patients is currently unknown.