The hypothalamic-pituitary-thyroid axis in critical illness E. Fliers MD, PhD Internist-endocrinologist Department of Endocrinology and Metabolism, Academic Medical Center F5-171, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands A. Alkemade MSc, PhD Student Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands W. M. Wiersinga MD, PhD Professor of Endocrinology Department of Endocrinology and Metabolism, Academic Medical Center F5-171, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands In severe illness, profound changes occur in the hypothalamic-pituitary-thyroid axis. The observed decrease in serum concentration of both thyroid hormones and thyrotropin (TSH) are not compatible with a negative feedback loop and suggest a major change in setpoint regulation of the hypothalamic-pituitary-thyroid axis. This is supported by post mortem studies showing a decreased expression of thyrotropin-releasing hormone in the hypothalamic paraventricular nucleus of patients with a decreased serum T3 level. In critical illness, serum T3 may even become undetectable without giving rise to an elevated concentration of serum TSH. It is currently not clearly established whether this re¯ects an adaptation of the organism to illness or instead a potentially harmful condition leading to hypothyroidism at tissue level. There is thus a need for randomized clinical trials in critically ill patients to investigate whether they may bene®t from a normalization of thyroid hormone concentration. Recent clinical studies in these patients involving the administration of hypothalamic peptides open up new ways of achieving this. Key words: thyroid hormone; thyrotropin (TSH); thyrotropin-releasing hormone (TRH); hypothalamus; pro-opiomelanocortin (POMC); neuropeptide Y (NPY); paraventricular nucleus (PVN); arcuate nucleus (ARC). During illness, profound changes may occur in the hypothalamic-pituitary-thyroid (HPT) axis. The most consistent change is a decrease in serum tri-iodothyronine (T3) level, but in severe illness, serum thyroxine (T4) may also decrease. The persistence of a normal or even decreased serum level of thyrotropin (TSH) in the face of decreased serum thyroid hormone concentrations implies a major change in HPT axis setpoint regulation. Since these abnormalities of thyroid hormone concentration usually occur 1521±690X/01/04045312 $35.00/00 * c 2001 Harcourt Publishers Ltd. Best Practice & Research Clinical Endocrinology and Metabolism Vol. 15, No. 4, pp. 453±464, 2001 doi:10.1053/beem.2001.0163, available online at http://www.idealibrary.com on 4