text: Hypothalamic-pituitary-thyroid axis downregulation Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the body's energy state. They may be stimulated by signals such as leptin, alpha-MSH, and catecholamines; and inhibited by glucocorticoids, neuropeptide Y, and agouti-related peptide.
  In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism. There may also be decreased central D3. This causes negative feedback on the HPT axis, and therefore reduced TRH gene expression in the PVN. This is exemplified by the common NTIS phenotype of low TSH even in the face of peripheral hypothyroidism.
  Cytokines
  Illness can cause inflammation, which often involves an increase in cytokines such as TNFa, IL-1, and IL-6. Cytokines are implicated in NTIS. IL-1β has been shown to decrease liver D1, as well as thyroid hormone receptor (THR) levels. IL-6 and TNFa downregulate D1 and suppress TSH, are negatively correlated with fT3, and are positively correlated with rT3. NF-κB also inhibits D1, and decreases the expression of Thyroid receptors α and β. IFNy inhibits thyroid and Tg release, and also inhibits the upregulation of TSH receptors.
  Thyroid hormone receptors
  In chronic liver and renal (kidney) failure,  increased THR expression occurs. In contrast, in acute illness such as sepsis and trauma,  decreased THR expression occurs.