Nonthyroidal Illness Syndrome Across the Ages

Abstract

In conditions of acute illness, patients present with reduced plasma T3 concentrations without a concomitant rise in TSH. In contrast, plasma concentrations of the inactive hormone rT3 increase, whereas plasma concentrations of T4 remain low-normal. This constellation of changes, referred to as nonthyroidal illness syndrome (NTIS), is present across all ages, from preterm neonates and over-term critically ill infants and children to critically ill adults. Although the severity of illness strongly correlates with the severity of the NTIS phenotype, the causality of this association remains debated, and pathophysiological mechanisms remain incompletely understood. In the acute phase of illness, NTIS appears to be caused predominantly by an increased peripheral inactivation of thyroid hormones, in which reduced nutritional intake plays a role. Current evidence suggests that these acute peripheral changes are part of a beneficial adaptation of the body to reduce expenditure of energy and to activate the innate immune response, which is important for survival. In contrast, in more severely ill and prolonged critically ill patients, an additional central suppression of the thyroid hormone axis alters and further aggravates the NTIS phenotype. Recent studies suggest that this central suppression may not be adaptive. Whether treatment of this central component of NTIS in prolonged critically ill patients, with the use of hypothalamic releasing factors, improves outcome remains to be investigated in large randomized control trials.

Keywords: adult; critical illness; pediatric; sepsis; thyroid hormone.

Figure 1.

Schematic diagram of the biphasic changes observed in NTIS present in response to critical illness. Changes in the hypothalamus–pituitary–thyroid axis and in peripheral thyroid hormone metabolism. D1, D2, and D3 are iodothyronine deiodinase type 1, type 2, and type 3, respectively.

Figure 2.

Illustration of the biphasic response of TSH to critical illness. Representative nocturnal TSH serum concentration profiles of a healthy volunteer and of two critically ill patients are shown to illustrate the differences between the acute and chronic phases of critical illness. [Adapted with permission from Van den Berghe G, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab. 1998;83(6):1827-1834.]

Figure 3.

Impact of critical illness on thyroid hormone concentrations upon PICU admission in infants and children. Infants are younger than 1 y old. Bars represent means, and whiskers represent the SE. The black boxplots represent healthy children, and the light-gray boxes represent critically ill patients. [Reproduced with permission from Jacobs A, Derese I, Vander Perre S, van Puffelen E, Verstraete S, Pauwels L, Verbruggen S, Wouters P, Langouche L, Garcia Guerra G et al: Non-thyroidal illness syndrome in critically ill children: prognostic value and impact of nutritional management. Thyroid. 2019;29(4):480–492.]

Figure 4.

Effect of accepting a very low macronutrient intake, by omitting parenteral nutrition (PN) until beyond the first week in ICU (Late-PN), as compared with early provision of full feeding with PN (early-PN) on NTIS. Bars (mean – SE) represent the changes (referred to as Δ) from the admission values to day 3 in the adult or pediatric ICU (or to the last day for patients with shorter ICU stay) in serum TSH, T4, T3, rT3, and the T3/rT3 ratio. The open and filled bars represent the patients randomized to the early-PN and late-PN groups, respectively. [Reproduced with permission from Jacobs A, Derese I, Vander Perre S, van Puffelen E, Verstraete S, Pauwels L, Verbruggen S, Wouters P, Langouche L, Garcia Guerra G et al: Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management. Thyroid 2019, 29(4):480-492; and Langouche L, Vander Perre S, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den Berghe G: Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab. 2013;98(3):1006-1013.]