Higher Caloric Exposure in Critically Ill Patients Transiently Accelerates Thyroid Hormone Activation

Liam McKeever; Sarah J. Peterson; Omar Lateef; Sally Freels; Tatiana L. Fonseca; Barbara M. L. C. Bocco; Gustavo W. Fernandes; Kelly Roehl; Kristen Nowak; Marisa Mozer; Antonio C. Bianco; Carol A. Braunschweig


J Clin Endocrinol Metab. 2020;105(2) 

In This Article

Abstract and Introduction


Introduction: The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients.

Objective: To explore the impact of calorie exposure on NTIS over time in critically ill patients.

Methods: Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio.

Results: Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1.

Conclusions: Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.


The capacity for caloric exposure to alter key physiologic responses to critical illness is an underdiscussed nuance in the field of nutrition support. While its consequences remain largely unknown, the modifications observed in thyroid economy are well characterized, likely affecting the energy homeostasis of most systems. A deeper understanding of this phenomenon is crucial to usher nutrition support research beyond the binary arguments about feeding as "good" or "bad" and into the richly complex reality of critical illness.

The hypothalamus releases thyrotropin releasing hormone (TRH), which stimulates the pituitary gland to secrete thyroid stimulating hormone (TSH), prompting the thyroid gland to synthesize and secrete thyroxine (T4) and triiodothyronine (T3).[1] On a daily basis, approximately 40% of the T4 that is secreted is activated to T3, the active form of thyroid hormone, via outer ring deiodination outside the thyroid parenchyma. Small amounts of T3 are also released directly from the thyroid gland and mix with the T3 derived from T4 activation.[2] T3 accelerates metabolic activity and its circulating levels largely define the rate at which nutrients are utilized.[3] At the same time, similar amounts of T4 (40%) are inactivated to reverse T3 (rT3) via inner ring deiodination, with the residual 20% being inactivated via hepatic sulfation[4] or glucuronidation.[5,6] While the rates at which T4 is activated or inactivated are relatively stable, they may change in response to environmental cues, caloric intake, health status, and certain drugs.[7] The flux through these pathways can be assessed by measuring the production and clearance rates of T4 and T3 through invasive techniques that utilize radiolabeled tracers,[8] or it can be estimated by examining deiodinase activity in biopsy samples of key tissues. However, given the invasive nature of these techniques, the circulating ratio of T3/rT3 is commonly utilized and it remains the best minimally invasive means to assess the activating and inactivating pathways of thyroid hormone in humans.[1,9]

Thyroid hormone homeostasis is greatly affected in severely ill patients.[10] At least two-thirds of all patients admitted to a general hospital exhibit typical modifications of the thyroid economy known as nonthyroidal illness syndrome (NTIS).[11] In most cases, there is generalized reduction in thyroid hormone production and extrathyroidal activation of T4, albeit without obvious signs or symptoms of hypothyroidism.[12] There is flatlining of TSH pulsatility, a drop in circulating T4 and T3 levels, and an increase in the levels of rT3. Notably, the expected increase in TSH secretion, which would otherwise be observed in healthy individuals as a result of the drop in circulating thyroid hormone levels, is absent.[12]

Food availability stimulates the thyroid gland, ensuring coupling between caloric intake and thyroid hormone signaling.[13,14] Similar to the reduction in NTIS, thyroidal activity is low in the absence of food or during caloric restriction, along with low circulating T3 levels and a slower rate of energy expenditure. This is reversed once caloric intake is restored, as seen in patients recovering from anorexia nervosa.[15] Notably, low serum T3 and T4 coexist with normal/low serum TSH.[16,17] In humans, T3 production rate was found to drop by about 50% after a 6-day fast, but the metabolic clearance rate of T3 was not affected.[18] In contrast, rT3 clearance was reduced by about 40% in these individuals, without changes in rT3 production.[19]

NTIS is caused by a combination of inflammatory cytokine activity[1] that alters both central and peripheral regulation of thyroid hormones, and caloric restriction, which lowers the levels of the fed-state hormone leptin.[20] Thus, it would not be not surprising that calorie exposure attenuates the changes in thyroid economy observed during NTIS,[21–23] but prospective research in the critically ill is sparse, while retrospective data are confounded by the fact that patients who are exposed to higher caloric intake, particularly through enteral nutrition (EN), are usually less critically ill. Prospective randomized controlled feeding trials (PRCTs) have demonstrated the ability of feeding to attenuate NTIS, but these have either been limited to surgical patients,[23] did not capture key variables,[24] or were subanalyses of a larger trial.[25] Further, none of these studies provided daily serial measurements to closely track the thyroid parameters through repeated measures analysis.

The present study was designed as a 7-day prospective randomized controlled feeding trial to explore the effect of feeding 100% vs 40% of estimated caloric needs (ECN) on thyroid economy in mechanically ventilated critically ill patients with systemic inflammatory response syndrome (SIRS). The objective was to determine if higher vs lower levels of EN support attenuated NTIS and to explore the progression of this response over time.