Non-thyroidal illness in the ICU: a syndrome with different faces

Abstract

Background: Critically ill patients typically present with low or low-normal plasma thyroxine, low plasma triiodothyronine (T3), increased plasma reverse T3 (rT3) concentrations, in the absence of a rise in thyrotropin (TSH). This constellation is referred to as nonthyroidal illness syndrome (NTI). Although it is long known that the severity of NTI is associated with risk of poor outcomes of critical illness, the causality in this association has not been well investigated.

Summary: In this narrative review, the different faces of NTI during critical illness are highlighted. Acute alterations are dominated by changes in thyroid hormone binding, peripheral thyroid hormone uptake, and alterations in the expression and activity of the type-1 and type-3 deiodinases. It was recently shown that at least part of these acute changes are brought about by concomitant macronutrient restriction, and this part appears adaptive and beneficial. However, the face of the NTI in the prolonged phase of critical illness is different, when patients are fully fed but continue to depend on intensive medical care. In that prolonged phase of illness, hypothalamic thyrotropin releasing hormone (TRH) expression is suppressed and explains reduced TSH secretion and whereby reduced thyroidal hormone release. During prolonged critical illness, and in the presence of adequate nutrition, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level. Infusing hypothalamic releasing factors in these prolonged critically ill patients can reactivate the thyroid axis and induce an anabolic response.

Conclusions: It is clear that the name "NTI" during critical illness refers to a syndrome with different faces. Tolerating the early "fasting response" to critical illness and its concomitant changes in thyroid hormone parameters appears to be wise and beneficial. This thus applies to the NTI present in the majority of the patients treated in intensive care units. However, the NTI that occurs in prolonged critically ill patients appears different with regard to both its causes and consequences. Future studies should specifically target this selected population of prolonged critically ill patients, and, after excluding iatrogic drug interferences, investigate the effect on outcome of treatment with hypothalamic releasing factors in adequately powered randomized controlled trials.

FIG. 1.

Changes in the central and peripheral thyroid axis in acute versus prolonged critical illness. The upper panel shows reduced thyrotropin releasing hormone (TRH) gene expression in the hypothalamus of prolonged ill patients. The central panel illustrates adaptations in nocturnal thyrotropin (TSH) secretion with a loss of pulsatility during prolonged critical illness. The bottom panel summarizes schematically the changes in circulating thyroid hormone concentrations and changes in peripheral deiodinase enzyme activity levels. D1, type-1 deiodinase; D2, type-2 deiodinase; D3, type-3 deiodinase. Figure reproduced, with permission, from Boonen et al. (5).

FIG. 2.

Effects of early macronutrient supplementation versus tolerating macronutrient deficit during the first three days of critical illness: partial reversal of nonthyroidal illness syndrome (NTI) in human patients. The bars (mean±standard error) represent the changes from the admission values (Δ) to day 3 in the intensive care unit (ICU; or last day for patients with a shorter ICU stay) in serum TSH, thryoxine (T4), triiodothyronine (T3), rT3, and T3/rT3. The open bars represent values of patients randomized to receiving early parenteral nutrition (early PN), whereas filled bars are presenting values from patients randomized to nutrient restriction (late PN). p-Values are those obtained with multivariable analysis, after adjustment for prespecified baseline risk factors. Figure reproduced, with permission, from Langouche et al. (38).

FIG. 3.

Effect of fasting versus feeding during critical illness in a rabbit model. Feeding critically ill rabbits reverses NTI compared with full fasting for 7 days after onset of illness. Figure adapted, with permission, from Mebis et al. (39).

FIG. 4.

Differences between the acute and the prolonged phase of critical illness in plasma hormone concentrations and in tissue expression of the monocarboxylate transporters. The upper panel represents the circulating thyroid hormone parameters in acutely stressed (light gray bars, n=22) and chronically ill patients (dark gray bars, n=64). The white bars designate the normal ranges. The central panel shows the relative MCT8 and MCT10 mRNA expression levels measured in liver and skeletal muscle of acutely stressed (light gray) and chronically ill (dark gray) patients. The lower panels represents the relative expression levels of MCT8 and MCT10 in liver and muscle of healthy control rabbits (white bar), saline-treated prolonged ill rabbits (dark gray), and T3+T4 treated (black bar) ill rabbits. Data are expressed as mean±standard error of the mean. *p<0.05 versus acute values. Figure reproduced, with permission, from Boonen et al. (5).

FIG. 5.

Effect of the combined infusion of TRH and a growth hormone (GH)-secretagogue on NTI during prolonged critical illness. A continuous infusion of TRH in combination with a GH-secretagogue in prolonged critically ill fed patients reversed the NTI as evidenced via a cross-over design: five days infusion of releasing peptides followed by five days placebo (filled symbols) or vice versa (open symbols). Figure reproduced, with permission, from Van den Berghe et al. (57).

FIG. 6.

The effect of dopamine infusion/withdrawal on plasma TSH concentrations and on plasma T4 and T3 concentrations. Upper panels: during dopamine infusion, TSH levels are suppressed, whereas within 20 minutes of withdrawal, TSH release shows a rebound, with higher levels the day after dopamine withdrawal. Lower panels: 24 hours after dopamine withdrawal, plasma T4 and T3 concentrations are much higher than during dopamine infusion. Figure adapted, with permission, from Van den Berghe et al. (46).