Series
Thyroid function in critically ill patients

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Summary

Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyronine, low thyroxine, and normal range or slightly decreased concentration of thyroid-stimulating hormone. This ensemble of changes is collectively known as non-thyroidal illness syndrome (NTIS). The extent of NTIS is associated with prognosis, but no proof exists for causality of this association. Initially, NTIS is a consequence of the acute phase response to systemic illness and macronutrient restriction, which might be beneficial. Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone, accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone. In some cases distinguishing between NTIS and severe hypothyroidism, which is a rare primary cause for admission to the ICU, can be difficult. Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients with NTIS, inducing an anabolic response. Whether this approach has a clinical benefit in terms of outcome is unknown. In this Series paper, we discuss diagnostic aspects, pathogenesis, and implications of NTIS as well as its distinction from severe, primary thyroid disorders in patients in the ICU.

Introduction

The hypothalamic–pituitary–thyroid (HPT) axis is controlled by a classic endocrine feedback loop. Thyrotropin-releasing hormone (TRH) is released at the level of the hypothalamus, which stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). In turn, TSH drives the thyroid gland to release thyroid hormones. The prohormone thyroxine (T4) is converted in peripheral tissues to the active hormone tri-iodothyronine (T3). Hypothalamic TRH neurons were identified as determinants of thyroid hormone setpoint regulation more than three decades ago, and this discovery was followed by thyroid hormone receptor (TR) β being shown to have a key role in thyroid hormone negative feedback at the level of both the hypothalamus and anterior pituitary. Thus, the HPT axis was assumed to have a fixed setpoint, aiming at individually determined serum concentrations of thyroid hormones.1 However, studies2 have shown that these serum concentrations can be variable and adaptive in response to environmental factors, including nutrient availability and inflammatory stimuli.

Substantial changes in plasma concentrations of thyroid hormones have been noted in a range of diseases, characterised by clearly decreased plasma T3, low plasma T4, and increased plasma reverse T3 (rT3) concentrations. Despite low T3 and T4, TSH is typically maintained within its normal range or is slightly decreased. This ensemble of changes in thyroid function tests is collectively known as the non-thyroidal illness syndrome (NTIS).3 In this Series paper we focus on the presentation, pathogenesis, metabolic consequences, and clinical management of thyroid dysfunction in critically ill patients. The distinction between NTIS and primary thyroid disorders in patients in the intensive care unit (ICU) can sometimes be difficult, which will also be briefly discussed.

Section snippets

Non-thyroidal illness

In both human beings and rodents, illness decreases serum concentrations of thyroid hormones without a concomitant rise in serum TSH. This effect represents a deviation from normal negative feedback regulation in the HPT axis. If a similar drop in serum T3 and T4 happened in the context of primary hypothyroidism, serum TSH would be substantially increased and the patient would need thyroid hormone replacement therapy. The combination of low serum T3 and serum TSH within the reference range in

HPT axis feedback regulation and local thyroid hormone metabolism

Severe illness induces large changes in thyroid hormone economy, resulting in a downregulation of the HPT axis both at the hypothalamic and pituitary levels with an associated decrease in circulating thyroid hormone concentrations.3 This finding points to substantial changes to the negative feedback regulation in the HPT axis during NTIS.2 In people, central downregulation of the HPT axis during NTIS was supported by the observation in autopsy samples of decreased TRH gene expression in the

Diagnosis and management of severe primary thyroid disorders in patients in the ICU

The high prevalence of NTIS in patients in the ICU and the extent of HPT axis changes in these patients can make it difficult to distinguish NTIS from untreated primary hypothyroidism. Levothyroxine treatment should be continued during a patient's stay in the ICU in those who are known to have hypothyroidism. Although this practice seems trivial, prescription and continuation of chronic treatment is not always a main focus of care in the ICU setting. Findings from a retrospective chart review

Treatment and management of NTIS

Whether interventions aimed at normalising thyroid hormone concentrations in patients with extended critical illness are beneficial has so far not been satisfactorily answered. The table contains clinical studies reporting interventions in patients with NTIS. Only a few, rather small, RTCs have assessed the effects of treatment with thyroid hormones in patients with NTIS. These trials report results obtained in a large range of patient groups—eg, patients with acute renal failure,29 burn injury,

Conclusions

From a classic perspective, NTIS is a syndrome that occurs during various illnesses and is identified by decreased plasma concentrations of thyroid hormones with unclear resulting effects. Recent studies have shown that the changes in thyroid economy during NTIS suggest substantial and complex changes at the level of the HPT axis, in terms of setpoint regulation, and at the organ level, in terms of local metabolism of thyroid hormones (figure 5). Whether the noted changes in critically ill

Search strategy and selection criteria

We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for articles published in English from inception to March 6, 2014, with the search terms “critically ill patients”, “intensive care”, or “sepsis” in combination with “thyroid dysfunction”, “euthyroid sick syndrome”, or “thyroid hormones”. References chosen were selected on the basis of their title.

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