Nonthyroidal illness syndrome (NTIS) is a common finding in critically ill patients, characterized by disruptions in the hypothalamus-pituitary-thyroid axis, resulting in altered levels of thyroxine (T4), triiodothyronine (T3), and reverse T3. This condition, often considered to be an adaptive response aimed at conserving energy, can become maladaptive in prolonged critical illness, contributing to poor outcomes in intensive care unit patients. The pathophysiology of NTIS involves cytokine-driven alterations in thyroid hormone (TH) metabolism, impaired hormone transport, and reduced receptor sensitivity, which-collectively-suppress thyroid function. Despite these insights, the therapeutic role of TH replacement in patients with NTIS remains uncertain. Low doses of levothyroxine and T3 have been trialed, particularly in patients with cardiovascular comorbidities, but clinical studies report conflicting results regarding their impact on mortality and overall patient outcomes. While some evidence suggests potential benefits of T3 administration in specific subgroups, such as patients with septic shock or severe coronavirus disease 2019, robust clinical trials have yet to conclusively demonstrate improved survival or recovery. The heterogeneity in NTIS presentation and treatment protocols, as well as the complex nature of TH regulation in critically ill patients, complicates efforts to establish clear guidelines for hormone therapy. Future research should prioritize individualized approaches, optimizing hormone dosing and timing, while aiming to elucidate the long-term effects of such interventions on critically ill patients to improve morbidity and mortality outcomes.

The hypothalamus-pituitary-thyroid (HPT) axis is a critical neuroendocrine system that regulates the production and release of thyroid hormones (TH), which are central to metabolism, energy balance, and overall physiological function. The axis starts at the hypothalamus, which secretes thyrotropin-releasing hormone (TRH). This stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH), which then acts on the thyroid gland to produce and release TH, primarily thyroxine (T4) and triiodothyronine (T3). A negative feedback mechanism ensures that elevated levels of T3 and T4 inhibit further secretion of TRH and TSH, maintaining hormonal balance and metabolic stability. This feedback loop supports normal growth, development, and energy regulation under normal physiological conditions[1].

TH are essential for regulating the basal metabolic rate, influencing oxygen consumption and energy expenditure across tissues. These hormones promote mitochondrial activity, enhance glucose and lipid metabolism, and stimulate protein synthesis, driving overall metabolic processes[2,3]. Beyond metabolism, TH are critical for growth and development, particularly during fetal and postnatal stages, where they are involved in brain maturation, neuronal differentiation, and synaptogenesis[4]. A deficiency in T4 during these critical periods can lead to irreversible developmental disorders, such as cognitive impairment and growth retardation, evident in conditions like cretinism[5].

In adulthood, TH continue to regulate anabolic and catabolic pathways, supporting tissue maintenance and metabolic homeostasis. Through the HPT axis, these hormones interact with other endocrine systems to modulate physiological functions based on energy demands.

The HPT axis plays a key role in maintaining metabolic homeostasis, but its functions are also closely integrated with the function of other major neuroendocrine systems. Τhe hypothalamus-pituitary-adrenal (HPA) axis being one of these systems, is activated in response to stress. Under stress conditions, the HPA axis increases the production of cortisol, a glucocorticoid that influences glucose metabolism. Cortisol can interfere with the sensitivity of the HPT axis, leading to reduced secretion of TRH and TSH, and thereby downregulating TH production[6]. This relationship contributes to the prioritization of immediate energy needs by reducing long-term metabolic demands under stress.

Another key interaction is between the HPT axis and the insulin signaling pathway. TH play a role in enhancing glucose uptake in tissues and modulating insulin sensitivity. TH increase glucose transporter expression, which aids in glucose uptake in skeletal muscle and adipose tissue[7]. On the other hand, insulin resistance, a hallmark of type 2 diabetes, can alter thyroid function by impacting the feedback mechanisms of the HPT axis, resulting in alterations in TSH and TH levels[8]. This interplay demonstrates the critical role of TH in coordinating energy distribution and metabolic responses under varying physiological conditions.

Thus, the HPT axis is not only essential for metabolism and growth but also operates in close collaboration with other neuroendocrine pathways, adapting the body's energy allocation based on environmental and internal cues.

While the HPT axis functions optimally in maintaining metabolic homeostasis under normal conditions, these regulatory mechanisms are altered in critically ill patients. A prime example of this alteration is seen in non-thyroidal illness syndrome (NTIS), which will be discussed in the following section. In critically ill patients, there are significant changes of the HPT axis, where the body typically enters a state known as NTIS, also referred to as sick euthyroid syndrome or low T3 syndrome (LT3). NTIS is characterized by decreased serum levels of T3, normal or decreased levels of T4, and increased serum levels of reverse T3 (rT3), while serum levels of TSH are usually normal or decreased[9]. Alterations affecting T4 and TSH concentrations occur sequentially, and their magnitude correlates with the severity of the illness[10]. These changes affect both the HPT axis and peripheral regulation and action of TH, manifesting in various tissues and organs depending on the degree of illness severity[11]. For instance, Peeters et al[12] demonstrated that low plasma concentrations of T3, T4, and TSH, along with elevated rT3, were associated with poor prognosis in critically ill patients admitted to the intensive care unit (ICU)[12]. This syndrome is largely driven by disruptions in TH binding proteins, altered TH transporter and receptor function, and dysregulation of deiodinase enzymes, which are responsible for converting T4 to T3. These factors contribute significantly to the abnormal hormone regulation observed in NTIS[11].

There are two distinct phases of critical illness: The acute phase and the prolonged phase[12]. In the acute phase, which occurs within the first hours to days of critical illness, there is a rapid and significant decline in plasma T3 concentration, accompanied by a marked increase in plasma rT3 levels. This pattern is accompanied by the disappearance of the normal pulsatile secretion of TSH[13,14]. In some cases, there is a transient elevation of plasma T4, which occurs in parallel with the rapid T3 decline, potentially reflecting a shift in deiodinase activity that favors the inactivation of T4 to rT3 rather than its conversion to T3[15]. In the prolonged phase of critical illness, which can last for several days to weeks, circulating T3 levels remain low, and T4 levels start to decrease as well. TSH concentrations, although typically within the normal range, may also be slightly reduced. This hormonal profile mimics that of central hypothyroidism, where diminished hypothalamic stimulation leads to reduced thyrotropic activity, resulting in decreased TH production[11]. On a cellular level, prolonged NTIS is associated with downregulation of TH receptors and impaired peripheral T3 action, which further exacerbates tissue-specific hypothyroidism.

It is well established that three types of deiodinases (D1, D2, and D3), belonging to the selenoprotein family, selectively remove iodide from T4 and its derivatives, playing an activating or inactivating role[16]. During critical illness, the TH alterations observed are likely linked to decreased monodeiodination of T4. This hypothesis was confirmed by Peeters et al[12], who demonstrated significantly reduced D1 activity in post-mortem liver samples from critically ill patients compared to the healthy population[17]. Consequently, impaired conversion of T4 into T3 and increased degradation of T4 into the inactive rT3 could be anticipated. Boelen et al[18] further suggested that decreased hepatic D1 activity and expression is possibly mediated by cytokines.

Several studies have examined the role of cytokines in the acute LT3[19,20]. Specifically, data from both human and animal studies highlight the significant role of interleukin (IL)-6 in the interaction between the thyroid and cytokines. A study involving hospitalized patients demonstrated a negative correlation between serum IL-6 levels and free T3 (FT3), and a positive correlation with rT3[19]. Similarly, Kimura et al[21] confirmed an inverse relationship between IL-6 levels and FT3 concentrations. Tumor necrosis factor-alpha (TNF-α) may also contribute to the pathogenesis of NTIS. When recombinant TNF-α was administered to healthy individuals, it reproduced the typical hormone profile of NTIS. However, IL-1 receptor antagonist infusion failed to prevent the endotoxin-induced alterations observed in NTIS[20]. Thus, endogenous IL-1 does not contribute to alterations in plasma TH levels and TSH concentrations, induced by mild endotoxemia. Consequently, despite the apparent modulatory role of cytokines in NTIS, the precise mechanisms regulating peripheral TH metabolism remain unclear.

Other mechanisms potentially contributing to NTIS include a decreased number and activity of T4 transporters. NTIS is characterized by a 30% to 65% reduction in T4 transport into peripheral tissues[22]. A decrease in T3 production is observed in proportion to the severity of the illness, whereas T3 clearance remains unaffected. Furthermore, the affinity of TH to their transport proteins is altered during acute illness[23]. Thyroxine-binding globulin levels decrease in prolonged illness, further modulating hormonal changes in NTIS[24].

At the genomic level, during prolonged critical illness, suppressed TRH gene expression in the hypothalamus is a key feature. The increased availability of T3 within the hypothalamus could explain the feedback inhibition of the TRH gene in LT3. Notably, over 80% of brain T3 is derived from local T4 to T3 conversion via D2[25].

Additionally, elevated dopamine and cortisol levels in the hypothalamus, as seen in critical illness, may contribute to central hypothyroidism in patients with NTIS. The same applies to high doses of pharmaceutical analogues administered to these patients[26,27]. The above mechanisms which contribute to the pathogenesis of NTIS are presented in Figure 1.

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Figure 1 Outline of the pathophysiology of nonthyroidal illness syndrome, focusing on the interactions between deiodinases, cytokines, and hormonal regulation. Reduced D1 activity in the liver leads to decreased thyroxine (T4) to triiodothyronine (T3) conversion, while D3 increases the production of reverse T3 (rT3). However, D2 in the brain remains active, allowing local T4 to T3 conversion and maintaining brain T3 levels, despite systemic disruptions. Elevated levels of dopamine and cortisol in the hypothalamus lead to the suppression of TRH gene expression, which in turn contributes to central hypothyroidism. The diagram also highlights the role of cytokines, particularly interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), in disrupting thyroid hormone metabolism. IL-6 negatively correlates with free T3 and positively with rT3 levels, while TNF-α reproduces the typical hormone profile of NTIS when introduced into healthy individuals. Additionally, a reduction in T4 transport to tissues and lowered thyroxine-binding globulin levels (reduced T4 and T3 transport, impaired hormone availability) further exacerbate the hormonal imbalance during prolonged illness. Together, these mechanisms contribute to the complex hormonal dysregulation seen in nonthyroidal illness syndrome. rT3: Reverse T3; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; NTIS: Nonthyroidal illness syndrome.

In the early acute phase of critical illness, NTIS reflects changes of an adaptive nature[11]. This phase is typically characterized by a catabolic state with mobilization of energy from stores (glycogen and muscle protein breakdown, free fatty acid mobilization, gluconeogenesis) and increased resting energy expenditure[28]. In line with type 1 allostasis, when energy requirements exceed total available energy (from stores and nutrition), the organism shifts towards a temporary path of energy conservation[29]. NTIS facilitates this by reducing the exposure of peripheral organs to the anabolic actions of T3. Some patients may enter a hypermetabolic state, which is associated with higher mortality rates, potentially reflecting the severity of the underlying condition[30] (Figure 2). However, certain patients exhibit a more moderate mitochondrial response with reduced metabolism and oxygen consumption, which has been hypothesized to be an adaptive mechanism with potential survival benefits[31].

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Figure 2 Τhe impact of nonthyroidal illness syndrome on metabolism and clinical outcomes. The complex interplay of metabolic changes, hormonal suppression, immune function, and clinical interventions during nonthyroidal illness syndrome, which can significantly affect patient outcomes during critical illness. Acute phase: In the early stages of critical illness, the body enters a catabolic state, characterized by the breakdown of muscle protein and mobilization of energy stores (glycogen, muscle, and fat). This phase includes both hypermetabolism (increased energy expenditure) and reduced metabolism, with certain patients experiencing higher mortality if their metabolic response becomes excessive. These changes result in energy mobilization, where the body increases glucose and lipid metabolism to fuel essential processes. Cytokines, such as interleukin-6 and tumor necrosis factor-alpha, and cortisol are elevated during this phase, further influencing the suppression of the hypothalamus-pituitary-thyroid (HPT) axis. Central suppression of the HPT axis: The elevated levels of cytokines and cortisol feedback to the hypothalamus, reducing the secretion of thyrotropin-releasing hormone (TRH), which in turn lowers thyroid-stimulating hormone (TSH) levels [central suppression of the HPT axis, leading to reduced thyroid hormone (T3 and T4) production]. This suppression is critical as it slows down metabolism, possibly as an adaptive mechanism to conserve energy during the acute phase of illness. Fasting and Parenteral Nutrition: During the early acute phase, fasting can exacerbate the downregulation of the HPT axis. Lower leptin levels contribute to this suppression, further reducing TRH and TSH levels. On the other hand, parenteral nutrition influences the body's metabolic responses by potentially increasing mortality if not administered appropriately. Both fasting and parenteral nutrition affect glucose and lipid metabolism, shifting the body's energy balance. Prolonged phase: As the illness persists, patients may enter the prolonged phase, during which prolonged protein breakdown leads to muscle wasting. Central suppression of the HPT axis continues, with further reduction in TRH and TSH levels. This prolonged metabolic dysregulation leads to decreased mitochondrial function, impaired immune responses, and an overall decline in metabolic efficiency. As a result, muscle and liver tissues show increased sensitivity to circulating thyroid hormones due to changes in hormone transport and receptor activity. Clinical outcomes: Throughout both phases, the impact of NTIS on metabolism can lead to different clinical outcomes. Hypermetabolism in the acute phase is associated with increased mortality, especially when the body's energy demands exceed its capacity to mobilize stores. Conversely, reduced metabolism during the acute and prolonged phases may be adaptive in some cases but can also impair immune responses, making recovery more difficult. The interventions, such as fasting and nutritional support, must be carefully managed to optimize clinical outcomes and prevent adverse effects.

The association of nutrition with NTIS has also been investigated. In healthy individuals, fasting leads first to peripheral and then to central downregulation of the HPT axis, similar to what is seen in critically ill patients[32], which indicates a common underlying mechanism. Suggested mediators for both conditions (from rodent models) are liver D1 downregulation and D3 upregulation[33]. There is evidence that a fasted state during the first days of ICU stay reinforces the development of NTIS[11] and withholding parenteral nutrition (PN) in this period seems to benefit recovery and survival[34]. Interestingly, what seems to be favorable in this occasion, is the change in peripheral TH metabolism, i.e. the increase of rT3/T3 ratio, whereas the central effect of fasting in lowering T4 and TSH during the early days is rather harmful[34]. A potential mechanism through which fasting induces central HPT downregulation is a low leptin signal to the hypothalamus, specifically acting on TRH secretion[32]. Other actions of leptin on hypothalamic nuclei, the pituitary and on deiodinase action have been examined. However, leptin levels did not show direct interdependence with TH levels in a study of ICU patients[34]. Within muscle cells, it has been proposed that increased D2 and decreased D3 activity result in higher T3 levels, promoting a shift in energy substrate utilization from lipids to glucose[35]. Positive effects of NTIS on immune responses have also been documented. In granulocytes, higher D3 expression and activity create an abundance of iodide, enhancing the bactericidal properties of the cells and facilitating bacterial clearance[32,35,36].

In patients admitted to ICU, NTIS is frequent and it has been associated with poor prognosis and increased mortality[37], especially in patients with low free T4 (FT4) levels, whereas T3 has been characterized as predictor of nonsurvival in other publications[38,39].

Prolonged critical illness can vary in its severity of metabolic dysfunction, depending on the underlying disease and pre-admission nutritional status[40]. During this phase, the reduced expression of TRH and loss of TSH pulsatility[41] may be further exacerbated by the administration of glucocorticoids and/or dopamine. Prolonged protein catabolism leading to muscle wasting is one of the detrimental effects of NTIS, and experimental treatment with TRH and growth-hormone-releasing peptide-2 infusion in humans has shown reduced markers of protein degradation, accompanied by normalization of TH levels[42]. NTIS also impairs mitochondrial respiration and ATP production, as observed in peripheral blood cells of patients with coronavirus disease 2019 (COVID-19), which can contribute to energy failure and a compromised immune response[43]. A study by Sciacchitano et al[44] demonstrated that the occurrence of NTIS in critically ill COVID-19 patients was associated with significant alterations in peripheral hydroelectrolytic balance, as measured by bioelectric impedance analysis (BIA) parameters. These findings further underscore the metabolic dysregulation observed in prolonged NTIS and its potential impact on clinical outcomes.

Additionally, peripheral tissues begin to display changes indicating increased sensitivity to circulating TH, including upregulation of the iodotyrosine and TH transporter MCT-8 in liver and muscle, increased D2 expression in muscle, and heightened expression of TH receptors in the liver[25,45,46]. However, it remains unclear whether these adaptations succeed in increasing intracellular and intranuclear T3 availability. The central suppression of the HPT axis in prolonged illness appears to be largely maladaptive, potentially hindering recovery[47].

Body composition and nutritional status pre-admission to ICU should also be examined in relation to NTIS and clinical outcomes. In critical illness, increased body weight seems to come with a certain advantage in terms of prognosis and mortality, which is known as the obesity paradox[48,49]. Recent studies have demonstrated that higher body mass index (BMI) is associated with prolonged mechanical ventilation duration but improved survival after an admission in ICU[48,49]. This paradoxical effect is supported by the observed J-shaped survival curve, where a moderate increase in BMI is associated with a lower mortality risk in critically ill patients, while both underweight and severe obesity correlate with worse clinical outcomes[48,49]. Having greater nutritional and metabolic reserves makes patients less susceptible to macro- and micro-nutrient deficiencies and to the detrimental effects of undernutrition[40]. As a result, they can endure the insult of critical illness for a prolonged period. The severity of NTIS has not been proven to have an association with BMI on its own[50]. To complicate matters further, obese individuals can develop NTIS in the absence of critical illness[51]. This is most likely linked to chronic inflammation and increased levels of proinflammatory cytokines[51]. Therefore, the evaluation of NTIS in overweight and obese individuals is challenging, as it might not reflect solely the severity of the acute illness, but a preexisting chronic inflammatory state.

The obesity paradox in critical illness raises important considerations for TH supplementation. While moderate increases in BMI are associated with improved survival, it remains unclear whether TH therapy should be tailored based on body composition. Obese patients exhibit altered metabolic reserves and chronic low-grade inflammation, which may influence their response to supplementation[11]. Additionally, lean body mass loss, rather than absolute BMI, may be a stronger predictor of adverse outcomes[40], highlighting the need for individualized therapeutic approaches. Muscle wasting in prolonged critical illness suggests that interventions targeting protein metabolism, possibly in conjunction with TH therapy, may be beneficial. However, further research is required to determine whether patients with greater muscle or fat reserves respond differently to TH replacement and whether body composition can serve as a reliable marker for therapy decisions (Figure 2).

NTIS is a common finding among critically ill patients, associated with adverse outcomes and increased mortality[9]. Despite advances in understanding NTIS and its potential therapeutic implications, there remains uncertainty regarding the efficacy and safety of TH replacement therapy.

Despite advances in understanding TH dysregulation in critically ill patients, key aspects of NTIS remain unresolved. Addressing these gaps is crucial for improving patient outcomes, particularly through personalized approaches to treatment.

While TH therapy may offer potential benefits for specific subgroups of critically ill patients, robust evidence is lacking to support its routine use in NTIS. Future research should prioritize personalized treatment approaches, guided by biomarkers and patient characteristics, to optimize the management of thyroid dysfunction and improve clinical outcomes.