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Introduction

Critical illness can be defined as any life-threatening condition requiring the support of failing vital organ function. During critical illnesses, hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss are noted, with concomitant changes in circulating hormone levels (Van den Berghe 2001). As a result of the acute stress response, activation of pituitary-adrenal axis occurs, and serum cortisol concentration rises rapidly. Thyroid hormones play a key role in body homeostasis by modulating metabolism and immune system function. Alterations of the hypothalamic-pituitary-thyroid (HPT) axis are a common finding in critical illness, mainly expressed as low levels of total 3,5,3′ -triiodothyronine (T3) and termed as “low T3 syndrome.” Sick patients with low serum T3 are often regarded as being clinically euthyroid, and as a consequence, the alternative term “euthyroid sick syndrome” was widely used in the past. “Nonthyroid illness syndrome (NTIS)” is now more commonly used to describe the typical changes in the thyroid-related hormone concentrations that can arise in the serum following any acute or chronic illness that is not caused by an intrinsic abnormality in thyroid function (Chopra 1997).

NTIS affects about 70 % of patients hospitalized with various diseases (Bermundez et al. 1975; Kaplan et al. 1982), and it is often associated with alterations in other endocrine axis, such as decrease in serum gonadotropin and sex hormone concentrations and increase in serum adrenocorticotropic hormone (corticotropin) and free cortisol levels. Thus, the NTIS should not be viewed as an isolated abnormal metabolic event but as part of a generalized systemic endocrine reaction to critical illness.

It has been demonstrated that these changes in thyroid hormone levels are associated with the duration and severity of the disease. Subsequent studies confirmed the association between NTIS and adverse outcomes in patients with sepsis, multiple trauma, acute respiratory distress syndrome, respiratory failure, and mechanical ventilation, as well as in the general intensive care unit (ICU) population (Chinga-Alayo et al. 2005; Inglesias et al. 2009; Giuseppe et al. 2009; Sharshar et al. 2011). Low T3 levels are also indentified as an independent predictor of short- and long-term survival in patients with myocardial infarction, heart failure, or acute stroke outside the ICU setting (Inglesias et al. 2009).

Even though NTIS has been studied for several decades now, it is still unclear whether these changes in the HPT axis during critical illness are representative of an associated pathology requiring thyroid hormone replacement therapy or are indeed an adaptive response to stress to decrease metabolic rate, which in turn may be beneficial to the sick patient.

In this chapter, the current knowledge on the adaptation mechanisms of thyroid gland during the development of critical illness is summarized. In order to correctly interpret thyroid function tests (TFTs) in the critically ill patient, the clinician should be familiar with the changes that occur during critical illness in the regulation of the hypothalamic-pituitary-thyroid axis and in thyroid hormone metabolism and the effects of commonly used medications on thyroid physiology.

Thyroid Axis in Health

In healthy subjects, the hypothalamus-pituitary-thyroid axis functions as a classical feedback system (Fig. 2). At the level of the hypothalamus, thyrotropin-releasing hormone (TRH) is released which stimulates the pituitary to secrete in a pulsatile and diurnal fashion TSH. TSH in turn drives the thyroid gland to release the T4 into the circulation. Conversion of T4 in peripheral tissues produces the active hormone T3 and reverse T3 (rT3) which is thought to be metabolically inactive. T4 and T3 in turn exert a negative feedback control on the level of the hypothalamus and pituitary.

The thyroid gland produces T4 in significantly larger quantities than the biologically active T3. Although released from the thyroid in a ratio of T4:T3 = 17:1, the circulating levels of each hormone are also determined by extra-thyroidal conversion of T4 to T3, which in healthy humans accounts for more than 80 % of T3 production (Pilo et al. 1990). In the circulation, thyroid hormone is bound to carrier proteins with only the amount of free or unbound hormone determining the activity level of thyroid hormone-regulated process. Only 0.03 % of total serum T4 and 0.3 % of total serum T3 are present in the free form, with the remaining part bound to thyroxine-binding globulin (TBG), thyroxine-binding prealbumin or transthyretin (TBPA), and albumin (Oppenheimer 1968). Normally, the amount of free hormone is kept constant by matching excretion to thyroid release. If changes do occur in total circulating hormone levels of healthy humans, these are mainly caused by altered amounts or affinity of carrier proteins. Free circulating T4 and T3 enter to their target cells in peripheral tissues via monocarboxylate transporters. In these cells, activation and inactivation of thyroid hormone are carried out by a group of three iodothyronine deiodinases, each of which is a selenoprotein encoded by a separate gene (Fig. 1). The deiodinases type 1, 2, and 3 (D1, D2, and D3) have distinct tissue distributions, substrate affinities, and physiological roles (Gereben et al. 2008a, b). All deiodinases are integral membrane proteins, and although their cellular localization varies, all their catalytic domains reside within the cell cytosol (Friesema et al. 2006). D1 and D2 activate T4 by removing an iodine atom from its outer ring (5′-deiodination), forming T3. In contrast, D3 inactivates both T3 and T4 by removing an iodine atom from the inner ring (5′-deiodanation) generating T2 and rT3, respectively, a reaction that can be also catalyzed by D1. D1 and D2 differ by their kinetic properties, substrate specificity, and susceptibility to inhibitory drugs as well as by their responses to changes in the thyroid hormone status. The higher levels of D1 activity in humans are found in the thyroid, liver, and kidney, while D2 is more widely expressed, being found in the pituitary, brain, thyroid, skin, skeletal, and heart muscle (Williams and Bassett 2011). The D1 and D3 isoenzymes are located in the plasma membrane, while D2 is retained in the endoplasmic reticulum. The T3 produced from D2 thus potentially has ready access to the nucleus due to its close proximity, while T3 produced by D1 is more readily exported into the plasma (Zoeld et al. 2006). The D3 contributes to thyroid hormone homeostasis protecting tissue from excess of thyroid hormones.

Fig. 1
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Scheme representing the different aspects of peripheral thyroid hormone metabolism. Thyroid hormone is taken up from the blood via thyroid hormone transporters and subsequently metabolized in the cell. Iodothyronine deiodinases convert thyroid hormone. T3 transfers to the nucleus and can then bind to its receptor (TR). TR forms a heterodimer with retinoid X receptor (RXR) and binds specific sequences in target genes (Reprinted with permission from Mebis et al. 2011)

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T4 and T3 regulate their own release by feedback inhibition on TSH secretion from the pituitary thyrotrope cells and at the level of the hypothalamus. T3 acts through binding with nuclear thyroid hormone receptors (TR). In the pituitary and in the hypothalamus, T4 acts via local conversion to T3 although T4 has also been shown to be able to bind TR and exert some biological effect (Bogazzi et al. 1997). In the hypothalamus, high levels of iodothyronines downregulate biosynthesis of TRH in the hypophysiotropic neurons of the paraventricular nucleus (Perello et al. 2006). These neurons project to the median eminence where TRH is released in the capillaries of the hypophysial portal system. So TRH positively regulates the biosynthesis and release of TSH from the pituitary, and together with the negative effect of thyroid hormones on TRH and TSH release from the hypothalamus and pituitary, a relatively stable concentration of TSH in the circulation is achieved. Therefore, the measurement of circulating TSH is regarded as a sensitive marker for thyroid gland dysfunction.

Thyroid Axis in Critical Illness

The pathophysiological mechanisms responsible for NTIS are complex and poorly understood. A wide range of mechanisms give rise to the hormonal changes seen in the NTIS. These changes include modifications to the hypothalamic-pituitary axis, altered binding of thyroid hormone to circulating binding proteins, modified entry of thyroid hormone into tissue, changes in thyroid hormone metabolism due to modified expression of the intracellular iodothyronine deiodinases, and changes in thyroid hormone receptor expression or function.

Critical illness is hallmarked by some very distinct neuroendocrine alterations that are quite different in the prolonged phase of critical illness as compared with the first few hours or days after the onset of a severe illness (Fig. 2). The acute and chronic changes in pituitary-thyroid function are a multidisciplinary dynamic process that develops over time. The acute-stage endocrine and metabolic profiles differ from the prolonged critical illness, which may relate to the metabolic and immunological alterations accompanying the medical conditions. The first reaction, which takes place within hours of the onset of acute illness, is the activation of the anterior pituitary gland, the associated suppression of anabolic pathways in the periphery (since 80–90 % of the circulating T3 are derived from T4), and the changes in receptor binding of thyroid hormones. The changes in the thyroid axis are so uniformly present in all types of acute illnesses that they have been interpreted as a beneficial and adaptive response, essential for survival, that does not warrant intervention. It is interesting that during recovery, T3 and rT3 normalize again, while in persistence of the disease, T3 levels remain suppressed. When patients are treated in the ICU for weeks or even months, a different set of hormonal changes may occur. The neuroendocrine abnormalities seem to predominate in prolonged disease with reduced TSH levels being the most frequent abnormality and suggesting a diminished hypothalamic-pituitary activity (Plikat et al. 2007). TSH levels show a transient rise during the first hours of acute illness but thereafter return to normal. When severe illness persists, TSH may become abnormally low. It seems that there is a timely overlap between acute- and chronic-phase metabolic alterations. The decrease in serum T3 and fT4 levels which develops over time gives us a good explanation why typical adaptations of the thyroid axis may not be present in critically ill patients on admission to the ICU (Williams and Bassett 2011; Chopra et al. 1975). Interestingly, the chronic phase of the euthyroid sick syndrome is characterized by reversibly diminished secretion of TSH which can be reactivated by thyrotropin-releasing hormone (TRH) administration (Oppenheimer 1968; Gereben et al. 2008a, b).

Fig. 2
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Schematic outline of thyroid axis in health, acute critical illness, and prolonged critical illness (Reprinted with permission from Mebis and van den Berghe 2009)

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Thyroid Hormones in Critical Illness

Triiodothyronine

The majority of critically ill patients have low serum T3 concentrations accompanied by an increase in rT3 levels, as do some ambulatory patients during severe illness (Tables 1 and 2). T3 low serum levels reflect altered thyroid homeostasis and mechanisms of adaptation in critical illness. Liver and skeletal muscle biopsies obtained within minutes after death from intensive care unit patients demonstrate reduced 5′-monodeiodinase activity and increased 5′-monodeiodinase activity (which converts T4 to rT3) (Peeters et al. 2003, 2005a). Moreover, patients with fatal illness have low tissue T4 and T3 concentrations (Peeters et al. 2005c; Arem et al. 1993).

Table 1 TSH values during critical illness and clinical outcome
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Table 2 Alterations in thyroid hormones during critical illness and their clinical correlation
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Inhibition of the enzyme 5′-deiodinase that catalyzes the conversion of T4 to T3 has been considered a possible mechanism resulting in NTIS (Fig. 3) (Burman and Wartofsky 2001; Mortoglou 2004). Several mechanisms such as poor nutrition, free oxygen radicals, cytokines, and drugs can contribute to the inhibition of 5′-monodeiodination and therefore to the low serum T3 concentrations in critically ill patients with nonthyroidal illness (Chopra et al. 1975; Chopra 1985b; Van der Poll et al. 1990; Stouthard et al. 1994; Corssmit et al. 1995).

Fig. 3
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Thyroxine metabolism in nonthyroidal illness. The inhibition of 5′-monodeiodinase in nonthyroidal illness leads to decreased conversion of T4 to T3 and reduced metabolism of reverse T3

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Serum Reverse Triiodothyronine

The conversion of reverse T3 to diiodothyronine (T2) is reduced in nonthyroidal illness because of inhibition of the 5′-monodeiodinase activity (Chopra 1976). This constitutes an additional mechanism of high serum rT3 values in patients with nonthyroidal illnesses, except in those with renal failure and some patients with AIDS (Kaptein 1996; Ricart-Engel et al. 1996).

Thyroxine

Serum T4 in nonthyroidal illness can be reduced within 24–48 h. The initial decline is predominantly due to decreased binding to carrier proteins such as TBG, TTR or TBPA, and albumin (Afandi et al. 2000). Many drugs including salicylates, phenytoin, carbamazepine, and furosemide may inhibit thyroid hormone binding to TBG competitively, resulting in an acute increase in free T4, with a subsequent physiological decrease in total T4 concentrations. The presence of circulating inhibitors of T4 binding, such as high concentrations of fatty acid, disordered iodine uptake by the thyroid, or abnormal peripheral metabolism, has been implicated to the low total and/or free T4 levels (Wartofsky and Burman 1982; Kaptein et al. 1981; Chopra 1998; Chopra et al. 1985a). Some drugs including phenytoin, carbamazepine, rifampin, and phenobarbital also may contribute to low total T4 concentration by accelerating its clearance. Despite the presence of low total T4 in these situations, serum concentrations of free T4 typically remain in the normal range in most patients unless the illness is severe and protracted (Chopra 1997). However, hypothalamic-pituitary suppression, present usually in prolonged critical illness, leads to decreased secretion of TSH with decrease of T4 production by the thyroid gland and a subsequently decline of free T4 levels in the circulation, a sign of severity of the disease and a predictor of high mortality (Ilias et al. 2007).

Thyrotropin

Under normal conditions, TSH synthesis is relatively stable and controlled by thyroid hormones, neuropeptides, and neurotransmitters. TRH is the main stimulating factor of TSH synthesis, and its effect is enhanced by catecholamines. Somatostatin and dopamine are the main inhibitory factors of TSH synthesis. In NTIS, TSH levels are commonly within the normal range and only in prolonged illness can be low. Serum TSH assays that have a detection limit of 0.01 mU/L should be used in assessing thyroid function in critically ill patients (Spencer et al. 1990). Some hospitalized patients have transient elevations in serum TSH concentrations (up to 20 mU/L) during recovery from nonthyroidal illness. Few of these patients prove to have hypothyroidism when reevaluated after recovery from their illness. Patients with serum TSH concentrations over 20 mU/L usually have permanent hypothyroidism (Burman and Wartofsky 2001; Table 2).

Most ICU patients suffer from sepsis. It is supposed that early alterations in the regulation of thyroid hormones economy during sepsis involve mainly peripheral mechanisms, such as impaired peripheral deiodination and reduced thyroid hormone secretion. The late phase of sepsis is associated with centrally induced hypothyroidism as suggested by restoration of T3 and T4 pulses by exogenous TRH infusion (De Jongh et al. 2001). In addition, postmortem examination showed diminished thyroid gland weight and follicular size (Van den Berghe et al. 1998), low expression of TRH messenger RNA in the hypothalamic paraventricular nuclei, and low concentrations of tissue T3 in patients who died while in the late phase of sepsis (Fliers et al. 1997; Arem et al. 1993). Common late alteration in thyroid metabolism is a decrease in the pituitary secretion of TSH that typically occurs in parallel with the decline in serum T4 concentrations (Wehmann et al. 1985). The causes are multifactorial and attributed to the effects of the illness per se, malnutrition and the suppressive effects of cytokines, and medications such as corticosteroids and dopamine (Papanicolaou 2000; Van den Berghe et al. 1994). If the illness persists, reduced TSH secretion likely contributes to low total and eventually low free T4 concentrations. Clinically, low T3 and T4 levels, in association with normal, low-normal, or decreased TSH, suggest the development of a variant of central hypothyroidism (Burmeister 1995). Such changes may be a self-protective adaptation to illness, as the body attempts to conserve energy. This state is usually transient, resolving once the patient shows signs of improvement. The recovery of the thyroidal axis begins with a rise in serum TSH and is eventually followed by normalization in T4 concentrations (Hamblin et al. 1986). Because of the difference in half-lives of T4 (days) and TSH (hours), the normalization of T4 lags behind the increase in TSH. As a result, the picture during the resolution of euthyroid sick syndrome may suggest primary hypothyroidism (Table 3).

Table 3 Drugs causing alterations in thyroid function and mechanisms involved
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Assessment of Thyroid Function in ICU

The decreased 5′-monodeiodinase activity is often not recognized because measurement of serum T3 is rarely utilized as a screening test for thyroid function (nor should it be). It is, however, useful to measure serum T3 and free T4 in hospitalized patients who have a low serum TSH concentration (Table 1) for the differential diagnosis of hyperthyroidism versus nonthyroidal illness. The serum T3 value should be high (or high-normal) in hyperthyroidism but low (or low-normal) in nonthyroidal illness. Rarely, a very sick patient with hyperthyroidism will have a low serum T3 concentration (Franklyn et al. 1994).

In the differential diagnosis of low serum T3 and T4 in the critically ill patient, intensivists should include the rare possibility of pituitary secondary hypothyroidism (low TSH). Measurements of rT3 had been considered useful in differentiating the two conditions in addition to the clinical lack of evidence of hypothalamic or pituitary disease. Subsequent studies however showed that rT3 does not accurately distinguish the two states (Burmeister 1995).

In assessing thyroid function in ICU, two important general principles must be considered (Stockigt 1996):

  • Thyroid function should not be assessed in seriously ill patients unless there is a strong suspicion of thyroid dysfunction.

  • When thyroid dysfunction is suspected in critically ill patients, measurement of serum TSH alone is inadequate for the evaluation of thyroid function.

Drugs in ICU

In the ICU, a wide variety of drugs are being used that can alter thyroid hormone physiology (Table 3). Drugs can interfere thyroid function at different levels:

  • Thyroid hormone binding

  • Metabolism

  • Transport

  • Thyroid production

  • Secretion of T4 and regulation of TSH secretion from the pituitary

One of the most widely used drugs in ICU is dopamine. Dopamine treatment depresses the thyroid axis per se and can aggravate the NTIS by suppression of the TSH secretion as well as the TSH response to TRH (Van den Berghe et al. 1996). The use of dopamine is associated with adverse outcome of ICU patients according the results of a recent study (Vincent et al. 2006). Although it is not proven whether iatrogenic hypothyroidism induced by dopamine is related to such adverse outcome, one should consider its possible adverse effects of this and other drugs on the thyroid hormone axis when prescribed for critically ill patients (in ICU).

Thyroid Dysfunction and Outcome

Although thyroid hormone changes are common during critical illness and thyroid function tests normalize when the patient recovers, it still remains controversial whether and to what extent these changes reflect a protective or a maladaptive process. Data from several studies suggest that baseline thyroid parameters are prognostic markers for patient outcome (Chinga-Alayo et al. 2005; Inglesias et al. 2009; Sharshar et al. 2011; Rothwell and Lawler 1995). A systematic review in pediatric patients with sepsis or septic shock showed a correlation between decreased thyroid function at baseline and worse outcome (Angelousi et al. 2011). A prospective study in adult critically ill patients in a medical ICU did not find prognostic value for T3 and free T4 levels on admission, but a decrease in free T4 levels during the course of the illness was related to adverse outcome (Mayer et al. 2011). In adult patients with acute respiratory distress syndrome, another study showed a difference in first-day free T3 but not T4 levels between survivors and non-survivors (Ture et al. 2005). The rT3 and the ratio of T3/r T3 on day 1 could already predict the chance of survival according to the results of another study in adult critically ill patients (Peeters et al. 2005a). Patients with traumatic brain injury also develop a low T3 syndrome, and in these patients, free T4 levels were found to be lower in non-survivors, while no difference was detected for T3 and TSH (Tanriverdi et al. 2007).

Thyroid Hormone Treatment During Nonthyroidal Syndrome

There is no consensus in the literature about correcting serum concentrations of thyroid hormone in critically ill patients affected by NTIS. Because if the changes of thyroid hormones during critical illness are physiologic, then treatment to restore thyroid hormone levels to the normal range could have deleterious effects. In contrast, if these changes are pathologic, treatment may improve an otherwise poor clinical outcome. What do we know from the literature is that:

  • Starvation-induced decrease in serum T3 concentrations is an adaptive and beneficial response in order to spare energy and prevent protein breakdown, and during the acute phase of illness, an effect of concomitant fasting could also be present.

  • Treatment with dopamine and high-dose systemic corticosteroids, used in ICU patients, decreases serum TSH concentrations in a rather pathologic pattern.

  • Alterations in deiodinase enzymes occur in tissues of humans who died in the setting of critical illness (Mebis et al. 2007; Peeters et al. 2003).

  • Transport of thyroid hormones into target tissues of critically ill patients may also be reduced (Peeters et al. 2005b).

However, clinical measurements of thyroid function with the use of parameters such as the Achilles tendon reflex time, cardiac QKD interval, and metabolic rate indicate a euthyroid state (Adler and Wartofsky 2007).

Since the presence of NTIS is associated with an increased mortality among critically ill patients, it could indicate an aberration that may delay recovery from acute illness and therefore would require intervention. According to the literature, only a few studies have examined the use of supplemental thyroid hormone therapy in such patients. Brent and Hershman (1986) examined the effect of thyroid hormone therapy in medical ICU patients. All patients included in the study had serum T4 levels <5 μg/dL with no evidence of intrinsic thyroid dysfunction and were given either T4 or placebo intravenously on a daily basis. There was no significant difference in mortality between the two groups, and the T4 replacement was detrimental to the restoration of normal pituitary-thyroid regulation. On the contrary, in organ donors, exogenous thyroid hormones stabilize the function of the cardiovascular system. On the other hand, trials with patients who suffered acute renal failure or undergone renal transplantation also failed to show any benefit (Acker et al. 2000, 2002).

One could argue that it is unlikely that levothyroxine therapy in the NTIS would have any benefit because of the pronounced inhibition of conversion of T4 to T3 in these patients. It is interesting that hepatic deiodinase is a selenoprotein, and selenium deficiency is commonly seen in septic patients. Thus, one could conclude that supplementation with selenium may result in a quicker normalization of T4 and rT3. Becker et al. examined the effect of treatment with T3 in 36 patients with acute burn injuries (Becker et al. 1982). Treatment with liothyronine (LT3) normalized serum T3 concentrations but resulted in no change in either mortality or basal metabolic rate. Since it is easier to diagnose the NTIS than to treat it properly, avoidance of thyroid hormone substitution seems a reasonable option at present.

Prolonged critical illness is a condition created over the last four decades, with the development of modern intensive care-supported medicine. Hormonal changes and system responses during this phase have not been selected by nature. But it is not known if hormonal changes associated with prolonged critical illness are advantageous. The question which should be answered is whether the thyroid hormone parameters in critically ill patients should be normalized and if it can be done safely. Before this question will be answered, TFTs should not be checked routinely in the intensive care setting unless there is serious suspicion of thyroid dysfunction, based on past history and clinical evaluation. The goal of TFT measurement in the ICU should mainly be the identification of previously unrecognized thyroid dysfunction that would require therapeutic intervention. When hypothyroidism is suspected (e.g., hypothermia, bradycardia, respiratory acidosis, pleural effusions, failure to wean) and the evaluation suggests central hypothyroidism, one should consider that the probability of NTIS is much higher than the pituitary or hypothalamic disease. If hyperthyroidism is suspected (e.g., tachyarrhythmias, widened pulse pressure, respiratory alkalosis, high-output heart failure) and low TSH is detected, true hyperthyroidism is unlikely unless the TSH is suppressed fully on a third-generation assay and the free T4 is elevated or at least in the upper limits of the normal range. In case that free T4 is low or low-normal, the patient is probably not hyperthyroid. Because of inaccuracy of all free T4 assays in this setting, however, repeating the free T4 by another method is advised before firmly establishing the diagnosis, especially if clinical suspicion persists.

Applications to Critical or Intensive Care

Assessment of thyroid function in patients with nonthyroidal illness who are hospitalized in an intensive care unit is difficult. It is recommended that thyroid function tests not be measured on seriously ill patients unless there is a strong suspicion of thyroid dysfunction. When thyroid dysfunction is suspected, measurement of serum TSH alone is inadequate for the evaluation of thyroid function. So, it is suggested measurement of a full thyroid panel including a total T4, a free T4, and a T3. Even then, the diagnosis may still be in doubt because all methods for assessing free T4 levels are unreliable in severe critical illness.

In critically ill patients with low serum T3 and/or low T4 concentrations and no other clinical signs of hypothyroidism, it is suggested not treating with thyroid hormone. In previously euthyroid patients undergoing CABG, it is recommend also not treating with thyroid hormone in the immediate postoperative period. The only recommendation of treatment concerns the brain-dead organ donors. But if there is additional evidence which suggests a diagnosis of hypothyroidism in critically ill patients, it is recommended to treat these patients with thyroid hormone replacement.

Application to Other Conditions

The majority of hospitalized patients have low serum T3 concentrations, as do some outpatients who are ill. Several diseases are associated with abnormal thyroid function tests including acute hepatitis, hepatoma, acute intermittent porphyria, acromegaly, nephrotic syndrome, Cushing’s syndrome, acute psychosis, and depression.

Some patients with acute psychiatric illnesses, particularly schizophrenia and severe depression, have transient elevations in serum T4 concentrations with or without low serum TSH concentrations. Hospitalized patients receive medications that have effects on thyroid function or on thyroid function tests.

It is recommend that thyroid function tests not be measured on hospitalized patients unless there is a strong suspicion of thyroid dysfunction. When thyroid dysfunction is suspected, it is suggested to measure a full thyroid panel (total T4, free T4, T3). In patients with low serum T3 and/or low T4 concentrations and no other clinical signs of hypothyroidism, it is recommended not treating with thyroid hormone. But if there is evidence suggesting a diagnosis of hypothyroidism, it is recommended to treat them with thyroid hormone replacement. In the absence of suspected myxedema coma, begin with half of the full replacement dose of levothyroxine.

Guidelines and Protocols

As it was said above, there is no consensus in the literature about correcting serum concentrations of thyroid hormone in patients affected by NTIS. The data on thyroid hormone replacement is experimental and there are no guidelines.

Conclusion

The evaluation of altered thyroid function parameters in systemic illness and stress remains a complex issue and has many pitfalls, because changes occur at all levels of the hypothalamic-pituitary-thyroid axis. Unique changes in thyroid function parameters are observed in various clinical states, including starvation and fasting, cardiac disease, renal disease, hepatic disease, infection, and sepsis. Many pharmacologic agents cause changes in thyroid economy that can complicate the interpretation of thyroid function parameters in systemic illness. Whether alterations in thyroid parameters during critical illness represent adaptive changes to conserve energy expenditure by reduced metabolic activity is still debatable. According to current data, thyroid hormone replacement therapy has not been shown to be beneficial in the vast majority of these patients. Some investigators would argue that systemic illness might induce a central hypothyroidism. Treatment with LT3 however, appears to slightly improve hemodynamic and neurohumoral variables in patients with congestive heart failure, and these benefits may represent a pharmacologic effect of T3 rather than a physiologic replacement hormonal effect.

Establishing thyroid dysfunction based on a single set of TFTs may be misleading. Careful clinical evaluation, knowledge of hospital course, and recent therapies are essential for the correct interpretation of such testing in this setting. Early pursuit of endocrine consultation may be helpful in difficult situations.

Summary

  • Critically ill patients present with low serum T3 levels and elevated rT3, but when illness is prolonged, also TSH secretion and circulation T4 levels are low.

  • It is recommended that thyroid function tests not be measured on seriously ill patients unless there is a strong suspicion of thyroid dysfunction.

  • When thyroid dysfunction is suspected in critically ill patients, measurement of serum TSH alone is inadequate for the evaluation of thyroid function. So it is suggested measurement of a full thyroid panel, including a total T4, a free T4, and a T3. However, the diagnosis may still be in doubt.

  • The acute changes in peripheral thyroid hormone metabolism should likely be considered as beneficial and adaptive and should not be treated.

  • Prolonged critically ill patients develop a neuroendocrine dysfunction of thyroid axis, superimposed on the peripheral changes of the acute phase. Currently, there is no evidence for treatment except in brain-dead organ donors.