Euthyroid sick syndrome. (Featured CME Topic: Thyroid Dysfunction/Disease).

ABNORMALITIES IN THYROID HORMONE HOMEOSTASIS occur in a variety of nonthyroidal illnesses. A decreased level of serum total triiodothyronine ([T.sub.3]) is the most common thyroid function abnormality in patients With acute illness (1) and can be detected Within 2 hours after the onset of severe physical stress. (2) As the severity of illness progresses, there is gradual development of a more complex syndrome associated with low levels of [T.sub.3] and thyroxine ([T.sub.4]. (3,4) Altered thyroid hormone levels have been reported in starvation, (5,6) acute and chronic medical illnesses, (7-9) bone marrow transplantation, (10) surgery, (11) trauma, (12) and, in fact, can be seen in any severe systemic illness. (13) Recovery from the underlying illness is accompanied by disappearance of the thyroid abnormalities. Based upon the conviction that patients with systemic illnesses are euthyroid, Wartofsky and Bunnan (14) in 1982 used the term euthyroid sick syndrome to describe the spectrum of thyroid abnormalities a ssociated With nonthyroidal illness. Recently, nonthyroidal illness syndrome, an alternative designation that does not presume the metabolic status of the patient, has been proposed. (1,15) This review Will focus on the pathogenesis, clinical significance, and management of the euthyroid sick syndrome or nonthyroidal illness syndrome.

PITUITARY-THYROIDAL AXIS DURING SYSTEMIC ILLNESS

Secretion of thyroid hormones from the thyroid gland is controlled by pituitary thyrotropin/thyroid-stimulating hormone (TSH) release, which is in turn controlled by hypothalamic thyrotropin-releasing hormone (TRH). Thyroxine and [T.sub.3], the main circulating thyroid hormones, exert feedback inhibition at the pituitary and hypothalamic level. (16) Thyroxine is nearly completely produced in the thyroid gland, and once secreted in the circulation, is peripherally deiodinated to [T.sub.3] in the liver and kidney. (16) Two peripheral enzymes deiodinate [T.sub.4]: 5'-monodeiodinase converts [T.sub.4] to its active metabolite, 3,5,3'-[T.sub.3] (16,17); whereas 5-monodeiodinase converts [T.sub.4] to reverse [T.sub.3] (3,3',5'-[T.sub.3]), a biologically inactive metabolite (Fig 1). In addition to peripheral deiodination, there is local deiodination of [T.sub.4] to [T.sub.3] in the pituitary gland. (16,18) More than 99% of [T.sub.4] and [T.sub.3] is bound to thyroxine-binding globulin (TBG), [T.sub.4]-binding preal bumin (TBPA, also termed transthyretin), and albumin. Only free, unbound [T.sub.3] (approximately 0.2% of the total [T.sub.3]) is metabolically active. Triiodothyronine enters the cell nucleus, binds to its nuclear receptor, and regulates transcription of thyroid hormone-responsive genes, resulting in the physiologic changes associated with thyroid hormone action. (16)

Critical illness is characterized by multiple and complex metabolic, immunologic, and endocrine alterations that follow a biphasic pattern. (20) Increased secretion of anterior pituitary hormones characterizes the initial neuroendocrine response to acute illness. After several days of systemic illness, reduced hypothalamic stimulation leads to impaired pulsatile release of several anterior pituitary hormones and reduced stimulation of the respective target tissues. In critical illness, many abnormalities' in the pituitary-thyroid axis have been demonstrated, including attenuated TRH response, decreased TSH release, decreased level of TBG, decreased total [T.sub.4] and [T.sub.3] levels, low tissue uptake of thyroid hormones, and altered thyroid hormone metabolism. (1,3,8,21) Although patients with nonthyroidal illness may present with a variety of abnormalities in thyroid function tests (Fig 2), most of these abnormalities can be classified into two major groups: 1) low [T.sub.3] state; and 2) low [T.sub.3] a nd [T.sub.4] state.

LOW [T.sub.3] STATE

During starvation or early in the course of a critical illness, levels of [T.sub.3] rapidly decrease. Low serum total-[T.sub.3] level has been recognized in more than 70% of hospitalized patients with nonthyroidal illness. (1,21) Reduction in [T.sub.3] concentration occurs within 2 to 24 hours of the onset of the illness. (2) Measured daily production rate of [T.sub.3] is decreased; however, the production rate of [T.sub.4] remains normal in patients with isolated low [T.sub.3] state. (22,23) Although the isolated low [T.sub.3] state usually represents the mildest form of nonthyroidal illness, the magnitude of the drop in [T.sub.3] level reflects the severity of illness. (24) A very low serum [T.sub.3] level has been associated with an increased mortality rate in patients with hepatic cirrhosis, congestive heart failure, and other systemic diseases. (25,27) The fall in [T.sub.3] level also correlates with the mortality rate in patients requiring intensive care unit admission. (28)

Several mechanisms are involved in the pathogenesis of low [T.sub.3] state (Table). Within hours after an acute insult or starvation, circulating [T.sub.3] level rapidly drops due to decreased conversion of [T.sub.4] to [T.sub.3], (20,29,30) resulting in low [T.sub.3] and high reverse-[T.sub.3] concentrations. (31) The serum concentration of reverse [T.sub.3] is increased in nonthyroidal illness, except in patients with renal failure. (32) Increased turnover of [T.sub.3] and [T.sub.4] in the hypermetabolic phase of illness may also contribute to low serum and tissue concentrations. (21,33) In addition, TSH secretion is suppressed in patients with nonthyroidal illness, resulting in decreased secretion of [T.sub.4] and T3 by the thyroid gland. (10) In critically ill patients, mean nocturnal TSH secretion and number of TSH surges are markedly reduced compared with control subjects. (21,34) Low [T.sub.3] levels positively correlate with nocturnal TSH secretion and with the number of TSH bursts. (21) Absent noctu rnal TSH secretion surge has been reported in 58% of patients with nonthyroidal illness. (34) During starvation, abnormalities in TSH secretion may represent an appropriate pituitary response to reduce body energy expenditure. (6) In more severe illnesses, however, abnormalities in pulsatile TSH secretion likely represent altered hypothalamic-pituitary function. In support of the latter concept are the findings that hypothalamic TRH gene expression is positively related to serum TSH and [T.sub.3] levels in this condition. (35)

In recent years, increasing emphasis has been placed on the role of inflammatory cytokines in the endocrine changes that occur during systemic illness. The cytokines tumor necrosis factor-alpha (TNF-[alpha]), interleukin-1 (IL-1), and interleukin-6 (IL-6) have been suggested as putative mediators of the acute [T.sub.3] syndrome. (36-38) The administration of TNF-[alpha] and IL-1 to humans or experimental animals has resulted in thyroid hormone abnormalities that resemble the euthyroid sick syndrome.

LOW [T.sub.3] AND [T.sub.4] STATE

Increased severity and duration of systemic illness are associated with low levels of [T.sub.3] and [T.sub.4]. (3,4) An estimated 30% to 50% of patients in intensive care units have low levels of [T.sub.3] and [T.sub.4], (3,39) and these levels are associated with increased morbidity and mortality rates. (40) Prospective studies have recognized longitudinal changes in serum thyroid hormone levels during the course of severe illness. In a study of patients with hematopoietic cancer or aplastic anemia who were treated with bone marrow transplantation, levels of total [T.sub.4] and -[T.sub.3], free-[T.sub.4], and free-[T.sub.3] declined sharply after transplantation and were associated with a reduction in serum TSH. Most patients who died during the hospital course had low total[T.sub.4] concentration at the time of death, whereas patients who recovered had a normal [T.sub.4] concentration at the time of discharge. (10) In a different study, the mortality rate in patients admitted to an intensive care unit dire ctly correlated with total [T.sub.4] concentration. Mortality rate in patients with total [T.sub.4] level <3 [mu]g/dL was 84%; the mortality rate in patients with [T.sub.4] levels between 3 and 5 [mu]g/dL was 50%; and for those patients with [T.sub.4] >5.0 [mu]g/dL, the mortality rate was l5%. (40) Among patients with low levels of [T.sub.4], those with very low [T.sub.3] levels had the worst survival rate. (41)

In patients with euthyroid sick syndrome, serum free-[T.sub.4] concentration is commonly below normal, (42) but free-[T.sub.4] levels have been reported to be normal or above normal. (43-45) This variability in free-T4 level reflects both the assay method used and the underlying illness. The results of free-[T.sub.4] assays can be influenced by the presence in the circulation of an inhibitor of serum binding of thyroid hormones, (15, 29) or by the plasma concentration of nonesterified fatty acids. (46, 47)

Serum TSH levels in patients with euthyroid sick syndrome may be normal, mildly reduced, or frankly suppressed. (7, 8, 48) The TSH levels have been reported to be normal in approximately 50%, subnormal in about 30%, and increased in approximately 12% of patients with nonthyroidal illness. (49) The TSH levels are markedly suppressed (<0.1 [micro]U/mL) in about 7% of patients, predominantly in those patients treated with dopamine or corticosteroids. (49) The presence of a low level of TSH, despite reduced levels of total [T.sub.4] and [T.sub.3], suggests altered pituitary thyrotroph or hypothalamic responsiveness to circulating thyroid-hormone levels. (8) In such patients, TSH response to TRH stimulation is usually blunted,50 although it has been reported to be normal. (51) Mild elevations of TSH levels are seen in patients who recover from their illness (39, 41, 48) however, serum level > 25 to 30 [micro]U/mL strongly suggests the diagnosis of primary hypothyroidism.

Several factors are implicated in the pathogenesis of low [T.sub.3] and low [T.sub.4] state in euthyroid sick syndrome, including low concentration of binding proteins, (14, 29, 51) circulating inhibitors of [T.sub.4] binding to serum proteins, (8, 29, 51) and altered thyroid-hormone metabolism. (36, 52, 53) As previously discussed, patients with low [T.sub.3] state have decreased nocturnal TSH secretion (34) and altered pulsatile TSH secretion. (36) The cytokines TNF-[alpha], IL-i, and IL-6 have been implicated as putative mediators of the low thyroid hormone levels." (4, 38, 54) Administration of TNF-[alpha], IL-1 and IL-6 to humans or experimental animals has caused changes in thyroid function that resemble euthyroid sick syndrome. (37, 38, 54) Interleukin-6 has been shown to reduce TSH secretion in rats, (55) inhibit TSH-stimulated expression of peroxidase messenger ribonucleic acid (mRNA) and thyroid hormone release in vitro, (56) and inhibit hepatic gene expression of TBG and albumin. (4) Exogenous IL-6 was recently shown to be associated with decreased serum TSH and [T.sub.3] levels in humans within 4 hours of administration. (57) Interleukin-1 infusion into rats lowers [T.sub.4] and TSH levels, and blunts the TSH response to TRH administration. (58) Levels of pituitary TSH-[beta] mRNA and hypothalamic pro-TRH mRNA are also lowered by IL-1 infusion into rats. (59) Similarly, injection of TNF-[alpha] into healthy volunteers and experimental animals results in reduced [T.sub.3] levels. (38) Intravenous administration of TNF-[alpha] into normal volunteers resulted in a 36% fall in [T.sub.3] level, a 48% rise in reverse [T.sub.3] level, and a 68% fall in TSH level over a 12-hour period. (38) In addition, high TNF-[alpha] levels that accompany severe illness are associated with decreased activity of 5'-deiodinase enzyme in the liver. (8)

Recently, Nagaya et a1 (60) reported that the activation of the transcription factor nuclear factor kappa B (NF-[kappa]B) by TNF-[alpha] interferes with thyroid hormone action. The TNF-[alpha] exerts its biological activities through the activation of the transcription factor NF-[kappa]B. Activation of NF-[kappa]B plays a pivotal role in immune and inflammatory responses by controlling gene expression of several cytokines. The activation of NF-[kappa]B by TNF-[alpha] has been shown to suppress [T.SUB.3]-dependent induction of 5'-deiodinase mRNA and enzyme activity in liver cells. (60) These results suggest that NF-[kappa]B activation by TNF-[alpha] may represent an important molecular factor in the pathogenesis of euthyroid sick syndrome, where the underlying disorder is associated with the increased level of TNF-[alpha].

Several pharmacologic agents used in intensive care units may alter the serum concentration of thyroid hormones. The serum free-[T.sub.4] concentration rapidly decreases in patients treated with dopamine or corticosteroids. Dopamine infusion induces or aggravates the low [T.sub.3] state through direct inhibition of TSH release and through reduction in peripheral conversion of [T.sub.4] to [T.sub.3] (21, 61) The duration of dopamine treatment positively correlates with the severity of low [T.sub.3] state. (61) Hypercortisolism, as the result of endogenous overproduction or of exogenous administration of glucocorticoids, may also suppress pituitary TSH release, (62) and may inhibit conversion of [T.sub.4] to [T.sub.3]. (63) On the other hand, high levels of total [T.sub.4] and free-[T.sub.4] may be seen in patients treated with amiodarone (64) or with iodinated radiocontrast agents (eg, iopanoic acid and ipodate given orally for cholecystography). (15,65) Serum concentrations of free-[T.sub.4] have been reporte d to be elevated in patients receiving heparin therapy. (66) This appears to be an in vitro artifact, explained by displacement of [T.sub.4] from binding proteins by increased free fatty acids due to heparin administration. (4) Even small amounts of heparin (0.08 units/kg intravenously, or 5,000 units subcutaneously) can lead to falsely elevated free-[T.sub.4] levels; however, such patients have normal total-[T.sub.4] levels and are clinically euthyroid. In addition, the use of certain pharmacologic agents that may increase or decrease serum concentration of [T.sub.4]-binding globulin or their binding to TBG (estrogen, oral contraceptives, high-dose salicylates, phenytoin) may result in altered levels of total thyroid hormones.

DIAGNOSIS OF THYROID DISEASE IN EUTHYROID SICK SYNDROME

During starvation and mild illness, a low [T.sub.3] concentration, or low [T.sub.3] and low [T.sub.4] levels in a patient with a low-normal TSH level, is the hallmark of euthyroid sick syndrome. As previously discussed, however, nonthyroidal illness may present with a spectrum of abnormalities in thyroid function that may complicate the diagnosis of euthyroid sick syndrome. Low [T.sub.3] levels with normal [T.sub.4] and TSH levels is the most common abnormality seen in euthyroid sick syndrome. Serum TSH levels are typically normal or reduced. (7,8,48) The TSH levels are normal/subnormal in approximately 80% of patients, and are markedly suppressed (<0.1 [mu]U/mL) in <10% of patients. Thus, in a patient with a systemic illness, low [T.sub.4] and [T.sub.3] levels and a normal or low-normal TSH level most likely indicate euthyroid sick syndrome. In the recovery phase of illness, mild elevation of TSH levels can be observed (39,41,48); however, serum level of TSH >30 [mu]U/mL is rarely seen in euthyroid sick syn drome and strongly suggests the diagnosis of primary hypothyroidism. Levels of TSH above 20 [mu]U/mL are found in <3% of patients with nonthyroidal illness. (49)

Differentiation between secondary hypothyroidism (pituitary or hypothalamic) and euthyroid sick syndrome may be difficult. Both conditions present with decreased levels of total [T.sub.4] [T.sub.3] and TSH. Many chronically ill patients are edematous, have associated infections, or have cardiopulmonary disorders that could easily mask evidence of thyroid disorders. Additional tests, including obtaining basal and/or stimulated cortisol, serum gonadotropin, and prolactin levels may be of help in such cases. If the serum cortisol level is normal or elevated, as would be expected in stressful situations, euthyroid sick syndrome is probably the cause, rather than pituitary dysfunction. If serum cortisol and gonadotropin levels are low, pituitary dysfunction should be suspected, and treatment with corticosteroids and thyroid hormone supplementation is indicated. In some instances, it may be difficult to exclude hyperthyroid patients, who may present with suppressed TSH levels and normal [T.sub.4] and [T.sub.3] lev els in the presence of infection or other catabolic illness. Hyperthyroid patients who are chronically ill or malnourished may have hypoproteinemia and low levels of TBG that lower their [T.sub.4] and [T.sub.3] levels. In such patients, an elevated free-[T.sub.4] level and a low or undetectable TSH level will confirm the diagnosis of hyperthyroidism. A previous history of thyroid illness, a history of external radiation, or the presence of goiter and/or a midline neck scar may indicate a primary thyroid condition.

As mentioned before, certain pharmacologic agents may alter the serum concentration of thyroid hormones and should be taken into account in the evaluation of patients with nonthyroidal illness. The concentrations of total [T.sub.3] free-[T.sub.4], and TSH are reduced in patients treated with dopamine or corticosteroids, (21,45) due to suppression of pituitary TSH release (62) and/or inhibition of conversion of [T.sub.4] to [T.sub.3]. (63) Levels of total and free-[T.sub.4] may be increased in patients treated with amiodarone (64) or iodinated radiocontrast agents. (15,65) Intravenous or subcutaneous heparin therapy may result in increased free-[T.sub.4] levels, (66) due to in vitro interference with the laboratory assay; however, most such patients remain clinically euthyroid and have normal total [T.sub.4] and TSH levels.

As a general rule, it is not prudent to rely solely on a single thyroid test in the evaluation of thyroid function of patients with critical illness. In such patients, a careful assessment of multiple tests may be needed to distinguish patients with euthyroid sick syndrome. (1) In many instances, it is reasonable to delay the final diagnosis for several days to weeks, or after recovery from the acute illness, to determine the correct thyroid status.

TREATMENT

With recovery from underlying illness, the spectrum of thyroid abnormalities observed in patients with euthyroid sick syndrome rapidly disappears. In critically ill patients, however, the presence of reduced [T.sub.3] and [T.sub.4] concentrations is associated with increased severity of illness and mortality rate. (10,40) The mortality rate in patients admitted to an intensive care unit is directly correlated with serum [T.sub.4] concentration. (40) Because of the increased incidence of mortality observed in patients with severe illness and low [T.sub.4] values, several interventional trials have examined the effect of thyroid hormone supplementation in patients with nonthyroidal illness. The administration of [T.sub.4] (levothyroxine) to critically ill adults has failed to demonstrate a reduction in the mortality rate. (41) Administration of [T.sub.4] to neonates with respiratory distress syndrome resulted in no differences in mortality rate or number of days on a ventilator; similarly, [T.sub.4] supplementa tion to pre term neonates showed no differences in neurodevelopment or weight. (67) The lack of beneficial effect with [T.sub.4] treatment may be due to the inability of these patients to convert administered [T.sub.4] to metabolically active [T.sub.3].

Several controlled studies in which [T.sub.3] was administered to adult and pediatric patients have provided equivocal results. There are few randomized controlled studies reporting the benefits of [T.sub.3] replacement. (68,69) In patients undergoing coronary bypass procedures, [T.sub.3] administration improved cardiac output and decreased systemic vascular resistance. (68,69) In a different study, the administration of [T.sub.3] at release of cross-clamp after myocardial revascularization resulted in improvement in cardiac indexes and decreased inotropic requirements, postoperative ischemia, mortality rate, and length of hospital stay. (70) Other investigators have examined the effect of [T.sub.3] administration on pulmonary function in sepsis. These studies showed improvement in respiratory drive, pulmonary histologic integrity, and surfactant availability. (71)

In contrast, other studies have shown little or no benefit from short-term administration of [T.sub.3]. In a large, prospective, randomized, double-blind, placebo-controlled trial, [T.sub.3] was administered to 211 adults who underwent myocardial revascularization or valve replacement; no benefit could be demonstrated in inotropic requirements or need for mechanical support. Adverse events were the same, despite [T.sub.3] administration. Similar studies of [T.sub.3] administration to the same spectrum of patients also failed to demonstrate differences in clinical outcome. (72,73) In the presence of these conflicting results, we do not recommend routine administration of thyroid hormones to patients with euthyroid sick syndrome. Even though no harm has been reported with the administration of [T.sub.3] to critically ill patients, evidence does not support the use of thyroid hormone supplements to correct thyroid hormone abnormalities. In critically ill patients with documented or suspected hypothyroidism, thyr oid hormone administration is indicated. If therapy is to be given, it cannot be with [T.sub.4], alone, because this may fail to promptly increase [T.sub.3] levels (due to impaired [T.sub.4]-to-[T.sub.3] conversion). In patients with a variety of underlying illnesses admitted to a medical intensive care unit, intravenous [T.sub.4]sufficient to raise the total [T.sub.4] and free [T.sub.4] to normal levels failed to increase [T.sub.3] concentrations, while reverse-[T.sub.3] levels did rise with treatment. (41) Therefore, to restore [T.sub.4] and [T.sub.3] concentrations to normal during critical illness, patients should be treated with a combination of [T.sub.4] and [T.sub.3]. The recommended replacement dose of [T.sub.3] is 50 [mu]g/day, given in divided doses. During treatment, frequent monitoring (every 48 hours) of levels of total and free [T.sub.4] and [T.sub.3] has been recommended, (15) and dosages should be adjusted to achieve a low-normal serum [T.sub.3] level.

TABLE.

Pathogenesis of Low Levels of [T.sub.3] and [T.sub.4] in Euthyroid Sick
Syndrome


Low [T.sub.3] State
 * Decreased 5'-deiodinase activity
 * Decreased concentration of binding proteins
 * Circulating inhibitors of binding of [T.sub.3] to serum proteins
 * Decreased tissue uptake of [T.sub.3] by peripheral tissues
 * Decreased TSH secretion
 * Hypercortisolism
 * Cytokines (IL-1, IL-6, TNF-[alpha])
 * Drugs (dopamine, glucocorticoids, propranolol)
Low [T.sub.4] State
 * Decreased concentration of [T.sub.4]-binding proteins
 * Circulating inhibitors of binding of [T.sub.4] to serum proteins
 * Decreased tissue uptake of [T.sub.4] by peripheral tissues
 * Decreased TSH secretion
 * Hypercortisolism
 * Cytokines (IL-1, IL-6, TNF-[alpha])
 * Drugs (glucocorticoids, dopamine, amiodarone, salicylates)

[T.sub.3] = Triiodothyronine, [T.sub.4] = thyroxine, IL = interleukin,
TSH = thyroid-stimulating hormone, TNF-[alpha] = tumor necrosis
factor-alpha.

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From the Department of Medicine, Division of Endocrinology and Metabolism, University of Tennessee Health Science center, Memphis.

Reprint requests to Guillermo Umpierrez, MD, Department of Medicine, University of Tennessee Health Science Center, 951 Court Aye, Room 340M, Memphis, TN 38163.