William M. Wiersinga
Changes in the function of the hypothalamic–pituitary–thyroid axis and in thyroid hormone transport and metabolism are common in patients with nonthyroidal illness. Illness in this context comprises virtually all nonthyroidal disorders, surgical and nonsurgical trauma, and inadequate caloric intake. Many patients with nonthyroidal illness also receive drugs that affect thyroid hormone regulation and metabolism, but for the sake of clarity pharmacologic interference is not considered an intrinsic part of the spectrum of changes in hypothalamic–pituitary–thyroid function that occurs in these patients.
The effects of illness are not confined to the thyroid axis; in fact, illness induces temporary changes in many neuroendocrine systems (1). The changes in thyroid function are therefore only one component of the neuroendocrine response to illness and can be viewed as part of the general adaptation to stress. It is thus reasonable to assume that these changes contribute to the maintenance of homeostasis in patients with any illness.
The changes in hypothalamic–pituitary–thyroid function are sometimes referred to as the sick euthyroid syndrome. This name is not appropriate, for several reasons. First, there is no single syndrome, but rather a constellation of changes of widely varying magnitude. Second, it is not clear that the patients are in fact euthyroid in those tissues that are targets for the action of thyroid hormone (2,3). The changes to be described here in humans and animals have been reviewed extensively (3,4,5,6,7); those that occur in animals are discussed here only to clarify aspects of the changes for which data from humans are lacking. Although these changes are heterogeneous, as is most evident from the particular changes in patients with specific disease entities, the majority of illnesses induce a rather uniform pattern of changes.
DESCRIPTION OF NONTHYROIDAL ILLNESS
Changes in Serum Thyroid Hormone and Thyrotropin Concentrations
Serum Triiodothyronine and Reverse Triiodothyronine Concentrations
A fall in serum triiodothyronine (T3) concentrations and a rise in serum reverse triiodothyronine (rT3) concentrations are the most common changes in patients with nonthyroidal illness, which is often referred to as the low T3 syndrome. Fasting induces these changes in serum T3 and rT3 concentrations within 24 to 36 hours, and the values return rapidly to baseline upon refeeding. The composition of the food is relevant: refeeding with glucose is more effective in restoring normal values than refeeding with equicaloric amounts of protein or fat (4). Similarly, serum T3 concentrations fall and serum rT3 concentrations rise within a few hours after initiation of general anesthesia and surgery, and return to normal in several days if the postoperative course is uncomplicated.
The low serum T3/high rT3 pattern is found in patients with most acute and chronic illnesses, including infectious diseases, infiltrative and metabolic disorders, cardiovascular diseases, pulmonary diseases, gastrointestinal diseases, cancer, burns, and trauma. Serum rT3 concentrations increase to supranormal values in patients with mild illnesses and do not increase much more in patients with more severe illnesses. In contrast, serum T3 concentrations decrease further as the severity of illness increases (Fig. 11D.1). Serum T3 concentrations are low or even undetectable in patients with critical illnesses, and they are persistently low in patients with chronic illnesses. The severity of the illness is in general reflected by the magnitude of the changes in serum T3 and rT3 concentrations. For example, there is an inverse relationship between serum T3 concentrations and glycosylated hemoglobin values in patients with diabetes mellitus and between serum T3 concentrations and serum creatinine concentrations in patients with renal insufficiency. Similarly, in patients who have a myocardial infarction, the size of the infarction is inversely related to the fall in serum T3 concentrations and directly related to the rise in serum rT3 concentrations.
FIGURE 11D.1. Serum thyroid hormone concentrations (filled circle, triiodothyronine (T3); open circle, reverse T3 (rT3); open triangle, thyroxine (T4); upside down open triangle, free T4 index; closed triangle, free T4, measured by equilibrium dialysis) in 504 newly hospitalized patients, divided as follows: group I, all values within the normal reference range; group II, serum rT3 values high but serum T3 and T4 values normal; group III, serum T3 values low but serum T4 values normal; group IV, serum T3 and T4 values low. The hospitalization days are given as median days for the survivors. (From Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499, with permission.)
In general, serum free T3 concentrations fall to a lesser extent than do serum total T3 concentrations, but the results of measurements of serum free T3 in patients with nonthyroidal illness depend greatly on the assay used. Indirect methods in which the fraction of serum T3 that is unbound is measured give low values (8,9) more often than when serum free T3 is measured directly (direct measurement of free T3 after physical separation from bound T3) (10,11).
Serum Thyroxine and Free Thyroxine Concentrations
Serum thyroxine (T4) concentrations do not change during fasting in healthy subjects, but they decrease in patients with protein-calorie malnutrition. Patients with mild to moderate nonthyroidal illnesses usually have normal serum T4 concentrations. Some severely ill patients have low serum T4 concentrations (Fig. 11D.1), and among them, serum T4 concentrations are inversely correlated with the mortality rate.
There is uncertainty about serum free T4 concentrations in patients with nonthyroidal illness; the results vary depending on the method of measurement (see Chapter 13). When measured directly, using methods that involve initial physical separation of free T4 from protein-bound T4 by equilibrium dialysis or ultrafiltration with minimal dilution of serum so as not to alter the equilibrium between free and bound T4, and quantification by radioimmunoassay, serum free T4 concentrations are usually normal or even high in patients with nonthyroidal illness, even in those who are critically ill and have low serum total T4concentrations (11). In contrast, the serum free T4 values are normal or low when measured indirectly, by two-step immunoassays in which free T4 is immunoextracted from serum, analogue immunoassays that use labeled analogues of T4 that bind to T4 antibodies but not to serum thyroid hormone–binding proteins, or index methods in which free T4 values are calculated as the product of the serum total T4 concentration and a test of the number of unoccupied serum protein-binding sites (thyroid hormone–binding ratio or T3-resin uptake) (Fig. 11D.1) (12,13,14). None of these methods for measuring serum free T4 is completely free of methodologic artifacts.
The issue is further complicated by the decrease in serum protein concentrations (especially the concentrations of transthyretin and albumin) that occur in some patients with severe nonthyroidal illnesses. The analogue methods may give falsely low values for serum free T4 due to differences in serum proteins between patients with nonthyroidal illness and the standard serum used in the assays. The two-step serum free T4 assays are better validated, but vulnerable to an in vitro effect of heparin (which falsely raises measured serum free T4 values) or the influence of sample dilution (which attenuates the effect of inhibitors of binding). Furthermore, the serum of some patients with nonthyroidal illness contains substances that inhibit the binding of T4 to serum binding proteins, which may explain in part results suggesting that T4 binding is decreased in some of the patients (15,16). Based on the most reliable assays, it appears that most patients with nonthyroidal illness, even critically ill patients, have serum free T4 concentrations that are within the normal reference range.
Serum Thyrotropin Concentrations
Serum thyrotropin (TSH) concentrations are normal in most patients with nonthyroidal illness, but may increase to slightly above the normal range (10 to 20 mU/L) for a few days soon after recovery begins (17,18). However, some critically ill patients who have low serum T4 concentrations also have low serum TSH concentrations (19), although the serum TSH concentrations are rarely as low as in patients with thyrotoxicosis. The serum TSH response to thyrotropin-releasing hormone (TRH) is usually proportional to the baseline serum TSH concentration. Thus, critically ill patients with low basal serum TSH concentrations have low serum TSH responses to TRH, and both findings are indicative of a poor prognosis (20). Additionally, critically ill patients are often treated with infusions of dopamine or high doses of glucocorticoids, both of which lower serum TSH concentrations, even in normal subjects (see section on regulation of thyrotropin secretion in Chapter 10).
Changes in Thyroid Hormone Kinetics
Kinetic studies of thyroid hormone production and metabolism have been conducted in normal subjects during fasting and in patients with chronic renal failure, cirrhosis, diabetes mellitus, mild illness, and critical illness. The results can be summarized as follows (21). In patients with low serum T3 concentrations, the production rate of T3 is decreased, but its metabolic clearance rate is unchanged. The decrease in T3 production is due to decreased extrathyroidal deiodination of T4 to T3, which normally provides ~80% of the daily T3 production (Fig. 11D.2). The fractional rate of transport of T3 into tissues is unaltered. For rT3, the production rate is unchanged, but the metabolic clearance rate is decreased, due to decreased extrathyroidal deiodination of rT3 to 3,3′-diiodothyronine. For T4 the metabolic clearance rate is usually normal, but it may be increased in patients with severe illnesses who have low serum T4concentrations, due at least in part to decreased production of one or more serum thyroid hormone–binding proteins. These severely ill patients also tend to have low serum TSH concentrations; therefore, they have low T4production rates. The fractional rate of transport of T4 from serum to tissues is reduced to ~50% of the normal value.
FIGURE 11D.2. Effect of nonthyroidal illness on serum concentrations, metabolic clearance rate (MCR), and production rate (PR) of triiodothyronine (T3) and reverse T3 (rT3; expressed as a percentage of the values in normal subjects). (From Doctor R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499, with permission.)
Changes in Hypothalamic–Pituitary–Thyroid Function
The failure of serum TSH concentrations to increase despite marked reductions in serum T3 and sometimes T4 concentrations, as occur in patients with thyroid disease, suggests that the sensitivity of TSH secretion to low serum thyroid hormone concentrations is decreased in patients with nonthyroidal illness. This could be due to changes in the thyrotrophs or to decreased TRH secretion. Evidence for the latter is a decrease in the amplitude (but not frequency) of the nocturnal pulses of TSH secretion; such decreases in pulse amplitude have been documented during fasting (22), after surgery (23), and in a wide variety of nonthyroidal diseases, including chronic renal insufficiency, diabetes mellitus, acute respiratory failure, infections, cancer, and critical illness (24,25,26,27,28). For example, fasting for 60 hours results in disappearance in the nocturnal surge in TSH secretion and a 50% reduction in 24-hour mean serum TSH concentrations (Fig. 11D.3), as well as decreases in serum T3 and increases in serum rT3 concentrations (22). Among patients with nonthyroidal illnesses, the nocturnal surge in TSH secretion is decreased in at least half, and the decrease is not closely related to changes in serum T3 or free T4concentrations (26). The pattern of 24-hour TSH secretion in these patients, therefore, is similar to that in many patients with central hypothyroidism (Fig. 11D.3) (29). If the abnormal pattern of TSH secretion persists for a week or longer in patients with nonthyroidal illness, then their T4 production rate should decrease, as it does in patients with central hypothyroidism.
FIGURE 11D.3. Serum TSH concentrations measured at frequent intervals for 24 hours in (top) 8 normal subjects before and after fasting for 60 hours, and (bottom) in 21 patients with nonthyroidal illness and 6 patients with central hypothyroidism caused by a pituitary adenoma. (From Romijn JA, Adriaanse R, Brabant G, et al. Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J Clin Endocrinol Metab 1990; 71:1631; and Adriaanse R, Romijn JA, Brabant G, et al. Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1313, with permission.)
In a study of premortem serum thyroid hormone concentrations and postmortem hypothalamic TRH gene expression in patients with nonthyroidal illness, the TRH messenger RNA (mRNA) content in the paraventricular nucleus was positively correlated with serum T3 and TSH concentrations, but not with serum T4 or free T4 concentrations (Fig. 11D.4) (30). In another study, the T3 content of the hypothalamus and anterior pituitary were, respectively, 64% and 46% lower in patients who died as a result of nonthyroidal illness, as compared with patients who died suddenly (31). Furthermore, the TSH that is secreted in patients with nonthyroidal illness is less glycosylated, and therefore less biologically active, than normal, a change that also occurs in patients with overt hypothalamic disease and TRH deficiency (32,33).
FIGURE 11D.4. Top: Macroscopic film autoradiograms of hypothalamic sections of two patients, showing the hybridization signal of thyrotropin-releasing hormone (TRH) messenger RNA (mRNA) in the paraventricular nucleus along the wall of the third ventricle. The left panel shows a low-intensity signal of a patient with low serum triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) concentrations measured < 24 hours before death. A high-intensity signal is seen in the right panel of a patient with normal serum concentrations who died from cardiac arrest. Bottom: Relationship between premortem serum TSH or T3 concentrations and total TRH mRNA in the paraventricular nucleus of 10 patients with nonthyroidal illness. To convert serum T3 values to ng/dL, multiply by 65.1. (From Fliers E, Guldenaar SEF, Wiersinga WM, et al. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 1997;82:4032, with permission.)
Little is known about the function of the thyroid gland itself in patients with nonthyroidal illness. The increase of serum TSH induced by exogenous TRH or that occurs during recovery from illness is followed by an increase in serum T3 and T4 concentrations, indicating that the thyroid gland can respond normally to TSH. Thyroid weight is lower and thyroid follicular size is reduced in deceased chronically ill patients, as compared with subjects with sudden death (34), possibly related to decreased TSH secretion in severe nonthyroidal illness.
Changes in Peripheral Thyroid Hormone Metabolism
In biopsies taken from intensive-care-unit patients immediately after death, liver iodothyronine deiodinase type 1 (D1) activity was decreased, whereas iodothyronine 5′-deiodinase type 3 (D3) activity was increased in liver and skeletal muscle (see Chapter 7) (35). Their premortem serum T3/rT3 ratio correlated positively with the D1 activity and negatively with the D3 activity in the liver; the levels of D1 and D3 mRNA levels corresponded with the activity of the respective enzyme. The fall in D1 activity, in accord with findings in tissues from starved and sick animals (36), will decrease the extrathyroidal conversion of T4 to T3 and of rT3 to 3,3′-diiodothyronine, thereby contributing to low serum T3 concentrations and high serum rT3 concentrations. The remarkable induction of the activity of D3, which degrades T3 to 3,3′-diiodothyronine, thereby further decreases the availability of T3. D3 is not detectable in normal liver or muscle, but is found in cardiac muscle in animals with heart failure (37).
The changes in iodothyronine deiodination also affect the serum concentrations of diiodothyronines (38,39). Nondeiodinative pathways of iodothyronine degradation are frequently increased in patients with nonthyroidal illness; serum concentrations of T3 sulfate are increased (40,41), although those of T4sulfate are normal (42). There may be increases in the products of ether-link cleavage, such as diiodotyrosine, and in the products of oxidative deamination of the alanine side chain of T4 and T3, which are, respectively, tetraiodothyroacetic acid and triiodothyroacetic acid, in patients with nonthyroidal illness (43).
There are few data on T3-nuclear receptors in patients with nonthyroidal illness (see Chapter 8). Liver T3-nuclear receptor-α1 and -β1 mRNA and protein levels in patients with hepatic diseases were unchanged, as compared with normal liver (44). In contrast, the number of receptors, but not their affinity, was decreased in the livers of animals that were fasted or had diabetes or cancer (7), and lipopolysaccharide injection in mice caused a major fall in T3-nuclear receptor-α1, -α2 and -β1 mRNA and protein expression in liver, and binding of the T3-nuclear receptor/retinoid X receptor heterodimers to DNA was reduced (45). The factors that cause these changes are unknown.
The thyroid hormone content of tissues is decreased in patients with nonthyroidal illness. The mean T3 concentrations in the cerebral cortex, liver, kidney, and lung were lower by 46% to 76% in patients who died of nonthyroidal illness, as compared with those who died suddenly, but the values in heart and skeletal muscle were similar (31). The mean T4 concentration in the liver was 66% lower in the patients with nonthyroidal illness, but the values in the cerebral cortex were similar in the two groups.
Thyroid Hormone Action in Tissue
Most if not all of the changes described earlier would seem to indicate that nonthyroidal illness leads to reduction in thyroid hormone production, especially in the production of T3, and therefore that the availability of T3 in tissues should be reduced. This raises the important but still incompletely answered question of what the level of thyroid hormone action is in the tissues of patients with nonthyroidal illness. During fasting, oxygen consumption and protein breakdown decrease so that energy is saved and organ function may be preserved. The lower T3 production rate during fasting might contribute to this useful metabolic adaptation; similar changes occur in hypothyroidism. Prolongation of the Achilles tendon reflex relaxation time in patients with anorexia nervosa and of the pulse-wave arrival time during hypocaloric feeding are compatible with a hypothyroid-like state in undernutrition (Table 1) (46,47).
TABLE 11D.1. SIMILARITIES AND DISSIMILARITIES BETWEEN CHANGES IN INTERMEDIARY METABOLISM AND PERIPHERAL TISSUE FUNCTION TESTS DURING FASTING, HYPOTHYROIDISM AND ILLNESS
Resting energy expenditure
Pulse-wave arrival time (QKd) (ref. 46)
Achilles tendon reflex half-relaxation time (ref. 47)
Serum angiotensin-converting enzyme (ref. 48)
Serum sex hormone-binding globulin (ref. 49)
Serum Osteocalcin (ref. 49)
Erythrocyte Na+, K+-ATPase (ref. 50)
↑, increase; ↓decrease; =, no change; Na+, K+-ATPase, sodium, potassium-adenosine triphosphatase; QKd, time interval between Q-wave electrocardiogram and arrival of pulse wave in brachial artery.
In contrast, the illness-induced changes in glucose, protein, and fat metabolism are opposite to those that occur in hypothyroidism (48,49,50). In theory, then, the occurrence of the low T3 syndrome could be a beneficial adaptation to illness, serving to minimize its catabolic effects.
PATHOGENESIS OF CHANGES IN THYROID FUNCTION IN NONTHYROIDAL ILLNESS
Inhibition of Iodothyronine 5′-Deiodinase
The decreased rate of extrathyroidal production of T3 and decreased metabolic clearance rate of rT3 during fasting and illness can be explained by a decrease in activity of D1, which catalyses both the 5′-monodeiodination of T4 to T3 and of rT3 to 3,3′-diiodothyronine. The decrease in D1 activity may be due to inhibition by drugs such as high doses of glucocorticoids and propranolol or amiodarone. The increase of cortisol secretion during illness does not appear to contribute to the decrease in D1 activity, because there is no consistent relationship between serum cortisol and T3 concentrations in patients with nonthyroidal illness, and the decrease in serum T3 concentrations after abdominal hysterectomy persists despite abolition of the postoperative increase in serum cortisol by afferent nerve blockade (51).
The decrease in liver D1 activity of patients with critical illness (35) might be causally related to cytokines, in view of the capacity of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon-γ to decrease D1 mRNA in vitro (52). Indeed, IL-1 and IL-6 inhibit the T3-induced induction of D1 mRNA and enzyme acitivity in cultured rat hepatocytes; this transcriptional effect can be partially overcome by exogenous steroid receptor coactivator-1 (SRC-1) (53). The proposed mechanism is competition for limiting amounts of nuclear receptor coactivators between the D1 promotor and the promoters of cytokine-induced genes. TNF-α impairs T3-dependent induction of D1 gene expression by activation of nuclear factor-kappa B, (NF-kB), possibly via sequestration of common cofactors shared between NF-kB and thyroid hormone receptors (54).
Inhibition of Plasma Membrane Transport of Iodothyronines
T4 and T3 enter cells by active, energy-dependent transport across the plasma membrane of the cells. Several biologic compounds inhibit cell uptake of T4 and T3, as determined by incubation of cultured rat hepatocytes with radioiodine-labeled T4 or T3 and subsequent measurements of iodide and T4 or T3 conjugates in the medium. This system allows discrimination between inhibition of transport (lowered iodide production without accumulation of conjugates) and inhibition of deiodination (lowered iodide production with accumulation of sulfates and glucuronides). In these cultures, the furan fatty acid 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF), indoxyl sulfate, and hippuric acid all inhibit iodide production, and conjugates do not accumulate. The serum of patients with chronic renal insufficiency has similar effects; the serum concentrations of CMPF and indoxyl sulfate (but not of hippuric acid) in these patients are above the minimum concentration required for in vitro inhibition of iodide production by these compounds (55). It follows that CMPF and indoxyl sulfate may be responsible for the low T3 syndrome in patients with chronic renal insufficiency by inhibiting cellular uptake and subsequent deiodination of T4. These compounds do not affect the uptake of T4 or T3 by cultured rat anterior pituitary cells, nor do they interfere with TSH release (56). Thus, the uptake of thyroid hormones into the pituitary is regulated differently than uptake into the liver.
Bilirubin and nonesterified fatty acids like oleic acid also inhibit T4 transport into hepatocytes. Inhibition of T4 transport by the serum of critically ill patients with high serum bilirubin concentrations correlated with the molar ratio of bilirubin to albumin and that of nonesterified fatty acids to albumin (57). There may be other inhibitors of T4 transport into cells as well. In a study of serum samples from patients with mild, moderate, or severe nonthyroidal illness, the degree of inhibition of T4 transport into rat hepatocytes was inversely correlated with the patients' serum T3 concentrations (58).
The liver is a major site for production of T3 and clearance of rT3, and inhibition of transport of T4 and rT3 (which share the same transport mechanism) into the liver might thus contribute to the characteristic decreases in production of T3 and clearance of rT3 that occur in patients with nonthyroidal illness. This fits with data indicating that cellular uptake of thyroid hormones is rate limiting for subsequent intracellular metabolism and nuclear binding, and with the observed reduction of the fractional transfer rate of T4 from plasma to tissues in patients with nonthyroidal illness (59). Further support for this hypothesis comes from studies in human subjects in whom the low T3 syndrome caused by caloric deprivation was associated with decreased T3 and especially T4 uptake into the liver (60,61). The decrease in uptake, which is an energy-dependent process, could well be due to a low adenosine triphosphate (ATP) content in the liver, as has been demonstrated in starvation and nonthyroidal illness by magnetic resonance spectroscopy (62). Fructose, which lowers hepatic ATP content, indeed decreases hepatic T4 uptake (63).
Inhibition of Thyroxine Binding to Serum Proteins
Serum concentrations of thyroxine-binding globulin (TBG), the main carrier protein for T4, are usually normal in patients with nonthyroidal illness, but some patients have slightly low concentrations. The serum concentrations of the two other carrier proteins, transthyretin and albumin, can be low as well. These decreases result in lower serum total T4 (and T3) concentrations but should not affect serum free T4 concentrations under equilibrium conditions. The rapid decrease of TBG (a member of the serpin superfamily) during sepsis and cardiopulmonary bypass might be due to cleavage by inflammatory serine proteases; the smaller TBG cleavage product has a reduced affinity for T4(64,65).
Another cause of decreased serum binding of T4 is the presence of inhibitors of binding. Both protein and nonprotein inhibitors of T4 binding to TBG or the other thyroid hormone–binding proteins have been found in the serum of patients with nonthyroidal illness in different studies (15,16,66,67,68). The non-protein-binding inhibitors include furosemide, fenclofenac, and salicylate. High doses of these drugs are competitive inhibitors of T4 binding to TBG. They therefore acutely raise serum free T4 concentrations, which inhibits TSH secretion, so that serum free T4 concentrations return to normal; serum T4concentrations decrease because the protein-binding sites are occupied by the drug (see Chapter 13).
Nonesterified fatty acids also have been proposed as a nonprotein inhibitor of T4 binding. Addition of nonesterified fatty acids to normal human serum increases the free T4 fraction by inhibiting T4 binding to albumin, but only if the molar ratio of nonesterified fatty acids to albumin is higher than 5:1, a value rarely reached even in critically ill patients (69). Heparin is a weak inhibitor of T4 binding to TBG. Its action is indirect, via activating serum lipoprotein lipase that then breaks down triglycerides to nonesterified fatty acids (and glycerol) in vitro, and can be prevented by adding protamine to the serum in vitro (70). Thus, these substances are unlikely to affect T4 binding appreciably in vivo.
Inhibitory Effects of Cytokines
Cytokines are important mediators of the acute phase response to tissue injury. It is thus plausible to suppose that cytokines cause some of the changes in hypothalamic–pituitary–thyroid function that occur in patients with nonthyroidal illness. Indeed, some cytokines, such as IL-1, IL-6, TNF-α, and interferon-γ inhibit the synthesis or secretion of TSH, thyroglobulin, T3, and thyroid hormone–binding proteins and decrease D1 mRNA and the binding capacity of T3-nuclear receptors in vitro in cultured human and animal cells (52,71). IL-1 and TNF-α act mainly in a paracrine and autocrine fashion; their serum concentrations are mostly undetectable or low, even during illness, and no quantitative relationships have been found between serum T3 or T4 concentrations and the serum concentrations of either of these cytokines in patients with nonthyroidal illness (72,73,74). Similarly, serum T3 concentrations are not correlated with serum interferon-γ, IL-8, and IL-10 concentrations in these patients (75). In contrast, IL-6 is a systemic cytokine that has endocrine actions, and there is an inverse correlation between serum T3 and IL-6 concentrations in patients with nonthyroidal illness (Fig. 11D.5) (74,76,77,78).
FIGURE 11D.5. The relationship between serum triiodothyronine (T3) and serum interleukin (IL)-6 concentrations (top) and a cytokine score, derived from the summation of serum IL-6, soluble tumour necrosis factors (TNF) receptors (sTNFaRp55 and sTNFaRp75), soluble IL-2 receptor, and IL-1 receptor antagonist concentrations in individual serum samples (bottom) in consecutive hospitalized patients with nonthyroidal disease. To convert serum T3values to ng/dL, multiply by 65.1. (From Boelen A, Platvoet-ter Schiphorst M, Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3′-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1695; and Boelen A, Platvoet-ter Schiphorst MC, Wiersinga WM. Soluble cytokine receptors and the low 3,5,3′-triiodothyronine syndrome in patients with nonthyroidal disease. J Clin Endocrinol Metab 1995;80:971, with permission.)
Soluble forms of membrane-bound cytokine receptors or receptor antagonists have the ability to modulate cytokine activity and are generated in response to the same inflammatory stimuli that induce cytokine production, and the serum concentrations of these proteins reflect the degree of activation of the cytokine network. Serum T3 concentrations are negatively correlated with the serum concentrations of soluble
TNF receptors (sTNFaRp55 and sTNFaRp75), soluble IL-2 receptors, and IL-1 receptor antagonist in patients with nonthyroidal illness (79). A cytokine score composed of the serum concentrations of soluble cytokine receptors and IL-6 is strongly inversely correlated with serum T3 concentrations in these patients (Fig. 11D.5). The serum concentrations of C-reactive protein, an acute-phase protein induced by IL-6, also are inversely correlated with serum T3concentrations in such patients (74,78).
Administration of single doses of TNF-α, interferon-α, or IL-6 to normal subjects results within hours in a 12% to 25% decrease in serum T3 concentrations, a 36% to 72% increase in serum rT3 concentrations, and a 13% to 32% decrease in serum TSH concentrations, whereas serum total and free T4 concentrations change little (80,81,82). A single dose of interferon-γ had no effect (83). Despite the resemblance of these changes to those that occur in patients with nonthyroidal illness, the findings do not prove that cytokines cause the changes in patients with nonthyroidal illness. Furthermore, administration of cytokines causes an influenza-like illness, with headache, nausea, and fever, which may cause the hormonal changes via other mechanisms. Chronic administration of cytokines to humans or experimental animals also results in transient changes in thyroid hormone metabolism and regulation, possibly explained by the capacity of cytokines—which operate both as a cascade and as a network—to modulate the production of other cytokines and cytokine receptors.
Administration of bacterial endotoxin to normal subjects is followed by a fall in serum T3, free T4, and TSH concentrations, and a rise in serum rT3concentrations. Blocking the action of IL-1 by coadministration of IL-1 receptor antagonist or the action of TNF-α by administration of recombinant dimeric TNF receptors has no effect on the endotoxin-induced changes (84,85). The results of studies of immunoneutralization of cytokines in animals have also been inconclusive (86). The best evidence to date for a causal role of cytokines in the pathogenesis of the changes in nonthyroidal illness comes from experiments with IL-6 knock-out mice (87), in which the decrease in serum T3 concentrations during induced illness is less than that of normal mice; hepatic D1 activity does not change in the knock-out mice but decreases in normal mice.
Inhibition of Thyrotropin-Releasing Hormone and Thyrotropin Secretion
The changes in the relationship between serum TSH and serum thyroid hormone concentrations in patients with nonthyroidal illness indicate a decrease in the sensitivity of TSH secretion to decreases in serum T4 and T3 concentrations. A decrease in sensitivity is further suggested by the smaller than normal increase in serum TSH concentrations in response to the small decreases in serum T4 and T3 concentrations induced by administration of inorganic iodide that occurs in patients with nonthyroidal illness (88). The cause of the change in sensitivity of the thyrotroph cells is not known, but the decrease in TRH gene expression in the paraventricular nucleus of the hypothalamus in patients with nonthyroidal illness is correlated with the decrease in serum TSH concentrations (30). Changes in brain thyroid-hormone metabolism or in serum cortisol and leptin concentrations, as well as induction of cytokines, could be involved in the down-regulation of TRH (see section on regulation of thyrotropin secretion in Chapter 10).
In humans, T3-nuclear receptors are found in the hypothalamic paraventricular nucleus and infundibular nucleus (the human homologue of the rat arcuate nucleus). Iodothyronine-5′-deiodinase type 2 (D2) is—at least in rats—not expressed in the paraventricular nucleus, but is present in the arcuate nucleus in tanycytes, specialized ependymal cells lining the wall of the third ventricle near the median eminence of the hypothalamus. In fasted rats, D2 activity in the arcuate nucleus is upregulated: the increase of locally produced T3 is likely responsible for lower TRH synthesis in the paraventricular nucleus, but which neurons of the arcuate nucleus projecting to the paraventricular nucleus mediate this effect is unknown (89). In systemic illness induced by bacterial lipopolysaccharide in rats, D2 activity increased markedly in the anterior pituitary and in tanycytes; the locally generated T3 may suppress the synthesis of pituitary TSH as well as that of TRH (90).
Adrenalectomy in rats results in an increase in TRH mRNA in the paraventricular nucleus, and administration of glucocorticoid reverses the increase (91). However, the hypercortisolism of critically ill patients probably does not contribute to the fall in TRH production, because TRH production remains low when adrenalectonized animals treated with corticosterone are given lipopolysaccharide (92).
The adipocyte-derived hormone leptin has been recognized as an important mediator of neuroendocrine changes during illness. Leptin binds to leptin receptors in the infundibular nucleus where neuropeptide-Y (NPY)-containing cells are key targets. NPY, agouti-related protein (AGRP), and α-melanocyte stimulating hormone (α-MSH) neurons project directly from the infundibular nucleus to hypophysiotropic TRH neurons in the paraventricular nucleus (93). NPY and AGRP (both suppressed by leptin) inhibit and α-MSH (induced by leptin) stimulates TRH gene expression (83,94,95). In starved animals, the fall in serum leptin concentrations is associated with a decrease of TRH mRNA in the paraventricular nucleus, and administration of leptin reverses the decrease in TRH mRNA (96). This effect is mediated via the arcuate nucleus, because ablation of the arcuate nucleus prevents the decrease in hypothalamic TRH and serum T4concentrations during fasting and prevents the reversal of these changes by leptin (97). In humans, however, administration of leptin only partially prevents the starvation-induced decrease in serum TSH concentrations, and does not prevent the fall in serum T3 concentrations or the rise in rT3 concentrations (98).
In patients with systemic illness serum leptin concentrations are often increased, like they do acutely in response to administration of TNF-α or IL-1, but the increase is not related to serum T3 and T4 concentrations (99,100). In rats, endotoxin increases serum leptin concentrations and propiomelanocortin but not NPY gene expression in the arcuate nucleus, which together would increase rather than decrease hypothalamic TRH production. Furthermore, serum leptin is negatively correlated with NPY mRNA expression in the infundibular nucleus of critically ill patients, and the NPY expression is—in contrast to the situation in food-deprived rodents—positively correlated with TRH mRNA expression in the paraventricular nucleus (101). There is thus no evidence that leptin is involved in the changes in peripheral thyroid hormone metabolism; leptin may be partially responsible for the decrease in TSH secretion during fasting, but probably has no role in systemic illness.
The role of cytokines (especially IL-1β) in the activation of the hypothalamic–pituitary–adrenal axis is well known. Cytokines also affect TRH production, at least in rats. The hypothalamic content of TRH mRNA decreases after administration of IL-1, inappropriate for the decrease in serum T3 and T4 concentrations that occurs at the same time (102). Interleukin-1β decreases the release of TSH (but not of other anterior pituitary hormones) in cultured rat anterior pituitary cells, an effect not mediated by thyroid hormone uptake or T3 nuclear receptor occupancy (103). The effect of TNF-α on TSH release is disputed. Interleukin-6 decreases TSH secretion, possibly by a direct effect on the thyrotrophs.
There are few studies on the handling of thyroid hormones in the pituitary during nonthyroidal illness, but the available data do not indicate that thyroid hormone uptake is altered (56). Up-regulation of D2 activity in the mediobasal hypothalamus and anterior pituitary, as found during critical illness, may contribute to suppression of production of TRH and TSH, respectively, and it is tempting to speculate that cytokines are involved. Experimental data support the notion that cytokines induce D2 activity in tanycytes via NF-kB binding sites in the promoter region of the D2 gene (54).
The down-regulation at the hypothalamus–pituitary level provides an explanation for the decreased sensitivity of TSH secretion to low serum T3 and T4concentrations in patients with nonthyroidal illness. Specifically, decreased TRH secretion is the likely cause of the decreased nocturnal TSH surge and the release of TSH of reduced biologic activity, phenomena akin to the changes in some patients with central hypothyroidism.
The changes in hypothalamic–pituitary–thyroid function that occur in patients with nonthyroidal illness thus occur as a result of changes in both the central and peripheral compartments of the thyroid endocrine system (Fig. 11D.6). Although a persistent decrease in TRH and TSH secretion might lead to a decrease in T4 production, the peripheral changes develop independent of changes in the hypothalamus and pituitary. It follows that the factors mediating the various changes are operative simultaneously both centrally and peripherally.
FIGURE 11D.6. A schematic diagram of the hypothalamic–pituitary–thyroid axis showing the changes that occur in patients with nonthyroidal illness (NTI) and the causes of those changes (for explanation, see text). bil, bilirubin; D1, iodothyronine 5′-deiodinase type 1; D3, iodothyronine 5-deiodinase type 3; GSH, glutathione; IS, indoxyl sulfate; MCR, metabolic clearance rate; NEFA, nonesterified fatty acids; PR, production rate; Se, selenium; TR, thyroid receptor; T3S, triiodothyronine (T3) sulfate.
CLINICAL IMPORTANCE OF THE CHANGES IN THYROID FUNCTION IN NONTHYROIDAL ILLNESS
The magnitude of the changes that occur in patients with nonthyroidal illness in general reflects the severity of the illness, and several of the individual changes have been linked to outcome in different studies. In general, the prognosis is poorer in patients with lower serum T3, T4, or TSH concentrations or higher serum rT3 concentrations. In a study of critically ill patients admitted to an intensive care unit, the sensitivity and specificity in predicting mortality were 75% and 80%, respectively, for a serum T4 concentration of < 3.1 µg/dL (40 nmol/L), 56% and 100% for an 8 AM serum cortisol concentration of >30 µg/dL (830 nmol/L), and 100% and 82% for the combination (104).
Diagnosis of Thyroid Disease in Nonthyroidal Illness
The prevalence of nonthyroidal illness depends on what groups of patients are evaluated. Among patients admitted to hospital medical services, the prevalence of a low serum T3 concentration is ~50%, that of a low serum T4 concentration is ~15% to 20%, and that of an abnormal (low or high) serum TSH concentration ~10%. The changes are less frequent among outpatients and more frequent among patients admitted to intensive care units.
The high prevalence of changes among hospitalized patients hampers the diagnosis of thyrotoxicosis or hypothyroidism among them, and therefore argues against screening them for thyroid dysfunction. In patients clinically suspected to have thyroid disease, the single most useful test is measurement of serum TSH. A normal result virtually excludes thyrotoxicosis or hypothyroidism (as it does among outpatients) (105,106).
A high serum TSH concentration is compatible with primary hypothyroidism, but also with nonthyroidal illness, if the elevation is slight (Fig. 11D.7). The combination of high serum TSH and low T4 concentrations increases the likelihood of hypothyroidism, but also can be found in patients recovering from a nonthyroidal illness. The finding of a high ratio of T3 to T4 in serum, a low thyroid hormone–binding ratio, and a low serum rT3 concentration favor the presence of hypothyroidism, because the opposite changes occur in nonthyroidal illness, but the diagnostic accuracy of any of these measurements is limited (107). Furthermore, in patients with hypothyroidism the high serum TSH concentrations may decrease, even into the normal range, during an acute illness, especially in those patients given dopamine or high doses of glucocorticoids (108).
FIGURE 11D.7. The proportion of patients with thyroid disease (Thyr. or Thyroid), nonthyroidal illness (NTI), and receiving glucocorticoid therapy (GC) among a large group of hospitalized patients, subdivided according to five ranges of serum thyrotropin TSH concentrations. (From Stockigt JR. Guidelines for diagnosis and monitoring of thyroid disease: nonthyroidal illness. Clin Chem 1996;42:188, modified with permission; and Spencer CA. Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 1988;63:1214, with permission.)
A low serum TSH value in any patient raises the possibility of thyrotoxicosis, especially if the serum free T4 concentration is high. This combination of test results is unfortunately also found in patients with nonthyroidal illness. However, the greater the extent of TSH suppression, the greater the likelihood of thyrotoxicosis (Fig. 11D.7). The combination of thyrotoxicosis and nonthyroidal illness may cause T4-thyrotoxicosis because the illness causes a decrease in serum T3 concentrations in patients with thyrotoxicosis just as it does in any other patient (Fig. 11D.8).
FIGURE 11D.8. Serum thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3) concentrations in a patient with thyrotoxicosis hospitalized for treatment of pneumonia. The initial values represented the biochemical pattern of T4-thyrotoxicosis, but with recovery from the pneumonia they evolved to those of classical thyrotoxicosis with high serum T4 and T3 concentrations. Serum thyrotropin values were undetectable at all times. To convert serum T4 values to µg/dL, multiply by 0.078; and to convert serum T3 and rT3 values to ng/dL, multiply by 65.1.
In some of these situations, history, physical examination, and the presence of high serum thyroid antibody concentrations can provide further clues to the presence or absence of thyroid disease. In many patients, however, no definite diagnosis can be established, and the most prudent policy is to repeat the thyroid function tests after the nonthyroidal illness has improved.
Thyroid Hormone Treatment of Patients with Nonthyroidal Illness
In obese subjects starting a hypocaloric diet, maintenance of baseline serum T3 concentrations by administration of T3 prevents the occurrence of hypothyroid-like effects such as a decrease in pulse rate and oxygen consumption and prolongation of the pulse-wave arrival time (46,109). In fasting normal subjects, prevention of the decrease in serum T3 concentrations by exogenous T3 administration increases protein breakdown and inhibits TSH secretion (110). These results suggest that the occurrence of the low T3 syndrome during periods of inadequate caloric intake has protective value in conserving energy and limiting proteolysis. However, administration of T3 during more prolonged fasting does not increase proteolysis, but does increase hepatic glucose appearance (109,111,112). The role of insulin might be important in this respect, because decreasing insulin secretion during fasting is a critical determinant of the shift from carbohydrate- to fat-based metabolism.
In severely ill patients with serum T4 concentrations < 5.0 µg/dL (65 nmol/L), intravenous administration of replacement doses of T4 (1.5 µg/kg/day) for 2 weeks did not reduce mortality as compared with untreated patients; during treatment the patients given T4 had serum T3 concentrations similar to those in the other group, but their serum T4 concentrations were higher and their serum TSH concentrations were lower (113). Likewise, administration of T3 to patients with severe burns did not reduce mortality despite restoration of normal serum free T3 index values (114), and T4 given intravenously to patients with acute renal failure actually increased mortality (115). In patients with chronic renal insufficiency, T3 administration increased proteolysis (116). Finally, administration of T4 or T3 to animals with nonthyroidal illness has no clinically beneficial effect and may in fact increase mortality (117,118,119). Taken together, the results of these studies argue against thyroid-hormone treatment of patients with nonthyroidal illness, including those with low serum TSH and T4 concentrations, and instead suggest that the changes are beneficial adaptations to illness.
In general, the acute-phase response to illness is not uniformly beneficial: when extreme, it can be fatal, as for example in patients with septic shock. The possibility remains that the changes may represent maladaptation. In adult patients undergoing coronary artery bypass surgery, serum T3 concentrations decrease by ~40% within minutes or hours after the operation. In studies in which supraphysiologic doses of T3 were given starting immediately after completion of bypass surgery, resulting in supranormal serum T3 concentrations, the cardiac index was slightly higher and systemic vascular resistance was slightly lower in the patients given T3, as compared with placebo. The need for inotropic drugs or mechanical assistance, the incidence of atrial fibrillation, and postoperative morbidity and mortality were lower in some but not all studies (120,121,122,123). In children with congenital heart disease T3 treatment, as compared with placebo, after cardiac surgery also increased cardiac output and decreased systemic vascular resistance (124,125). The overall utility of T3administration after cardiac surgery is still not fully established.
TABLE 11D.2. CHANGES IN SERUM THYROID HORMONE AND THYROTROPIN CONCENTRATIONS IN PTIENTS WITH NON THYROIDAL ILLNESS
Serum free T4
Surgical trauma, burns
Chronic renal failure
=, no change; ↓ or ↑; direction of change compared with values in normal subjects; HIV, human immunodeficiency virus; rT3, reverse triiodothyonine; T4 thyroxine; TSH, thyrotropin.
Lastly, co-infusion of growth hormone–releasing peptide (GHRP-2) plus TRH (but not TRH alone) in protracted critical illness induced restoration of pulsatile growth hormone and TSH release, near-normal serum T4 and T3 values, and a shift toward anabolic metabolism (126). This interesting finding corroborates the neuroendocrine component of nonthyroidal illness.
SPECIFIC TYPES OF NONTHYROIDAL ILLNESS
Chronic Renal Insufficiency
Serum T3 concentrations are low, but serum rT3 concentrations may not be high in patients with chronic renal insufficiency (Table 11D.1). This poses a conceptual problem because hepatic uptake of rT3 as well as that of T4 is thought to be inhibited in these patients. Serum free T3 and free T4 concentrations are lower in the patients than in normal subjects, independent of the assay method used, and increase slightly after hemodialysis (126,127). After transplantation, serum T3 concentrations reflect graft function (128). A high frequency of goiter, up to 43% in one study, has been described in patients with chronic renal insufficiency, and has been attributed to high serum inorganic iodide concentrations (129).
Patients with cirrhosis have changes in serum thyroid hormone and TSH concentrations similar to those of patients with nonthyroidal illness in general. In those with infectious hepatitis, serum T4 and T3 concentrations are often high, due to an increase in serum TBG concentrations; their serum free T4 and T3 concentrations are usually normal. The findings are similar in patients with chronic active hepatitis and primary biliary cirrhosis, except in those with substantial hepatic insufficiency, in whom the concentrations decrease.
Human Immunodeficiency Virus Infection
Patients with asymptomatic human immunodeficiency virus (HIV) infection or those with the acquired immunodeficiency syndrome (AIDS) who have no opportunistic infections or hepatic dysfunction have normal serum T4 and T3 concentrations. Their serum free T4 index values and free T4 concentrations are normal or slightly low (130,131). Some of the patients have slightly high serum TBG concentrations, which tend to be inversely related to the percentage of CD4 cells, and serum TBG values have been used as a surrogate marker for disease progression (132). Serum TSH concentrations can be slightly high as well, but the small changes in TBG and TSH are different from those in nonthyroidal illness, and their pathogenesis and relevance are unknown. The prevalence of subclinical hypothyroidism may be increased in patients with HIV infection, especially in patients receiving highly active antiretroviral therapy (HAART) (133,134,135). The HAART-associated lipodystrophy characterized by peripheral fat wasting and central adiposity is apparently not related to thyroid function (136).
Patients with AIDS complicated by Pneumocystis carinii infections or other serious infections have the typical findings of patients with other severe nonthyroidal illness (137).
Patients with posttraumatic stress disorder may have slightly high serum T4, T3, and TBG concentrations, but their serum free T4 and free T3 concentrations are normal (138). Among patients with acute psychosis who are hospitalized, ~10% have some abnormality in thyroid function, including high or low serum TSH concentrations and high serum T4 concentrations (139,140). The changes are somewhat dependent on the particular psychiatric disorder; patients with substance abuse are more likely to have high serum TSH concentrations, whereas those with mood disorders tend to have high serum T4 concentrations (with low, normal, or high serum TSH concentrations). The tests usually become normal in 7 to 10 days.
Patients with rapid cycling bipolar disorder may have slightly low serum T4 concentrations and high serum TSH concentrations. Those with major depression tend to have higher than average serum T4 and free T4 concentrations (although the values are usually within the respective normal ranges) and low basal and TRH-stimulated serum TSH concentrations (141), in line with a decreased TRH mRNA in the paraventricular nucleus (142). The hypercortisolism and hyperthyroxinemia in patients with depression may inhibit D2 activity in the brain, resulting in low intracerebral T3 content. This may exaggerate the decrease in brain serotonin concentrations that occurs in depressed patients. Such a mechanism may explain why administration of T3 might be effective in patients with depression refractory to tricyclic antidepressant drugs, as has been reported in some but not all studies (143,144). A recent study, however, found that the efficacy and the rapidity of the response to selective serotonin reuptake inhibitors was not increased by adding T3 (145).
Patients with nonthyroidal illness have many changes in hypothalamic–pituitary–thyroid function, the magnitude of which roughly correlates with the severity of the illness. The changes include central down-regulation by inhibition of the hypothalamus–pituitary–thyroid axis and peripheral down-regulation by inhibition of the extrathyroidal production of T3. The central and peripheral changes can occur independently of each other. The pathogenesis of these changes is almost certainly multifactorial, with various mechanisms simultaneously operative at different levels. Overall, the changes are apparently geared to limit the impact of T3 on its target organs, which from a teleologic point of view might be a beneficial adaptation during starvation and illness to conserve energy and substrates and minimize excessive tissue catabolism. Although severe nonthyroidal illness may represent maladaptation, the limited data available suggest that administration of thyroid hormone to patients with nonthyroidal illness does not improve the outcome of their illness, but high doses of T3 given directly after cardiac surgery may have some clinical utility. The ill-chosen term “nonthyroidal illness syndrome” might better be replaced by thyroid hormone adaptation syndrome.
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