Material in this review has appeared in articles previously published in J Endocrinological Investigation, ENDOCRINOLOGY (Edition VII), and Critical Care Clinics.
Serum thyroid hormone levels drop during starvation and illness. In mild illness, this involves only a decrease in serum triiodothyronine (T3) levels. However, as the severity and duration of the illness increase, there is a drop in both serum T3 and thyroxin (T4), without an elevation of TSH. This decrease of serum thyroid hormone levels is seen in starvation, sepsis, surgery, myocardial infarction, bypass, bone marrow transplantation, and in fact probably any severe illness(1-9) The condition has been called the “euthyroid sick syndrome” (ESS). An alternative designation, which does not presume the metabolic status of the patient, is “non-thyroidal illness syndrome,” or NTIS. For more than 3 decades the interpretation of these changes has been debated Many observers have considered the changes in hormone level to be laboratory artifacts, or if valid, not representative of true hypothyroidism, or if hypothyroidism was present, that it was a beneficial response designed to “spare calories” (1-21). More recently evidence has accumulated that central hypothyroidism, and altered peripheral metabolism of T4 and T3, combine to produce a state marked by diminished serum and tissue supplies of thyroid hormones. Nevertheless, some observers accept the low hormone levels as valid, but maintain that this is a (unique) situation in which such lack of hormone is not truly hypothyroidism (i.e., the “euthyroid sick syndrome”). Lastly, there is even greater uncertainly about hormone replacement therapy, in considerable part because the opinion that replacement treatment should not be given has been repeated so many times, even though there is effectively no factual support for that view. Indeed, we seriously need controlled clinical trials in order to answer the question. It can not be solved by oft-stated opinions.
LOW T3 STATES
Starvation, and more precisely carbohydrate deprivation, appears to rapidly inhibit deiodination of T4 to T3 by Type 1 iodothyronine-deiodinase (ID-1) in the liver, thus inhibiting generation of T3, and preventing metabolism of reverse T3 (10). Consequently there is a drop in serum T3 and elevation of reverse T3. In addition, there is often a signficant drop in TBG levels, which further lowers totalT3, but may transiently increase freeT3.Since starvation induces a decrease in basal metabolic rate (11), it has been argued, teleologically, that this decrease in thyroid hormone represents an adaptive response by the body to spare calories and protein by inducing hypothyroidism. Several studies document that treatment with T3 during experimental starvation, not surprisingly, induces an increase in nitrogen excretion (12,13). This data has been interpreted as a reason against giving thyroid hormone to patients with NTIS. But it should be noted that 1) the observations are only in acute short term studies, not in the prolonged phase of NTIS, and that 2) any increase in caloric requirement could be easily satisfied. Patients who have only a drop in serum T3, representing the acute and mildest form of the NTIS, do not show clinical signs of hypothyroidism. Nor has it been shown that this decrease in serum T3 (in the absence of a drop in T4) has an adverse physiological effect on the body, or that it is associated with increased mortality.
NON-THYROIDAL ILLNESS SYNDROME WITH LOW SERUM T4
As the severity of illness over several days and weeks, and often associated starvation, progresses, there is the gradual development of a more complex syndrome associated with low T3 and usually low T4 levels. Generally TSH levels are low or normal (14), despite the low serum hormone levels, and reverse T3 levels are normal or elevated. The existence of a “normal” TSH in the presence of low T3 and T4 must be considered abnormal, since it is a failure of normal feed back regulation. A large proportion of patients in an intensive care unit setting have various degrees of severity of this chronic faze of NTIS, with low T3 and T4. Girvent et al note that NTIS is highly prevalent in elderly patients with acute surgical problems, and is associated with poor nutrition, higher sympathetic response, and worse postoperative outcome (15). Low T3 and T4 levels are strong predictors of fatal outcome among children in the ICU (16). among patients with lung cancer (17, and in a host of other similar situations. A marked decrease in serum T4 is associated with a high probability of death. NTI was found in a group of 20 patients with severe trauma, among whom 5 died, and the drop in T3 correlated with the Apache II score (22). NTI found in patients undergoing bone marrow transplantation was associated with a high probability of fatal outcome (23) NTIS was typical in elderly patients undergoing acute surgery and associated with a worse prognosis ( 24). When serum T4 levels drop below 4ug/dl, the probability of death is about 50%, and with serum T4 levels below 2ug/dl, the probability of death reaches 80% ( 22-25 ). Obviously such associations do not prove that hypothyroidism is the cause of these complications or deaths, but the fact of low thyroid hormone levels must at least raise the consideration of treatment.
But, surprisingly, during the past three decades many endocrinologists have assumed (teleologically) that NTIS is a beneficial physiologic response (18-21). However it seems illogical to consider NTIS as an evolutionarily derived physiologic response, since survival with the severity of illness seen in NTIS patients would be almost impossible except in modern ICUs.
PHYSIOLOGIC INTERPRETATIONS OF NTIS
Several conceptual explanations of NTIS can be followed through the literature:
1. The abnormalities represent test artifacts, and assays would indicate euthyroidism if a proper test were employed, and this response which should not be altered by treatment. Much data proves this view incorrect
2. The serum thyroid hormone abnormalities are due to inhibitors of T4 binding to proteins, and tests do not appropriately reflect free hormone levels. Proponents of this concept may or may not take the position that a binding inhibitor is present throughout body tissues, rather than simply in serum, and that the binding inhibitor may also inhibit uptake of hormone by cells or prevent binding to nuclear T3 receptors, and thus inhibit action of hormone. No data is available to prove this problem is important.
3. In NTIS, T3 levels in the pituitary are normal because of enhanced local deiodination. Thus the pituitary is actually euthyroid, while the rest of the body is hypothyroid. This presupposes uniquely normal intrapituitary T3 as the cause of peripheral hypothyroidism, and this has been proven not to be true.
4. Serum hormone levels are in fact low, and the patients are biochemically hypothyroid, but this is (teleologically) a beneficial physiologic response and should not be altered by treatment. Please review the data below.
5. Lastly, NTIS is a form of secondary hypothyroidism, the patient’s serum and tissue hormone levels are truly low, tissue hypothyroidism is present, this is probably disadvantageous to the patient, and therapy should be considered or initiated if serum thyroxin levels are depressed below the danger level of 4 ug/dl. While this understanding is at least compatible with the known facts, no available evidence proves that T3/T4 treatment is beneficial, or derogatory.
SERUM HORMONE LEVELS AND TISSUE HORMONE SUPPLIES IN NTIS
Serum T3 and Free T3 : With few exceptions, reports on NTIS indicate that serum T3 and Free T3 levels are low (28-34, 35). Chopra and coworkers reported that freeT3 levels were low (Fig.1) (35), or in a second report, normal (31). However it is important to note that in the second report the patients with “NTIS” actually had average serum T4 levels that were above the normal mean, and did not have severe, or even significant, NTIS. Liver Iodothyronine D1 normally produces up to 80% of circulating T3 via T4>T3 deiodination, the remainder coming from the thyroid directly, or by a contribution from ID2 in muscle (14). ID1 in liver is down-regulated in severe illness, and this is certainly an important contributor to the low T3 in blood. One presumed cause is reduced nutrition, especially of carbohydrate, but direct effects of cytokines on liver may also be involved The problem presumably is exacerbated by hypothyroidism, which also down-regulates ID1.
Figure 1. Free T3 concentrations in different groups of patients, as reported by Chopra et al, reference 35. In this report, patients with NTIS have significantly lowered Free T3 levels than do normal subjects.
Serum rT3 is normal or elevated, and is not a reliable indicator of abnormal thyroid hormone supply. While it may be expected that rT3 should always be elevated, this is not true, and often it is within the normal range. The enzyme responsible for deiodination of T4 to rT3, ID3, is actually induced. Peeters et al (37) found in patients with NTIS serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced in liver and skeletal muscle, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways that contribute to the low T(3) syndrome of severe illness. Further metabolism of rT3 via the 5′-deiodinase is inhibited by decreased function of the same enzyme (ID1) that generates T3 from T4. However formation of rT3 is limited by the low level of substrate (T4) in serum and in tissues, and perhaps by inhibition of T4 entry into cells. Personal experience treating patients with NTIS (unpublished) shows that when T4 is given and repletes serum T4 levels, generation of rT3 rapidly increases, and levels become significantly elevated.
Serum T4 : Serum T4 levels are reduced in NTIS in proportion to the severity and, probably length of the illness ( 12, 18-30). In acute, short term, trauma such as cardiac bypass (38), or short term starvation (39), there is no drop in serum T4. However, with increasing severity of trauma, illness, or infection, there is a drop in T4 which may become extreme. As indicated, serum T4 levels below 4 ug/dl are associated with a marked increased risk of death (up to 50%), and once T4 is below 2, prognosis becomes extremely guarded. In neonates, low total T4 and TSH are associated with a greater risk of death and severe intraventricular hemorrhage, and it is suggested that thyroid hormone supplementation might be a potential benefit in infants with the lowest T4 values (31)
Total serum T4 is reduced because of the sequence- low TRH > low TSH > low T4 thyroidal secretion. Also,T4 is reduced because of a reduction in TBG. One reason for this reduction appears to be because of cleavage of TBG. Schussler’s group recognized a rapid drop TBG to 60% of baseline within 12 hours after bypass surgery, and their data suggest that this is due to cleavage of TBG by protease, which causes TBG to lose its T4 binding activity (40). Further studies by this group demonstrated the presence of a cleaved form of TBG present in serum of patients with sepsis (41). The impact of meningococcal sepsis on peripheral thyroid hormone metabolism and binding proteins was studied in sixty-nine children with meningococcal sepsis. All children had decreased total T3 and (TT3)/rT3 ratios without elevated TSH. Lower TT4 levels were related to increased turnover of TBG due to elastase activity. Lowered TBG is a definite, and partial, explanation for lower total T4 and T3 in NTIS (42).
Serum Free Thyroxin : A major problem in understanding NTIS is in analyzing data on the level of free T4. Free T4 is believed by most workers to represent hormone availability to tissues. The results of Free T4 assays in NTIS are definitely method dependent, and may be influenced by a variety of variables including (alleged) inhibitors present in serum, or the effect of agents such as drugs, metabolites, or free fatty acids in the serum or assay. Assays which include an estimate of total T4 and TBG capacity (“Free thyroxin index assays”) to estimate free hormone usually return low values for free thyroxin in NTIS, and there is no objective data proving that these are incorrect.. Methods using T3 analogs in the assay also give levels that are depressed. The free T4 levels determined by dialysis vary widely, as do T4 levels measured by ultra-filtration (28-33), but the majority of reports are of normal or low, and in some samples, elevated values.(29,30,43-45)
In theory, methods utilizing equilibrium dialysis may allow dilution of dialyzable inhibitors. Compounds such as 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indoxyl sulfate and hippuric acid, can accumulate in severe renal failure (46). However these compounds probably do not interfere with serum hormone assays. Free fatty acids, if elevated to 2 – 5 mmol/l, can displace T4 binding to TBG and elevate free T4. Free fatty acids almost never reach such levels in vivo (47, 48). However, even small quantities of heparin (0.08 U/kg given iv, or 5,000 U given sc) can lead to in vitro generation of free fatty acids during extended serum dialysis for “freeT4” assay, and falsely augment apparent free hormone levels ( 49). This is probably a widespread and serious problem which explains many instances of apparently elevated free T4 levels in patients with acute illness.
Results obtained using ultrafiltration also are variable. Wang et al. (50) found that, in patients with NTIS, free T4 measured by ultrafiltration was uniformly low (average of 11.7 ng/liter), but when measured by equilibrium dialysis, free T4 was near normal, at 18 ng/liter. By ultrafiltration, free T3 was also, not surprisingly, found to be low and similar to free T3 by radioimmune assay. Chopra et al. (35) reported free T3 measured by dialysis in patients with NTIS, and found free T3 to be markedly reduced whereas free T4 was within the normal range. However, it must be noted that, in this study, their patients had an average T4 in the normal range (6.9 ug/dl), and these patients would not be expected to have low free T4 levels. Surks et al. ( 28) studied free T4 levels by equilibrium dialysis and by ultrafiltration of undiluted serum. Although the authors state that the results in patients with NTIS were “similar to or higher than those in 12 normal subjects”, in fact 7 of 9 patients had levels below the normal mean, ± 2 SD, when measured by dialysis, 6 of 9 were low when measured by ultrafiltration, and 7 of 9 were low when measured by standard resin-uptake-corrected free T4. The means of the NTIS patients in this study were all clearly below the mean of normals.
Thus, although FreeT4 is low in most assays that involve a correction for TBG levels, there is still some question as to the true free T4 in patients with NITS. One important reason for the variable reports is the sharp drop in TBG occurring immediately after any severe body trauma, including operations (40). This drop would cause a transient increase in freeT4, which would return to normal within a few days if TBG concentrations stabilized, or drop below normal if total T4 supply was then reduced as in chronic NTIS. It is of interest that this problem does not carry over to estimates of free T3, which are depressed in most studies. There might be two reasons for this difference. Firstly, the depression of total T3 is proportionately greater than of total T4. Secondly, factors which affect thyroid hormone binding are more apt to alter T4 assays than T3, since T4 is normally more tightly bound to TBG than is T3.
IS THERE EVIDENCE FOR SUBSTANCES IN SERUM WHICH CAN AFFECT T4 BINDING TO PROTEINS?
Mendel et al ( 51) carefully review the studies that have claimed the presence of dialyzable inhibitors of binding and point out that many of these studies must be viewed with caution (46,47,53-55). Numerous artifacts are present in both dialysis assays and ultrafiltration assays. They also point out, that, while the low free T4 by resin uptake assays found in NTIS generally do not agree with the clinical status of the patient, it is equally true that clinical assessment generally does not fit with the high free T4 results found by some equilibrium dialysis assays in NTIS. Most importantly, an argument that completely refutes the importance of factors in serum inhibiting binding of thyroid hormone is provided in the clinical study of Brent and Hershman (Fig.2)( 56). These researchers gave 1.5 ug of T4 per kg body weight to 12 of 24 patients with severe NTIS and followed serum hormone levels over 14 days. T4 levels returned to the normal range within three days of normal T4 replacement therapy. Thus the thyroxin pool was easily replenished, and T4 levels reached normal values. Not surprisingly, because of reduced T4>T3 deiodination, T3 levels did not return to the normal range until the end of the study period in the few patients that survived. However, the ability of intravenous thyroxin to promptly restore the plasma pool to normal clearly shows that an inhibitor of binding could not be the cause of low serum T4 in this group of severely ill patients.
With growing acceptance of decreased thyroid secretion and decreased peripheral T3 production as causes of low T4 and T3, there has been little emphasis on serum T4 binding inhibitors in recent literature. Some contribution by low TBG levels may, or may not (see below) play a role, but any role for binding inhibitors in producing this syndrome must be marginal.
Figure 2. Patients with severe NTIS were randomized and left untreated or given T4 iv over two weeks. Serum T3, T4, and TSH concentrations are shown for the survivors of the control (#1 – 3), and T4-treated ( #4 – 6), groups during the study period and at the time of follow-up. Upper and lower lines designate the normal range. Note the prompt recovery of T4 values to the normal range immediately following i.v. treatment with T4. Also note the elevated TSH levels in some patients. T3 levels did not return to normal following T4 treatment for up to two weeks. (Reference 56).
Serum TSH in NITS is typically normal or reduced and may be markedly low, although usually not less than 0.05 uU/ml (14, 28, 29, 32, 35), reviewed in (20) and ( 57). Some authors suggest that near normal TSH levels indicate a euthyroid state, but to use usual endocrinological logic, these TSH levels, if not actually below the normal range, are inappropriately low for the observed serum T4 and T3. Third generation assays with sensitivity down to .001 U/ml may allow differentiation of patients with hyperthyroidism (rarely a clinical problem) to be separated from those with NTIS, although there can be overlap in these very disparate conditions (58). Serum TSH in patients with NTIS may have reduced biological activity, perhaps because of reduced TRH secretion and reduced glycosylation. Some patients are found with a TSH level above normal, and elevation of TSH above normal commonly occurs transiently if patients recover from NTIS(Fig.3)( 20, 33, 56). This elevation of TSH strongly suggests that the patients are recovering from a hypothyroid state, during which the ability of the pituitary to respond had been temporarily inhibited.
Figure 3. T3 and TSH concentrations are shown in patients with nonthyroidal illness who were eventually discharged from hospital (left panels). The broken line indicates Â± 2 SD of the mean value in the normal subjects. The right panel displays T3 and TSH concentrations in patients with NTIS who died. Subjects are indicated by numbers. Note the elevated TSH in some patients who recovered, and the generally dropping T3 and low TSH levels in patients who died. (Reference 33)
Responsiveness of the pituitary to TRH during NTIS is variable: many patients respond less than normal (59) and others respond normally (60). Normal responsiveness in the presence of low TSH may suggest that there is an hypothalamic abnormality as a cause of the low TSH and low T4. There is also a diminution, or loss, of the diurnal rhythm of TSH (61), and in some studies there is evidence for reduction of TSH glycosylation with lower TSH bioactivity ( 62). A logical hypothesis is that hypothalamic function is impaired in patients with NITS, leading to low TRH secretion, which leads to low TSH secretion which is one proximate cause of the low thyroid hormone levels. In clinical studies, in the ICU setting, it has been shown that administration of TRH leads to increased TSH secretion and temporary normalization of T3 and T4 levels in the patients (63). This seems to provide very powerful proof of the sequence noted above.
There is other evidence of diminished hypothalamic function in patients with serious illness. Serum testosterone drops rapidly, as does FSH and LH ( 64, 65). Typically serum cortisol is elevated as part of a stress response, but this is not always the case. Some patients develop hypotension in association with apparent transient central hypo-adrenalism, and have low or normal serum ACTH, and cortisol levels under 20 ug/dl. The patients respond dramatically to cortisol replacement, and may manifest normal adrenal function at a later time if they recover. Centrally-mediated hyposomatotropism, hypothyroidism, and pronounced hypoandrogenism were observed in a study of patients in the catabolic state of critical illness. In these patients, pulsatile LH secretion and mean LH secretions are very low, even in the presence of extremely low circulating total testosterone and low estradiol. Pulsatile GH and TSH secretion are also, as is known, suppressed. IL-1b levels are normal, whereas IL-6 and tumor necrosis factor are elevated. Exogenous iv GnRH partially returned the serum testosterone levels toward normal, but did not completely overcome the hypoandrogenism, suggesting that combined deficiency of GH, GNRH, and TSH secretagogues may be important in this low androgen syndrome (66).
T4 ENTRY INTO CELLS AND GENERATION OF T3
Thyroid hormone is transported actively into tissues by several specific transporters including MCT8, and in the pituitary OATP1C1. In the cell it is metabolized by enzymes which activate it to T3, or inactivate it to rT3, or promote excretion via sulfation or glucuronidation. Iodotyrosine deiodinase type 1 (ID1) is found in liver, kidney and thyroid, and the enzyme present in liver is considered a main source of T3, possibly providing 80% of the total, the remainder coming largely from the thyroid. ID1 is down-regulated in hypothyroidism, and in NTIS, reducing serum T3 levels. ID2 is present in brain and pituitary, and is responsible for local production of T3 in those tissues. Recent data show that D2 present in muscle may also contribute to serum T3. ID2 is up-regulated by hypothyroidism, and is up-regulated in NTIS. The third enzyme, ID3, deiodinates the inner thyronine ring, converting T4 to rT3 and T3 to T2. It’s activity in liver is up-regulated in NTIS.
Using deiodination of T4 as an index of cellular transport of T4 into rat hepatocytes, Lim et al. (72) and Vos et al. (73) found that serum from patients with NTIS inhibited T4 uptake. Sera from critically ill NTI patients caused reduced T4 uptake compared to control sera in one study, and the authors considered elevated NEFA and bilirubin, and reduced albumin, to play a role. Serum from patients with mild NTIS did not cause impaired deiodination of T4 and T3 ( 74). Inhibition of uptake of T4 into hepatocytes caused by sera of patients with NTIS also was observed by Sarne and Refetoff (75). The monocarboxylate transporter 8 is important in transport of T4 into liver and other tissues. Peeters et al (76) found that MCT8 mRNA did not appear to correlate with tissue hormone levels in liver and muscle in NTIS, and Rodrigues-Perez et al reported that MCT8 mRNA was reduced in adipose tissue during NTIS (77). Van den Berghe’s group reported that MCT8 but not MCT10 T4 transporters was increased in skeletal muscle and liver of patients with severe NTIS, and that both were increased in a rabbit model of NTIS. In the latter model, T4 treatment lowered transporter levels, seeming to indicate that the changes found are a response to tissue hypothyroidism (78). Suffic e it to say that, while entry of T4 into tissues may be diminished, the role of transporters in the change is uncertain, but probably not a primary cause of the problem.
There is a diminution in the “reducing equivalents” available for the deiodination of T4 to T3 in liver, and presumably elsewhere, thus lowering the function of the Type I iodothyronine deiodinase (79). In animals, there is also a drop in the level of Type I iodothyronine deiodinase enzyme, apparently partially due to hypothyroidism, since it can be reversed by giving T3. Recently a study was performed on blood, liver, and skeletal muscle biopsies of patients immediately after death in intensive care unit settings. Liver T4 Deiodinase 1 was found to be down-regulated, and Deiodinase 3 was induced in liver and muscle, especially in situations associated with poor tissue perfusion. These changes contribute to the low generation of T3 and more rapid inactivation of T3 in NTIS (80). In theory inhibition of cellular uptake would cause tissue hypothyroidism, reduced T3 generation and serum T3 levels, and elevated serum T4, which is not observed.. It is likely that reduced hormone supply in NTIS is caused by multiple factors, and that reduced cell uptake is one of the factors. T4 is converted to T3, although inefficiently. In addition, T4 is rapidly converted to rT3, by an intracellular process, suggesting that entry into cells is not seriously impaired, but the pathways of intracellular deiodination are abnormal.
THYROID HORMONE IN TISSUES
There are few significant data on thyroid hormone in tissues of patients with NTIS 81). In one study there was of a dramatically reduced level of T3 in tissues.(Table 4). While most samples had very low levels of T3 compared to normal tissues, some patients with NTIS showed sporadically and inexplicably high levels of T3 in certain tissues, especially skeletal muscle and heart.
Peeters et al investigated 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines (76)
Table 4. Tissue T3 Concentrations in NTIS (nmol T3/kg Wet Weight)
Control Group NTI Group Mean SD P Mean SD Cerebral Cortex 2.2 0.9 < .05 1.2 1.1 Hypothalamus 3.9 2.2 < .01 1.4 1.2 Anterior Pituitary 6.8 2.5 < .005 3.7 1.1 Liver 3.7 2.3 < .01 0.9 0.9 Kidney 12.9 4.3 < .001 3.7 2.8 Lung 1.8 0.8 < .01 0.8 0.5 Skeletal Muscle 2.3 1.2 NS >10.9 Heart 4.5 1.5 NS >16.3 Abbreviations: NS = Not significantly different. Data from ref 56
THYROID HORMONE RECEPTOR EXPRESSION IN TISSUES
Information on expression of TRs in human tissues during illness is limited. Increased expression of the mRNA for thyroid hormone receptor a1, a2, and b1 in cardiac tissue of patients with dilated cardiomyopathy has been reported. a1 and a2 isoforms also had increased expression in ischemic heart disease. The cause of this alteration is unknown (82). Thyroid hormone receptor levels in humans during NTIS are not known with certainty. One study suggests that levels are normal. In a study of patients with non-septic shock NTIS, mRNA for THRB1, THRA1 and RXRgamma were reduced in skeletal muscle and adipose tissue in man. Importantly, this was not associated with increased expression of NFKB1, which has been proposed as a moderator of the NTIS syndrome(77). In animals, starvation and illness are associated with a reduction in thyroid hormone receptor levels. In experimental studies in mice, LPS induces NTIS and this is associated with an early decrease in binding of the RXR/TR dimer to DNA due to limiting amounts of RXR, and later an up to 50% decrease in levels of RXR and TR protein (83-84).
THYROID HORMONE TURNOVER
Kaptein et al. (67,68) studied thyroxin and triiodothyronine kinetics in groups of patients who were critically ill, all of whom had total T4 below 4 /dl, low FT4 Index, low normal free T4 by dialysis, and TSH which was normal or slightly elevated. Kinetic analysis is generally taken to be the most accurate measure possible of actual production and availability of the hormones in the body. In these patients, the mean T4 by dialysis was significantly below the normal mean. There was on average a 35% decrease in thyroxin disposal (or “production”) per day. The T4 production rate in NTIS was significantly below the mean of 17 normal subjects (p < .005). In a similar study of T3 kinetics (68), free T3 was found to be 50% of normal serum values, and the production rate of T3 was reduced by 83% (Table 2). In another study, T4 “appearance” in subjects with NTIS was found to be less than 50% of normal values, and 40% of the “appearance” in another comparison group with low TBG levels (69). These three studies document a dramatic reduction in provision of T4 and T3 to peripheral tissues, which would logically indicate that the effects of hormone lack (hypothyroidism) could be present. A curious phenomena related to this exceptional set of data is that the members of this group repeatedly refer to the findings as showing “normal” production of T4 and T3 in NTIS ( for example (70),J Lo Presti, in Euthyroid Sick Syndrome Update, presented at the Endocrine Society, June 2008). One study has reported normal thyroidal secretion of T3 in patients with NTIS due to uremia (71). However, this was a calculated, rather than directly measured value, was exceedingly variable, and does not negate the extreme reduction in T3 supply due to diminished T4> T3 conversion.
Table 2. T3 Kinetics in the Low T4 State of Nonthyroidal Illness
Case Number Total T3 (ng/dl) Free T3 (pg/dl) PR (μg/d/m 2 ) Normal Subjects (n = 12) Mean 162 503 23.47 ±SE 5 46 2.12 Sick Patients 3 30 272 6.18 5 42 247 5.67 6 25 151 5.41 7 34 266 8.39 12* 45 282 6.07 Mean 35 244 6.34 ± SE 4 24 0.53 P <0.001 <0.001 <0.005 * Patient receiving dopamine. Data are from ref 68. All P values are for unpaired t tests
ORGAN SPECIFIC RESPONSES IN NTIS
There are wide variations in responses to thyroid hormone supply and action in different tissues, and between the response to acute illness and chronic illness. These involve TH levels, TH transporters, deiodinases, TH receptors, and enzyme responses which are under different regulation in individual tissues (84.1,84.2 ). In an animal model of NTIS, hypothalamic,TH transporters MCT10 and OATP1C1 (but not MCT8) were increased, and hypothalamic D2, a major source of local T3, was up-regulated , but there was no corresponding increase in tissue T3. . TRalpha and beta mRNA expression levels were not altered (84.3). Tissue levels of T3 and T4 are reduced in chronic NTIS in both experimental models and in humans. Thus the low TRH mRNA levels in the hypothalamus are not due to (hypothesized) local tissue hyperthyroidism but probably reflect the action of neural signals and cytokines. Data on the pituitary are few. D2 levels have not shown consistent changes in animal models TRrbeta2 levels are reported to be reduced in acute NTIS. In humans with fatal illness, pituitary T3 levels were low. The overall picture is of central down-regulation of the hypothalamus and pituitary and low levels of tissue T3 despite increments in transporter activity and D2 deiodinase. Together these findings fit with the observed correction of TSH and TH levels in human NTIS through administration of TRH. Liver D1 and D3 activity are reduced in acute NTIS, but some evidence suggests this does not have an important effect on serum hormone levels. In man MCT8 and MCT10 may be reduced in acute but not chronic NTIS . Several enzymes that are responsive to TH have reduced activity in acute NTIS in animals. The data fit with reduced metabolic activity in this organ . In chronic NTIS in man, reduced serum T3 and T4 and normal or elevated RT3 are characteristic. Liver T3 is low in chronic human NTIS, and is directly related to serum T3. MCT8, but not MCTt10, are increased in liver and muscle in prolonged NTIS (84.31). Expression levels of TRalpha and beta mRNA are reported to be reduced, or conversly, increased. Metabolic activity is probably reduced, but likely in relation to reduced oxygenation and nutrients, as well as TH activity. In a rabbit model of chronic NTIS, serum and liver T3 and liver D1 activity were low. Interestingly (and perhaps important therapeutically) replacement to “normal” amounts of T4 or T3 did not reverse these abnormalities, but 3-5 fold increments, or TRH administration, did so ( 84.4). The response in muscle is less well defined. D2 increases and D3 is decreased in acute NTIS in muscle in an animal model , and there is evidence for decreased TR expression. Changes in enzyme responses do not show a consistent pattern . In chronic NTIS, human muscle D3 is augmented, while D2 has been found low, or increased . Muscle MCT8 is increased (84.31) , and this has been proposed as a “ compensatory ” response to hypothyroidism, since TH treatment in a rabbit model of NTIS returns the transporters to normal. Enzymatic activity is presumed low but good data are lacking . Prolonged infusion of lipopolysaccharide in pigs induced a severe NTIS state, associated with generally low tissue TH levels , reduced TH transporters, and low THR – beta levels, suggesting reduced TH sensitivity and hypothyroidism(84.6), as also found by Lado-Abeal et al(84.7)
ARE PATIENTS WITH NTIS CLINICALLY HYPOTHYROID?
It is straightforward that the usual clinical parameters of hypothyroidism are absent in patients with NTIS. Howeer, these patients usually present with an acute illness and are diagnostically challenging in view of their complicated state. Many are sedated, febrile, have extensive edema, have sepsis or pneumonia, may have hypermetabolism associated with burns, have severe cardiac or pulmonary disease, often are intubated and unresponsive, and in general, have features that could easily mask evidence of hypothyroidism. Further, the common clinical picture of hypothyroidism does not develop within 2 – 3 weeks of severe thyroid hormone deprivation, but rather requires a much longer period for expression. And generally these patients have low T4 levels ,not zero levels. General laboratory tests are also suspect. Thus starvation or disease-induced alterations in cholesterol, liver enzymes, TBG, CPK, and even BMR generally rule out the use of these associated markers for evidence of hypothyroidism. Angiotensin converting enzyme levels are low (85), as seen in hypothyroidism, while TEBG and osteocalcin levels are not altered ( 86). Antithrombin III levels are reduced in a septic rat model of NTIS. T3 supplementation returned the sepsis-induced decrease in ATIII levels toward normal (87). Basically, it is difficult to judge whether or not hypothyroidism is present on clinical grounds.
MECHANISM OF THYROID HORMONE SUPPRESSION IN NTIS
It is probable that the causes of NTIS are multifactorial, and may differ in different groups of patients. Specifically, the changes in liver disease and renal disease are probably somewhat different from those occurring in other forms of illness (v.i.).
Strong evidence suggests that an alteration in hypothalamic and pituitary function causes low production of TSH and thus T4,which in turn helps cause the low production of T3. It has been demonstrated in rats that starvation is associated with low serum thyroid hormone levels, and low leptin. Administration of leptin is believed to act via the arcuate nucleus to stimulate secretion of alpha-MSH, which acts on the periventricular nuclei to cause TRH secretion, leading to partial correction of the low serum T4 levels. Possibly low leptin levels could relate to NTIS in humans, but to date reports indicate leptin is not reduced (see below).
In rats, starvation reduces hypothalamic mRNA for TRH, reduces portal serum TRH, and lowers pituitary TSH content ( 88). A recent study documents low TRH mRNA in hypothalamic periventricular nuclei ( 89) in NTI patients (Fig 4), documenting the primary role of diminished hypothalamic function. Responses to administered TRH vary in different reports, being suppressed or even augmented ( 59,60). Administration of TRH has been suggested as an effective means of restoring serum hormone levels to normal in individuals with NTIS. A recent report of great significance by Van den Berghe and co-workers proves that administration of TRH to patients with severe NTIS leads directly to increased TSH levels, increased T4 levels, and increased T3 levels (Fig.-5, see below) ( 63). This data is strong support (albeit not proof) for the role of diminished hypothalamic function as an important factor causing NTIS.
Figure 4. In situ hybridization study demonstrating mRNA for TRH in the periventricular nuclei of a subject who died with NTIS in Panel A, and a subject who died accidentally in Panel B. mRNA for TRH is significantly reduced in patients with NTIS. (Reference 89)
Quite possibly the production of TRH, and responses to TRH, are reduced by cytokines, to be discussed below, or by glucocorticoids ( 90). The diurnal variation in glucocorticoid levels partially control the normal diurnal variation in TSH levels, perhaps by affecting pituitary responsiveness to TRH ( 91). High levels of glucocorticoids in Cushing’s disease suppress TSH and cause a modest reduction in serum hormone levels ( 92). High levels of glucocorticoids are known to suppress pituitary response to TRH in man ( 90). Stress induced elevation of glucocorticoids in animals causes suppression of TSH and serum T4 and T3 hormone levels ( 93). Thus stress induced glucocorticoid elevation may be a factor affecting TRH and TSH production.
Why should pituitary production of TSH be diminished in the presence of low serum thyroid hormone levels?. It has been suggested that there is augmented intra-pituitary conversion of T4 to T3, thus allowing the pituitary to remain “euthyroid”, while the rest of the body is actually hypothyroid. There is some experimental support for this idea in a uremic rat model of NTIS ( 94). However data provided by Van den Berghe and co-workers(95) refute this hypothesis. In a well studied rabbit model, chronic NTIS was associated with decreased hypothalamic TRH mRNA, increased D2, MCT10 and OA TP1C1 mRNAs, but low tissue T4 and T3.
Another suggestion is that some other metabolite of thyroxin might be involved in control of pituitary responsiveness. For example, possibly triac or tetrac generated by metabolism of thyroxin could control pituitary responsiveness, but there is no experimental proof of this idea, and even if true, would mean that the pituitary was normal but the rest of the body hypothyroid. As suggested above, elevated serum cortisol levels could play a role. The most obvious possibility is that low TSH stems from diminished TRH production, as described above. It must also be remembered that the defect in pituitary function is not restricted to TSH, but that LH, and FSH, are also suppressed in seriously ill patients, and testosterone is reduced, in contrast to the generally augmented glucocorticoid response. Quite possibly these changes are the effect on the hypothalamus of neural integration of multiple factors including stress, starvation, glucocorticoids, and cytokines.
Certainly one important cause of the drop in serum T3 is a decreased generation of T3 by Type 1 iodothyronine deiodinase in liver and reduced degradation of reverse T3( 96). If reduced entry of T4 into cells was a primary event and the major problem, then serum T4 levels would become elevated rather than suppressed. Some studies have suggested that individuals with NTIS may have selenium deficiency and that this may contribute to a malfunction of the selenium- dependent iodothyronine deiodinase ( 97). However supplements of 500 mg of selenium, given to patients in a surgical ICU during the first five days after serious injury, caused only modest changes in thyroid hormones. The data did not suggest a major role for selenium deficiency in this condition.
The overall degradation of thyroid hormone, both thyroxin and T3, is radically diminished in the NTIS syndrome in the presence of low hormone serum levels. The reduced degradation cannot produce the lowering of serum hormone levels; a primary reduction in degradation would increase serum hormone. The change in degradation must be secondary to the low hormone supply. Schussler and co-workers have observed a sharp drop in TBG levels during cardiac bypass surgery, which their studies indicate is due to some selective consumption of TBG. It is possible that this occurs because of activation of SERPIN proteases at sites of inflammation which cleave the TBG into an inactive form (40).
Vandenberge has proposed that the changes in endocrine function seen during severe illness have a biphasic course. Quite possibly the initial suppression of T3 levels represents a genetically engineered adaptive response of the organism, allowing reduced metabolic rate, and conservation of energy and protein stores for a longer period of time, while the animal or man goes through a period of temporary starvation. However, the circumstances surrounding severe illness, and the resuscitative efforts applied in an intensive care unit over one or more weeks, presumably have not resulted in some genetically induced metabolic response, since survival under such extreme organ failure is a very recent phenomenon. This second phase of the syndrome, with associated suppression of thyroid hormone and other pituitary hormones, and a variety of other changes, represents in this construction a maladaptive response. Patients in this situation tend to have elevated insulin levels, nitrogen wasting, retention of fats if calories are made available, and a variety of other metabolic abnormalities including neuropathy and cardiomyopathy. These authors consider that provision of multiple hormonal support, including thyroid hormone, growth hormone, and androgens, may be beneficial (95, 97-100).
CYTOKINES IN NTIS
In a series of septic patients studied shortly after admission to an ICU, total T4, free T4, total T3, and TSH were depressed, and IL-1b, sIL-2R, IL-6, and TNFalpha were elevated(101). The hypothalamo-pituitary-adrenal axis was activated as expected The data suggest central suppression of TSH as the cause of the problem, but the relation to cytokines is unclear, as seen in the following reports. Hermus et al. (102) showed that continuous infusion of IL-1 in rats cause suppression of TSH, T3, and free T4. Higher doses of IL-1 were accompanied by a febrile reaction and suppression of food intake, which presumably played some role in the altered thyroid hormone economy. IL-1 did not reproduce the diminution in hepatic 5′-deiodinase activity believed to be so characteristic of NTIS. IL-1 is also known to impair thyroid hormone synthesis by human thyrocytes, and is enhanced in many diseases associated with NTIS ( 103). Van der Poll et al. ( 104) studied the effect of IL-1 receptor blockade in human volunteers, to determine if it could alter the NTIS induced by endotoxin. Blockade of IL-1 activity was achieved by infusing recombinant human IL-1 receptor antagonist, but this did not prevent the drop in T4, free T4, T3, and TSH, or rise in reverse T3 caused by endotoxin. This is evidence against an important role for IL-1.
Interferon-gamma (100 mg/m2 ) administered subcutaneously to normal volunteers did not alter TNFa levels, caused a small elevation of IL-6 levels, and thus dId not support a role for Interferon-gamma in the pathogenesis of the euthyroid sick syndrome in humans (105).
TNF is another pro-inflammatory cytokine that is thought to be involved in many of the illnesses associated with NTIS. Infusion of recombinant TNF in man, by Vanderpool et al., produced a decrease in serum T3 and TSH, and increase in rT3. Free T4 was transiently elevated in association with a significant rise in FFA levels. These studies suggest that TNF could be involved. However, Chopra et al. (106) did not find TNF to be closely correlated with hormone changes in NTIS. Van der Poll et al (107, 108) gave human subjects endotoxin, which caused lowering of T4, free T4, T3 and TSH. TNF blockade by a recombinant TNF receptor-IgG fusion protein did not alter the response, indicating that TNF did not cause the changes in hormone economy induced by administration of endotoxin.
Nagaya et al (109) have proposed a mechanism through which TNF could reduce serum T3. TNF alpha was found during in vitro studies to activate NFkappa B, which in turn inhibits the T3 induced expression of 5’- DI, which would lead to lower T3 generation in liver. IL-1 also prevented induction of D1 in liver cells, and expression of SRC-1 overcame this block . These data provide a theoretical biochemical route via which cytokines (IL-1) secreted during NTIS could lower T3 production in liver.
Serum IL-6 is often elevated in NTIS (110), and its level is inversely related to T3 levels (111).IL-10 similarly is commonly elevated in NTIS (112). Stouthard et al. (113) gave recombinant human IL-6 chronically to human volunteers. Short term infusion of IL-6 caused a suppression of TSH, but daily injections over 42 days cause only a modest decrease in T3, and a transient increase in reverse T3, and in free T4 concentrations (Fig.6). IL-6 could be involved in the NTIS syndrome, although the mechanism was not defined. In an animal model of NTIS studied by Wiersinga and collaborators (114), antibody blockade of IL-6 failed to prevent the induced changes in thyroid hormone economy typical of NTIS. Boelen et al. studied the levels of IFN , IL-8, and IL-10 in patients with NTIS and found no evidence that they had a pathogenic role (115). Short term administration of recombinant IFN-gamma to normal subjects caused a minimal elevation of IL-6, no alteration in TNF, and did not significantly alter thyroid hormone levels( 116). Michalaki et al observed that serum T3 drops early after abdominal surgery as an early manifestation of the NTIS syndrome, prior to an increase in serum IL-6 or TNFalpha, suggesting that these changes in cytokines do not induce the drop in T3 (117).
The potential interaction between cytokines and the hypothalamic pituitary thyroid axis is certainly complicated, and cytokines themselves operate in a network. For example, IL-1 and TNF can stimulate secretion of IL-6. Activation of TNF and IL-1 production is associated with the occurrence of cytokine inhibitors in serum, which are actually fragments of the cytokine receptor, or actual receptor antagonists. “Soluble TNF receptor” and “IL-1 RA” are receptor antagonists, which can inhibit the function of the free cytokines. These molecules are increased in many infectious, inflammatory, and neoplastic conditions. Boelen et al. ( 118) found evidence that the NTIS is “an acute phase response” generated by activation of a cytokine network. Soluble TNF, soluble TNF receptor, soluble IL-2 receptor antagonist, and IL-6 all inversely correlated with serum T3 levels. At least we can be convinced that these cytokine changes co-occur with changes in T3 and probably play a pathogenic role by mechanisms yet unknown. To date it seems highly likely that cytokines secreted as part of the response to shock, infection and tissue damage play a crucial part in development of NTIS, acting via the hypothalamus, or directly on the pituitary, thyroid, or peripheral tissues including liver. However it is not possible to define the mechanisms precisely at this time.
OTHER FACTORS ALTERING SERUM T4 SUPPLY
Altered CNS metabolism -In healthy men going through two 4.5 hour long sessions of induced hypoglycemia, TSH, fT3 and fT4 are significantly reduced. Perinatal asphyxia, recognized by low Apgar scores, is associated with a depression of TSH, T4 and T3, and the reductions are greatest in infants with hypoxic/ischemic encephalopathy. In this study 6 of 11 infants with FT4 < 2ng/dl died. These data suggest that reduced substrate or O2 supply to the CNS could induce hypothalamic/pituitary dysfunction.(119,120)
Administration of glucagon to dogs caused a significant fall in serum T3, suggesting that the stress-induced hyperglucagonemia may be a contributor to the NTIS syndrome by altering intracellular metabolism of T4 (121).
Dopamine given in support of renal function and cardiac function must play a role in many patients who develop low hormone levels while in an intensive care unit setting. Dopamine inhibits TSH secretion directly, depresses further the already abnormal thyroid hormone production, and induces significant worsening of the low hormone levels. Withdrawal of dopamine infusion is followed by a prompt dramatic elevation of TSH, a rise in T4 and T3, and an increase of the T3/rT3 ratio ( 89). All of these changes suggested to Van den Berghe et al. (1122) that dopamine makes some patients with NTIS hypothyroid, inducing a condition of iatrogenic hypothyroidism, and that treatment (presumably by administering thyroid hormone), “should be evaluated”.
Leptin plays a key role in control of thyroid hormone levels during starvation in animals. During starvation, leptin levels drop. With this there is diminished stimulation of TRH, thus diminished secretion of TSH, and lowered thyroid hormone levels. Administration of leptin appears to work via the arcuate nucleus of the hypothalamus to induce production of POMC and thus aMSH, and reduce AGRP. aMSH normally stimulates the melanocortin 4 receptor (MC4R), whereas AGRP suppresses it. Presumably through these actions, a lack of leptin during starvation leads to diminished stimulation of the MC4R receptor on the TRH neurons in ventricular nuclear centers, and thus diminished TRH secretion. Administration of leptin partially reverses this sequence. These actions appear to be part of an energy conserving scheme related to thyroid changes during starvation and are associated with leptin-induced increase in appetite, decreased energy expenditure, and modified neuroendocrine function. Naturally the relevance of this to human physiology is as yet unclear, but the data strongly suggests that leptin is involved in the down-regulation of thyroid function during acute starvation.(123-125)
In clinical trials, stimulation of growth hormone secretion, by GH secretogogues, lead to increased insulin and leptin levels in severely ill ICU patients . Studies of leptin levels in patients with NTIS have to date indicated they are normal or elevated, not low. (126,127)
Atrial natriuretic peptides, including amino acids 1 – 30, amino acids 31 – 67, known as vessel dilator, and 79 – 98 (kaliuretic hormone), and 99 – 126 (atrial natriuretic hormone), derived from the ANH prohormone, significantly decreased circulating concentrations of total T4, free T4, and free T3, when given to healthy humans for 60 minutes. A reciprocal increase in TSH lasted for two or three hours after cessation of the administration of these hormones, suggesting that the effect was a direct inhibition of thyroid hormone release from the thyroid gland, rather than an action of the hormones upon the hypothalamus or pituitary. No data is available on these factors in NTIS (128). Low levels of selenium have also been associated with NTIS, possibly having an action via deiodinases (129).
Rocchi et al recently reported (130) that administration of CFA to mice leads to development of an NTIS syndrome within one day, and that this is mediated via toll-like receptors and Fc receptors, via mast cell activation and possibly release of cytokines such as TNF-alpha,IL-6, IL-12 and IL-18.
VARIATIONS IN THE SYNDROME IN RENAL DISEASE
In End stage renal disease (ESRD) the typical features of NTIS are present, including a 60% drop in T3 production, but with the exception of elevated rT3. So far there has been so clear explanation for this anomaly, but it does not alter interpretation of the remaining patho-physiologic abnormalities. Some very unique studies have been directed at this condition, using an animal model of ESRD. In this model there is clear evidence that the low thyroid hormone levels are associated with reduced enzyme levels (alpha-GPD and MDH) in liver that are typical of hypothyroidism, and are returned to normal by administration of thyroid hormone (131). In studies on patients with ESRD given T3, protein turnover was increased by administration of T3, as in the animal model (132). This response was interpreted to be a reason to avoid T4/T3 replacement therapy, since among other things, it could increase the need for dialysis. However an alternative explanation is that this increase in protein metabolism could represent a potentially beneficial response, restoring a hypothyroid state toward normal. Among patients undergoing hemodialysis, leptin levels, IL-2 and IFN gamma are elevated along with lowered serum T3, suggesting a pro-inflammatory cytokine response(133).
Typically the endocrinologist is presented with a severely ill patient in whom there is no prior history suggestive of pituitary disease, in whom clinical findings of hypothyroidism are either absent or masked by other disorders, with a T4 and FTI (by an index method) that are low, a low or normal TSH, and , if measured, a low T3. If T4 is below 4 ug/dl in this setting the diagnosis of NTIS, associated with a potentially fatal outcome, may be assumed. RT3 may be normal or elevated, and is not diagnostic. An elevated TSH suggests the presence of prior hypothyroidism, which should be treated. Finding positive antithyroid antibody titers supports the diagnosis of primary hypothyroidism, but does not prove it.
Serum cortisol should be measured. Transient apparently central hypoadrenalism is an unusual but recognized phenomenon is severe illness( 134-136). Cortisol should be above 20 ug/dl, and commonly is above 30. If below 20, ACTH should be drawn and the patient should be given supportive cortisol therapy. Serum cortisol should certainly be determined if thyroid hormone is to be given. Since CBG may be reduced, it is advisable to measure serum free cortisol if possible. It is useful to determine FSH in post-menopausal women as a sign of pituitary function, but this is less clearly valuable in men. If there is a reason to consider hypopituitarism, a CAT scan of the pituitary is appropriate, or at least a skull film.
Aspirin, dilantin and carbamazepine can lower T4 and FTI as measured by several “Index” methods, Dopamine used in the setting of severe illness can induce clear-cut hypothyroidism. Hyperthyroidism is the typical cause of suppression of TSH below 0.1uU/ml, but is rarely difficult to exclude this diagnosis in the setting of severely depressed T4 and T3.
IS THYROID HORMONE TREATMENT OF NTIS ADVANTAGEOUS OR DISADVANTAGEOUS?
The most common argument given against T3/T4 replacement is that is would void the “caloric sparing” function of the metabolic changes in NTIS. (Interestingly, this is clearly tacit agreement that the state represents hypothyroidism, which would be corrected by giving hormone.) But a logical counter is that if more calories are needed, they can easily be supplied. Patients in the ICU with severe illness are routinely supported metabolically by every possible therapeutic modality, including blood, albumin, lipids, vitamins, colloids, amino acids, and carbohydrates. We do not hesitate to treat hypothyroidism because the treatment may induce more energy expenditure, Rather, this is considered a sign of successful therapy.
Two valuable studies are available on replacement therapy using thyroid hormone in patients with NTIS. In the study by Brent and Hershman ( 56), replacement with 1.5 ug T4 i.v. per kilogram body weight daily, in 12 patients, promptly returned serum T4 levels to normal (thereby proving that a binding defect was not the cause of the low T4) , but did not normalize T3 levels over a period of 2 – 3 weeks. However, in both the treated and control group, mortality was 80% ( 49). Clearly, this excellent small study, which used for primary therapy what would now be considered the wrong hormone, failed to show either an advantageous, or disadvantageous, effect. It is possible that the failure to show a positive effect was due to the failure of T3 levels to be restored to normal. In a study of severely burned patients given 200 ug T3 daily, again there was no evidence of a beneficial or disadvantageous effect ( 137). Mortality was not so great, as in the Brent and Hershman study, but it is entirely possible that the high levels of T3 provided worsened the hypermetabolism known to be present in burn patients, and could have, at these levels, been disadvantageous. However both studies indicate that T4 and T3 can be given to patients in this condition without a dangerous response.
An important study by Acker et al certainly advises caution regarding T4 therapy in patients with acute renal failure. Numerous studies in animals have documented a beneficial effect of T4 therapy in experimental acute renal failure(138). In a randomized controlled prospective study of patients with acute renal failure, they treated patients with 150 mg of thyroxin four times intravenously over two days. The single difference recognized in the subsequent laboratory data was a partial suppression of TSH. T4 treatment had no effect on any measure of ARF severity. Among other questions, it is not clear that serum T3 levels were ever altered. However, mortality was higher in the thyroxin group (43 vs. 13%) than in the control group. It is of interest that, as the authors state, “the observed mortality in the controls in this study was less than that typically seen in our institution in ARF and ICU patients, whereas the 43% mortality noted in the thyroid group better approximates both our experience and that reported in the literature for ICU patients.” It will be difficult to replicate this study (although this writer believes it should be replicated). But it is uncertain whether the small dose of thyroxin administered over two days actually is related to the mortality, considering that the mortality in the treated group was that usually observed, whereas the control happened to have a much lower mortality (139). The same group has also studied the effect of thyroid hormone treatment on post-transplant acute tubular necrosis. T3 treatment during the post-transplant period did not alter outcome in a beneficial or derogatory manner (140).
Studies from animals are often quoted in the literature as an argument against treatment of NTIS, or for the therapy. A study of sepsis induced in animals showed no difference in mortality, but some animals treated with thyroid hormone died earlier than did those that were untreated ( 141). Chopra et al. induced an NTIS in rats by injection of turpentine oil. The reduction in T4, T3, Free T4 Index, and TSH were associated with no clear evidence of tissue hypothyroidism, and urinary nitrogen excretion was normal. Thyroid hormone replacement with T4 or T3 did not significantly alter enzyme activities or urinary nitrogen excretion ( 142). Healthy pigs were subjected to 20 minutes of regional myocardial ischemia by Hsu and collaborators ( 143), and this was associated with a drop in T3, free T3, and elevated rT3. Some animals were treated with 0.2 ug T3 per kilogram for five doses over two hours. While myocardial infarction size was not altered, the pigs treated with T3 showed a more rapid improvement in cardiac index. Oxygen consumption did not alter. It should be noted that the T3 levels fell back to normal levels within four hours of the last T3 dose, suggesting that more prolonged therapy might have been beneficial. Katzeff et al (144) studied a model of NTI induced by caloric restriction in young rats. In these animals T3 was reduced, and there was a decrease in LV relaxation time, SERCA2 mRNA, and alpha-MHC mRNA. All changes were reversed to normal values by supplementation with T3, suggesting that the low-T3 syndrome was related to the pathological cardiac changes. Sepsis and multisystem organ failure are often associated with disseminated intravascular coagulation and consumption of coag inhibitors such as antithrombin-III. Chapital studied a model of sepsis in rats, and showed that T3 supplementation reduced the decrease in ATIII levels, which presumably would reflect a beneficial effect (145).Dogs subjected to hemorrhagic shock recover more cardiovascular function when given T3 intravenously than did untreated animals (146).Neurological outcome after anoxia is improved in dogs by T3 treatment (147).
In a study of patients after heart transplant, patients with the low T3 syndrome (NTIS) had higher mortality, higher incidence of acute rejection, highest number of re-operations, and higher incidence of infections, compared to those without NTIS (147.1) . Low free T 3 levels are reported to be associated with an increased incidence of fibrillation after cardiac surgery in elderly patients. 147.2 Short term studies on T3 replacement of patients in shock, in patients with respiratory disease, in subjects who are brain dead and potential organ donors, and in patients undergoing coronary artery bypass grafts, all suggest modest cardiovascular benefits from the administration of T3 through . One study reports benefit by replacing T3 to elevate the depressed T3 levels in premature infants(148). A few studies found no apparent effects. Children treated with T3 postoperatively when they have undergone cardiac surgery also require less cardiac support . T3 administration (one dose of approximately 6 ug iv) did not alter cardiac performance in brain dead transplant donors.(149-150) Coronary artery bypass, as studied by Klemperer and collaborators ( 39), was associated with a drop in serum T3. Administration of T3 iv elevated T3 above normal and augmented cardiac output and reduced need for pressor support, but had no other effect. In this study, however, the patients had a very favorable prognosis and minimal NTIS, and the study primarily shows that administration of T3 had no adverse effect under these circumstances. Choi et al reported, in a randomized placebo controlled prospective study of patients undergoing cardiac valvular surgery, that T3 20ug q 12 h orally before and the day after operation caused a significant lowering in the need for vasopressors (151). In a meta-analysis of the acute NTIS syndrome associated with operations, short term treatment with T3 augments cardiac function, but was not been shown to alter the already low mortality (151.1). T3 replacement therapy (3 days of 20ug/m 2 /day) in patient with dilated cardiomyopathy increased ventricular performance, and lowered heart rate, plasma norepinephrine, natriuretic peptide and aldosterone, compared to placebo(152). Similar data was presented by Hamilton et al (153). In a study reported several years ago,T3 administration to critically ill neonates with severe respiratory distress appeared to improve survival. Infants of less than 37 weeks gestational age, or weighing less than 220 grams, were given prophylactic doses of thyroxin and T3 daily and had a lower mortality rate than untreated infants (148).
Goarin et al studied the effect of T3 administration in brain dead organ donors and found that, although it returned T3 levels to normal, it did not improve hemodynamic status or myocardial function (154). The general outcome of these studies is that they weakly support the use of T3, and none of the studies found evidence of damage caused by treatment(155-156).However most of these studies relate to the acute drop in T3 seem promptly after trauma, rather than the changes seen in the chronic phase of NTIS.
In summary, it can be stated that there is no clear evidence that thyroxin or triiodothyronine treatment of the NTIS in animals or man is disadvantageous, and no certain proof that it is advantageous. However, what evidence there is suggests it may be beneficial. The argument has been raised that administration of thyroid hormone in NTIS would prevent the elevation in TSH commonly seen in recovering patients. This seems rather specious. More objectively, the elevation of TSH is another suggestion that the few patients who survive the ordeal were originally hypothyroid, and were left untreated. Lastly, it is unlikely that administration of replacement hormone during NTIS would be harmful , even if all of the evidence presented above suggesting hypothyroidism was erroneous, and the patients were in fact euthyroid. Some authors (162) point out the potential cardiovascular dangers of administration of T3, but the illustrations provided have to do with toxic doses of T3, rather than replacement, and seem irrelevant. The data on hand do not provide a clear answer regarding replacement T3/T4 treatment, and controlled trials are sorely needed. Unfortunately, it appears that the advocacy of “no therapy” has been so effective that the needed clinical trials have been discouraged. At this time the clinician must decide that either 1) this form of tissue thyroid hormone deficiency is unique and should not be altered since it may provide some un-demonstrated physiologic advantage (in contrast to every other hypothyroid condition), or 2) replacement therapy of hypothyroidism is potentially beneficial in this circumstance, and is probably safe, based on the two extensive clinical trials described above.
IF THYROID HORMONE REPLACEMENT IS GIVEN, WHAT SHOULD IT BE?
Clearly, the high mortality rate in patients with T4 under 4ug/dl suggests that this is a target group in whom thyroid hormone administration should be considered. In this group of patients there appears to be no obvious contraindication to replacement therapy, with the possible exception of people who have cardiac decompensation or arrhythmias. Even here the evidence is uncertain. There is no clear evidence that administration of replacement doses of T3 to patients with low cardiac output is disadvantageous, and in fact current studies using intravenous T3 in these patients indicate it is well tolerated and may be beneficial (153). Arrhythmias obviously also raise a question, but again, there is no evidence that replacement of thyroid hormone to a normal level would cause trouble in control of arrhythmias. Thus, even in this group of patients, it is reasonable to suggest therapy. It should also be noted that among patients with NTIS there will certainly be patients who are clearly hypothyroid based on known disease, treatment with dopamine, or elevated TSH, who need replacement therapy by any standard.
If therapy is to be given, it cannot be thyroxin alone, since this would fail to promptly elevate T3 levels (56). Treatment must be with oral, or if this is impractical, intravenous T3, and probably should be at the partial replacement level of approximately 50 ug/day given in divided doses. It may be appropriate to give slightly higher doses, such as 75 ug/day for 3 – 4 days to increase the body pool more rapidly, followed by replacement doses as described. Coincidentally, it is appropriate to start replacement with T4. Serum levels of T4 and T3 should be followed at frequent intervals (every 48 hours), and dosages adjusted to achieve a serum T3 level approximating at least low normal, 70-100ng/dl, prior to the next scheduled dose. If treatment is successful, T3 administration can gradually be reduced, and thyroxin administration increased to replacement levels as deiodination increases. Because of the marked diminution in T4 to T3 deiodination, and shunting of T4 toward reverse T3, replacement with T4 may initially only lead to elevation of reverse T3 and have very little effect upon T3 levels, or physiologic action. In this situation, continued administration of T3 would be preferred.
One cannot envisage that replacement of thyroxin or T3 can “cure” patients with NTIS. The probable effect, if any is achieved, will be a modest increment in overall physiologic function and decrease in mortality. Perhaps this would be 5%, 10%, or 20%. If effective, thyroid hormone replacement will be one of many beneficial treatments given the patient, rather than a single magic bullet that could reverse all the metabolic changes going wrong in these severely ill patients.
ADDITIONAL SUPPORTIVE HORMONAL THERAPY TO CONSIDER
Although this discussion concentrates on the potential value of treating patients with NTIS with replacement thyroid hormone, several important recent studies expand the concept to other areas, including treatment of the associated hyperglycemia, relative adrenal insufficiency, and possible use of GHRH and testosterone. Van den Berghe and co-workers have suggested that the acute and prolonged critical illness responses are entirely different neuroendocrine conditions. In protracted severe illness, patients are kept alive with conditions that previously caused death. However, this process has unmasked a variety of nonspecific wasting syndromes including protein loss, accumulation of fat stores, hyperglycemia and insulin resistance, hypoproteinemia, hypercalcemia, potassium depletion, and hypertriglyceridemia. In prolonged illness, cortisol values are elevated, although ACTH levels are low, indicating that other mechanisms are driving the steroid response. Growth hormone secretory pulses are reduced, and the mean concentration is low in prolonged critical illness. FSH and LH are reduced, and testosterone levels are reduced. These authors maintain that the reduced neuroendocrine drive, present in the chronic phase of illness in an intensive care setting, is unlikely to be an evolutionary preserved beneficial process. They suggest that the administration of hypothalamic physiotropic releasing peptides may be a safer strategy than the administration of peripherally active hormones (86). Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Van den Berghe et al carried out a prospective randomized study on ICU patients on mechanical ventilation, maintaining blood glucose at a level between 80 and 110 mg/dl, versus allowing glucose to range between a level of 180 – 200 mg/dl. Intensive insulin therapy reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care (98). This strict blood sugar control can lead to bouts of hypoglycemia, and slightly higher values are currently aimed for. In isolated brain injury patients, intensive insulin therapy reduced mean and maximal intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors. Seizures and diabetes insipidus occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs. Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation (99). Prevention of catabolism, acidosis, excessive inflammation, and impaired innate immune function may explain previously documented beneficial effects of intensive insulin therapy on outcome of critical illness.(95)
Severe burns are known to be associated with a hypermetabolic state and a strong sympathetic response. Beta blockade given as propranolol to reduce the resting heart rate by 20% decreased resting energy expenditure and increased net muscle protein balance significantly in a group of burn patients. It is logical that this would be a significant benefit (163). Severe sepsis, which is of course associated with NTIS, is frequently associated with relative adrenal insufficiency, and possibly systemic inflammation-induced glucocorticoid receptor resistance. In a prospective randomized study, Annane et al studied a seven day treatment of patients with septic shock, by giving hydrocortisone, 50 mg q6h, and 9-alpha-fludrocortisone, 50 mg once daily. The risk of death in this treated group was significantly reduced without increasing any adverse effects. . The treatment was clearly most beneficial, in individuals who responded poorly to a 250 mg ACTH test, which was conducted prior to the therapy. Non-response was defined as a response of 9 mg/dl or less, between the lowest, and highest concentration taken after the ACTH injection. Samples were taken in this study at 30 and 60 minutes (164). The severity of the illness was suggested by the statistics that 63% died in the placebo group, and 53% in the corticosteroid treatment group. The authors recommend that all patients with catecholamine dependent septic shock should be given a combination of hydrocortisone and fludrocortisone as soon as a short corticotrophin stimulation test is performed, and the treatment should be continued for seven days in non-responders. Hamrahian et al advise caution in using total serum cortisol measurements in patients with serum albumin levels below 21.5gm/dl. They observed that these patients may have low total cortisol because of low CBG, but have normal or elevated free cortisol levels (1165)
Pulsatile GNRH treatment, in patients with prolonged severe illness and the NTIS, only partially overcomes the associated hypogonadotropic hypogonadism. This indicates that there is both a hypothalamic and an end organ defect in this condition. However, the administration of androgen in this situation has not so far been shown to be beneficial (166).
In contrast to the generally beneficial effects of hormonal therapy described above, high levels of growth hormone given to critically ill patients were found by Takala et al to augment mortalit y. The dosage used was 0.1 mg/kg bw, for up to 21 days. Mortality rate was nearly double. These authors suggest that GH may have an adverse effect upon immunity, cause fluid retention, and cause hyperglycemia (167).
NTIS is typically associated with poor nutrition unless supportive measures are taken, and undernutrition is a known inducer of NTIS. Yet nutritional support is not uncomplicated. Parenteral feeding of rabbits (in contrast to fasting) in a model of chronic NTIS resulted in a normalization of low T3 levels, but did not correct low T4 levels(167.01) .Use of early parenteral alimentation for patients in the ICU with NTIS was recommended by Perez-Guisado et al (167.1), who found it decreased length of hospital stay. However a study by Langouche et al (167.2) found, in contrast, that adding parenteral nutrition sooner than one week in the ICU increased complications and delayed recovery
TREATMENT WITH HYPOTHALAMIC RELEASING HORMONES
Van Den Berghe and collaborators have pioneered studies on the effects of hypothalamic releasing hormones in patients with severe NTIS. The logic supporting this approach is that it corrects a major cause of the low hormonal state, and may allow normal feed-back control and peripheral regulation of hormones, thus being more physiological than replacing the peripheral hormone deficit directly. Extensive studies document restoration of T4 and T3 levels following administration of TRH and GH secretagaugue (63). In a rabbit model of NTIS treatment with GHRP-2 and TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion (168).
In NTIS there are suppressed pulsatile GH, TSH, LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS), thyroid hormones, and total and estimated free testosterone levels, whereas free estradiol (E2) estimates are normal. Ureagenesis and breakdown of bone tissue are increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count are elevated; serum lactate is normal. Coadministration of GHRP-2, TRH and GnRH reactivated the GH, TSH and LH axes in prolonged critically ill men and evoked beneficial metabolic effects which were absent with GHRP-2 infusion alone and only partially present with GHRP-2 + TRH. These data underline the importance of correcting the multiple hormonal deficits in patients with prolonged critical illness to counteract the hypercatabolic state (169).
Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive (170). While outcome studies using this approach are not available, it is quite possible that treatment of NTIS by use of hypothalamic releasing hormones may be a preferred approach.
This review has presented the arguments for administration of replacement T3 and T4 hormone in patients with NTIS. However, it is impossible to be certain at this time that it is beneficial to replace hormone, or whether this could be harmful. Only a prospective study will be adequate to prove this point, and probably this would need to involve hundreds of patients. Ongoing studies document the beneficial effects of replacement of other hormones in these acutely and severely ill patients. Possibly therapy will ultimately involve replacement of peripheral hormones, or may instead be via GHRP, TRH, GNRH, insulin, adrenal steroids, and leptin.
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