Nonthyroidal Illness Syndrome: A Form of Hypothyroidism

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Chapter 15

Nonthyroidal Illness Syndrome

A Form of Hypothyroidism

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 of the illness increases, there is a drop in both serum T3 and thyroxine (T4). 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.19 The condition has been called the euthyroid sick syndrome (ESS). An alternative designation, which does not presume the metabolic status of the patient, is nonthyroidal illness syndrome, or NTIS.

Low T3 States

Starvation, and more precisely carbohydrate deprivation, appears to rapidly inhibit deiodination of T4 to T3 by type 1 iodothyronine deiodinase in the liver, thus inhibiting generation of T3 and preventing metabolism of reverse T3 (rT3).10 Consequently there is a drop in serum T3 and elevation of reverse T3. 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 some degree of hypothyroidism. Patients who have only a drop in serum T3, representing the 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 physiologic effect on the body or that it is associated with increased mortality.

Nonthyroidal Illness Syndrome With Low Serum T4

As the severity of illness, 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 thyroid-stimulating hormone (TSH) levels are low or normal despite the low serum hormone levels, and rT3 levels are normal or elevated. A large proportion of patients in an intensive care unit setting have various degrees of severity of NTIS with low T3 and T4. Plikat et al. found that 23% of patients admitted to an ICU during a 2-year period had low free T3, low free T4, and low or normal TSH, and that these findings gave a greatly increased risk of death.12 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.13 Surprisingly, during the past 3 decades, many endocrinologists have assumed that NTIS is a beneficial physiologic response,1417 but actual evidence for this view is unavailable.

A marked decrease in serum T3 and T4 in NTIS is associated with a high probability of death. NTIS 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.18 NTIS found in patients undergoing bone marrow transplantation was associated with a high probability of fatal outcome.19 NTIS was typical in elderly patients undergoing acute surgery and was associated with a worse prognosis.20 All of 45 non-dopamine-treated children with meningococcal septicemia had low T3, T4, and thyroxine-binding globulin (TBG), without elevated TSH. When serum T4 levels drop below 4 g/dL, the probability of death is about 50%, and with serum T4 levels below 2 g/dL, the probability of death reaches 80%.2123 Obviously such associations do not prove that hypothyroidism is the cause of these complications or deaths, but the fact of hypothyroidism must at least raise the consideration of treatment.

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 proper tests were employed.

2. The serum thyroid hormone abnormalities are due to inhibitors of T4 binding to proteins, and the 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.

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 enhanced intrapituitary T4 > T3 deiodination as the cause.

4. Serum hormone levels are artifactually low, the patients are biochemically euthyroid, and this is (teleologically) a beneficial physiologic response which should not be altered by treatment.

5. 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.

6. Lastly, NTIS is in part 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 initiated if serum thyroxine levels are depressed below the danger level of 4 µg/dL.

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.2430 Chopra and co-workers reported that free T3 levels were low (Fig. 15-1),31 or in a second report, often normal.32 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 significant NTIS. Sapin et al. compared free T3 levels found in patients with NTIS by direct dialysis, microchromatography, analogue, two-step immune extraction, and a labeled antibody RIA method.30 Results were significantly below normal by five of the methods and low in the most severe cases by one method. Faber et al. evaluated thyroid hormone levels in 34 seriously ill patients, most of whom had low T4 and free T4 index values, and found generally normal free T3 and free T4 using an ultrafiltration technique.33 A point to consider is that some ultrafiltration techniques fail to exclude thyroid hormone–binding proteins from the filtrate and give spuriously high free hormone values.34

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FIGURE 15-1 Free T3 concentrations in different groups of patients, as reported by Chopra et al.31 In this report, patients with NTIS have significantly lowered free T3 levels than normal subjects. NTIS, Nonthyroidal illness syndrome; T3, triiodothyronine.

Serum rT3 may be reduced, 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. Peeters et al.35 found in patients with NTIS, serum TSH, T4, T3, and the T3/rT3 ratio were lower, whereas serum rT3 was higher than in normal subjects (P < 0.0001). Liver D1 is down-regulated, and D3 (which is not evident in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. The level of rT3 reflects the action of several enzymes and presumably, as well, tissue metabolic function. Induction of D3 would tend to increase rT3. Degradation of rT3 is reduced by decreased function of the same D1 enzyme that generates T3. Moreover, 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 hormone levels, generation of rT3 rapidly increases, and levels often become significantly elevated.

Serum T4

Serum T4 levels are reduced in NTIS in proportion to the severity and, probably, length of the illness.2435 In acute, short-term trauma such as cardiac bypass36 or in short-term starvation,37 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 µg/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. It is suggested that thyroid hormone supplementation might be a potential benefit in infants with the lowest T4 values.27

Total serum T4 is reduced in part 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 in 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.38 Further studies by this group demonstrated the presence of a cleaved form of TBG present in serum of patients with sepsis.39

The impact of meningococcal sepsis on peripheral thyroid hormone metabolism and binding proteins was studied in 69 children with meningococcal sepsis. All children had decreased total T3 and total T3/rT3 ratios without elevated TSH. Lower total T4 levels were related to increased turnover of TBG by elastase. Lowered TBG is a partial explanation for lower total T4 and T3 in NTIS.40

Serum Free Thyroxine

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, although it is in fact intracellular T3 that binds to the receptors. The results of free T4 assays in NTIS are definitely method dependent. They 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 TBG capacity to estimate free hormone typically return low values for calculated free thyroxine in NTIS. Methods using T3 analogs in the assay also give levels that are depressed. The free T4 level determined by dialysis varies widely, as does T4 measured by ultrafiltration2529; the majority of reports are of normal or low values but in some samples, elevated values.25,26,4143

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.44 However, these compounds probably do not interfere with serum hormone assays. Free fatty acids, if elevated to 2 to 5 mmol/L, can displace T4 binding to TBG and elevate free T4. Free fatty acids almost never reach such levels in vivo.45,46 However, even small quantities of heparin (0.08 units/kg given IV, or 5000 units given SC), commonly given to patients in an ICU, can lead to in vitro generation of free fatty acids during extended serum dialysis for “free T4” assay and falsely augment apparent free hormone levels.47 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.48 found that in patients with NTIS, free T4 measured by ultrafiltration was uniformly low (average of 11.7 ng/L), but when measured by equilibrium dialysis, free T4 was near normal, at 18 ng/L. By ultrafiltration, free T3 was also (not surprisingly) found to be low and similar to free T3 by radioimmune assay. Chopra32 found 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 clearly below the mean of normals.

Thus, although free T4 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 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.49 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.44,45,5053 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.

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. 15-2).54 These researchers gave 1.5 µg of T4 per kg body weight daily to 12 of 24 patients with severe NTIS and followed serum hormone levels over 14 days. T4 levels returned to the normal range within 3 days of therapy. Thus the thyroxine 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 who survived. However, the ability of intravenous thyroxine in replacement doses to promptly restore the plasma pool to normal clearly shows that neither a loss of serum TBG nor an inhibitor of binding could be the main cause of low serum T4 in this group of severely ill patients.

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FIGURE 15-2 Patients with severe NTIS were randomized and left untreated (control, solid lines) or given IV T4 (thyroxine-treated group, dashed lines) over 2 weeks.54 Serum T3, T4, and TSH concentrations are shown for the survivors of the control (filled circles) and T4-treated groups (open circles) during the study period and at the time of follow-up. NTIS, Nonthyroidal illness syndrome; IV, intravenous; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

TSH Levels

Serum TSH in NTIS is typically normal or reduced and may be markedly low, although usually not less than 0.05 µU/mL.16,24,25,28,29,31,55 However, to use usual endocrinology logic, these TSH levels are almost always inappropriately low for the observed serum T4 and T3. Third-generation assays with sensitivity down to 0.001 U/mL may allow differentiation of patients with hyperthyroidism from those with NTIS, although there can be overlap in these very disparate conditions.56 Serum TSH in patients with NTIS may have reduced biological activity, perhaps because of reduced thyrotropin-releasing hormone (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. 15-3).16,29,54 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.

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FIGURE 15-3 T3 and TSH concentrations are shown in patients with nonthyroidal illness who were eventually discharged from hospital (left panels).29 The broken line indicates ±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.29 NTIS, Nonthyroidal illness syndrome; SD, standard deviation; T3, triiodothyronine; TSH, thyroid-stimulating hormone.

Responsiveness of the pituitary to TRH during NTIS is variable: many patients respond less than normal,57 and others respond normally.58 “Normal” responsiveness in the presence of low TSH may suggest that there is a 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,59 and in some studies, there is evidence for reduction of TSH glycosylation, with lower TSH bioactivity.60 A logical alternative explanation is that the low TSH is in fact the proximate cause of the low thyroid hormone levels. Hypothalamic function is impaired in patients with NTIS and, because of low TRH, results in low TSH and thus low output of thyroid hormones by the thyroid.

There is other evidence of diminished hypothalamic function in patients with serious illness. Serum testosterone drops rapidly, as do follicle-stimulating hormone (FSH) and luteinizing hormone (LH).61,62 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 hypoadrenalism, have low or normal serum ACTH, and cortisol levels under 20 µg/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 growth hormone (GH) and TSH secretion are also, as is known, suppressed. Interleukin 1 β (IL-1β) levels are normal, whereas IL-6 and tumor necrosis factor α (TNF-α) are elevated. Exogenous IV gonadotropin-releasing hormone (GnRH) partially return serum testosterone levels toward normal but do not completely overcome hypoandrogenism, suggesting that combined deficiency of GH, GnRH, and TSH secretagogues may be important in this low androgen syndrome.63

Thyroid Hormone Turnover

Kaptein et al.64,65 studied a group of patients who were critically ill, all of whom had total T4 below 4 µg/dL, low fT4 index, low normal free T4 by dialysis, and TSH which was normal or slightly elevated. In these patients, the mean T4 by dialysis was significantly below the normal mean. There was on average a 35% decrease in thyroxine disposal per day (Table 15-1). The T4 production rate in NTIS was significantly below the mean of 17 normal subjects (p < 0.005). In a similar study of T3 kinetics,65 free T3 was found to be 50% of normal serum values. The production rate of T3 was reduced by 83% (Table 15-2). These two 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) should be present. A third study reported dramatically reduced total T4 and T3 turnover, with normal thyroidal secretion of T3 in patients with NTIS due to uremia.66 However, this was a calculated rather than directly measured value, was highly variable, and does not negate the extreme reduction in T3 supply due to diminished T4>T3 conversion in peripheral organs.

T4 Entry into Cells and Generation of T3

Using deiodination of T4 as an index of cellular transport of T4 into rat hepatocytes, Lim et al.67 and Vos et al.68 found that serum from patients with NTIS inhibited T4 uptake. Sera from critically ill NTIS patients caused reduced T4 uptake compared to control sera in one study, and the authors considered elevated nonesterified fatty acids (NEFA) and bilirubin and reduced albumin to play a role. Serum from patients with mild NTIS did not cause impaired deiodination of T4 and T3.69 Inhibition of uptake of T4 into hepatocytes caused by sera of patients with NTIS also was observed by Sarne and Refetoff.70 There is a diminution in the “reducing equivalents” available for the deiodination of T4 to T3 in liver, and presumably elsewhere, thus lowering transport and the function of the type 1 iodothyronine deiodinase.71 In animals, and probably in man, there is also a drop in the level of type 1 iodothyronine deiodinase enzyme, apparently 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 its increased metabolism in NTIS, thus lowering the intracellular T3 levels.35

In theory, reduced 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 at a reduced rate. 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.72 In one study, there was of a dramatically reduced level of T3 in tissues (Table 15-3). 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.73 investigated 79 patients who died after intensive care, some of whom received 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.73

Information on expression of TRs in human tissues during illness is limited. Increased expression of the messenger ribonucleic acid (mRNA) for thyroid hormone receptors α1, α2, and β1 has been reported in cardiac tissue of patients with dilated cardiomyopathy; α1 and α2 isoforms also had increased expression in ischemic heart disease.74 Rodriguez-Perez et al. studied subcutaneous fat and skeletal muscle in patients with septic shock.75 In muscle, mRNA for TRβ1 and RXR gamma was reduced, and mRNA for RXR alpha was increased, compared to normals. In adipose tissue, MCT8, TRβ1, TRα1, and RXR gamma mRNAs were lower. The authors conclude that in these patients, tissue responses were oriented toward decreased hormone levels and decreased hormone action. 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.7677

Are Patients with NTIS Clinically Hypothyroid?

It is straightforward that the clinical parameters of severe hypothyroidism are absent in patients with NTIS. However, these patients usually present with a serious illness and are diagnostically challenging in view of their complicated state. Many are febrile, have extensive edema, have sepsis or pneumonia, may have hypermetabolism associated with burns, have severe cardiac or pulmonary disease, and in general have features that could easily mask evidence of hypothyroidism. Further, the common clinical picture of hypothyroidism does not develop within 2 to 3 weeks of complete thyroid hormone deprivation, but rather requires a much longer period for expression. General laboratory tests are also suspect. Thus starvation or disease-induced alterations in cholesterol, liver enzymes, TBG, creatine kinase, and even basal metabolic rate generally rule out the use of these associated markers for evidence of hypothyroidism. Angiotensin-converting enzyme levels are low,78 as seen in hypothyroidism, while high-affinity testosterone-binding globulin (TeBG) and osteocalcin levels are not altered.79 Antithrombin III levels are reduced in a septic rat model of NTIS. T3 supplementation returned the sepsis-induced decrease in antithrombin III levels toward normal.80