Nonthyroidal Illness Syndrome: A Form of Hypothyroidism

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Chapter 15

Nonthyroidal Illness Syndrome

A Form of Hypothyroidism

Leslie J. De Groot

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.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 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,^14–17 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%.^21–23 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.24–30 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

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.24–35 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 ultrafiltration 25–29; the majority of reports are of normal or low values but in some samples, elevated values.^{25,26,41–43}

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.^{44,45,50–53} 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.

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.

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.

Table 15-1

T₄ Kinetics in the Low T₄ State of Nonthyroidal Illness ⁶⁴

All P values are for unpaired t tests.

FT₄, Free thyroxine; PR, production rate; TT₄, total thyroxine.

^*Patients receiving dopamine.

Table 15-2

T₃ Kinetics in the Low-T₄ State of Nonthyroidal Illness ⁶⁵

FT₃, Free triiodothyronine; PR, production rate; TT₃, total triiodothyronine.

^*Patient receiving dopamine.

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.

Table 15-3

Tissue T₃ Concentrations in Nonthyroidal Illness Syndrome (nmol of T₃/kg of Wet Weight)⁷²

NS, Not significantly different; NTI, nonthyroidal illness; T₃, triiodothyronine. *Patients receiving dopamine.

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.^76–77