The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 1 151-164
Copyright © 1999 by The Endocrine Society
Dangerous Dogmas in Medicine: The Nonthyroidal Illness Syndrome
Leslie J. De Groot
Thyroid Study Unit, University of Chicago, Chicago, Illinois
60637
Address all correspondence and requests for reprints to: Dr. Leslie J. De Groot, Thyroid Study Unit, University of Chicago, Chicago, Illinois 60637.
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Introduction
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For more than 3 decades it has been known
that serum thyroid hormone levels drop during starvation and illness.
In mild illness, this involves only a decrease in serum
T3 levels. However, as the severity of the
illness increases, there is a drop in both serum
T3 and T4 (1). This
decrease in serum thyroid hormone levels is seen in starvation (2),
sepsis (3, 4), surgery (5), myocardial infarction (6, 7), bypass (8),
bone marrow transplantation (9), and, in fact, probably any severe
illness. Based on the conviction that patients with these abnormalities
are not hypothyroid despite the low hormone levels in blood, the
condition has been called the euthyroid sick syndrome. An alternative
designation, which does not presume the metabolic status of the
patient, is nonthyroidal illness syndrome (NTIS). NTIS seems a
preferable name in light of present knowledge and will be used in this
review.
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Low T3 states
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Starvation in man and animals causes a prompt decline in serum
T3 and serum free T3 along
with a drop in basal metabolic rate (BMR). As noted previously, almost
any severe infection, trauma, or illness likewise causes a drop in
serum T3 levels, but it is often difficult to
differentiate the effects of these problems from short term starvation.
Starvation, more precisely carbohydrate deprivation, appears to rapidly
inhibit deiodination of T4 to
T3 by type 1 iodothyronine deiodinase in the
liver, thus inhibiting the generation of T3 and
preventing the metabolism of rT3 (10).
Consequently, there is a drop in serum T3 and an
elevation in rT3. As starvation induces a
decrease in the BMR (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. This would
logically be a beneficial response for an otherwise well animal or man
facing temporary starvation. Patients who have only a drop in serum
T3, representing the mildest form of NTIS, do not
show clinical signs of hypothyroidism, nor has it been shown that this
decrease in serum T3 has an adverse physiological
effect on the body or that it is associated with increased
mortality.
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NTIS with low serum T4
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As the severity of illness, and often the associated starvation,
progresses, there is the gradual development of a more complex syndrome
associated with low T3 and low
T4 levels. In this state serum free
T4 levels are commonly below normal, but may be
normal or above normal, as described below. Generally, TSH levels are
low or normal despite the low serum hormone levels, and
rT3 levels are normal or elevated. The depression
of serum T3 alone represents the least marked
abnormality in NTIS, but there is no clear separation of this response
from the more severe syndrome. Rather, there seems to be a gradual
progression from a low T3 level to the most
advanced condition in serious illness, associated with extremely low
T3 and T4 levels. Most
patients with serious illness in the hospital have low serum
T3 levels. A large proportion of patients in an
intensive care unit setting have various degrees of severity of NTIS
with low T3 and T4
levels.
The reason for interest in this syndrome is not simply to understand
its physiology. A marked decrease in serum T4 is
associated with a high probability of death. When serum
T4 levels drop below 4 µg/dL, the probability
of death is about 50%; with serum T4 levels
below 2 µg/dL, the probability of death reaches 80% (12, 13, 14, 15).
Obviously, this raises the question of whether replacement of thyroid
hormone would be beneficial in such patients and could increase their
chance of survival. The dogma in endocrinology, accepted and supported
by most individuals in the field over the past 3 decades (15, 16, 17), has
been that this is a beneficial physiological response and that "it is
difficult to advocate or even defend treatment of NTI patients" (18).
However, as described below, there is no factual basis for this
dogma.
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Physiological interpretations of NTIS
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Five 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. 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 the action of hormone. 3) In NTIS, T3
levels in the pituitary are normal because of enhanced local
deiodination. Thus, the pituitary is actually euthyroid, whereas the
rest of the body is hypothyroid. This presupposes enhanced
intrapituitary T4
T3
deiodination as the cause. 4) Serum hormone levels are, in fact, low,
and the patients are biochemically hypothyroid, but this is
(teleologically) a beneficial physiological response and should not be
altered by treatment. 5) Lastly, 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 T4 levels are depressed below the danger
level of 4 µg/dL.
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What are the serum hormone levels and tissue hormone supplies in
NTIS?
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Serum T3 and free
T3. With few exceptions, reports on NTIS
indicate that serum T3 and free
T3 levels are low (19, 20, 21, 22, 23, 24). Chopra and co-workers
have recently reported that free T3 levels were
low (Fig. 1
) (25) or, in a second report,
normal (26). However, it is important to note that in the latter report
the patients with "NTIS" actually had average serum
T4 levels that were above the normal mean.
Although it is uncertain which study should be given precedence, it is
clear that most of the subjects in the latter report did not have
severe NTIS.
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Figure 1. Free T3 concentrations in
different groups of patients, as reported by Chopra et
al. (25 ). In this report, patients with NTIS have significantly
lowered free T3 levels than those in normal subjects.
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Serum T4. Serum
T4 levels are reduced in NTIS in proportion to
the severity and probably the length of the illness (17, 18, 19, 20, 21). In acute,
short term trauma, such as cardiac bypass (27), or short term
starvation (28), 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, the prognosis becomes extremely
guarded.
Serum free T4. The major problem in
understanding the 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 (FFA) in the serum or assay.
Assays that employ a resin uptake method to estimate free hormone
usually return low values for calculated free T4 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 (19, 20, 21, 22, 23), but the majority of reports are
of normal or low, and in some samples even elevated, values.
In theory, methods using equilibrium dialysis may allow dilution of
dialyzable inhibitors, including compounds such as
3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indoxyl sulfate,
and hippuric acid, which can accumulate in severe renal failure (29).
However, in the absence of renal failure, these compounds are not
present in serum at a sufficiently high level to interfere in any
assay. FFA, if elevated to 2–5 mmol/L, can displace
T4 binding to albumin and elevate free
T4. FFA almost never reach such levels in
vivo (30, 31). However, even small quantities of heparin (0.08
U/kg, iv, or 5000 U, sc) can lead to in vitro generation of
FFA during extended serum dialysis and falsely augment apparent free
hormone levels (32). As heparin is so universally employed for the
prevention of thrombotic episodes in patients in intensive care units
and in other settings during severe illness, this is probably a
widespread and serious problem, which may explain many instances of
apparently elevated free T4 levels in patients
with acute illness.
One of the most thorough comparative studies of serum
T4 assays was reported in 1982 by Melmed et
al. (20). Free T4 was measured by six
methods, including dialysis, and was found to be uniformly reduced as
measured by all methods in patients in the MICU, whereas results
were more variable for patients with liver disease or chronic renal
failure (see below). A problem to be noted in reviewing these reports
has to do with the categorization of patients. Patients reported with
NTIS who have normal serum T4 typically will not
have reduced free T4 by most assay methods.
However, when patients with low serum T4 are
studied separately, the results become more uniform. In an extensive
comparison of methods by Kaptein and associates (21), free
T4, measured by five methods, was extremely low
in patients with NTIS who had a serum T4 level
under 3 µg/dL. However, free T4 was in the
normal range in patients when measured by two commercial methods and by
equilibrium dialysis. Uchimura et al. (33) studied the
effect of dilution of serum on free T4 and found
that it caused up to a 30% reduction in apparent free
T4. This reduction caused by dilution of course
also applied to serum standards. Thus, values obtained by study of
undiluted serum or diluted serum or using indirect methods for
establishing the free T4 concentration all gave
values that closely correlated. Nelson and Weiss (34) also studied the
effect of serum dilution on free T4. They found
that using a tracer dialysis method, there was progressive reduction in
free T4 values with serum dilution. The change
with dilution of free T4 in serum from a normal
patient and from a patient with NTIS varied in parallel. Thus, by this
method, despite dilution, values for the NTIS patient appeared low.
However, using a method that they believe is more appropriate,
measuring T4 in the dialysate by direct RIA, sera
from patients with low T3 syndrome frequently
gave high values when undiluted and normal or even low values when
diluted. Nelson and Weiss are convinced that the direct RIA method is
correct, and that the alterations reflect the presence of dialyzable
inhibitors in the serum altering the measurement of free
T4.
Results obtained using ultrafiltration also are variable. Wang et
al. (35) found that in patients with NTIS, free
T4 measured by ultrafiltration was uniformly low
(average, 11.7 ng/L), but when measured by equilibrium dialysis, free
T4 was near normal (18 ng/L). By ultrafiltration,
free T3 also, not surprisingly, was found to be
low and similar to free T3 by RIA. The
researchers suggest that the observations with ultrafiltration are more
apt to be erroneous due to the effect of inhibitors of binding, in
contrast to the results of dialysis, which they assume are correct.
Chopra et al. (25) recently 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 µg/dL), and these
patients would not be expected to have low free
T4 levels. The second study from this group
recently published is noted above. Surks et al. (19) studied
T4 levels by equilibrium dialysis and
ultrafiltration of undiluted serum. Although the researchers report
that the results in patients with NTIS were "similar to or higher
than those in 12 normal subjects," in fact seven of nine patients had
levels below the normal mean (±2 SD) when measured by
dialysis, six of nine were low when measured by ultrafiltration, and
seven of nine were low when measured by standard resin uptake-corrected
free T4. The means of the NTIS patients in this
study were clearly below the normal mean.
Thus, it is still a question as to whether the free
T4 in patients with NITS is actually low or
normal, and even sometimes elevated. 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 that of
total T4. Secondly, factors that affect thyroid
hormone binding are more apt to alter T4 assays
than T3, as T4 is normally
more tightly bound to TBG than is T3.
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Is there evidence for substances in serum that can affect
T4 binding to proteins?
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In patients with advanced renal disease who have not been recently
dialyzed, there is possibly an accumulation of substances, as noted
above, that can alter binding of T4 (29). These
materials could be dialyzed out promptly during assays of free hormone
and therefore cause the assay to record an apparently low free
T4. Evidence for dialyzable and nondialyzable
inhibitors of T4 binding has been presented by
Chopra (36). The material in serum was thought possibly to be fatty
acids. In contrast, Mendel and colleagues (37) found no evidence for an
inhibitor of T4 binding to serum proteins in a study of a
series of 111 patients from acute care wards. It should be noted that
almost all subjects had T4 values within the
normal range. Only 3 had values below 4 µg/dL. Thus, the patients may
not have been optimal for studying evidence of a binding inhibitor. As
reviewed by Mendel et al. (37), one of the main concerns
regarding an inhibitor of binding is the potential effect of elevated
FFA levels in starving NTIS patients. Levels of FFA above 5 mmol/L,
with a molar ratio of FFA to albumin of more than 5, may produce this
abnormality. In the patients studied by Liewendahl (30) and Csako
et al. (38) and in the study by Mendel et al.
(37), FFA levels were below this level. Thus, FFA levels in serum
samples taken from patients ordinarily are not high enough to cause a
problem, although remarkably elevated FFA levels were found in the
series of patients reported by Chopra et al. (39). A more
serious problem may occur if low doses of heparin have been given, as
noted above. FFA can be generated during the incubation procedure, as
reported by Jaume et al. (32). In this situation, there may
be a progressive increase in FFA during prolonged dialysis, causing a
spurious increase in the free T4 fraction. Mendel et
al. (37) carefully reviewed 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. Numerous artifacts are
present in both dialysis assays and ultrafiltration assays. They also
point out, that although the low free T4 levels
found by resin uptake assays 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.
A strong argument against the importance of factors in serum inhibiting
binding of thyroid hormone is provided in the clinical study of Brendt
and Hershman (Fig. 2) (40). These
researchers gave 1.5 µg T4/kg BW 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 T4 pool was easily
replenished, and T4 levels reached normal values.
Not surprisingly, because of reduced
T4T3 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 T4 to restore the
plasma pool to normal clearly shows that an inhibitor of binding could
not be the predominant cause of low serum T4 in
this group of severely ill patients.
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Figure 2. Patients with severe NTIS were randomized
and left untreated or were given T4 iv over 2 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. The shaded area designates the normal range.
Note the prompt recovery of T4 values to the normal range
immediately after iv treatment with T4. Also note the
elevated TSH levels in some patients. T3 levels did not
return to normal after T4 treatment for up to 2 weeks
(40 ).
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TSH levels
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Serum TSH in NITS is typically normal or reduced and may be
markedly low, although it is usually not less than 0.05 µU/mL (19,
20, 22, 25; reviewed in Refs. 17, 41). However, to use usual
endocrinological logic, these TSH levels are almost always
inappropriately low for the observed serum T4.
Third generation assays with sensitivities as low as 0.001 µU/mL may
allow differentiation of patients with hyperthyroidism (a rare problem
in differential diagnosis) to be separated from those with NTIS,
although there can be overlap in these very disparate conditions (42).
There is a suggestion that 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 if
patients recover (Fig. 3) (17, 23, 40).
This elevation of TSH strongly suggests that the patients are
recovering from a hypothyroid state.
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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 ±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 (23 ).
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Responsiveness of the pituitary to TRH during NTIS is variable; many
patients have a less than normal response (43), and others respond
normally (44). Normal responsiveness in the presence of low TSH may
suggest that there is a hypothalamic abnormality that is a cause of the
low TSH and low T4. There is also a diminution,
or loss, of the diurnal rhythm of TSH (45), and in some studies there
is evidence for a reduction of TSH glycosylation with lower TSH
bioactivity (46). That TSH is not elevated in the presence of low
T4 is taken to mean that the patients are not
hypothyroid. An easy and perhaps more logical alternative explanation
is that the low TSH is, in fact, the proximate cause of the low thyroid
hormone levels. As will be shown later, there is reason to believe that
hypothalamic function is impaired in patients with NITS, and that this
may, because of low TRH, result 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 does FSH and
LH (47, 48).
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Thyroid hormone turnover
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The daily turnover (tissue supply) of thyroid hormone can be
estimated from the serum hormone concentration and the disappearance
curve of injected isotopically labeled T4 or
T3. Daily degradation of T4
and T3 has long been considered the most exact
method for analyzing the supply of thyroid hormone to the body tissues.
In numerous studies, there is a marked correlation with clinical status
in patients with normal function or hyper- or hypothyroidism. There are
few studies of T4 and T3 metabolism
in patients with NTIS. Among those available are the outstanding
studies by Kaptein et al. (49, 50), who studied a group of
patients who were critically ill, all of whom had total
T4 below 4 µ/dL, low free
T4 index, free T4 by
dialysis that was low normal, and TSH that was normal or slightly
elevated. In these patients, the mean T4
determined by dialysis was significantly below the normal mean. There
was, on the average, a 35% decrease in T4 disposal per
day. Although the researchers state that the T4 production
rate was normal, the T4 production rate in NTIS
was significantly below the mean of 17 normal subjects
(P < 0.005; Table 1).
The MCR of T4 from serum was more rapid in the critically
ill patients, which may in part be related to reduced TBG levels. In a
similar study of T3 kinetics (50), free
T3 was found to be 50% of normal serum values.
The production rate of T3 was reduced by 83%
(Table 2). The MCR of
T3 during the period after initial distribution
was actually slower than that in normal subjects, in contrast to the
findings with T4. These two studies document a
dramatic reduction in provision of T4 and
T3 to peripheral tissues, which would logically
indicate that the effects of a lack of hormone (hypothyroidism) should
be present. However, the researchers observe that "use of
T4 therapy would not appear to be appropriate,
since there is no proof of an overt deficiency of free
T4," and the "low T3
levels may be of adaptive significance in reducing protein catabolism,
potentially making T3 therapy detrimental"
(50). The reasons to object to this teleological analysis have been
given, and whether reduced protein catabolism could be beneficial will
be discussed below. One study reported normal thyroidal secretion of
T3 in patients with NTIS due to uremia (Table 3) (51). However, this was a calculated,
rather than directly measured, value, was exceedingly variable, and did
not negate the extreme reduction in T3 supply due
to diminished T4T3
conversion.
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T4 entry into cells
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Using deiodination of T4 as an index of
cellular transport of T4 into rat hepatocytes,
Lim et al. (52) and Vos et al. (53) found that
serum from critically ill NTI patients caused reduced uptake compared
to control serum and considered elevated nonesterified fatty
acids and bilirubin, and reduced albumin, to play a role. Serum
from patients with mild NTIS did not cause impaired deiodination of
T4 and T3 (54). Inhibition
of uptake of T4 into hepatocytes caused by sera
of patients with NTIS also was observed by Sarne and Refetoff (55). In
theory, reduced cellular uptake would cause tissue hypothyroidism,
reduced T3 generation and serum
T3 levels, and elevated serum
T4. Except for the serum T4
levels, this hypothesis would explain many of the changes in hormone
economy seen in NTIS and would also suggest a need for replacement
hormone therapy. It is likely that the reduced hormone supply in NTIS
is caused by multiple factors, and that reduced cell uptake is one of
the factors.
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Thyroid hormone in tissues
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Only one study has provided significant data on thyroid hormone in
tissues of patients with NTIS (56). The general finding was of a
dramatically reduced level of T3 in all tissues
(Table 4). Although 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. These levels exceeded a level that could be brought about by
contamination with serum T3 and suggest, if the
assays are correct, that there may have been, for some reason, a
deposition of T3 in these tissues. This
mysterious and important observation awaits clarification, but the main
finding of this study is the generally low level of
T3 in tissues.
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Are patients with NTIS hypothyroid?
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It is clear that the usual clinical parameters of hypothyroidism
are absent in patients with NTIS. However, these patients usually
present with an acute illness and are diagnostically challenging in
view of their complicated states. 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 even 2–3 weeks, but requires a much longer period for
expression (57).
General laboratory tests are also suspect. Thus, starvation or
disease-induced alterations in cholesterol, liver enzymes, TBG,
creatine phosphokinase, and even BMR generally rule out the use of
these associated markers for evidence of hypothyroidism.
Angiotensin-converting enzyme levels are low (58), as seen in
hypothyroidism, whereas TEBG and osteocalcin levels are not
altered (59).
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Mechanism of thyroid hormone suppression in NTIS
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It is probable that the cause of NTIS is 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 (see below).
Certainly, one important cause of the drop in serum
T3 is a decreased generation of
T3 by type 1 iodothyronine deiodinase in liver
and a reduced degradation of rT3. The net result
is a drop in serum T3 and, if substrate
T4 is present in sufficient amount, an increment in serum
levels of rT3. This drop in
T3 is induced by starvation, especially by
carbohydrate starvation, and is possibly related to the reduction in
reducing equivalents needed in the liver in the enzymatic process for
T4 deiodination to T3 (60). Possibly,
as described above, entry of thyroid hormone into cells is abnormal, so
that T4 substrate is not adequately provided to
the intracellular enzymes. However, it is logical to assume that if
reduced entry 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 (61).
However, the bulk of evidence does not favor selenium deficiency.
As described above, another major hypothesis is that part of the change
in serum hormone levels is due to the presence of inhibitors of binding
of T4, and perhaps T3, to
serum proteins. This evidence has been discussed above and need not be
reviewed again here. The most compelling evidence against this concept
as a major problem in humans is the observations by Brendt and Hershman
(40). Repletion of T4 iv served to elevate hormone levels
to normal in patients with NTIS. Seemingly, this rules out a binding
inhibition as a major factor in the depression of hormone levels.
An alteration in binding of hormones to serum might logically affect
turnover. In fact, as described above, the MCR (liters of serum cleared
of thyroid hormone per day) for T4 is augmented in patients
with NTIS, and that for T3 is normal. The changes
recognized in the study by Kaptein et al. (49, 50) are
modest and may reflect only an alteration in serum binding protein
levels rather than another effect. However, it is the total micrograms
of T3 and T4 produced each
day, rather than the kinetics, that correlate with the metabolic
effect.
The overall degradation of thyroid hormone, both T4 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.
Considerable evidence suggests that an alteration in hypothalamic and
pituitary function causes the low production of thyroid hormone. In
rats, starvation reduces hypothalamic messenger ribonucleic acid (mRNA)
for TRH, reduces portal serum TRH, and lowers pituitary TSH content
(62). A recent study documents low TRH mRNA in hypothalamic
paraventricular nuclei (63) in NTI patients (Fig. 4). Responses to administered TRH vary in
different reports, being suppressed or even augmented (43, 44).
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) (64). These data are strong
documentation of the role of diminished hypothalamic function as a, or
perhaps the, cause of NTIS.
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Figure 4. In situ hybridization study
demonstrating mRNA for TRH in the periventricular nuclei of a subject
who died with NTIS (A) and a subject who died accidentally (B). The
level of mRNA for TRH is significantly reduced in patients with NTIS
(63 ).
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Figure 5. The study demonstrates the effect of
infusion of 1 µg/kg·h TRH compared with placebo, TRH plus GHRP-2 (1
µg/kg·h), or the combined treatment. Values for mean serum TSH and
basal and pulsatile TSH secretion are shown in the upper
panel, and 24-h changes in peripheral thyroid hormone levels in
the three study groups are shown in the lower panel. TRH
infusion increased TSH secretion and TSH, T4,
T3, and rT3 levels (64 ).
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Quite possibly the production of TRH and responses to TRH are induced
by cytokines, to be discussed below, or glucocorticoids (65). The
diurnal variation in glucocorticoid levels at least in part controls
the normal diurnal variation in TSH levels, perhaps by affecting
pituitary responsiveness to TRH (66). High levels of glucocorticoids in
Cushing’s disease suppress TSH and cause a modest reduction in serum
hormone levels (67). High levels of glucocorticoids are known to
suppress the pituitary response to TRH in man (65). Stress-induced
elevation of glucocorticoids in animals causes suppression of TSH and
serum T4 and T3 hormone
levels (68). Thus, possibly, stress-induced glucocorticoid elevation
may be one factor affecting TRH and TSH production.
Pituitary production of TSH is probably radically suppressed in most
patients with the euthyroid sick syndrome, who have low levels of TSH
in the presence of reduced levels of serum T3 and
T4. At a minimum, pituitary responsivity must be
abnormal, considering that TSH is normal or suppressed when it should
be elevated, in the presence of low serum hormone levels. As we have
been able to ascertain, no studies on the effect of administered human
TSH have been reported to date (NTIS may constitute yet another use of
recombinant human TSH.)
Why should pituitary production of TSH be diminished in the presence of
low serum thyroid hormone levels? One idea, without proof, is that it
represents a response to hyperthyroidism, which has not been
documented. Another possibility is that there is augmented
intrapituitary conversion of T4 to
T3, thus allowing the pituitary to remain
"euthyroid" while the rest of the body is actually hypothyroid.
There is experimental support for this idea in a uremic rat model of
NTIS (69). Another suggestion is that some other metabolite of
T4 may be involved in the control of pituitary
responsiveness. For example, possibly Triac or Tetrac
generated by metabolism of T4 could control pituitary
responsiveness (70), but there is no experimental proof of this idea,
and even if true, it would mean that the pituitary was normal but the
rest of the body was 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 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.
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Cytokines in NTIS
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Much current attention is centered on the role of cytokines in
developing the euthyroid sick syndrome through an effect on the
hypothalamus, the pituitary, or possibly elsewhere. Hermus et
al. (71) showed that continuous infusion of interleukin-1 (IL-1)
in rats caused 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 (73). Vanderpool et al. (74) studied
the effect of IL-1 receptor blockade in human volunteers to determine
whether 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 the rise in
rT3 caused by endotoxin. This is evidence against
an important role for IL-1.
Tumor necros factor-
(TNF) is another proinflammatory cytokine
that is thought to be involved in many of the illnesses associated with
NTIS. Infusion of recombinant TNF in man, as reported by Vanderpool
et al., produced a decrease in serum
T3 and TSH and an 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 when
recombinant IL-6, given to humans, activates the hypothalamic pituitary
axis, and as noted above, this could secondarily suppress TSH
production. However, Chopra et al. (76) did not find TNF
to be closely correlated with hormone changes in NTIS.
Serum IL-6 is often elevated in NTIS (77), and its level is inversely
related to T3 levels (78). Stouthard et
al. (79) 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 caused only a modest decrease in
T3 and a transient increase in
rT3 and 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 (80),
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 interferon-
, IL-8, and IL-10 in patients with
NTIS and found no evidence that they had a pathogenic role (81).
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Figure 6. IL-6 was administered over 6 weeks, and
changes in thyroid hormone levels and TSH were recorded. Except for a
transient elevation in rT3 and a minimal suppression of
T3, no significant alteration in hormone levels was
produced.
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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 the 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 receptor
antagonist are receptor antagonists that can inhibit the
function of the free cytokines. These molecules are increased in many
infectious, inflammatory, and neoplastic conditions. Boelen et
al. (82) found evidence that 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. The
researchers concluded that the elevations of soluble TNF receptor
and IL-6 were independent determinants of serum
T3 and accounted for 35% and 14%, respectively,
of the change in T3. At least we can be convinced
that these cytokine changes cooccur with changes in
T3 and may play a pathogenic role by mechanisms
yet unknown.
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Other factors altering serum T4 supply
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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 (83).
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 in the T3/rT3
ratio (78). All of these changes suggested to Van den Berghe et
al. (84) that dopamine makes some patients with NTIS hypothyroid,
inducing a condition of iatrogenic hyperthyroidism, and that treatment
(presumably by administering thyroid hormone) "should be
evaluated."
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Thyroid hormone changes in patients with liver and renal
disease
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Patients with alcoholic liver disease, as reported by Walfish
et al. (85), tend to have low serum T3
levels, slightly reduced T4 levels, and elevated
free T4 indexes because of low binding proteins.
These changes were associated with increased mortality. In chronic
biliary cirrhosis and chronic active hepatitis, as studied by
Liewendahl (86), elevated TBG may be found associated with normal free
T3 and free T4 levels.
Chopra et al. (87) studied patients with hepatic cirrhosis
and found free T4 to be significantly elevated,
T3 to be markedly reduced, free
T3 to be low, and TSH to be slightly above
normal. Assessment of a variety of clinical parameters suggested that
the patients were euthyroid. The researchers concluded that in this
instance, euthyroidism is maintained by the high normal or slightly
elevated serum free T4 levels. It should be noted
that the mean free T4 level in the patients
studied by Chopra was 3.9 ng/100 mL, which falls well within the range
of normal reported by the researchers of 1.8–4.2 ng/dL and is not
characteristic of NTIS. It is probable that some of the distinctive
effects of liver disease on thyroid hormone economy are due to changes
in the synthesis of TBG, possibly the effect of hyperestrogenism, and
probably reduced deiodination of T4 to
T3 in the liver.
Kaptein et al. (88) studied patients with acute renal
failure and found decreased serum T4 and
T3 levels and normal or elevated levels of free
T4 and TSH in patients with acute renal failure,
but not in those with critical illness. In this group of patients,
rT3 levels tended to be normal. Ramirez et
al. (89) studied patients receiving chronic hemodialysis and found
a striking prevalence of goiter (58%) and low serum T4,
T3, and TSH levels. TRH caused an increase in
serum TSH and T3 levels, suggesting a suppression
of pituitary function in these patients. Lim and co-workers (90)
studied the thyroid hormone supply in a uremic rat model and found
changes similar to those seen in uremic man, including low serum
T3, low serum T4, low serum
TSH, and low liver T3 content.
T3 treatment of the animals increased low liver
enzyme activity, and the researchers conclude that the reduction in
liver T3 content in the uremic rat and the low
enzyme activity indicate hypothyroidism. The T3
nucle
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Introduction
Low T3 states
