Euthyroid Sick Syndrome: Is It a Misnomer?
Inder J. Chopra
Department of Medicine, University of California Center for the
Health Sciences, Los Angeles, California 90024
Address all correspondence and requests for reprints to: Inder J. Chopra, M.D., Department of Medicine, University of California School of Medicine, Los Angeles, California 90024.
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Introduction
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THE TERM euthyroid sick syndrome (ESS)
identifies abnormalities in thyroid function tests observed in patients
with systemic nonthyroidal illnesses (NTIs) and those undergoing
surgery or fasting (1, 2). The term nonthyroidal illness syndrome
(NTIS) has also been employed to describe these abnormalities (3).
These abnormalities result from variable, usually reversible,
disturbances in the hypothalamo-pituitary-thyroid axis, thyroid hormone
binding to serum proteins, tissue uptake of thyroid hormones, and/or
thyroid hormone metabolism. Several recent reviews have addressed these
issues (3, 4, 5, 6). I shall focus mainly on the clinical diagnosis,
significance, and treatment of ESS.
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NTIS
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Abnormalities of thyroid function in NTIS have been classified as
1) low T3 syndrome, 2) low T3-low
T4 syndrome, 3) high T4 syndrome, and 4) other
abnormalities (7).
Although serum concentrations of total T3 and
T4 are now measured routinely by similar RIAs, several
methods have been employed for measurement of the small, biologically
active, free fraction of T3 and T4 (8, 9, 10, 11, 12, 13, 14).
Most workers in the field view the measurement of free thyroid hormones
by equilibrium dialysis as the gold standard, and the ultrafiltration
method is comparable or a close second. Until recently, tracer
equilibrium dialysis was believed to be the most accurate procedure for
measurement of free T3 or T4. This is expected
to be increasingly replaced by the newer, more accurate, equilibrium
dialysis/RIA (12, 14); reasonably priced kits are available
commercially for free T4 measurement by this procedure
(Nichols Diagnostics, San Juan Capistrano, CA) and should be
available soon for free T3 measurement. A detailed
discussion of methods of measurement of free thyroid hormones is beyond
the scope of this minireview, and the reader is referred to several
studies comparing available procedures (9, 10, 13). The analog methods
for free thyroid hormone measurements are popular in several countries
outside of the United States. These methods yield free thyroid hormone
readings in NTI that are similar to those from the index method and
different from those by the tracer equilibrium dialysis or equilibrium
dialysis/RIA procedures (9, 10, 13). For this review, I have relied
mainly on free thyroid hormone levels measured by the newer equilibrium
dialysis/RIA procedure when data are available, or those measured by
tracer dialysis and/or ultrafiltration procedures.
Low serum total T3 is the most common abnormality in NTI.
It is observed in about 70% of hospitalized patients. Serum total
T3 may vary from undetectable to normal in patients with
systemic illness, and the mean value is approximately 40% of the
normal level. The serum free T3 concentration as measured
by direct equilibrium dialysis/RIA [free T3(D)] is also
decreased, but less severely, and the mean value is approximately 60%
that of normal (14). The serum free T3 concentration
measured by ultrafiltration is either normal or reduced (11). Low
values were observed in patients given dopamine. It is curious that
free T3 was often low in NTI when measured by equilibrium
dialysis (14) and typically normal when measured by ultrafiltration
(11). The discrepancy is possibly explained by the lower total
T3 and more severe NTI in patients determined by
equilibrium dialysis than by ultrafiltration. Free T3 in
systemic illness has also been measured by a variety of other
techniques and has been found to be low, but the accuracy of these
procedures is questionable in NTI patients (8, 10, 15). When measured,
the daily production rate (PR) of T3 is decreased in NTI
(16, 17), which supports the finding in NTI of low free
T3(D). Serum total T4 and free
T4(D) and, when measured, daily PR-T4 are
normal in the low T3 syndrome (12, 16, 18, 19). A decreased
serum free T3(D) concentration and PR-T3 at a
time when the serum free T4(D) concentration and
PR-T4 are normal reflect decreased conversion of
T4 to T3 in NTI (12, 16, 18, 19). The serum
concentration of rT3 is increased in NTI, except in renal
failure (20). However, daily PR-rT3 is normal, and the
increase in the serum rT3 level is related mainly to the
delayed MCR of rT3, which is predominantly due to decreased
activity of the type I iodothyronine 5'-monodeiodinase (5'-MDI) in
tissues (16); 5'-MDI deiodinates T4 to T3 and
rT3 to 3,3'-diiodothyronine (T2) (21).
The low T3 and low T4 syndrome is observed in
severely ill, frequently moribund, patients, usually admitted to
medical intensive care units. Low serum total T4 correlates
with a bad prognosis (22). The serum concentration of free
T4, as measured by equilibrium dialysis/RIA [free
T4(D)], is normal in most NTI patients with low total
T4 (12). Interestingly, total T4 is often low
in NTI patients even when their serum concentration of immunoassayable
T4-binding globulin (TBG) is clearly normal (8). However,
the free T4 index is frequently low in these patients (7, 9, 10). This combination of findings in NTI has been explained by the
presence in the circulation of an inhibitor of serum (and resin)
binding of thyroid hormones (15, 23). The nature of the inhibitor is
not known. We and others have considered a role for nonesterified fatty
acids in some cases, especially when serum albumin is low (15, 24, 25).
An inhibitor of serum binding of thyroid hormones is present in tissues
(26), and its nature or its leakage into the circulation are not known.
Some investigators do not agree with the existence of such an inhibitor
in the sera of NTI patients (27). On the basis of experiments involving
mixing of normal sera with NTI sera, Mendel et al. (27) were
unable to document the existence of an inhibitor in NTI. They suggested
that diminished serum binding of T4 in NTI patients with
normal immunoassayable TBG is a result of high level of desialylated
TBG (27). This may indeed be the case, but direct measurements of
desialylated TBG were not performed. Interestingly, however, the
researchers observed that desialylated TBG has markedly decreased
avidity for T4, but its avidity for T3 remains
unchanged (27). Therefore, the finding of clearly decreased serum
binding of T3, evidenced by a markedly elevated dialyzable
fraction of T3, in several NTI patients with normal
immunoassayable TBG (8) supports the possibility of a thyroid hormone
binding inhibitor in NTI. When present, a decreased serum concentration
and/or affinity of thyroid hormone binding proteins, especially TBG,
can explain the findings of low total T4 and normal free
T4(D) in NTI. Decreased serum binding of T4 in
NTI is associated with an increased MCR, which, too, contributes to a
decreased serum concentration of total T4. Interestingly,
however, the increase in the MCR of T4 in NTI is not as
much as expected from the degree of reduction in serum binding of
thyroid hormones (4).
The serum free T4 concentration is low in NTI patients
treated with dopamine and corticosteroids, which decrease serum TSH
levels (11, 28, 29, 30). Besides low TSH, factors that may contribute to
the low T4 of NTI include abnormalities in TSH secretion,
decreased biological activity of TSH, and diminished thyroidal response
to TSH (31, 32).
High serum total T4 is seen in some NTI patients, who have
elevated serum concentrations of TBG. Serum TBG is elevated in acute
intermittent porphyria (33) and several liver diseases, including
chronic hepatitis and primary biliary cirrhosis (34). The serum
concentration of free T4(D) is normal in these patients in
the absence of thyroid disease. Serum total T3 may be
normal, but free T3(D) or the free T3 index is
low normal or low as in other patients with NTI. The serum
concentration of rT3 is elevated in NTI patients with high
T4.
Both serum total and free T4(D) concentrations are often
increased in NTI patients treated with amiodarone and iodinated
radiocontrast agents, e.g. iopanoic acid and ipodate used
for oral cholecystography (13, 35, 36). These agents decrease hepatic
uptake of T4 and 5'-monodeiodination of T4 (to
T3) and, in addition, may precipitate hyperthyroidism in
patients with autonomous thyroid nodules by invoking the Jod Basedow
phenomenon (37, 38). The effect of a single dose of oral
cholecystography agents on serum T4 typically lasts less
than 24 h (36, 37, 39). NTI patients with high total and free
T4(D), especially those who have ingested iodine-containing
agents, should be followed carefully for the appearance of typical
hyperthyroidism (38). Serum T3 may be normal or even low
initially because of the effects of the drug and/or NTI on peripheral
conversion of T4 to T3, and it may increase
dramatically during follow-up.
The serum concentration of free T4(D) is elevated in NTI
patients given heparin (40). This is an in vitro artifact
explained by displacement of T4 from binding proteins by
fatty acids generated from the action of lipase(s) on plasma
triglycerides. Total T4 and the free T4 index
are normal in these patients, who are clinically euthyroid.
Infection with human immunodeficiency virus (HIV) produces unusual
alterations in thyroid function, including increases in T4
and TBG, paradoxical decreases in rT3 and the
rT3/T4 ratio, and the maintenance of a normal
T3 and T3/T4 ratio even in severely
ill patients. Serum T3 decreases, however, in critically
ill patients with HIV and pneumocystis infection (41). The basis for
the differences in thyroid hormone abnormalities in HIV compared to
those in other NTIs is not known.
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Pathogenesis of the NTIS
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Some factors that may contribute to major abnormalities of the
NTIS are listed in Fig. 1
. They have recently been
critically reviewed (3, 4, 5, 6). There is evidence for decreased conversion
of T4 to T3 in extrathyroidal tissues in the
NTIS (16, 17, 18, 19), and this may, in turn, be related to decreased activity
and/or concentration of 5'-MDI (42). 5'-MDI has now been cloned in the
rat and man, and it turns out that it belongs to a small group of
selenocysteine-containing proteins (43, 44). No data are available on
the tissue content of the 5'-MDI protein or its messenger ribonucleic
acid in human NTIS. However, the hepatic content of 5'-MDI protein was
decreased in the fasting rat, studied as a model of NTIS (42).
Diminution in the uptake of T4 by tissues can also explain
the decreased generation of T3 in tissues (5). However,
this abnormality should be associated with an elevated serum
concentration of free T4(D), which is clearly not the case
(see above) (45). One could argue that decreased T4 to
T3 conversion in NTI should also be associated with
increased free T4(D). However, T4 is
metabolized not just by 5'-MDI, but also by type III iodothyronine
deiodinase, conjugation and side-chain alteration (21, 46); these
alternate routes of T4 metabolism are not known to be
impaired in NTI and may compensate for T4 not metabolized
by 5'-MDI.

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Figure 1. Some factors that may contribute to major
abnormalities of NTIS. The reader is referred to previous reviews
(36) for detailed discussion of these factors.
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Alterations in serum binding of thyroid hormones is clearly an
important factor contributing to changes in thyroid hormone levels in
NTI (see above). Serum albumin binds compounds, e.g. fatty
acids, that are capable of displacing thyroid hormones from TBG. The
fall in serum albumin in NTI enhances the activity of such low affinity
competitors of T4 on TBG (15, 24, 25). Additionally, much
has been written on abnormalities in the synthesis, secretion,
structure, regulation, and effectiveness of TSH in NTI (3, 4, 5, 6, 31, 32).
There has been much interest recently in the roles of cytokines in the
pathogenesis of the NTI (3). However, their significance remains
unclear. Proinflammatory cytokines [tumor necrosis factor-
(TNF
), interleukins (e.g. IL-1 and IL-6), and
interferon-
], when administered to man or experimental animals,
have caused changes in thyroid function tests that resemble NTIS
(47, 48, 49, 50). However, humans or animals so treated manifest substantial
systemic illness, and it is unclear whether the thyroid hormone changes
observed are due to the sickness induced by cytokines or the cytokines
per se. In this respect, it is curious that
lipopolysaccharide-induced NTIS in mice, although associated with
increases in circulating TNF
and IL-6, was not prevented by
immunoneutralization of IL-1 receptor, TNF
, IL-6, or interferon-
(51) (Wiersinga, W. M., personal communication).
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Clinical significance of NTIS
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Abnormal thyroid function tests are observed at least as
frequently in systemic NTIS as in thyroid diseases (4, 52, 53). Thyroid
function abnormalities in NTI may at times mimic and at other times
mask the biochemical abnormalities observed in true thyroid disease.
Furthermore, the severity and the nature of changes in thyroid function
test have implications for the prognosis of the systemic illness. Thus,
a low serum T3 level predicts increased mortality form
liver cirrhosis, advanced congestive heart failure (54, 55), and
possibly several other systemic illnesses. Similarly, low total
T4 is associated with increased mortality from systemic
illness, and those patients with low T4 who have very low
serum T3 levels have the worst prognosis (22, 55, 56).
Previous studies have suggested that there exist tissue factors that
can inhibit the binding of thyroid hormones to serum proteins and the
ability of polymorphonuclear leukocytes to phagocytose
Escherichia coli (26, 57). However, it is not known whether
the two effects are due to the same or even similar factors and whether
the thyroid hormone binding inhibitor considered above in serum is
similar to that extracted from tissues. In any case, leakage of tissue
elements in the circulation in systemic illnesses may explain the
correlation between the fall in serum T4 and the increased
mortality in NTI; this requires further study.
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Diagnosis of thyroid disease in NTI
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It can be challenging to establish the diagnosis of thyroid
disease in patients manifesting NTIS. The difficulty exists in
hyperthyroid patients who may exhibit normal total T4 and
T3 on account of a diminution in serum binding of thyroid
hormones. However, serum free T4 and free T3
determinations by equilibrium dialysis/RIA (12) or ultrafiltration (45)
should yield appropriately diagnostic elevated values. The free
T4 index and analog methods for free T4
determination frequently yield low values in NTI and should be
interpreted with caution. Serum TSH measured by the ultrasensitive RIA
is typically undetectable (<0.10 mU/mL) in hyperthyroidism, whereas it
is undetectable in less than 7% patients with NTI, usually those who
have been treated with dopamine or corticosteroids (30). Definite
diagnosis of hypothyroidism can also be difficult in the setting of
NTI. However, primary hypothyroidism is a strong possibility if serum
TSH is above 2530 µU/mL. Serum TSH is supranormal in
12%
patients with NTI, and it is above 20 µU/mL in less than 3% of
patients (30, 58). A subnormal free T4(D) concentration in the absence
of treatment of NTI patients with TSH-suppressive drugs,
e.g. dopamine, corticosteroids, and anticonvulsants
(e.g. phenytoin and carbamozeprine) is strongly suggestive
of hypothyroidism. As Hashimotos thyroiditis is a common cause of
hypothroidism in our patient population, findings of goiter and
positive antithyroid antibodies (e.g. thyroid peroxidase and
thyoglobulin autoantibodies) in serum are strong points favoring the
diagnosis of primary hypothyroidism. An elevated serum rT3
level argues against the diagnosis of hypothyroidism, when serum TSH is
more than 10 µU/mL (59). As an individual test, serum rT3
does not help in the diagnosis of hypothyroidism in NTI patients. Low,
normal, and high serum rT3 values are observed in patients
with TSH values varying between low and 10 µU/mL (normal, 0.55.0
µU/mL). However, likely hypothyroid patients with serum TSH levels
above 20 µU/mL do not demonstrate supranormal rT3 (59).
It is prudent not to rely solely on any one thyroid function test in
the setting of NTI, and a combination of tests should be considered in
separating primary hypothyroid from euthyroid patients with the NTIS.
The diagnosis of secondary (or tertiary) hypothyroidism may require
additional work-up. The serum TSH level may be low, normal, or
minimally elevated in secondary hypothyroidism. Plasma cortisol is
clearly elevated or high normal, whereas PRL and gonadotropin levels
are typically normal in NTI without a specific pituitary or
hypothalamic disease. On the other hand, decreased plasma cortisol and
gonadotropin levels and elevated PRL levels support a diagnosis of a
central (pituitary or hypothalamic) lesion as the basis for secondary
hypothyroidism (60, 61). In view of several above-mentioned
complexities, it is often reasonable to wait for a week or so after
recovery from an acute NTI before evaluating thyroid status.
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Are patients with NTIS hypothyroid?
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Many believe that patients with NTIS are metabolically euthyroid
even though serum levels of the most active thyroid hormone,
T3, are clearly in the hypothyroid range. A normal serum
TSH in most NTI patients is clearly an important element in this
belief. However, several studies demonstrating abnormalities in the
synthesis, secretion, glycosylation, regulation, and/or effectiveness
of TSH in NTI (see above) lead one to question the normalcy of TSH in
the face of low serum levels of active thyroid hormone (T3)
in NTI. The transient increase in serum TSH during recovery from NTI
suggests that TSH is suppressed in an illness (62). Pituitary TSH
suppression may be related to the stress of an illness, and the
resulting elevated cortisol and catecholamine levels and associated
caloric deprivation (4, 62, 63). The basis for the apparent euthyroid
status in NTI remains unclear, but one or more of the following
explanations may be considered: 1) a moderate degree and a short
duration of reduction in thyroid hormone (T3) levels, 2)
insensitivity of the clinical diagnosis of (mild) hypothyroidism, and
3) increased sensitivity of body tissues to T3. Although
available data are limited and conflicting, a number of studies support
the opposite viewpoint. Thus, oxygen consumption in response to
T3 has been found to be decreased (not increased) in
fasting rats compared to fed rats (64). There is also information
suggesting a decreased effect of low T3 on TSH in fasting
subjects with the low T3 syndrome (65, 66). Similarly,
there is a decrease (not an increase) in the binding of T3
to nuclear receptors to T3 in diabetes mellitus and fasting
in the rat (67, 68). There is also evidence for a diminution in thyroid
hormone effects at the postreceptor level (69). One study, however, has
suggested an increase in T3 receptor number and affinity in
NTIS (70). Studies in the 1970s suggested low T3 to be
protective against protein breakdown in fasting (71, 72). However, a
recent study was unable to document hypercatabolic effects of
T3 in fasting obese subjects (73). Finally, 4) there may
exist in the sera of NTI patients high levels of thyromimetic compounds
other than T3. A high serum concentration of T3
sulfate in NTI is of interest in this regard (74, 75). Increased
exposure of body tissues to 3,5,3'-triiodothyroacetic acid has also
been suggested in NTI (76).
Overall, it seems that although several patients with NTI may be
euthyroid because of a short duration of NTIS, normal free
T3, and/or a contribution of non-T3 thyroactive
substances, there are others, especially those with a prolonged NTI
(and those who manifest low free T4 by dialysis), who may
indeed be biochemically hypothyroid and may benefit from treatment with
thyroid hormone. This idea is supported by data indicating that tissues
of patients dying from NTI contain much decreased levels of thyroid
hormones compared to tissues of control subjects who died suddenly, and
that the degree of thyroid hormone deficiency varied from one organ to
another (77). The issue of secondary hypothyroidism in NTI patients
treated with dopamine has been noted above (13, 28, 29). Decreased
levels of serum markers of thyroid hormone action, e.g.
angiotensin-converting enzyme, have also been documented in NTI
(78).
Some studies have examined the effects of thyroid hormone replacement
in NTI. Treatment with T4 was not beneficial (79). This may
be explained by diminished conversion of T4 to
metabolically more active T3 in NTI. For the same reason,
treatment with T4 may not be useful even in NTI patients
with low free T4(D) values. Studies evaluating treatment of
NTI patients with T3 have described either no benefit (80)
or appreciable improvement (81, 82, 83, 84, 85, 86). T3 treatment of
patients undergoing cardiothoracic or coronary bypass procedures showed
benefits measured by cardiac output, decreased systemic vascular
resistance, need for drugs for cardiac or inotropic support, and use of
diuretics (87, 88, 89, 90, 91, 92, 93, 94). These benefits have been related to restoration of
aerobic metabolism in ischemic myocardium (88), increase in inotropy
(95), increase in high energy phosphate stores (96), and increase in
uptake of glucose in the plasma membrane (97). There has been no
evidence of increased risk from replacement doses of T3
(92, 93, 94, 98). Whether the observed effects of T3 in the
above-mentioned studies were pharmacological or physiological is not
known. It is encouraging, however, that short term treatment with
near-replacement doses of T3 was associated with several
beneficial effects in NTIS. Clearly, more should be learned about the
appropriate patient population, dose-response issues, and any adverse
effects of treatment of the NTIS with T3.
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Summary
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Alterations in thyroid function tests are very common in patients
with NTI. Multiple, complex, and incompletely understood mechanisms are
involved in these abnormalities. Knowledge of these abnormalities is
necessary to avoid errors in the diagnosis of thyroid disease.
Measurement of serum TSH, free T4, and free T3
levels by direct equilibrium dialysis/RIA methods probably yield most
useful (accurate) information in the setting of NTI. Patients with low
free T4 by these methods and normal or low TSH have
secondary hypothyroidism. This may be due to NTI per se,
drugs administered for treatment of NTI, or associated pituitary or
hypothalamic disease; the latter consideration may require evaluation
of cortisol reserve, PRL, and/or gonadotropins. A serum TSH level above
2025 µU/mL probably reflects primary hypothyroidism; accompanying
findings of goiter, low free T4, and positive antithyroid
antibodies help establish the diagnosis. An elevated serum
concentration of rT3 argues against hypothyroidism. Studies
have demonstrated no discernible benefit of treatment of NTI patients
with T4. Some studies have shown a few benefits of
treatment with T3 in selected cases, but much more needs to
be learned. There is no evidence of harm by treatment of NTI patients
with up to replacement doses of T3. As some NTI patients
may indeed be hypothyroid, the term ESS should be replaced with
NTIS.
Received June 11, 1996.
Revised August 14, 1996.
Revised October 2, 1996.
Accepted October 8, 1996.
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References
|
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-
Chopra IJ. 1982 Euthyroid sick syndrome:
abnormalities in circulating thyroid hormones and thyroid hormone
physiology in nonthyroid illness (NTI). Med Grand Rounds. 1:201212.
-
Wartofsky L, Burman KD. 1982 Alterations in
thyroid function in patients with systemic illness: the "euthyroid
sick syndrome." Endocr Rev. 3:164217.[Medline]
-
Chopra IJ. 1996 Nonthyroidal illness syndrome or
euthyroid sick syndrome? Endocr Pract. 2:4552.
-
Kaptein EM. 1991 The effects of systemic illness
on the thyroid hormone metabolism. In: Wu SY, ed. Thyroid hormone
metabolism. Oxford: Blackwell; 211237.
-
Docter R, Krenning EP, de Jong M, Hennemann G. 1993 The sick euthyroid syndrome: change in thyroid hormone serum
parameters and hormone metabolism. Clin Endocrinol (Oxf). 39:499518.[Medline]
-
Wong TK, Hershman JM. 1992 Changes in thyroid
function in nonthyroid illness. Trends Endocrinol Metab. 3:812.
-
Chopra IJ, Hershman JM, Pardridge WM, Nicoloff JT. 1983 Thyroid function in nonthyroidal illness. Ann Intern Med. 98:946957.[Medline]
-
Chopra IJ, Solomon DH, Hepner GW, Morgenstein A. 1979 Misleadingly low free T4 index
(FT4I) and usefulness of reverse (T3
rT3) measurement in nonthyroid illnesses. Ann Intern Med. 90:905912.[Medline]
-
Chopra IJ, Van Herle AJ, Chua Teco GN, Nguyen AH. 1980 Serum free thyroxine in thyroidal and non-thyroidal illnesses: a
comparison of measurements by radioimmunoassay, equilibrium dialysis
and free thyroxine index. J Clin Endocrinol Metab. 51:135143.[Medline]
-
Kaptein EM, MacIntyre SS, Weiner JM, Spencer CA,
Nicoloff JT. 1981 Free thyroxine estimates in nonthyroidal
illness: comparison of eight methods. J Clin Endocrinol Metab. 52:10731077.[Abstract]
-
Faber J, Kirkegaard C, Rasmussen B, et al. 1987 Pituitary-thyroid axis in critical illness. J Clin Endocrinol
Metab. 65:315320.[Abstract]
-
Nelson JC, Tomei RT. 1988 Direct determination of
free thyroxin in undiluted serum by equilibrium
dialysis/radioimmunoassay. Clin Chem. 34:17371744.[Abstract/Free Full Text]
-
Kaptein EM. 1993 Clinical application of free
thyroxine determinations. Clin Lab Med. 13:653672.[Medline]
-
Chopra IJ, Taing P, Mikus L. 1996 Direct
determination of free triodothyronine (T3) in undiluted
serum by equilibrium dialysis/radioimmunoassay. Thyroid. 6:255259.[Medline]
-
Chopra IJ, Huang TS, Beredo A, Solomon DH, Chua Teco
GN. 1986 Serum thyroid hormone binding inhibitor in nonthyroid
illnesses. Metabolism. 35:152159.[Medline]
-
Chopra IJ. 1976 An assessment of daily turnover and
significance of thyroidal secretion of reverse T3 in man. J Clin Invest. 58:3240.[Medline]
-
Kaptein EM, Robinson WJ, Grieb DA, Nicoloff JT. 1982 Peripheral serum thyroxine, triiodothyronine and reverse
triodothyronine kinetics in the low thyroxine state of acute
nonthyroidal illnesses. J Clin Invest. 69:526535.[Medline]
-
Eisenstein Z, Hagg S, Vagenakis AG, et al. 1978 Effect of starvation on the production and peripheral metabolism of
3,3',5'-triiodothyronine in euthyroid obese subjects. J Clin
Endocrinol Metab. 47:889893.[Abstract]
-
Suda AK, Pittman CS, Shimizu T, Chambers Jr JB. 1978 The production, and metabolism of 3,5,3'-triiodothyronine and
3,3',5'-triiodothyronine in normal and fasting subjects. J Clin
Endocrinol Metab. 47:13111319.[Medline]
-
Chopra IJ, Chopra U, Smith SR, Reza M, Solomon DH. 1975 Reciprocal changes in serum concentrations of
3,3',5'-triiodothyronine (reverse T3) and
3,3',5-triiodothyronine (T3) in systemic illnesses. J
Clin Endocrinol Metab. 41:10431049.[Abstract]
-
Chopra IJ, Solomon DH, Chopra U, Wu SY, Fisher DA,
Nakamura Y. 1978 Pathways of metabolism of thyroid hormones. Recent Prog Horm Res. 34:521567.[Medline]
-
Slag MF, Morley JE, Elson MK, Crowson TW, Nettle FQ,
Shafer RB. 1981 Hypothyroxinemia in critically ill patients as a
predictor of high mortality. JAMA. 245:4345.[Abstract]
-
Chopra IJ, Chua Teco GN, Nguyen AH, Solomon DH. 1979 In search of an inhibitor of thyroid hormone binding to serum
proteins in nonthyroid illnesses. J Clin Endocrinol Metab. 49:6369.[Medline]
-
Chopra IJ, Huang TS, Solomon DH, Chaudhary GN. 1986 The role of thyroxine (T4)-binding serum proteins in oleic
acid induced increase in free T4 in nonthyroidal
illness. J Clin Endocrinol Metab. 63:776779.[Abstract]
-
Mendel C, Frost P, Cavalieri RR. 1986 Effect of
free fatty acids on the concentration of free thyroxine in human serum:
the role of albumin. J Clin Endocrinol Metab. 63:13941399.[Abstract]
-
Chopra IJ, Solomon DH, Chua Teco GN, Eisenberg JB. 1982 The presence of an inhibitor of serum binding of thyroid hormones
in extrathyroidal tissues. Science. 215:407409.[Medline]
-
Mendel CM, Lauaghton CW, McMahon FA, Cavalieri RR. 1991 Inability to detect an inhibitor of thyroxine-serum protein
binding in sera from patients with nonthyroid illness. Metabolism. 40:491502.[Medline]
-
Kaptein E, Keltzy O, Spencer C, et al. 1980 Effects
of prolonged dopamine infusion on anterior pituitary function in normal
males. J Clin Endocrinol Metab. 51:448491.
-
Van den Berghe G, de Zegher F, Lawers P. 1994 Dopamine and the sick euthyroid syndrome in critical illness. Clin
Endocrinol (Oxf). 41:731737.[Medline]
-
Spencer CA, Eigen A, Shen D, et al. 1987 Specificity of sensitive assays of thyrotropin (TSH) used to screen for
thyroid disease in hospitalized patients. Clin Chem. 33:13911396.[Abstract/Free Full Text]
-
Lee H-Y, Suhl J, Pedary AE, Hershman JM. 1987 Secretion of thyrotropin with reduced concanavalin-A-binding activity
in patients with patients with severe nonthyroid illness. J Clin
Endocrinol Metab. 65:942945.[Abstract]
-
Huang TS, Wu HP, Huang LS, Lai MY, Ho SW, Chopra
IJ. 1989 A study of thyroidal response to thyrotropin (TSH) in
decompensated liver cirrhosis. Thyroidology. 1:137142.[Medline]
-
Hollander CS, Scott RL, Tschudy DP, Perlroth M, Waxman
A, Sterling K. 1967 Increase iodine and thyroxine binding in acute
porphyria. N Engl J Med. 177:995100.
-
Schussler GC, Schaffner F, Korn F. 1978 Increased
serum thyroid hormone binding and decreased free hormone in chronic
active liver disease. N Engl J Med. 299:510515.[Abstract]
-
Kaptein EM, Egodage PM, Hoopes MT, Burger AG. 1988 Amiodarone alters thyroxine transfer and distribution in humans. Metabolism. 37:11071113.[Medline]
-
Felicetta JV, Green WL, Nelp WB. 1980 Inhibition of
hepatic binding of thyroxine by cholecystographic agents. J Clin
Invest. 65:10321040.[Medline]
-
Green WL. 1991 Effect of drugs on thyroid hormone
metabolism. In: Wu SY, ed. Current issues in endocrinology and
metabolism: thyroid hormone metabolism-regulation and clinical
implications. Boston: Blackwell; 239266.
-
Birkhauser M, Busset R, Burger TH, Burger A. 1977 Diagnosis of hyperthyroidism when serum thyroxine alone is raised. Lancet. 2:5356.[Medline]
-
Suzuki H, Kadena N, Takeushi K, Nakagawa S. 1980 Effects of three day oral cholecystography on serum iodothyronines and
TSH concentrations: comparison of the effects among some
cholecystography agents and the effects of iopanoic acid on the
pituitary thyroid axis. Acta Endocrinol (Copenh). 92:477488.
-
Jaume JC, Mendel CM, Frost PH, Greenspan FS, Laughton
CW. 1996 Extremely low doses of heparin release lipase activity
into the plasma and can thereby cause artifactual elevations in the
serum free thyroxine concentration as measured by equilibrium dialysis. Thyroid. 6:7984.[Medline]
-
Lo Presti JS, Fried JC, Spencer CA, Nicoloff JT. 1989 Unique alternations of thyroid hormone indices in the acquired
immunodeficiency syndrome (AIDS). Ann Intern Med. 110:970975.[Medline]
-
Santini F, Chopra IJ. 1992 A radioimmunoassay of
rat type I iodthyronine 5'-monodeiodinase (5'-MD). Endocrinology. 131:25212526.[Abstract]
-
Berry MJ, Banu L, Larsen PR. 1991 Type I
iodothyronine deidinase is a selenocysteine-containing enzyme. Nature. 349:438440.[CrossRef][Medline]
-
Mandel SJ, Berry MJ, Kieffer JD, Harney JW, Warne RL,
Larsen PR. 1992 Cloning and in vitro expression of the
human selenoprotein, type I iodothyronine deiodinase. J Clin
Endocrinol Metab. 75:11331140.[Abstract]
-
Surks MI, Hupart KH, Pan C, Shapiro LE. 1988 Normal
free thyroxine in critical nonthyroidal illnesses measured by
ultrafiltration of undiluted serum and equilibrium dialysis. J
Clin Endocrinol Metab. 67:10311039.[Abstract]
-
Kohrle J. 1994 Thyroid hormone deiodination in
target tissuea regulatory role for the trace element selenium. Exp
Clin Endocrinol. 102:6389.[Medline]
-
Van der Poll T, Romijn JA, Wiersinga WM, Sauerwein
HP. 1991 Tumor necrosis factor: a putative mediator of the sick
euthyroid syndrome. J Clin Endocrinol Metab. 79:13421346.[Abstract]
-
Stothard JML, Van der Poll T, m Endert E, et al. 1994 Effects of acute and chronic interleukin-6 administration on
thyroid hormone metabolism in humans. J Clin Endocrinol Metab. 79:13421346.[Abstract]
-
Boelen A, Platvoet-ter Schiphorst MC, Wiersinga WM. 1993 Association between serum interleukin-6 and serum T3
in nonthyroidal illness. J Clin Endocrinol Metab. 77:16951699.[Abstract]
-
Sato K, Satoh T, Shizume K, et al. 1990 Inhibition
of 125I organification and thyroid hormone release by
interleukin-1, tumor necrosis factor-
, and interferon-
in human
thyrocytes in suspension culture. J Clin Endocrinol Metab. 70:17351743.[Abstract]
-
Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wieringa
WM. 1995 The role of cytokines in the LPS-induced sick euthyroid
syndrome in mice. J Endocrinol. 146:475483.[Abstract]
-
Helffand M, Crapo LM. 1990 Screening for thyroid
disease. Ann Intern Med. 112:840849.[Medline]
-
DeGroot LJ, Mayor G. 1992 Admission screening by
thyroid function tests in an acute general care teaching hospital. Am J Med. 93:558564.[Medline]
-
Hepner GW, Chopra IJ. 1979 Serum thyroid hormones
in patients with liver disease. Arch Intern Med. 139:11171120.[Abstract]
-
Hamilton MA. 1993 Prevalence and clinical
implications of abnormal thyroid hormone metabolism in advanced heart
failure. Ann Thorac Surg. 56(Suppl 1):S48S52.
-
Maldonado LS, Murata GH, Hershman JM, Braunstein
GD. 1992 Do thyroid function tests independently predict survival
in the critically ill? Thyroid. 2:119123.[Medline]
-
Huang TS, Hurd RE, Chopra IJ, Stevens P, Solomon DH,
Young LS. 1984 Inhibition of phagocytosis and chemiluminescence in
human leukocytes by a lipid soluble factor in normal tissues. Infect
Immun. 46:544551.[Medline]
-
Spencer CA. 1988 Clinical utility and cost
effectiveness of sensitive thyrotropin assays in ambulatory and
hospitalized patients. Mayo Clin Proc. 63:12141222.[Medline]
-
Burmeister LA. 1995 Reverse
T3 does not reliably differentiate hypothyroid
sick syndrome from euthyroid sick syndrome. Thyroid. 5:435442.[Medline]
-
Jurney TH, Cocrell JL, Lindberg JS, et al. 1987 Spectrum of serum cortisol response to ACTH in ICU patients:
correlation with degree of illness and mortality. Chest. 92:292295.[Abstract]
-
Rosen HN, Greenspan SL, Landsberg L, Faix JD. 1994 Distinguishing hypothyroxinemia due to euthyroid sick syndrome from
pituitary insufficiency. Isr J Med Sci. 30:74650.[Medline]
-
Bacci V, Schussler GC, Kaplan TC. 1982 The
relationship between serum triiodothyroine and thyrotropin during
systemic illness. J Clin Endocrinol Metab. 54:12291235.[Abstract]
-
Kohler PO, OMalley BW, Rayford PL, Lipsett MB, Odell
WD. 1967 Effect of pyrogen on blood levels of pituitary trophic
hormones. Observations of the usefulness of the growth hormone response
in the detection of pituitary disease. J Clin Endocrinol Metab. 27:219226.[Medline]
-
Wimpfheimer C, Saville E, Voirol MJ, Danforth E, Burger
A. 1979 A starvation-induced decreased sensitivity of resting
metabolic rate to triiodothyronine. Science. 205:10721073.
-
Burger AG, Weissel M, Berger M. 1980 Starvation
induces a partial failure to triiodothyronine to inhibit thyrotropin
response to thyrotropin releasing hormone. J Clin Endocrinol
Metab. 51:10641067.[Abstract]
-
Maturlo SJ, Rosenbaum RL, Surks MI. 1980 Variation
in plasma free thyroid hormone concentrations in patients with
nonthyroidal diseases. J Clin Invest. 66:451456.[Medline]
-
DeGroot LJ, Coleoni AH, Rue PA, Seo H, Martino E,
Refettoff S. 1977 Reduced nuclear triidothyronine receptors in
starvation induced hypothyroidism. Biochem Biophys Res Commun. 79:173178.[Medline]
-
Wiersinga WM, Frank HJL, Chopra IJ, Solomon DH. 1982 Alterations in hepatic nuclear binding of triiodthyronine in
experimental diabetes mellitus in rats. Acta Endocrinol (Copenh). 99:7985.[Medline]
-
Dillman WH, Schwartz HL, Oppenheimer JH. 1978 Selective alterations in hepatic enzyme response after reduction of
nuclear triiodothyronine receptor sites by partial hepatectomy and
starvation. Biochem Biophys Res Commun. 80:259266.[Medline]
-
Erken De, Clemons GK. 1988 Modulation of thyroid
hormone receptors by non-thyroidal stimuli. J Recept Res. 8:839852.[Medline]
-
Gardner DF, Kaplan, Stanley CS, Utiger RD. 1979 The
effect of T3 replacement on the metabolic and pituitary
responses to starvation. N Engl J Med. 300:579584.[Abstract]
-
Vignati L, Finley RJ, Haag S, Aoki TT. 1978 Protein
conservation during prolonged fast: a function of triiodothyronine
(T3) levels. Trans Assoc Am Physicians. 91:169179.[Medline]
-
Byerley LO, Heber D. 1996 Metabolic effect of
triiodothyronine replacement during fasting in obese subjects. J
Clin Endocrinol Metab. 81:968976.[Abstract]
-
Chopra IJ, Wu SY, Chua Teco GN, Santini F. 1992 A
radioimmunoassay for measurement of 3,5,3'-triiodothyronine sulfate:
studies in thyroidal and nonthyroidal disease, pregnancy and neonatal
life. J Clin Endocrinol Metab. 75:189194.[Abstract]
-
Santini F, Chiovato L, Bartalena L, et al. 1996 A
study of serum 3,5,3'-triiodothyronine sulfate concentration in
patients with systemic non-thyroidal illness. Eur J Endocrinol. 134:4550.[Medline]
-
Nicoloff JT, Lo Presti JS. 1994 An integrated
assessment of prereceptor regulation of thyroid hormone metabolism. In:
Wu SY, Visser TJ, eds. Thyroid hormone metabolism, molecular biology
and alternate pathways. Ann Arbor: CRC Press; 7584.
-
Arem R, Wiener GJ, Kaplan G, Kim HS, Reichlin SW, Kaplan
MM. 1993 Reduced tissue thyroid hormone in fatal illness. Metabolism. 42:11021108.[Medline]
-
Brent GA, Hershman JM, Reed AW, Sastre A, Lieberman
J. 1984 Serum angiotensin-converting enzyme in severe nonthyroidal
illnesses associated with low serum thyroine concentration. Ann Intern
Med. 100:680685.[Medline]
-
Brent GA, Hershman JM. 1986 Thyroxine therapy in
patients with severe nonthyroidal illnesses and low serum thyroxine
concentration. J Clin Endocrinol Metab. 63:18.[Abstract]
-
Becker RA, Vaughan GM, Ziegler MG, et al. 1982 Hypermetabolic low triiodothyronine syndrome of burn injury. Crit Care
Med. 10:870875.[Medline]
-
Hesch RD, Husch M, Kodding R, Hoffken B, Meyer T. 1981 Treatment of dopamine-dependent shock with triiodothyronine. Endocr Res Commun. 8:299301.
-
Meyer T, Husch M, van den Berg E, Kodding R, Hoffken B,
Hesch RD. 1979 Treatment of dopamine-dependent shock with
triiodothyronine: preliminary results. Dtsch Med Wochenschr. 104:17111714.[Medline]
-
Dulchavsky SA, Maitra SR, Maurer J, Kennedy PR, Geller
EG, Dreis DJ. 1990 Beneficial effects of thyroid hormone
administration on metabolic and hemodynamic function in hemorrhagic
shock. FASEB J. 4:A952.
-
Novitzky D, Cooper DK, Reichart B. 1987 Hemodynamic
and metabolic responses to hormonal therapy in brain-dead potential
organ donors. Transplantation. 43:852855.[Medline]
-
Dulchavsky SA, Hendrick SR, Dutta S. 1993 Pulmonary
biophysical effects of triidothyronine (T3) augmentation
during sepsis-induced hypothyroidism. J Trauma. 35:104109.[Medline]
-
Dulchavsky SA, Kennedy PR, Geller ER, Maitra SR, Foster
WM, Langenbach EG. 1991 T3 preserves respiratory
function in sepsis. J Trauma. 31:753759.[Medline]
-
Novitzky D, Cooper DKC, Zuhdi N. 1986 Triiodothyronine therapy in the cardiac transplant recipient. Transplant Proc. 20:6588.
-
Novitzky D, Cooper DKC, Chaffin JS, et al. 1990 Improved cardiac allograft function following triiodothyronine therapy
to both donor and recipient. Transplantation. 49:311316.[Medline]
-
Novitzky D, Cooper DKC, Barton C, et al. 1989 Triiodothyronine as an inotropic agent after open heart surgery. J
Thorac Cardiovasc Surg. 98:972978[Abstract]
-
Orlowski JO, Spees Ek. 1993 Improved cardiac
transplant survival with thyroxine treatment of hemodynamical unstable
donors: 95.2% graft survival at 6 and 30 months. Transplant Proc. 25:33053306.[Medline]
-
Jeevanandam V, Todd B, Hellman S, et al. 1993 Use
triiodothyronine replacement therapy to reverse donor myocardial
dysfunction: creating a larger donor pool. Transplant Proc. 25:33053306.[Medline]
-
Klempere JD, Klein I, Gomez M, et al. 1995 Thyroid
hormone treatment after coronary-artery bypass surgery. N Engl
J Med. 333:15221527.[Abstract/Free Full Text]
-
Bennett Guerrero E, Jimenez Jl, White WD. 1996 Cardiovasular effects of intravenous triiodothyronine in patients
undergoing coronary artery bypass graft surgery. JAMA. 275:687692.[Abstract]
-
Hsu RB, Huang TS, Chu SH. 1995 Effects of
triiodothyronine adminstration in experimental myocardial injury. J
Endocrinol Invest. 18:702709.[Medline]
-
Novitzky D, Human P, Cooper DKC. 1988 Inotropic
effect of triiodothyronine following myocardial ischemia and
cardiopulmonary bypass: an experimental study in pigs. Ann Surg. 96:600607.
-
Novitzky D, Human PA, Cooper DKC. 1988 Effect of
triiodothyronone (T3) on myocardial high energy phosphates
and lactate after ischemia and cardiopulmonary bypass. J Thorac
Cardiovasc Surg. 96:600607.[Abstract]
-
Segal J. 1989 A rapid, extranuclear effect of
3,5,3'-triidothyronine on sugar uptake by several tissues in the rat
in vivo. Evidence for a physiogical role for the thyroid
hormone action at the level of the plasma membrane. Endocrinology. 124:27552764.[Abstract]
-
Hamilton MA, Stevenson LW. 1996 Thyroid hormone
abnormalities in heart failure: possibilities for therapy. Thyroid6
:527529.