|Hypermetabolism, Thyroid function, fT3, fT4, TSH, Critically ill patients.
|The metabolic responses to sepsis involve every organ and
tissue of the body and yet, surprisingly, little is known about
the underlying mechanisms. During sepsis and other critical
illnesses, the state of stress results in hypermetabolism,
increased energy expenditure, hyperglycemia and muscle loss
[1,2]. Critical illness is often associated with alterations in
thyroid hormone concentrations in patients with no previous
intrinsic thyroid disease [3-5]. Euthyroid Sick Syndrome (ESS)
is the commonest endocrine change seen in critically ill
|It is described as abnormalities in circulating thyroid hormone
levels without pre-existing hypothalamic pituitary or thyroid
gland dysfunction in the setting of a Non-Thyroidal Illness
(NTI) . It reverts back to normal after recovery from the
NTI. ESS is characterized by low triiodothyronine (T3), low or
normal thyroxine (T4) and normal Thyroid Stimulating
Hormone (TSH). Three patterns are described in ESS; Type1
or low T3 syndrome (seen in moderately sick patients), type 2
or low T4 syndrome (low T3 and T4, seen in very sick patients
and associated with poor prognosis) and type 3 or low TSH
syndrome. These probably reflect different stages on a
continuum and severity of illness .
|The most common thyroid hormonal change reported in
critically ill patients is reduced serum T3 level. Under normal circumstances 100% of T4 and 10-20% of T3 are directly
secreted by the thyroid gland. 5`deiodinase causes peripheral
monodeiodination of T4 contributing to 80-90% of T3 and also
increases the clearance of the inactive isomer reverse T3 (rT3)
(which is derived by the action of 5` deiodinase on T4) .
|Critical illness decreases 5`deiodinase activity, thereby,
decreasing T4 to T3 conversion and rT3 clearance .
Increased metabolic clearance of T4 in critical illness further
diverts T4 to form the inactive isomer rT3 [10,11].Thus, T3
decreases and rT3 increases . Several mechanisms can
contribute to the inhibition of 5`-monodeiodination and
therefore to the low serum T3 concentration in critically ill
patients with nonthyroidal illness:
|1. Exogenous glucocorticoid therapy .
|2. Circulating inhibitors of deiodinase activity, such as free
(non-esterified) fatty acids .
|3. Treatment with drugs that inhibit 5`-monodeiodinase
activity, such as amiodarone and high doses of propranolol.
|4. Cytokines (such as tumor necrosis factor, interferon- alpha,
NF-kB and interleukin-6) [15-17].
|Serum total T4 levels can be decreased (i.e., low T4 syndrome)
typically in patients with more chronic and severe systemic
illness [18-20]. Majority of patients have serum free-T4 either
being normal or slightly decreased, but occasionally elevated
. This variability in free-T4 level reflects both the assay method used and the underlying illness. As the severity of
illness, progresses, there is gradual development of a more
complex syndrome associated with low T3 and low T4 levels
that may correlate with the bad prognosis .
|Serum TSH alterations in euthyroid patients with non-thyroidal
illnesses include transiently reduced or elevated basal TSH
values, blunted TSH response to TRH, diminished or absent
diurnal rhythms of TSH, and altered TSH glycosylation and
|Some hospitalized patients have transient elevations in serum
TSH concentrations (up to 20 mU/L) during recovery from
nonthyroidal illness. Few of these patients prove to have
hypothyroidism when re-evaluated after recovery from their
illness. Patients with serum TSH concentrations over 20 mU/L
usually have permanent hypothyroidism . The present
study was conducted to evaluate the magnitude of alteration in
thyroid hormone profile in non-thyroidal illnesses.
Material and Methods
|In this single centre, retrospective, observational study, 340
inpatients (91 Males; 249 Females) admitted to medical wards
and ICUs, irrespective of diagnosis were included. Patients
with previous thyroid disorders and those with family history
of thyroid disorders were excluded.
|Fasting venous blood samples received from these patients
were subjected for hormone analyses. Admission into wards or
ICUs was based on the presentation of the patient and
underlying clinical conditions unrelated to the study objectives.
fT3, fT4 and TSH levels were assessed using
chemilumniscence slide technique.
|The normal reference range for thyroid hormones in our
laboratory is as follows: fT3 (4.26-8.10 pmol/l), fT4 (10.0-28.2
pmol/L) and TSH (0.465-4.68 mIU/l). Any deviation from the
normal range is considered to be abnormal (low or elevated).
We did not repeat the hormonal assays a second time or prior
to discharge in survivors.
|Thyroid profile was assessed in 340 critically ill inpatients. Out
of these 249 (73.2%) were females and 91 (26.8%) were males.
201 (59.1%) of the patients showed abnormality in one or more
than one parameter of thyroid function tests (TFTs) (Figure 1 and Figure 2). Mean values of fT3, fT4 and TSH were as
shown in Table 1.
|Out of all the critically ill patients screened for thyroid
disorders, 73.2% were found to be females. This
preponderance of the female patients in the present study might
be attributed to the fact that thyroid disorders being more
common in females are more likely to raise physician’s
suspicion. This may be the reason for high screening rate in the
female patients. Moreover, hormonal differences between the
two genders, working traditions, body weight, meal schedules,
dietary factors or ingestion of drugs among other factors may be responsible for the observed gender differentiation in this
study. Furthermore, it was found that in critically ill patients,
low fT3 (50%) was the commonest abnormality followed by
high TSH (12.4%), low TSH (8.8%) and low fT4 (4.7%)
concentration. Occurrence of thyroid hormones abnormalities
in sick patients confirms the previous observations that
euthyroid sick syndrome is a common disorder in hospitalized
sick patients. Half of the critically ill patients had low fT3
levels, which is mainly due to inhibition of deiodinase activity.
Low fT4 levels were found in very few patients as serum
concentrations of free T4 remain in the normal range in most
patients unless the illness is severe and protracted.
|Multiple alterations in serum thyroid function test findings
have been recognized in patients with a wide selection of Non-
Thyroidal Illness Syndrome (NTIS) without evidence of preexisting
thyroid or hypothalamic- pituitary disease. The most
prominent alterations are low serum triiodothyronine (T3) and
elevated reverse T3 (rT3), leading to the general term “low T3
syndrome.” TSH, T4, free T4 (fT4), and Free T4 Index (FTI)
also are affected in variable degrees based on the severity and
duration of the NTIS. As the severity of the NTIS increases,
both serum T3 and T4 levels drop and gradually normalize as
the patient recovers . In the work of Sahana et al., NTIS
was detected in 80% of the ICU patients  while Tognini et
al., reported lower prevalence of 31.9% .
|Changes in thyroid hormones (especially T3) and TSH may be
seen as early as 24 h after the onset of non-thyroidal illness
. During recovery from intercurrent illness, thyroid
hormones and TSH concentrations return to normal, although
in some patients TSH may become overtly elevated for a short
period of time. This rise in TSH typically precedes the increase
in T4 and T3 concentrations, suggesting that it is required for
the restoration of euthyroidism .
|The goal of TFTs in the ICU should mainly be the
identification of previously unrecognized thyroid dysfunction
that would require therapeutic intervention. When
hypothyroidism is suspected clinically in an ICU patient (e.g.
hypothermia, bradycardia, respiratory acidosis, pleural
effusions, failure to wean), and the evaluation suggests central
hypothyroidism, one should consider, that the probability of
euthyroid sick syndrome is much higher than the pituitary or
hypothalamic disease. If hyperthyroidism is suspected (e.g.
tachyarrhythmias, widened pulse pressure, respiratory
alkalosis, high-output heart failure) and low TSH is detected,
true hyperthyroidism, is unlikely unless the TSH is suppressed
fully on a third-generation assay and the free T4 is elevated or
at least in the upper limits of the normal range . In
conclusion, a common pitfall in the interpretation of thyroid
function tests is to overlook the confounding effects of ‘Non-
Thyroidal Illness’ (NTI). NTI (or sick euthyroid syndrome) is a
relatively common finding following any acute or chronic
illness which could be deliberated as a secondary adaptive
change. It is important to be aware of this transient
phenomenon in order to avoid inappropriate diagnosis and
treatment. However, the knowledge of hypothalamic-pituitarythyroid
axis, various factors governing thyroid hormone action at the cellular level and interpretation of different ranks of
thyroid function tests may be considered to be central in
establishing the correct diagnosis and further management.
Tables at a glance
Figures at a glance
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