Tariq Saeed Mufti, Asif Jielani


Critical illness is characterized by multiple and
complex metabolic, immunological and endocrine
alterations1. Abnormalities in thyroid homeostasis also
occur in variety of non-thyroid illnesses. Changes in
thyroid hormone metabolism in critical illnesses
appear to reflect a continuum which relates primarily
to the severity of the underlying disorders2,3. The
prevalence of one or more abnormalities of thyroid
function tests in patients with non thyroidal medical
illnesses has been reported from 40% to 70%4,5. The
condition is reported in starvation6, sepsis 7, surgery 8,
myocardial infarction9, CABG surgery 10, bone marrow
transplantation11, and, in fact, probably any severe
Girvent et al12 noted that such changes are
highly prevalent in elderly patients with acute surgical
problems, and is associated with poor nutrition and
higher sympathetic response. The general hormonal
response to critical illness involves activation of the
pituitary-adrenal axis, inhibition of the pituitarythyroid & pituitary- gonadal axes13. These normal
responses distort standard reference intervals. In case
of the pituitary-thyroid axis, evaluation is further
complicated by changes in nutrition and major effects
of medication. Evidence suggests that these patients
may not really be euthyroid, especially at the tissue
Based upon the fact that patients with systemic
illness are clinically euthyroid, Wartofsky and
Bunnan15 in 1982 used the term sick euthyroid
syndrome to describe spectrum of thyroid
abnormalities associated with non thyroidal illness.
Euthyroid Sick Syndrome (ESS) and Non thyroidal
illness syndrome (NITS) are terms used alternatively
in the literature16,17.
The interpretational difficulty due to NTIS
leading to mismanagement of co-existing goiter, a
pathology of sizable incidence in certain geographical
distribution including Pakistan, is a significant
Initial data of thyroid function tests from
Institute of Nuclear Medicine, Oncology and
Radiotherapy (INOR), Pakistan is indicative of this
incidence where 51 out of 648 tests on patients with
goiter showed abnormalities of T3, T4, & TSH which
were un-interpretable18.
The most prominent alterations are low
serum triiodothyronine (T3) and elevated reverse T3
(rT3), leading to the general term low T3 syndrome.
Thyroid-stimulating hormone (TSH), thyroxine (T4),
free T4, and free T4 index (FTI) are also affected in
variable degrees based on the severity and duration of
the NTI. As the severity of the NTI increases, both
serum T3 and T4 levels may drop and gradually
normalize as the patient recovers.
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
bioactivity19,20. Slightly decreased serum TSH has
been documented in elderly patients20, in healthy
centenarians22. Food may also affect TSH secretion23.
TSH levels might be considered as a sensitive marker
of a lack of thyroid hormone since the concentrations
of TSH sharply increase in primary hypothyroidism
even before serum T4 and T3 fall below the normal
reference range (so called sub-clinical
hypothyroidism)24. In NTIS, however, despite the
decrease in serum T3 (and T4 in severe cases), the
concentrations of TSH typically remain within low to
normal range25.Conversely, there is a blunted response
of TSH to thyrotropin-releasing hormone (TRH), and
low TSH levels are associated with poor prognosis26.
Taken together, these findings suggest that a major
change in thyroid hormone set point regulation occurs
in NTI. Accordingly, prolonged critically ill patients
show diminished TSH pulsatility, characterized by an
absent nocturnal TSH surge and decreased TSH pulse
amplitude27. On occasion, transient TSH elevation
occurs while the patient is still ill. The
pathophysiology of this apparent thyroid gland
resistance to TSH is not clear28.
Levels of T3 rapidly decrease during
starvation e.g. post operative period or early in the course
of a critical illness. Low serum total-T3 level has been
recognized in more than 70% of hospitalized patients
with non-thyroidal illness29. Starvation, and more
precisely carbohydrate deprivation, appears to rapidly
inhibit deiodination of T4 to T3 by Type 1
iodothyronine-deiodinase in the liver, thus inhibiting
generation of T3, and preventing metabolism of
reverse T3, resulting in low T3 and high reverse T3
concentration30. The serum concentration of reverse T3
is increased innon-thyroidalillness, except in patients with
renal failure and HIV infection32.Alteration in reverse T3
J Ayub Med Coll Abbottabad 2006; 18(4) 2
metabolism appear to be disease specific. Both free and
total reverse T3 levels increase as a result of reduced
clearance of reverse T3, however, production rate of rT3
remains normal. Reduced metabolic clearance is
predominantly due to decreased activity of the type I
iodothyronine 59-monodeiodinase (5`-MDI) in
tissues); 5`-MDI de-iodinates T4 to T3 and rT3 to 3,
39-diiodothyronine (T2)31. Thus, serum reverse T3
levels do not reliably differentiate patients with
euthyroid sick patients, and are not clinically useful32.
Increased turnover of T3 and T4 in the hyper
metabolic phase of illness may also contribute to low
serum and tissue T3 concentrations2. Total T3, free
T3 levels and T3 daily production rate are decreased
in non-thyroid illness33 while Total T4, free T4 and
daily production rate of T4 is normal in low T3
Although the isolated low T3 state usually
represents the mildest form of non-thyroidal illness, the
magnitude of the drop in T3 level reflects the severity
of illness. A very low serum T3 level has been
associated with an increased mortality rate in patients
with hepatic cirrhosis, congestive heart failure, and
other systemic dis eases35.
Serum total T4 levels can be decreased (ie, low T4
syndrome) typically inpatients with more chronic and
severe systemic illness36-38. Majority of patients have
serum freeT4 either being normal or slightly
decreased, but occasionally elevated39. 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 correlates with the bad prognosis 40. A
marked decrease in serum T4 is associated with a high
probability of death41. Mortality rate in patients with
total T4 level <3mg/dL was 84%; the mortality rate in
patients with T4 levels between 3 and 5 mg/dL was
50%; and for those patients with T4 >5.0 mg/ dL, the
mortality rate was 15%42,43. Among patients with low
levels of T4, those with very low T3 levels had the
worst survival rate44.
High serum total T4 is seen in situations
where thyroid binding globulin is elevated (acute
intermittent porphyria, chronic hepatitis, and primary
biliary cirrhosis)45. T4 level is elevated, TSH level is
norma l or elevated, and T3 level is normal or high.
Heparin, amiodarone and iodinated contrast agents
increase T4 levels by inhibiting peripheral conversion
of T4 to T3. In HIV multiple abnormalities have been
described: increased T4 and TBG, decreased
reverseT3, and normal T3 even in the setting of severe
illness. Elevated levels of total and free T4 have been
reported in patients with acute psychiatric illness. 46
Interpretation of bio-chemical markers of
thyroid disease in patients with goiter presenting with
non-thyroid illness is challenging. As a practical
matter, the changes in patients with non thyroidal
illness must be distinguished from those resulting
from thyroid disease, which is often rightly suspected
in patients with other illnesses. Clinical evaluation of
the signs and symptoms of hypothyroidism may be
extremely difficult, to discern in a patient in the ICU
who typically has multiple medical problems and may
be receiving medication for sedation. Inter current

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