in patients with nonthyroidal illness has been termed the ‘sick euthyroid syndrome’. Causes include decreased peripheral conversion of T4 to T3; changes in the concentration of binding; increased plasma concentrations of free fatty acids, which displace thyroid hormones from their
and a discrepancy caused by specific or nonspecific assay
Laboratory tests of thyroid function are required to assist in
the screening, diagnosis and monitoring of thyroid disease.
Most laboratories offer a standard ‘profile’ of T3/T4/
TSH. Measurement of plasma total T4 concentration was
formerly widely used as test of thyroid function, but has
a major disadvantage in that it is dependent on binding
proteins concentration as well as thyroid activity. For
example, a slightly elevated plasma total T4 concentration,
compatible with mild hyperthyroidism, can occur with
normal thyroid function, if there is an increase in plasma
binding protein concentration. With the introduction of
more reliable assays for free T4 (FT4), there is now little
if any justification for laboratories continuing to measure
total T4 as a test of thyroid function.
Plasma total T3 concentration is almost always raised
in hyperthyroidism (usually to a proportionately greater
extent than total T4, hence, it is the more sensitive test
for this condition) but may be normal in hypothyroidism.
However, total T3 concentrations, like those of total T4,
are dependent on the concentration of binding proteins
in plasma and their measurement is being superseded by
measurements of free T3 (FT3).
For both, the clinician and pathologist, protein binding
can provide a major obstacle to the laboratory assessment
It is a known fact that both T3 and T4, when they are
released into the blood, are extensively bound to plasma
proteins. There are two types of plasma proteins, which
are present in large concentration in blood: TBG—which
has a very high affinity for T3 and T4 and TBPA—which
has low affinity but high capacity for binding. Therefore,
maximum T4 is bound to TBG and very little to TBPA.
The precise physiological function of TBG is unknown. It
has been suggested that the extensive binding of thyroid
hormones to TBG provides a buffer, which maintains the
free hormone levels constant in the face of any tendency
to change. The binding may also reduce the amount of
thyroid hormones lost through the kidneys.
Total thyroid hormone concentration is dependent
upon the concentration of binding proteins present in
the blood. If these were to increase, the temporary fall in
free hormone concentration caused by increased protein
binding would stimulate TSH release and this would
restore the free hormone concentrations to normal.
Conversely, if the protein concentrations were to fall, the
reverse would occur. In either situation, there would be a
change in the concentrations of the total hormones, but
the free hormone concentrations would remain normal.
Thus, measurement of total hormone concentrations can
This is a matter of considerable practical importance
since changes in the concentrations of the binding proteins
occur in many circumstances. Further, certain drugs, for
example, salicylates and phenytoin, will displace thyroid
hormones from their binding proteins, thus reducing the
total, but not the free hormone concentrations, once a
new steady state is attained. If an attempt is made to assess
thyroid status in a patient who is not in a steady state, the
results may be bizarre and misleading.
Only small amounts of T4 and T3 are excreted by the
kidneys due to the extensive protein binding. The major
route of thyroid hormone degradation is by deiodination
and metabolism in tissues, but they are also conjugated in
the liver and excreted in bile (Fig. 24.5).
a. In the initial steady state, TBG is one-third saturated
b. TBG levels increase causing more T4 to be bound, thus
reducing the free T4 concentration. This stimulates
TSH secretion which leads to an increase in the release
c. The new T4 is redistributed between the bound and
the free states leading to a new steady state with the
same free T4 level but an increased total T4.
Importance of Free T4 and Free T3
1. In pregnancy, the normal range for FT4 in euthyroid
women decreases as the pregnancy progresses. There
is an increase in TBG, due to the increased estrogen
levels, and in total T4, but these are disproportionate,
causing the level of free T4 to fall. Thyroid status, as
assessed clinically, does not change.
2. Free T3 is a sensitive test for hyperthyroidism. In
hyperthyroid patients, both FT3 and FT4 are usually
elevated (FT3 to a proportionately greater extent) but
3. In a small number of patients with hyperthyroidism
the FT3 concentration is elevated but the FT4 is not
(though it is usually high-normal)—a condition called
4. Occasionally, FT4 is elevated but not FT3. This is
usually due to concomitant nonthyroidal illness
resulting in decreased conversion of T4 to T3, and FT3
concentration increases when this illness resolves.
5. One can encounter abnormal total T4 test results in
the absence of thyroid disease. Free T4 (FT4) in these
circumstances remains constant and is a more useful
6. Free T4 provides reliable results in patients displaying
abnormalities in serum T4 binding particularly if
alterations are caused by severe nonthyroidal illness
or hereditary dysalbuminemias.
7. Free T3 and free T4 are important in patients with
suspected thyrotoxicosis in whom serum T4 is normal
and serum TSH is low, to distinguish T3 thyrotoxicosis
from subclinical thyrotoxicosis.
8. In the estimation of the serum FT3 : FT4 ratio, a high
ratio(>0.024 on a molar basis or >20 calculated as ng/
mg) that persists during antithyroid drug treatment
may indicate that patients with hyperthyroid Graves’
disease are unlikely to achieve remission. This ratio
usually is lower in patients with iodide-induced
thyrotoxicosis or thyrotoxicosis caused by thyroiditis
than in those with thyrotoxicosis caused by Graves’
9. To detect early recurrence of thyrotoxicosis after
cessation of antithyroid therapy.
10. To establish the extent of active hormone excess during
high-dose replacement or suppressive therapy with T4
or when an intentional T4 overdose has been taken.
11. For diagnosis of amiodarone-induced thyrotoxicosis,
which should not be based on T4 excess because of the
occurrence of euthyroid hyperthyroxinemia in many
FIG. 24.5: Effect of an increase in TBG concentration
Thyroid Hormone-Binding-Proteins (Fig. 24.6)
a. TBG concentration (or affinity):
1. Genetic (inherited) determination
2. Nonthyroidal illness (HIV infection, infectious
and chronic active hepatitis, estrogen-producing
tumors acute intermittent porphyria)
3. Physiology (pregnancy, newborn)
4. Drug use (oral contraceptives, estrogens, tamoxifen, methadone)
c. Albumin binding (familial dysalbuminaemic hyperthroxinemia)
d. T4 binding by antibodies (autoimmune thyroid
disease, hepatocellular carcinoma).
1. Genetic (inherited) determination
2. Nonthyroidal illness (major illness or surgical
3. Drug use (androgens, anabolic steroids, large
b. TBG-binding capacity (drugs bound to TBG, such as
If a sensitive serum TSH assay is used together with a valid
serum free T4 estimate, a sensitive and specific assessment
of thyroid status can usually be made from the general
relation between the two hormones.
Figure 24.7 emphasises the distinction between
primary target gland failure (high serum TSH, low free T4:
A), failure of TSH secretion (both low: B), autonomous or
abnormally stimulated target gland function (high serum
free T4, low TSH: C), and primary excess of TSH or thyroid
hormone resistance (both high: D).
The relationship between serum TSH and free T4
concentrations in normal subjects (N) and patients with
various abnormalities of thyroid function: A, primary
hypothyroidism; B, central (secondary) hypothyroidism;
possible methodologic artefact, an unrecognized binding
abnormality, generalized thyroid hormone resistance,
or TSH-induced thyrotoxicosis. Findings that fall in the
undefined areas suggest that an additional factor may be
modifying the feedback relationship or that samples have
been taken in nonsteady-state conditions. Serum free T4 is
shown on a linear scale, whereas the scale for serum TSH
Problems in the Interpretation of
It is difficult to guarantee reliable thyroid function results
in patients with nonthyroidal illness. Abnormal results may
occur in patients with infections, malignancy, myocardial
infarction, following surgery, etc. who do not have thyroid
It is difficult to guarantee reliable thyroid function results
in patients with nonthyroidal illness. Abnormal results may
occur in patients with infections, malignancy, myocardial
infarction, following surgery, etc. who do not have thyroid
FIG. 24.6: disease. Thyroid hormones and TBG
Fig. 24.7: TSH-FT4 relationship
Typically, during the acute phase of an illness, free
T3 (FT3) concentration and less often, free T4 (FT4)
concentration is decreased. The TSH is usually normal but
may be undetectable in the severely ill. During recovery,
TSH may rise transiently into the hypothyroid range as
free hormone concentrations return to normal. In chronic
illness, for example, chronic renal failure, free hormone
concentrations are decreased (to an extent that may reflect
the severity of the underlying disease); TSH is usually
normal, but it is occasionally decreased.
The occurrence of abnormalities of thyroid function tests
in patients with nonthyroidal illness has been termed the
fatty acids, which displace thyroid hormones from their
which can inhibit TSH secretion.
Furthermore, many drugs can influence the results of
tests of thyroid function. Many times, the levels of FT3, FT4
Common Causes of TSH/FT4/FT3 Discrepancies
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