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CME EDUCATIONAL OBJECTIVE: Readers will follow up the finding of a low thyrotropin (TSH) level with appropriate
CREDIT diagnostic investigations
Serum levels of free thyroid hormones should be used ■■ LOW TSH HAS MANY CAUSES
when interpreting an abnormal TSH level, especially in
the acute and inpatient settings. A low serum TSH level, ie, less than 0.4 μIU/
mL (μIU/mL = μU/mL = mIU/L = mU/L) can
A low TSH level is not always the result of suppression by result from a variety of conditions that must be
elevations in circulating thyroid hormones. included in the differential diagnosis—not just
overt or subclinical hyperthyroidism (FIGURE 1). In
diagnosing the correct cause, patience is a virtue.
A low TSH level in the setting of normal levels of free
thyroid hormones should always be reassessed in 4 to 6 Follow up the finding of a low TSH
weeks before making a diagnosis. by measuring free T4 and free T3
The finding of a low TSH level should always
Overt hyperthyroidism is usually associated with a be followed up by measuring the thyroid hor-
frankly suppressed TSH (< 0.1 μIU/mL). mones, ie, T4 and triiodothyronine (T3).
The levels of free T4 and free T3 should
be used, not total levels, when interpreting
an abnormal TSH value. This especially ap-
doi:10.3949/ccjm.77a.10056 plies in the acute and inpatient settings, in
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LOW TSH
Normal free T4, Toxic nodular goiter (negative for thyroid receptor antibody [TRAB],
high free T3 no ophthalmopathy)
Early Graves disease (usually positive for TRAB, possible ophthalmopathy)
Natural thyroid preparations
High free T4, Order High Toxic nodular goiter (negative for TRAB, no ophthalmopathy) a
normal or iodine 123 uptake Graves disease (usually positive for TRAB, possible ophthalmopathy) a
high free T3 uptake Elevated hCG (rarely) a
scan
Low Thyroiditis a,b
uptake Ectopic hyperthyroidism a
Exogenous T4-T3 therapy
Struma ovarii (very rare)
Large deposits of functioning thyroid cancer metastases (very rare)
Iodine-induced hyperthyroidism (Jod-Basedow effect)
Amiodarone
a
Refer to an endocrinologist if suspected; b Repeat tests for TSH, free T4, and free T3 in 6–8 weeks. See text for details
FIGURE 1
which many patients are malnourished and pregnant or taking an estrogen-containing
consequently have low serum levels of thy- contraceptive, the total T4 and T3 levels may
roid-binding globulin and albumin. In this be high, secondary to an increase in thyroid-
situation, total T4 and T3 levels may be low binding globulin synthesis, but the free T4 and
and not accurately represent a patient’s true free T3 are normal (in the absence of a patho-
thyroid status. Likewise, in women who are logic process).
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PANTALONE AND NASR
T4 and T3
Onset
Level
Normal range
(euthyroid)
TSH
Disequilibrium state = the period during the hypothyroid phase of thyroiditis in which the thyroid-stimulating hormone (TSH) level
transiently remains low or inappropriately normal in the setting of low levels of free thyroid hormones; T4 = thyroxine;
T3 = triiodothyronine
by high thyroid hormone levels, other condi- the patient should be referred to an endocri-
tions, or medications. If thyroid hormone lev- nologist for further evaluation.
els are low, a low TSH value can be the result
of a central process (hypothalamic or pituitary ■■ LOW TSH, NORMAL FREE T4,
or both). NORMAL FREE T3
Severe euthyroid sick syndrome (also
called “nonthyroidal illness” or “low T3 syn- Subclinical hyperthyroidism
drome”). In this condition, the free T3 level Subclinical hyperthyroidism is defined as low
is usually low, and in severe cases the free T4 TSH, normal free T4, and normal free T3 lev-
level can also be low.1,2 els. Symptoms of hyperthyroidism such as
Disequilibrium state, which is seen in the fatigue, insomnia, weight loss, palpitations,
hypothyroid phase of resolving thyroiditis (FIG- tremor, or heat intolerance generally play a
URE 2). This will be discussed later, in the sec- role in whether therapy is considered, but not
tion on thyroiditis. in making the diagnosis of subclinical hyper-
thyroidism. To make the correct diagnosis, it
■■ LOW TSH, LOW FREE T4, HIGH FREE T3 is crucial to confirm that this pattern of test
results persists by repeating these tests over
T3 toxicosis from an exogenous source the next few months.
The combination of low TSH, low free T4, Exogenous thyrotoxicosis, by far the most
and elevated free T3 concentrations is consis- common form of subclinical thyrotoxicosis,
tent with ingestion of supratherapeutic doses results from taking levothyroxine (T4) or lio-
of exogenous T3, ie, liothyronine (Cytomel). thyronine (T3), or both, either in uninten-
Rarely is T3 therapy used alone to treat tional supratherapeutic doses in patients with
hypothyroidism. An exception is in patients hypothyroidism or in intentionally high doses
who undergo thyroid hormone withdrawal in to suppress TSH in patients with a history of
anticipation of radioactive iodine treatment differentiated thyroid cancer.
after having undergone total thyroidectomy Endogenous thyrotoxicosis. Subclinical
Consequences for differentiated thyroid cancer. hyperthyroidism from an endogenous cause is
of subclinical T3 therapy, when used, is often given in the result of an underlying pathophysiologic
combination with T4 therapy, either levothy- process, the same processes responsible for
hyperthyroid- roxine (Synthroid and others) or as part of overt states of hyperthyroidism (eg, Graves
ism: atrial a T4-T3 natural thyroid preparation derived disease, toxic nodular thyroid disease) (see the
from porcine thyroid tissue (Armour Thyroid, discussion of overt hyperthyroidism in a later
fibrillation, Nature-Throid). Natural thyroid preparations section).
bone loss may contain large amounts of T3, and when The course of endogenous subclinical hy-
they are given in supratherapeutic doses, they perthyroidism depends on the underlying cause
can cause a similar profile (low TSH, low free and on the level of TSH suppression.3–5 Sub-
T4, and elevated free T3). However, the free clinical hyperthyroidism secondary to a multi-
T4 level is usually in the normal range because nodular goiter is estimated to progress to overt
the preparations also contain T4. hyperthyroidism in about 5% of patients per
year,6 but in patients with nodular thyroid dis-
T3 toxicosis from an endogenous source ease and TSH levels of 0.1 μIU/mL or lower,
Sometimes the thyroid gland produces dispro- one study reported progression to overt hyper-
portionately large amounts of T3, usually from thyroidism in approximately 10% of patients
an autonomous nodule. Although the free T4 per year.3
level may be low in this situation, it is usually The risk of subclinical Graves disease pro-
in the normal range. gressing to overt hyperthyroidism has been
Serum thyroglobulin can be assayed to help difficult to estimate, given the relapsing and
determine whether the source of excess T3 is remitting nature of the disease. Rosario3,4 re-
exogenous (in which case the thyroglobulin ported that subclinical Graves disease pro-
level is low) or endogenous (in which case the gressed to overt hyperthyroidism in 2 years in
thyroglobulin is elevated). If it is endogenous, 6 (40%) of 15 patients who had TSH levels
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PANTALONE AND NASR
lower than 0.1 μIU/mL, but in no patients common in the general population, and often
who had TSH levels of 0.1 to 0.4 μIU/mL. no test results from before the onset of a criti-
These patients were younger than 65 years. In cal illness are available to help the clinician
a group age 60 and older with endogenous sub- separate overt thyroid disease from euthyroid
clinical hyperthyroidism and a TSH level be- sick syndrome. Furthermore, patients are of-
tween 0.1 and 0.4 μIU/mL, Rosario4 reported ten unable to provide a history (or to relate
that progression to overt hyperthyroidism was their symptoms) of overt thyroid disease, mak-
uncommon, occurring in about 1% of patients ing abnormal thyroid function tests difficult
per year. to interpret in the hospital. When previous
Thus, periodic reassessment of thyroid values are available, they can be invaluable in
function tests in patients with subclinical hy- correctly interpreting new abnormal results.
perthyroidism is crucial in monitoring for dis- Thyroid function test values in euthyroid
ease progression, especially in those with frank- sick syndrome can vary depending on the se-
ly suppressed TSH values (< 0.1 μIU/mL). verity of illness. A low free T3, a normal free
Adverse outcomes associated with subclin- T4, and a low-normal TSH are the most com-
ical hyperthyroidism are mainly cardiac ar- mon abnormalities seen in euthyroid sick
rhythmias (atrial fibrillation) and accelerated syndrome. The free T3 level is low because
loss of bone mineral density. of decreased peripheral conversion of T4 to
Cooper7 notes that definitive treatment T3 during critical illness. However, euthyroid
(radioactive iodine ablation, antithyroid sick syndrome can present with a spectrum of
drugs, or surgery) “seems reasonable” for older abnormal thyroid function tests, further com-
patients (age > 60 years) with a TSH level plicating interpretation and diagnosis. Serum
lower than 0.1 μIU/mL and for certain pa- TSH levels have been reported to be normal
tients with TSH levels of 0.1 to 0.4 who are in about 50%, low in 30%, and high in 12% of
at high risk, eg, those with a history of heart patients with nonthyroidal illness.8 However,
disease, osteoporosis, or symptoms of hyper- marked suppression of serum TSH (< 0.1 μIU/
thyroidism. mL) was observed only in about 7% of pa-
tients, mainly in those whose clinical picture Previous test
Normal variant was confounded by medications (dopamine or results can be
The normal range for TSH, as for other sub- corticosteroids, or both) that have indepen-
stances, is defined as the mean value in the dent TSH-lowering effects (see below).8 invaluable
general population plus or minus 2 standard when
deviations. This range includes 95% of the Drugs that suppress TSH
population, so that 2.5% of people have a Many drugs used in the hospital and intensive
interpreting
level higher than this range, and 2.5% have a care unit can alter thyroid function tests inde- new abnormal
level lower than this range. pendently of systemic illness, further compli- results
But some people with lower levels of TSH, cating the clinical picture.
especially in the range of 0.1 to 0.4 μIU/mL (3 Glucocorticoids, in high doses, have been
standard deviations below the mean) are actu- shown to transiently suppress serum TSH.9,10
ally euthyroid. These people have historically Octreotide (Sandostatin) and other so-
been classified as having subclinical hyperthy- matostatin analogues also transiently suppress
roidism, as there is no means of differentiating TSH.11–14 However, these drugs (and gluco-
these “normal” euthyroid people from people corticoids) do not appear to result in central
with asymptomatic subclinical hyperthyroid- hypothyroidism.10,15–17
ism. They need to be followed, since they may Dopamine, given in pharmacologic doses
have true subclinical hyperthyroidism that for a prolonged time, has been shown to re-
may manifest symptomatically in the future, duce the serum TSH level in both critically ill
possibly warranting treatment. and normal healthy people.18
Dobutamine (Dobutrex) in pharmacologic
Euthyroid sick syndrome doses has been likewise shown to lower TSH
Euthyroid sick syndrome is common during levels, although the serum TSH level was not-
critical illness. However, thyroid disease is ed to remain within the normal range in those
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LOW TSH
who had a normal TSH value at baseline.19 ■■ Low TSH, Normal free T4, Low Free T3
Amiodarone. Although most patients Euthyroid sick syndrome and/or medica-
who take amiodarone (Cordarone, Pacerone) tion effect. When the TSH level is low sec-
remain euthyroid, the drug can cause hy- ondary to euthyroid sick syndrome or a drug,
pothyroidism or hyperthyroidism. Initially, or both, the free T3 level is usually found to
amiodarone usually causes a decrease in T3 via be also low, which may be solely related to a
inhibition of 5´-deiodinase, with a transient component of euthyroid sick syndrome or sec-
reciprocal increase in TSH.20 ondary to the drugs themselves, as drugs such
When amiodarone induces thyrotoxicosis, as corticosteroids and amiodarone inhibit the
the condition can be subclinical, manifested conversion of T4 to T3.
by a low TSH in the setting of normal levels of
thyroid hormones, or as overt thyrotoxicosis ■■ LOW TSH, NORMAL FREE T4, HIGH FREE T3
with a low TSH and elevated levels of thyroid
hormones. See further discussion below on Toxic nodular goiter vs early Graves disease
amiodarone’s effects on thyroid function. If the free T3 is elevated and the TSH is low
Patients taking drugs that lower TSH are (suppressed), even in the absence of symp-
often critically ill and may also have a compo- toms, a diagnosis of subclinical hyperthyroid-
nent of euthyroid sick syndrome, resulting in ism would be inappropriate, because by defi-
a mixed picture. nition the free T4 and free T3 levels must be
normal for a diagnosis of subclinical hyperthy-
Elevated human chorionic gonadotropin roidism. The diagnostic possibilities are toxic
The alpha subunit of human chorionic go- nodular goiter and early Graves disease.
nadotropin (hCG) is homologous to the The combination of high T3, suppressed
alpha subunit of TSH. Thus, hCG in high TSH, and normal T4 is usually associated with
concentrations has mild thyroid-stimulating toxic nodular goiter, whereas T3 and T4 are
activity. typically both elevated in Graves disease (al-
The serum hCG concentration is highest though T3 is usually more elevated than T4).24
If excess T3 is in the first trimester of pregnancy and hCG’s The patient should undergo iodine 123 nu-
exogenous, thyroid-stimulating activity can suppress the clear imaging (“iodine uptake and scan”). Dif-
serum TSH level, but in most cases the TSH fuse uptake of iodine 123 supports the diagnosis
thyroglobulin level remains within the “normal range” of of Graves disease; patchy and nodular areas of
is low; pregnancy.21,22 The hCG levels observed dur- increased iodine 123 uptake support the diag-
ing the first trimester of pregnancy are usually nosis of a toxic nodular goiter (FIGURE 3).
if endogenous, associated with a low TSH and normal free The patient should also be tested for TSH
thyroglobulin thyroid hormone levels. In pregnant women receptor antibodies (TRAB), both stimulat-
is elevated who are not on T4 therapy for hypothyroid- ing and blocking, which are very specific for
ism, a persistently suppressed TSH (< 0.1 μIU/ Graves disease.
mL) after the first trimester or elevations of
the free thyroid hormones at any point during Natural thyroid preparations
pregnancy suggest that the suppressed TSH is Natural thyroid preparations, which can con-
secondary to autonomous thyroid function, as tain large amounts of T3, can also yield the
seen in Graves disease and toxic nodular goi- combination of normal free T4 and high free
ters, warranting further investigation. Iodine T3. Since these preparations contain both T4
radioisotope imaging studies are forbidden and T3, they usually result in low TSH, normal
during pregnancy. free T4, and elevated free T3 levels when given
If the hCG concentration is markedly in supratherapeutic doses. However, if these
elevated and for a prolonged time, as in hy- preparations are consumed in large enough
peremesis gravidarum and gestational tropho- quantities, both the free T4 and free T3 can
blastic disease (hydatidiform mole, a benign be elevated. This is in contrast to suprathera-
condition, and choriocarcinoma, a malignant peutic monotherapy with T3 (liothyronine),
condition), overt hyperthyroidism can devel- which usually results in low TSH, low free T4,
op, with elevated free T4 and free T3.21,23 and high free T3.
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PANTALONE AND NASR
FIGURE 3. Left, an iodine 123 scan from a patient with Graves disease. Note the diffuse
homogenous uptake of the thyroid gland. Right, an iodine 123 scan from a patient with a
toxic multinodular goiter. Note the nodular areas of increased intensity with suppression
(low uptake) of the surrounding thyroid tissue.
■■ LOW TSH, HIGH FREE T4, becomes saturated with “cold” (nonradiola-
NORMAL OR HIGH FREE T3 beled) iodine from the contrast medium and
cannot take up more iodine (radiolabeled) for
If the free T4 level is high, the free T3 level is the radionuclide scan. For this reason, iodine
usually high as well. Patients should undergo 123 imaging should not be performed for 6 to
iodine 123 nuclear imaging. 8 weeks after an exogenous load of iodine. In
this circumstance, the history and physical
If iodine 123 uptake is high examination, as well as laboratory testing (for
Graves disease vs toxic nodular goiter. If TRAB), must be relied on to make the correct
iodine 123 uptake is high, a low (suppressed) diagnosis.
TSH level, in conjunction with elevations of Elevated human chorionic gonadotropin. Periodically
the free thyroid hormones, is consistent with Iodine 123 nuclear imaging studies are forbid- reassess the
overt hyperthyroidism secondary to autono- den during pregnancy. Therefore, all women
mous (TSH-independent) thyroid function. of childbearing age should have a pregnancy thyroid function
Graves patients usually test positive for test before undergoing radioisotope imaging. tests in patients
TRAB, and they may have related ophthal- If thyrotoxicosis from hCG is suspected (eg,
mopathy, whereas patients with toxic nodular in cases of hydatidiform mole or choriocarci-
with subclinical
goiter are TRAB-negative and do not have noma), ultrasonography of the uterus should hyperthyroidism
Graves ophthalmopathy.24–27 be done to rule out a viable pregnancy before
Patients with either Graves disease or pursuing radioisotope imaging.
toxic nodular goiter have increased iodine Treatment options for the usual causes
123 uptake; however, the pattern of uptake in of hyperthyroidism (toxic nodular goiter or
Graves disease is diffuse, whereas it is patchy Graves disease) include radioactive iodine
or nodular when toxic nodular goiter is the ablation (unless the patient was exposed to
underlying etiology (FIGURE 3).24,27 Complicat- a recent cold iodine load), antithyroid drugs
ing matters, the pattern of uptake in Graves (methimazole or propylthiouracil), or surgi-
disease may be patchy if the patient has been cal resection (partial or complete thyroidec-
pretreated with antithyroid drugs such as pro- tomy).27
pylthiouracil or methimazole (Tapazole). Patients with overt hyperthyroidism
Review of the patient’s history is impor- should be referred to an endocrinologist for a
tant, as a recent iodine load (eg, intravenous thorough evaluation and discussion of the di-
contrast medium that contains iodine) can agnosis and the treatments that are available.
transiently worsen thyrotoxicosis while caus- Beta-blockers can be used to ameliorate the
ing the iodine 123 uptake to be low. The symptoms of thyrotoxicosis such as palpita-
reason for the low uptake is that the gland tions, anxiety, and tremor.
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LOW TSH
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PANTALONE AND NASR
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