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					REVIEW
CME       EDUCATIONAL OBJECTIVE: Readers will follow up the finding of a low thyrotropin (TSH) level with appropriate
CREDIT    diagnostic investigations

          KEVIN M. PANTALONE, DO                    CHRISTIAN NASR, MD
          Endocrinology and Metabolism Institute,   Endocrinology and Metabolism Institute,
          Cleveland Clinic                          Cleveland Clinic




Approach to a low TSH level:
Patience is a virtue
■ ABSTRACT
                                                                                                               A patient She says thatpresents to the out-
                                                                                                                    34-year-old woman

                                                                                                               postpartum.
                                                                                                                            endocrinology clinic 4 months
                                                                                                                                         2 months ago she
     Confronted with a low serum level of thyrotropin (thy-
     roid-stimulating hormone, TSH), physicians should not                                                     developed palpitations, heat intolerance, and
     jump to the conclusion that it is due to a hyperthyroid                                                   difficulty sleeping. Her primary care physician
     state, as other conditions and some drugs can be associ-                                                  diagnosed postpartum thyroiditis after labora-
                                                                                                               tory evaluation revealed that her thyrotropin
     ated with a TSH level that is slightly low (0.1–0.4 μIU/
                                                                                                               (thyroid-stimulating hormone, TSH) level
     mL) or frankly suppressed (< 0.1 μIU/mL). This review                                                     was low at 0.005 μIU/mL (reference range
     discusses how to approach a low TSH, stressing the                                                        0.4–5.5), and that her free thyroxine (T4) lev-
     frequent need to reassess thyroid function before making                                                  el was elevated at 2.4 ng/dL (reference range
     a diagnosis, the underlying processes and the drugs that                                                  0.7–1.8). She was prescribed atenolol (Tenor-
     can be responsible, and the degree of TSH suppression                                                     min) to treat the symptoms.
     and its role in the evaluation.                                                                               On follow-up testing 6 weeks later, her
                                                                                                               TSH level had risen, but it was still low at
■ KEY POINTS                                                                                                   0.085 μIU/mL, and her free T4 level was now
                                                                                                               low at 0.6 ng/dL. She was referred to an endo-
     A low TSH value should always be followed up by                                                           crinologist for further management.
     measuring the thyroid hormones, ie, thyroxine (T4) and                                                        How should this patient be further evalu-
     triiodothyronine (T3).                                                                                    ated and managed?

     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
                                                                CLEVELAND C L I N I C J O U R N A L O F M E D I C I N E   VOLUME 77 • NUMBER 11   NOVEMBER 2010   803
                             LOW TSH




      Approach to the finding of a low thyrotropin level

      Low thyrotropin (thyroid-stimulating hormone, or TSH)

      Measure free thyroxine (T4) and free triiodothyronine (T3)

               Low free T4,                                                Central hypothyroidism a
               low free T3                                                 Severe euthyroid sick syndrome a,b
                                                                           Disequilibrium state a,b

               Low free T4,                                                Exogenous T3 toxicosis (serum thyroglobulin low)
               high free T3                                                Endogenous T3 toxicosis (serum thyroglobulin high) a

               Normal free T4,                                             Subclinical hyperthyroidism b
               normal free T3                                               Exogenous thyroid hormone
                                                                            Endogenous thyroid hormone
                                                                              Mild toxic nodular goiter (single or multiple nodules)
                                                                              Mild Graves disease
                                                                           Normal variant
                                                                           Euthyroid sick syndrome
                                                                           Medication effects
                                                                           Elevated human chorionic gonadotropin (hCG)

               Normal free T4,                                             Euthyroid sick syndrome
               low free T3                                                 Medication effects

               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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  Natural history of thyroid function tests in patients with thyroiditis
                                                                                  Disequilibrium state

                                                           T4 and T3
             Onset
 Level




                                         Normal range
                                          (euthyroid)




                                                          TSH

           Baseline                  Hyperthyroid phase                            Hypothyroid phase                          Recovery
         euthyroidism                (weeks to months)                             (weeks to months)

   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


FIGURE 2                                                                                                                                      Use free T4
    However, depending on the analytical                                      FIGURE 1 outlines how to interpret a low                        and free T3
method, even measurements of the free hor-                                TSH level and formulate the appropriate diag-
mones may be affected by the protein changes                              nosis and plan. In this process, it is crucial to                   levels,
that occur during severe illness or pregnancy.                            consider the patient’s history, to note signs or                    not total
Also, some drugs can affect free hormone                                  symptoms of thyroid disease (hyperthyroidism
levels by displacing the hormones from their                              or hypothyroidism), and to ask about medi-
                                                                                                                                              levels, when
binding proteins.                                                         cation exposure. Furthermore, repeating the                         evaluating
    Most commercial laboratories estimate the                             thyroid function tests (and reviewing previous                      a low TSH
levels of free thyroid hormones by indirect                               values) to observe the trend is consistently in-
methods. Short of measuring the free thyroid                              valuable when deriving a diagnosis.
hormones directly using equilibrium dialysis
and ultrafiltration (the gold standard), no test                          ■ LOW TSH, LOW FREE T4, LOW FREE T3
or assay is 100% accurate. Even the determi-
nation of free hormone levels can be flawed                               The history of present illness (especially if the
if the assay is unreliable. Some clinicians still                         illness is prolonged and critical), a review of
prefer the free thyroid index (FTI) and T3 or                             previous thyroid function tests, and, some-
T4 resin uptake to assess free T4, and the total                          times, a complete evaluation of the remaining
T3 to assess T3 status.                                                   hypothalamic-pituitary axes are crucial in cor-
    The degree of TSH suppression should also                             rectly interpreting this combination of thyroid
be taken into account. A frankly suppressed                               function tests. Clinical judgment is required,
TSH level (< 0.1 μIU/mL) would favor overt                                and referral to an endocrinologist is warrant-
thyrotoxicosis in the correct clinical context                            ed. The diagnostic possibilities are:
(ie, if the levels of free T4, free T3, or both                               Central hypothyroidism. A low TSH
were normal or high).                                                     level is not always due to suppression caused
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                     LOW TSH



                    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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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
                                          CLEVELAND C L I N I C J O U R N A L O F M E D I C I N E   VOLUME 77 • NUMBER 11   NOVEMBER 2010   807
                     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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Graves disease                                             Toxic nodular goiter




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



                If iodine 123 uptake is low                                        lithium therapy).28 Other forms of thyroiditis,
                A low (suppressed) TSH level, in conjunction                       which may or may not be painful, include
                with elevations of the free thyroid hormones                       those induced by amiodarone, radiation, or
                and low uptake of iodine 123, is consistent                        trauma.
                with overt hyperthyroidism secondary to:                                Regardless of the cause, watchful waiting
                •	 Thyroiditis                                                     is warranted while monitoring thyroid func-
                •	 Ectopic hyperthyroidism due to T4-T3 thera-                     tion tests to ensure that recovery takes place.28
                    py, struma ovarii (very rare), or large depos-                 Beta-blockers are often used to decrease symp-
                    its of functioning thyroid cancer metastases                   toms during the transient hyperthyroid state
                    (very rare)                                                    observed early in the course of thyroiditis.
                •	 Iodine-induced hyperthyroidism (Jod-Base-                            Ectopic hyperthyroidism. Ingestion of ex-
                    dow effect)                                                    ogenous T4, T3, or both can suppress thyroid
                •	 Amiodarone-induced thyrotoxicosis.27,28                         function. This can occur with supratherapeu-
                    Thyroiditis, ie, destruction or inflamma-                      tic T4 and T3 (usually for hypothyroidism)
                tion of thyroid tissue with subsequent release                     and also factitiously or in patients abusing the
                of preformed thyroid hormones into the cir-                        drugs to lose weight. A useful way to differ-
                culation, results in thyrotoxicosis. The sever-                    entiate exogenous from endogenous causes of
                ity and duration of thyrotoxicosis depends not                     thyrotoxicosis is to measure serum thyroglobu-
                only on the size of the injured thyroid gland                      lin, which would be decreased in the former
                and the store of preformed thyroid hormones,                       and elevated in the latter.
                but also on the extent and duration of the thy-                         Ectopic production of T4 and T3 can oc-
                roid destruction and injury.                                       cur, albeit rarely, as in cases of struma ovarii or
                    Subacute thyroiditis usually lasts several                     in patients with large deposits of functioning
                weeks to a few months, and typically follows                       thyroid cancer metastases.29–31 Struma ovarii
                a pattern of:                                                      is a very rare ovarian teratoma (accounting
                •	 Transient hyperthyroidism due to release                        for 1% of all ovarian tumors), and even when
                    of thyroid hormone stores                                      present it does not usually result in thyrotoxi-
Patients with   •	 A brief period of euthyroidism                                  cosis.29,30 However, the diagnosis should be
toxic nodular   •	 Hypothyroidism, as the store of preformed                       considered in the appropriate clinical context,
                    thyroid hormone is exhausted and thyroid                       ie, in the setting of thyrotoxicosis and a pelvic
goiter are          inflammation and destruction subside, and                      mass; radioiodine uptake would be elevated in
TRAB-negative       then                                                           the pelvis in those cases.
                •	 Recovery (usually, unless the thyroid is                             Likewise, thyrotoxicosis secondary to func-
and do not have     not capable of recovery), during which the                     tioning thyroid cancer metastases is also rare
ophthalmopathy      TSH level rises in response to low levels of                   but should be considered in the right clinical
                    thyroid hormones in the circulation, and                       context (iodine-avid tissue throughout the
                    the recovering thyroid begins to resume                        body noted on radioiodine whole-body imag-
                    thyroid hormone synthesis.28                                   ing).
                    There is a brief period during the hypo-                            Iodine-induced hyperthyroidism develops
                thyroid phase of thyroiditis during which the                      in patients with underlying thyroid disease
                TSH level remains low (or inappropriately                          (toxic nodular goiter or Graves disease) and
                normal), even though the free thyroid hor-                         is caused by an exacerbation of autonomous
                mone levels are also low; this period is com-                      (TSH-independent) thyroid function by an
                monly called the “disequilibrium state” (FIGURE                    iodine load (eg, intravenous contrast medium
                2). This state is due to the slow recovery of the                  that contains iodine, or amiodarone therapy
                pituitary thyrotrophs as they escape tonic sup-                    [see below]).
                pression by excess thyroid hormones.                                    Amiodarone-induced thyrotoxicosis. In
                    The classic entity of de Quervain thyroid-                     various reports, the incidence of amiodarone-
                itis (subacute granulomatous thyroiditis) is                       induced thyrotoxicosis ranged from 1% to
                painful, whereas other forms are painless (eg,                     23%.32 There are two types.
                autoimmune lymphocytic thyroiditis, post-                               Type 1 is a form of iodine-induced hy-
                partum, or related to cytokine [interferon] or                     perthyroidism. It can occur in patients with
  810   CLEVELAND CLINIC JOURNAL OF MEDICINE   VOLUME 77 • N U M B E R 1 1   NOVEMBER 2010
                                                                                                               PANTALONE AND NASR



autonomous thyroid function when they are                                  ■ CASE CONCLUDED
exposed to amiodarone, which contains 37%
iodine by weight.                                                          Our patient’s thyroid function tests were re-
    Type 2 occurs in patients with no un-                                  peated at the time of her endocrinology con-
derlying thyroid disease and is probably a                                 sult, 2 weeks after she was noted to have a low
consequence of a drug-induced destructive                                  TSH in the setting of low free T4, which sug-
thyroiditis. Mixed or indeterminate forms of                               gested central hypothyroidism. Her TSH level
amiodarone-induced thyrotoxicosis encom-                                   was now 3.5 μIU/mL, and her free T4 level was
passing several features of both type 1 and type                           0.8. Thus, her low TSH in the setting of the
2 may also be observed.20                                                  low free T4 noted 2 weeks earlier reflected a
    The treatment varies by type: antithyroid                              disequilibrium state, which occurs during the
drugs (thionamides) in type 1 and corticoste-                              hypothyroid phase of thyroiditis (FIGURE 2).
roids in type 2.20 It can be difficult to discern                              Repeated measurements of her thyroid
between the two entities, and combination                                  function tests verified complete recovery and
therapy with antithyroid drugs and predni-                                 resolution of her thyroiditis. No levothyroxine
sone may be needed. One of the drugs is then                               therapy was required, and no further investiga-
withdrawn, and the effect on the levels of free                            tion was performed.                          ■
thyroid hormones is monitored. This helps
determine which drug is working, pointing to                               ACkNOwLEDgmENTs: We thank Nada Johnson from the
                                                                           Department of Endocrinology, Cleveland Clinic, for her skillful
the correct diagnosis and treatment.                                       help with the preparation of the figures.

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                                                          CLEVELAND C L I N I C J O U R N A L O F M E D I C I N E   VOLUME 77 • NUMBER 11         NOVEMBER 2010          811

				
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