Download PHYSIOLOGY The thyroid gland releases two forms of thyroid

PHYSIOLOGY
The thyroid gland releases two forms of thyroid hormone, thyroxine (T4) and triiodothyronine
(T3), in a molar ratio of 14:1. All of the T4 in the body is made within the thyroid, whereas
80% of T3 is derived in the peripheral tissues through removal of an iodine residue from T4 at
the 5′-position. Most T3 production from T4 occurs in the liver and kidney, but other tissues,
including the pituitary gland and central nervous system, also possess this ability. The
peripheral conversion of T4 to T3 is decreased by several medications, including propranolol,
corticosteroids, propylthiouracil, iopanoic acid, and amiodarone. This conversion is also
acutely downregulated during the course of most nonthyroidal illnesses. T3 affects the
physiologic function of virtually all the tissues in the body by regulating the transcription of
thyroid hormone–dependent genes through binding to a specific nuclear receptor.
The synthesis and release of thyroid hormone is controlled by pituitary-derived thyroidstimulating hormone (TSH), under the influence of thyrotropin-releasing hormone (TRH)
from the hypothalamus. TSH stimulates such basic thyrocyte functions as iodine uptake,
organification, and the synthesis and release of thyroid hormone. Both T4 and T3 are
extensively (more than 99%) bound to protein in the circulation, a process that serves the dual
purpose of preventing excessive tissue uptake while maintaining a readily accessible reserve
of thyroid hormone. The three principal binding proteins for T4 and T3 are thyroxine-binding
globulin (TBG) (70%), albumin (15% to 20%), and transthyretin (10% to 15%). Several
common medications affect levels of TBG and therefore total T4 and total T3 levels, without
generally affecting free thyroid hormone levels. For example, estrogen, 5-fluorouracil, and
methadone increase serum TBG levels, whereas androgens, corticosteroids, L-asparaginase,
and niacin each decrease these levels.
Key processes regulated by thyroid hormone include basal metabolism, fetal central nervous
system development, thermogenesis, and lipogenesis. The serum half-life of T3 is
approximately 1 to 1.5 days whereas that of T4 is approximately 8 days.
EVALUATION OF THYROID FUNCTION
Common tests of thyroid function are shown in Table 18. Testing in suspected thyrotoxicosis
includes measurement of serum TSH and serum free T4. Although serum TSH is suppressed
with most causes of thyrotoxicosis, it may be inappropriately normal or elevated in the rare
Table 18. Common Tests of Thyroid Function
Test
Normal
Range
Indication
Serum thyroidstimulating hormone
(TSH)
0.5 – 5
mU/L
Serum free thyroxine
(FT4)
10.3 – 30.6 Suspected thyroid
pmol/L
dysfunction
(0.8 – 1.8
ng/dL)
Suspected thyroid
dysfunction
Comment
Misleading results in
some forms of pituitary
disease
Normal ranges vary
depending on assay
Serum free
triiodothyronine (FT3)
1.5 – 7
pmol/L
T3 thyrotoxicosis
May substitute with total
T3 (binding protein
dependent)
Serum thyroglobulin
3 – 40
ng/mL
Suspected subacute
thyroiditis
Variable levels with
nodular thyroid disease
Serum thyroidstimulating
immunoglobulin (TSI)
0 – 125%
Graves' disease in
pregnancy; euthyroid
ophthalmopathy
Very expensive test, not
generally needed to
diagnose Graves' disease
Serum thyrotropin< 10%
binding inhibitory
immunoglobulin (TBII)
Same as TSI; also useful in
assessing fluctuating
thyroid function in Graves'
disease
TBII detects both
blocking and stimulating
antibodies against the
TSH receptor
Anti-thyroid peroxidase < 2 U/mL
antibodies
Suspected Hashimoto's
thyroiditis
Predictive value for
development of overt
hypothyroidism
Radioactive iodine
uptake
10% – 30% Biochemical thyrotoxicosis Contraindicated in
of dose at
pregnancy and
24 hours
breastfeeding
instance of a patient with hyperthyroidism caused by a TSH-producing pituitary tumor. In the
latter circumstance, an elevated serum free T4 may be the best clue to the true diagnosis.
Patients with a normal free T4 value and an undetectable TSH may have predominately T3thyrotoxicosis; serum total or free T3 should be tested in this circumstance. Patients with
confirmed biochemical evidence of thyrotoxicosis should next undergo nuclear medicine
testing (contraindicated in pregnant and breastfeeding patients) to include a thyroid scan and
24-hour radioactive iodine uptake (RAIU). The RAIU gives a quantitative assessment of the
degree of thyroid hyperfunction and assists with the differential diagnosis in a thyrotoxic
patient (Table 19). The thyroid scan shows where in the thyroid this uptake is occurring.
Thyroid antibody testing is rarely needed to determine the cause of thyrotoxicosis. Table 19.
Measurement of Radioactive Iodine Uptake in Thyrotoxicosis
Radioactive Iodine
Uptake
Level
Specific Disorders
Range
(%)
High
> 30%
Hyperfunction (Graves' disease, toxic multinodular goiter, autonomous
thyroid nodules, thyroid-stimulating hormone-producing tumors)
Normal
10% –
30%
Euthyroid; mild hyperfunction
Low
< 10%
Thyroiditis; severe iodine excess, amiodarone-induced thyrotoxicosis
(type 2)
Testing for hypothyroidism should include a serum TSH and generally a serum free T4 level.
Although pituitary and hypothalamic causes of hypothyroidism are uncommon, the diagnosis
will likely be missed if one relies solely on serum TSH testing. Antibodies against thyroid
peroxidase (TPO) signify Hashimoto's thyroiditis, and in conjunction with a marginally
elevated serum TSH level, have predictive value for future overt hypothyroidism. Thyroid
imaging is generally not indicated in hypothyroidism.
THYROTOXICOSIS
The term thyrotoxicosis refers to any cause of thyroid hormone excess, whereas
hyperthyroidism specifically refers to the subset of thyrotoxic patients with an increase in
thyroid hormone production and release, as that which occurs in Graves' disease, autonomous
thyroid nodules, and toxic multinodular goiter. These latter causes of thyrotoxicosis are
associated with an increased thyroid uptake of iodide (measured as an elevated RAIU)
because iodide is a key substrate in thyroid hormone synthesis. Conversely, causes of
thyrotoxicosis resulting from thyroid destruction, such as subacute thyroiditis and postpartum
thyroiditis, are associated with a decreased thyroid uptake of iodide by the damaged thyroid
tissue. Subacute thyroiditis is a nonautoimmune inflammation of the thyroid that generally
presents with a firm and painful thyroid and is believed to be a post-viral illness. Exogenous
T4 or T3 used therapeutically or surreptitiously decreases serum TSH, which in turn leads to a
low RAIU and a suppressed serum thyroglobulin level.
GRAVES DISEASE
Graves' disease is the most common cause of overt thyrotoxicosis in the United States. This
disease is characterized by diffuse goiter, thyrotoxicosis, an elevated RAIU, and a thyroid
scan showing diffuse increased activity. Extrathyroidal manifestations including
ophthalmopathy, dermopathy, and acropachy occur in approximately 20%, 1%, and 0.1%,
respectively, of unselected patients with Graves' disease, respectively (1). Patients with
Graves' disease have an unregulated production of T4 and T3 because of the presence of
autoantibodies against the TSH receptor. Because these antibodies cannot be removed,
therapy for Graves' disease is directed at disabling the thyroid gland by using thionamide
antithyroid drugs, radioactive iodine (131I), or surgical removal. Antithyroid drugs, including
methimazole and propylthiouracil, are selected as primary therapy by approximately 30% of
American thyroidologists, whereas nearly 70% prefer radioiodine. Surgery is generally
reserved for patients with concurrent suspicious thyroid nodules and those who cannot
tolerate antithyroid drugs or unwilling to use radioiodine. Most thyrotoxic patients are given
β-adrenergic blocking agents such as atenolol 50 to 100 mg once or twice daily or propranolol
40 mg every 6 to 8 hours unless such therapy is contraindicated.
Typical starting doses for antithyroid drugs are methimazole 20 to 30 mg once daily or
propylthiouracil 200 to 300 mg in three divided doses. Adverse reactions to antithyroid drugs
include minor manifestations such as rash or urticaria, mild elevations of aminotransferases,
arthralgias, or transient leukopenia, which occur in 1% to 5% of patients treated, and severe
but rare reactions such as agranulocytosis, hepatic necrosis, and vasculitis, which occur in less
than 0.5% of treated patients. Significant rash in reaction to one antithyroid drug generally
requires substitution with the alternative drug, whereas development of agranulocytosis
precludes further use of either drug. Thyroid function tests are monitored at intervals from 1
to 3 months in patients taking antithyroid drugs in order to allow dose adjustment, generally
downward. Monitoring of the leukocyte count or liver-associated laboratory tests is variably
recommended during antithyroid drug therapy; all patients are advised to immediately report
new-onset fever, pharyngitis, pruritus, or jaundice. The likelihood of achieving a remission
from Graves' disease is only 50% after completing 1 year of antithyroid drug therapy, which
is perhaps the greatest drawback to use of these drugs as primary therapy (2).
Radioiodine therapy is generally given as a single oral capsule containing 10 to 30 mCi of
131
I. An empirical dose of 12 to 15 mCi is frequently used in the United States, but patients
with larger glands or lower RAIU are often given larger amounts to ensure adequate dosing.
Mathematical formulas are available for calculating a radioiodine dose based on estimated
gland size and RAIU, but these do not offer an advantage over empiric therapy. Patients
treated with radioiodine are generally rendered hypothyroid within 2 months of receiving 15
mCi of 131I. Only 5% to 10 % of affected patients require additional therapies with radioiodine
for thyrotoxicosis that persists beyond 6 months from the initial treatment. Adjunctive therapy
with antithyroid drugs is occasionally used either before or after radioiodine therapy in an
attempt to decrease the risk of a transient worsening of thyrotoxicosis after thyroid ablation.
However, since antithyroid drugs render the thyroid radioresistant, this therapy is generally
reserved for patients with severe thyrotoxicosis or comorbidities and must be stopped for
several days before and after giving the radioiodine. Radioiodine therapy appears to increase
the risk of developing new or worsened Graves' ophthalmopathy compared with antithyroid
drugs or surgery, occurring in up to 15% of patients treated (3). Such aggravation is generally
mild and most patients return to their baseline eye status within 2 to 3 months. Patients with
preexisting moderate ophthalmopathy have been treated with corticosteroids concurrent with
the radioiodine therapy, a practice which may decrease the risk of disease progression. Those
with severe eye disease should probably not be treated with radioiodine. Tobacco smoking
has been repeatedly linked to Graves' ophthalmopathy, although the mechanism is unclear (4).
TOXIC MULTINODULAR GOITER
Toxic multinodular goiter is the end result of a gradual evolution starting from sporadic goiter
and progressing through a nontoxic multinodular state. Thyroid scanning shows multiple
areas of increased uptake or autonomy, with variable degrees of suppression in the remaining
thyroid tissue; RAIU is either elevated or inappropriately high-normal for a patient with a
suppressed serum TSH. Individual nodules within a multinodular goiter grow independently
of TSH, gradually increasing in size and synthetic capacity. Biochemical evolution occurs
from euthyroidism through subclinical hyperthyroidism and ultimately to overt thyrotoxicosis.
A clinical correlate of this slow progression is the increased prevalence of toxic multinodular
goiter with age. During the evolution of autonomous function, multinodular goiter patients are
at risk for iodine-induced thyrotoxicosis and should be monitored closely after exposure to
iodinated contrast or medications containing large amounts of iodine, such as amiodarone.
Antithyroid drugs can be used to restore euthyroidism, but unlike in Graves' disease, this
therapy does not result in a lasting remission after these drugs are stopped. Radioiodine is the
treatment of choice, with typical doses in the 15 to 30 mCi range. Ideally, non-nodular thyroid
tissue recovers normal function and euthyroidism is restored, but occasionally hypothyroidism
ensues. Thyroidectomy is occasionally recommended for patients with large, compressive
substernal goiters, those with concurrent suspicious “cold” nodules, and those who refuse rad
ioiodine and are intolerant to antithyroid drugs.
TOXIC ADENOMA
Autonomously-functioning thyroid nodules (also known as hot nodules or toxic adenomas)
generally develop slowly and, as in toxic multinodular goiter, are characterized by a gradual
biochemical progression, often passing through a prolonged period of subclinical
hyperthyroidism. Approximately 70% of toxic adenomas studied in a European population
had activating mutations of the TSH receptor within the tumor that were thought to be the
primary cause of both tumor formation and thyrotoxicosis (5). The amount of thyroid
hormone produced by an autonomous nodule is roughly proportional to its size – overt
hyperthyroidism generally does not occur until nodules are greater than 3 cm in diameter.
Surgical removal of the toxic adenoma can usually be accomplished with a
hemithyroidectomy, leaving the contralateral side to recover normal function. Radioiodine is
also an effective form of therapy, although in some cases scatter radiation to the contralateral
thyroid lobe leads to permanent hypothyroidism. RAIU is typically lower in patients with
toxic adenoma than in those with Graves' disease, so higher doses of 131I (15 to 30 mCi) are
commonly used.
DESTRUCTIVE THYROIDITIS
here are at least nine varieties of thyroiditis (Table 20), several of which may present with
thyrotoxicosis (6). Among the latter varieties, postpartum thyroiditis, silent thyroiditis, druginduced thyroiditis, and subacute thyroiditis, are fairly common, whereas traumatic thyroiditis
and acute thyroiditis are relatively rare. In general, thyroid dysfunction caused by thyroiditis
is less severe than that seen with other forms of endogenous thyrotoxicosis; RAIU is
universally low during the thyrotoxic stage because of transient thyroid damage.
Postpartum thyroiditis occurs in up to 10% of pregnancies in the United States. It is an
autoimmune disorder possibly unmasked in predisposed women as immune surveillance
rebounds after pregnancy. Women with positive anti-TPO antibodies during pregnancy are
more likely to develop postpartum thyroiditis than are those with negative serology. The
classic description involves a thyrotoxic stage starting 1 to 6 months after delivery, followed
by a hypothyroid stage in which damaged thyroid tissue is unable to supply ample thyroid
hormone production, to finally a euthyroid stage, at 9 to 12 months after delivery (Figure 4).
There are variations on this theme, however, with some women first presenting with
hypothyroidism several months after delivery because of a mild or unrecognized thyrotoxic
stage (7). Silent thyroiditis very closely resembles postpartum thyroiditis, in terms of an
autoimmune association and a triphasic pattern, but silent thyroiditis occurs in the absence of
pregnancy. Silent thyroiditis is also seen in some types of drug-induced thyroid dysfunction,
such as in patients taking lithium. β-adrenergic blockers can be used to treat thyrotoxic
symptoms in patients with both postpartum thyroiditis and silent thyroiditis, but antithyroid
drugs have no utility because new hormone synthesis is already low during the destructive
phase of these disorders. During the hypothyroid stage, therapy with levothyroxine is
occasionally required for patients with moderate symptoms or serum TSH greater than 15 to
20 mU/L. Levothyroxine therapy should be withdrawn after 3 to 6 months to determine
whether the patient has recovered full thyroid function.
Subacute thyroiditis presents with moderate to severe pain in the thyroid bed, sometimes
radiating to the ears. Patients appear moderately ill with malaise, low-grade fever, and fatigue
that sometimes eclipse symptoms of thyrotoxicosis. The thyroid is firm and painful to
palpation. In addition to laboratory evidence of thyrotoxicosis, the erythrocyte sedimentation
rate is elevated and mild anemia is common. Thyroid ultrasound shows diffuse heterogeneity
and decreased or normal color-flow Doppler, rather than the enhanced flow characteristic of
Graves' disease. β-blockers and anti-inflammatory therapy are the mainstays of therapy.
Nonsteroidal anti-inflammatory agents provide some pain relief, but most patients with
moderate symptoms require corticosteroid therapy, such as prednisone 40 mg daily for 1 to 2
weeks followed by a gradual taper over 2 to 4 weeks. As with silent and postpartum
thyroiditis, levothyroxine is occasionally required during the hypothyroid stage, but should be
withdrawn after 3 to 6 months and recovery of normal function that is verified with thyroid
function testing.
Table 20. Varieties of Thyroiditis
Type of
Thyroiditis
Synonym(s)
Comments
Acute
Suppurative thyroiditis, thyroid Infectious (bacterial, fungal, tuberculous,
abscess
parasitic)
Subacute
Granulomatous thyroiditis, de
Quervain's thyroiditis
Postpartum
Painless postpartum thyroiditis Autoimmune, thyrotoxicosis followed by
hypothyroidism and then euthyroidism
Silent
Painless thyroiditis
Autoimmune
Drug-induced
None
Amiodarone, lithium, alpha-interferon,
interleukin-2
Traumatic
Palpation thyroiditis
Radiation thyroiditis
Seat belt injury, choking injury
Hashimoto's
Chronic lymphocytic
thyroiditis
Autoimmune, may present with transient
thyrotoxicosis
Postviral, thyrotoxicosis followed by
hypothyroidism and then euthyroidism
Riedel's
Fibrous thyroiditis
Sclerosing
Figure 4. Triphasic changes in thyroid hormone levels associated with destructive thyroiditis.
Measurement of TSH and iodine-123 uptake show thyrotoxicosis during the first 3 months,
followed by hypothyroidism for 3 months and then by euthyroidism.
T4 = thyroxine; TSH = thyroid-stimulating hormone.
Adapted with permission from: Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J
Med. 2003;348:2646-55.
AMIODARONE INDUCED THYROTOXICOSIS.
Amiodarone therapy leads to thyrotoxicosis in approximately 3% of patients treated with this
drug in the United States (8). Two basic mechanisms have been identified in the development
of amiodarone-induced thyrotoxicosis (AIT). The first (type 1 or goitrous AIT) is related to
the high iodine content of amiodarone (37% by molecular weight) and is essentially an
iodine-induced thyrotoxicosis. Type 1 disease tends to occur in patients with pre-existing
thyroid autonomy, such as toxic multinodular goiter or subclinical Graves' disease. In
contrast, patients with type 2 AIT develop a destructive thyroiditis apparently caused by a
direct toxic effect of amiodarone and do not necessarily have pre-existing thyroid disease.
RAIU is more likely to be elevated in type 1 and suppressed in type 2 AIT, whereas
inflammatory markers such as IL-6 are more likely to be elevated in type 2 disease. Colorflow Doppler is also more likely to be increased in type 1 than in type 2 AIT. The distinction
between type 1 and type 2 is not always so clear, however, and some patients have elements
of both types. Ideally, type 1 disease is better treated with antithyroid drugs such as
methimazole, 30 mg daily, (and rarely, perchlorate), to prevent new hormone synthesis,
whereas type 2 disease is better treated with anti-inflammatory therapy such as prednisone, 40
mg daily. When clear distinction of type 1 from type 2 AIT is not possible, a combination of
prednisone, 40 mg daily, and methimazole, 30 to 40 mg daily, should be used until the patient
has stabilized, at which time the drugs may be individually tapered. Thyroidectomy is
occasionally required in patients who prove refractory to medical therapy.
SUBCLINICAL HYPERTHYROIDISM
Subclinical hyperthyroidism is defined biochemically as a suppressed serum TSH value
resulting from an increase in serum T4 and/or T3 within the confines of the normal range.
Subclinical hyperthyroidism is a disorder that has become widely recognized with
improvements in the sensitivity of the TSH assay over the past 20 years. Not all patients with
a suppressed serum TSH and normal free T4 have subclinical hyperthyroidism; other causes of
this pattern are listed in Table 21. Causes of subclinical hyperthyroidism are the same as
overt hyperthyroidism, although excessive thyroid hormone therapy is an important additional
cause of subclinical disease. A patient with a persistently suppressed TSH value should
undergo thyroid scanning and RAIU measurement to determine the cause. A high-normal
RAIU is not uncommon in patients with subclinical hyperthyroidism. The thyroid scan shows
a diffuse uptake pattern in patients with mild Graves' disease or focal increased areas of
uptake in patients with toxic multinodular goiter or solitary hot nodules.
Table 21. Causes of a Low Serum Thyroid-Stimulating Hormone and Normal Free Thyroxine
Disorder
Subclinical thyrotoxicosis
Comment
Toxic multinodular goiter, toxic adenomas, mild Graves'
disease, excessive replacement therapy
Total triiodothyronine
thyrotoxicosis
Early Graves' disease, autonomous thyroid nodules
Drug effect
Corticosteroids, octreotide
Non-thyroidal illness
Expanded normal range
Transitional thyroid state
Recovery from thyroiditis
Central hypothyroidism
Thyroid-stimulating hormone may be low, normal, or elevated
A recent consensus conference examining the association between subclinical thyroid disease
and clinical manifestations concluded that the evidence linking a serum TSH less than 0.1
mU/L to cardiac arrhythmias was “good” and that linking to osteoporosis was “fair” (9). The
evidence that restoration of euthyroidism leads to improvement in each of these areas was
rated as “fair.” For lesser degrees of TSH suppression (0.1 to 0.45 mU/L), the evidence was
rated as either insufficient or nonexistent. Rather than proving that treatment of subclinical
hyperthyroidism is not necessary, this shows the need for additional well-designed clinical
studies in this area.
The decision to treat patients with subclinical hyperthyroidism should therefore be based on
the degree of serum TSH abnormality and the clinical status of the patient. Patients older than
65 years or with underlying heart disease or osteoporosis and a serum TSH less than 0.1
mU/L should be approached with an aim to restore euthyroidism, whereas observation alone
is an option for healthy younger patients with a serum TSH between 0.1 to 0.45 mU/L (10).
Therapeutic options in subclinical hyperthyroidism are similar to overt disease, with the
exception that patients with mild Graves' disease and small goiters are more likely to achieve
a remission on antithyroid drugs, and lower doses, such as methimazole, 5 to 10 mg once
daily, or propylthiouracil, 50 mg twice daily, may be sufficient to restore euthyroidism.
Similar doses of these medications may be used in patients with subclinical hyperthyroidism
due to toxic multinodular goiter or toxic adenoma, but unlike Graves' disease, a lasting
correction requires definitive therapy – usually with radioiodine.
Disorders of thyroid hypofunction range from mild subclinical disease to overt disease to
myxedema coma. Hypothyroidism is more common than thyrotoxicosis. The Third National
Health and Nutrition Examination Survey (NHANES III) survey showed that 4.6 % of
Americans studied had biochemical evidence of overt or subclinical hypothyroidism
compared with 1.3% for thyrotoxicosis (11). Hashimoto's thyroiditis is the most common
cause of hypothyroidism in the United States, followed by iatrogenic causes such as prior
radioiodine therapy for Graves' disease or thyroidectomy for thyroid cancer and nodular
thyroid disease.
HYPOTHYROIDISM
A persistent elevation in serum TSH level is the first biochemical indication of
hypothyroidism. Anti-thyroid peroxidase antibodies are frequently positive at this stage in
patients with Hashimoto's thyroiditis. Both the degree of TSH elevation and the titer of antiTPO antibodies are predictive of progression to overt thyroid failure, which occurs at a rate of
approximately 4% to 5% per year. Transient elevation in serum TSH may occur in the
absence of permanent hypothyroidism, such as during the course of a nonthyroidal illness or
during recovery from destructive thyroiditis. In a patient with an isolated elevation in serum
TSH, it is prudent to repeat the test in 2 to 4 weeks rather than committing the patient to
lifelong replacement therapy. Positive anti-TPO antibodies confirm true thyroid disease, give
predictive data about the rate of progression, and indicate that the patient and family members
are at increased risk for other autoimmune endocrine deficiencies, such as those caused by
Addison's disease, type 1 diabetes mellitus, and premature ovarian failure. There is no role for
a thyroid scan, RAIU test, or thyroid ultrasound in patients with acquired thyroid failure.
Treatment of permanent hypothyroidism consists of providing exogenous thyroid hormone in
an amount that corrects the deficit without exposing the patient to iatrogenic thyrotoxicosis. In
the early stages of Hashimoto's thyroiditis, a low dose of levothyroxine, such as 0.025 to 0.05
mg daily, is generally sufficient to normalize the serum TSH level. With progressive thyroid
failure, the dose requirement increases, so in the late stages of Hashimoto's thyroiditis or after
a total thyroidectomy, an average dose of 1.6 µg/kg is required. In elderly patients or those
with underlying cardiac disease, a low initial dose of thyroid hormone is used, such as 0.025
mg daily, and gradually increased at 2-week intervals to avoid precipitation of angina or an
arrhythmia.
Two areas of recent controversy over optimal thyroid hormone replacement therapy include
the question of whether adding liothyronine (LT3) to levothyroxine therapy provides benefit
and whether generic and brand prescriptions for levothyroxine are interchangeable or
bioequivalent. Because the thyroid directly releases 20% of the body's T3 (the remainder is
generated through peripheral conversion of T4), it has been proposed that an ideal replacement
regimen would contain both levothyroxine and liothyronine. Although a 1999 study suggested
improved mood and psychological test scores in patients receiving combination therapy, four
subsequent studies have refuted these results (12). Additional controversy followed a 2004
FDA determination that several different formulations of levothyroxine, including generic
brands, were bioequivalent. The FDA method used to determine bioequivalence has been
criticized for its failure to measure serum TSH changes in patients receiving alternative
formulations. It is therefore advised that confirmatory testing be performed after switching
brands of levothyroxine, to assure that a dose adjustment is not required. A corollary to this
recommendation is that formulations should not be interchanged without the knowledge of the
patient and provider.
The goal of replacement therapy is to keep the TSH in the 1 to 2.5 mU/L range. Although
most TSH assays give a normal range of approximately 0.5 mU/L to 4.5 mU/L, it appears that
after rigorously excluding patients with occult thyroid disease, the true normal range is
narrower than previously believed, perhaps extending to an upper limit of only 2.5 mU/L (13).
SUBCLINICAL HYPOTHYROIDISM
Like subclinical thyrotoxicosis, subclinical hypothyroidism has a biochemical definition: an
elevation of serum TSH level caused by a decrease in serum free T4 within the confines of the
normal range. Most patients with subclinical hypothyroidism have Hashimoto's thyroiditis.
Not all patients with an elevated TSH and normal free T4 have subclinical hypothyroidism
(Table 22). Table 22. Causes of an Elevated Serum Thyroid-Stimulating Hormone and
Normal Free Thyroxine
Disorder
Comment
Subclinical hypothyroidism
—
Discordant thyroid-stimulating hormone
release
Thyroid-stimulating hormone-producing
pituitary tumors
Transitional thyroid state
Recovery from hypothyroidism
Nonthyroidal illness
Expanded normal range
Drug effect
Amiodarone
Thyroid-stimulating hormone-receptor
inactivating mutation
Affects thyroid and pituitary thyroidstimulating hormone action
The degree of TSH elevation and the titer of anti-thyroid peroxidase antibody predict the risk
of progression to overt disease. In one study, patients with a TSH level greater than 12 mU/L
and high titers of anti-thyroid peroxidase antibodies were 15 times more likely to develop
overt hypothyroidism than patients with a serum TSH level less than 6 mU/L and negative
anti-thyroid peroxidase antibodies (14).
A recent consensus conference on subclinical thyroid disease concluded that the evidence
linking subclinical hypothyroidism to systemic symptoms, cardiac dysfunction, adverse
cardiac endpoints, and low-density lipoprotein cholesterol elevation was “insufficient” or
nonexistent for TSH values ranging from 4.5 to 10 mU/L, whereas the association between
lipid elevation and a serum TSH greater than 10 mU/L was rated as “fair.” The association
between any degree of TSH elevation and progression to overt disease was listed as “good.”
The evidence that restoration of euthyroidism leads to improvement in any of these areas was
listed as “insufficient” or nonexistent. This consensus statement again points to the need for
additional well-designed clinical studies in this area. The decision to begin levothyroxine
therapy in a patient with persistent elevation in serum TSH but normal free T4 values should
be individualized. If replacement therapy is begun, particular care should be taken to avoid
overtreatment — particularly in the elderly.
Structural disorders of the thyroid gland
Structural disorders of the thyroid gland include solitary thyroid nodules, simple and
multinodular goiter, and thyroid cancer. Structural disorders are more common than
functional disorders and more likely to require surgical intervention because of concerns
about cancer or to correct anatomic problems related to goiter.
THYROID NODULES
Thyroid nodules can be detected by palpation in approximately 5% of the adult population in the
United States. With high-resolution ultrasound, thyroid nodules are detectable in more than 25% of
adults, and the prevalence is higher in women and the elderly (15). Approximately 5% of thyroid
nodules represent thyroid cancer. Older men with thyroid nodules are more likely to have cancer
than are younger women. The diagnostic approach to the thyroid nodule is shown in Figure 5. I
Figure 5. Initial approach to the thyroid nodule.
sotopic thyroid scanning is generally not useful because both benign and malignant nodules
tend to be hypofunctional or “cold” on thyroid scan. Conversely, thyroid ultrasound is useful
for: 1) confirming that a mass is of thyroid origin in patients with a difficult examination; 2)
distinguishing a solitary nodule from a multinodular thyroid; 3) measuring the size of the
nodule to facilitate future follow-up; and 4) viewing certain ultrasound features, such as
stippled calcification, which have predictive value for thyroid cancer.
Most patients with thyroid nodules require a fine-needle aspiration biopsy. Patients with
suspicious results on biopsy are often managed with a unilateral lobectomy, whereas those
with malignancy generally undergo total thyroidectomy. Patients with clearly benign biopsy
results are generally followed conservatively. Suppressive therapy with thyroid hormone is no
longer widely used because most randomized prospective trials have shown no net reduction
in nodule size and concerns are increasing about ill effects arising from iatrogenic
thyrotoxicosis.
MULTINODULAR GOITER
Many patients with multinodular goiter develop foci of autonomous function first manifested
on thyroid function testing as a suppressed serum TSH. However, most nodules in a
multinodular goiter remain nonfunctional. For nonfunctional nodules the risk of malignancy is
small. Most thyroidologists perform fine-needle aspiration biopsy on individual nodules
greater than 1 to 1.5 cm in diameter or on nodules that appear to be growing
disproportionately to other nodules. Some patients with multinodular goiter have extension of
the goiter substernally, into the mediastinum. Clinical manifestations of a substernal goiter
include tracheal deviation (sometimes pronounced), dyspnea, and dysphagia. Extension of the
arms above the head leads to further narrowing of the thoracic inlet and can result in facial
flushing, venous congestion, lightheadedness, and dyspnea, known as Pemberton's sign (16).
Patients experiencing compressive symptoms caused by multinodular goiter are generally
managed surgically, although a number of European studies have shown significant reduction
in nontoxic goiter volume using radioiodine therapy.
THYROID CANCER
The incidence of thyroid cancer, in contrast to many common malignancies, has continued to
rise over the past 30 years (17). The four main types of thyroid cancer are papillary (75%),
follicular (15% to 20%), medullary (less than 5%), and anaplastic (less than 5%) (Table 23).
Table 23. Subtypes of Thyroid Cancer
Subtype
Frequency
Tumor Marker
Metastatic Spread
10-Year Survival
Papillary
75% – 80%
Thyroglobulin
Lymphatic
98%
Follicular
15% – 20%
Thyroglobulin
Hematogenous
92%
Medullary
< 5%
Calcitonin
Lymphatic and hematogenous
80%
Anaplastic
< 5%
None
Direct extension
13%
Papillary thyroid cancer and follicular thyroid cancer are treated with total thyroidectomy
followed generally by radioiodine therapy with 131I, at doses approximately 5 to 10 times
higher than that used to treat Graves' disease. Radioiodine ablation serves the dual purpose of
destroying normal thyroid tissue remnants, which would otherwise produce thyroglobulin and
therefore be mistaken for persistent cancer, and of eradicating any microscopic foci of
residual tumor. Surveillance for recurrent papillary thyroid cancer or follicular thyroid cancer
involves either hypothyroid or recombinant human TSH-stimulated thyroglobulin
measurement and whole body scanning using a tracer dose of 131I. Clinical predictors of a
poor prognosis in patients with thyroid cancer are age greater than 45 to 50 years at diagnosis,
tumor size greater than 4 to 5 cm, male gender, local invasion, and distant metastases.
Medullary thyroid cancer (MTC), which is derived from the calcitonin-producing C-cells, is
treated with total thyroidectomy and varying degrees of neck dissection to remove involved
lymph nodes. Radioiodine is not taken up by C-cells and is not a treatment option for MTC.
Although approximately 75% of cases of MTC are sporadic, MTC in the remaining cases is a
component of inherited syndromes such as multiple endocrine neoplasia (MEN) type 2 or
familial MTC. MEN type 2a consists of MTC (95% to 100% penetrance),
hyperparathyroidism (10% to 20% penetrance), and pheochromocytoma (40% to 50%
penetrance); MTC type 2b consists of MTC, pheochromocytoma, mucosal neuromas, and a
marfanoid body habitus. Inherited forms of MTC are associated with germ-line mutations in
the RET proto-oncogene, and a commercial assay allows screening for familial disease in
patients presenting with a new diagnosis of MTC. Calcitonin and carcinoembryonic antigen
serve as markers for MTC; persistent or rising levels suggest active disease.
MEDICATION AFFECTING THE THYROID
Many drugs interact with the thyroid gland, either directly or indirectly; others primarily
affect the interpretation of thyroid function tests without changing the euthyroid state (18).
Table 24 provides a list of common medications with thyroid effects, arranged according to
the mechanism of the interaction. Table 24. Common Medications with Effects on Thyroid
Function
Inhibition of thyroid-stimulating hormone synthesis or release
Bexarotene
Corticosteroids*
Dopamine
Octreotide
Decreased thyroid hormone synthesis or release
Iodine
Lithium
Methimazole
Propylthiouracil*
Perchlorate
Decreased conversion of total thyroxine to total triiodothyronine
Amiodarone*
Corticosteroids*
Ipodate/Iopanoic acid
Propranolol (high doses)
Propylthiouracil*
Decreased thyroxine-binding globulin
Androgen therapy
Corticosteroids*
L-asparaginase
Niacin
Increased thyroxine-binding globulin
Estrogen
Raloxifene
Tamoxifen
5-fluorouracil
Heroin, methadone
Enhanced metabolic clearance rate of thyroid hormone
Carbamazepine*
Dilantin*
Phenobarbital
Rifampin
Sertraline (?)
Displacement of thyroid hormone from binding proteins
Aspirin
Carbamazepine*
Dilantin*
Furosemide
Heparin
Salsalate
Drugs that inhibit absorption or enterohepatic circulation
Aluminum hydroxide
Calcium
Cholestyramine/colestipol
Iron
Sucralfate
Drugs that cause thyroiditis
Amiodarone*
Interferon-alpha
Interleukin-2
Lithium
*Drugs with more than one mechanism of interaction.
Several medications interact at more than one level. Estrogen therapy, long known to
increase thyroid-binding globulin levels, has recently been found to increase the
levothyroxine dose requirement in hypothyroid women. Although these observations have
been made in women starting estrogen therapy, the reverse is also likely – after stopping
estrogen, a reduced thyroid hormone requirement can be expected.
NONTHYROIDAL ILLNESS In response to a severe nonthyroidal illness, T3 and free T3
levels decrease, reverse T3 levels increase, and the TSH levels respond variably (low, normal,
and high values are possible); free T4 levels are little affected unless the illness is critical, at
which time low levels have been observed (19). Mediated by cytokines and other
inflammatory mediators, these changes are believed to be adaptive in nature, serving to
prevent excessive catabolism. Treatment with thyroid hormone is not beneficial.
PREGNANCY
Physiologic changes in the course of normal pregnancy affect thyroid physiology. Increased
estrogen levels lead to a doubling of circulating thyroid binding globulin concentration. A
suppressed serum TSH value occurs in approximately 10% of pregnant women during the
first and second trimesters of pregnancy, believed to be a result of hCG cross-stimulation of
the TSH receptor. No specific therapy is generally required.
Whereas women with intact thyroid glands can increase production of T4 and T3 in response
to increased thyroid binding globulin binding of thyroid hormone, hypothyroid women
cannot; the dose of replacement hormone may have to be increased by up to 50% in
approximately 75% of hypothyroid women who become pregnant (20). Frequent monitoring
of thyroid function during pregnancy is important because recent studies have show a
decreased intelligence in children born to mothers documented to have an elevated serum
TSH level during pregnancy (21). Following delivery, dose requirements generally return to
prepregnancy levels.
Poorly controlled hyperthyroidism during pregnancy is associated with worse maternal and
fetal outcomes, including pre-eclampsia and congestive heart failure in the mother, fetal
death, and low infant birth weight. Graves' disease is the most common cause of overt
hyperthyroidism during pregnancy. Distinguishing mild Graves' disease from an hCGmediated thyrotoxicosis in early pregnancy may be challenging. Diagnostic use of
radioisotopes is contraindicated in pregnancy. Positive thyroid-stimulating immunoglobulins
or thyrotropin-binding inhibitory immunoglobulins suggest Graves' disease, whereas negative
antibodies and a temporal association with hyperemesis gravidarum (helpful if present, but
not necessary) suggest hCG-mediated disease.
Graves' disease causing overt hyperthyroidism during pregnancy should be treated with
thionamide antithyroid drugs. Therapeutic use of radioiodine is contraindicated during
pregnancy. Both propylthiouracil and methimazole are able to cross the placenta and cause
fetal goiter and hypothyroidism. Propylthiouracil is generally favored versus methimazole
because of the possible association between methimazole and aplasia cutis, a rare scalp defect,
and esophageal or choanal atresia. The lowest dose of thionamide that maintains euthyroidism
should be used during pregnancy to minimize effects on the fetal gland.
Pregnant women found to have thyroid nodules during the first or second trimester should
undergo fine-needle aspiration biopsy; if thyroid cancer is detected, thyroidectomy may be
considered in the second trimester. Surgery in the first trimester is generally avoided because
of concerns about spontaneous abortion; surgery in the third trimester is avoided because of
concerns about precipitating labor prematurely. Thyroid cancer detected during pregnancy
does not appear to behave more aggressively than in the nonpregnant state. In one study,
women in whom surgery was delayed until after pregnancy had similar long-term thyroid
cancer outcomes to those who underwent surgery during pregnancy (22). Radioiodine
ablation therapy is contraindicated while breastfeeding because 131I is excreted into breast
milk for many weeks after exposure.
EMERGENCIES
Life-threatening thyrotoxicosis or thyroid storm is a rare, occasionally iatrogenic disorder
characterized by multisystem involvement and a high mortality rate if the diagnosis and
prompt aggressive therapy are delayed. A point scale has been derived to facilitate the early
diagnosis of thyroid storm (Table 25) (23). Common precipitants of thyroid storm include
iatrogenic causes, such as therapy with radioiodine, abrupt cessation of antithyroid drugs, and
thyroid or nonthyroidal surgery in a patient with unrecognized or inadequately treated
thyrotoxicosis, as well as acute nonthyroidal illnesses (Table 26). Each pharmacologically
accessible step in thyroid hormone production and action is targeted in the treatment of
patients with thyroid storm (Table 27).
Table 25. Point Scale for the Diagnosis of Thyroid Storm
Thermoregulatory Dysfunction
Temperature
Points
99.0 – 99.9
5
100.0 – 100.9
10
101.0 – 101.9
15
102.0 – 102.9
20
103.0 – 103.9
25
≥ 104.0
30
Cardiovascular
Tachycardia
Points
100 – 109
5
110 – 119
10
120 – 129
15
130 – 139
20
≥ 140
25
Atrial Fibrillation
Absent
Points
0
Present
10
Congestive heart failure
Points
Absent
0
Mild
5
Moderate
10
Severe
20
Gastrointestinal–Hepatic Dysfunction
Manifestation
Points
Absent
0
Moderate (diarrhea, abdominal pain nausea / vomiting)
10
Severe (jaundice)
20
Central Nervous System Disturbance
Manifestation
Points
Absent
0
Mild (agitation)
10
Moderate (delirium, psychosis, extreme lethargy)
20
Severe (seizure, coma)
30
Precipitant History
Status
Points
Positive
0
Negative
10
Scores Totaled
Diagnosis
Points
Thyroid storm
> 45
Impending storm
25 – 44
Storm unlikely
< 25
Adapted from: Burch HB, Wartofsky L. Life Threatening Thyrotoxicosis, Endocrin Metabol
Clin North Am. 1993;22:263.
Table 26. Precipitants of Thyroid Storm
Associated with a rapid rise in thyroid hormone levels
Thyroid surgery
Withdrawal of antithyroid drugs
Radioiodine therapy
Thyroid palpation
Iodinated contrast dyes
Massive thyroid hormone overdose
Associated with an acute or subacute nonthyroidal illness
Nonthyroid surgery
Stroke
Pulmonary embolism
Parturition (labor)
Diabetic ketoacidosis
Emotional stress
Trauma
Infection
Table 27. Drugs and Doses in Thyroid Storm
Drug
Dosing
Comment
Propylthiouracil
500 – 1000 mg load, then
250 mg every 4 hr



Blocks new hormone synthesis
Blocks T4-to-T3 conversion
Alternate drug: methimazole
Propranolol
60 – 80 mg every 4 hr

Consider invasive monitoring in
congestive heart failure patients
Blocks T4-to-T3 conversion in high
doses
Alternate drug: esmolol infusion


Iodine (saturated solution
5 drops orally every 6 hr

Do not start until 1 hour after
antithyroid drugs
of potassium iodide)
Hydrocortisone
300 mg intravenous load,
then 100 mg every 8 hr


Blocks new hormone synthesis
Blocks thyroid hormone release


Blocks T4-to T3 conversion
Prophylaxis against relative adrenal
insufficiency
Alternate drug: dexamethasone

T3 = total triiodothyronine; T4 = total thyroxine.
MYXEDEMA COMA
Life-threatening hypothyroidism is a rare disorder, characterized by progressive obtundation,
hypothermia, and generally the presence of a precipitating event such as infection, trauma,
cold exposure, or the use of sedatives. Most cases of myxedema coma have been described in
elderly women and are more likely to occur during the winter. Cardiovascular manifestations
include peripheral vasoconstriction, decreased heart rate, and decreased cardiac muscle
contractility, all of which contribute to a diminished cardiac output. In addition, a pericardial
effusion may occur in patients with severe hypothyroidism. Figure 6 illustrates the spectrum
of cardiovascular abnormality in patients with severe hypothyroidism. The diagnosis of
myxedema coma requires a high index of suspicion and, in the appropriate clinical setting,
often a decision to treat based on a presumptive diagnosis alone. Treatment involves replacing
thyroid hormone intravenously, generally with levothyroxine alone because oral absorption is
greatly impaired. Whether liothyronine should also be provided is controversial. Typical
initial doses of intravenous levothyroxine are 200 to 500 µg, followed by 50 to 100 µg daily.
If liothyronine is given simultaneously; the recommended doses range from 2.5 to 10 µg
intravenously every 12 hours. Corticosteroid therapy should be given simultaneously,
particularly if concurrent adrenal insufficiency is suspected, because restoration of
euthyroidism might otherwise precipitate an adrenal crisis. Close attention to respiratory and
cardiovascular status is required. Myxedematous patients are prone to carbon dioxide
retention and hypoxia and frequently require mechanical ventilation. Plasma volume status
should be carefully monitored because these patients are generally hypovolemic and may
poorly tolerate diuresis. Invasive monitoring may be required in patients whose plasma
volume status is unclear. Aggressive rewarming should be avoided because the resultant
vasodilation may precipitate hypotension. Identification and treatment of precipitants should
be undertaken. Infection is the most common precipitant yet it is easily overlooked because
severely hypothyroid patients are less likely to mount a fever or develop substantial
leukocytosis. Therefore, after blood, urine, and sputum cultures are obtained, patients with
myxedema coma should be treated with empiric broad-spectrum