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Clinics in Family Practice Volume 4 Number 3 September 2002
Copyright 2002 W. B. Saunders Company
Review article
THYROID DISORDERS
George R. Wilson, MD *
From the Department of Community Health and Family Medicine
University of Florida Health Science Center
Jacksonville, Florida, USA
* Address reprint requests to Department of Community Health and
Family Medicine, Shands Jacksonville Medical Center, 655 West
Eighth Street, Jacksonville, FL 32209-6511 E-mail address: [email protected]
PII S1522-5720(02)00037-5
Disorders of the thyroid gland are common in primary care medicine and most can be
diagnosed and treated satisfactorily by the primary care physician. An understanding of the
various diseases, applicable diagnostic tests, therapeutic choices, and complications is
essential to this end. This article reviews the anatomy and physiology of the thyroid gland,
common thyroid diseases, current treatment recommendations, and available diagnostic
modalities. Some uncommon diseases of special interest in primary care are included for
academic completeness.
Thyroid diseases exist in one of three functional states; euthyroid, hyperthyroid, or
hypothyroid, with each being defined by the total bound and free level of circulating
thyroid hormone. The presence of any one of these states in an individual does not prove
disease, nor does it depend on the etiology of any particular abnormal thyroid function. All
three states may exist at different times during the course of an illness and each state can
exist with or without disease and with or without clinical findings.
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The euthyroid state is defined by normal serum T4 and T3 levels and can be found in
association with diseases such as goiter, adenoma, cysts, and malignancies. For a person to
be clinically euthyroid, the effect of thyroid hormone at the cellular level must be normal.
Increased levels of total circulating T4 and T3 define the hyperthyroid state, but this is not
synonymous with thyrotoxicosis. Diseases associated with a hyperthyroid state include
Graves disease, thyroiditis, toxic adenoma, toxic multinodular goiter, and thyrotoxicosis of
any etiology. Diseases that only increase total thyroid transport proteins also result in a
hyperthyroid state, but clinically the patient is euthyroid. Decreased levels of total
circulating T4 and T3 define the hypothyroid state. This state may be associated with
goiter, thyroiditis, iodine deficiency, and iatrogenic causes. Hypothyroidism also can be the
result of decreased levels of transport proteins, again with the patient being clinically
euthyroid.
Accurate assessment of thyroid function and determination of either the presence or
absence of disease requires data in addition to levels of circulating thyroid hormone. These
data include serum free thyroid hormone levels, thyrotropin levels, and antithyroid antibody
titers. With this battery of tests, most commonly seen thyroid disorders can be readily
diagnosed. Imaging studies and fine needle aspiration complete the assessment in 90%
95% of patients with thyroid disease who present in the primary care setting.
The most common cause of thyroid disorders worldwide is iodine deficiency. In the United
States, where iodine deficiency is rare, the most common cause of thyroid disease is
autoimmunity [1] . In contrast to this, the two most common thyroid disorders found in the
United States are simple diffuse goiter and thyroid nodules. The exact incidence of thyroid
disease is not known but one can get an idea of its prevalence from a 20-year English study
that found a 10% incidence of thyroid disorders in the general female population and a 2%
incidence in the general male population [2] .
Thyroid disorders occur at a rate of 6080 per 1000 adults worldwide and affect as much as
5% of the adult population in the United States [3] . Because most thyroid diseases have an
insidious onset or closely mimic other, more common disorders, they are easily missed and,
although rarely fatal, can cause significant morbidity. Early recognition is key to
minimizing that morbidity. With the exception of conditions such as simple goiter or a
visible nodule, patients who ultimately are diagnosed with thyroid disease rarely present to
the physician with complaints suggesting a thyroid disorder. Presenting complaints of
thyroid disease can range from dysphagia, ear pain, hoarseness, and superior vena cava
syndrome to neck pain, fever, heartburn, constipation, and tiredness. It behooves the
physician to be alert and include thyroid disorders in a wider range of differential
diagnoses. Diagnosis of a thyroid disorder on clinical grounds alone is difficult and, unless
the patient presents with specific complaints or concerns, easy to overlook. This was clearly
shown in one study of 3000 women with known abnormal thyroid function tests. These
women were examined clinically by a primary care physician and a specialist, neither of
whom performed especially well. The primary care physician, using clinical findings alone,
was able to diagnose a thyroid abnormality only 10% of the time. The specialist did not fare
much better at 33% [4] . These findings not only point out the difficulty often encountered in
making a clinical diagnosis of thyroid disease, they also raise the question whether routine
screening for thyroid disorders, outside the neonatal period, in the general population is
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warranted. Are there select patient populations at increased risk who would benefit from
routine screening [5] ? The three populations at highest risk who might benefit from routine
screening are neonates, postmenopausal women, and elderly people.
As a group, neonates are at highest risk for permanent injury if thyroid dysfunction is not
recognized and treated early. Routine screening for thyroid dysfunction in neonates in the
United States has virtually eliminated delayed diagnosis, thus preventing the sequelae of
congenital hypothyroidism. Unfortunately this is not common practice throughout the
world, especially where iodine deficiency is prevalent and congenital hypothyroidism and
endemic cretinism are common [6] .
Postmenopausal women have a 10% incidence of unrecognized hypothyroidism [7] [8] .
Untreated hypothyroidism can exacerbate or accelerate diseases such as hyperlipidemia and
osteoporosis. Routine screening in this population could provide early diagnosis and
appropriate treatment of hypothyroidism, thereby helping prevent these complications.
Signs and symptoms of hypothyroidism and apathetic thyrotoxicosis closely mimic
dementia and depression, both common disorders in the elderly. The similarities between
these diseases place members of this group at increased risk for missed diagnosis and
significant comorbidity. It is therefore essential that the functional status of the thyroid be
included in the evaluation of depression and dementia.
ANATOMY
The thyroid gland sits at the base of the neck, between the foramen cecum (at the base of
the tongue) and the sternal notch. It normally consists of two lobes with an average length
of 34 cm. These are joined at the inferior poles by the horizontal isthmus that lies just
inferior to the cricoid cartilage. The gland may be found somewhat higher in young women
with thin necks. Older men with kyphosis or emphysema may have the gland displaced
caudally below the sternal notch, making palpation difficult. Rarely there is ectopic
displacement to the retrosternal area, and ectopic thyroid tissue can be found inferior to the
cervical thyroid or even as low as the pericardial space.
The thyroid gland is located in the V made by the insertion of the sternocleidomastoid
muscles on the clavicles and is attached to the pretracheal fascia. Having the patient extend
the neck and swallow causes the gland to move, which aids in visualization. Observing
movement is useful in differentiating an enlarged thyroid gland from cervical fat often
found in young women, because the fat does not move.
To adequately palpate the gland, have the patient flex the neck. This relaxes the
sternocleidomastoid muscles and allows for easier access. Place both hands on the neck and
have the patient swallow. This helps raise the gland from an inferior position and provides
an opportunity to examine the lower poles of both lobes. It also aids in defining the lower
limits of a nodule.
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Histologically, the thyroid gland consists of five primary elements: follicular cells, colloid,
interstitial tissue, C cells, and lymphoid cells. The most prominent element is the
follicular cell, which produces colloid. The functional unit of the gland is the thyroid
follicle. The follicle is where colloid is stored and where synthesis of thyroid hormone
occurs. The remaining cellular elements are C cells that are few in number, and lymphoid
cell clusters. C cells are located in the intrafollicular space and produce calcitonin and,
rarely, somatostatin. Lymphoid cells are found scattered throughout the gland stroma in
small clusters.
FUNCTIONAL PHYSIOLOGY
Biosynthesis of thyroid hormones is unique among endocrine glands because final
assembly occurs extracellularly in the follicular lumen. Thyroid peroxidase (TPO) oxidizes
iodine stored in thyroglobulin to form mono-iodo-tyrosine (MIT), and di-iodo-tyrosine
(DIT). MIT and DIT are then assembled into the final products, T4 and T3, which are
stored in the follicular colloid for future use.
Thyroglobulin (Tg) is an iodo-protein, produced by the follicular cells of the thyroid gland.
It comprises the major portion of intraluminal colloid and is the most important protein of
the thyroid gland [9] . Thyroglobulin provides a matrix for the synthesis of thyroid hormones
and a vehicle for subsequent storage. Thyroglobulin levels tend to be increased in
pregnancy, in newborns, and in diseases such as Graves disease, subacute thyroiditis, and
metastatic thyroid cancer [10] . When stimulated by thyrotropin (TSH), thyroglobulin from
the colloidal space is internalized by thyroid cells and enzymatically degraded to release T4
and T3 into the peripheral circulation. Thyroglobulin levels increase in the presence of
decreased T3 and with intramuscular administration of thyrotropin.
The primary thyroid hormones are thyroxine (T4 or tetra-iodo-thyronine) and T3 (tri-iodo-
thyronine). Thyroxine is produced in the thyroid follicle and is the most abundant hormonal
product of the thyroid gland. Roughly one third to one half of T4 in the peripheral
circulation is converted into T3 by de-iodination and this process is responsible for 70%
90% of circulating T3. T3 is two to four times more calorigenic than T4. The precise role of
T4 has not been fully defined, but it seems the primary function may be to serve as a
prohormone and reservoir for production of the more metabolically active T3 [11] .
Thyrotropin (TSH) regulates the function of the thyroid follicular cells, thyroid hormone
synthesis and secretion, proliferation of thyroid cells, and thyroid size. The efficiency with
which this process occurs is modulated in large part by the organic iodine content of the
cells. Insufficient iodine stores can cause excess thyrotropin production, resulting in gland
hyperplasia and hypertrophy with resultant goiter formation. When thyrotropin production
is decreased or absent, follicular cells do not manufacture adequate quantities of MIT and
DIT, limiting the amount of T4 and T3 produced. Colloid formation is independent of
circulating thyrotropin levels. Without a functioning colloid inhibitory feedback
mechanism, the amount of colloid produced and stored by the gland becomes excessive,
leading to an enlarged thyroid gland.
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Both T4 and T3 seem to have an inhibitory effect on thyrotropin production and secretion,
but actual inhibition may be by T3 that has been de-iodinated from T4 in the pituitary gland [12] . Research suggests a secondary inhibitory pathway at the level of the hypothalamus with
suppression of TRH secretion and release [13] .
Reverse T3 (rT3) is a thyroid hormone only identified in humans [14] . It is 3,3,5 tri-iodo-
thyronine and differs from normal T3 (3,5,3 tri-iodo-thyronine) by the location of iodine
on the molecule. Although the actual source of rT3 is not precisely known, it seems as
much as 95%98% is produced in similar fashion to T3, by de-iodination of circulating T4 [14] . The exact function and purpose of rT3 also is not known, but it has been shown to
increase in hyperthyroidism and decrease in hypothyroidism [14] . One interesting fact about
rT3 is that it is increased in several nonthyroid disease states, including cirrhosis, neoplasm,
toxemia of pregnancy, following major surgery, and in prolonged fasting states. Reverse T3
inhibits the calorigenic activity of T4 and T3, which may explain why it is found in states
of physiologic stress.
Once T4 and T3 leave the follicular lumen, nearly all (>99.9%) is bound to thyroid
transport proteins. The overall function of the thyroid hormone transport system is to
provide an extrathyroidal source of T4 and T3 that is only released on demand, and a
buffering action that protects target tissues from circulating thyroid hormones [15] . This
system ensures continuous replenishment of a free T4 and free T3 pool that is available in
minute quantities at the cellular level. The thyroid hormone transport system has three
primary proteins: thyroid binding globulin (TBG), transthyretin (TTR), and albumin.
Thyroxine is found bound to TBG in concentrations 1020 times greater than T3, and
neither bound T4 nor bound T3 are directly available to tissues. Only the unbound or free
portion of T4 and T3 are metabolically available at the cellular level. The free portion of T4
represents only approximately 0.02% of total serum T4 and the free portion of T3
represents only approximately 0.1% of total serum T3 [16] . Although most T3 (>99.5%) is
bound to TBG, it is not as tightly bound as T4, allowing easier release into the free state.
Thyroid binding globulin binds the major portion (70%) of circulating thyroid hormones,
but transthyretin is physiologically more important because its lower affinity for thyroid
hormone provides more immediate delivery of T4 and T3 into the unbound thyroid pool,
and thus to cells. Circulating levels of thyroid transport proteins are not constant and
fluctuate with various disease states. Increases or decreases in the levels of circulating
transport proteins result in corresponding increases or decreases in the absolute levels of
total serum T4 and T3. Because of stable free T4 and free T3 pools, these fluctuations do
not routinely affect the overall thyroid state (hyper-, hypo- or euthyroid).
Normal thyroid function, in circulating levels of T4, T3, free T4, free T3, and the
thyrotropin feedback system, seems to remain stable throughout life. Without intrinsic
disease of the hypothalamic-pituitary-thyroid axis, age does not seem to have an adverse
effect on the function of the thyroid gland or its component parts. Although changes in
measurable levels of total serum T4 and T3 occur as a result of changes in transport protein
concentrations, free T4 and free T3 levels remain constant. And whereas thyroid function
seems to remain stable throughout life, it also seems to be independent of environmental
factors such as temperature, altitude, hypoxia, and exercise. The only significant
environmental factor that has been shown to have a demonstrable effect on overall thyroid
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function is the calendar. Seasonal measurements of thyrotropin levels routinely show a
decline in the spring and an increase in the winter, with variation as much as 30% between
seasons [17] .
Outside of disease, other conditions have an effect on thyroid function. This is particularly
true in pregnancy. Human chorionic gonadotropin has a direct stimulatory effect on the
function of the thyroid gland with increased TBG levels and decreased free T4 and free T3
concentrations. Also during pregnancy, iodine stores are depleted because of increased
renal clearance, making the thyroid more sensitive to iodine deficiency disorders.
Calcitonin is produced by the thyroid C cells and inhibits osteoclastic bone metabolism.
Calcitonin release occurs in response to increased ionized serum calcium to help maintain
calcium homeostasis.
THYROTOXICOSIS
Thyrotoxicosis is a hypermetabolic state that occurs when free T4, free T3, or both are
increased, and it is a potential complication of nearly all diseases of the thyroid. Thyroid
storm is a term applied to severe thyrotoxicosis, during which a marked increase in
metabolic state, usually accompanied by organ system failure, places the individual at risk
for death. Hyperthyroidism, however, represents sustained increases in thyroid hormone
biosynthesis and secretion by the thyroid gland and may or may not represent
thyrotoxicosis [18] .
As with many thyroid disorders, thyrotoxicosis has a predilection for females, tends to be
more common in northern Europeans, and is rare in blacks. The most common cause of
spontaneous thyrotoxicosis is Graves disease, accounting for 60%90% of all cases. Silent
and postpartum thyroiditis is next most common. Other less common but not rare causes of
thyrotoxicosis include toxic multinodular goiter, autonomous functioning adenoma, and
ingestion of exogenous thyroid hormone. When thyrotoxicosis occurs acutely it is most
often caused by thyroiditis. Thyrotoxicosis associated with Graves disease has a more
insidious course, evolving over a more protracted period. If a patient is thyrotoxic and the
thyroid gland is not palpable, consider painless thyroiditis, unsuspected Graves disease, or
exogenous thyroxine.
Thyroid hormone works at the cellular level in target organs, not by way of release of
catecholamines. This accounts for the wide diversity of symptoms seen in thyrotoxicosis
and the variation in symptoms between different age groups. Symptoms in younger
individuals are usually the result of sympathoadrenal activity [19] . These include tremor,
anxiety, hyperactivity, warm/moist skin, tachycardia, wide pulse pressure, and systolic
hypertension. In the older individual, with altered sympathetic and parasympathetic
function, symptoms of thyrotoxicosis more often tend to be things such as cardiovascular
dysfunction, dyspnea, weight loss, and proximal muscle weakness. Cardiovascular
symptoms in elderly people usually consist of resting tachycardia, wide pulse pressure,
exercise intolerance, and dyspnea on exertion. Atrial fibrillation is not common, but when it
does occur, it occurs more often in older individuals. Other cardiovascular effects that
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affect young and old are decreased peripheral resistance, decreased cardiac filling times,
increased blood volume, and fluid retention. Individuals with pre-existing coronary artery
disease may have ischemic congestive heart failure as a result of their hypermetabolic state,
but this generally improves with appropriate antithyroid therapy. Atrial flutter, paroxysmal
supraventricular tachycardia, premature ventricular beats, and ventricular fibrillation are
rare as a complication of thyrotoxicosis and, should they occur, may represent unsuspected
coronary artery disease.
Signs and symptoms of congestive heart failure are common in young and old individuals
with thyrotoxicosis; however, thyrotoxicosis does not cause congestive heart failure [19] .
Dependent peripheral edema, especially of the lower extremities and sacral area, occurs
frequently with thyrotoxicosis, but not because of congestive heart failure. Thyrotoxicosis
causes a decrease in effective circulating arterial volume. This causes an increase in
aldosterone secretion. The elevated levels of aldosterone result in increased sodium and
water retention, leading to edema. All symptoms suggestive of congestive heart failure
resolve quickly with appropriate antithyroid therapy. Periorbital edema, when seen in
association with thyrotoxicosis, is caused by Graves disease, not fluid retention.
Weight loss is generally considered to be a symptom of thyrotoxicosis; however, it is not
consistent between populations. Thyrotoxicosis causes loss of fat and lean body mass, with
lean body mass being lost in greater proportion. Loss of lean body mass contributes to the
muscle weakness seen in thyrotoxicosis and helps explain why this is often the presenting
complaint in elderly patients. Hyperphagia, seen more often in young patients, and fluid
retention, seen in both, can be offsetting to loss of body mass. This can mask the actual
amount of tissue loss and may only become apparent when a euthyroid state is re-
established [20] . Weight loss by age group has an especially wide range, but is definitely
skewed toward elderly patients. In 20-year-old patients, weight loss, as a clinical finding,
occurs in approximately 52% of cases. At 40 years of age, this increases to 67%, and at 70
years of age it is approximately 82% [21] . Weight loss statistics like these are common in
other diseases, such as malignancy, depression, and chronic lung disease, so a thorough
evaluation is required to insure weight loss is caused by the thyrotoxicosis and not from
other concurrent disease processes.
The absence of the signs or symptoms generally associated with thyrotoxicosis does not
rule out the diagnosis, nor is there correlation between severity of symptoms and
abnormality of laboratory tests [22] . Thyroid storm is a case in point. Thyroid storm is a rare
complication of thyrotoxicosis, but it is perhaps the only acute thyroid disease that has a
mortality rate that can be as high as 75%, depending on how quickly it is recognized and
treated [23] . Diagnosis of thyroid storm is based on clinical findings alone and does not
relate to measured levels of circulating T4, T3, or thyrotropin. Thyroid storm is often
precipitated by infection that can mask the thyrotoxic state. Clinical findings in thyroid
storm include hyperpyrexia (>102 F), tachycardia out of proportion to temperature,
gastrointestinal dysfunction (nausea, vomiting, diarrhea, jaundice), and dysfunction of the
central nervous system (marked hyperirritability, anxiety, confusion, apathy, coma). There
is usually pronounced decompensation in function of one or more organ systems. Any
patient presenting with goiter, fever, and marked tachycardia should be considered to be in
thyroid storm and treated accordingly. Treatment of thyroid storm includes antithyroid
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drugs, beta-adrenergic blocking drugs, antipyretics, aggressive fluid replacement, and
treatment of any underlying infection.
After Graves disease and thyroiditis, all other causes of thyrotoxicosis are rare, with none
accounting for more than 2% of the total. Factitious thyroiditis is the most common
nonthyroid cause of thyrotoxicosis and seems similar to Graves disease on routine
laboratory tests. If the etiology of the thyrotoxic state is unclear, however, differentiation is
done easily with radioisotope imaging. The thyroid gland enhances in Graves disease but
does not in factitious thyrotoxicosis.
Apathetic thyrotoxicosis is an uncommon presentation of thyrotoxicosis, but it represents
the most common mental disorder associated with excess thyroid hormone production or
release [24] . Symptoms include apathy, lethargy, pseudodementia, weight loss, and
depressed mood. It usually occurs in elder patients without symptoms of tachycardia,
hyperphagia, sweating, warm skin, or goiter [24] . This syndrome is easily confused with
depression or dementia and, unless specifically looked for, is easy to miss. A screening
thyrotropin level should be included in every depression or dementia workup.
Laboratory diagnosis of thyrotoxicosis is easy and uncomplicated. Circulating levels of
free T4 or free T3 are increased with low to immeasurable levels of thyrotropin (
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thyroid storm. Severe thyrotoxic symptoms unresponsive to all of the above regimens may
respond to sodium ipodate at 500 mgm per day.
Once acute symptoms are controlled, treatment of the primary cause can be considered.
This could include watchful waiting in the case of thyroiditis, surgery for an autonomously
functioning adenoma, or 131[I] in Graves disease.
Subclinical thyrotoxicosis is a laboratory diagnosis, defined by normal free T4 and freeT3
levels with a low thyrotropin level (20 mU/L). Subclinical hypothyroidism is
defined by normal T4, normal T3, and mildly elevated thyrotropin (520 mU/L). Again,
clinical symptoms and findings may or may not correlate with these laboratory values.
On average, postmenopausal women have a 10% incidence of subclinical hypothyroidism [8] . As already indicated, diagnosis of hypothyroidism is difficult by clinical examination
alone [4] . Early detection and treatment could positively impact associated diseases such as
osteoporosis, hyperlipidemia, and heart disease [26] [27] . The American College of Physicians
recommends thyrotropin screening in all women over the age of 50 years [5] [7] [28] . When
this is done, initial screening identifies women with overt hypothyroidism, providing
opportunity for intervention. It also identifies women with subclinical disease. Although
there is no disagreement about treating women with overt (albeit mild) disease, there is
disagreement as to whether empiric treatment of subclinical disease is beneficial. Some
experts suggest that treatment of subclinical disease may decrease risks for hypothyroid-
induced cardiovascular disease and osteoporosis should the person progress to overt disease [26] [27] [29] . And, although this remains controversial, there is a subgroup of individuals with
subclinical hypothyroidism that can be identified by way of laboratory testing for whom the
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treatment conundrum is less controversial. Members of this subgroup have normal thyroid
hormone levels, increased thyrotropin levels and, in addition, the presence of antithyroid
antibodies. This group, with elevated antithyroid antibody titers, is especially at risk,
converting to overt disease at the rate of 5%20% per year [7] .
Central hypothyroidism is caused by the absence of circulating thyrotropin as a result of
pituitary or hypothalamic failure. The incidence of this, as an isolated lesion, is so
extremely rare as not to be considered. Thus, when central hypothyroidism is seen, it is
almost always in conjunction with some other pituitary failure syndrome. In these cases, the
predominant symptoms are caused by the absence of other pituitary hormones, not because
of hypothyroidism. Laboratory tests show low T4, low T3, and low thyrotropin.
Hypothyroidism involves most organ systems to varying degrees. The level of involvement
at each target organ correlates with the duration and amount of decrease in circulating T4.
Organ systems most affected are the integument, cardiovascular, gastrointestinal,
musculoskeletal, hemopoietic, endocrine, and neuropsychiatric.
Thyroid hormone effects and regulates epidermal growth. Ninety percent of individuals
with inadequate circulating T4 have scaly skin because of overproduction of keratin.
Alopecia and brittle hair and nails are also common. Decreased skin perfusion is often
noted and, although this may represent a cardiovascular effect, it may also represent a
physiologic response to conserve core heat in a hypometabolic state [30] .
Cardiovascular effects of hypothyroidism include increased peripheral resistance, decreased
systolic blood pressure, increased diastolic blood pressure, bradycardia, and impaired left
ventricular contractility. Pericardial effusion occurs in up to 50% of individuals, and cases
of Torsades de Pointes (long QT interval with ventricular tachycardia) have been reported [27] . As is the case with the cardiac symptoms seen in thyrotoxicosis, none of the changes
that occur are caused by decreased myocardial function and they all correct with euthyroid
doses of levothyroxine. Total serum cholesterol levels are consistently increased over
baseline.
Hypomotility is the most common symptom affecting the gastrointestinal tract, ranging
from mild obstipation to pseudo-obstruction and paralytic ileus. Dysphagia is not
uncommon. Atrophic gastritis is seen occasionally, and in long-standing hypothyroidism
this can lead to decreased absorption of vitamin B12 and pernicious anemia [31] .
Anemia is one of the most common findings in hypothyroidism, occurring in 25%50% of
individuals [31] . The two primary causes for this are depleted B12 stores and decreased renal
blood flow. Primary treatment of the anemia is T4 replacement, but depleted B12 stores
may need to be replaced until the gastric mucosa has had a chance to regenerate.
Hypothyroidism is a rare cause of acquired von Willebrand disease, and adults newly
diagnosed with this clotting disorder should have a thyrotropin level drawn [32] [33] [34] .
The endocrine system is universally affected by decreased circulating T4. Growth hormone
secretion is decreased and the action of growth hormone at the cellular level is depressed.
Prolactin is increased and can be a cause of galactorrhea [35] . Hypothyroidism is the cause
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of galactorrhea in approximately 5% of cases. Obtaining a thyrotropin level before a CT or
MRI scan of the head in the evaluation of galactorrhea is indicated [36] . Schmidt syndrome
is primary adrenocortical insufficiency in association with primary hypothyroidism that
occurs most often in women between the ages 20 and 50 years. It has a genetic
predisposition and an autoimmune basis. Addison disease can present with an elevated
thyrotropin level that corrects with replacement of glucocorticoid. If the thyrotropin value
is >20 mU/L, however, this represents Schmidt syndrome and treatment must include T4
replacement. Schmidt syndrome may represent a form of chronic autoimmune thyroiditis.
Neuropsychiatric disease is common in hypothyroidism. Symptoms vary from mild to
severe, and include inattentiveness, inability to concentrate, slowing of thought process,
inability to calculate, inability to understand complex questions, poor recent memory, poor
late memory, decreased ability to perform activities of daily living, decreased learning
capability, and it often leads to perseveration. Review of these symptoms in the context of
elderly patients suggests that evaluation of any person for early dementia requires a serum
thyrotropin level.
Hypothyroidism has minimal effect on either the pulmonary or renal system. However,
hypothyroidism has been shown to be a significant cause of sleep apnea [37] . Although
obesity is without doubt the most common cause of sleep apnea in men, a screening
thyrotropin level to rule out this treatable cause is indicated in every sleep apnea evaluation [37] .
Treatment of hypothyroidism, whether subclinical or overt, is easy using levothyroxine.
The goal of therapy in primary hypothyroidism is T4 dosing sufficient to achieve a serum
thyrotropin level in the normal range (0.55.0 mU/L). Treating to a low thyrotropin level
(
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of those treated. Of the remaining 62%, 46% showed no change and only 16% got worse,
which again supports the idea that judicious T4 replacement in patients at risk for ischemic
myocardial events is safe and appropriate [42] .
AUTOIMMUNE DISEASE
Most disease states that commonly affect the thyroid gland fall within the general
classification of autoimmune diseases [43] . The antibodies that form have either direct
destructive effect on the thyroid gland or cause abnormal function of some phase of thyroid
metabolism. The most common and best understood of these autoantibodies are
thyroglobulin antibodies (Tg abs), TSH receptor-stimulator antibodies (TSH RS abs), TSH
receptor-blocker antibodies (TSH RB abs), and thyroid peroxidase antibodies (TPO abs).
Histologically, it can be seen easily that the primary process that occurs with autoimmune
disease of the thyroid is cytotoxicity, although the exact mechanism of injury to the gland is
not well understood [44] . This process has been definitively identified with TPO antibodies
but probably occurs with others also [43] .
Autoimmune diseases usually occur when there is failure of T-cell tolerance as a result of
a combination of genetic and non-genetic factors [44] . These factors make the patient
susceptible to several nonthyroid autoimmune diseases; thus, it is common to see other
autoimmune diseases in individuals with thyroid autoimmune disease [45] . There also seems
to be a relationship between other areas of disease and health and the presence or absence
of thyroid antibodies. For example, it has been shown that depressed postmenopausal
women are three times more likely to have high serum antithyroid antibody titers than
normal individuals, even when the depressed individuals are clinically and serologically
euthyroid [46] . Also, low or absent titers for antithyroid antibodies are consistently found in
healthy centenarians [47] . These two examples of a relationship between antithyroid
antibody levels and either disease or health, respectively, suggest that antithyroid antibodies
contribute in some way to nonthyroid disease, or conversely, there is an unidentified factor
related to the development of antithyroid antibodies that protects and tempers the aging
process [29] .
Thyroid peroxidase antibodies (TPO abs) and thyroglobulin antibodies (Tg abs) are found
in most individuals (90%) with chronic autoimmune thyroiditis (Hashimoto thyroiditis) [1] [48] . Thyroid peroxidase antibodies are considered to be the primary cause of the disease [49] .
Both of these antibodies are found in a wide variety of individuals who seem to have
normal thyroid function, however, so the exact significance of their presence is not clear.
Thyroglobulin antibodies in particular are found in 10% of normal people, 20% of people
with thyroid cancer, and in 40%70% of individuals with Graves disease. They are also
detectable in approximately 15% of women over age 60 years [50] .
TSH receptor-stimulator antibodies (TSH RS abs) were first identified more than 45 years
ago and were originally called LATS (long acting thyroid stimulator) because of their
perceived action on the thyroid gland. They have since been identified as the cause of
Graves disease. Laboratory testing for these antibodies is still qualitative, but there is some
predictive value to them. Euthyroid patients with TSH RS abs are at high risk for
-
developing Graves disease at some point in the future, and individuals whose titers remain
high on antithyroid therapy are at increased risk for relapse [51] . At present, laboratory
technique is not sufficiently sensitive to determine, at the outset, which patient is at risk,
but when this becomes available, it will greatly improve the treatment decision-making
process in early Graves disease [52] . TSH receptor-blocker antibodies (TSH RB abs) are
occasionally found in Graves disease but the significance is not known. Hypothyroid
individuals are routinely found to have blocker antibodies.
The role of TPO abs in nonthyroid disease is unclear, but several studies suggest a
relationship. One study of patients with the goitrous form of autoimmune thyroiditis with
high serum TPO abs has shown an improved prognosis with breast cancer compared with
control subjects [53] . A second study reported an increased incidence of Helicobacter pylori
infection in patients with hypothyroidism secondary to the atrophic form of the disease [54] .
The clinical implications of both of these studies are unclear but, as noted previously, they
do seem to demonstrate a definitive relationship between antithyroid antibodies and health
and disease.
GRAVES DISEASE
Graves disease is an autoimmune thyroid disorder that is caused by the presence of TSH
receptor-stimulator antibodies. TSH receptor-stimulator antibodies (TSH RS abs) have been
identified as a G immunoglobulin (IgG) that attaches itself to receptor sites in the
follicular cell of the thyroid gland, causing the cell to act as if stimulated by pituitary
secreted thyrotropin [55] . When this occurs, the thyroid gland functions in an autonomous
manner, stimulated internally by the TSH RS abs, and the normal thyroxine-thyrotropin
negative-feedback system is ineffective. The net result is excess production of T4 and T3 in
the follicle, initially causing hyperthyroidism and ultimately thyrotoxicosis. Also, because
of the presence of these autoantibodies, Graves disease has an extremely high recurrence
rate of 40%70% [56] .
Two other antithyroid antibodies are found in Graves disease that do not seem to have
direct causative effect on the disease but are important for other reasons. The first is TSH
receptor-blocking antibody (TSH RB abs), and when it is present it seems to ameliorate, to
some degree, symptoms experienced by the patient with Graves disease. This antibody
binds to the same receptor site as TSH RS abs but it has an opposite effect, blocking
cellular response to TSH, thereby countering the affect of the TSH RS abs. This blocking
effect results in a less pronounced hyperthyroid state. The other antithyroid antibody found
in some patients with Graves disease is thyroid peroxidase antibody. Approximately 20%
of patients with Graves disease develop chronic autoimmune thyroiditis as a result of this
antibody [57] .
Although it is well known that Graves disease is a response to TSH RS abs, it is not known
why some individuals produce these antibodies [56] . Theories suggest antibody formation is
of viral origin, environmental factors, stress-related, or even pregnancy-induced, but none
of these satisfies all cases [58] [59] . Some factors that are common and, if not causative, may
serve as a catalyst are female gender between 3060 years of age, family history of
-
autoimmune thyroid disease, history of other autoimmune diseases, cigarette smoking, and
a history of neck irradiation.
Graves disease is identified by five specific clinical findings, although each may not be
clinically evident in every case. The five clinical findings include thyrotoxicosis, goiter,
ophthalmopathy, local myxedema, and acropachy. As already discussed, the cause of the
thyrotoxicosis seen in Graves disease is clear, but there is no ready explanation as to the
cause of the other four clinical findings.
Antithyroid antibodies were discovered in the 1950s. Soon thereafter it was shown that a
cause and effect relationship existed between these newly discovered antithyroid antibodies
and Graves disease. The presence of these antibodies only helped to explain the acute
symptoms (thyrotoxicosis), however, and not those that seemed to come later (eg,
ophthalmopathy, myxedema). Thus, it was speculated that the clinical findings in Graves
disease were caused by two substances, not one. The substance that was believed to be
responsible for the late findings of the disease was labeled LATS (long acting thyroid
stimulator). It was many years later when it was finally recognized that LATS was actually
the same as TSH RS abs. At the present time it is unclear whether TSH RS abs is
responsible for all the clinical findings of Graves disease or if there is still another
unidentified substance waiting to be uncovered. Goiter is the most common clinical finding
in Graves disease, after thyrotoxicosis, and it occurs in nearly 100% of patients [60] . Goiter
is, in fact, so common that when it occurs in a postmenopausal woman with thyrotoxicosis,
it is sufficient for diagnosis until proven otherwise.
Ophthalmopathy of Graves disease is common and, although not always clinically evident,
it can be found in 70% of cases if measurements are made by way of computed tomography
(CT) [61] . Clinically significant ophthalmopathy, however, occurs in only approximately
10%25% of cases. Of these, approximately 5% are considered severe with potential for
blindness.
Ophthalmopathy occurs five times more often in women than men and usually appears
coincident with the onset of thyrotoxicosis. Smokers are more prone to develop
ophthalmopathy, and when it occurs in men it is more often severe [62] . Twenty-eight
percent of all cases of unilateral ophthalmopathy are the result of Graves disease, however,
when ophthalmopathy occurs in Graves disease it is almost always bilateral. The incidence
of unilateral disease in Graves is so uncommon that its occurrence requires clinical
evaluation for unrelated, coincidental, retrobulbar disease [63] . The usual course from onset
of symptoms for approximately two thirds of patients with Graves ophthalmopathy is a
gradual worsening during the first 36 months, which is followed by a stable period of
variable length, and finally spontaneous resolution. Of the remaining one third of
individuals who are affected, half remain stable indefinitely and half worsen with time [64] .
Complications of ophthalmopathy are the result of increased retrobulbar connective tissue
and hypertrophy and fibrosis of the extraocular muscles. Untreated severe proptosis leads to
exposure keratitis and blindness caused by corneal drying.
Initial treatment for ophthalmopathy is generally not indicated unless there is significant lid
retraction or optic nerve injury. Steroids, cyclosporine A, and octreotide have been used
-
with some success [65] . Surgical debulking of the retrobulbar space is reserved only for
severe cases but it does not prevent fibrosis. There is one study that looked at the effect
definitive treatment for Graves disease had on ophthalmopathy. This study compared the
degree and severity of ophthalmopathy as it related to the various treatment options. The
study showed a worsening of ophthalmopathy in 33% of patients who were treated with 131[I] early in their disease. This compared with a worsening in only 10% of patients treated
with antithyroid drugs and 16% of patients treated surgically (thyroidectomy) [66] .
The last two clinical findings in Graves disease are localized myxedema and thyroid
acropachy. Localized myxedema is skin thickening. It is uncommon, rarely occurs
independent of clinically significant ophthalmopathy, and is usually limited to the pretibial
areas. Treatment is topical application of glucocorticoids. Acropachy is soft-tissue swelling
of the hands and feet. It is extremely rare and virtually unheard of as an isolated finding.
There is no specific treatment for acropachy.
Laboratory results necessary to diagnose Graves disease include an elevated serum free T4
and free T3, absence of thyrotropin (20. In all other causes of
thyrotoxicosis the ratio of T3 to T4 is
-
THYROIDITIS
Thyroiditis occurs in several forms that are differentiated by cause and symptomatology [70]
. Terminology is somewhat confusing, as each form of thyroiditis is known by many
names. The most common forms are chronic autoimmune thyroiditis, silent thyroiditis,
postpartum thyroiditis, and subacute thyroiditis. Three of these four are autoimmune
diseases, whereas the fourth, subacute thyroiditis, is most likely of viral origin [71] . Silent
thyroiditis and postpartum thyroiditis can recur, but, together with subacute thyroiditis, they
are considered to be self-limited diseases. Autoimmune thyroiditis, however, is a chronic
progressive disease [71] [72] [73] . Chronic autoimmune thyroiditis is associated with high serum
levels of antithyroid peroxidase antibodies (TPO abs) and occasionally has high serum
levels of antithyroglobulin antibodies also. The destructive process in autoimmune
thyroiditis is different from that seen in silent or postpartum thyroiditis, occurring gradually
over a protracted period, and it is not a self-limited disease. Autoimmune thyroiditis rarely
presents with thyrotoxicosis and the end result of the disease process is stromal fibrosis
and overt hypothyroidism. Silent and postpartum thyroiditis, on the other hand, are
destructive forms of thyroiditis that are associated with antithyroid (microsomal) and
antithyroglobulin antibodies. They usually present with overt thyrotoxicosis and are self-
limited without residual injury to the thyroid gland.
With all four forms of thyroiditis, the primary mechanism of injury to the thyroid gland is a
cytotoxic, destructive process that releases stored thyroid hormone into the peripheral
circulation. When this occurs it may precipitate a hyperthyroid state of short, but sometimes
intense, duration. Once the thyroid hormone stores are depleted, the acute hyperthyroid
phase is replaced by a transient period of hypothyroidism that is eventually followed by a
return to a euthyroid state. The degree of thyroidal injury is the major determinant of the
severity of the hyperthyroid phase and the duration of the hypothyroid phase. Long-term
prognosis in all but chronic autoimmune thyroiditis is return to a euthyroid condition.
Presenting symptoms of thyroiditis range from thyrotoxicosis to frank goiter to overt
hypothyroidism. Accurate diagnosis is important to prevent inappropriate treatments early
in the course of the disease and to adequately address long-term potential and followup [74] .
For patients presenting with goiter or pregnancy, this becomes especially important. Early
determination that thyroiditis is the cause of thyrotoxicosis rather than some other disease
process, such as Graves disease, is essential, because the hyperthyroid state created by
thyroiditis is caused by excessive release of thyroid hormone (a destructive process) and
not by overproduction. Because antithyroid drugs have minimal affect on circulating
thyroid hormone, their use in treating thyrotoxicosis seen in association with thyroiditis is
not beneficial and may, in fact, significantly delay recovery to a euthyroid state.
Decisions concerning which laboratory tests to obtain in thyroiditis are made based on
presenting symptoms and can range throughout the thyroid spectrum, depending on where
the patient is in the course of the disease. When symptoms are acute, circulating levels of
thyroid hormone are significantly increased, whereas thyrotropin is normal to slightly
decreased. Findings such as this should make for high clinical suspicion of thyroiditis. An
acute phase radioisotope scan, if obtained, shows marked decrease in thyroid gland activity
-
(2% at 24 hours) that effectively eliminates Graves disease and other overproduction
processes. During the posthyperthyroid phase, thyrotropin levels may be elevated and may
remain elevated for many weeks before returning to normal. This period of increased
thyrotropin represents a self-limited subclinical hypothyroidism and treatment is not
generally indicated as long as the patient is improving clinically.
Chronic Autoimmune Thyroiditis
Chronic autoimmune thyroiditis is a destructive process with a predilection for women [75] .
It accounts for most hypothyroidism in countries, such as the United States, where dietary
iodine is adequate [1] [76] . This disease is also known as Hashimoto thyroiditis and chronic
lymphocytic thyroiditis, and it occurs in two forms, goitrous and atrophic. It is unclear why
one form occurs versus the other [49] . The various names given to this disease provide some
descriptive, but not substantive, benefit to understanding the nature of the disease but not
its cause, which seems to be an autoimmune process with production of multiple
antithyroid antibodies [48] . Antithyroid peroxidase antibodies (TPO abs) and
antithyroglobulin antibodies (Tg abs) are present in >90% of patients with autoimmune
thyroiditis, and it seems the primary destructive antibody is the cytotoxic TPO abs. As with
all of the autoimmune thyroid diseases, the precipitating events for antibody formation in
chronic autoimmune thyroiditis is not known, but excess dietary iodine, radiation, lithium,
chronic hepatitis, and hepatitis C have been implicated [77] . There is no evidence to support
an infectious cause.
Initial presentation of autoimmune thyroiditis is usually subclinical or overt
hypothyroidism, painless goiter, or both [78] . Rare presentation with thyrotoxicosis occurs,
and when it does, especially if accompanied by goiter, differentiation from Graves disease
is important because of differences in long-term medical management [79] . Early treatment
of the goitrous form of the disease with levothyroxine, even with normal thyrotropin levels,
yields a one-third resolution of goiter within 2 years. Continued treatment can increase
goiter resolution as much as 71% at 48 years [80] . Early treatment of the atrophic form of
the disease with levothyroxine does not seem to offer any benefit [81] . Chronic autoimmune
thyroiditis progresses to overt hypothyroidism at approximately 5% per year [2] . Annual
screening with serum thyrotropin levels is appropriate to provide early recognition of overt
hypothyroidism.
There is a definite association between chronic autoimmune thyroiditis and primary B-cell
lymphoma of the thyroid. One study that looked at patients with primary thyroid lymphoma
found a 100% incidence of autoimmune thyroiditis [82] . Thus, any change in the size or
characteristics of the thyroid gland in patients with a history of chronic autoimmune
thyroiditis requires aggressive evaluation, including imaging and tissue sampling.
Silent Thyroiditis and Postpartum Thyroiditis
Silent and postpartum thyroiditis are autoimmune disorders, diagnosed by elevated levels
of antithyroid (microsomal) antibodies [81] . There is no strong evidence to support that they
-
represent two distinct disease entities and, for purposes of this article, they are treated as the
same disease [83] .
Thyroiditis can occur spontaneously (silent or sporadic) or can be associated with
pregnancy (postpartum) [10] . When associated with pregnancy, recurrent episodes occur in
approximately 70% of subsequent pregnancies [84] . It is also common in individuals with a
family history of similar disease or with other autoimmune thyroid disorders [10] [85] . Women
who are positive for antithyroid antibodies in the first trimester of pregnancy or at delivery
have an especially high incidence of the disease. Silent/postpartum thyroiditis is considered
self-limiting, but the incidence of hypothyroidism 24 years after the initial episode in all
individuals is approximately 20% [86] . The incidence of hypothyroidism increases with
multiparity, history of spontaneous abortion, absence of a hyperthyroid (thyrotoxic) phase,
or presence of severe hypothyroidism during the initial attack. It is more common in
individuals with high antithyroid antibody titers. Results of laboratory tests in
silent/postpartum thyroiditis have been previously described.
Pain is unusual in this form of thyroiditis and there are few other clinical symptoms once
the hyperthyroid phase has passed. Because there are so few acute symptoms outside of the
short-lived thyrotoxic phase, treatment is not required [87] . In rare cases in which the
hypothyroid phase is prolonged as determined by low free T4 levels, not elevated
thyrotropin levels, short-term replacement of thyroxine may be required, but this can
generally be discontinued in 36 months.
Although silent/postpartum thyroiditis is sometimes suggested as a cause for postpartum
depression, clinical studies have not shown this to be the case [88] . Routine screening for
this disorder in postpartum depression is not indicated. Signs and symptoms of
hypothyroidism can mimic depression, however, and, although perhaps not causative, the
presence of hypothyroidism can make management of postpartum depression more
difficult. Excluding hypothyroidism as a comorbid condition may be justified.
Subacute Thyroiditis
Subacute thyroiditis is also known as De Quervain thyroiditis, giant cell thyroiditis, and
pseudo-granulomatous thyroiditis. As with many other thyroid diseases, the multitude of
names have descriptive value but not substantive value.
The exact cause of subacute thyroiditis is unknown, but it does not seem to be an
autoimmune mediated disease as is the case with other forms of thyroiditis. Most of the
evidence, albeit circumstantial, strongly suggests subacute thyroiditis is secondary to a viral
infection [71] . Evidence to support this conclusion includes the fact episodes of the disease
often follow upper respiratory infections with a prodrome of fever, muscle aches, and
malaise. The disease also tends to be seasonal and geographic, corresponding closely with
peaks in enterovirus infections. Adenovirus, Coxsackie virus, Epstein-Barr virus, and
influenza virus have also been associated with the disease [71] .
-
Subacute thyroiditis is unique in how it presents compared with other forms of thyroiditis.
The most common presenting complaint is a painful and tender neck. Other symptoms
include fever, malaise, and sore throat, closely resembling mononucleosis. When a
diagnosis of seronegative mononucleosis is made, subacute thyroiditis should be considered
as an alternative.
Results of thyroid function tests in subacute thyroiditis vary depending on the phase of the
disease. Antithyroid antibody titers are usually negative, thyrotropin levels are generally
normal to slightly low, and erythrocyte sedimentation rates are high. This latter is in
contradistinction to silent/postpartum thyroiditis in which the erythrocyte sedimentation
rate is normal. Abnormal liver enzymes are not uncommon and can further confuse the
diagnosis [89] .
Subacute thyroiditis is self-limited, usually resolving in 13 months. An enlarged thyroid
gland may persist for several months, but all symptoms and physical findings should be
gone by 6 months. There is rarely any long-term sequelae and, because the recurrence rate
is
-
cellular and glandular activity and leading to increased mass [92] . De novo goiter formation
seems to represent some form of failure in the hypothalamic-pituitary-thyroid feedback
system. The most common cause for this failure worldwide is iodine deficiency, but the
exact mechanism by which this occurs in individuals in areas with adequate iodine intake is
not clear. There is speculation about a thyroid growth-stimulator, but this has not yet
been identified [93] . Goiter formation can also be precipitated by some food groups that are
known to be goitrogenic, however, this occurs primarily in iodine deficient areas of the
world.
Pregnancy is known to stimulate the thyroid gland [10] . In the United States, a large portion
of dietary iodine comes from iodized salt. Severe restriction of salt intake during pregnancy
may result in marginal dietary iodine intake, especially in individuals who do not eat fish.
This can lead to goiter formation. When dietary iodine is taken during pregnancy in
quantities well above daily requirements, it can cause neonatal goiter formation.
Unsuspected dietary sources include such things as food supplements or health foods.
Goiter formation in the fetus is caused by the sensitive inhibitory effect of iodine on the
fetal thyroid gland. Fortunately this goiter formation is a benign process and the goiter
resolves spontaneously a few months after birth.
Nodular and multinodular goiters are variations of the same process and can present as a
toxic or nontoxic condition [40] . Nontoxic goiter progresses to nodular development that,
when long-standing, may organize into adenomas. Nontoxic nodular or multinodular goiter
is generally a benign process in a euthyroid individual, and cosmetic considerations or local
symptom relief determines treatment. Diagnosis is made clinically with confirmation by
ultrasonography. Patients with goiter should not be given iodine-rich radiographic contrast
agents because of a risk for precipitating iodine-induced thyrotoxicosis.
Toxic adenoma and toxic multinodular goiter are effectively the same disease except for the
number of functional units. Toxic multinodular goiter accounts for
-
Cysts and nodules are frequent findings at ultrasound. They increase in frequency with age
and are more common in women. Most cysts and nodules found are
-
causing thyrotoxicosis and have an increased incidence of malignancy [94] [95] [97] .
Adenomas, on average, become functional at the rate of approximately 4% per year. For
this reason, careful observation of an adenoma in an older person is important because
unrecognized thyrotoxicosis can exacerbate coexisting diseases [101] . It is also important to
monitor for changes in size. Rapid enlargement of a stable nodule, with or without pain,
suggests either hemorrhage or an anaplastic process. Rapid growth of any thyroid mass in a
patient with a history of nonthyroid cancer suggests metastatic disease.
Malignancies
In the general population of the United States the incidence of primary malignancy of the
thyroid is extremely rare, being 2.5 cm or an
enlarging adenoma in a euthyroid individual. An adenoma that fits these criteria has a 5%
15% incidence of being malignant [100] [103] [104] [105] . Other risk factors include history of head
and neck irradiation in childhood and a family history of thyroid malignancy. Papillary and
follicular carcinomas are minimally aggressive and have a slow rate of growth; thus,
individuals who are diagnosed and treated early have a better than 95% cure rate [106] .
Diffuse sclerosing adenocarcinoma is a variant of follicular carcinoma that is found in
young people, and one that usually involves the entire gland. This tumor, at the time of
diagnosis, is often metastatic to regional lymph nodes and occasionally to the lungs. Initial
presentation can be an enlarged, sometimes cystic, cervical node.
Medullary carcinoma, also known as C cell carcinoma, can occur sporadically in the
population or in association with other endocrine abnormalities. Specific examples include
multiple endocrine neoplasia IIA (MEN IIA, or Sipple syndrome) and MEN IIB (mucosal
neuroma syndrome). Prognosis for medullary carcinoma when it occurs in Sipple syndrome
is better than when found in association with MEN IIB or when it arises de novo.
Medullary carcinoma almost always produces calcitonin and this is often the trigger for
-
initial diagnosis. The natural course of the disease is local invasion of lymphatics and blood
vessels with metastases to cervical lymph nodes. Patients presenting with renal calculi,
hypercalcemia, or malignant hypertension should be evaluated for possible medullary
carcinoma.
Lymphoma within the thyroid gland can be primary or secondary. Primary lymphoma has a
high association with chronic autoimmune thyroiditis [82] . Secondary lymphoma appears in
the thyroid gland in approximately 20% of cases [82] .
NONTHYROID DISEASES AFFECTING THE HYPOTHALAMIC-
PITUITARY-THYROID AXIS
Serious illness has been shown to affect laboratory tests for thyroid function, but there is no
clear evidence that this reflects a disease state [107] . Because there does not seem to be any
direct adverse effect from these changes on the overall clinical condition of the patient, this
condition has become known as the sick euthyroid syndrome.
In general terms, the sick euthyroid syndrome is of academic interest alone and does not
have direct bearing on the clinical course of the patient. Several studies, however, have
looked at the predictive value of abnormal thyroid function tests when applied to survival
outcomes in patients seriously ill with nonthyroid diseases. In these studies, mortality was
predicted based on the level of circulating thyroxine, independent of other thyroid
parameters. If serum T4 was 30 ugm/dL had a 56% sensitivity and a 100% specificity. What was most
interesting was that when these two were combined (ie, a T4 level 30 ugm/dL, the sensitivity for predicting mortality increased to 100% and the
specificity increased to 86%. The studies concluded that the predictive value for death in
seriously ill patients with nonthyroid diseases, using these parameters, was better than the
APACHE II score commonly in use [108] .
DRUG AFFECT ON THYROID FUNCTION
Drugs affect thyroid function in a variety of ways: inhibition of synthesis and secretion of
thyroid hormone, competition for thyroid hormone transport in the circulation, altered
thyroid hormone metabolism, and interference with action of thyroid hormone at the target
tissue.
Synthesis and Secretion
Drugs that affect synthesis and secretion of thyroid hormone and have therapeutic benefit
are the antithyroid drugs in the class thionamides. These drugs are used in the acute
treatment of thyrotoxicosis. The three drugs in this class are propylthiouracil (PTU),
methimazole (MMI), and carbimazole. Carbimazole is converted to MMI in vivo and is
-
available only in Europe. PTU and MMI inhibit thyroid hormone synthesis by interfering
with thyroid peroxidase; however, PTU has the added advantage over MMI of inhibiting
extrathyroidal conversion of T4 to T3. Because of this extra benefit, PTU tends to be the
drug most often used in the United States. Neither PTU nor MMI can inhibit release
(secretion) of thyroxine from the thyroid gland. PTU has a shorter half-life than MMI,
providing the additional advantage of making titration easier.
PTU and MMI are used orally. In conditions in which they would be of most benefit,
hyperthyroid states and iodine deficiency states, they are absorbed quickly from the
gastrointestinal tract. The side effect profile of both drugs is mild, with pruritis, urticarial
rash, and fever being most common. The major serious side effect is agranulocytosis, but
this occurs in
-
significance of these effects is not known but may account for variable responses in patients
when medication changes are made.
Transport
Salicylates, nonsteroidal anti-inflammatory drugs, furosemide, heparin, and enoxaparin
compete for binding sites on thyroid hormone transport proteins. Use of these drugs in
acute disease can potentially exacerbate thyrotoxic symptoms by release of thyroid
hormone into the free circulation. When these drugs are used in stable patients, they can
cause false elevations of laboratory values for total T4 and T3 levels. Thyrotropin, free T4,
and free T3 levels of patients who have thyroid disease and who are taking any of these
medications should be monitored on a regular basis.
Metabolism
Phenytoin, phenobarbital, carbamazepine, and rifampin stimulate hepatic enzymatic
activity, thus shortening thyroid hormone clearance times and increasing conversion of T4
to T3. Sucralfate, cholestyramine, calcium carbonate, aluminum hydroxide, soy products,
and ferrous sulfate inhibit absorption of exogenous levothyroxine from the gut.
Several drugs affect metabolism by inhibition of the de-iodination of T4 to T3 in the
peripheral circulation. These drugs fall into two categories, iodinated and noniodinated. The
iodinated compounds include lipid soluble radiographic contrast materials and amiodarone.
The noniodinated compounds include PTU, dexamethasone, and beta-adrenergic blocking
agents. This inhibitory affect is not generally significant clinically but can adversely affect
laboratory values and must be accounted for in the clinical setting.
Action
Drugs that affect action at the tissue level and have therapeutic benefit block the effect of
thyroid hormone on target tissues [23] [67] . These drugs include beta-adrenergic blocking
agents that block the effect of excess thyroid hormone at the cellular level, and
benzodiazepines that block T3 uptake at the cell level. Calcium channel blocking agents
inhibit uptake of thyroid hormone by hepatic and muscle cells.
DIAGNOSTIC MODALITIES IN THYROID DISEASE
Thyroid disease is evaluated and diagnosed using the clinical laboratory, radiographic
imaging studies, and tissue sampling. The clinical laboratory is the primary modality and
provides most of the information necessary to adequately assess a thyroid disorder.
Additional diagnostic or confirmatory data are obtained from radioisotope scanning and
ultrasound imaging. If a definitive diagnosis is not determined with laboratory and imaging
studies, tissue can be obtained with fine needle aspiration or surgery.
-
Clinical Laboratory
Laboratory studies for the diagnosis of thyroid disorders are few and simple to understand.
Most of the thyroid gland's functions can be assessed with a serum thyrotropin level, serum
total and free T4 levels, and serum total and free T3 levels. Thyroglobulin levels and
thyroid binding globulin levels help decipher inconsistencies in the function tests.
Additional diagnostic studies include antithyroid antibody levels for antithyroglobulin
antibodies (Tg abs), antithyroid peroxidase antibodies (TPO abs), TSH receptor-stimulator
antibodies (TSH RS abs), and TSH receptor-blocker antibodies (TSH RB abs) [114] . Serum
levels also can be determined for transthyretin (TTR) should there be a question concerning
thyroid hormone transport. The meaning, use, and implication of each of these tests, in
relation to specific diseases, were discussed earlier.
The single most useful screening test for thyroid dysfunction is serum thyrotropin [115] .
Normal thyrotropin levels (0.55.0 mU/L) effectively rule out hyperthyroidism and
hypothyroidism. When the serum thyrotropin level is in the normal range, obtaining serum
T4 and T3 levels is not indicated. With the exceptions of a thyrotropin-producing pituitary
adenoma or pituitary failure, hyperthyroidism and hypothyroidism can be diagnosed
exclusively from a serum thyrotropin level. Thyrotropin levels between 520 mU/L are
consistent with subclinical hypothyroidism. Levels greater than 20 mU/L are consistent
with overt hypothyroidism. Thyrotropin levels to diagnose subclinical hyperthyroidism are
less than 0.5 mU/L when serum T4 and T3 levels are normal. Thyrotropin levels less than
0.01 mU/L are diagnostic of thyrotoxicosis. Regular measurement of serum thyrotropin is
used to titrate levothyroxine replacement doses in hypothyroid patients and to regulate the
dose of antithyroid drugs in thyrotoxic patients [114] .
Altered thyroid transport-protein binding can increase or decrease total serum T4 or T3
levels without affecting euthyroid status. When this occurs, the condition is known as
euthyroid hyperthyroxinemia or euthyroid hypothyroxinemia. Coincident levels of free T4
and free T3 are normal.
Thyroid binding globulin increases with oral estrogen and pregnancy; this causes an
increase in total serum thyroid hormone but it does not affect free T4 and free T3 levels [10] .
A thyrotropin level and free T4 and T3 levels help explain and support a diagnosis of
euthyroid state.
Antithyroid antibody titers are required to accurately diagnosis Graves disease, chronic
autoimmune thyroiditis, silent thyroiditis, and postpartum thyroiditis. Pre- and post-
treatment antibody levels are useful, but not definitive, in predicting remission and relapse
potential [51] [52] .
Imaging Studies
Imaging studies that are used to assess and diagnosis thyroid disorders include
ultrasonography, scintigraphy, computed tomography imaging, and magnetic resonance
-
imaging [116] . Ultrasonography provides anatomic information and scintigraphy provides
functional information; thus, these two modalities often are used in concert to provide a
more complete evaluation of the thyroid gland. Computed tomography and magnetic
resonance imaging do not provide information about the functional status of the thyroid
gland and, except for special situations, neither provides sufficiently unique information on
anatomic structures to warrant the extra effort and expense required to obtain them. The
exception would be evaluation of retrotracheal or retrosternal spaces and evaluation of
invasive tumor.
Ultrasound imaging relies on tissue interface differential for information. It is not effective
in discerning echogenically neutral tissues nor can it visualize retrotracheal or retrosternal
thyroid tissue. Ultrasonography is used to define simple cysts, complex or mixed cysts,
nodules, and adenomas, and it is extremely accurate in localizing lesions for fine needle
aspiration. Ultrasound is accurate in defining gland size and in goiter identification (80%
90%) compared with clinical examination (40%), although it cannot differentiate goiter
from lymphoma [117] . Given that lesions
-
over-the-counter health supplements can also interfere. A careful clinical history identifies
most of these.
One final precaution: pregnancy is an absolute contraindication to scintigraphic study and
nursing is a relative contraindication. If it is essential to obtain an isotope study in a nursing
mother, use 99m[Tc]and discontinue nursing for 2 days following the study. Before
resuming nursing, a fresh sample of breast milk should be collected and screened for
radioactivity to ensure there is no residual radiation.
Fine Needle Aspiration
The primary use of fine needle aspiration (FNA) is to drain simple and complex cysts in
low risk individuals and to determine if a thyroid mass is operable (ie, not lymphoma or a
metastatic nonthyroid malignancy) [104] . Fine needle aspiration is performed using
ultrasound as a guide [118] [119] . It is easy to do, safe, and reliable. Complications of FNA are
limited to local hematoma and occasionally an acute swelling of the gland that resolves
spontaneously in 2448 hours. Treatment is limited to ice pack. Concerns about seeding
of tumor cells along the needle track are unjustified [120] . Pregnancy and nursing are not
contraindications to FNA.
Fine needle aspiration is especially useful in palpable nodules, providing an 80% chance for
diagnosis [105] . Appropriate lesions for FNA include areas of hypofunction on scintiscan,
new low-functioning nodules among many pre-existing ones, solid remnants remaining in
an aspirated cyst, and a hypofunctioning nodule found in a patient with Graves disease [103] .
Fine needle aspiration is not used to diagnose autonomously functioning nodules or
functional hyperplastic nodules. Complex cysts can have malignant components; therefore,
FNA must be considered a rule-in procedure rather than a rule-out procedure. Negative
cytology or histology is not sufficient to exclude a malignant process [117] . Approximately
half of aspirated cysts reaccumulate fluid. Should a cyst refill after three aspirations,
excision is indicated, even in a low-risk individual with negative cytologies [103] .
Fine needle aspiration should not be used in lieu of surgical exploration in patients for
whom there is a high index of suspicion for malignancy unless surgical intervention is
contraindicated.
SUMMARY
Thyroid disorders and diseases are common, occurring in as much as 10%15% of the
general population. By extension, the numbers of individuals presenting to the primary care
office with known or unknown thyroid disease must be at least 10%15% or more. This
article reviews thyroid diseases that are most common, including pathophysiology,
diagnosis, and treatment. It defines subclinical and overt disease, discusses diagnostic
dilemmas, and highlights some diagnostic and therapeutic traps.
-
Key Points
Thyroid disorders are common, occurring in as musch as 10% of the general
population.
Simple diffuse goiter is the most common thyroid disorder in the United States.
The most common cause of thyroid disorders in the United States is autoimmune
disease.
The evaluation, diagnosis and treatment of the majority of thyroid disorders is
relatively uncomplicated and well within the capabilities and scope of practice of
the family physician.
Early diagnosis of many thyroid disorders is important in the prevention and
treatment of co-morbidities such as fetal wasting, osteoporosis, anemia,
neuropsychiatric disorders, and cardiomyopathy.
Routine screening for thyroid disorders is appropriate in select patient populations.
Diagnosis of thyroid disorders on clinical grounds is extremely difficult and
requires a high index of suspicion.
The diagnosis of thyroid disorders is based on interpretation of applicable
laboratory data rather than clinical presentation.
Diagnosis of thyroid disorders is straightforward in the majority of disease entities
using a small battery of tests (TSH, free T4, free T3, TPO abs, TSH RS abs).
Primary thyroid malignancy is extremely rare, accounting for less than 2.0% of all
cancers.
Incidentalomas are benign and, when found, do not require additional evaluation.
Annual clinical examination to screen for enlargement is all that is recommended.
Radiographic modalities are not indicated to diagnosis most thyroid disorders.
The primary care physician has the training, patient-access, and, with the information in
this article, knowledge necessary to significantly affect undiagnosed thyroid disease. This
can be accomplished through increased clinical awareness and with appropriate screening
of at-risk populations. This article provides information, in a current and concise format, to
the primary care physician, necessary to facilitate early diagnosis and treatment in the
primary care setting.
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