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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.

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

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.

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.

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

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

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

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 (

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

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

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

(

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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