www.turner-white.com Hospital Physician October 2006 43 T he clinical spectrum of thyroid disease varies
from asymptomatic subclinical disease detected
by laboratory screening to overt thyroid storm
and myxedema coma. However, laboratory de- tection of subclinical or early thyroid disease usually
occurs before these overt manifestations of disease de-
velop. The clinician must maintain a high degree of sus-
picion for thyroid disease as its signs and symptoms can
mimic those of other common diseases (eg, fatigue, dys-
pnea, palpitations associated with anemia). This article
reviews the signs and symptoms of thyroid disease and
briefly discusses aspects of the laboratory evaluation. LaboraTory EvaLuaTion Thyroid-stimulating hormone (TSH), or thyrotro- pin, is produced by the pituitary gland in response to
thyrotropin-releasing hormone and stimulates produc-
tion and secretion of thyroid hormones. Measurement
of the TSH serum concentration is the initial test of
choice for evaluating thyroid function (Figure 1). An
increased level of TSH points to a diagnosis of hypothy-
roidism. If the TSH level is low, then free thyroxine (FT 4 ) should be measured to evaluate for thyrotoxicosis. The
FT 4 assay has replaced the older method of determin- ing free thyroxine, known as the FT 4 index, in which the triiodothyronine (T 3 ) resin uptake method was used. FT 4 is measured rather than total T 4 because 70% to 80% of T 4 is bound to thyroid-binding globulin, making the total T 4 assay susceptible to error due to variations in thyroid- binding globulin. 1 Measurement of free T 3 is helpful in the clinical diagnosis of thyrotoxicosis when the FT 4 val- ues are unexpectedly normal (ie, T 3 thyrotoxicosis). Radioactive iodine uptake (RAIU) scans are useful in differentiating among the types of thyrotoxicosis. High
iodine uptake is seen in diseases that cause increased
thyroxine synthesis, including Graves disease, toxic mul-
tinodular goiter, toxic adenoma, and molar pregnancy.
Low uptake is seen in diseases that cause inflammation
and release of thyroxine, including subacute thyroiditis,
thyrotoxicosis factitia, iodine ingestion, and postpartum
thyroiditis. HypErTHyroidism Although there is controversy as to the exact defi- nitions, the term hyperthyroidism typically is used to
describe the disease process in which excessive thy-
roid hormone is synthesized and excreted (eg, toxic
nodular goiter, Graves disease), whereas the term
thyrotoxicosis is mainly used to describe conditions in
which there is excessive circulatory thyroid hormone
(eg, thyroiditis). 2 Causes of thyrotoxicosis are shown in Table 1. Graves disease is the most common cause of
hyperthyroidism in the United States, accounting for
60% to 80% of cases of hyperthyroidism. 3 Graves dis- ease is sometimes associated with other autoimmune
disorders, including type 1 diabetes mellitus, Addisons
disease, pernicious anemia, celiac disease, collagen
diseases, vitiligo, and the autoimmune polyglandular
syndromes. R e v i e w o f C l i n i c a l S i g n s Series Editor: Bernard M. Karnath, MD Signs and Symptoms of Thyroid Dysfunction Bernard M. Karnath, MD Nasir Hussain, MD ThyroiD DySfuncTion Graves disease is the most common cause of hy- perthyroidism in the United States. Common signs and symptoms of hyperthyroidism include nervousness, fatigue, palpitations, weight
loss, and heat intolerance. Hashimotos thyroiditis is the most common cause of hypothyroidism in the United States. Common signs and symptoms of hypothyroidism include lethargy, cold intolerance, weight gain,
constipation, coarse dry skin, hair loss, hoarse voice,
bradycardia, and psychomotor retardation. Dr. Karnath is an associate professor of medicine and Dr. Hussain is an
associate professor of medicine; both are in the Division of General Medi-
cine, University of Texas Medical Branch, Galveston, TX. K a r n a t h & H u s s a i n : T h y r o i d D y s f u n c t i o n : p p . 4 3 4 8 44 Hospital Physician October 2006 www.turner-white.com Clinical presentation Many organ systems can be involved in the clinical picture of hyperthyroidism (Table 2). The most com-
mon symptoms of hyperthyroidism include nervous-
ness, fatigue, palpitations, weight loss, and heat intol-
erance. 4 The symptoms of hyperthyroidism are more common in patients younger than 50 years, 4 except for atrial fibrillation, which is more likely to occur in
patients older than 70 years. 5 Thyrotoxicosis is a known cause of a high-output cardiac state. 6 OMalley and col- leagues 7 reported a case that presented solely as heart failure before the more classic manifestations of hyper-
thyroidism appeared. Severe pulmonary hypertension
has also been reported as an atypical sole manifestation
of hyperthyroidism. 8 Marvisi and colleagues 9 evaluated 34 patients with hyperthyroidism and found a strong
association between lower TSH values and increased
pulmonary arterial pressure. Thyroid storm, the most severe manifestation of hyperthyroidism, results from untreated hyperthyroid-
ism and may be precipitated by infection, trauma, a
surgical procedure, and diabetic ketoacidosis. The
signs and symptoms include fatigue, fever, tachycardia,
dyspnea, restlessness, confusion, psychosis, and coma.
Patients with thyroid storm may progress to cardiovas-
cular collapse and shock. Atrial arrhythmias are com-
mon. Thyroid storm is a medical emergency and is
diagnosed based on clinical symptoms rather than on
laboratory hormone values. Thyrotoxic periodic paralysis is another rare com- plication of hyperthyroidism. It is seen mainly in Asian
men between 20 and 40 years of age, with a male/
female ratio of approximately 20:1, despite the higher
incidence of hyperthyroidism in women. Thyrotoxic pe-
riodic paralysis is a reversible disorder characterized by
acute muscle weakness and hypokalemia. The attacks of
periodic paralysis are precipitated by hypokalemia that is caused by a transcellular shift rather than total body
depletion of potassium. Attacks often are preceded by
symptoms of muscle weakness and cramps. 10 Etiology Graves disease. Graves disease is an autoimmune disease in which antibodies against thyrotropin receptors
within the follicular cells of the thyroid gland develop.
These thyroid-stimulating antibodies lead to an increase
in synthesis and release of thyroid hormone and enlarge-
ment of the thyroid gland (goiter; Figure 2). 3 Signs and symptoms of Graves disease include those of hyperthy-
roidism. Age can strongly influence the clinical findings
of Graves disease. Thyroid enlargement occurs in 90%
of patients younger than 50 years but occurs in only 50%
of patients older than 70 years. 5,11 Other manifestations specific to Graves disease include ophthalmopathy (eye-
lid retraction or lag and periorbital edema) and exoph-
thalmos (Figure 3). The ocular findings in patients with
Graves disease are not universal, with clinically apparent
Graves ophthalmopathy occurring in only one third
of patients. Graves dermopathy (also termed pretibial
myxedema) is another manifestation, albeit rare. It is
characterized by lymphocytic and mucopolysaccharide
infiltration of the dermis most commonly located over
the pretibial region. The cause of Graves ophthalmopa-
thy and dermopathy is unknown, but cross-reactivity
between antigens of the thyroid gland and other tissues
has been suggested. 2 Toxic solitary or multinodular goiter. A toxic mul- tinodular goiter (Plummers disease) has at least 2
autonomously functioning nodules that secrete excess
thyroid hormone. Toxic nodular goiter is the second
most common cause of hyperthyroidism in the United
States, although 1 study showed that it is the most com-
mon cause of spontaneous hyperthyroidism in patients
older that 55 years. 12 Many patients are asymptomatic TSh Low normal high fT 4 Low Secondary hypothyroidism (pituitary disorder) Euthyroid sick syndrome Primary hypothyroidism normal Subclinical hyperthyroidism Normal No further testing Consider repeating test Subclinical hypothyroidism high Thyrotoxicosis (see discussion of RAIU) Medications (amiodarone, levothyroxine) Secondary hyperthyroidism (TSH-secreting pituitary tumor) figure 1. Laboratory evaluation of thyroid disease. FT 4 = free thyroxine; RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone. www.turner-white.com Hospital Physician October 2006 45 K a r n a t h & H u s s a i n : T h y r o i d D y s f u n c t i o n : p p . 4 3 4 8 and are incidentally found to have hyperthyroidism
after screening laboratory results are obtained. On
physical examination, a goiter may be present with
one or more nodules. A toxic solitary thyroid nodule
has autonomous function that results in hyperthyroid-
ism. On RAIU scan, the nodule appears hot with in-
creased uptake of radioactive iodine when the remain-
der of the thyroid gland is suppressed. Thyroiditis. Subacute thyroiditis, also called de Quer- vains thyroiditis, is a painful condition of the thyroid
gland that manifests with tenderness in the neck and
low-grade fever. It is sometimes confused with pharyn-
gitis. Patients frequently have a history of a prior viral
upper respiratory tract infection. On physical examina-
tion, the thyroid is enlarged, firm, and tender. Hyperthy-
roidism occurs early in the disease due to inflammatory
destruction of the thyroid gland and the release of pre-
formed thyroid hormone, resulting in decreased uptake
on RAIU scan. Subacute thyroiditis is a self-limited pro-
cess characterized by a clinical course of hyperthyroid-
ism, hypothyroidism, and return to normal thyroid func-
tion. Laboratory findings early in the disease include
an increase in T 4 and T 3 , a decrease in TSH, and a high erythrocyte sedimentation rate. Shortly after pregnancy, women are at risk for post- partum thyroiditis and Graves disease. Postpartum
thyroiditis presents with a nonpainful goiter, usually
1 to 6 months after childbirth. Differentiating between
the 2 diseases with an RAIU scan can be difficult in the Table 1. Summary of Thyrotoxicosis cause Mechanism clinical findings Laboratory findings Primary hyperthyroidism TSH FT 4 Graves disease TSH-receptor stimulating antibodies Ophthalmopathy, goiter with bruit Diffuse RAIU Toxic multinodular goiter (toxic adenoma, Plummers disease) Multiple autonomous functioning nodules Multinodular goiter Multinodular RAIU Toxic solitary goiter Solitary hyperfunctioning nodule Solitary nodule Hot nodule on RAIU Hashimotos thyroiditis Chronic lymphocytic infiltration of thyroid gland Painless goiter RAIU Subacute thyroiditis (de Quervains) Inflammation leading to leakage of stored hormone Fever, neck pain, viral infection RAIU
ESR Postpartum thyroiditis Inflammation leading to leakage of stored hormone Small, nonpainful goiter RAIU Drug induced Amiodarone
Lithium Goiter (lithium) RAIU (amiodarone)
RAIU (lithium) Factitious Exogenous thyroid hormone ingestion No goiter FT 4 RAIU Secondary hyperthyroidism Pituitary tumor Increased thyrotropin
secretion Goiter Abnormal MRI
TSH FT 4 Molar pregnancy, choriocarcinoma, hyperemesis gravidarum hCG with TSH-like activity Serum hCG ESR = erythrocyte sedimentation rate; FT 4 = free thyroxine; hCG = human chorionic gonadotropin; MRI = magnetic resonance imaging; RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone. Table 2. Manifestations of Hyperthyroidism General Fatigue, heat intolerance, sweating, weight loss Dermatologic Pruritus, warm moist skin Ophthalmologic Ophthalmopathy (eyelid lag or retraction, exophthalmos) of Graves disease Neck Goiter Pulmonary Dyspnea, tachypnea, signs of pulmonary hypertension Cardiac Palpitations, tachycardia, atrial fibrillation, high-output cardiac state Gastrointestinal Increased stool frequency Genitourinary Menstrual disorders, infertility Neuromuscular Muscular weakness, fine tremor, hyperreflexia, periodic paralysis (Asian men) Psychiatric Anxiety, nervousness K a r n a t h & H u s s a i n : T h y r o i d D y s f u n c t i o n : p p . 4 3 4 8 46 Hospital Physician October 2006 www.turner-white.com postpartum period if the patient is breast feeding be-
cause the radioactive iodine is secreted into the breast
milk. HypoTHyroidism Hypothyroidism is the most common pathological hormone deficiency. 13 It is more common in women and its incidence increases with age. Worldwide, the most
common cause of hypothyroidism is iodine deficiency,
while in the United States the most common cause is
Hashimotos thyroiditis, followed by post-ablation hypo-
thyroidism after radioactive iodine therapy for hyper-
thyroidism. Other causes include thyroidectomy and
pituitary dysfunction (Table 3). Hashimotos thyroiditis is the most common cause of goiter in the United States and is also the most com-
mon type of thyroiditis. 14 Early Hashimotos thyroiditis is associated with a firm goiter, but later in the disease
process a shrunken fibrotic hypofunctioning thyroid
gland develops. The disease is characterized by the
presence of high concentrations of serum thyroid anti-
body. The most frequently detected antibodies are an-
tithyroid peroxidase (anti-TPO) and antithyroglobulin
(anti-Tg). In its initial phase, Hashimotos thyroiditis
(autoimmune chronic lymphocytic thyroiditis) can
cause hyperthyroidism that presents as a painless goiter caused by lymphocytic infiltration of the thyroid gland. subclinical Hypothyroidism The term subclinical hypothyroidism refers to a hypo- thyroid condition in which patients are asymptomatic or
mildly symptomatic with mild TSH elevations but have
normal serum FT 4 and free T 3 concentrations. As hypo- thyroidism is the most common pathological hormone
deficiency, many expert groups recommend screening
women for thyroid disease after age 50 years. Because
of widespread screening, the prevalence of subclinical
hypothyroidism has risen. Although the US Preventive
Services Task Force has determined that there is insuffi-
cient evidence to support or recommend against routine
screening, 15,16 3 expert groups (the American Associa- tion of Clinical Endocrinologists [AACE], the American
Thyroid Association [ATA], and the Endocrine Society)
have formulated a consensus statement on screening
for early thyroid dysfunction stating that the potential
benefits of early detection and treatment of subclinical
thyroid dysfunction significantly outweigh the potential
side effects that could result from early detection. 17 This expert group therefore recommended routine screen-
ing for subclinical thyroid dysfunction in adults without
specifying age and frequency. Individually, the ATA rec-
ommends screening both men and women beginning
at age 35 years and every 5 years thereafter, while the
AACE recommends screening older patients, especially
women. Clinical presentation Manifestations of hypothyroidism can range from asymptomatic subclinical detection to overt myxedema,
which is rarely seen due to widespread screening for thy-
roid disease. The manifestations of hypothyroidism re-
sult from hypometabolism and involve many organ sys-
tems (Table 4). Common signs and symptoms include
lethargy, cold intolerance, weight gain, constipation,
coarse dry skin, hair loss, hoarse voice, bradycardia, and
psychomotor retardation. The onset of signs and symp-
toms may be subtle. In 1 study of patients with suspected
hypothyroidism, the findings most likely to occur were
bradycardia, abnormal ankle reflexes, and coarse skin. 18 Neuromuscular involvement in hypothyroidism is evidenced by muscle weakness and a prolonged relax-
ation phase of the ankle jerk. 19 Patients with thyroid dysfunction should be questioned about musculoskel-
etal complaints. Musculoskeletal problems include ad-
hesive capsulitis, carpal tunnel syndrome, Dupuytrens
contracture, fibromyalgia syndrome, and trigger fin-
ger. 20 Finally, it is important to note that no single sign can identify the patient with hypothyroidism, nor can figure 2. Goiter of Graves disease. figure 3. Graves ophthalmopathy. www.turner-white.com Hospital Physician October 2006 47 K a r n a t h & H u s s a i n : T h y r o i d D y s f u n c t i o n : p p . 4 3 4 8 the physical examination exclusively confirm or rule
out hypothyroidism, hence the need to evaluate thyroid
function. The most extreme form of hypothyroidism is myx- edema coma, a life-threatening complication of long-
standing hypothyroidism that is characterized by coma
with extreme hypothermia, areflexia, bradycardia, and
respiratory depression with hypercapnia. Precipitat-
ing factors include exposure to cold, illness, infection,
trauma, and use of sedative medications in hypothy-
roid patients. spECiaL ConsidEraTions
Euthyroid sick syndrome The term euthyroid sick syndrome refers to abnorm- al findings on thyroid function tests in patients with
severe illnesses not caused by primary thyroid or pitu-
itary dysfunction. Conditions associated with euthyroid
sick syndrome include malnutrition, anorexia nervosa,
trauma, myocardial infarction, chronic renal failure,
diabetic ketoacidosis, cirrhosis, and sepsis. Patients with
the euthyroid sick syndrome have suppressed or nor-
mal levels of serum TSH, making it difficult to deter-
mine whether the patient has secondary hypothyroid-
ism or the euthyroid sick syndrome. The measurement
of other pituitary hormones may be useful in differenti-
ating between sick euthyroid syndrome and secondary
hypothyroidism in rare cases. There is no role for levo-
thyroxine treatment in sick euthyroid syndrome. 21 Gestational Thyrotoxicosis Gestational thyrotoxicosis is a transient increase in thyroid secretion leading to thyrotoxicosis of varying
degrees of severity that can occur when human chori-
onic gonadotropin (hCG) levels are very high. As hCG
is a thyroid stimulator, a state of hyperstimulation of the
thyroid gland is common in early pregnancy. hCG val- ues are higher in women with hyperemesis gravidarum,
molar pregnancy, and choriocarcinoma. Gestational
thyrotoxicosis is closely associated with hyperemesis
gravidarum, a state of persistent severe vomiting during
pregnancy in the first trimester. 22 medication Effects Thyrotoxicosis factitia results from the ingestion of excess amounts of thyroid hormone, which leads to
hyperthyroidism in the absence of a goiter. In thyro-
toxicosis factitia, the serum level of thyroglobulin is not
elevated and is generally low in contrast to other causes
of hyperthyroidism. Medications can effect thyroid function or alter the Table 3. Summary of Hypothyroidism cause Mechanism clinical findings Laboratory findings Primary hypothyroidism TSH FT 4 Cretinism Iodine deficiency Large goiter Hashimotos thyroiditis Lymphocytic infiltration Painless goiter Post-radiation therapy Post-ablation History of Graves disease Neck surgery Thyroidectomy Surgical scar Secondary hypothyroidism TSH FT 4 Pituitary dysfunction Infarction, tumor, infiltration (sarcoidosis) Panhypopituitarism FT 4 = free thyroxine; TSH = thyroid-stimulating hormone. Table 4. Manifestations of Hypothyroidism General Fatigue, weight gain, anemia, cold intolerance Dermatologic Dry coarse skin, brittle hair, hair loss, nonpitting peripheral edema Ears, eyes, throat Hearing loss, hoarse voice, periorbital edema, facial puffiness Neck Goiter Pulmonary Dyspnea, pleural effusions, hypoventilation, sleep apnea Cardiac Bradycardia, congestive heart failure, pericardial effusions Gastrointestinal Anorexia, constipation Genitourinary Menstrual disorders, decreased libido, impotence, infertility Neuromuscular Muscle weakness, delayed ankle jerk relaxation phase Psychiatric Depression, psychomotor retardation, coma Adapted with permission from Felz MW, Forren AC. Profound hypo-
thyroidisma clinical review with eight recent cases: is it right before
our eyes? South Med J 2004;97:491. K a r n a t h & H u s s a i n : T h y r o i d D y s f u n c t i o n : p p . 4 3 4 8 48 Hospital Physician October 2006 www.turner-white.com levels of thyroid-binding globulin, leading to altered
findings on thyroid function tests. A full discussion
of all medications that effect thyroid function is be-
yond the scope of this article. However, 2 medications,
lithium and amiodarone, require special attention as
they both can cause hyperthyroidism and hypothyroid-
ism through complex effects on the thyroid gland. 23 Lithium is frequently used in the treatment of bipolar
manic-depressive disorder. This drug inhibits thyroid
hormone release and has been associated with the
development of goiter as the normal thyroid gland at-
tempts overcome this effect. Lithium generally causes
hypothyroidism but rarely can cause thyrotoxicosis.
Amiodarone is a commonly used antiarrhythmic drug
with a high iodine content. Amiodarone can cause thy-
rotoxicosis via an iodine-induced increase of thyroid
hormone synthesis (type 1) or cytotoxic damage of
the thyroid gland (type 2). Amiodarone can also cause
hypothyroidism. ConCLusion Thyroid disease can mimic a variety of common com- plaints. Early detection of thyroid disease is important
to prevent progression to life-threatening manifesta-
tions that include thyroid storm and myxedema coma.
TSH serum concentration is the initial test of choice
for evaluating thyroid function. RAIU scans are used
to differentiate among the types of thyrotoxicosis. Sub-
clinical hypothyroidism is quite common, and an expert
group recently has recommended routine screening for
subclinical thyroid dysfunction in adults. Because the
symptoms and signs of hypothyroidism can be subtle,
clinicians cannot rely exclusively on physical examina-
tion to confirm or rule out hypothyroidism. Hp rEfErEnCEs 1. Supit EJ, Peiris AN. Interpretation of laboratory thyroid function tests for the primary care physician. South Med
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3. Weetman AP. Graves disease. N Engl J Med 2000;343: 123648. 4. Trivalle C, Doucet J, Chassagne P, et al. Differences in the signs and symptoms of hyperthyroidism in older and
younger patients. J Am Geriatr Soc 1996;44:503. 5. Nordyke RA, Gilbert FI Jr, Harada AS. Graves disease. Influence of age on clinical findings. Arch Intern Med
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(Oxf) 1985;22:5837. 12. Diez JJ. Hyperthyroidism in patients older than 55 years: an analysis of the etiology and management. Gerontol-
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J Fam Pract 2004;53:6535. 17. Gharib H, Tuttle RM, Baskin HJ, et al. Subclinical thy- roid dysfunction: a joint statement of management from
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the American Thyroid Association, and the Endocrine
Society. J Clin Endocrinol Metab 2005;90:5817. 18. Indra R, Patil SS, Joshi R, et al. Accuracy of physical examination in the diagnosis of hypothyroidism: a cross-
sectional, double-blind study. J Postgrad Med 2004;50:
711. 19. Felz MW, Forren AC. Profound hypothyroidisma clini- cal review with eight recent cases: is it right before our
eyes? South Med J 2004;97:4908. 20. Cakir M, Samanci N, Balci N, Balci MK. Musculoskeletal manifestations in patients with thyroid disease. Clin En-
docrinol (Oxf) 2003;59:1627. 21. Umpierrez GE. Euthyroid sick syndrome. South Med J 2002;95:50613. 22. Tan JY, Loh KC, Yeo GS, Chee YC. Transient hyperthyroid- ism of hyperemesis gravidarum. BJOG 2002;109:6838. 23. Dickstein G, Shechner C, Adawi F, et al. Lithium treat- ment in amiodarone-induced thyrotoxicosis. Am J Med
1997;102:4548. Copyright 2006 by Turner White Communications Inc., Wayne, PA. All rights reserved.