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Thyroid Function
and Disease
Sponsored by
ACCESS Medical Group
Department of Continuing Medical Education
Funded by an unrestricted educational grant from Abbott Laboratories.
The Thyroid Gland and
Thyroid Hormones
Anatomy of the Thyroid Gland
Follicles: the Functional Units of
the Thyroid Gland
Follicles Are the Sites
Where Key Thyroid
Elements Function:
• Thyroglobulin (Tg)
• Tyrosine
• Iodine
• Thyroxine (T4)
• Triiodotyrosine (T3)
The Thyroid Produces and
Secretes 2 Metabolic Hormones
• Two principal hormones
– Thyroxine (T4 ) and triiodothyronine (T3)
• Required for homeostasis of all cells
• Influence cell differentiation, growth, and
metabolism
• Considered the major metabolic hormones
because they target virtually every tissue
Thyroid-Stimulating Hormone
(TSH)
• Regulates thyroid hormone
production, secretion, and growth
• Is regulated by the negative feedback
action of T4 and T3
Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism
Biosynthesis of T4 and T3
The process includes
• Dietary iodine (I) ingestion
• Active transport and uptake of iodide (I-) by
thyroid gland
• Oxidation of I- and iodination of thyroglobulin
(Tg) tyrosine residues
• Coupling of iodotyrosine residues (MIT and
DIT) to form T4 and T3
• Proteolysis of Tg with release of T4 and T3 into
the circulation
Iodine Sources
• Available through certain foods (eg,
seafood, bread, dairy products),
iodized salt, or dietary supplements,
as a trace mineral
• The recommended minimum intake is
150 g/day
Active Transport and I- Uptake by
the Thyroid
•
•
•
Dietary iodine reaches the circulation
as iodide anion (I-)
The thyroid gland transports I- to the
sites of hormone synthesis
I- accumulation in the thyroid is an
active transport process that is
stimulated by TSH
Iodide Active Transport is Mediated by the
Sodium-Iodide Symporter (NIS)
•
NIS is a membrane protein that mediates
active iodide uptake by the thyroid
– It functions as a I- concentrating mechanism
that enables I- to enter the thyroid for
hormone biosynthesis
•
•
NIS confers basal cell membranes of thyroid
follicular cells with the ability to effect “iodide
trapping” by an active transport mechanism
Specialized system assures that adequate
dietary I- accumulates in the follicles and
becomes available for T4 and T3 biosynthesis
Oxidation of I- and Iodination of
Thyroglobulin (Tg) Tyrosyl Residues
• I- must be oxidized to be able to
iodinate tyrosyl residues of Tg
• Iodination of the tyrosyl residues then
forms monoiodotyrosine (MIT) and
diiodotyrosine (DIT), which are then
coupled to form either T3 or T4
• Both reactions are catalyzed by TPO
Thyroperoxidase (TPO)
• TPO catalyzes the oxidation steps
involved in I- activation, iodination of Tg
tyrosyl residues, and coupling of
iodotyrosyl residues
• TPO has binding sites for I- and tyrosine
• TPO uses H2O2 as the oxidant to activate
I- to hypoiodate (OI-), the iodinating
species
Proteolysis of Tg With Release of
T4 and T3
• T4 and T3 are synthesized and stored within the Tg
molecule
• Proteolysis is an essential step for releasing the
hormones
• To liberate T4 and T3, Tg is resorbed into the
follicular cells in the form of colloid droplets, which
fuse with lysosomes to form phagolysosomes
• Tg is then hydrolyzed to T4 and T3, which are then
secreted into the circulation
Conversion of T4 to T3 in
Peripheral Tissues
Production of T4 and T3
• T4 is the primary secretory product of the
thyroid gland, which is the only source of T4
• The thyroid secretes approximately 70-90 g
of T4 per day
• T3 is derived from 2 processes
– The total daily production rate of T3 is about
15-30 g
– About 80% of circulating T3 comes from
deiodination of T4 in peripheral tissues
– About 20% comes from direct thyroid secretion
T4: A Prohormone for T3
• T4 is biologically inactive in target
tissues until converted to T3
– Activation occurs with 5' iodination of the
outer ring of T4
• T3 then becomes the biologically
active hormone responsible for the
majority of thyroid hormone effects
Sites of T4 Conversion
• The liver is the major extrathyroidal T4
conversion site for production of T3
• Some T4 to T3 conversion also occurs
in the kidney and other tissues
T4 Disposition
• Normal disposition of T4
– About 41% is converted to T3
– 38% is converted to reverse T3 (rT3), which is
metabolically inactive
– 21% is metabolized via other pathways, such as
conjugation in the liver and excretion in the bile
• Normal circulating concentrations
– T4 4.5-11 g/dL
– T3 60-180 ng/dL (~100-fold less than T4)
Hormonal Transport
Carriers for Circulating Thyroid
Hormones
• More than 99% of circulating T4 and T3 is
bound to plasma carrier proteins
– Thyroxine-binding globulin (TBG), binds about 75%
– Transthyretin (TTR), also called thyroxine-binding
prealbumin (TBPA), binds about 10%-15%
– Albumin binds about 7%
– High-density lipoproteins (HDL), binds about 3%
• Carrier proteins can be affected by physiologic
changes, drugs, and disease
Free Hormone Concept
• Only unbound (free) hormone has metabolic
activity and physiologic effects
– Free hormone is a tiny percentage of total
hormone in plasma (about 0.03% T4; 0.3% T3)
• Total hormone concentration
– Normally is kept proportional to the concentration
of carrier proteins
– Is kept appropriate to maintain a constant free
hormone level
Changes in TBG Concentration Determine
Binding and Influence T4 and T3 Levels
• Increased TBG
– Total serum T4 and T3 levels increase
– Free T4 (FT4), and free T3 (FT3) concentrations
remain unchanged
• Decreased TBG
– Total serum T4 and T3 levels decrease
– FT4 and FT3 levels remain unchanged
Drugs and Conditions That Increase Serum
T4 and T3 Levels by Increasing TBG
• Drugs that increase TBG • Conditions that increase
TBG
– Oral contraceptives and
–
–
–
–
–
other sources of estrogen
Methadone
Clofibrate
5-Fluorouracil
Heroin
Tamoxifen
– Pregnancy
– Infectious/chronic active
hepatitis
– HIV infection
– Biliary cirrhosis
– Acute intermittent
porphyria
– Genetic factors
Drugs and Conditions That Decrease Serum T4 and
T3 by Decreasing TBG Levels or Binding of
Hormone to TBG
• Drugs that decrease
serum T4 and T3
–
–
–
–
–
–
Glucocorticoids
Androgens
L-Asparaginase
Salicylates
Mefenamic acid
Antiseizure medications,
eg, phenytoin, carbamazepine
– Furosemide
• Conditions that decrease
serum T4 and T3
– Genetic factors
– Acute and chronic illness
Thyroid Hormone Action
Thyroid Hormone Plays a Major Role
in Growth and Development
• Thyroid hormone initiates or sustains
differentiation and growth
– Stimulates formation of proteins, which exert
trophic effects on tissues
– Is essential for normal brain development
• Essential for childhood growth
– Untreated congenital hypothyroidism or chronic
hypothyroidism during childhood can result in
incomplete development and mental retardation
Thyroid Hormones and the Central
Nervous System (CNS)
• Thyroid hormones are essential for neural
development and maturation and function
of the CNS
• Decreased thyroid hormone concentrations
may lead to alterations in cognitive function
– Patients with hypothyroidism may develop
impairment of attention, slowed motor function,
and poor memory
– Thyroid-replacement therapy may improve
cognitive function when hypothyroidism is
present
Thyroid Hormone Influences
Cardiovascular Hemodynamics
Thyroid hormone
Mediated Thermogenesis
(Peripheral Tissues)
Release Metabolic
Endproducts
T3
Elevated Blood
Volume
Increased
Cardiac Output
Cardiac
Chronotropy and
Inotropy
Local
Vasodilitation
Decreased
Systemic
Vascular
Resistance
Decreased
Diastolic Blood
Pressure
Laragh JH, et al. Endocrine Mechanisms in Hypertension.
Vol. 2. New York, NY: Raven Press;1989.
Thyroid Hormone Influences the
Female Reproductive System
• Normal thyroid hormone function is
important for reproductive function
– Hypothyroidism may be associated
with menstrual disorders, infertility,
risk of miscarriage, and other
complications of pregnancy
Doufas AG, et al. Ann N Y Acad Sci. 2000;900:65-76.
Glinoer D. Trends Endocrinol Metab. 1998; 9:403-411.
Glinoer D. Endocr Rev. 1997;18:404-433.
Thyroid Hormone is Critical for Normal
Bone Growth and Development
• T3 is an important regulator of skeletal
maturation at the growth plate
– T3 regulates the expression of factors and other
contributors to linear growth directly in the growth
plate
– T3 also may participate in osteoblast differentiation
and proliferation, and chondrocyte maturation
leading to bone ossification
Thyroid Hormone Regulates
Mitochondrial Activity
• T3 is considered the major regulator of
mitochondrial activity
– A potent T3-dependent transcription factor of the
mitochondrial genome induces early stimulation of
transcription and increases transcription factor
(TFA) expression
– T3 stimulates oxygen consumption by the
mitochondria
Thyroid Hormones Stimulate
Metabolic Activities in Most Tissues
• Thyroid hormones (specifically T3) regulate
rate of overall body metabolism
– T3 increases basal metabolic rate
• Calorigenic effects
– T3 increases oxygen consumption by most
peripheral tissues
– Increases body heat production
Metabolic Effects of T3
• Stimulates lipolysis and release of free fatty acids
and glycerol
• Induces expression of lipogenic enzymes
• Effects cholesterol metabolism
• Stimulates metabolism of cholesterol to bile acids
• Facilitates rapid removal of LDL from plasma
• Generally stimulates all aspects of carbohydrate
metabolism and the pathway for protein degradation
Thyroid Disorders
Overview of Thyroid Disease States
• Hypothyroidism
• Hyperthyroidism
Hypothyroidism
• Hypothyroidism is a disorder with multiple
causes in which the thyroid fails to
secrete an adequate amount of thyroid
hormone
– The most common thyroid disorder
– Usually caused by primary thyroid gland failure
– Also may result from diminished stimulation of the
thyroid gland by TSH
Hyperthyroidism
• Hyperthyroidism refers to excess synthesis
and secretion of thyroid hormones by the
thyroid gland, which results in accelerated
metabolism in peripheral tissues
Typical Thyroid Hormone Levels
in Thyroid Disease
TSH
T4
T3
Hypothyroidism
High
Low
Low
Hyperthyroidism
Low
High
High
Prevalence of Thyroid Disease
The Colorado Study
At a statewide health fair in Colorado (N=25 862), participants
were tested for TSH and total T4 levels
• 9.5% of subjects had elevated TSH; most of them had subclinical
hypothyroidism (normal T4 with TSH >5.1 IU/mL)
• Among the subjects already taking thyroid medication (almost 6%
of study population), 40% had abnormal TSH levels, reflecting
inadequate treatment
• Among those not taking thyroid medication, 9.9% had a thyroid
abnormality that was unrecognized
• There may be in excess of 13 million cases of undetected thyroid
failure nationwide
Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.
Prevalence of Thyroid
Disease by Age
• The incidence of thyroid disease increases with age
Elevated TSH, %
(Age in Years)
Male
18
25
35
45
55
65
75
3
4.5
3.5
5
6
10.5
16
5
6.5
9
13.5
15
21
Female 4
Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.
Prevalence of Thyroid Disease
by Gender
• Studies conducted in various communities over the
past 30 years have consistently concluded that thyroid
disease is more prevalent in women than in men
– The Whickham survey, conducted in the 1970s and later
followed-up in 1995, showed the prevalence of undiagnosed
thyrotoxicosis was 4.7 per 1000 women and 1.6 to 2.3 per
1000 men
– The Framingham study data showed the incidence of thyroid
deficiency in women was 5.9% and in men, 2.3%
– The Colorado study concluded that the proportion of subjects
with an elevated TSH level is greater among women than
among men
Increasing Prevalence of Thyroid
Disease in the US Population
National Health and Nutrition Examination
Surveys (NHANES I and III)
• Monitored the status of thyroid function in a sample
of individuals representing the ethnic and
geographic distribution of the US population
• NHANES III measured serum TSH, total serum T4,
and thyroid antibodies to thyroglobulin (TgAb) and
to thyroperoxidase (TPOAb)
• Hypothyroidism was found in 4.6%; of those, 4.3%
had mild thyroid failure
• Hyperthyroidism was found in 1.3%
Hypothyroidism: Types
• Primary hypothyroidism
– From thyroid destruction
• Central or secondary hypothyroidism
– From deficient TSH secretion, generally due to sellar
lesions such as pituitary tumor or craniopharyngioma
– Infrequently is congenital
• Central or tertiary hypothyroidism
– From deficient TSH stimulation above level of pituitary—ie,
lesions of pituitary stalk or hypothalamus
– Is much less common than secondary hypothyroidism
Bravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid.
8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.
Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.
Primary Hypothyroidism:
Underlying Causes
• Congenital hypothyroidism
– Agenesis of thyroid
– Defective thyroid hormone biosynthesis due to enzymatic defect
• Thyroid tissue destruction as a result of
–
–
–
–
Chronic autoimmune (Hashimoto) thyroiditis
Radiation (usually radioactive iodine treatment for thyrotoxicosis)
Thyroidectomy
Other infiltrative diseases of thyroid (eg, hemochromatosis)
• Drugs with antithyroid actions (eg, lithium, iodine, iodinecontaining drugs, radiographic contrast agents, interferon
alpha)
• In the US, hypothyroidism is usually due to chronic
autoimmune (Hashimoto) thyroiditis
Clinical Features of
Hypothyroidism
Tiredness
Puffy Eyes
Forgetfulness/Slower Thinking
Enlarged Thyroid (Goiter)
Moodiness/ Irritability
Hoarseness/
Deepening of Voice
Depression
Inability to Concentrate
Persistent Dry or Sore Throat
Thinning Hair/Hair Loss
Difficulty Swallowing
Loss of Body Hair
Slower Heartbeat
Dry, Patchy Skin
Menstrual Irregularities/
Heavy Period
Weight Gain
Cold Intolerance
Infertility
Elevated Cholesterol
Constipation
Family History of Thyroid
Disease or Diabetes
Muscle Weakness/
Cramps
Mild Thyroid Failure
Definition of Mild Thyroid Failure
• Elevated TSH level
(>4.0 IU/mL)
• Normal total or free serum T4
and T3 levels
• Few or no signs or symptoms of
hypothyroidism
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed.
Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000;1001.
Causes of Mild Thyroid Failure
• Exogenous factors
– Levothyroxine underreplacement
– Medications, such as lithium, cytokines, or
iodine-containing agents (eg, amiodarone)
– Antithyroid medications
– 131I therapy or thyroidectomy
• Endogenous factors
– Previous subacute or silent thyroiditis
– Hashimoto thyroiditis
Biondi B, et al. Ann Intern Med. 2002;137:904-914.
Prevalence and Incidence of Mild
Thyroid Failure
• Prevalence
– 4% to 10% in large population screening surveys
– Increases with increasing age
– Is more common in women than in men
• Incidence
– 2.1% to 3.8% per year in thyroid antibody-positive
patients
– 0.3% per year in thyroid antibody-negative patients
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.
Biondi B, et al. Ann Intern Med. 2002;137:904-914.
Populations at Risk for
Mild Thyroid Failure
• Women
• Prior history of Graves disease or
postpartum thyroid dysfunction
• Elderly
• Other autoimmune disease
• Family history of
– Thyroid disease
– Pernicious anemia
– Type 1 Diabetes mellitus
Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.
Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.
Perros P, et al. Diabetes Med. 1995;12:622-627.
Mild Thyroid Failure Affects
Cardiac Function
• Cardiac function is subtly impaired in patients
with mild thyroid failure
• Abnormalities can include
– Subtle abnormalities in systolic time intervals and
myocardial contractility
– Diastolic dysfunction at rest or with exercise
– Reduction of exercise-related stroke volume,
cardiac index, and maximal aortic flow velocity
• The clinical significance of the changes is
unclear
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and
Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams &
Wilkins; 2000:1004.
Mild Thyroid Failure May Increase
Cardiovascular Disease Risk
• Mild thyroid failure has been evaluated as a
cardiovascular risk factor associated with
– Increased serum levels of total cholesterol and
low-density lipoprotein cholesterol (LDL-C) levels
– Reduced high-density lipoprotein cholesterol
(HDL-C) levels
– Increased prevalence of aortic atherosclerosis
– Increased incidence of myocardial infarction
The Rotterdam Study
Design and Objectives
• A population-based cross-sectional cohort study
conducted in a district of Rotterdam, the
Netherlands
– Cohort included 3105 men and 4878 women aged 55
and older
– Thyroid status was determined from a random sample
of 1149 elderly women (mean age 69 ± 7.5 years)
selected from the study
• The study's objective was to investigate whether
mild thyroid failure and thyroid autoimmunity are
associated with aortic atherosclerosis and
myocardial infarction
Mild Thyroid Failure Increases Risk
of Myocardial Infarction (MI)
• Findings from the Rotterdam Study
– Mild thyroid failure contributed to 60% of MI cases
in patients with diagnosed mild thyroid failure, and
14% of all MI instances in the study population
– Mild thyroid failure appeared to be a strong
indicator of risk for aortic atherosclerosis and MI
in older women
– Thyroid autoimmunity by itself was not associated
with aortic atherosclerosis or MI
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Mild Thyroid Failure Associated With
Aortic Atherosclerosis
Patients, %
100
Presence of Aortic Atherosclerosis
Condition Present
Condition Absent
50
0
Women With
Mild Thyroid
Failure
Euthyroid
Women
Women
With Mild
Thyroid
Failure and
Antibodies
to Thyroid
Peroxidase
Euthyroid
Women
Without
Antibodies to
Thyroid
Peroxidase
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Relationship Between Thyroid
Hormone and LDL Receptors
• Low-density lipoprotein (LDL) specifically binds
and transports <1% of total circulating T4
– LDL facilitates entry of T4 into cells by forming a T4LDL complex that is recognized by the LDL receptor
– LDL receptors are down-regulated by cholesterol
loading and up-regulated by cholesterol deficiency
• Hypothyroidism is usually accompanied by
elevated total- and LDL-cholesterol caused by
increased cholesterol synthesis
Colorado Study
Cholesterol End Points
Treating mild thyroid failure may aid in the treatment of
hyperlipidemia and prevent associated cardiovascular
morbidity
• As TSH levels rise, cholesterol levels rise concomitantly
Mean Total
Cholesterol (mg/dL)
Mean Cholesterol by TSH
280
270
260
250
240
230
220
210
200
270
Abnormal TSH
267
Euthyroid
238
216
223
226
239
229
209
<0.3 0.3-5.1 >5.1- >10-15 >15-20 >20-40 >40-60 >60-80 >80
10
TSH (IU/mL)
Canaris GJ, et al. Arch Intern Med.2000;160:526-534.
Four Stages in the Development of
Hypothyroidism
Stage
FT4
Earliest
Normal
Second
Normal
Consensus
for Treatment
FT3
Within population
reference range
High
None
Controversial
(5-10 IU/mL)
Third
Fourth
Normal
High
(>10 IU/mL)
Low
Treat with
LT4*
High
(>10 IU/mL)
Uniform:
Treat with LT4
* Treat if patient falls into
predefined categories.
Chu J, et al. J Clin Endocrinol Metab. 2001;86:4591-4599.
The Rate of Progression of Mild Thyroid
Failure to Overt Hypothyroidism
• Mild thyroid failure is a common disorder that
frequently progresses to overt hypothyroidism
– Progression has been reported in about 3% to
18% of affected patients per year
– Progression may take years or may rapidly occur
– The rate is greater if TSH is higher or if there are
positive antithyroid antibodies
– The rate may also be greater in patients who were
previously treated with radioiodine or surgery
Disorders Characterized by
Hyperthyroidism
Signs and Symptoms of
Hyperthyroidism
Nervousness/Tremor
Mental Disturbances/
Irritability
Hoarseness/
Deepening of Voice
Persistent Dry or Sore Throat
Difficulty Swallowing
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/
Vision Changes
Enlarged Thyroid (Goiter)
Menstrual Irregularities/
Light Period
Palpitations/
Tachycardia
Impaired Fertility
Weight Loss or Gain
Heat Intolerance
Increased Sweating
Frequent Bowel Movements
Warm, Moist Palms
First-Trimester Miscarriage/
Excessive Vomiting in Pregnancy
Sudden Paralysis
Family History of
Thyroid Disease
or Diabetes
Hyperthyroidism
Underlying Causes
• Signs and symptoms can be caused by any
disorder that results in an increase in circulation
of thyroid hormone
–
–
–
–
–
–
Toxic diffuse goiter (Graves disease)
Toxic uninodular or multinodular goiter
Painful subacute thyroiditis
Silent thyroiditis
Toxic adenoma
Iodine and iodine-containing drugs and radiographic
contrast agents
– Trophoblastic disease, including hydatidiform mole
– Exogenous thyroid hormone ingestion
Graves Disease
(Toxic Diffuse Goiter)
• The most common cause of hyperthyroidism
– Accounts for 60% to 90% of cases
– Incidence in the United States estimated at 0.02%
to 0.4% of the population
– Affects more females than males, especially in the
reproductive age range
• Graves disease is an autoimmune disorder
possibly related to a defect in immune
tolerance
Chronic Autoimmune Thyroiditis
(Hashimoto Thyroiditis)
• Occurs when there is a severe defect in thyroid
hormone synthesis
– Is a chronic inflammatory autoimmune disease characterized
by destruction of the thyroid gland by autoantibodies against
thyroglobulin, thyroperoxidase, and other thyroid tissue
components
– Patients present with hypothyroidism, painless goiter, and
other overt signs
• Persons with autoimmune thyroid disease may have
other concomitant autoimmune disorders
– Most commonly associated with type 1 diabetes mellitus
Thyroid Nodular Disease
• Thyroid gland nodules are common in the
general population
• Palpable nodules occur in approximately 5%
of the US population, mainly in women
• Most thyroid nodules are benign
– Less than 5% are malignant
– Only 8% to 10% of patients with thyroid nodules
have thyroid cancer
Multinodular Goiter (MNG)
• MNG is an enlarged thyroid gland containing
multiple nodules
– The thyroid gland becomes more nodular with
increasing age
– In MNG, nodules typically vary in size
– Most MNGs are asymptomatic
• MNG may be toxic or nontoxic
– Toxic MNG occurs when multiple sites of autonomous
nodule hyperfunction develop, resulting in
thyrotoxicosis
– Toxic MNG is more common in the elderly
Thyroid Carcinoma
• Incidence
– Thyroid carcinoma occurs relatively infrequently compared to
the common occurrence of benign thyroid disease
– Thyroid cancers account for only 0.74% of cancers among
men, and 2.3% of cancers in women in the US
– The annual rate has increased nearly 50% since 1973 to
approximately 18 000 cases
• Thyroid carcinomas (percentage of all US cases)
–
–
–
–
–
–
Papillary (80%)
Follicular (about 10%)
Medullary thyroid (5%-10%)
Anaplastic carcinoma (1%-2%)
Primary thyroid lymphomas (rare)
Metastatic from other primary sites (rare)
Association Between Goiters, Thyroid
Nodules, and Thyroid Carcinoma
• Risk factors for carcinoma associated with
presence of thyroid nodules
– Solitary thyroid nodules in patients >60 or <30 years
of age
– Irradiation of the neck or face during infancy or
teenage years
– Symptoms of pain or pressure (especially a change
in voice)
• Solitary nodules tend to present a higher but
not significantly increased risk of cancer
compared with nodules in multinodular goiters