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 µ 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 µ g of T4
per day
• T3 is derived from 2 processes
– The total daily production rate of T3 is about 15-30 µ 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 µ 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

– Oral contraceptives and TBG
other sources of estrogen – Pregnancy
– Methadone – Infectious/chronic active
– Clofibrate hepatitis
– 5-Fluorouracil – HIV infection
– Heroin – Biliary cirrhosis
– Tamoxifen – 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 • Conditions that decrease

serum T4 and T3 serum T4 and T3
– Glucocorticoids – Genetic factors
– Androgens – Acute and chronic illness
– L-Asparaginase
– Salicylates
– Mefenamic acid
– Antiseizure medications,
eg, phenytoin, carbama-
zepine
– Furosemide
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 Local
Release Metabolic
Mediated Thermogenesis Endproducts Vasodilitation
(Peripheral Tissues)

Decreased
T3 Systemic
Vascular
Elevated Blood Resistance
Volume

Increased Cardiac Decreased

Cardiac Output Chronotropy and Diastolic Blood
Inotropy 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 µ 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)

18 25 35 45 55 65 75
Male 3 4.5 3.5 5 6 10.5 16
Female 4 5 6.5 9 13.5 15 21

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, iodine-
containing drugs, radiographic contrast agents, interferon
alpha)
• In the US, hypothyroidism is usually due to chronic
autoimmune (Hashimoto) thyroiditis
 Clinical Features of
Hypothyroidism
Tiredness PuffyEyes

Forgetfulness/SlowerThinking EnlargedThyroid(Goiter)

Moodiness/ Irritability Hoarseness/

Deepeningof Voice
Depression
Persistent DryorSoreThroat
InabilitytoConcentrate
ThinningHair/HairLoss DifficultySwallowing

Lossof BodyHair SlowerHeartbeat

Dry, PatchySkin Menstrual Irregularities/

HeavyPeriod
Weight Gain Infertility
ColdIntolerance
ElevatedCholesterol Constipation
MuscleWeakness/
FamilyHistoryof ThyroidDiseaseor
Cramps
Diabetes
Mild Thyroid Failure
Definition of Mild Thyroid Failure

• Elevated TSH level

(>4.0 µ 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
Presence of Aortic Atherosclerosis Condition Present
100
Condition Absent
Patients, %

50

0
Women With Euthyroid Women Euthyroid
Mild Thyroid Women With Mild Women
Failure Thyroid Without
Failure and Antibodies to
Antibodies Thyroid
to Thyroid Peroxidase
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 T4-
LDL 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 Cholesterol by TSH
280
Abnormal TSH 270 267
Cholesterol (mg/dL)

270
260 Euthyroid
Mean Total

250
238 239
240
226 229
230 223
220 216
209
210
200
<0.3 0.3-5.1 >5.1- >10-15 >15-20 >20-40 >40-60 >60-80 >80
10
TSH (µ IU/mL)

Canaris GJ, et al. Arch Intern Med.2000;160:526-534.

 Four Stages in the Development of
Hypothyroidism
Consensus
Stage FT4 FT3 for Treatment

Earliest Normal Within population None

reference range

Second Normal High Controversial

(5-10 µ IU/mL)
Third Normal High Treat with
(>10 µ IU/mL) LT4*
Fourth Low High Uniform:
(>10 µ IU/mL) 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
Hoarseness/
Nervousness/Tremor
Deepeningof Voice

Persistent DryorSoreThroat
Mental Disturbances/ Irritability
DifficultySwallowing
DifficultySleeping
BulgingEyes/UnblinkingStare/ Vision Palpitations/

Changes Tachycardia

EnlargedThyroid(Goiter) ImpairedFertility

Menstrual Irregularities/ Weight LossorGain

Heat Intolerance
Light Period
IncreasedSweating
Frequent Bowel Movements
Warm,Moist Palms Sudden Paralysis
FamilyHistoryof
First-TrimesterMiscarriage/
ThyroidDisease
ExcessiveVomitinginPregnancy
orDiabetes
 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