Thyroid Function and Disease

1
Thyroid Functionand Disease
Sponsored by ACCESS Medical Group Department of
Continuing Medical Education Funded by an
unrestricted educational grant from Abbott
Laboratories.
2
The Thyroid Gland and Thyroid Hormones
3
Anatomy of the Thyroid Gland
4
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)

5
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

6
Thyroid-Stimulating Hormone (TSH)

• Regulates thyroid hormone production, secretion,
  and growth
• Is regulated by the negative feedback action of
  T4 and T3

7
Hypothalamic-Pituitary-Thyroid AxisNegative
Feedback Mechanism
8
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

9
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

10
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

11
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

12
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

13
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

14
Proteolysis of Tg With Release ofT4 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

15
Conversion of T4 to T3 in Peripheral Tissues
16
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

17
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

18
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

19
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)

20
Hormonal Transport
21
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

22
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

23
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

24
Drugs and Conditions That Increase Serum T4 and
T3 Levels by Increasing TBG

• Drugs that increase TBG
• Oral contraceptives and other sources of estrogen
• Methadone
• Clofibrate
• 5-Fluorouracil
• Heroin
• Tamoxifen

• Conditions that increase TBG
• Pregnancy
• Infectious/chronic active hepatitis
• HIV infection
• Biliary cirrhosis
• Acute intermittent porphyria
• Genetic factors

25
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,
  carbama-zepine
• Furosemide

• Conditions that decrease serum T4 and T3
• Genetic factors
• Acute and chronic illness

26
Thyroid Hormone Action
27
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

28
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

29
Thyroid Hormone Influences Cardiovascular
Hemodynamics
Thyroid hormone Mediated Thermogenesis (Peripheral
Tissues)
Local Vasodilitation
Release Metabolic Endproducts
Decreased Systemic Vascular Resistance
T3
Elevated Blood Volume
Decreased Diastolic Blood Pressure
Cardiac Chronotropy and Inotropy
Increased Cardiac Output
Laragh JH, et al. Endocrine Mechanisms in
Hypertension. Vol. 2. New York, NY Raven
Press1989.
30
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.
200090065-76. Glinoer D. Trends Endocrinol
Metab. 1998 9403-411. Glinoer D. Endocr Rev.
199718404-433.
31
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

32
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

33
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

34
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

35
Thyroid Disorders
36
Overview of Thyroid Disease States

• Hypothyroidism
• Hyperthyroidism

37
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

38
Hyperthyroidism

• Hyperthyroidism refers to excess synthesis and
  secretion of thyroid hormones by the thyroid
  gland, which results in accelerated metabolism in
  peripheral tissues

39
Typical Thyroid Hormone Levels in Thyroid Disease

• TSH T4 T3
• Hypothyroidism High Low Low
• Hyperthyroidism Low High High

40
Prevalence of Thyroid Disease
The Colorado Study
At a statewide health fair in Colorado (N25
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 gt5.1 ?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.
2000160523-534.
41
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 F
emale 4 5 6.5 9 13.5 15 21

• Canaris GJ, et al. Arch Intern Med.
  2000160523-534.

42
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

43
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

44
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
  pituitaryie, 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 853631-3635.
45
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

46
Clinical Features of Hypothyroidism
Tiredness
Puffy Eyes
Enlarged Thyroid (Goiter)
Forgetfulness/Slower Thinking
Moodiness/ Irritability
Hoarseness/Deepening of Voice
Depression
Persistent Dry or Sore Throat
Inability to Concentrate
Thinning Hair/Hair Loss
Difficulty Swallowing
Loss of Body Hair
Slower Heartbeat
Dry, Patchy Skin
Menstrual Irregularities/Heavy Period
Weight Gain
Infertility
Cold Intolerance
Constipation
Elevated Cholesterol
Muscle Weakness/Cramps
Family History of Thyroid Disease or Diabetes
47
Mild Thyroid Failure
48
Definition of Mild Thyroid Failure

• Elevated TSH level (gt4.0 ?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.
2001864585-4590. Braverman LE, Utiger RD, eds.
The Thyroid A Fundamental and Clinical Text. 8th
ed. Philadelphia, Pa Lippincott, Williams
Wilkins 20001001.
49
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. 2002137904-914.
50
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.
2001864585-4590. Caraccio N, et al. J Clin
Endocrinol Metab. 2002871533-1538. Biondi B, et
al. Ann Intern Med. 2002137904-914.
51
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.
2002871533-1538. Carmel R, et al. Arch Intern
Med. 19821421465-1469. Perros P, et al.
Diabetes Med. 199512622-627.
52
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.
2001864585-4590. Braverman LE, Utiger RD, eds.
The Thyroid A Fundamental and Clinical Text. 8th
ed. Philadelphia, Pa Lippincott, Williams
Wilkins 20001004.
53
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

54
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

55
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. 2000132270-278.
56
Mild Thyroid Failure Associated With Aortic
Atherosclerosis
Presence of Aortic Atherosclerosis
Condition Present
100
Condition Absent
Patients,
50
0
Euthyroid Women Without Antibodies to Thyroid
Peroxidase
Women With Mild Thyroid Failure
Euthyroid Women
Women With Mild Thyroid Failure and Antibodies to
Thyroid Peroxidase
Hak AE, et al. Ann Intern Med. 2000132270-278.
57
Relationship Between Thyroid Hormone and LDL
Receptors

• Low-density lipoprotein (LDL) specifically binds
  and transports lt1 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

58
Colorado Study Cholesterol End Points

• Treating mild thyroid failure may aid in the
  treatment of hyperlipidemia and prevent
  associated cardiovascularmorbidity
• As TSH levels rise, cholesterol levels rise
  concomitantly

Mean Cholesterol by TSH
280
Abnormal TSH
270
267
270
Euthyroid
260
250
Mean Total Cholesterol (mg/dL)
239
238
240
229
226
230
223
216
220
209
210
200
lt0.3
0.3-5.1
gt5.1-
gt10-15
gt15-20
gt20-40
gt40-60
gt60-80
gt80
10
TSH (?IU/mL)
Canaris GJ, et al. Arch Intern Med.2000160526-53
4.
59
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 ?IU/mL)
• Third Normal High
  Treat with (gt10 ?IU/mL) LT4
• Fourth Low High Uniform
• (gt10 ?IU/mL) Treat with LT4

Treat if patient falls into predefined
categories.
Chu J, et al. J Clin Endocrinol Metab.
2001864591-4599.
60
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

61
Disorders Characterized by Hyperthyroidism
62
Signs and Symptoms of Hyperthyroidism
Hoarseness/Deepening of Voice
Nervousness/Tremor
Mental Disturbances/ Irritability
Persistent Dry or Sore Throat
Difficulty Swallowing
Difficulty Sleeping
Palpitations/Tachycardia
Bulging Eyes/Unblinking Stare/ Vision Changes
Impaired Fertility
Enlarged Thyroid (Goiter)
Weight Loss or Gain
Menstrual Irregularities/Light Period
Heat Intolerance
Increased Sweating
Frequent Bowel Movements
Sudden Paralysis
Warm, Moist Palms
Family History ofThyroid Diseaseor Diabetes
First-Trimester Miscarriage/ Excessive Vomiting
in Pregnancy
63
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

64
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

65
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

66
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

67
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

68
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)

69
Association Between Goiters, Thyroid Nodules, and
Thyroid Carcinoma

• Risk factors for carcinoma associated with
  presence of thyroid nodules
• Solitary thyroid nodules in patients gt60 or lt30
  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