Thyroid Functionand 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 AxisNegative 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 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

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– 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

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

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

Local

Vasodilitation

Decreased Systemic Vascular

Resistance

Decreased Diastolic Blood

Pressure

Cardiac Chronotropy and

Inotropy

Increased Cardiac Output

Elevated Blood Volume

T3

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 multiplecauses 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

• 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

The Colorado Study

Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.

Prevalence of Thyroid Disease

At a statewide health fair in Colorado (N=25 862), participants were tested for TSH and total T4 levels

Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.

Prevalence of Thyroid Disease by 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

• The incidence of thyroid disease increases with age

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

Tiredness

Forgetfulness/Slower Thinking

Moodiness/ Irritability

Depression

Inability to Concentrate

Thinning Hair/Hair Loss

Loss of Body Hair

Dry, Patchy Skin

Weight Gain

Cold Intolerance

Elevated Cholesterol

Family History of Thyroid Disease or

Diabetes

Muscle Weakness/

Cramps

Constipation

Infertility

Menstrual Irregularities/

Heavy Period

Slower Heartbeat

Difficulty Swallowing

Persistent Dry or Sore Throat

Hoarseness/

Deepening of Voice

Enlarged Thyroid (Goiter)

Puffy Eyes

Clinical Features of Hypothyroidism

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 AtherosclerosisPresence of Aortic Atherosclerosis

Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Women With Mild Thyroid

Failure

Euthyroid

Women

Women With Mild Thyroid

Failure and Antibodies to Thyroid

Peroxidase

Euthyroid Women Without

Antibodies to Thyroid

Peroxidase

0

50

100

Pat

ient

s, %

Condition Present

Condition Absent

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

Treating mild thyroid failure may aid in the treatment of hyperlipidemia and prevent associated cardiovascularmorbidity

• As TSH levels rise, cholesterol levels rise concomitantly

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

Mea

n T

ota

l C

ho

lest

ero

l (m

g/d

L)

TSH (IU/mL)

Mean Cholesterol by TSH

Colorado Study Cholesterol End Points

Euthyroid

Abnormal TSH

209

229238 239

223

270 267

216

226

200

210220

230

240

250260

270

280

<0.3 0.3-5.1 >5.1-10

>10-15 >15-20 >20-40 >40-60 >60-80 >80

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(>10 IU/mL) LT4*

Fourth Low High Uniform: (>10 IU/mL) Treat with LT4

Chu J, et al. J Clin Endocrinol Metab. 2001;86:4591-4599.

* Treat if patient falls into predefined categories.

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

Nervousness/Tremor

Mental Disturbances/ Irritability

Difficulty Sleeping

Bulging Eyes/Unblinking Stare/ Vision

Changes

Enlarged Thyroid (Goiter)

Menstrual Irregularities/

Light Period

Frequent Bowel Movements

Warm, Moist Palms

First-Trimester Miscarriage/

Excessive Vomiting in Pregnancy

Hoarseness/

Deepening of Voice

Persistent Dry or Sore Throat

Difficulty Swallowing

Palpitations/

Tachycardia

Impaired Fertility

Weight Loss or Gain

Heat Intolerance

Increased Sweating

Family History of

Thyroid Disease

or Diabetes

Signs and Symptoms of Hyperthyroidism

Sudden Paralysis

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