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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) .

growth.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. and metabolism • Considered the major metabolic hormones because they target virtually every tissue .

secretion. and growth • Is regulated by the negative feedback action of T4 and T3 .Thyroid-Stimulating Hormone (TSH) • Regulates thyroid hormone production.

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 .

dairy products). as a trace mineral • The recommended minimum intake is 150 µ g/day . seafood.Iodine Sources • Available through certain foods (eg. iodized salt. or dietary supplements. bread.

Active Transport and I.Uptake by the Thyroid • • • Dietary iodine reaches the circulation as iodide anion (I-) The thyroid gland transports the sites of hormone synthesis I.accumulation in the thyroid is an active transport process that is stimulated by TSH .

accumulates in the follicles and becomes available for T4 and T3 biosynthesis .concentrating mechanism that enables 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.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.

must be oxidized to be able to iodinate tyrosyl residues of Tg • Iodination of the tyrosyl residues then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).and Iodination of Thyroglobulin (Tg) Tyrosyl Residues • I. which are then coupled to form either T3 or T4 • Both reactions are catalyzed by TPO .Oxidation of I.

Thyroperoxidase (TPO) • TPO catalyzes the oxidation steps involved in I. the iodinating species .activation.and tyrosine • TPO uses H2O2 as the oxidant to activate Ito hypoiodate (OI-). and coupling of iodotyrosyl residues • TPO has binding sites for I. iodination of Tg tyrosyl residues.

which are then secreted into the circulation . which fuse with lysosomes to form phagolysosomes • Tg is then hydrolyzed to T4 and T3.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.

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 .

which is metabolically inactive – 21% is metabolized via other pathways.5-11 µ g/dL – T3 60-180 ng/dL (~100-fold less than T4) . such as conjugation in the liver and excretion in the bile • Normal circulating concentrations – T4 4.T4 Disposition • Normal disposition of T4 – About 41% is converted to T3 – 38% is converted to reverse T3 (rT3).

Hormonal Transport .

binds about 3% • Carrier proteins can be affected by physiologic changes. drugs. binds about 75% – Transthyretin (TTR). binds about 10%-15% – Albumin binds about 7% – High-density lipoproteins (HDL). also called thyroxine-binding prealbumin (TBPA).Carriers for Circulating Thyroid Hormones • More than 99% of circulating T4 and T3 is bound to plasma carrier proteins – Thyroxine-binding globulin (TBG). 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 .

and free T3 (FT3) concentrations remain unchanged • Decreased TBG – Total serum T4 and T3 levels decrease – FT4 and FT3 levels remain unchanged .Changes in TBG Concentration Determine Binding and Influence T4 and T3 Levels • Increased TBG – Total serum T4 and T3 levels increase – Free T4 (FT4).

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 Methadone Clofibrate 5-Fluorouracil Heroin Tamoxifen – Pregnancy – Infectious/chronic active hepatitis – HIV infection – Biliary cirrhosis – Acute intermittent porphyria – Genetic factors .

carbamazepine – Furosemide • Conditions that decrease serum T4 and T3 – Genetic factors – Acute and chronic illness . eg.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. phenytoin.

Thyroid Hormone Action .

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 Hormone Plays a Major Role in Growth and Development • Thyroid hormone initiates or sustains differentiation and growth – Stimulates formation of proteins.

slowed motor function. and poor memory – Thyroid-replacement therapy may improve cognitive function when hypothyroidism is present .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.

NY: Raven Press. . Vol. Endocrine Mechanisms in Hypertension. et al.Thyroid Hormone Influences Cardiovascular Hemodynamics Thyroid hormone Mediated Thermogenesis (Peripheral Tissues) Release Metabolic Endproducts Local Vasodilitation T3 Elevated Blood Volume Increased Cardiac Output Cardiac Chronotropy and Inotropy Decreased Systemic Vascular Resistance Decreased Diastolic Blood Pressure Laragh JH.1989. 2. New York.

Glinoer D. Endocr Rev.18:404-433. 2000. Trends Endocrinol Metab. 1997. . Glinoer D. Ann N Y Acad Sci. infertility.900:65-76. and other complications of pregnancy Doufas AG. 1998. et al. risk of miscarriage.Thyroid Hormone Influences the Female Reproductive System • Normal thyroid hormone function is important for reproductive function – Hypothyroidism may be associated with menstrual disorders. 9:403-411.

and chondrocyte maturation leading to bone ossification .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.

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 .

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

Typical Thyroid Hormone Levels in Thyroid Disease TSH Hypothyroidism Hyperthyroidism High Low T4 Low High T3 Low High .

9% had a thyroid abnormality that was unrecognized • There may be in excess of 13 million cases of undetected thyroid failure nationwide Canaris GJ. 40% had abnormal TSH levels. 9. most of them had subclinical hypothyroidism (normal T4 with TSH >5.Prevalence of Thyroid Disease The Colorado Study At a statewide health fair in Colorado (N=25 862). Arch Intern Med. reflecting inadequate treatment • Among those not taking thyroid medication.5% of subjects had elevated TSH. .160:523-534.1 µ IU/mL) • Among the subjects already taking thyroid medication (almost 6% of study population). 2000. participants were tested for TSH and total T4 levels • 9. et al.

% (Age in Years) 18 Male 3 25 4.5 15 75 16 21 Female 4 Canaris GJ. et al. Arch Intern Med. .5 65 10.5 6.Prevalence of Thyroid Disease by Age • The incidence of thyroid disease increases with age Elevated TSH.5 5 35 3.5 45 5 9 55 6 13. 2000.160:523-534.

3 per 1000 men – The Framingham study data showed the incidence of thyroid deficiency in women was 5.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.9% and in men. conducted in the 1970s and later followed-up in 1995.7 per 1000 women and 1. 2.6 to 2.3% – The Colorado study concluded that the proportion of subjects with an elevated TSH level is greater among women than among men . showed the prevalence of undiagnosed thyrotoxicosis was 4.

total serum T4.6%. of those. and thyroid antibodies to thyroglobulin (TgAb) and to thyroperoxidase (TPOAb) • Hypothyroidism was found in 4. 4.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.3% .3% had mild thyroid failure • Hyperthyroidism was found in 1.

lesions of pituitary stalk or hypothalamus – Is much less common than secondary hypothyroidism Bravernan LE. 8th ed.Hypothyroidism: Types • Primary hypothyroidism – From thyroid destruction • Central or secondary hypothyroidism – From deficient TSH secretion. 85:3631-3635. Philadelphia. 2000. . Werner & Ingbar's The Thyroid. eds. et al. 2000. Utiger RE. J Clin Endocrinol Metab. 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. Persani L. Pa: Lippincott Williams & Wilkins.

hypothyroidism is usually due to chronic autoimmune (Hashimoto) thyroiditis . hemochromatosis) • Drugs with antithyroid actions (eg. iodine. radiographic contrast agents. lithium. interferon alpha) • In the US. iodinecontaining drugs.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.

P tc ySin ry a h k Wig t Gin eh a CldIn le n e o to ra c E v te Co s ro le a d h le te l F m H to o T y idD e s o a ily is ry f h ro is a e r D b te ia e s Cn tip tio os a n Ms leWa n s / uc e k es C ms ra p P ffyEe u ys E la e T y id(Gite n rg d h ro o r) Ha e e s o rs n s / De e in o V ic epn g f o e P rs te t D o S reT ro t e is n ry r o h a D u Sa wg iffic lty wllo in S w rH a e t lo e e rtb a Mn tru l Irre u ritie / e s a g la s Ha yP rio ev e d In rtility fe .Clinical Features of Hypothyroidism T d es ire n s F rg tfu e s lo e T in in o e ln s /S wr h k g Mo in s / Irrita ility o d es b Dp s io e re s n In b toCn e tra a ility o c n te T in in Hir/HirL s h n g a a os L s o B d Hir os f o y a D .

Mild Thyroid Failure .

Braverman LE.86:4585-4590. Philadelphia.1001. 2001. et al. J Clin Endocrinol Metab.Definition of Mild Thyroid Failure • Elevated TSH level (>4. The Thyroid: A Fundamental and Clinical Text. eds. Williams & Wilkins. 8th ed. Utiger RD. Pa: Lippincott. 2000.0 µ IU/mL) • Normal total or free serum T4 and T3 levels • Few or no signs or symptoms of hypothyroidism McDermott MT. .

or iodine-containing agents (eg. et al. amiodarone) – Antithyroid medications – 131I therapy or thyroidectomy • Endogenous factors – Previous subacute or silent thyroiditis – Hashimoto thyroiditis Biondi B.137:904-914. 2002. .Causes of Mild Thyroid Failure • Exogenous factors – Levothyroxine underreplacement – Medications. Ann Intern Med. such as lithium. cytokines.

J Clin Endocrinol Metab. Ann Intern Med.137:904-914.87:1533-1538.8% per year in thyroid antibody-positive patients – 0. 2002. et al.3% per year in thyroid antibody-negative patients McDermott MT.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 – 2.86:4585-4590. . 2002. Caraccio N. 2001. Biondi B. et al.1% to 3. et al. J Clin Endocrinol Metab.

Carmel R. Arch Intern Med. et al. Diabetes Med. . 1982.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. 1995. et al. J Clin Endocrinol Metab. 2002. Perros P.142:1465-1469.87:1533-1538. et al.12:622-627.

Pa: Lippincott. J Clin Endocrinol Metab. et al. Williams & Wilkins.86:4585-4590. 2000:1004. Philadelphia. Braverman LE. 8th ed. and maximal aortic flow velocity • The clinical significance of the changes is unclear McDermott MT. . The Thyroid: A Fundamental and Clinical Text. Utiger RD.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. 2001. eds.

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 .

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 . 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.The Rotterdam Study Design and Objectives • A population-based cross-sectional cohort study conducted in a district of Rotterdam.

Ann Intern Med. et al. . 2000.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.132:270-278.

% 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. Ann Intern Med.132:270-278. 2000.Mild Thyroid Failure Associated With Aortic Atherosclerosis 100 Presence of Aortic Atherosclerosis Condition Present Condition Absent Patients. et al. .

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 Cholesterol by TSH
280 270 260 250 240 230 220 210 200 270 267

Mean Total Cholesterol (mg/dL)

A n rml T H bo a S E th ro u y id

238 216 209 223 226 229


<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
Stage Earliest Second Third Fourth FT4

Within population reference range High
(5-10 µ IU/mL)

Consensus for Treatment

Normal Normal Low

Controversial Treat with LT4* Uniform: Treat with LT4


(>10 µ IU/mL)

(>10 µ IU/mL)

* 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 .

ot a s F t-T e te M c rria e irs rims r is a g / Ec s iv V m ginP g a c x e s e o itin re n n y De e in o V ic epn g f o e P rs te t D o S reT ro t e is n ry r o h a D u Sa wg iffic lty wllo in P lp tio s a ita n / T c y a ia a h c rd Ima dF rtility p ire e Wig t L s o Gin e h os r a Ha In le n e e t to ra c In re s dS e tin c a e wa g Sudden Paralysis F m H to o a ily is ry f T y idD e s h ro is a e o D b te r ia e s .Signs and Symptoms of Hyperthyroidism Ha e e s o rs n s / Nrv u n s /T mr e o s e s re o Mn l D tu a c s Irrita ility e ta is rb n e / b D u S e in iffic lty le p g B lg gEe /Ub k gS re V io u in y s n lin in ta / is n Ca g s hne E la e T y id(Gite n rg d h ro o r) Mn tru l Irre u ritie / e s a g la s L h P rio ig t e d F q e t B wl Mv mn re u n o e o e e ts WrmMis P lm a .

including hydatidiform mole – Exogenous thyroid hormone ingestion .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.

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 0.4% 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 .02% to 0.

and other overt signs • Persons with autoimmune thyroid disease may have other concomitant autoimmune disorders – Most commonly associated with type 1 diabetes mellitus . and other thyroid tissue components – Patients present with hypothyroidism. thyroperoxidase. painless goiter.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.

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 .Thyroid Nodular Disease • Thyroid gland nodules are common in the general population • Palpable nodules occur in approximately 5% of the US population.

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.Multinodular Goiter (MNG) • MNG is an enlarged thyroid gland containing multiple nodules – The thyroid gland becomes more nodular with increasing age – In MNG. resulting in thyrotoxicosis – Toxic MNG is more common in the elderly .

and 2.Thyroid Carcinoma • Incidence – Thyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid disease – Thyroid cancers account for only 0.3% 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) .74% of cancers among men.

Thyroid Nodules.Association Between Goiters. 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 .