Thyroid Function


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Thyroid Function

  1. 1. Thyroid Function and Disease Sponsored by ACCESS Medical Group Department of Continuing Medical Education Funded by an unrestricted educational grant from Abbott Laboratories.
  2. 2. The Thyroid Gland and Thyroid Hormones
  3. 3. Anatomy of the Thyroid Gland
  4. 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. 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. 6. Thyroid-Stimulating Hormone (TSH) • Regulates thyroid hormone production, secretion, and growth • Is regulated by the negative feedback action of T4 and T3
  7. 7. Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism
  8. 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. 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. 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. 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. 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. 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. 14. 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
  15. 15. Conversion of T4 to T3 in Peripheral Tissues
  16. 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. 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. 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. 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. 20. Hormonal Transport
  21. 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. 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. 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. 24. 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
  25. 25. 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, phenytoi n, carbama-zepine – Furosemide
  26. 26. Thyroid Hormone Action
  27. 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. 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. 29. 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.
  30. 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. 2000;900:65-76. Glinoer D. Trends Endocrinol Metab. 1998; 9:403-411. Glinoer D. Endocr Rev. 1997;18:404-433.
  31. 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. 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. 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. 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. 35. Thyroid Disorders
  36. 36. Overview of Thyroid Disease States • Hypothyroidism • Hyperthyroidism
  37. 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. 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. 39. Typical Thyroid Hormone Levels in Thyroid Disease TSH T4 T3 Hypothyroidism High Low Low Hyperthyroidism Low High High
  40. 40. Prevalence of Thyroid Disease The Colorado Study At a statewide health fair in Colorado (N=25 862), participants were tested for TSH and total T4 levels • 9.5% of subjects had elevated TSH; most of them had subclinical hypothyroidism (normal T4 with TSH >5.1 IU/mL) • Among the subjects already taking thyroid medication (almost 6% of study population), 40% had abnormal TSH levels, reflecting inadequate treatment • Among those not taking thyroid medication, 9.9% had a thyroid abnormality that was unrecognized • There may be in excess of 13 million cases of undetected thyroid failure nationwide Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.
  41. 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 Female 4 5 6.5 9 13.5 15 21 Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.
  42. 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. 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. 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 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.
  45. 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. 46. Clinical Features of Hypothyroidism Tiredness Puffy Eyes Forgetfulness/Slower Thinking Enlarged Thyroid (Goiter) 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 Elevated Cholesterol Constipation Muscle Weakness/ Family History of Thyroid Cramps Disease or Diabetes
  47. 47. Mild Thyroid Failure
  48. 48. 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.
  49. 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. 2002;137:904-914.
  50. 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. 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.
  51. 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. 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.
  52. 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. 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.
  53. 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. 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. 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. 2000;132:270-278.
  56. 56. 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.
  57. 57. 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
  58. 58. 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 ( IU/mL) Canaris GJ, et al. Arch Intern Med.2000;160:526-534.
  59. 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 (>10 IU/mL) LT4* Fourth Low High Uniform: (>10 IU/mL) Treat with LT4 * Treat if patient falls into predefined categories. Chu J, et al. J Clin Endocrinol Metab. 2001;86:4591-4599.
  60. 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. 61. Disorders Characterized by Hyperthyroidism
  62. 62. Signs and Symptoms of Hyperthyroidism Hoarseness/ Nervousness/Tremor Deepening of Voice Mental Disturbances/ Persistent Dry or Sore Throat Irritability Difficulty Swallowing Difficulty Sleeping Bulging Eyes/Unblinking Stare/ Palpitations/ Vision Changes Tachycardia Enlarged Thyroid (Goiter) Impaired Fertility Weight Loss or Gain Menstrual Irregularities/ Light Period Heat Intolerance Increased Sweating Frequent Bowel Movements Sudden Paralysis Warm, Moist Palms Family History of First-Trimester Miscarriage/ Thyroid Disease Excessive Vomiting in Pregnancy or Diabetes
  63. 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. 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. 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. 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. 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. 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. 69. 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