Pathophysiology of Thyroid Disorders. PHCL 415 Hadeel Alkofide April 2010

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1 Pathophysiology of Thyroid Disorders PHCL 415 Hadeel Alkofide April

2 Learning Objectives Understand the pathophysiology of hyperthyroidism & hypothyroidism Describe the signs & symptoms of hyperthyroidism & hypothyroidism Outline the changes seen in thyroid function tests (free and total triiodothyronine [T3] & thyroxine [T4], force-time integral [FTI] & thyroid-stimulating hormone [TSH]) & the radioactive iodine uptake (RAIU) scan in hyperthyroidism & hypothyroidism 2

3 Outline Introduction Epidemiology Causes/Classification Pathophysiology Manifestations (signs & symptoms) Diagnosis 3

4 Introduction 4

5 Introduction Thyroid Physiology The difference between T3 & T4 Common thyroid disorders 5

6 Thyroid Physiology The thyroid gland synthesizes the hormones thyroxine (T4) & triiodothyronine (T3), iodine-containing amino acids that regulate the body's metabolic rate Adequate levels of thyroid hormone are necessary: Infants for normal development of the CNS Children for normal skeletal growth & maturation Adults for normal function of multiple organ systems 6

7 Thyroid Physiology Triiodothyronine (T3) & thyroxine (T4) are the two biologically active thyroid hormones produced by the thyroid gland in response to hormones released by the pituitary & hypothalamus The hypothalamic thyrotropin-releasing hormone (TRH) stimulates release of thyroid-stimulating hormone [TSH]) from the pituitary in response to low circulating levels of thyroid hormone 7

8 Thyroid Physiology TSH promotes hormone synthesis & release by increasing thyroid activity When sufficient synthesis has occurred, high circulating thyroid hormone levels block further production by inhibiting TSH release As the serum concentrations of thyroid hormone decrease, the hypothalamic-pituitary centers again become responsive by releasing TRH & TSH 8

9 Thyroid Physiology T3 is 4 times more potent than T4, but its serum concentration is lower T4 is the major circulating hormone secreted by the thyroid About 80% of the total daily T3 production results from the peripheral conversion of T4 to T3 through deiodination of T4 Certain drugs & diseases can modify the conversion rate of T4 to T3 and decrease the serum T3 levels 9

10 Thyroid Physiology T3 & T4 exist in the circulation in free (active) & protein-bound (inactive) forms About 99.97% of circulating T4 is bound, only 0.03% exists as the free form This affinity for plasma proteins accounts for T4's slow metabolic degradation & long half-life of 7 days In contrast, T3 is considerably less strongly bound to plasma proteins The lower protein-binding affinity of T3 accounts for its threefold greater potency & shorter half-life of 1.5 days 10

11 Thyroid Physiology

12 Common Thyroid Disorders Hypothyroidism: clinical syndrome that results from a deficiency of thyroid hormone Hyperthyroidism: or thyrotoxicosis is the hypermetabolic syndrome that occurs when the production of thyroid hormone is excessive Goiter: Diffuse thyroid enlargement most commonly results from prolonged stimulation by TSH Thyroid nodules & neoplasms 12

13 Epidemiology 13

14 Epidemiology General Hypothyroidism Hyperthyroidism 14

15 Epidemiology Thyroid disease is common, affecting approximately 5% to 15% of the general population Females are 3-4 times more likely than males to develop any type of thyroid disease 15

16 Hypothyroidism The prevalence of hypothyroidism is 1.4% to 2% in females and 0.1% to 0.2% in males The incidence increases in persons older than 60 years to 6% of women & 2.5% of men Hypothyroidism can be caused by either primary (thyroid gland) or secondary (hypothalamic-pituitary) malfunction Primary hypothyroidism is more common than secondary causes 16

17 Hyperthyroidism Hyperthyroidism affects about 2% of females & about 0.1% of males The prevalence of hyperthyroidism in older patients varies between 0.5% & 2.3% 17

18 Causes 18

19 Causes Hypothyroidism Etiologic Classification Congenital Pathogenetic Mechanism Aplasia or hypoplasia of thyroid gland Defects in hormone biosynthesis or action Acquired Hashimoto's thyroiditis Severe iodine deficiency Lymphocytic thyroiditis Autoimmune destruction Diminished hormone synthesis, release Diminished hormone synthesis, release Thyroid ablation Thyroid surgery 131 I radiation treatment of hyperthyroidism External beam radiation therapy of head & neck cancer Diminished hormone synthesis, release 19

20 Causes Hypothyroidism Etiologic Classification Pathogenetic Mechanism Acquired Drugs Iodine, inorganic Iodine, organic (amiodarone) Thioamides (propylthiouracil, methimazole) Potassium perchlorate Diminished hormone synthesis, release Thiocyanate Lithium Amiodarone 20

21 Causes Hypothyroidism Etiologic Classification Pathogenetic Mechanism Acquired Hypopituitarism Deficient TSH secretion Hypothalamic disease Deficient TRH secretion 21

22 Causes Hypothyroidism Hashimoto's thyroiditis, an autoimmune disorder, is the most common cause of primary hypothyroidism & appears to have a strong genetic 22

23 Causes Hyperthyroidism Etiologic Classification Pathogenetic Mechanism Thyroid hormone overproduction Graves' disease Toxic multinodular goiter Follicular adenoma Pituitary adenoma Pituitary insensitivity Hypothalamic disease Germ cell tumors: choriocarcinoma, hydatidiform mole Thyroid-stimulating hormone receptorstimulating antibody (TSH-R [stim] Ab) Autonomous hyperfunction Autonomous hyperfunction TSH hypersecretion (rare) Resistance to thyroid hormone (rare) Excess TRH production Human chorionic gonadotropin stimulation 23

24 Causes Hyperthyroidism Etiologic Classification Pathogenetic Mechanism Thyroid gland destruction Lymphocytic thyroiditis Granulomatous (subacute) thyroiditis Hashimoto's thyroiditis Release of stored hormone Release of stored hormone Transient release of stored hormone Drug effect Thyrotoxicosis medicamentosa, thyrotoxicosis factitia Amiodarone Interferon alpha Ingestion of excessive exogenous thyroid hormone Excess iodine &/or thyroiditis Thyroiditis 24

25 Causes Hyperthyroidism Graves' disease is the most common cause of hyperthyroidism Toxic autonomous nodular goiters, both multi- and uninodular, account for a large proportion of the remaining causes 25

26 Pathophysiology 26

27 Pathophysiology Hypothyroidism Hashimoto's Thyroiditis Hypothyroidism Graves' Disease 27

28 Pathophysiology Hypothyroidism Hypothyroidism is characterized by abnormally low serum T4 & T3 levels Free thyroxine levels are always depressed The serum TSH level is elevated in hypothyroidism (except in cases of pituitary or hypothalamic disease) 28

29 Pathophysiology Hashimoto's Thyroiditis In the early stages of Hashimoto's thyroiditis, the gland is diffusely enlarged, firm, rubbery, & nodular As the disease progresses, the gland becomes smaller In the late stages, the gland is atrophic & fibrotic, weighing as little as g Microscopically, there is destruction of thyroid follicles & lymphocytic infiltration with lymphoid follicles 29

30 Pathophysiology Hashimoto's Thyroiditis Autoimmune disease The pathogenesis of Hashimoto's thyroiditis results from an impaired immune surveillance, causing dysfunction of normal suppressor T lymphocytes & excessive production of thyroid antibodies by plasma cells 30

31 Pathophysiology Hashimoto's Thyroiditis The destruction of thyroid cells by circulating thyroid antibodies produces an underlying defect or block in the intrathyroidal, organo-binding of iodide As a result, inactive hormones or insufficient amounts of active hormones are synthesized, & this eventually produces hypothyroidism 31

32 Pathophysiology Hashimoto's Thyroiditis The clinical presentation of Hashimoto's thyroiditis can be variable, depending on the time of diagnosis: The typical presentation is hypothyroidism & goiter (thyroid gland enlargement) Patients can present with hypothyroidism & no goiter Euthyroidism & goiter Rarely (<5%) with hyperthyroidism (Hashi-toxicosis) 32

33 Pathophysiology Hyperthyroidism Whatever the cause of hyperthyroidism, serum thyroid hormones are elevated Both the free thyroxine (FT4) & the free thyroxine index (FT4I) are elevated In 5 10% of patients, T4 secretion is normal while T3 levels are high (so-called T3 toxicosis) Total serum T4 & T3 levels are not always definitive because of variations in concentrations of thyroid hormone binding proteins 33

34 Pathophysiology Graves' Disease Graves' disease is the most common cause of hyperthyroidism The thyroid gland is symmetrically enlarged The gland may double or triple in weight Microscopically, the follicular epithelial cells are columnar in appearance and increased in number & size 34

35 Pathophysiology Graves' Disease Graves' disease is an autoimmune disorder Characterized by one or more of the following features: Hyperthyroidism Diffuse goiter Ophthalmopathy (exophthalmos) Dermopathy (pretibial myxedema) Acropachy (thickening of fingers or toes) 35

36 Pathophysiology Graves' Disease The production of excessive quantities of thyroid hormone is attributed to a circulating IgG or thyroid receptor antibody (TRAb), which has a TSH-like ability to stimulate hormone synthesis The peak incidence of Graves' disease occurs in the third or fourth decade of life, the duration of the disease is unknown, & its clinical course is characterized by remission & relapse 36

37 Pathophysiology Graves' Disease Patients with hyperthyroidism from Graves' disease may later develop hypothyroidism by one of several mechanisms 1. Thyroid ablation by surgery or 131 I radiation treatment 2. Autoimmune thyroiditis, leading to thyroid destruction 3. Development of antibodies that block TSH stimulation (TSH- R [block] Ab) 37

38 Manifestations 38

39 Manifestations Clinical Manifestations Hypothyroidism Symptoms Signs Long term complication (Myxedema Coma) Hyperthyroidism Symptoms Signs Thyroid storm 39

40 Manifestations Hypothyroidism Symptoms Slow thinking Lethargy, decreased vigor Dry skin; thickened hair; hair loss; broken nails Diminished food intake; weight gain Constipation Menorrhagia; diminished libido Cold intolerance 40

41 Manifestations Hypothyroidism Signs Round puffy face; slow speech; hoarseness Hypokinesia; generalized muscle weakness; delayed relaxation of deep tendon reflexes Cold, dry, thick, scaling skin; dry, coarse, brittle hair; dry, longitudinally ridged nails Periorbital edema Ascites; pericardial effusion; ankle edema Mental depression Anemia Decreased metabolic rate 41

42 Manifestations Hypothyroidism Signs Bradycardia ( HR) Hypertension Goiter (primary hypothyroidism) Thickening of tongue Thinning of outer eyebrows Yellowing of skin 42

43 Manifestations Hypothyroidism Myxedema Coma The end stage of long-standing, uncorrected hypothyroidism The classic features are hypothermia, delayed DTRs, & may reach to coma Other predominant features include hypoxia, carbon dioxide retention, severe hypoglycemia, hyponatremia, & paranoid psychosis 43

44 Manifestations Hypothyroidism Myxedema Coma Precipitating factors include cold weather or hypothermia, stress (e.g., surgery, infection, trauma), coexisting disease states such as MI, diabetes, hypoglycemia, or fluid & electrolyte abnormalities (especially hyponatremia), & medications such as sedatives, narcotic analgesics, antidepressants, & other respiratory depressants & diuretics Mortality rates of 60% to 70% despite treatment 44

45 Manifestations Hyperthyroidism Symptoms Alertness, nervousness, irritability, tremors Poor concentration Muscular weakness, fatigability Palpitations Voracious appetite, weight loss Hyperdefecation (increased frequency of bowel movements) Heat intolerance 45

46 Manifestations Hyperthyroidism Signs Hyperkinesia, rapid speech Proximal muscle (quadriceps) weakness, fine tremor Fine, moist skin; fine, abundant hair; onycholysis Lid lag, stare, chemosis, periorbital edema, proptosis Accentuated first heart sound, tachycardia, atrial fibrillation (resistant to digitalis), widened pulse pressure, dyspnea Increased metabolic rate 46

47 Manifestations Hyperthyroidism Thyroid Storm The clinical manifestations of thyroid storm include acute onset of high fever, hyperglycemia & involvement of the following organ systems: Cardiovascular (tachycardia, pulmonary edema, hypertension, shock) CNS (tremor, emotional lability, confusion, psychosis, apathy, stupor, coma) GI (diarrhea, abdominal pain, nausea & vomiting, liver enlargement, jaundice, elevations of bilirubin & PT) 47

48 Manifestations Hyperthyroidism Thyroid Storm Thyroid storm develops in about 2% to 8% of hyperthyroid patients The pathogenesis of thyroid storm is not well understood, but the condition can be described as an exaggerated or decompensated form of thyrotoxicosis Decompensated means failure of body systems to adequately resist the effects of thyrotoxicosis 48

49 Diagnosis 49

50 Diagnosis Diagnosis Thyroid Function Tests How to diagnose Hypothyroidism & Hyperthyroidism? 50

51 Diagnosis Thyroid Function Tests The principal laboratory tests recommended in the initial evaluation of thyroid disorders are: TSH FT4 Positive thyroid antibodies indicate an autoimmune thyroid etiology Other tests: total T3 (TT3), free T3 (FT3) or FT3 index (FT3I), RAIU & scan, TRAb, ultrasound, & FNA biopsy 51

52 Diagnosis Thyroid Function Tests Free & Total Serum Hormone Levels Tests of the Hypothalamic-Pituitary-Thyroid Axis Tests of Gland Function Tests of Autoimmunity 52

53 Diagnosis Free & Total Hormone Levels Free Thyroxine, Free Thyroxine Index, Free Triiodothyronine, & Free Triiodothyronine Index The FT4 & FT3 are the most reliable tests for the evaluation of hormone concentrations 53

54 Diagnosis Free & Total Hormone Levels Total Thyroxine & Total Triiodothyronine TT4 & TT3 measure both free & bound (total) serum T4 & T3 Because the bound fraction is the major fraction measured, situations that change the hormone's affinity for TBG or the TBG level will influence the results E.g. falsely elevated levels of TT4 & TT3 are common in the euthyroid pregnant woman TT3 can be low in older patients & nonthyroidal illnesses because the peripheral conversion of T4 to T3 is decreased 54

55 Diagnosis Free & Total Hormone Levels Total Thyroxine & Total Triiodothyronine Careful interpretation of these tests is necessary TT3 is particularly helpful in detecting early relapse of Graves' disease & in confirming the diagnosis of hyperthyroidism despite normal TT4 levels The TT3 is not a good indicator of hypothyroidism because TT3 can be normal Measurement of only the total hormone levels is less reliable than either the free hormone 55

56 Diagnosis Tests of Hypothalamic-Pituitary-Thyroid Axis Thyroid Stimulating Hormone (TSH) The serum TSH or thyrotropin is the most sensitive test to evaluate thyroid function TSH, secreted by the pituitary, is elevated in early or subclinical hypothyroidism (when thyroid hormone levels appear normal) & when thyroid hormone replacement therapy is inadequate TSH can be abnormal even if the FT4 remains within the normal range because the TSH is specific for each person's physiological set point 56

57 Diagnosis Tests of Gland Function Radioactive Iodine Uptake RAIU, a measure of iodine utilization by the gland, is an indirect measure of hormone synthesis It is elevated in hyperthyroidism & in early hypothyroidism A low or undetectable RAIU occurs in hypothyroidism, thyrotoxicosis factitia, & subacute thyroiditis RAIU is used to calculate the dose of RAI therapy for treatment of Graves' disease & to determine the activity of one or several nodules in a gland. The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism. 57

58 Diagnosis Tests of Gland Function Radioactive Iodine Uptake The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism A tracer dose of 131 I is administered, & the radioactivity of the gland is measured at 5 & 24 hours after ingestion It is necessary to measure both the 5- & 24-hour RAIU so that patient with rapid turnover of iodine will not be missed In some hyperthyroid patients, the 5-hour uptake is elevated, but the 24-hour uptake can fall to normal or subnormal levels 58

59 Diagnosis Tests of Gland Function Imaging Study Thyroid Scan A scan of the gland is performed simultaneously with the RAIU The scan provides information concerning gland size & shape, & identifies hypermetabolic ( hot ) & hypometabolic ( cold ) areas 59

60 Diagnosis Tests of Gland Function Thyroid Ultrasound A thyroid ultrasound can provide information about gland size & number of clinically palpable or nonpalpable nodules or cysts in the thyroid gland 60

61 Diagnosis Tests of Autoimmunity Thyroperoxidase & Antithyroglobulin Antibodies Thyroperoxidase (TPO) & antithyroglobulin (ATgA) antibodies to the thyroid gland indicate an autoimmune process About 60-70% of patients with Graves' disease & 95% of patients with Hashimoto's thyroiditis have +ve antibodies to both thyroid antigens 61

62 Diagnosis Tests of Autoimmunity Thyroperoxidase & Antithyroglobulin Antibodies Positive antibodies alone do not indicate thyroid disease because 5-10% of asymptomatic patients, as well as patients with other nonthyroidal autoimmune disorders, have positive antibodies Clinically, the TPO is more specific than ATgA in assessing disease activity 62

63 Diagnosis Tests of Autoimmunity Thyroid Receptor Antibodies TRAbs are IgG immunoglobulins that are present in virtually all patients with Graves' disease Like TSH, these immunoglobulins can stimulate the thyroid gland to produce thyroid hormones 63

64 Diagnosis Tests of Autoimmunity High titers of TRAb are useful in: Thyroid Receptor Antibodies Diagnosing otherwise asymptomatic Graves' disease (i.e., ophthalmopathy) Predicting the risk of relapse of Graves' disease after discontinuing medication Predicting the risk of neonatal hyperthyroidism in utero through transplacental passage of TRAb from the pregnant mother Otherwise, TRAb measurement is expensive & offers no additional information in patient with Graves' disease 64

65 Summary of commonly used tests in thyroid disorders 65

66 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels FT 4 Direct measurement of free thyroxine No interference by alterations in TBG Most accurate determination of FT 4 levels; might be higher than normal in patients on thyroxine replacement 66

67 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels FT 4 I Calculated free thyroxine index Euthyroid sick syndrome Estimates direct FT 4 measurement; compensates for alterations in TBG 67

68 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels TT 4 Total free & bound T 4 Alterations in TBG Specific & sensitive test if no alterations in TBG 68

69 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels TT 3 Total free & bound T 3 Alterations in TBG levels; T 4 to T 3 Euthyroid sick syndrome Useful in detecting early, relapsing, & T 3 toxicosis Not useful in evaluation of hypothyroidism 69

70 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels FT 3 Direct measurement of free T 3 Most accurate determination of FT 4 No interference levels; might be by alterations in TBG lower than normal in patients on thyroxine replacement 70

71 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Measurement of Circulating Hormone Levels FT 3 I Calculated free T 3 index Euthyroid sick syndrome Estimates direct FT 3 measurement; compensates for alterations in TBG 71

72 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Tests of Thyroid Gland Function RAIU Gland's use of iodine after trace dose of either 123 I or 131 I False decrease with excess iodide intake False elevation with iodide deficiency Useful in hyperthyroidism to determine RAI dose in Graves'; does not provide information regarding hormone synthesis 72

73 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Tests of Thyroid Gland Function Scan Gland size, shape, & tissue activity after 123 I 154 I scan blocked by antithyroid/ thyroid medications Useful in nodular disease to detect cold or hot areas 73

74 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Test of Hypothalamic-Pituitary-Thyroid Axis TSH Pituitary TSH level Dopamine, glucocorticoids, metoclopramide, thyroid hormone, amiodarone, metformin Most sensitive index for hyperthyroidism, hypothyroidism, & replacement therapy 74

75 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Tests of Autoimmunity ATgA Antibodies to thyroglobulin Nonthyroidal autoimmune disorders Present in autoimmune thyroid disease; undetectable during remission 75

76 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Tests of Autoimmunity TPO Thyroperoxidase antibodies Nonthyroidal autoimmune disorders More sensitive of the two antibodies; titers detectable even after remission 76

77 Diagnosis Common Thyroid Function Test Tests Measures Assay Interference Comments Tests of Autoimmunity TRAb Thyroid receptor stimulating antibody Confirms Graves' disease; detects risk of neonatal Graves' 77

78 How to diagnose hypothyroidism & hyperthyroidism? 78

79 Diagnosis How to Diagnose? First look at signs & symptoms Major differences between hypothyroidism & hyperthyroidism? Diagnostic test 79

80 Diagnosis Diagnostic Tests Hypothyroidism TSH Hyperthyroidism TSH TT 4 TT 4 TT 3 TT 3 FT 4 FT 4 FT 4 I FT 4 I FT 3 I FT 3 I 80

81 Diagnosis Diagnostic Tests Hypothyroidism Positive antibodies (in Hashimoto's) Cholesterol AST Decrease radioiodine uptake by thyroid gland Na, Hyponatremia (from excess secretion of antidiuretic hormone) Hyperthyroidism Alkaline phosphatase Cholesterol AST Increased radioiodine uptake by thyroid gland Calcium CPK Hct/Hgb 81

82 References Pharmacotherapy: A Pathophysiologic Approach, 7e Pathophysiology of Disease: An Introduction to Clinical Medicine, 6e Applied Therapeutics: The Clinical Use of Drugs, 9e 82

83 Thank You 83

4) Thyroid Gland Defects - Dr. Tara

4) Thyroid Gland Defects - Dr. Tara Thyroid Pituitary Axis TRH secreted in the hypothalamus stimulates production and Secretion of TSH TSH stimulates secretion of T3, T4 T4 has negative feedback on secretion