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The Thyroid Prof. Sophia Ish-Shalom MD The Thyroid Thyroid Anatomy Thyroid Hormones Thyroid Axis T3 T3 Thyroid Hormone Biosynthesis Thyroglobulin Large glycoprotein 5496 AA MW 660000 Thyroid peroxydase • Membrane bound glycoprotein • Mediates oxydation of iodide ions and incorporation iodine into thyrosine residues on thyroglobulin Thyroid Hormones- Metabolic Actions Nuclear receptor activation RNA and protein synthesis: Na/K ATPase ATP turnover oxygen consumption calorigenic effect • Tissue growth • Brain maturation Laboratory Evaluation of Thyroid Function Serum TSH the most sensitive screening test of thyroid function Most of the circulating T4 and T3 is bound to TBG TT3 0.2% free 0.02% free FT4 Agents/Conditions that Thyroxine-Binding Globulin (TBG) • pregnancy • oral contraceptives • other estrogen sources • tamoxifen/SERMs • genetics • perphenazine • Newborn • infectious/chronic active hepatitis • biliary cirrhosis • acute intermittent porphyria Agents/Conditions that Thyroxine-Binding Globulin (TBG) • Androgens • Glucocorticoids in high dosage • Chronic liver disease • Severe systemic disease • Active acromegaly • Nephrosis • Genetics מחלות בלוטת התריס • שנוי בצורת הבלוטה – הגדלת כל הבלוטה ( זפק)goiter , – הגדלת חלק מהבלוטה (קשרית, )nodule • שנוי בתפקוד הבלוטה – תת פעילות הבלוטה – פעילות יתר של בלוטת התריס • שילוב של שניהם Goiter Due to Iodine Deficiency קשרית בבלוטת התריס • הינה ההפרעה השכיחה ביותר בבלוטת התריס • שכיחותה באוכלוסיה היא 4 %ועולה עם הגיל • שכיחה יותר בנשים • ממצאי נתיחה שלאחר המוות: ב 50 %-מהמבוגרים נמצאו קשריות רובן בלתי משישות (קשרית משישה <1ס”מ). קשרית בבלוטת התריס • רב הקשריות הן שפירות • רק כ 20 % -15 %-מהקשריות הן ממאירות • קרצינומה בבלוטת התריס מהווה 1 %מכלל הממאירויות ו 0.5 % -מכלל מקרי התמותה שקשורים בממאירות אנמנזה .1גיל .2מין .3הקרנת הצוואר או הראש בילדות .4התגלתה לאחרונה צמחה במהירות .5אינה כואבת .6תלונות של צרידות ,דיספגיה או דיספנאה .7תלונות שמחשידות להיפו או היפרתירואידזם .8תלונות ססטמיות :חום .9סיפור משפחתי בדיקה גופנית .1קשרית בודדת/קשרית דומיננטית בבלוטה מרובת קשריות .2מאפייני הקשרית :גודלה, קונסיסטנציה -קשה אינה מובילית אינה רגישה .3הגדלת בלוטות לימפה צוואריות .4צרידות .5סימני היפו/היפרתירואידזם אבחנה • לבדיקות מעבדה אין ערך באבחנה בין קשרית ממאירה לשפירה. • עם זאת מומלץ לבדוק את תפקודי בלוטת התריס :היפרתירואידזם יכול להצביע על קיומה של ( autonomous toxic adenomaשהינה שפירה ברב המקרים). בדיקת הבחירה היאFNAC: • בדיקה רגישה ()5% - 2% FALSE NEGATIVE וספציפית ( )1% - 0% FALSE POSITIVEבטוחה מהימנה ומדויקת לאבחן בין קשרית ממאירה לשפירה • תשובת ה :FNAC-ממאיר ,שפיר ,חשוד • חסרונה :חוסר יכולת להבדיל בין גידול פולקולרי ממאיר ושפיר • ל %20 - %11 -מהחולים נמצאת קשרית חשודה בבדיקת ה ,FNAC-מתוכן ל %20 -יש ממאירות בבלוטת תריס מפוי בלוטת התריס Technecium99m Tc O4 • • נשאר בבלוטה 6שעות • זמן מחצית חיים 6שעות ,קרינה עובר Trappingולא אורגניפוקציה – 100 mr 1mCi – 5mCiלבדיקה 500mr מיפוי • • • • • TECNECIUM למיפוי יש ערך רק בזיהוי autonomous toxic adenoma עיקר השמוש במיפוי הוא במקרים של קשרית פולקולרית תוצאות המיפוי הן: 85% - 80%מהקשריות הן קרות מתוכן כ 25% - 10%-הן ממאירות 10 %הן warmמתוכן 10 %ממאירות 5 %הן hotומתוכן 5 % -1 %ממאירות Thyroid Scan – Cold Nodule שמושי ה:U.S- .1אבחנה בין קשרית ציסטית לסולידית .2מעקב אחר גודלה של קשרית שלא הוצאה .3גילוי קשריות שאינן משישות ( 0.3מ”מ) .4חסר יכולת לאבחן בין קשרית ממאירה לשפירה. ציסטה • FNACמהווה כלי אבחנתי וטיפולי במקרה של ציסטה. • אינדיקציות ל lobectomy-במקרה של ציסטה הן: .1ציסטה שחוזרת לאחר 3אספירציות .2ציסטה שקוטרה גדול מ 4-ס”מ .3צי סטה מורכבת ()complex cyst • U.Sחסר יכולת לאבחן בין קשרית ממאירה לשפירה. Thyroid Nodule Evaluation Algorithm TSH TSH TSH -Normal thyroid scan Thyroid Carcinoma Papillary • 50% of malignant tumors of the thyroid • Metastasis to local lymph nodes Follicular • 25% of malignant tumors of the thyroid • Metastasis to local lymph nodes, lung, bone, liver • Metastasis taking up I131 Thyroid Carcinoma Medullary carcinoma • 10% of malignant tumors of the thyroid • Neuroendocrine – Originates from parafollicular cells – Functional – calcitonin producing • Metastasizes early • Some patients with distant metastasis may live for many years MEN IIb Thyroid Carcinoma Anaplastic • 10% of malignant tumors of the thyroid • 75% mortality in 1 year Hyperthyroidism – Causes Disorders associated with thyroid hyperfunction • Abnormal thyroid stimulator – Graves’ disease – Trophoblastic tumor Intrinsic thyroid autonomy • Hyprfunctionning adenoma • Toxic multinodular goiter Excess production of TSH (very rare) Hyperthyroidism – Causes Disorders not associated with thyroid hyperfunction • Disorders of hormone storage – Subacute thyroiditis – Chronic thyroiditis with transient thyrotoxicosis • Extrathyroidal source of hormone – Thyrotoxicosis facticia – Ectopic thyroid tissue –Struma ovarii –Functional follicular carcinoma Hyperthyroidism Skin - appendages Warm, moist skin; sweating; fine, thin hair; pretibial dermopathy (Graves' disease) Eyes, face Upper lid retraction (wide stare); periorbital edema; exophthalmos, diplopia (Graves' disease) CNS Nervousness, hyperkinesia, variable emotional states Hyperthyroidism Cardiovascular peripheral resistance cardiac output, stroke volume, heart rate, pulse pressure, contractility congestive heart failure (high-output); arrhythmogenic; angina Respiratory Dyspnea; vital capacity Hyperthyroidism Hematopoietic Anemia ( RBC turnover); erythropoiesis Reproductive fertility; menstrual irregularity; gonadal steroid metabolism Metabolic basal rate; negative nitrogen balance, hyperglycemia; free fatty acids, cholesterol and triglycerides; hormone degradation; requirement for fat-and water-soluble vitamins; enhanced drug detoxification Hyperthyroidism Gastrointestinal appetite; bowel movement frequency; hypoproteinemia Musculoskeletal Weakness; fatigue; hypercalcemia, osteoporosis, deep tendon reflex Renal renal blood flow; GFR; mild polyuria Graves' disease • Lymphocytes: release TSH receptor-stimulating antibody (TSH-R ab [stim]) {thyroidstimulating immunoglobulin} )TSI) • TSH-R ab [stim] binds to the TSH receptor and activates the thyroid • Duration of activation is longer than with physiological TSH Graves' disease Four major presentations: • Hyperthyroidism • Diffuse goiter • Ophthalmopathy • Dermopathy Ophthalmopathy Characterized by: • Inflammatory orbital content infiltrate (lymphocytes, mast cells, plasma cells) • Enlargement of orbital musculature (lymphocytes infiltration, mucopolysaccharides, edema, fat) • Eventually - muscle fiber degeneration; Loss of striations; Fibrosis Stare Left Exophtalmus Graves’ Ophtalmopathy Pretibial Mixedema Treatment of Thyrotoxicosis • Antithyroid drugs – Thioamides • Betablockers – Propranolol • Radioactive iodine • Surgery Thioamides Major drugs for thyrotoxicosis: Propylthiouracil • rapidly absorbed • bioavailability: 50 - 80% (incomplete absorption/large first-pass effect) • metabolism: glucuronidation by the liver; excreted by the kidney • short half-life (1.5 hours) but accumulated by the thyroid Propylthiouracil Crosses placental barrier (increased protein binding compared to methimazole makes propylthiouracil preferable for use in pregnancy since less free drug is available to cross into the fetus) Methimazole • about 10 times more active than propylthiouracil • well absorbed • accumulated by the thyroid • crosses the placental barrier Mechanism of Action: thioamides • Major action: inhibits thyroidal peroxidase-catalyzed reactions, blocking iodine organification: thus preventing hormone synthesis. Mechanism of Action: thioamides • Propylthiouracil and methimazole (too a much reduced degree) inhibit peripheral deiodination of T4 and T3 thioamides Mechanism of Action: thioamides • Slow onset of pharmacological effect: (since synthesis, not release is affected, a month may be required before T4 stores are depleted.) Toxicity: thioamides Frequency of adverse effects: 3-12%. • Most common: maculopapular pruritic rash • Rare: urticarial rash, vasculitis, arthralgia, lupus-like reaction, hepatitis, lymphadenopathy, cholestatic jaundice, hypoprothrombinemia, polyserositis. Toxicity: thioamides • • Most serious potential reaction: agranulocytosis - risk 0.3% - 0.6 % of patients; reversible upon discontinuation; cross sensitivity between propylthiouracil and methimazole possibly increased risk in: • elderly • patients receiving high-dose methimazole Radioactive Iodine Treatment • 131I is the radioactive isotope used for treating thyrotoxicosis. Mechanism of Action: • Rapidly absorbed, concentrated in the thyroid • Incorporated into thyroid follicles • Beta emission is the basis for therapeutic efficacy • Thyroid parenchymal destruction occurs within a few weeks. Radioactive Iodine - Pathology • epithelial swelling, necrosis • follicular disruption • leukocyte infiltration • edema Radioiodine -Therapeutic Advantages • good efficacy • easy to administer • low expense • pain free treatment Contraindications • 131I- not administered to pregnant women or nursing mothers • 131I crosses placental barrier and excreted in breast milk Adrenergic receptor blocking drugs • Rationale: reduction of sympathetic manifestations in thyrotoxicosis: • Agent of choice: propranolol (nonselective beta-receptor antagonist) Subacute Thyroiditis • Subacute thyroiditis - granulomatous or De Quervain's thyroiditis • Spontaneously remitting inflammatory condition of the thyroid gland that may last for weeks to several months • It has a tendency to recur SAT - Characteristics • The gland is typically involved as a whole • Thyroidal RAIU • Transient hyperthyroxinemia • Elevation of the serum Tg concentration • Erythrocyte sedimentation rate • Sometimes the WBC during the early acute phase FT4, Thyroglobulin and TSH During SAT days Thyroid Storm Fulminating in symptoms of thyrotoxicosis • "Medical storm" is now likely to be seen in undertreated patients • Precipitated by surgery or complicating illness, often sepsis Presenting syndrome • • • • • extreme irritability high fever, 41oC tachycardia supraventricular arrhythmia ventricular arrhythmia • • • • • hypotension vomiting diarrhea delirium coma Thyroid Storm - Treatment • • • • • Manage dehydration: IV Saline Glucocorticoids - dexamethasone (possible reduction in adrenal reserve, blockage of peripheral conversion of T4 T3) Block hormone synthesis by large dose propylthiouracil; Followed by large doses of iodine, oral or parenteral; Sodium ipodate may be used instead of iodine Propranolol - in the absence of CHF Digitalis may be required to control elevated ventricular rates in the presence of atrial fibrillation Iodine I - - Iodide ion Iodine - Iodine molecule in any organic form I2 - Molecular Iodine • • • Intake • • • • • 10מקג'/יום -באזורי חסר מ 100-150 1960-מקג/יום 200-500מקג/יום -כעת ,מזון ,תרופות במלח בישול ,ויטמינים0.01-0.005 % - I- : cretinism תרופות :אקספקטורנטים ,חומרי ניגוד – 1-3גר' Iodineליום Iodides Actions on the thyroid: • Inhibit organification • Inhibit hormone release - major action • Mechanism: perhaps inhibition of thyroglobulin proteolysis • thyroidal size and vascularity • May induce hyperthyroidism (jodbasedow) • May precipitate hypothyroidism Iodides - Therapeutic Uses • Short-term management of thyroid storm • Preoperative preparation for surgery (due to reduction in gland vascularity, size, and fragility) Iodides - Major Disadvantages • • • • • • Iodide therapy increases intraglandular iodine concentration May delay initiation of thioamides treatment May delay use of radioactive iodine treatment Avoid in pregnancy: iodide crosses the placenta and may cause fetal goiter Iodide as monotherapy: not appropriate; Iodide block lasts only 2-8 weeks; Withdrawal at this time may exacerbate thyrotoxicosis Iodide use should be initiated only after thioamide treatment and not used if radioactive iodine therapy is planned Etiology of Hypothyroidism Primary • Hashimoto thyroiditis – with goiter – Idiopathic thyroid atrophy • RAI therapy for Graves’ • S.p thyroidectomy • Excessive iodine intake • Subacute thyroididtis • Rare – Iodine defficiency – Lithium therapy – Inborn error of hormone synthesis Etiology of Hypothyroidism Secondary • Pituitary defects • Adenoma • Irradiation Tertiary • Hypothalamic Peripheral resistance to thyroid hormone Hypothyroidism • תת פעילות של בלוטת התריס היא מחלה שכיחה באוכלוסיה מבוגרת ,פוגעת ב 8% -מהנשים וב - 2%מהגברים > גיל 50 • הסיבות השכיחות ביותר לתת פעילותשלל בלוטת התריס בארץ: – autoimmune thyroid disease – thyroid ablation therapy – מצב אחרי כריתה כירורגית של בלוטת התריס Hypothyroidism Hypothyroidism Hypothyroidism in the Elderly Hypothyroidism - Treatment • Levothyroxine - synthetic tetraiodothyronine sodium salt • Synthetic T4 is identical to that produced in the human thyroid gland • Single, fasting, daily dose Myxedema - crisis Myxedema Coma/Crisis • • • סיבוך נדיר של תת פעילות של בלוטת התריס מתרחשת בד"כ בנשים קשישות הסובלות מתת פעילות של בלוטת התריס – שאינן מקבלות טיפול – מקבלות טיפול חלקי או בלתי מספיק כאשר מתוסף גורם דחק •חדש טראומה • זהום • קור סביבתי • מחלה סיסטמית • דימום • ארוע מוחי • טיפול תרופתי hypnotics : anesthetics, analgesics sedatives • אי ספיקת לב Myxedema Coma – Clinical Presentation • Hypothermia usually, but not always Special thermometers that record << 32°C may have to be used to determine the patient's actual temperature and to monitor rewarming • Absence of fever in the presence of infection • pulse pressure, normal systolic pressure, diastolic pressure, pulse and respiration • Coarse or thinning hair; facial swelling or coarseness; periorbital nonpitting edema; macroglossia; enlargement of tonsils, nasopharynx, larynx Myxedema Coma – Clinical Presentation • • • • • Thyroid - enlarged, not palpable, or a scar may suggest previous thyroidectomy Lungs - Slow respirations, congestion, pleural effusions, consolidation Heart - Soft or distant heart sounds, diminished apical impulse, enlarged heart, pericardial effusion Abdomen - Distension secondary to ileus and/or ascites, or absent bowel sounds Extremities - Cold, nonpitting edema of hands and feet Myxedema Coma – Clinical Presentation • Skin/nails - Pale, dry, scaly, thickened skin; dry brittle nails; ecchymoses, purpura, sallow due to carotenemia • Neuromuscular - Confusion, stupor, obtundation, coma, slow speech, seizures, reflexes with slow relaxation • Drugs • Tranquilizers • Sedatives • Anesthetics • Analgesics • Narcotics • Amiodarone • Lithium • Phenytoin • Laboratory Evaluation If myxedema coma is suspected, treatment must be initiated immediately without waiting for the results of lab tests • Free T4 and (TSH) o Free T4 and T3 o TSH level may be primary thyroid disorder If not o secondary hypothyroidism o severe illness o and/or drugs: dopamine or high dose glucocorticoids TSH • Laboratory Evaluation If myxedema coma is suspected, treatment must be initiated immediately without waiting for the results of lab tests • Free T4 and (TSH) o Free T4 and T3 o TSH level may be primary thyroid disorder If not o secondary hypothyroidism o severe illness o and/or drugs: dopamine or high dose glucocorticoids TSH Laboratory Evaluation • • • • • Serum electrolytes and serum osmolality: Hyponatremia with serum osmolality Serum creatinine usually is due to decreased renal perfusion Serum glucose: Hypoglycemia is common but also may suggest adrenal insufficiency Creatine phospho kinase (CPK): CPK levels often are , and fractionation will indicate the source to be skeletal muscle, not cardiac, unless a myocardial infarction was the precipitating event Hematocrit < 30% Laboratory Evaluation • • • • • • • Arterial blood gases: PCO2 and PO2 Random serum cortisol should be determined before beginning intravenous steroids Imaging Studies: Chest x-ray - Cardiomegaly, pericardial effusion, congestive heart failure, pleural effusion Other Tests: Electrocardiogram - Sinus bradycardia, amplitude QRS complexes, QT interval, flattened or inverted T waves Procedures • • • Temperature monitoring requires use of a rectal probe to determine true core temperature and to monitor rewarming Blood transfusion: Transfuse packed red blood cells if the hematocrit < 30% to prevent myocardial ischemia Pan-culture for sepsis. All patients should have a chest x-ray and be cultured for a source of infection. It is recommended to initially treat all patients with myxedema coma with broadspectrum antibiotics with modification of the antibiotic regimen based on culture results Procedures • • • • Endotracheal intubation: ventilatory drive, CO2 retention, and hypoxemia all necessitate mechanical respiratory assistance to prevent cardiovascular collapse and worsening of hypoxia and hypercapnia Cardiac monitoring in an intensive care unit Patients are at risk of myocardial ischemia Central venous pressure or Swan-Ganz catheter monitoring: Hypotension is a sign of loss of blood volume, either from bleeding or vascular redistribution, and must be corrected immediately Treatment Volume status • IV glucose and normal saline • Volume should be limited because patients usually are volume-overloaded and prone to congestive heart failure from reduced cardiac function of hypothyroidism • If Na <120 mEq/L small amounts of hypertonic saline by intravenous furosemide to improve volume status Treatment For hypotension that does not improve with fluid replacement • Whole blood transfusion • Cautious administration of dopamine • Generally, hypotension is resistant to the usual drugs until thyroid hormone and glucocorticoids (if insufficient) are given Treatment • Levothyroxine 200-500 mcg IV loading dose 50-100 mcg/d IV to 50-200 mcg/d PO when patient is ambulatory • Steroid therapy: Hydrocortisone at 100 mg every 8 hours , after a baseline cortisol level is drawn and continued unless the random cortisol drawn on admission indicates adrenal function without abnormalities, at which time hydrocortisone may be stopped without tapering Euthyroid Sick Syndrome • הפרעות בתפקודים מעבדתיים של בלוטת התריס המופיעות תוך מחלה (בד"כ קשה) ,ללא עדות למחלה ראשונית או משנית של בלוטת התריס • • לעתים מהווים סימן פרוגנוסטי השינויים חולפים לאחר החלמה Euthyroid Sick Syndrome Sick euthyroid syndrome (SES) - probably more common cause of thyroid hormone level abnormalities than intrinsic thyroid disease Changes in thyroid hormone economy • thyroid hormonal synthesis • hormone transport in circulation • action and metabolism in peripheral tissues • regulatory mechanisms (TSH) • • ESS classification Normal-T4 variant - T3 production secondary to peripheral 5'- monodeiodination of T4 serum T3 levels-reflecting disease severity Low-T4 variant - serum T4 levels sufficiently to attain hypothyroid concentrations, secondary to significantly T4 production rates and serum total & free T3 Typically associated with TSH secretion (unknown cause) • High-T4 variant - Unusual (frequency = 1% of SES) Most frequently observed in elderly women חשיבות ESS • אין לפרש שנוי ברמות הורמוני בלוטת התריס במצב זה כמחלה של בלוטת התריס • עדיין לא ידוע אם מצב זה הוא מצב הסתגלות מגן או מצב הגורם נזק • טיפול בהורמוני תריס בחולים עם T4 & T3 אינו משפר את מצבם • תפקודי תריס חוזרים לנורמה לאחר החלמה מהמחלה