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Thyroid Physiology and Thyroiditis

Thyroid Physiology and Thyroiditis. Heidi Chamberlain Shea, MD Endocrine Associates of Dallas. Case Presentation. 23 year old female G2P2 6 months post partum Palpitations that were intermittent for a couple of weeks and now resolved

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Thyroid Physiology and Thyroiditis

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  1. Thyroid Physiology and Thyroiditis Heidi Chamberlain Shea, MD Endocrine Associates of Dallas

  2. Case Presentation • 23 year old female • G2P2 • 6 months post partum • Palpitations that were intermittent for a couple of weeks and now resolved • Now with 1 month of increased fatigue, hair loss and 10 pound weight gain

  3. Case Presentation • What is her diagnosis? • Tests that should be done? • Pathophysiology of her disease process?

  4. Thyroid Trivia • “Bronchocele” • Greek for tracheal outpouch • 1500 AD described by Leonardo da Vinci • 1656 AD “thyroid” • Thomas Wharton • Shield shaped cartilage

  5. Thyroid Trivia • Largest endocrine gland • 20 grams in adult • Each lobe • 2-2.5cm in width and thickness • 4cm in height • Isthmus • 0.5cm thick • 2cm height and width

  6. Thyroid • Derived from endoderm at base of tongue • Recognizable after 1 month of fetal life • Isthmus lies over 2nd and 3rd tracheal rings • 2cm wide x 2 cm height x 0.5cm thick • Adult 15-20 grams

  7. Largest of the endocrine glands Blood flow 5x the weight of the gland/minute Hormones produced 93% thyroxine (T4) 7% triiodothyronine (T3) 4x the potency of thyroxine Responsible for the basal metabolic rate Deficiency = 40-50% fall in metabolic rate Excess = 60-100% increase in metabolic rate Thyroid

  8. Thyroid Histology • Multiple closed follicles (100-300 micrometers) • Cuboidal epithelial cells secrete colloid into the follicles • Colloid = thyroglobulin • Large glycoprotein with 70 tyrosine amino acids • Endoplasmic reticulum and Golgi apparatus synthesize and secrete

  9. HYPOTHALAMUS (-) HYPOTHALAMIC- PITUITARY PORTAL SYSTEM (-) TRH (+) POSTERIOR ANTERIOR PITUITARY PITUITARY TSH THYROID GLAND T4, T3 (T4 --> T3)

  10. TRH • Produced by Hypothalamus • Release is pulsatile, circadian • Downregulated by T4, T3 • Travels through portal venous system to adenohypophysis • Stimulates TSH formation

  11. TSH • Produced by Adenohypophysis Thyrotrophs • Upregulated by TRH • Downregulated by T4, T3 • Travels through portal venous system to cavernous sinus, body. • Stimulates several processes • Iodine uptake • Colloid endocytosis • Growth of thyroid gland

  12. Thyroid Physiology • Uptake of Iodine by thyroid • Coupling of Iodine to Thyroglobulin • Storage of MIT / DIT in follicular space • Re-absorption of MIT / DIT • Formation of T3, T4 from MIT / DIT • Release of T3, T4 into serum • Breakdown of T3, T4 with release of Iodine

  13. Thyroid and Iodine • 50 mg of iodides are needed per year • 1 mg/week • Iodized salt • 1 part Na iodide to 100,000 parts NaCl • Iodides are ingested and oxidized to iodine in the thyroid • Nascent iodine(Io) or I3- • Peroxidase enzyme (hydrogen peroxide) • 1/5 of ingested iodine utilized for hormone synthesis

  14. Iodide Circulation

  15. Iodine uptake • Na+/I- symport protein controls serum I- uptake • Based on Na+/K+ antiport potential • Stimulated by TSH • Inhibited by Perchlorate

  16. Iodide Pump • Thyroid gland actively pumps iodide into the cell via the basal membrane (iodide trapping) • Iodide 30x the concentration of blood • Able to concentrate to 250x the concentration in blood • Rate of iodide trapping • TSH dependent

  17. Thyroid Hormone Synthesis • Tyrosine backbone • Iodine • Iodinase enzyme (enzyme I) attaches iodine to thyroglobulin • Number of iodines determine activity of thyroid hormone • Thyroxine (4 iodines) • Triiodothyronine (3 iodines)

  18. MIT / DIT Formation • Thyroid Peroxidase (TPO) • Apical membrane protein • Catalyzes iodide oxidation to reactive iodine • Binds to Tyrosine residues of Thyroglobulin • Antagonized by thionamides • Coupling enzyme • MIT with DIT= T3 • Two DIT’s= T4 • Pre-hormones secreted into follicular space

  19. Transport of T3 and T4 • When in circulation • 93% thyroxine and 7% triiodothyronine • Conversion to active (T3) is by slow deiodination process • 99% of T4 and T3 bound to plasma proteins • Causes slow release of hormone to tissue • Thyroxine-binding globulin (TBG) • Tyroxine-binding prealbumin and albumin

  20. Secretion of Thyroid Hormone • Stimulated by TSH • Endocytosis of colloid on apical membrane • Coupling of MIT & DIT residues • Catalyzed by TPO • MIT + DIT = T3 • DIT + DIT = T4 • Hydrolysis of Thyroglobulin • Release of T3, T4 • Release inhibited by Lithium

  21. Thyroid Hormones

  22. Thyroglobulin Storage • Thyroglobulin molecule • 30 thyroxine molecules • Few triiodothyronine • Sufficient supply for 2-3 months • Deiodinase enzyme recycles iodine when thyroglobulin utilized

  23. Thyroid Hormone • Metabolic effect of thyroxine noticed 2-3 days after release • Steady state of thyroid hormone 10-12 days after ingestion • Half life of 15 days • Due to steady state, thyroid hormone is typically adjusted every 4-6 weeks • Check T4 vs. TSH in the short term assessment

  24. Thyroid Hormone • Majority of circulating hormone is T4 • 98.5% T4 • 1.5% T3 • Total Hormone load is influenced by serum binding proteins • Thyroid Binding Globulin 70% • Albumin 15% • Transthyretin 10% • Regulation is based on the free component of thyroid hormone

  25. Hormone Binding Factors • Increased TBG • High estrogen states (pregnancy, OCP, HRT, Tamoxifen) • Liver disease (early) • Decreased TBG • Androgens or anabolic steroids • Liver disease (late) • Binding Site Competition • NSAID’s • Furosemide IV • Anticonvulsants (Phenytoin, Carbamazepine)

  26. Hormone Degradation • T4 is converted to T3 (active) by 5’ deiodinase • T4 can be converted to rT3 (inactive) by 5 deiodinase • T3 is converted to rT2 (inactive)by 5 deiodinase • rT3 is inactive but measured by serum tests

  27. Nervous system Forgetfulness and mental slowing Paresthesias Carpal tunnel Ataxia and decreased hearing Tendon jerk slowed with prolonged relaxation phase Cardiovascular Bradycardia Decreased cardiac output Pericardial effusion Reduced voltage on EKG and flat T waves Dependent edema Hypothyroidism Symptoms

  28. Gastrointestinal Constipation Achlorhydria with pernicious anemia Ascitic fluid with high protein Renal Reduced excretion of water load Hyponatremia Decreased renal blood flow and glomerular filtration Pulmonary Responses to hypoxia and hypercapnia are decreased Pleural effusions high protein Musculoskeletal Arthralgia Joint effusions Muscle cramps CK can be elevated Anemia Normochromic normocytic Megaloblastic Pernicious anemia HypothyroidismSymptoms

  29. Skin and hair Loss of lateral eye brows Dry, cool skin Facial features Coarse and puffy Orange skin Carotene Reproductive system Menorrhagia from anovulatory cycles Hyperprolactinemia No inhibition of thyroid hormone Metabolism Hypothermia Intolerance to cold Increased cholesterol and triglyceride Decreased lipoprotein receptors Weight gain HypothyroidismSymptoms

  30. Thyroid Hormone • Metabolic effect of thyroxine noticed 2-3 days after release • Steady state of thyroid hormone 10-12 days after ingestion • Half life of 15 days • Due to steady state, thyroid hormone is typically adjusted every 4-6 weeks • Check T4 vs TSH in the short term assessment

  31. HypothyroidismEtiologies • Thyroiditis • Thyroid ablation • External radiotherapy • Pharmacologic agents • Infiltrative disorders • Embryologic variants

  32. Thyroiditis • Decreased uptake on uptake scan • Transient • Euthyroidism returns with time • Lead to chronic thyroid dysfunction • Etiology • Infectious • Post-partum • Auto-immune • Transient • Chronic • Drug

  33. Thyrotoxic phase Short phase Increased T3 and T4 Symptoms of hyperthyroidism Thionamides not effective Thyroid synthesis low Can use beta-blockers Hypothyroid phase Transient or permanent Symptomatic patients need replacement Can check for recovery with stopping after 3-6 months Thyroiditis

  34. ThyroiditisTime Course Williams Text of Endocrinology, Fig 11.50

  35. Etiology Bacterial 90% Fungal Mycobacterial Parasitic Syphilitic Symptoms Thyroid pain and tenderness Fever Dysphagia Dysphonia Treatment Treat the infection Infectious Thyroiditis

  36. Chronic Lymphocytic Silent Thyroiditis Hashimoto’s Women 3.5/1000 Men 0.8/1000 Frequency increases with age Familial history Associated with autoimmune diseases Antibodies Thyroid peroxidase More specific Thyroglobulin Elevated in many types of thyroid inflammation Autoimmune Thyroiditis

  37. Postpartum thyroiditis 2-21% of pregnancies Can occur up to one year post partum Usually transient and returns to euthyroid state Treat Hypothyroidism Symptoms with ‘hyperthyroidism’ Presence of TPO AB increases risk of long term hypothyroidism Thyroiditis

  38. Transient/Destructive Thyroiditis • Subacute • 20% of thyrotoxic cases • De Quervain’s thyroiditis • Giant cell thyroiditis • Pseudogranulomatous thyroiditis • Subacute painful thyroiditis • Symptoms • Pain • Fever • Increased ESR • Hoarseness or dysphagia • Treatment • ASA, NSAID • Steroid rarely

  39. Comparison of Thyroiditis

  40. Lithium Inhibits thyroid hormone secretion Hypothyroidism 3.4% prevalence Interferon-α Hyper/Hypothyroidism Transient thyroiditis TPO AB increases risk of thyroid dysfunction Interleukin-2 Aminoglutethimide Ethionamide Sulfonamides Drug Induced Thyroid Dysfunction

  41. Drug Induced Thyroid Dysfunction • Amiodarone • 75 mg iodine/200 mg • Hypothyroidism • Thyrotoxicosis • Type I and Type II • Increased blood flow vs. decreased blood flow • Not responsive to thionamides

  42. Riedel’s thyroiditis Invasive Fibrous Thyroiditis Thyroid tissue replaced by fibrous tissue Rapidly enlarging neck mass Compressive symptoms Surgical removal Steroids and tamoxifen Amyloidosis Sarcoidosis Hemochromatosis Cystinosis Pneumocystis carinii Lymphoma HypothyroidismInfiltrative Disorders

  43. 1.3 ug/kg/day 75-100 ug per day Elderly or patients with angina 12.5-25 ug/day Carefully increase every month IV dosing Use 60% of oral dose Levothyroxine Synthroid Levoxyl Unithroid Armour Thyroid T3/T4 preparation Dessicated pig thyroid Not a consistent amount of T3/T4 Most T3 preparations give higher than 1:11 ratio of T3:T4 Thyroid Hormone Replacement

  44. Case Presentation • 23 year old female • G1P1 • 6 months post partum • Palpitations that were intermittent for a couple of weeks and now resolved • Now with 1 month of increased fatigue, hair loss and 10 pound weight gain

  45. Case Presentation • What is her diagnosis? • Post partum thyroiditis • Tests that should be done? • TSH 15 uIU/ml, Free T4 1.2 ng/dl • TPO AB negative • Pathophysiology of her disease process? • Transient • Treatment • Levothyroxine therapy • Recheck every 6-8 months • After 3-6 months may be able to wean replacement

  46. Post Partum ThyroiditisTime Course Changes in free T4 Williams Text of Endocrinology, Fig 11.51

  47. Williams Text of Endocrinology, Fig 12.6

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