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Endocrine Physiology Thyroid Bob Bing-You, MD, MEd, MBA Medical Director Maine Center for Endocrinology A case of fatigue • 28 y.o. white female c/o 4 month h/o increasing fatigue • 2 children, ages 4 and 7 • Sleeping all day, weight up 15 lbs, labile moods • Dry skin, constipation, no periods for 6 mos • She’s worried she’s pregnant…. Laboratory Testing • Thyrotropin Stimulating Hormone [TSH] = >100 [NR 0.27-4.2 mU/ml] • Free T4 = 0.4 ug% [0.7-1.8] • Total T3 = 70 ug% [80-200] • Thyroid “antibodies” [anti-thyroglobulin, anti-microsomal] “moderately positive” Diagnosis? • • • • A. Secondary hyperthyroidism B. Primary hypothyroidism C. Lab error D. Fictitious hyperthyroidism History of the Thyroid • • • • • 1st described 1656 lubricated the trachea vascular shunt to the brain larger size gave grace to women 1700’s:no important physiological role More History • 1835: Graves noticed thyroid enlargement and eye problems • 1874: atrophy and deficiency noted • 1891: Murray treated 1st case with thyroid extract Thyroid Hormone • Lack of thyroid secretion causes BMR to fall 40% • Extreme thyroid hormone excesses can cause BMR >60-100% above normal • Thyroid secretion under control of anterior pituitary gland Thyroid Gland • Composed of large number of closed follicles • Hormone stored with large glycoprotein Thyroglobulin • Traps iodide Iodine • Average ingestion 1 mg. per week • Breads, ice cream, sea kelp • Iodide pump on thyroid cell membrane can concentrate in cell 40 x concentration in blood Hormone Biosynthesis • Organification: – iodide oxidized to iodine – combines with tyrosine residues to form monoiodotyrosine and diiodotyrosine – MIT and DIT combine with TG to make T3 and T4 • 5-6 T4 molecules/TG, 1 T3/3-4 TGs • Can store up to 3 months requirement • exocytosis at colloid border for release Thyroid Hormone Physiology • • • • Thyroxine, Triiodothyronine T3 4 x more potent than T4 Free components are biologically active 99% protein-bound, mainly Thyroid Binding Globulin [TBG] • High affinity of TBG for T4 • Half-life T4 7 days, 1 day for T3 If you were to change T4 dose, how long would you wait to recheck a TSH? • • • • A. 7 days B. 3 weeks C. 6 weeks D. 10 weeks How about T3 then? • • • • A. 1 day B. 5 days C. 6 weeks D. None of the above. Daily Production • T4 – 10-15 ug/kg/day – Or…..80 – 100 ug/day • T3 – 30-40 ug/day Thyroid Hormone Physiology • Gland secretion 80% T4, 20% T3 • Deiodinase in peripheral tissues/pituitary convert T4 to T3 and reverseT3 [rT3] Mechanism of Action • Free forms enter cells • T4 converted to T3 by 5’-deiodinase • T3 binds to nuclear receptors, RNA formation, protein synthesis • actions delayed by hours or days Effects of Thyroid Hormones • Increase metabolic rate almost all tissues [except brain, lungs, spleen] • Increase protein synthesis • Increase >100 cellular enzyme systems • Cell mitochondria increase size and number Growth • Can accelerate growth in children when in excess, and vice versa • Growth effect mainly through promoting protein synthesis Excess Effects on Metabolism • Stimulates almost all aspects of carbohydrate metabolism [e.g., glycolysis] • Can deplete fat stores, increase FFA in blood • Decrease LDL • Weight up and down! More effects with higher levels • • • • • • • Increases blood flow, vasodilation Need for heat elimination Heart rate very sensitive index Increases respiratory rate and depth Increased GI motility Weaken muscles due to protein catabolism Fine tremor 10-15x/second Key Points • Iodine physiology key to thyroid hormone production • Thyroid hormone effects just about everything! • Know differences between T4 vs. T3 A case of fatigue • 28 y.o. white female c/o 4 month h/o increasing fatigue • 2 children, ages 4 and 7 • Sleeping all day, weight up 15 lbs, labile moods • Dry skin, constipation, no periods for 6 mos • She’s worried she’s pregnant….. Laboratory Testing • Thyrotropin Stimulating Hormone [TSH] = >100 [NR 0.27-4.2 mU/ml] • Free T4 = 0.4 ug% [0.7-1.8] • Total T3 = 70 ug% [80-200] • Thyroid “antibodies” [anti-thyroglobulin, anti-microsomal] “moderately positive” Primary vs Secondary • Primary: direct problem with gland secreting end product • Secondary: problem with gland controlling final gland Causes Primary Hypothyroidism Autoimmune Thyroid Disease [“Hashimoto’s Disease”] – – – – Very common [5-20 per 1000] Women > men Age [4th-5th decade] Antibodies may be positive • Surgery • Congenital Primary Hypothyroidism • TSH is most sensitive test for diagnosis and Rx adjustment • Pituitary/Thyroid & Thermostat/Furnace analogy • Low long-term morbidity, no mortality T4 supplementation • Brand names – T4, ~$14/month – – – – Levoxyl Synthroid Unithroid Levothroid • Brand names – T3 ~$ 35/month – Cytomel – Triostat Thyroid Pharmacokinetics • T4 best absorbed in duodenum and ileum – 80% oral preparation absorbed • T3 95% absorbed • Both less absorbed with severe hypothyroidism Thyroid Pharmacokinetics • Half-life – T4 = 7 days – T3 = 1 day • Oral supplementation typical route; IV available, 75% of oral dosing • Synthetic formulation preferred vs. animal [“Armour”] • Brand and generic are not the same dose! TSH is the most sensitive test for screening because: • • • • • A. Least expensive B. Comes in a thyroid panel C. Is a pituitary hormone D. Changes more with small T3 changes E. Involved in negative feedback T4 vs. T3?? • T4 is just fine – Long-term experience of majority of healthy patients – No case report of inability to convert to T3 • T3 advocates – More natural, few studies showing small QOL improvement • Adverse effects [sx’s, a-fib, bone loss] TSH is most sensitive test for diagnosis and Rx adjustment Dosing Considerations • • • • • Weight-based Severity of symptoms Cardiac failure Coronary artery disease Renal disease Drug Interactions • Malabsorption – Iron, sucralfate, bile acid resins, AlOH • Changes in TBG – Oral estrogen, liver inflammation [e.g. Niacin] • Increased clearance: phenytoin, carbamazepine • Anti-coagulants – Hypothyroidism prolong bleeding Hypothyroidism & Surgery? • Intraoperative hypotension; less responsive to pressor agents • Lower cardiac rate • Slow to wean from vent • Less fever manifestations • More heart failure in cardiac surgery pts. • More constipation, ileus; more confusion • No significant increase mortality Take-home Points - Hypothyroid • • • • TSH most sensitive and cost-effective test Signs and symptoms not very specific T4 supplementation fairly easy Hypothyroid patients do generally well with surgery Questions?? A Case of More Fatigue! • 44 y.o. white male, 2 month h/o fatigue with exertion • Normally runs 4-6 miles/day, more winded • Sweats, loose stools, resting pulse up to 88 • Weight down 10 lbs. Aunt had “thyroid problem.” • Diagnosis? Laboratory Testing • TSH <0.2 • Total T4 13 [8.5 – 12.5] • Total T3 222 [80 – 200] And the diagnosis is…. • • • • • A. Secondary hypothyroidism B. Quanternary hyperthyroidism C. Primary hyperthyroidism D. Primary hypothyroidism E. None of the above Primary Hyperthyroidism • Causes – “productive” • Graves Disease • Multi- or single autonomous nodules – “destructive” • Thyroiditis: painless or subacute – exogenous Graves Disease • • • • Women 30-60 years old Opthalmopathy ~10% Dermopathy <5% TSII [Thyroid Stimulating Immunoglobulin] • High concordance rate, 2-hit hypothesis [?Yersinia] Thyroiditis • • • • May be viral cause for inflammation “leaky” thyroid Painless form often post-partum May have antecedent URI symptoms Drug Causes • Amiodarone – Long half-life, can cause productive or destructive picture, hypothyroidism – Blocks T4 to T3, uptake not helpful • Lithium – More hypo- than hyperthyroidism • Iodinated contrast agents Evaluation • TSH for screening • T 4 and T3 needed for severity • 24 hour iodine uptake – Productive vs. destructive • TSII [TSH-like antibodies] – Other antibodies non-specific [I.e., antithyroglobulin, anti-microsomal] Hyperthyroidism & Surgery? • • • • More hypertension Higher chance tachyarrhythmias ?higher catecholamine binding sites Probably no increase mortality Treatment - General • Beta-blockers – Propanolol 80-180 mg/day • Better inhibition of T4/T3 conversion – Good for adrenergic sx’s – Can’t use in asthma and heart failure • Hydration Anti-thyroid Medications • • • • Propylthiouracil, Methimazole [Tapazole] 1928: rabbits fed cabbage developed goiters Thioamides developed 1940’s Concentrated in thyroid, inhibit biosynthesis by blocking organification of iodine • PTU also blocks T4/T3 conversion Pharmacokinetics • PTU rapidly absorbed, peak 1 hr; Tapazole variable • MMI ½ life = 4-6 hours • PTU ½ life = 1-2 hours PTU/MMI • Immunosuppressive actions – Decrease TSII production – Decrease intrathyroidal T cells • PTU more protein-bound – Pregnancy, breast-feeding PTU/MMI • Dosing depends on severity – MMI can be once a day • Adverse effects – Pruritis, GI 2-5% – Metallic taste – Rare [1/600] agranulocytosis, hepatocellular damage Other agents • Saturated Solution Potassium Iodide [SSKI] 5-10 drops several times daily – also decreases vascularity pre-op • Lithium 300 mg qid • Glucocorticoids – Block T4/T3 conversion – Prednisone 50-60 mg/day Thyroid “Storm” • Life-threatening, usually with underlying major illness [e.g., acute infection] • Fever, tachycardia, N/V, acute abdomen, cardiac failure, agitation….continuum • Rx = hydration, high doses of PTU and IV glucocorticoids, then SSKI few hours later Radioactive Iodine • I131 for beta particles • Usually one-time dose • Goal= ablation with subsequent hypothyroidism • No long-term side effects in 50 years • ~$1,000/treatment Thyroiditis Treatment • 24 hour iodine uptake <5% • Symptomatic treatment only [beta-blockers] • Hypothyroid phase possible, lasting 2-3 mos, may need LT4 • ~20% permanently hypothyroid Graves Disease Treatment • RAI vs. medical Rx vs. surgery • 25-30% remission rate after 2 years of medical Rx Autonomous nodules • Multinodular goiters – common in elderly – RAI preferred • Single “hot” nodules – RAI preferred – Usually euthyroid post-RAI Take-home Points - Hyperthyroid • Graves disease vs. thyroiditis differentiation • TSH still best screening lab • Medical Rx 1st option for treatment over surgery • Cardiovascular effects biggest concern perioperatively Euthyroid Sick Syndrome • • • • Low, normal, or mildly high TSH Low Total T4 Normal Free T4 [watch out for heparin] Low TT3 and Free T3 Euthyroid Sick Syndrome • • • • Blockage of T4 to T3 conversion Less binding to TBG “recovery phase” Bottom line: no evidence to suggest replacement Rx improves outcomes