Endocrine Physiology Thyroid

1. Endocrine PhysiologyThyroid Bob Bing-You, MD, MEd, MBA Medical Director Maine Center for Endocrinology

2. 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….

3. 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”

4. Diagnosis? • A. Secondary hyperthyroidism • B. Primary hypothyroidism • C. Lab error • D. Fictitious hyperthyroidism

6. 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

7. More History • 1835: Graves noticed thyroid enlargement and eye problems • 1874: atrophy and deficiency noted • 1891: Murray treated 1st case with thyroid extract

8. 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

10. Thyroid Gland • Composed of large number of closed follicles • Hormone stored with large glycoprotein Thyroglobulin • Traps iodide

11. 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

12. 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

15. 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

16. 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

17. How about T3 then? • A. 1 day • B. 5 days • C. 6 weeks • D. None of the above.

18. Daily Production • T4 • 10-15 ug/kg/day • Or…..80 – 100 ug/day • T3 • 30-40 ug/day

19. Thyroid Hormone Physiology • Gland secretion 80% T4, 20% T3 • Deiodinase in peripheral tissues/pituitary convert T4 to T3 and reverseT3 [rT3]

20. 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

21. 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

22. Growth • Can accelerate growth in children when in excess, and vice versa • Growth effect mainly through promoting protein synthesis

23. 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!

24. 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

25. Key Points • Iodine physiology key to thyroid hormone production • Thyroid hormone effects just about everything! • Know differences between T4 vs. T3

26. 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…..

27. 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”

28. Primary vs Secondary • Primary: direct problem with gland secreting end product • Secondary: problem with gland controlling final gland

30. 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

31. Primary Hypothyroidism • TSH is most sensitive test for diagnosis and Rx adjustment • Pituitary/Thyroid & Thermostat/Furnace analogy • Low long-term morbidity, no mortality

33. T4 supplementation • Brand names – T4, ~$14/month • Levoxyl • Synthroid • Unithroid • Levothroid • Brand names – T3 ~$ 35/month • Cytomel • Triostat

34. Thyroid Pharmacokinetics • T4 best absorbed in duodenum and ileum • 80% oral preparation absorbed • T3 95% absorbed • Both less absorbed with severe hypothyroidism

35. 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!

36. 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

37. 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

38. Dosing Considerations • Weight-based • Severity of symptoms • Cardiac failure • Coronary artery disease • Renal disease

39. 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

40. 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

41. 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

42. Questions??

43. 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?

44. Laboratory Testing • TSH <0.2 • Total T4 13 [8.5 – 12.5] • Total T3 222 [80 – 200]

45. And the diagnosis is…. • A. Secondary hypothyroidism • B. Quanternary hyperthyroidism • C. Primary hyperthyroidism • D. Primary hypothyroidism • E. None of the above

47. Primary Hyperthyroidism • Causes • “productive” • Graves Disease • Multi- or single autonomous nodules • “destructive” • Thyroiditis: painless or subacute • exogenous

48. Graves Disease • Women 30-60 years old • Opthalmopathy ~10% • Dermopathy <5% • TSII [Thyroid Stimulating Immunoglobulin] • High concordance rate, 2-hit hypothesis [?Yersinia]

49. Thyroiditis • May be viral cause for inflammation • “leaky” thyroid • Painless form often post-partum • May have antecedent URI symptoms

50. 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