Hypothyroidism

1. Hypothyroidism Kommerien Daling, MD Chiefs Conference August 14th 2008

2. Overview • Definitions • Epidemiology • Physiology • Symptomatology • Causes of hypothyroidism • Evaluation & treatment • Screening

3. Definitions • Goiter: enlarged thyroid gland, diffuse or nodular. toxic, non-toxic or under-active. • Hypothyroidism: deficiency of thyroid hormone. primary, secondary or tertiary • Subclinical hypothyroidism: TSH concentration above the statistically defined upper limit of the reference range when serum free T4 [thyroxine] concentration is within its reference range

4. Epidemiology • Overt hypothyroidism – prevalence 0.1-2% • Prevalence in HLD – 4.2% • Subclinical hypothyroidism – prevalence 4- 8.5%, 20% in women > 60 • Goiter – 16% in a UK study • Nodules in 50% on autopsies, in 40% with high resolution ultrasound

5. Epidemiology • 95 % is primary hypothyroidism • Hashimoto’s thyroiditis most common cause of hypothyroidism and goiter in non- iodine deficient regions, USA • Appalachia: Hashimoto’s prevalence 6% • Worldwide: 2 billion people I deficient • US urinary iodine excretion 168mcg/L in 2002, 320mcg/L in 1971. • 7% of pregnant women in 2002 vs 1% in 1971 with urinary iodine < 50mcg/l

6. Thyroid hormone biosynthesis Thyroid hormone synthesis includes the following steps: (1) iodide (I-) trapping by the thyroid follicular cells; (2) diffusion of iodide to the apex of the cells; (3) transport of iodide into the colloid; (4) oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid; (5) combination of two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3); (6) uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT; (7) release of T4 and T3 into the circulation; and (8) deiodination of DIT and MIT to yield tyrosine. T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. Modified from Scientific American Medicine, Scientific American, New York, 1995.

7. TSH activity • Increases iodide uptake and transport • Stimulates iodination/organification • Stimulates T4 and T3 synthesis • Increases thyroglobulin levels, TPO, lysosomal activity, T3/4 secretion • Stimulates membrane phospholipase C  thyroid cell hypertrophy  goiter • dopamine, dobutamine, octreotide & stress decrease TSH secretion • glucocorticoids decrease TRH secretion

8. Serum binding proteins • TBG, TTR (transthyretin), albumin, LP • Act as storage and buffer, help maintain free hormone within narrow limits, immediate bioavailability • T4 99.97% bound, TBG 75%, TTR 10%, Albumin 12%, lipoprotein 3% • T3 99.5% bound, TBG 80%, TTR 5%

9. T4 to T3 • Free T3 is 3-5 times more active than free T4 • 80% of T3 is formed by deiodination of T4 in peripheral tissues • Deiodinase type 1 in liver, kidney, thyroid • Deiodinase type 2 in brain, muscle, pituitary & placenta (type 2 not PTU sensitive) • Deiodinase activity uio nutritional, hormonal & illness related factors • Deiodinase type 3: T4  rT3 (elevated in NTIS)

10. Pathways of thyroid hormone metabolism Thyrotropin-releasing hormone (TRH) increases the secretion of thyrotropin (TSH), which stimulates the synthesis and secretion of trioiodothyronine (T3) and thyroxine (T4) by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in the liver and many other tissues by the action of T4 monodeiodinases. Some T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine may be reabsorbed. Drug interactions may occur at any of these sites.

11. Mechanism Symptoms Signs Slowing of metabolic processes Fatigue and weakness Cold intolerance Dyspnea on exertion Weight gain Cognitive dysfunction Mental retardation (infant) Constipation Growth failure Slow movement and slow speech Delayed relaxation of tendon reflexes Bradycardia Carotenemia Accumulation of matrix substances Dry skin Hoarseness Edema Nerve entrapment Coarse skin Puffy facies and loss of eyebrows Periorbital edema Enlargement of the tongue Other Decreased hearing Myalgia and paresthesia Depression Menorrhagia Arthralgia Pubertal delay infertility Diastolic hypertension Hair loss Pleural and pericardial effusions Ascites Galactorrhea Ataxia Major symptoms and signs of hypothyroidism

12. Diagnosis of hypothyroidism • Diagnosis based on labs. Symptoms non- specific Indications to test: • signs or symptoms • goiter • presence of other lab abnormalities (eg Na, lipids, anemia, CK, chol, prolactin) • Presence of hypothalamic or pituitary d/o • Post partum status

13. Diagnostic evaluation • TSH – excellent 1st test (95% is primary dz) • Repeat if abnormal, with fT4 • Distinguish between primary and central (2ndary, 3tiary) • Then distinguish between overt, subclinical

14. DDx of elevated TSH • Primary hypothyroidism • Transient • Recovery from NTIS • Pituitary adenoma • Primary adrenal insufficiency • T4 resistance • TSH resistance at receptor level

15. fT4 low, TSH low • Central hypothyroidism • Imaging indicated to distinguish hypothalamic from pituitary disease • Evaluate for 2dary adrenal insufficiency

16. Algorithm subclinical hypothyroidism

17. USPSTF recommendation for Screening • The USPSTF concludes the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults. • Yield of screening is greater in high-risk groups (e.g., postpartum women, people with Down syndrome, and the elderly), the USPSTF found poor evidence that screening these groups leads to clinically important benefits • There is good evidence that over-treatment with levothyroxine occurs in a substantial proportion of patients, but the long-term harmful effects of over-treatment are not known

18. Screening • The 2002 consensus group's expert panel recommended against population-based screening but "encouraged" assessment in high-risk groups: • Women > 60 • women with a family history of thyroid disease, • prior thyroid dysfunction, • symptoms suggestive of hyperthyroidism or hypothyroidism, abnormal thyroid gland on examination, • type 1 diabetes • personal history of autoimmune disorder Consensus group consisted of members of the ATA, AACE, & ES

19. AAFP recommendation for Screening it is common practice to screen patients with dyslipidemia for hypothyroidism

20. Cost analysis 5 yr-ly screening • F @ 35yo: $9,000/QALY (4000/2000) • F @ 60yo: $5,000/QALY (2000/cost saving) • M: cost x 2.5 • breast cancer screening: $5,000/QALY • HTN screening: $22,000/QALY Medicare does not pay for screening: use symptom

21. Screening in the very elderly? • >85 yo:  TSH associated with survival • evidence for benefit of not treating requires RCT

22. Other tests • fT3 not very useful: often wnl even in severe hypothyroidism • T3 may be low in 70% of hospital patients • rT3 to support dx of NTIS • THBI, T3 resin uptake (T7), free T4 index • Ultrasound (leading to incidentalomas)

23. Nodule &incidentalomaalgorithm REFER to endocrinologist for cost saving

24. Causes of hypothyroidism • Chronic AI thyroiditis – Hashimoto’s • Transient: painless, post partum, subacute thyroiditis • Iatrogenic: injury, medication induced • Defenciency or excess iodine • Infectious thyroiditis • Infiltrative disease • Central hypothyroidism • GRTH –generalized resistance to thyroid hormone

25. age female goiter prior thyroiditis H/O AI-dz, FH of AI Down’s, Turner’s, primary PHTN, MS, excess iodine intake previous injury: (XRT, surgery, chemical exposure – PCBs, resorcinol vigorous physical exam) Risk Factors for thyroiditis

26. Hashimoto’s disease • Goitrous (more common) or atrophic • Humoral and cellular inflammatory proces • In 90% elevated, TPO> TGB> TSHR, Na/I transporter antibodies • Cytotoxic T cells • high incidence in elderly women – ? estrogen deficiency

27. Hashimoto’s disease ctd • Assoc w/ high I intake: anti thyroid antibodies  • smoking assoc w/ onset of hypothyroidism in pre-existent Hashimoto’s • Course: slow onset (months to years), usually permanent, remissions occur • usually presents with non specific sx or goiter, rarely with myxedematous coma, precipitated by stress/infection

28. Hashimoto’s disease ctd • Antibodies can confirm clinical diagnosis, but not strictly necessary to obtain • Ultrasound not necessary, however, useful for assesment of nodules • RAI uptake not indicated

29. Transient hypothyroidism • Silent (painless) thyroiditis = subacute lymphocytic thyroiditis (Hashimoto variant) • Post partum thyroiditis, incidence 8-10%, need to differentiate from Graves, re-eval in 2-4wks • Subacute granulomatous thyroiditis (Quervain), neck pain, diffuse goiter, ? Post viral, 15% permanent • following subtotal thyroidectomy • following RAI for Graves – delayed TSH response

30. Transient hypothyroidism ctd

31. Infiltrative disease • Riedel’s fibrous thyroiditis, often euthyroid • Infectious: strep, staph,TB, PCP • Sarcoid (infiltrative vs associated AI dz) • leukemia • hemochromatosis

32. Iodine deficiency • Iodine deficiency most common cause of goiter & hypothyroidism worldwide • Effect of I deficiency aggravated by goitrogen foods, with anti-thyroid properties (Africa, South America)

33. Examples of foods that contain goitrogens Goitrogens • Cruciferous vegetables including: • Broccoli • Brussel sprouts • Cabbage • Cauliflower • Kale • Kohlrabi • Mustard • Rutabaga • Turnips • Millet • Cassava • Peaches • Peanuts • Radishes • Soybean and soy products, including tofu • Spinach • Strawberries

34. Iodine excess • High I inhibits organification • Wolff Chaikoff effect protects normal subject from sudden I increase through iodination inhibition • High I can cause hypothyroidism in pre- existent Hashimoto’s Excess I in tonics, cough meds, kelp, topical betadine, radiocontrast, • amiodarone (40%)

35. Iatrogenic thyroid dz • total thyroidectomy  hypo in 2-4wks, variable in Graves: majority within 1yr, 0.5-1%/yr there after • RAI for Graves  hypo after months – yrs, or transient • RAI for toxic multinodular goiter  hypo in significant minority • external neck XRT, gradual, dose dependent, subclin for years. S/p Hodgkins XRT: 30% hypo/20yrs

36. Amiodarone:  &  effects, inhibits iodination hypothyroidism found in 7%/21months, mostly in pre-existing thyroid dz Loads autonomous nodules  hyper thyroiditis hyper if euthyroid: T3, fT4, TSH= Lithium:  I transport, T3/T4 release goiter in 50%, hypothyroidism in 20%. Do not withhold Li, treat with T4 Interferon α, interleukin 2  de novo development of Ab (10-15%)  10% dvp dz Medication effects • Monitor TSH Q 6-12 months

37. Medication effects ctd • TSH secretion inhibition: Dopamine, dobutamine, octreotide, glucocorticoids • TSH : metoclopramide • Metformin  TSH, fT4= • Absorption : iron, cholestyramine, ppi, calcium, high fiber diet • Metabolism : anti-epileptic drugs • TBG : estrogen, SERMs, methadone, 5FU • TBG : androgens • deiodinase inhibition: PTU, methimazol, propranolol • Monitor TSH in 4-6 wks after medication change

38. Medication effects ctd • blocks TBG binding: salicylates, some NSAIDs, furosemide • fT4 – heparin iv lipoprotein lipase stimulation  ffa  displace fT4 In short: Review the medication list !!

39. Treatment goals • improvement of symptoms • normalisation of TSH • reduction of goiter • avoid oversuppletion : risk of A-fib in elderly risk of bone loss

40. T4 Treatment • No tx required for transient hypothyroidism • In most cases life-long treatment • T4 treatment reverses all clinical manifestations • Synthetic T4 80% absorbed, on empty stomach, ½ life is 7days • Athyroid pt on T4 achieves pre-op T3 levels • Advantage of pro-hormone: physiologic feedback mechanisms regulate T3 levels • FDA approves brand substitution, endocrine societies don’t

41. T4 Treatment ctd • Average adult dose: Hashi 1.6 mcg/kg/day central 1.9 athyroid 2.1 • timing of dosing may affect fT4 level • initial dose in young: may start full dose • initial dose in frail & >50-60: start 50 or 25, go up by 12.5 – 25/ 3-6wks • recovery starts in 2wks, full recovery in months • full dose vs step-up: quicker lab improvement, clinical improvement equal • Compliance problems: Q week dosing, but not in elderly.

42. Monitoring • Initially Q3-6wks, fT4 normalizes first, then TSH • when stable: TSH Q 1 year • recheck TSH within 4-6 wks of pertinent medication change, change of hormonal status • Central hypothyroidism: monitor fT4

43. T3 replacement ? • Cytomel, Armour thyroid, Thyrolar • Use is NOT recommended • potency/bio-availability varies • T3 treatment leads to wide T3 levels throughout the day • fT4 levels remain low  leads to confusion and inappropriate dosing adjustments

44. Evidence for treatment of suclinical hypothyroidism ?

45. Treatmant of Subclinical hypothyroidism • recent Cochrane review, cited in AFP journal 4/08: • no survival or  CV morbidity (cohort study) • CV mortality for TSH>5, all cause mortality = • QOL/emotional/symptom scores: equal • small  in cognitive function (1 small study)

46. Treatment: special situations • Pregnancy: T4 need @ 8wks, plateau @ 16 wks, TBG, T4 clearance, T4 transfer to fetus. Increase by T4 30% at pregnancy onset, TSH Q4wks, Q trimester when stable • Surgical patient: if hypo: higher freq of ileus, hypotension, Na, CNS dysfx, F with serious infections,  sensitivity to opiods & anaesthesia

47. Treatment: special situations ctd • Unclear indications: obesity, HLD. At least avoid oversuppletion !!!! • Thyroid carcinoma: life long T4 to suppress TSH, if meta’s: TSH < 0.01, others 0.05-0.5, 10 yrs dz free: low normal range • If worsening sx following start of T4 tx: suspect adrenal insufficiency / adrenal crisis. • Myxedema coma: 80% mortality. T4 iv treatment, corticosteroids, do not wait for lab results

48. Bibliography • AFP journal • UpToDate • Publications form the American Thyroid Association, American Association of Clinical Endocrinologists, and the Endocirne Society • Pathophysiology of Disease: An Introduction to Clinical Medicine, 5th Edition Stephen J. McPhee, William F. Ganong • Emedicine

49. Kundalini yoga Idiots think, saints do! Yogi Bhajan