1. THYROID TREATMENT AND VITAMIN D UPDATE A CPMC Regional CME Event - An Integrated Approach Saturday October 27, 2012

2. HYPOTHYROIDISM Diana M. Antoniucci, MD, MAS Sutter Pacific Medical Foundation Division of Endocrinology, Diabetes and Osteoporosis Assistant Clinical Professor Medicine University of California, San Francisco

3. IN YOUR OFFICE… 56 yo man presents complaining of fatigue and constipation His PMHx is significant for coronary artery disease What is the best screening test for thyroid disease?

4. HYPOTHYROIDISM 2% of adult women 0.1-0.2% of adult men

5. Fatigue Forgetfulness/Slower Thinking Moodiness/ Irritability Depression Inability to Concentrate Thinning Hair/Hair Loss Loss of Body Hair Dry, Patchy Skin Weight Gain Cold Intolerance Elevated Cholesterol Family History of Thyroid Disease or Diabetes 1 Muscle Weakness/ Cramps Constipation Infertility Menstrual Irregularities/ Heavy Period Slower HR and low voltage ECG Difficulty Swallowing Persistent Dry or Sore Throat Hoarseness/ Deepening of Voice Small or Enlarged Thyroid (Goiter) Peri-orbital Edema CLINICAL FEATURES

6. DIFFERENTIAL DIAGNOSIS Hashimoto’s, or autoimmune thyroiditis – most common Drugs: amiodarone, lithium, interferon, iodide Iatrogenic: post surgical, post RAI rx or post XRT for neck cancer Rare causes: iodine deficiency, central hypothyroidism, peripheral resistance to thyroid hormone.

7. THYROID TESTS Thyroid Function Tests (TFTs): - TSH – good to screen initially - Free T4 – needed to follow patients and to rule out central thyroid disease - Total or Free T3 – to r/o or r/i T3 thyrotoxicosis only - Thyroglobulin – thyroid cancer or presumed subacute thyroiditis Thyroid antibodies - TPO and Tg Ab’s: sensitive for autoimmune thyroid dz, esp. Hashimoto’s - TSH rcptr stimulating immunoglobulins (TSI): specific for Graves’ disease

8. BACK TO OUR CASE… His TSH is elevated at 63 uIU/ml (0.4-4.5) What other laboratories/studies should you order? How could you make a diagnosis of Hashimoto’s?

9. RESULTS His TPO antibodies and TG antibodies are positive No need to check ultrasound in this setting Thyroglobulin level also not necessary Should you treat? If so with what?

10. HYPOTHYROIDISM THERAPY Standard: synthetic thyroxine (T4) - Little intrinsic activity - Converted to T3 in peripheral tissues - Most physiologic replacement Controversy of generics vs brand bioequivalence - 1997 study Synthroid, Levoxyl and 2 generics 1 - Used FDA recommended methodology to determine bioequivalence All 4 preparations were bioequivalent 1 Dong BJ et al. JAMA 1997; 277:1205

11. HYPOTHYROIDISM THERAPY Preferable to stay with one formulation when possible (generics – request same manufacturer) Levoxyl reportedly easier to absorb than Synthroid Tirosint – supposed to be unaffected by concomitant food intake

12. HYPOTHYROIDISM THERAPY Estimated weight based replacement dose: - 1.6 mcg/kg/d Dose depends on cause of hypothyroidism and stage of disease - Athyroid patients tend to need higher doses Starting dose depends on age, co-morbidities and TSH

13. HYPOTHYROIDISM THERAPY In young healthy patients, can start full expected dose (1.6 mcg/kg/d) Older patients start at 25-50 mcg/d Goal of therapy - Symptom amelioration - TSH 1-2 uIU/ml Adjust no more often than every 6-8 weeks Small adjustments are best: - 12 mcg to at most 25 mcg increments in dose

14. BACK TO YOUR OFFICE 56 yo hypothyroid man with hx of CAD START LOW AND GO SLOW: Start low doses of LT4 and slowly increase dose, be particularly careful in patients with heart disease Start LT4 12.5-25 mcg po qd. Recheck TFTs in 4-6 weeks and increase dose as needed Given his CAD, would start very low, increase every 4 weeks until approaching final expected dose

15. ANOTHER DAY IN YOUR OFFICE… 28 yo woman with long standing hypothyroidism On stable replacement dose levothyroxine 112 mcg/d for years She reports fatigue, constipation and more irregular cycles TSH: 9.5 uIU/ml (0.4-4.5) Talking to her you discover she added prenatal vitamins to her regimen…

16. HOW TO TAKE LEVOTHYROXINE Ideally: - 1 st thing in AM - Empty stomach - No food for 30 min - Delay any calcium containing foods at least 1 hr. Move any iron or calcium containing supplements to dinner time.

17. IN THE OFFICE She moves prenatal vitamin to dinner time 6 weeks later, TSH is back down to 1.2 uIU/ml 4 months later, repeat TSH is 3.5 uIU/ml What happened? Pregnancy test is now positive!

18. HYPOTHYROIDISM IN PREGNANCY Requirement of levothyroxine increase 25-50% in pregnancy It is common for TSH to rise early on Recommendations are to maintain TSH <2.5 uIU/ml throughout pregnancy Check TSH, FT4 and TT4 every 4 weeks in first 16 weeks and adjust as needed Management of hypothyroidism in pregnancy is a very appropriate referral to endocrinology Journal of Clinical Endocrinology & Metabolism, 97: 2543–2565, 2012).

19. AND ANOTHER PATIENT… 34 yo woman with 5 year history hypothyroidism TSH has been between 1-2 uIU/ml (0.4-4.5) for a few yrs Reports continued fatigue and not feeling same as before hypothyroidism Should you treat her with combination T4 and T3?

20. HYPOTHYROID PT WITH PERSISTENT SYX Symptoms reported: - Fatigue - Diminished concentration and working memory - Poorer psychological well being Start with evaluation by PCP: - H&P - Labs: CMP, CBC, ESR, celiac dz testing, sleep apnea screening or testing Then Endo evaluation: - 25OHD - Adrenal evaluation Consider possibility of depression

21. TREATMENT WITH COMBINATION THERAPY Multiple randomized trials Systematic review of 11 randomized trials - One trial (n=35): beneficial effects on mood, quality of life and psychometric performance of T4-T3 combo vs T4 alone - Remainder failed to show benefit Subanalysis in one study 1 homozygous polymorphisms in a deiodinase (in 16% people) - Worse baseline neuro-cognitive scores - Significant improvement with combo T4/T3 rx 1 Panicker V et al J Clin Endocrinol Metab 2009; 94: 1623

22. TREATMENT WITH COMBINATION THERAPY Not necessary Up to 16% hypothyroid patients may benefit No genetic test available now Trial in still symptomatic patients is reasonable - T4:T3 ratio of 10:1 to 14:1 - Typically 2.5-5 mcg liothyronine qd to bid added to T4 - Goals of therapy same

23. T3 CONTAINING PREPARATIONS Include desiccated thyroid (Armour), T4-T3 preparations (Thyrolar, Naturethroid) Wide fluctuations in serum T3 concentrations Often unavailable due to manufacturing issues T4/T3 Ratio is not physiological No clear benefit and more difficult to dose and adjust Consider referral for convertion to T4 or T4+T3 Avoid in pregnancy

24. PEARLS TSH best screening test No need to order Tg or ultrasound in patients with hypothyroidism Always review how patients are taking LT4 pills Aim for TSH 1-2 If still symptomatic, consider T3 addition Sensitivity to TSH changes and how much TSH changes in response to dose changes are somewhat variable Refer if: - Pregnancy - Worried about co-morbidities - TSH is not responding as expected - Patients still fatigued even at goal TSH and other causes of fatigue ruled out