1. هوالطیف

3. Subclinical thyroid dysfunction  Is a common clinical problem (Hypo > Hyper)  Abnormal TSH  Normal T4, FT4, FT4I

4. Changing TSH Reference Limits ~4.0 0.3-0.4 ~5.0 0.5 ~10.0 ? 20042004 ~2.5 0.3-0.4 RIA 1970-85 2 nd gen IMA 1985-90 3 rd gen IMA 1990-00 TSH (mIU/L)

5. National Health & Nutrition Examination Survey NHANES III 0.31.02.03.04.0 Frequency (%) No thyroid disease 13,344 95% TSH 0.3-2.5 Mean TSH 1.49 TSH (mIU/L) Total 17,353 subjects

6. NHANES III Effect of Age on TSH NHANES III Effect of Age on TSH 12-1920-2930-3940-4950-5960-6970-79  80Avg Age (yr) TSH (mIU/L 1.49

7. 28.030.954.685.296.5 8.314.413.518.130.65.55.8 NHANES III Positive Correlation of TPOAb and  TSH NHANES III Positive Correlation of TPOAb and  TSH 0.10.41.01.52.02.53.03.54.04.5510>20 5.7 Subclinical/Overt Hypothyroidism Typical TSH Reference Range Subclinical Hyperthyroidism TSH (mIU/L ) TPOAb (%)

8. So What is Normal TSH Range? TSH reference range of 0.5-5.0 is considered normal based on results of general cross- sectional population studies More recent studies of rigorously screened normal euthyroid volunteers show serum TSH levels 0.5-2.5 mIU/L New TSH reference intervals should be established in studies that exclude subsets with goiter, TPOAb, FHx thyroid dis, meds Target TSH for T4 treatment is now 0.3-3.0

9.  FT4, FT3 Low TSH Clinical Hyper Clinical Hypo Low FT4  TSH Normal FT4 & FT3 Subcl Hyper Normal FT4 TPOAb + Subcl Hypo New TSH range Unequivocally Euthyroid New Spectrum of Thyroid Dysfunction New Spectrum of Thyroid Dysfunction 0.010.110100 0.52.5 TSH (mIU/L)

11. Subclinical Hypothyroidism Subclinical Hypothyroidism Serum TSH >5.0 mIU/L Normal FT4 and FT3 Mild symptoms may be present Definition :

12. Subclinical Hypothyroidism Prevalence : Whickham Study  1.1 - 9% in 12 studies (1977-2002)  Women 2.7-11.6%; Men 1.9-3.4%; Elderly women 8.8-11.6%  White, non-Hispanic 4.8%  Black, non-Hispanic 1.6%  Mexican-American 3.9%  75% with TSH = 5-10 mIu/l Hollowell, 2002; Canaris, 2000; Vanderpump, 1995; Parle, 1991

13. Subclinical Hypothyroidism Whickham Study: Risk of Progression Annual risk 20-yr cumulative Positive test (%) incidence (%) TSH N, Ab + 2.127 TSH , Ab – 2.633 TSH , Ab + 4.355

14. Subclinical Hypothyroidism Whickham Study: Follow-Up  1,877 subjects  Lower risk with young age, lower TSH, Ab neg  Prevalence increased in women with age: 4.5% in 75  Prevalence in men >65 was 6.2%

15. Subclinical Hypothyroidism Colorado Study  25,862 subjects surveyed  Mean age 55  TSH > 5.0 in 9.5%  TSH 5.0 -10 in 74%  TSH >10 in 26%

16. Subclinical Hypothyroidism Causes Autoimmune Thyroiditis Subacute Thyroiditis Post 131 I or Surgery Postpartum Thyroiditis Medications (ATD,Lithium,I 131 )

17. Potential Side Effects   TC and LDLc   Lpa   Homocysteine  LV diastolic dysfunction   Atherosclerosis

18. 5-10 10-15 15-20 20-40 40-60 60-80 >80 LowNormal Colorado Study Mean Cholesterol Levels P<0.001 TSH levels

19. Colorado Study Mean Cholesterol Levels P<0.003 TSH levels

20. Rotterdam Study  Population study of 7,983 (1990-1993)  1,149 women evaluated for Lpids, TSH, Aortic calcifications, ECG and MI  Follow-up chart review in 1996

21. Rotterdam Study Association of MTF with Risk of Atherosclerosis and MI Rotterdam Study Association of MTF with Risk of Atherosclerosis and MI Aortic atherosclerosis Myocardial infarction * * * * Euthyroid Mild hypothyroidism (TSH >4.0) Odds ratio

22. 52-year-old woman with mild fatigue and obesity; thyroid exam is normal TSH= 5.6 FT4 = 1.1 TPO= 420 Q: Do you Rx with T4? a. Yes b. No Case:

23.  Prevent progression to overt hypothyroidism  Reduce TC and CV risk  Improve symptoms Subclinical Hypothyroidism Why Treat?

24.  RCT, 63 F  34 with SCH  Mean TSH 11-14 (range 5-50)  Duration of LT4 therapy = 48 wk  TC  3.8%, LDL C  8.2%  Risk reduction of CAD mortality 17% Subclinical Hypothyroidism Basel Study

25.  Younger pt  TSH >5  TPOAb+   cholesterol Subclinical Hypothyroidism Favoring Treatment ■ Goiter ■ Symptoms ■ Infertility ■ Pregnancy

26. Hypothyroidism: Recommendations for therapy Thyroxin therapy = Euthyrox ® TPO-Antibodies positive Elevated TSH Symptoms, goiter, elevated total or LDL cholesterol, pregnancy, or ovulatory dysfunction with infertility TSH  10 mU/L Check TSH, fT4, TPO-Ab obtain lipid profile TPO-Antibodies negative Annual follow-up (TSH, fT4) or thyroxine therapy TSH < 10 mU/L No symptoms, goiter, elevated total or LDL-C, pregnancy, or ovulatory dysfunction with infertility Adapted from Cooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345(4):260-5

27. Pharmacological Considerationson Thyroid Hormones In the normal adult In the normal adult – 100 µg T4 is secreted by the thyroid daily – 30 µg T3 is produced daily (80% from peripheral de-iodination of T4, 20% from thyroid secretion) Administration of Levothyroxine sodium closely mimics glandular secretion Administration of Levothyroxine sodium closely mimics glandular secretion – Conversion to T3 is appropriately regulated in the tissues – Stable serum T3 concentrations between levothyroxine doses Levothyroxine has a long half-life of approximately 7 days Levothyroxine has a long half-life of approximately 7 days – Small fluctuations in serum concentrations between doses Levothyroxine is the treatment of choice for the routine management of hypothyroidism Levothyroxine is the treatment of choice for the routine management of hypothyroidism

28. Initial Dosing of Levothyroxine in Primary Hypothyroidism Newborns Newborns – 10 - 15 µg/kg/day, i.e. 50 µg/day Children Children – 4-5 µg/kg/day, i.e. 12.5 - 50 µg/day Adults: Adults: – approximately 1.6 µg/kg/day (e.g., 100-125 µg/day for a 70 kg adult) – Patients with known coronary disease: up to 25 µg/day Older patients Older patients – Patients > 60 years with long duration of hypothyroidism: 50 µg/day or less – Patients without clinically overt cardiac disease: 50 µg/day Treatment may aggravate angina in ~20% of patients Treatment may aggravate angina in ~20% of patients

29. Factors That Increase Levothyroxine Requirement Pregnancy, estrogen, tamoxifen, raloxifene Pregnancy, estrogen, tamoxifen, raloxifene Small bowel disease Small bowel disease Drugs or dietary supplements that reduce absorption Drugs or dietary supplements that reduce absorption – Large amounts of fiber, bran, soy protein – Aluminium- or iron-containing drugs, calcium carbonate Drugs that increase metabolism Drugs that increase metabolism – Rifampin, carbamazepine, phenytoin, phenobarbital Drugs that reduce T4 to T3 conversion Drugs that reduce T4 to T3 conversion – Amiodarone, betablockers, propylthiouracil, glucocorticoids and iodine containing contrast media Others (mechanism not known) Others (mechanism not known) – Sertraline, chloroquine/proguanil, lovastatin

30. Case: 46-year-old woman with hypothyroidism is on thyroxine (T4) 0.125 mg daily Q: What do you consider optimal target TSH? a. 0.1b. 1.0 c. 5.0d. 10.0

31. CONCLUSION :  Subclinical thyroid dysfunction is a common (hypo > hyper) clinical problem  Lab TSH reference range should be reset at 0.3-3.0  TSH therapeutic goal should be at 0.3-3.0  Patients with TSH >5 would likely benefit form T4 Rx  TSH >2.5 is associated with a higher risk for clinical hypothyroidism

32. استخراج و طراحی اهداف انتهایی و تقویتی از ماتریس CP  پس از تكميل ماتريس CP اولين قدم در استخراج اهداف ترمينال را طـــــرح سوالات هدايت‌كننده ( Leading Questions ) زير آغاز مي‌شود (به اسلایدهای بعد توجه کنید)  بعد از پاسخ به اين سوالات بكمك قانون ABCD و چك‌ليست SMART و چك‌ليست تکمیلی آنها را بصورت اهداف واضح درآوريم