1. Impact of “Mild-Subclinical” Thyroid Disease on Cardiovascular Health Harry L. Uy, MD UP College of Medicine Class 1986 Private Practice, Endocrinology Clinical Associate Professor UTHSC-San Antonio

2. Should mild thyroid dysfunction be treated? Is there any clinical consequence if this is left untreated?

3. Subclinical Hyperthyroidism Definition Normal T4, FT4, TT3, FT3 TSH = Low –Not necessarily below the limit of detection Some patients have symptoms of “mild hyperthyroidism” – more often than not, this remains unrecognized

4. Subclinical Hyperthyroidism Small Increase in Free T4 = Large Decrease in TSH 0.8 ng/dl 1.8 ng/dl4.5 mU/L 0.45 mU/L Free T4TSH Normal RangeChangeNormal RangeChange

5. Subclinical Hyperthyroidism: Definition and Prevalence Usually asymptomatic 1 Low or undetectable serum TSH 1 Normal or borderline serum FT 4 and FT 3 1 Variable prevalence (0.7% to 6.0%) 2 More common in women 3 More common in older people than overt hyperthyroidism 4 Most common cause is overtreatment with L-thyroxine 1. Ross DS. Mayo Clin Proc. 1988;63:1223. 2. Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016. 3. Sawin CT. Adv Intern Med. 1991;37:223. 4. Sawin CT et al. N Engl J Med. 1994;331:1249.

6. Common Causes of Subclinical Hyperthyroidism Exogenous Excessive thyroid hormone replacement Thyroid hormone suppressive therapy Endogenous Thyroid gland autonomy: thyroid adenoma or multinodular goiter Graves’ disease Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016.

7. Physiological Effects of Subclinical Hyperthyroidism ↓  bone density ↑  serum osteocalcin ↑  urinary hydroxyproline and pyrrolidine links ↑  heart rate ↑  risk of atrial fibrillation ↑  cardiac contractility 2 ↑  LV mass index ↑  intraventricular septal and posterior wall thickness 1. Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016. 2. Biondi B et al. J Clin Endocrinol. 1993;77:334.

8. Total and LDL cholesterol Liver enzymes Creatine kinase Sex hormone binding globulin Time asleep at night Mood (using multidimensional scale for state of well-being) Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016 Other Biological Effects of Subclinical Hyperthyroidism

9. Frost, L. et al. Arch Intern Med 2004;164:1675-1678. Hyperthyroidism Risk of Atrial Fibrillation or Flutter A Population-Based Study

10. Frost, L. et al. Arch Intern Med 2004;164:1675-1678.

11. Incidence of Atrial Fibrillation (%) 3025 20 15 10 5 0 Low Thyrotropin (TSH <0.1) Years 0123456789 10 High Thyrotropin Normal Thyrotropin Slightly Low Thyrotropin Serum Thyrotropin Values at Baseline Sawin CT et al. New Engl J Med. 1994;331:1249. Subclinical Hyperthyroidism Atrial Fibrillation

12. 2007 subjects > 60 yo (1193 women, 814 men) TSH measured; 10 year follow-up Relative Risk 4 2 0 3.1* < 0.1 Subclinical Hyperthyroidism Risk of Atrial Fibrillation Sawin CT, NEJM 331: 1249, 1994 0.1-0.4TSH mU/L0.4-5.0> 5.0 1.6 1.0 1.4

13. Subclinical Hyperthyroidism Atrial Fibrillation Mean age (66-68), prevalence of underlying CV disease (57-65%) similar in all 3 groups Auer et al. Am Heart J. 2001 2.3% 12.7% 13.8% 0% 2% 4% 6% 8% 10% 12% 14% 16% Controls (n=22,300) Subclinical Hyperthyroidism (n=725) (TSH<0.03) Overt Hyperthyroidism (n=613) *P<0.01 * *

14. Thyroid Function Status and Isovolumetric Contraction Time (ICT) ICT (ms) 80 70 60 50 40 30 20 10 0 Overt hyper I Overt hyper II Subclin hyper Normal euthyroid Mild thyroid failure Overt hypo II Overt hypo I ∗,∗,†,∗,†,†,‡,†,‡ § ‡ º Tseng KH et al. J Clin Endocrinol Metab. 1989;69:633. ∗ P<.0005 vs normal euthyroid; † P<.0005 vs overt hyper I; ‡ P<.05 vs euthyroid controls; § P<.05 vs overt hypo I;  P<.005 vs normal euthyroid.

15. Survival vs Thyroid Function 1191 subjects in Birmingham, UK Enrollment 1988-89, Analyzed 1999 > 60 y/o, Mean age 70 y/o 509 died during the 10 yrs Exclusions: Thyroid Hormone or ATD Parle J et al Lancet 358:861,2001

16. Survival vs Serum TSH Age > 60 yrs Parle J et al Lancet 358:861,2001 100 80 60 45 S u r v i v a l ( % ) TSH <0.5 >5.0 2.1-5.0 1.3-2.0 0.5-1.2 Cardiovascular events were responsible for the excess mortality No difference between TSH < 0.1 and TSH 0.1-0.5 mU/L

17. Subclinical Hyperthyroidism Concerns n Osteoporosis n Atrial fibrillation n Cardiac dysfunction n Progression to overt disease

18. Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016. Prevention and Treatment of Subclinical Hyperthyroidism Endogenous Because low TSH is often transient, careful monitoring is needed Consider antithyroid drug treatment or radioiodine therapy (depending on etiology) Exogenous Careful titration of L-thyroxine to maintain normal TSH Use smallest L- thyroxine dose needed to meet therapeutic goals

19. Subclinical Hypothyroidism Definition Elevated TSH (80-85% < 10 mU/L) Normal Free T4 + Anti-TPO antibodies in 60-80% “Mild hypothyroidism” “Mild thyroid failure”

20. Subclinical Hypothyroidism Small Decrease in Free T4 = Large Increase in TSH 0.8 ng/dl 1.8 ng/dl Free T4 Normal RangeChange 4.5 mU/L 0.45 mU/L TSH Normal RangeChange

21. Progression of Mild Thyroid FailureYears NORMAL RANGE TSH Overt Hypothyroidism Mild Thyroid Failure Euthyroid T3T3T3T3 T4T4T4T4 Adapted from Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44.

22. Subclinical Hypothyroidism Prevalence - Women 25% 20% 15% 10% 5% 0% Whickham (n=2,779) Colorado (n=25,862) Age ~ 30 yr.~ 50 yr.~ 80 yr. Tunbridge W, Clin Endo 7:481, 1977 Canaris G, Arch Intern Med 160:526, 2000 Hollowell J, J Clin Endo Metab 87: 489, 2002 NHANES (n=17,353)

23. Diagnosing Mild Thyroid Failure: The Challenge Insidious onset Patients often have few specific clinical symptoms or signs Symptoms are ordinary and nonspecific Specific age- and gender-related presentations Ladenson PW. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:878.

24. Subclinical Hypothyroidism Issues n Lipid elevation n CAD risk factor n Cardiac function n Progression to overt disease

25. Why Treat Patients With Mild Thyroid Failure With L-Thyroxine? Prevent progression to overt hypothyroidism 1 Alleviate symptoms 1,2 Normalize serum lipids 1,3 Normalize cardiac function 2,4 May help depression 5 1. Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44. 2. Cooper DS et al. Ann Intern Med. 1984;101:18. 3. Kinlaw WB. Thyroid Today. 1991;14:1. 4. Nystrom E et al. Clin Endocrinol. 1988;29:63. 5. Hennessey JU, Jackson IMD. The Endocrinologist. 1996;18:214.

26. Types of Lipid Abnormalities in Patients With Hypothyroidism33.6% 1.5% 8.6% 56.3% Hypercholesterolemia (  200 mg/dL) Hypertriglyceridemia (  150 mg/dL) Hypercholesterolemia and mild hypertriglyceridemia Normal Lipids N = 268 O’Brien T et al. Mayo Clin Proc. 1993;68:860.

27. LDL-C Levels Increase With Increasing Hypothyroidism Grade C=controls. *P<.01 vs controls. P<.001 vs controls. C=controls. *P<.01 vs controls. † P<.001 vs controls. LDL-C (mg/dL) ** Hypothyroidism Grade * C1234* 55†55† 1.13.08.622.744.463.7 Basal TSH (mU/L) 144 133 137 168 191 246250235 220 205 190 175 160 145 130 overt Staub JJ et al. Am J Med. 1992;92:631.

28. Subclinical Hypothyroidism Lipid Changes with LT4 Therapy 0 5 10 Total Cholesterol LDL Cholesterol Meta-analysis: 13 Studies 247 patients Mean TSH 4.8-19.0 mU/L Danese M, J Clin Endo Metab 85:2993, 2000 Cholesterol Reduction (mg/dl) -7.9 mg/dl -10.3 mg/dl (No subgroup with TSH < 12)

29. Group 1 (N=6) Group 2 (N=6) Group 3 (N=7) BeforeAfter 450 400 350 300 250 200 150 100 50 0 TC* LDL-C* TC* LDL-C* TC* LDL-C* TSH before: 7.0 mU/L TSH after: 1.9 mU/L TSH before: 18.6 mU/L TSH after: 1.5 mU/L TSH before: 154.9 mU/L TSH after: 1.8 mU/L *=mg/dL. 1 Values are means ±SD. Diekman T et al. Arch Intern Med. 1995;155:1490. Effect of L-Thyroxine Treatment on Lipid Levels in Dyslipidemia 1

30. Effect of L-Thyroxine Therapy on Hypercholesterolemia in Patients With Mild Thyroid Failure “The decrease in total cholesterol achieved with L-thyroxine replacement] substitution therapy in patients with subclinical hypothyroidism [mild thyroid failure] may be considered as an important decrease in cardiovascular risk favoring treatment.” Tanis BC et al. Clin Endocrinol. 1996;44:643.

31. Cardiovascular Changes Often Associated With HypothyroidismHypothyroidism ECG changes Apparent cardiomegaly Decreased myocardial contractility, myocardial oxygen demand, cardiac output Increased diastolic pressure, peripheral vascular resistance Klein I, Ojamaa K. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:799.

32. Subclinical Hypothyroidism Issues n Lipid elevation n CAD risk factor n Cardiac function n Progression to overt disease

33. Random Sample: 1149 Females (age: 69 +/- 7.5 yr) TSH Elevated: 10.8% (> 4 mU/L) End Points: Aortic Atherosclerosis (Aortic Calcification) Myocardial Infarction ( EKG) Methods: Cross-sectional Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study Hak AE,l Ann Int Med 132:270, 2000

34. 01234 Aortic Calcification Myocardial Infarction High TSH + TAB High TSH Euthyroid Odds Ratio Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study Hak AE,l Ann Int Med 132:270, 2000 *Adjusted for age, BP, BMI, smoking, lipids

35. When to Suspect Mild Thyroid Failure Hypercholesterolemia 1,2 Refractory depression 2 Previous episode of postpartum thyroiditis 2 Goiter 1 Family or personal history of thyroid disease 1 Over 40 with nonspecific complaints 2 Insidious weight change Unexplained infertility 2 Overweight 1. Ayala AR, Wartofsky L. The Endocrinologist. 1997;44:401. 2. Weetman, AP. British Journal Med. 1997;314:1175.

36. Hypothyroidism: Many Causes, One Treatment Goal: normalize TSH level regardless of cause of hypothyroidism 1 Treatment: once daily dosing with L-thyroxine (1.6  g/kg/day) 2 Monitor TSH levels at 6 to 8 weeks, after initiation of therapy or dosage change 3 If lipids are elevated, recheck when euthyroid 1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883. 2. AACE. Endocrine Pract. 1995;1:56. 3. Singer PA et al. JAMA. 1995;273:808.

37. Management of Hypothyroidism: Special Patient Populations Special Patient Populations Heart Disease 2 Postmenopausal Age >50 years 1 Psychiatric Illness 3 Use of Certain Drugs 2 Chronic Illness Pregnant/postpartum 2 1. Singer PA et al. JAMA. 1995;273:808. 2. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883. 3. Whybrow PC. AMA. 1994;21:47.

38. 1. Stall GM et al. Ann Intern Med. 1990;113:265. 2. Ridgway EC. Family Practice Recertification. 1992;14:127. Over-Replacement Risks Reduced bone density/osteoporosis 1 Tachycardia, arrhythmia, 2 atrial fibrillation In elderly or patients with heart disease, angina, arrhythmia, or myocardial infarction 2 Under-Replacement Risks Continued hypothyroid state Long-term end-organ effects of hypothyroidism Increased risk of hyperlipidemia Over- and Under-Replacement Risks

39. Consensus Statement: Subclinical Thyroid Dysfunction: - A Joint Statement – AACE, ATA, Endocrine Society. Gharib H. et al. JCEM 90:581-585. Subclinical Hypothyroidism Treatment reasonable for patients with TSH levels >10 mU/liter Treatment should be considered with TSH levels of 4.5-10 mU/liter with key determinant being the clinical judgment of the provider Subclinical Hyperthyroidism Treatment recommended with TSH <0.1 mU/liter even if asymptomatic and with room to observe and monitor in patients with partial TSH suppression (0.1-0.4 mU/liter) Consensus Statement

40. Subclinical Thyroid Disease and the Heart “When the Thyroid Speaks…the Heart Listens” MA Sussman Circ. Res 2001