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Cardiovascular Disease Risk and Mild Thyroid Failure

Cardiovascular Disease Risk and Mild Thyroid Failure. Sponsored by ACCESS Medical Group Department of Continuing Medical Education Funded by an unrestricted educational grant from Abbott Laboratories. Introduction to Mild Thyroid Failure. Definition of Mild Thyroid Failure.

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Cardiovascular Disease Risk and Mild Thyroid Failure

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  1. Cardiovascular Disease Risk and Mild Thyroid Failure Sponsored by ACCESS Medical Group Department of Continuing Medical Education Funded by an unrestricted educational grant from Abbott Laboratories.

  2. Introduction to Mild Thyroid Failure

  3. Definition of Mild Thyroid Failure • Elevated thyroid stimulating hormone ([TSH]; >4.0 IU/mL) • Normal total or free serum T4 and T3 levels • Few or no signs or symptoms of hypothyroidism McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

  4. Causes of Mild Thyroid FailureExogenous and Endogenous Factors • Exogenous factors • Levothyroxine underreplacement • Medications containing lithium, cytokines, or iodine • Antithyroid medications • Iodine131 therapy or thyroidectomy • Endogenous factors • Hashimoto thyroiditis • Previous subacute or silent thyroiditis Biondi B, et al. Ann Intern Med. 2002;137:904-914. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins.

  5. Causes of Mild Thyroid FailureHashimoto Thyroiditis • Hashimoto thyroiditis • Causes an autoimmune reaction that destroys thyroid proteins • Results in hypothyroidism • Symptoms include tiredness, forgetfulness, or depression Surks MI. The Thyroid Book: What Goes Wrong and How to Treat It. Yonkers, NY: Consumer Reports Books; 1993.

  6. Prevalence and Incidence of Mild Thyroid Failure • Prevalence • 4% to 10% in large population screening surveys • 7% to 26% in studies of the elderly • Higher in women than men • Incidence • 2.1% to 3.8% per year in thyroid antibody–positive patients • 0.3% per year in thyroid antibody–negative patients McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538. Biondi B, et al. Ann Intern Med. 2002;137:904-914.

  7. NHANES IIIPatient Populations and Mean TSH Levels Serum TSH Levels <0.4 mIU/L Serum TSH Levels >4.5 mIU/L Male Female Male Female 6 7 5 6 5 4 4 3 Patients, % Patients, % 3 2 2 1 1 0 0 African American Mexican American All White African American Mexican American All White Patient Populations Patient Populations Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

  8. Populations at Risk for Mild Thyroid Failure • Women • Elderly • Family history of • Thyroid disease • Pernicious anemia • Type 1 diabetes mellitus • Rheumatoid arthritis • Lupus Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538. Carmel R, et al. Arch Intern Med. 1982;142:1465-1469. Perros P, et al. Diabetes Med. 1995;12:622-627. University of California Davis Health System Web site. Available at: http://www.ucdmc.ucdavis.edu/ucdhs/health/a-z/38Hypothyroidism/doc38risks.html. Accessed April 17, 2003.

  9. Role of Thyroid Hormone in Normal Cardiovascular Effects • Cardiac effects • Directly affects the heart and peripheral vascular system • Increases myocardial inotropy and heart rate • Changes in cardiac function are mediated by T3 regulation of cardiac-specific genes • Coronary effects • Dilate peripheral arteries to increase cardiac output Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196.

  10. Mild Thyroid Failure and Cardiovascular Disease • Cardiac manifestations • Left ventricular mass • Left ventricular systolic and diastolic function • Cardiac function • Myocardial infarction (MI) • Coronary artery disease • Elevated total cholesterol levels, low-density lipoprotein cholesterol (LDL-C) levels, and triglyceride levels • Aortic atherosclerosis • Elevated lipoprotein(a) levels • Hyperhomocysteinemia Biondi B, et al. Ann Intern Med. 2002;137:904-914. Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196.

  11. Cardiac Manifestations of Mild Thyroid Failure

  12. Increased Left Ventricular Mass With Mild Thyroid Failure 100 90 P<.01 80 70 60 Left Ventricular Mass Index, g/m2 50 40 30 20 10 0 Patients With Mild Thyroid Control Group Failure Di Bello V, et al. J Am Soc Echocardiogr. 2000;13:832-840.

  13. Slowed Left Ventricular Relaxation in Mild Thyroid Failure Cardiovascular Abnormalities Leading to LV Dysfunction on Effort in Mild Thyroid Failure Mild Thyroid Failure Heart Vascular Smooth Muscle Slowed LV Relaxation at Rest Impaired LV Diastolic Filling on Exercise Increased Vascular Tone at Rest Impaired Peripheral Vasodilation on Exercise LV Systolic Dysfunction on Effort Biondi B, et al. Thyroid. 2002;12:505-510.

  14. Mild Thyroid Failure Impacts Heart Function 100 • During exercise, vital capacity was statistically significantly (P<.001) reduced in patients with mild thyroid failure compared with euthyroid patients and control patients • The author concluded that mild thyroid failure impacts heart function and patients with mild thyroid failure should receive appropriate and efficacious treatment to prevent any cardiac manifestations • Perk et al also found that mild thyroid failure can lead to angiographic CAD progression P=.001 97 Vital Capacity, % 94 91 Euthyroidism Control Group* Mild Thyroid Failure *The control group was comprised of gender- and age-matched healthy individuals Kahaly GJ. Thyroid. 2000;10:665-679. Perk M, et al. Can J Cardiol. 1997;13:273-276.

  15. Mild Thyroid Failure Increases Risk of Myocardial Infarction • Population-based cross-sectional study • Data collected from August 1990 through July 1993 • Random sample of 1149 women • 55 years of age • 1055 women had mild thyroid failure or were euthyroid • 975 women included in aortic atherosclerosis analysis • 1036 women included in analysis of MI incident Hak AE, et al. Ann Intern Med. 2000;132:270-278.

  16. Mild Thyroid Failure Increases Risk of Myocardial Infarction (cont.) • Mild thyroid failure contributed to 60% of MI cases in patients with diagnosed mild thyroid failure • Mild thyroid failure contributed to 14% of all MI instances in the study population • Mild thyroid failure is independently associated with MI Hak AE, et al. Ann Intern Med. 2000;132:270-278.

  17. Mild Thyroid Failure and Coronary Artery Disease

  18. Mild Thyroid Failure and Coronary Artery Disease Mild Thyroid Failure Aortic Atherosclerosis Risk Elevated Lipid Levels Hyperhomo- cysteinemia Elevated Lipoprotein(a) Levels Abnormal Vascular Reactivity Luboshitzky R, et al. Thyroid. 2002;12:421-425. Wartofsky L. Diabetes Endocrinol. 2001;3.

  19. Mild Thyroid Failure Associated With Aortic Atherosclerosis Presence of Aortic Atherosclerosis* (1.1-4.3) (1.2-3.1) † † Euthyroid Women Without Antibodies to Thyroid Peroxidase Women With Mild Thyroid Failure Euthyroid Women Women With Mild Thyroid Failure and Antibodies to Thyroid Peroxidase *Numbers in parentheses are 95% confidence intervals. †Reference risk. Hak AE, et al. Ann Intern Med. 2000;132:270-278.

  20. Mild Thyroid Failure Associated With Aortic Atherosclerosis (cont.) • Mild thyroid failure is associated with a greater prevalence of aortic atherosclerosis • Thyroid autoimmunity is not associated with aortic atherosclerosis • More research should be conducted to further confirm this association Hak AE, et al. Ann Intern Med. 2000;132:270-278.

  21. Mild Thyroid Syndrome Elevates Serum Lipid Levels *Total-C indicates total cholesterol; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

  22. Cholesterol Levels Elevate With Increasing TSH Levels 280 Abnormal 270 267 270 Euthyroid 260 250 239 238 Mean Total Cholesterol 240 Level, mg/dL 229 230 226 223 220 216 209 210 200 <0.3 0.3- >5.1- >10- >15- >20- >40- >60- >80 5.1 10 15 20 40 60 80 TSH, mIU/mL Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

  23. Mild Thyroid Failure Elevates Serum Lipid Levels • Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

  24. Mild Thyroid Failure Decreases LDL Receptor Expression • Patients with mild thyroid failure have statistically significant (P<.001) increased levels of oxidized LDL compared with patients in the control group • Changes in LDL-C levels in patients with mild thyroid failure are associated with decreases in LDL receptor expression, leading to an increased risk of elevated LDL-C and CAD development 74 72 P<.001 70 68 66 Oxidized LDL-C Level, mU/L 64 62 60 58 56 Mild Thyroid Failure Control Group* *Control group consists of euthyroid patients Duntas LH, et al. Thyroid. 2002;12:1003-1007. Diekman MJM, et al. J Clin Endocrinol Metab. 2000;85:1857-1862.

  25. Hyperhomocysteinemia Increases Coronary Artery Disease Risk • Hyperhomocysteinemia increases CAD risk • Patients with hyperhomocysteinemia and CAD have an almost 4 times higher mortality rate than patients with lower homocysteine levels • Hyperhomocysteinemia is present in patients with mild thyroid failure, increasing their CAD risk 5 4.5 4 3.5 3 Mortality Ratio 2.5 2 1.5 1 0.5 0 20 9-14.9 15-19.9 Homocysteine Level, mol/L Boushey CJ, et al. JAMA. 1995;274:1049-1057. Catargi B, et al. Thyroid. 1999;9:1163-1166. Nygård O, et al. N Engl J Med. 1997;337:230-236. Hussein WI, et al. Ann Intern Med. 1999;131:348-351.

  26. Elevated Lipoprotein(a) Levels Increase CAD Risk 300 • Elevated lipoprotein(a) levels are associated with an increased risk of CAD development and MI occurrence • Patients with mild thyroid failure have higher lipoprotein(a) levels, which increases their risk of CAD P<.005 250 200 Lipoprotein(a) Levels, 150 U/L 100 50 0 Patients With Mild Thyroid Failure Control Group* PROCAM. Lipoprotein(a) and cardiovascular risk. Available at: http://www.chd-taskforce.de/pdf/sk_procam_03.pdf. Accessed April 17, 2003. Kung AW, et al. Clin Endocrinol. 1995;43:445-449. *Control group consisted of age- and gender-matched healthy patients.

  27. Endothelial Function in Patients With Mild Thyroid Failure and CAD Risk 2-4 >4-10 Flow-mediated vasodilatation is impaired in patients with mild thyroid failure, which could contribute to the development of CAD. Lekakis J, et al. Thyroid. 1997;7:411-414.

  28. Mild Thyroid Failure Testing and Treatment

  29. Thyroid Function Testing • Biochemical testing or cytopathologic evaluation can detect thyroid disease in patients with subtle symptoms • Most accurate way to detect abnormal thyroid levels is by testing TSH levels • Serum-based testing is available • TT4 and TT3 • Free T4 and free T3 • Thyroid hormone-binding plasma proteins, thyroxine-binding globulin, transthyretin/prealbumin, and albumin testing are also available Baloch Z, et al. Thyroid. 2003;13:3-126. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

  30. Relationship Between TSH Levels and Free T4 1000 100 10 TSH Level, mIU/L Normal 1.0 0.1 0.01 Undetectable Euthyroid Hyperthyroid Hypothyroid Free T4 Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460.

  31. NCEP Adult Treatment Panel III Guidelines for Thyroid Function Testing • Patients with mild thyroid failure can have elevated LDL-C • “Any person with elevated LDL-C or other form of hyperlipidemia should undergo evaluation before initiating drug therapy to rule out causes of secondary dyslipidemia, including hypothyroidism.” National Institute of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Washington, DC: National Institutes of Health; 2002.

  32. Additional Testing Guidelines for Patients Who May Be at Risk for Mild Thyroid Failure • American College of Cardiology/American Heart Association • Thyroid function should be measured because of CAD risk • American Diabetes Association • All patients with type 1 diabetes • Patients with type 2 diabetes as clinically indicated • American Association of Clinical Endocrinologists • Every patients with diagnosed depression should be tested Abbott Laboratories. Data on file.

  33. Serum Thyroid HormonesTypical Reference Ranges *For measurement methods that employ physical separation, the upper limit of normal free T4 may extend beyond 2.5 ng/dL Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000. Abbott Laboratories. Data on file.

  34. Thyroid Function Testing Frequency in Specific Patient Populations The Endocrine Society Web site. Available at: http://www.endo-society.org/pubrelations/pressReleases/archives/1999/hypothyroid.cfm. Accessed April 17, 2003. Loyola University New Orleans Web site. Available at: http://www.loyno.edu/~msthomas/hypo.html. Accessed April 17, 2003.

  35. Treatment Goals for Mild Thyroid Failure • Prevent progression to overt hypothyroidism • Reduce cardiovascular disease risk • Maintain TSH levels in the normal range • Lower LDL-C, total cholesterol, and triglycerides Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.

  36. Levothyroxine Treatment Reduces Lipoprotein(a) Levels in Patients With Mild Thyroid Failure • Lipoprotein(a) levels in patients with mild thyroid failure had a statistically significant (P<.001) mean decrease after treatment with levothyroxine • Levothyroxine therapy is effective in lowering lipoprotein(a) levels and had beneficial effects on lipid profiles 170 160 150 140 Lipoprotein(a) Levels, mg/L 130 120 110 100 Before Levothyroxine Treatment After Levothyroxine Treatment Yildirimkaya M, et al. Endocrin J. 1996;43:731-736.

  37. Levothyroxine Treatment Reduces Serum Lipid Levels • Levothyroxine adequately reduced TSH levels • Levothyroxine therapy prevented progression to overt hypothyroidism • Levothyroxine therapy lowers mean lipid levels, thereby reducing cardiovascular disease risk Danese MD, et al. J Clin Endocrinol Metab. 2000;85:2993-3001.

  38. Levothyroxine Reduces Cholesterol Levels Patients Treated With Levothyroxine Patients With Elevated TSH Levels Treated With Levothyroxine 0 -.05 -0.1 -0.15 Decrease in Lipid Levels, mmol/L -0.2 P<.015 -0.25 P<.004 -0.3 P<.03 -0.35 -0.4 Total-C* LDL-C* *Total-C indicates total cholesterol; LDL-C, low-density lipoprotein cholesterol. Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.

  39. Levothyroxine Reduces Cardiovascular Mortality • Mild thyroid failure has negative clinical and metabolic effects • Levothyroxine treatment • Improves LDL-C levels and total cholesterol levels • Improves clinical signs and symptoms of mild thyroid failure • Reduces morbidity and mortality in patients with mild thyroid failure Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.

  40. Progression No Progression 6 P=.01 P=.02 5 4 3 Patients, n 2 1 0 Levothyroxine Treatment Prevents Coronary Artery Disease Progression Inadequate Levothyroxine Replacement Adequate Levothyroxine Replacement Fixed/Decremental Dose of Levothyroxine Therapy Fixed/Incremental Dose of Levothyroxine Therapy Perk M, et al. Can J Cardiol. 1997;13:273-276.

  41. Levothyroxine Cautions • Using levothyroxine in the presence of ischemic heart disease • Possible MI, aggravation of angina, or cardiac arrhythmias • Using levothyroxine in the elderly or in patients with CAD • Initiated at lower doses (25 to 50 g/d) and gradually titrated up at 6- to 8-week intervals Perk M, et al. Can J Cardiol. 1997;13:273-276. Kohno A, et al. Endocr J. 2001;48:565-572. Physician’s Desk Reference. 57th ed. Montvale, NJ: Medical Economics Company; 2002.

  42. Conclusions • Mild thyroid failure is a serious illness that warrants clinical attention • Affects heart rate, LV function, cardiac output, and systemic vascular resistance • Increases total cholesterol levels, LDL-C levels, and triglyceride levels and decreases HDL-C levels in patients • Factors contributing to CAD

  43. Conclusions (cont.) • Levothyroxine treatment is effective in treating patients with mild thyroid failure • Stabilizes TSH concentrations • Reduces total cholesterol levels, LDL-C levels, and triglyceride levels • Prevents progression of CAD • May reduce cardiovascular morbidity and mortality in patients

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