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Impact of “Mild-Subclinical” Thyroid Disease on Cardiovascular Health

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.

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Impact of “Mild-Subclinical” Thyroid Disease on Cardiovascular Health

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  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 HyperthyroidismDefinition • 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 HyperthyroidismSmall Increase in Free T4 =Large Decrease in TSH Free T4 TSH Normal Range Change Normal Range Change 1.8 ng/dl 4.5 mU/L 0.8 ng/dl 0.45 mU/L

  5. Subclinical Hyperthyroidism:Definition and Prevalence • Usually asymptomatic1 • Low or undetectable serum TSH1 • Normal or borderline serum FT4 and FT31 • Variable prevalence (0.7% to 6.0%)2 • More common in women3 • More common in older people than overt hyperthyroidism4 • Most common cause is overtreatment withL-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 ↑ heart rate ↑ risk of atrial fibrillation ↑ cardiac contractility2 ↑ LV mass index ↑ intraventricular septal andposterior wall thickness ↓ bone density ↑ serum osteocalcin ↑ urinary hydroxyproline and pyrrolidine links 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. Other Biological Effects of Subclinical Hyperthyroidism Total and LDL cholesterol Liver enzymes Creatine kinase Sex hormone binding globulin Time asleep at night Mood (using multidimensionalscale for state of well-being) Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016

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

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

  11. 30 25 20 15 10 5 0 Subclinical HyperthyroidismAtrial Fibrillation Serum Thyrotropin Values at Baseline Low Thyrotropin (TSH <0.1) Incidenceof AtrialFibrillation (%) HighThyrotropin Slightly LowThyrotropin NormalThyrotropin 10 0 1 2 3 4 5 6 7 8 9 Years Sawin CT et al. New Engl J Med. 1994;331:1249.

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

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

  14. Thyroid Function Status and Isovolumetric Contraction Time (ICT) 80 70 º ‡ 60 § 50 ICT(ms) †,‡ 40 ∗,† 30 20 ∗ 10 0 Mildthyroid failure Overthyper I Overthyper II Subclinhyper Normaleuthyroid Overthypo II Overthypo I ∗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. Tseng KH et al. J Clin Endocrinol Metab. 1989;69:633.

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

  17. Subclinical HyperthyroidismConcerns • Osteoporosis • Atrial fibrillation • Cardiac dysfunction • Progression to overt disease

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

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

  20. Subclinical HypothyroidismSmall Decrease in Free T4 =Large Increase in TSH Free T4 TSH Normal Range Change Normal Range Change 1.8 ng/dl 4.5 mU/L 0.8 ng/dl 0.45 mU/L

  21. Progression of Mild Thyroid Failure MildThyroidFailure Overt Hypothyroidism Euthyroid TSH NORMAL RANGE T3 T4 Years Adapted from Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44.

  22. Subclinical HypothyroidismPrevalence - Women Whickham (n=2,779) 25% 20% 15% 10% 5% 0% Colorado (n=25,862) NHANES (n=17,353) 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

  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 HypothyroidismIssues • Lipid elevation • CAD risk factor • Cardiac function • Progression to overt disease

  25. Why Treat Patients WithMild Thyroid Failure With L-Thyroxine? • Prevent progression to overt hypothyroidism1 • Alleviate symptoms1,2 • Normalize serum lipids1,3 • Normalize cardiac function2,4 • May help depression5 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 Hypothyroidism 8.6% 56.3% Hypercholesterolemia (>200 mg/dL) Hypertriglyceridemia (>150 mg/dL) 33.6% Hypercholesterolemia and mild hypertriglyceridemia Normal Lipids 1.5% N = 268 O’Brien T et al. Mayo Clin Proc. 1993;68:860.

  27. 250 235 220 205 190 175 160 145 130 LDL-C Levels Increase With Increasing Hypothyroidism Grade 246 ** 191 LDL-C(mg/dL) * 168 144 137 133 C 1 2 3 4* 5† Hypothyroidism Grade overt Basal TSH (mU/L) 1.1 3.0 8.6 22.7 44.4 63.7 C=controls.*P<.01 vs controls. †P<.001 vs controls. Staub JJ et al. Am J Med. 1992;92:631.

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

  29. Effect of L-Thyroxine Treatment on Lipid Levels in Dyslipidemia1 Group 1 (N=6) Group 2 (N=6) Group 3 (N=7) 450 TC* 400 TC* 350 Before After LDL-C* TC* 300 LDL-C* LDL-C* 250 200 150 100 50 0 TSH before: 7.0 mU/LTSH after: 1.9 mU/L TSH before: 18.6 mU/LTSH after: 1.5 mU/L TSH before: 154.9 mU/LTSH after: 1.8 mU/L *=mg/dL. 1Values are means ±SD. Diekman T et al. Arch Intern Med. 1995;155:1490.

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

  32. Subclinical HypothyroidismIssues • Lipid elevation • CAD risk factor • Cardiac function • Progression to overt disease

  33. Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study 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 Hak AE,l Ann Int Med 132:270, 2000

  34. Euthyroid High TSH High TSH + TAB Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study Myocardial Infarction Aortic Calcification 0 1 2 3 4 Odds Ratio *Adjusted for age, BP, BMI, smoking, lipids Hak AE,l Ann Int Med 132:270, 2000

  35. When to Suspect Mild Thyroid Failure • Hypercholesterolemia1,2 • Refractory depression2 • Previous episode of postpartum thyroiditis2 • Goiter1 • Family or personal history of thyroid disease1 • Over 40 with nonspecific complaints2 • Insidious weight change • Unexplained infertility2 • 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 hypothyroidism1 • Treatment: once daily dosing with L-thyroxine(1.6 μg/kg/day)2 • Monitor TSH levels at 6 to 8 weeks, after initiation of therapy or dosage change3 • 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. Postmenopausal Pregnant/postpartum2 Use of Certain Drugs2 Heart Disease2 Age >50 years1 Psychiatric Illness3 Chronic Illness SpecialPatientPopulations Management of Hypothyroidism: Special Patient Populations 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. Over- and Under-Replacement Risks Over-Replacement Risks • Reduced bone density/osteoporosis1 • Tachycardia, arrhythmia,2 atrial fibrillation • In elderly or patients with heart disease, angina, arrhythmia, or myocardial infarction2 Under-Replacement Risks • Continued hypothyroid state • Long-term end-organ effects of hypothyroidism • Increased risk of hyperlipidemia 1. Stall GM et al. Ann Intern Med. 1990;113:265. 2. Ridgway EC. Family Practice Recertification. 1992;14:127.

  39. Consensus Statement 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: Subclinical Thyroid Dysfunction: - A Joint Statement – AACE, ATA, Endocrine Society. Gharib H. et al. JCEM 90:581-585.

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

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