Subclinical Hypothyroidism & Metabolic Disease. Overview. Subclinical Hypothyroidism (SCH) Subclinical Hypothyroidism (SCH)

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1 Subclinical Hypothyroidism & Metabolic Disease Michael D. Loughner, M.D. Endocrinology Associates, Denver, CO (p), (fax) May 2010 Overview Subclinical Hypothyroidism (SCH) Definition, prevalence, natural history SCH and Lipids SCH and Novel CV Risk Factors SCH and CV Disease SCH: When To Treat SCH: Treatment Controversies Subclinical Hypothyroidism (SCH) AKA Mild Thyroid Failure

2 Adults: Women: 8% Men: 4% Prevalence of SCH > age 60: Women: 15% Men: 8% Etiology of SCH Autoimmune (Hashimoto s) Thyroiditis Persistent TSH elevation in subacute thyroiditis, postpartum thyroiditis, painless thyroiditis Drugs: amiodarone, lithium, etc. Thyroid injury: surgery, radiation Infiltrative disease (sarcoidosis, hemochromatosis, etc.) Natural History of SCH Initial TSH Normalization (TSH <5 miu/l) Overt Hypothyroidism (TSH >20 miu/l or low free T4) miu/l 52% 6% miu/l 13% 40% miu/l 5% 86% p <0.001 JCEM Oct;89(10):

3 Natural History of SCH TPO-Antibody status Normalization (TSH <5 miu/l) Overt Hypothyroidism (TSH >20 miu/l or low free T4) Positive 30% 32% Negative 62% 8% p =0.006 JCEM Oct;89(10): SCH and Lipids SCH and Lipids 1960s: autopsy studies revealed higher prevalence of coronary arteriosclerosis in those with myxedema relative to controls 1980s: demonstrated that LDL receptor activity is regulated by thyroid hormone Lancet Oct 14;(2)7520: PNAS USA Apr;78(4):

4 Elevated Total and LDL Cholesterol in SCH Colorado Thyroid Disease Prevalence Study (25,862 subjects from statewide health fair) 9% had SCH (TSH >5.1 miu/l and normal T4) Total Chol* LDL* HDL * p < Trig SCH Euthyroid Arch Intern Med Feb 28; 160(4): Elevated Total and LDL Cholesterol in SCH 2108 participants from community health survey in Australia Total Chol* LDL* SCH Euthyroid * p < No difference seen in mean HDL or triglyceride levels Clin Endocrinol (Oxf) Dec;63(6): Altered Lipids Across TSH Reference Range Increasing TSH levels across the reference range ( miu/l) were linearly associated with deranged lipid concentrations p <0.001 for trend p <0.001 for trend Eur J Endocrinol Feb;156(2):181-6.

5 No Threshold For Lipid Effect For every 1 miu/l elevation in TSH: Men: Increase in total cholesterol of 6.2 mg/dl Women: Increase in total cholesterol of 3.5 mg/dl Clin Endocrinol (Oxf) Feb;50(2): Does LT4 treatment have a beneficial effect on lipid profile in SCH? Total and LDL Cholesterol Improve with LT4 Treatment in SCH Total Chol * LDL Pre-Treatment mo LT4 rx * p = 0.05 p = 0.02 No significant change in HDL or triglycerides with restoration of euthyroidism Greater decrease noted in those subjects with higher baseline total chol values JCEM Sep;85(9):

6 Total and LDL Cholesterol Improve with LT4 Treatment in SCH * * * * LDL-lowering effect with LT4 treatment more pronounced in subjects with TSH >12 miu/l or with increased LDL at baseline No effect of LT4 treatment on lipids except in subjects with baseline chol >240 mg/dl Thyroid Nov;17(11): Thyroid Function Associated with Metabolic Syndrome Both free T4 and TSH significantly associated with HOMA-IR (p<0.001 and p=0.024 respectively) Free T4, but not TSH, significantly associated with 4 of 5 components of the metabolic syndrome (abdominal obesity, triglycerides, HDL, and BP) independent of insulin resistance JCEM Feb;92(2): Insulin Resistance Modifies Relationship Between Lipids and Thyroid Function Association of TSH with LDL varies depending on the absence or presence of IR p=0.02 More insulin resistant Insulin Resistance More insulin sensitive JCEM Mar;86(3):

7 SCH and Novel Cardiovascular Risk Factors SCH and CRP hscrp: Consistently associated with CAD Mildly increased CRP levels, even within the normal reference range, have been linked to the metabolic syndrome, suggesting a pre- or proinflammatory state Med Sci Monit May;8(5):HY1-9. Free T4 Inversely Correlated with CRP Atherosclerosis Jan;172(1):7-11.

8 Thyroid Failure Associated with Elevated CRP p =0.016 hscrp (mg/l) Atherosclerosis Feb;166(2): No Effect of LT4 Treatment on CRP in SCH Vast majority of studies that have assessed LT4 treatment in SCH have failed to show an effect on lowering of CRP? Because autoimmune thyroid disease is the most common cause of SCH? Thyroid Nov;17(11): SCH and Arterial Stiffness Arterial Stiffness: Risk factor for CV disease Leads to augmented central BP and increased cardiac afterload JCEM Jun;91(6):

9 Arterial Stiffness Decreases with LT4 Treatment in SCH AIc = corrected Augmentation Index * p<0.02 compared with SCH subjects pre-lt4 rx TSH 8.8 TSH 1.3 TSH 1.4 * * JCEM Jun;91(6): SCH and Endothelial Dysfunction Endothelial Dysfunction: Arterial endothelium plays a vital role in maintenance of vascular integrity and function via release of vasodilator and vasoconstrictor substances NO is the most important vasodilator substance and has decreased availability in endothelial dysfunction Precursor for the development of atherosclerosis Circulation Mar 7;101(9): SCH Associated with Endothelial Dysfunction p <0.05 Flow-Mediated Vasodilation (%) Thyroid Aug;14(8):605-9.

10 Increased Intima-Media Thickness in SCH IMT: Sonographic parameter of atherosclerosis p < Carotid IMT (mm) JCEM May;89(5): Intima-Media Thickness Decreases with LT4 Treatment in SCH p <0.001 p =0.03 Carotid IMT (mm) TSH 6.0 TSH 1.3 TSH 5.7 TSH 6.0 JCEM May;89(5): Does SCH increase the risk of congestive heart failure?

11 SCH and CHF Health ABC TSH HR 1.07 ( ) TSH HR 2.58 ( ) TSH 10.0 HR 3.26 ( ) Cardiovascular Health Study TSH HR 0.92 ( ) TSH HR 1.88 ( ) Arch Intern Med Nov 28;165(21): J Am Coll Cardiol Sep 30;52(14): Does SCH increase the risk of coronary artery disease? SCH and Coronary Artery Disease Ann Intern Med Jun 3;148(11):

12 Age and TSH Reference Range TSH Levels in NHANES Reference Population Age Age Age 80+ JCEM Dec;92(12): Age and TSH Reference Range TSH Levels in NHANES Reference Population Age 20-29, TSH 3.56 Age 50-59, TSH 4.03 Age 80+, TSH 7.49 JCEM Dec;92(12): Risk of CV Disease in SCH is Dependent Upon Age CV Disease <65 years RR 1.68 ( ) 65 years RR 1.02 ( ) CV Mortality <65 years RR 1.37 ( ) 65 years RR 0.85 ( ) JCEM Aug;93(8):

13 Elevated TSH May Be Protective in the Oldest Old TSH < 0.3 TSH TSH >4.8, FT4 low TSH >4.8, FT4 normal JAMA Dec 1;292(21): Hypothetical Relationship Between Age and Effect of SCH on CV Disease Endocr Rev Feb;29(1): SCH: When To Treat? Confirm diagnosis of SCH with repeated TSH measurements 2 months apart

14 SCH: When To Treat? What does the data tell us? Prevention of overt hypothyroidism? Yes, when TSH 10 miu/l or positive TPO-antibody Improvement in lipid profile? Yes, at all TSH levels, though magnitude of effect correlates with baseline TSH and total/ldl cholesterol Lower risk of CV disease? No RCTs to support this, though several novel CV risk factors improve with treatment (arterial stiffness, IMT) Symptoms (fatigue, memory, etc.) improve? Yes, when TSH 10 miu/l SCH: Treatment Controversies (TSH miu/l) Fatigue/weight gain Therapeutic trial of LT4 is reasonable Asymptomatic Follow, more closely if TSH miu/l Over age 65 Follow, more closely if TSH miu/l If treat, start slow and less aggressive goal TSH Thank you Michael D. Loughner, M.D. 850 E. Harvard Ave., Suite 405 Denver, CO (p), (fax)