Subclinical thyroid disease and high normal free T4 predict

presence of AF

Rachel H. Kon, M.D.GIM Journal ClubJuly 24,2007

Produces hormones with significant effects on heart, cellular metabolism, growth, and development High levels of thyroid hormones cause

damage to heart over time*

Populations at high risk for heart disease and thyroid disease are similar Increasing prevalence of overt thyroid

disease with age 12% of adults have subclinical thyroid disease

and increases with age• Biondi et al, Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab. 2000;85:4701-4705.

Overt vs. subclinical Overt: ↑or↓ free T4 ± T3 with opposite ↓or↑

TSH Subclinical: normal free T4 and T3 with TSH

out of normal range Euthyroid

Normal serum TSH

Serum Thyroid Stimulating Hormone (TSH) More sensitive index of thyroid function Best test for detecting primary thyroid disease

Serum Free Thyroxine (T4) Elevated in overt hyperthyroidism Elevated during Amiodarone therapy

usually within normal range Needed to distinguish hypothalamic or pituitary disease

Serum Free Triiodothyronine (T3)

0.1 24.5

Normal TSH

0.4

5.5

Overt Hyperthyroidi

sm

Subclinical Hyperthyroidi

sm

Euthyroid

Subclinical Hypothyroidis

m

Overt Hypothyroidis

m

Free T4(ng/dL)

0.71.55

010

Serum TSH (mU/L)

Normal free T4

Effect of long exposure to mild excess of thyroid hormone on cardiac function Increased average heart rate Increased interventricular septal wall

thickness Increased mean LV posterior wall thickness Increased mean LV mass Enhanced LV function Impaired LV diastolic filling

Subclinical hyperthyroidism assoc. with increased prevalence of atrial fibrillation

• Biondi et al, Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab. 2000;85:4701-4705.•Cappola et al, Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033-1041.•Sawin et al, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-1252.

AF is an independent risk factor for cardiovascular events and stroke

Affects 2.2 million Americans 5-15% of overt hyperthyroidism patients have

AF Chronic disorder linked to subclinical thyroid

dysfunction but significance of assoc. unknown Screening for mild thyroid dysfunction may help

recognize those at risk for AF Treating mild thyroid dysfunction may

prevent/treat AF

Smoking Diabetes Mellitus Hypertension Heart Failure Ischemic Heart Disease

-> Major AF risk factors defined in Framingham population

Clinical Questions to Answer: Define relationship between thyroid

status and presence of AF on ECG Studied population with higher

prevalence of both AF and thyroid disease: Elderly

Population who would benefit most from reduced risk of cardiac events and stroke

What risk factors are independent predictors of AF in this cohort?

Population-base cross-sectional study Birmingham, England 5860 subjects Primary care setting 65 yo and older

Median 72, Range 65-98

Current thyroid dysfunction treatment History of Overt Hyperthyroidism

Measured serum for: TSH [reference range: 0.4-5.5 mU/L] free T4 [reference range: 0.70-1.55

ng/dL] free T3 [reference range: 227.3-

422.1pg/dL] Resting 12-lead ECG

All read by a single cardiologist blinded to thyroid status and patient details

Patient survey and chart review to identify all current drug treatments and major risk factors for AF the subjects had before study

Thyroid Status Subjects

Overt Hyperthyroid 14

Subclinical Hyperthyroid 126

Euthyroid 5519

Subclinical Hypothyroid 167

Overt Hypothyroid 23

Total 5849

*11 subjects did not fit into one of these 5 diagnostic categories and were excluded from analyses based on thyroid status

Thyroid Status

Whole Cohort Male Female

Overt Hyperthyroid

0% 0% 0%

Subclinical Hyperthyroid

9.5% 11.1% 8.3%

Euthyroid 4.7% 6.5% 2.9%

Subclinical Hypothyroid

4.2% 6.8% 2.8%

Overt Hypothyroid

0% 0% 0%

All Subjects 4.8% 6.6% 3.1%279 cases of AF in cohort: 150 cases of AF newly dx in study, 129 were previously dx

*Table adapted from Gammage et al table 1

Significantly higher prevalence of AF in subclinical hyperthyroid vs. Euthyroid group

and whole cohort (p=0.01)AF more prevalent in males vs females

(p<0.001)

Whole Cohort With AF Without AF

Median free T4 1.14 ng/dL 1.10 ng/dL

IQR 0.12-1.27 ng/dL 1.00-1.22 ng/dL

Significantly higher free T4 in AF patients (p< 0.001)

No significant difference in TSH concentration between patients with and without AF

When exclude subjects with previously undiagnosed overt hyperthyroidism and hypothyroidism , still independent predictor of AF (p<0.001)

Increased serum free T4 is an independent predictor of AF (p=0.004)

Normal Range for free T4: 0.70 – 1.55 ng/dL

When excluded subjects taking amiodarone, still independent predictor of AF (p=0.01)

Higher prevalence of AF in patients with higher free T4 concentrations

Taking into account identified risk factors for AF in the study subjects , the following are still independent predictors of AF Increased free T4 Subclinical hyperthyroidism Age Male sex DM HTN Heart Failure

Serum TSH, smoking and Ischemic heart disease were not significant independent

predictors of AF in this cohort

Decreased Selection Bias Large Sample Size (N =5860) Population in primary care setting not specialist

At cardiology or endocrine practices the cases of both AF and mild thyroid dysfunction would be more prevalent and not reflect the general population

Decreased Measurement Bias Same cardiologist performed all ECG readings Reader blinded to thyroid status

Decreased Confounding Bias By excluding patients with conditions known to cause of

AF Patients taking amiodarone or having overt thyroid

disease excluded By reviewing charts for other AF risk factors and

medications that may be the cause for increased prevalence of AF in the study group

Prevalence/Cross-sectional study Single point in time Appropriate for finding concomitant diseases

No follow-up of subsequent development of AF in patients with high normal free T4 or subclinical hyperthyroidism without AF at the time of this study

Cross-sectional study only explores one-point in time Can not measure endpoints such as

cardiovascular events or mortality in this cohort

Can not determine if AF in study subjects is paroxysmal or persistant

With increasing incidence of hyperthyroidism in elderly, should we . . . Screen those >65yo for mild thyroid disease? Treat mild thyroid disease in elderly to prevent

AF and subsequent stroke? Should mild thyroid dysfunction be

treated? Look for mild thyroid disease in those with AF?

Treat mild elevations of free T4 if found? Treat those with mild thyroid dysfunction to

prevent AF? Should free T4 be the value to follow in AF

patients rather then TSH?

Would treating subclinical thyroid disease prevent or reverse AF?

Would reducing serum free T4 concentration, even within the normal range, help control AF?

Does increased serum free T4 correlate with paroxysmal AF or persistant AF?

Gammage MD, Parle JV, Holder RL, Roberts LM, Hobbs FD, Wilson S, Sheppard MC, Franklyn JA. Association Between Serum Free Thyroxine Concentration and Atrial Fibrillation. Arch Intern Med. 2007;167:928-934.

Biondi B et al. Subclinical hyperthyroidism: clinical features and treatment options. European Journal of Endocrinology 2005; 152:1-9.

Biondi et al, Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab. 2000;85:4701-4705.

Cappola et al, Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033-1041.

Sawin et al, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-1252.