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  • Lets start with . . Prevalence of both disorders increase with age
  • Definition is a laboratory diagnosis.
  • To review Not bound to thyroxine-binding globulin (TBG), free fraction responsible for hormone actions. T4 is converted to T3 in the periphery, the more potent form of the hormone.
  • Think of thyroid dysfunction as a spectrum
  • Incredibly common Well-known causal relationship between hyperthyroidism and AF, though significance in subclinical disease unknown
  • The article I am presenting is the Gammage et al study from the May 14 th 2007 issue of Archives of Internal Medicine. 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. Take framingham RFs and see if independent predictors in this cohort
  • Took all subjects and measured TSH, FT4, and FT3, did an ECGm and reviewed their chart for meds and RFs
  • Results: The distribution of subjects into the classes of thyroid dysfunction has the greatest number in the euthyroid category.
  • Based on thyroid status, the prevalence of AF is shown here. You can see that the euthyroid group has similar prevalence to the cohort as a whole, but the subclinical hyperthyroid group . . .
  • The novel finding in this study relates to AF and free T4. Surprisingly, TSH was not After logistic regression analysis of presence of AF vs risk factors for AF, AF and free T4 still significantly associated IQR – interquartile range = range covered by middle half of data Q3 – Q1
  • This shows the relationship between AF prevalence and free T4 graphically
  • I felt the strengths of this study include their efforts to decrease bias.
  • What do these findings tell us about screening elderly populations for mild thyroid disease and should we treat it?
  • This leads us to needed future studies . . .
  • Transcript

    • 1. Subclinical thyroid disease and high normal free T4 predict presence of AF Rachel H. Kon, M.D. GIM Journal Club July 24,2007
    • 2.
      • 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.
    • 3.
      • 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
    • 4.
      • 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)
    • 5. 0.1 24.5 Normal TSH 0.4 5.5 Overt Hyperthyroidism Subclinical Hyperthyroidism Euthyroid Subclinical Hypothyroidism Overt Hypothyroidism  Free T4 (ng/dL) 0.7 1.55 0 10 Serum TSH  (mU/L) Normal free T4
    • 6.
      • 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.
    • 7.
      • 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
    • 8.
      • Smoking
      • Diabetes Mellitus
      • Hypertension
      • Heart Failure
      • Ischemic Heart Disease
      -> Major AF risk factors defined in Framingham population
    • 9.
      • 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?
    • 10.
      • Population-base cross-sectional study
      • Birmingham, England
      • 5860 subjects
      • Primary care setting
      • 65 yo and older
        • Median 72, Range 65-98
    • 11.
      • Current thyroid dysfunction treatment
      • History of Overt Hyperthyroidism
    • 12.
      • 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
    • 13. *11 subjects did not fit into one of these 5 diagnostic categories and were excluded from analyses based on thyroid status Thyroid Status Subjects Overt Hyperthyroid 14 Subclinical Hyperthyroid 126 Euthyroid 5519 Subclinical Hypothyroid 167 Overt Hypothyroid 23 Total 5849
    • 14. 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) 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%
    • 15. 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) 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
    • 16. Higher prevalence of AF in patients with higher free T4 concentrations
    • 17.
      • 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
    • 18.
      • 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
    • 19.
      • Prevalence/Cross-sectional study
        • Single point in time
        • Appropriate for finding concomitant diseases
    • 20.
      • 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
    • 21.
      • 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?
    • 22.
      • 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?
    • 23.
      • 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.