Cases Management of Common Thyroid Disorders Douglas C. Bauer, MD UCSF Division of General Internal Medicine No Disclosures 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 79 yr old man with 1 yr of fatigue and lassitude and no findings except TSH=9.0, anti-tpo positive 45 yr old women, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1 Topics Covered Rational use of thyroid tests Subclinical thyroid disease What can to wrong? Too much Too little Too big Screening for dysfunction Page 1
Thyroid Tests: stsh Very sensitive to circulating thyroid hormone levels Excellent correlation with TRH stimulation (stsh < 0.1) Requires intact pituitary-hypothalamic axis; 4-6 weeks to equilibrate Falsely low: severe illness, corticosteriods, dopamine Normal range 0.5-4.4 mu/l; $58 Normal TSH in NHANEs TSH values skewed upwards in elderly: Normal or disease? NHANEs: >13,000 people 12 to 80+ years (Surks, 2007) Exclude anyone with known thyroid disease or drugs that could effect TSH Median TSH 1.39 miu/l 97.5 th Percentile: < 60 around 4.0 miu/l 60-69 up to 4.3 miu/l 70-79 up to 5.9 miu/l 80+ up to 7.5 miu/l Thyroid Tests: Free Thyroxine Measures unbound hormone Replacing index assays Gold standard: Equilibrium dialysis Other immunoassays: Improving Normal range, 9-24 pmol/l; $64 Are Both stsh and Free T4 Necessary? American Thyroid Association says Yes Others recommend stsh first Simultaneous ordering common in clinical practice UCSF outpatient data Results when both tests ordered on the same specimen (N=3143) Each test classified as low, normal or high Page 2
Diagnostic Redundancy of stsh and Free T4 Subclinical Thyroid Disease Free T4 (pmol/l) stsh (miu/l) < 0.5 0.5 5 > 5.5 < 9 4 16 49 9-24 536 2024 309 > 24 174 30 1 Subclinical hypothyroidism Abnormally high sensitive TSH and normal thyroid hormone levels Subclinical hyperthyroidism Abnormally low sensitive TSH and normal thyroid hormone levels Suggested Testing Strategy Thyroid Antibodies If stsh is normal, STOP If stsh is low, measure T4, consider T3 If stsh is high, measure T4, consider TPO antibodies Anti-thyroperoxidase, TPO (titer<100, $78) Similar to anti-microsomal Most sensitive thyroid autoantibody Specificity a problem TSH receptor antibody (absent, $112) Causes Grave s disease Rarely found in normal individuals Page 3
Thyroid Scans Technetium 99 ($450) Low radiation, quick Useful for nodules in some circumstances Useful to determine cause of hyperthyroidism High uptake: Grave s, toxic nodule Low uptake: thyroiditis, thyroxine use Hyperthyroidism: Epidemiology Etiology: Iatrogenic Over replacement (30-50% given rx) Suppression of CA, goiters, and nodules Autoimmune (Grave s disease): thyroid stimulating autoantibodies Autonomous nodule(s). Occasionally T3 TSH secreting tumors Hyperthyroidism: Prevalence Population based prevalence of suppressed TSH: Author age men women Bagchi (1990) >55 1.8% 2.7% Falkenberg (1991) >60 1.9% Parle (1991) >60 5.5 6.3% Bauer (1993) >55 5.8% Page 4
Crook s Index* Hyperthyroidism in the Elderly Symptom/Sign Present Absent Palpitation +2 0 Cold prefer. +5 0 Hyperkinetic +4-2 Weight loss +3 0 Lid lag +1 0 *hyperthyroid if 10 or more Weight loss, palpitations, and nervousness less common Tachycardia, exophthalmos, tremor less common Atrial fibrillation more common 8-10% are completely asymptomatic Subclinical Hyperthyroidism: Cardiac Effects Systolic time intervals shortened Clinical significance uncertain Reduced exercise tolerance Increased incidence of atrial fibrillation (Swain, 1994) Prospective cohort, N = 2000 RR = 3.1 (1.7, 5.5) if stsh < 0.1 Subclinical Hyperthyroidism: Skeletal Effects Florid hyperthyroidism causes fractures Effect on BMD, bone loss controversial Increased fracture risk (Bauer, 2001) - Prospective study, 9407 older women - TSH < 0.1 vs. normal - Hip fracture: RR = 3.6 (1.0, 12. 9) - Vertebral fracture: RR = 4.5 (1.3, 15.6) Effect of accelerated bone turnover? Page 5
Subclinical Hyperthyroidism: Natural History Exogenous: Well established Endogenous: Little longitudinal data (Parle, 1991) 50 untreated individuals >60 1 developed overt hyperthyroidism After 1 year, stsh normal in half! Who Should Be Treated? Exogenous (iatrogenic) Dose reduction unless contraindicated Endogenous (subclinical) Repeat and follow if uncomplicated Consider treatment as if overt when TSH<0.1 and atrial fibrillation or osteoporosis present Endogenous (overt) Rule out thyroiditis. They get beta blocker Everyone else gets beta blocker and... Hyperthyroidism: Treatment Anti-thyroid drugs (PTU and methimazole) Remission: 30-50% after 12-18 mo Side effects: rash, fever, arthritis, agranulocytosis (all rare) Radioiodine Best treatment for hot nodules Remission: everyone Side effects: transient thyroiditis (rare), hypothyroid (50%), worsening exophthalmous Page 6
Radioiodine and Mortality Franklyn, 1998-7209 hyperthyroid pts, 15 yr follow-up - All cause mortality: 13% higher than age and sex matched populations - CV deaths increased, but not cancer Mechanism unknown, clear dose-response Unable to adjust for other potential confounders Hypothyroidism: Epidemiology Etiology Autoimmune (Hashimoto s) Iodine deficiency Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) Pituitary/ hypothalamic disease Hypothyroidism: Prevalence Population based prevalence of elevated TSH: Author Age Men Women Tunbridge(1977) >65 6.0% 10.9% Bagchi(1990) >55 1.8% 2.7% Parle(1991) >60 2.9% 11.6% Bauer(1993) >55 5.4% Page 7
Billewicz Index* Overt Hypothyroidism in the Elderly Symptom/Sign Present Absent Bradykinesia +11-3 Cold interance +4-5 Coarse skin +7-7 Pulse <75 +4-4 Delayed AJ +15-6 *hypothyroid if > 30 Classic features often missing Neuropsychiatric complaints common: depression, weakness, memory loss Other clues: hypercholesterolemia, elevated CK, pleural effusion Subclinical Hypothyroidism: CV Outcomes Observational studies: total cholesterol unchanged, but higher LDL and lower HDL? What about atherosclerosis? Rotterdam population-based study (Hak, 2000) Aortic atherosclerosis RR = 1.7 (1.1, 2.6) CHD RR = 2.5 (0.7, 9.5) Cardiovascular Health Study (Cappola, 2003) CHD RR = 1.1 (0.9, 1.3) Australian population-based study (Walsh, 2005) CHR RR = 1.8 (1.2, 2.7) Meta Analysis of Subclinical Hypothyroidism and CHD Ochs, N. et. al. Ann Intern Med 2008;148:832-845 Page 8
Subclinical Hypothyroidism and CHF Events Among 2730 Adults Aged 70-79 in Health ABC Subclinical Hypothyroidism: Other Outcomes Observational studies of neuropsychiatric symptoms Not reliably related to subclinical hypothyroidism Four small double blinded trials, stsh > 5-7 Randomized to thyroxine or placebo No significant change in weight, lipids, other laboratory values (too small for CV outcomes) Psychometric testing: Inconsistent improvement in symptoms and memory scores Rodondi, et al., Arch Intern Med 2005 Subclinical Hypothyroidism: Natural History and When to Treat After persists >6 mo spontaneous resolution infrequent Antibodies predict overt hypothyroidism If TPO positive, 5%/yr If TPO negative, 2%/yr When to treat? Little data Goiter or considering pregnancy Many treat if symptoms, TPO positive or TSH>10 Hypothyroidism: Treatment Replace with thyroxine (T4) T3 + T4 benefit unproven Typical replacement dose 1.6 mcg/kg Elderly or CAD: start low (0.025-0.05 mg/d), gradually increase dose Maintain TSH within the normal range Wait 6 weeks after dose change Monitor yearly (noncompliance, reduced T4 clearance) Page 9
What About Treatment of Symptomatic but Euthyroid Patients? Forget It. Symptoms of hypothyroidism common Real but not detected by usual tests? Double blind RCT (Pollock, 2001) Euthyroid subjects, 25 symptomatic 18 not symptomtic 3 mo. of T4 (0.1/d) or placebo, crossover TSH fell with T4, but no difference in cognitive or psychological function Thyroid Nodules: Epidemiology and Evaluation Nodules are common (and cancer is rare) 90% women over age 60 have one or more thyroid nodules at autopsy Risk factors for cancer: neck irritation, FH Evaluation: FNA first 75% benign, 20% suspicious, 5% malignant Best centers: false negative 2% false positive 1% Thyroid Nodules: Treatment Cancer - Histology is important (papillary best) - Surgery +/- 131 I ablation - Suppression with T4? TSH = 0.1-0.4 Benign nodules - Many shrink spontaneously - Meta analysis of T4 suppression Smaller: 26% vs. 12% (NNT=7) Larger: 8% vs. 17% (NNT=11) - T4 doesn t prevent new nodules Screening Cost-effectiveness Danese and Sawin, 1995 Cost-utility analysis, stsh-based screening Modeled progression, symptoms and CAD Screening every 5 year from 35-65: $9,223 per QALY in women $22,595 per QALY in men Sensitivity analysis: cost of TSH key ($25) Page 10
Screening for Subclinical Thyroid Disease US Preventive Task Force, 1996 routine screening is not recommended. ACP, 1998 reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid disease. US Preventive Task Force, 2004 evidence is insufficient to recommend for or against routine screening. Fair evidence that the the TSH test can detect subclinical thyroid disease, but poor evidence that treatment improves clinically important outcomes. Screening Cost-effectiveness Effects on HDL, fractures not included. Cost of testing overestimated ($3/TSH) Published analyses underestimate cost-effectiveness Other unresolved issues: Age to start screening? Optimal frequency? Summary Take Home Points stsh is best test Subclinical thyroid disease is common, associated with morbidity, and treatable Low threshold to treat subclinical hypo until large trials available Treatment threshold for subclinical hyper less certain Screening with stsh is cost-effective Cases 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 79 yr old man with 1 yr of fatigue and lassitude and no findings except TSH=9.0, anti-tpo positive 45 yr old women, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1 Page 11