Mastering Thyroid Disorders Douglas C. Bauer, MD UCSF Division of General Internal Medicine
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 suppession ever since, TSH=0.1
Thyroid Tests: stsh Very sensitive to circulating thyroid hormone levels Excellent correlation with TRH stimulation (stsh( < 0.1) Requires intact pituitary-hypothalamic axis; 4-66 weeks to equilibrate Falsely low: severe illness, corticosteriods,, dopamine Normal range 0.5-4.8 mu/l; $58
Thyroid Tests: Free Thyroxine Measures unbound hormone Replacing index assays Gold standard: Equilibrium dialysis Other immunoassays: Improving Normal range, 9-249 pmol/l; $64
Are Both stsh and Free T4 Necessary? American Thyroid Association: Yes Others recommend stsh first UCSF outpatient data Results when both tests ordered on the same specimen (N=3143) Each test classified as low, normal or high
Diagnostic Redundancy of stsh and Free T4 Free T4 (pmol/l) stsh (mu/l) < 0.5 0.5-5.5 > 5.5 < 9 4 16 49 9-24 536 2024 309 > 24 174 30 1
Subclinical Thyroid Disease 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 If stsh is normal,, STOP If stsh is low,, measure T4, consider T3 If stsh is high,, measure T4, consider TPO antibodies
Thyroid Antibodies Anti-thyroperoxidase thyroperoxidase,, TPO (titer<100, $78) Similar to anti-microsomal Most sensitive thyroid autoantibody Specificity a problem TSH receptor antibody (absent, $112) Causes Grave s s disease Rarely found in normal individuals
Thyroid Scans Technetium 99 ($450) Low radiation, quick Useful for nodules in some circumstances Useful to determine cause of hyperthyroidism A. High uptake: Grave s, toxic nodule B. Low uptake: thyroiditis, thyroxine use
Hyperthyroidism: Epidemiology Etiology: Iatrogenic A. Over replacement (30-50% given rx) B. Suppression of CA, goiters, and nodules Autoimmune (Grave s 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%
Crook s s Index* 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
Hyperthyroidism in the Elderly 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?
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) Follow if uncomplicated Consider treatment if atrial fibrillation or osteoporosis present Endogenous (overt) Rule out thyroiditis Tx everyone else with beta blocker and...
Hyperthyroidism: Treatment Anti-thyroid thyroid drugs (PTU and methimazole) Remission: 30-50% after 12-18 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
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) 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%
Billewicz Index* 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
Overt Hypothyroidism in the Elderly 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( 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
Subclinical Hypothyroidism and CHF Events Among 2730 Adults Aged 70-79 in Health ABC Rodondi, et al., Arch Intern Med 2005
Subclinical Hypothyroidism: Other Outcomes Observational studies of neuropsychiatric symptoms Conflicting evidence Four small double blinded trials, stsh > 5-75 Randomized to thyroxine or placebo No significant change in weight, lipids, other laboratory values Psychometric testing: Treated felt better and had better memory scores
Subclinical Hypothyroidism: Natural History Many good studies Spontaneous resolution infrequent Antibodies strongly influence outcome If TPO positive, overt hypothyroidism 5%/yr
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 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)
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) 25 symptomatic,, 18 controls All euthyroid 3 mo of T4 (0.1/d) or placebo, cross-over over TSH fell with T4 tx 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 and 131 I ablation - Suppression with T4? TSH = 0.1-0.4 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 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)
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 thetsh 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 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 suppession ever since, TSH=0.1