Management of Common Thyroid Disorders
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1 Management of Common Thyroid Disorders Douglas C. Bauer, MD UCSF Division of General Internal Medicine No Disclosures
2 Cases 68 yr old woman with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 79 yr old woman with 1 yr of fatigue and lassitude and no findings except TSH=9.0, anti-tpo positive 45 yr old woman, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1
3 Topics Covered Rational use of thyroid tests Subclinical thyroid disease What can to wrong? Too much Too little Too big Screening for dysfunction
4
5 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 mu/l; $58
6 TSH: What Is the Upper Limit of Normal Over Age 80? miu/l miu/l miu/l miu/l 25% 25% 25% 25% miu/l 6.0 miu/l 7.5 miu/l 8.5 miu/l
7 Normal TSH in NHANEs TSH values skewed upwards in elderly: Normal or disease? NHANEs: >13,000 people 12 to 80+ years 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 up to 4.3 miu/l up to 5.9 miu/l 80+ up to 7.5 miu/l Surks et al, Arch Int Med, 2007
8 Thyroid Tests: Free Thyroxine Measures unbound hormone Replacing index assays Gold standard: Equilibrium dialysis Other immunoassays: Improving Normal range, pmol/l; $64
9 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 Bauer et al, Amer J Med, 1998
10 Diagnostic Redundancy of stsh and Free T4 Free T4 (pmol/l) stsh (miu/l) < > 5.5 < >
11 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
12 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
13 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
14 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
15 Hyperthyroidism: Epidemiology Etiology: Iatrogenic Over replacement (30-50% given rx) Suppression of CA, goiters, and nodules Autoimmune (Grave s s disease): thyroid stimulating autoantibodies Autonomous nodule(s). Occasionally T3 TSH secreting tumors
16 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) > % Bauer (1993) >55 5.8%
17
18 Crook s Index* Symptom/Sign Present Absent Palpitation +2 0 Cold prefer Hyperkinetic +4-2 Weight loss +3 0 Lid lag +1 0 *hyperthyroid if 10 or more
19 Overt 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
20 Subclinical Hyperthyroidism Does NOT Cause Which of the Following? 1. Reduced exercise tolerance 2. Fractures 3. Anxiety 4. Atrial fibrillation 25% 25% 25% 25% Reduced exercise toler... Fractures Anxiety Atrial fibrillation 10
21 Subclinical Hyperthyroidism: Cardiac Effects Systolic time intervals shortened Clinical significance uncertain Reduced exercise tolerance Increased incidence of atrial fibrillation Prospective cohort, N = 2000 RR = 3.1 (1.7, 5.5) if stsh < 0.1 Swain et al, Jama, 1994
22 Subclinical Hyperthyroidism: Skeletal Effects Florid hyperthyroidism causes fractures Effect on BMD, bone loss controversial Increased fracture risk - 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? Bauer et al, Ann Int Med, 2001
23 Subclinical Hyperthyroidism: Natural History Exogenous (iatrogenic): Persists unless dose reduced Endogenous: 2024 untreated adults, two TSH<0.4 Most persist at 2 (82%) and 5 yr. (67%) Lower TSH at baseline persists Few progress to overt (<1%) Valdiveloo et al, JCEM, 2011
24 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... Endocrine Society Guidelines, JCEM, 2011
25 Hyperthyroidism: Treatment Anti-thyroid thyroid drugs (PTU and methimazole) Remission: 30-50% after 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 Endocrine Society Guidelines, JCEM, 2011
26
27 Radioiodine and Mortality? Administrative database in the UK 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, but clear dose- response Unable to adjust for other potential confounders Franklyn et al, 1998
28 Hypothyroidism: Epidemiology Etiology Autoimmune (Hashimoto s) s) Iodine deficiency Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) Pituitary/ hypothalamic disease
29 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%
30
31 Billewicz Index* Symptom/Sign Present Absent Bradykinesia Cold interance +4-5 Coarse skin +7-7 Pulse < Delayed AJ *hypothyroid if > 30
32 Overt Hypothyroidism in the Elderly Classic features often missing Neuropsychiatric complaints common: depression, weakness, memory loss Other clues: hypercholesterolemia, elevated CK, pleural effusion
33 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( Cappola,, 2003) CHD RR = 1.1 (0.9, 1.3) Australian population-based study (Walsh, 2005) CHR RR = 1.8 (1.2, 2.7)
34 Meta Analysis of Subclinical Hypothyroidism and CHD 11 prospective cohort studies Subject-level pooling of 42,000 adults Primary outcomes: CHD event or CHD death Overall results: CHD RH=1.23 (0.98, 1.56) CHD Event CHD Death TSH (0.9, 1.2) 1.1 (0.9, 1.3) TSH (1.0, 1.4) 1.4 (1.0, 2.0) TSH (1.3, 2.8) 1.6 (1.1, 2.3) Rodondi, Jama, 2010
35 Subclinical Hypothyroidism and CHF Events Among 2730 Adults Aged in Health ABC Rodondi et al, Arch Intern Med, 2005
36 Subclinical Hypothyroidism: Other Outcomes Observational studies of neuropsychiatric symptoms Not reliably related to subclinical hypothyroidism Four small double blinded trials, stsh > 5-75 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
37 Subclinical Hypothyroidism: Natural History and When to Treat If 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
38 Hypothyroidism: Treatment Replace with thyroxine (T4) T3 + T4 benefit unproven Typical replacement dose 1.6 mcg/kg Elderly or CAD: start low ( mg/d), gradually increase dose Maintain TSH within the normal range Wait 6 weeks after dose change Monitor yearly (noncompliance, reduced T4 clearance in elderly)
39 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 33 mo. of T4 (0.1/d) or placebo, cross- over TSH fell with T4, but no difference in cognitive or psychological function
40 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%
41 Thyroid Nodules: Treatment Cancer - Histology is important (papillary best) - Surgery +/- 131 I ablation - Suppression with T4? TSH = 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
42 Screening for Thyroid Dysfunction 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
43 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)
44 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? Not before 50 Optimal frequency? Every 5 years
45 Summary Take Home Points stsh is best test. T4 often unnecessary 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 and should be considered in women >50
46 Cases 68 yr old woman with new atrial fibrillation and no other findings except TSH=0.04, normal free T4 79 yr old woman with 1 yr of fatigue and lassitude and no findings except TSH=9.0, anti-tpo positive 45 yr old woman, enlarged thyroid with dominant nodule since 1999, FNA benign. On T4 suppression ever since, TSH=0.1
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