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UCSF Division of General Internal Medicine

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1 UCSF Division of General Internal Medicine
Update on the Thyroid Douglas C. Bauer, MD UCSF Division of General Internal Medicine No Disclosures

2 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


4 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 mU/L; $58

5 Thyroid Tests: Free Thyroxine
Measures unbound hormone Replacing “index” assays Gold standard: Equilibrium dialysis Other immunoassays: Improving Normal range, 9-24 pmol/L; $64

6 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

7 Diagnostic Redundancy of sTSH and Free T4
sTSH (mU/L) < > 5.5 < > Free T4 (pmol/L)

8 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”

9 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

10 Thyroid 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

11 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

12 Hyperthyroidism: Epidemiology
Etiology: Iatrogenic A. Over replacement (30-50% given rx) B. Suppression of CA, goiters, and nodules Autoimmune (Grave’s disease): thyroid stimulating autoantibodies Autonomous nodule(s). Occasionally T3 TSH secreting tumors

13 Hyperthyroidism: Prevalence
Population based prevalence of suppressed TSH: Author age men women Bagchi (1990) > % 2.7% Falkenberg (1991) > % Parle (1991) > % Bauer (1993) > %


15 Crook’s Index*

16 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

17 Subclinical Hyperthyroidism: Cardiac Effects
Systolic time intervals shortened Clinical significance uncertain Reduced exercise tolerance Increased incidence of atrial fibrillation Swain, Prospective cohort, N = RR = 3.1 (1.7, 5.5) if sTSH < 0.1

18 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?

19 Subclinical Hyperthyroidism: Natural History
Exogenous: Well established Endogenous: Little longitudinal data Parle, untreated individuals >60 1 developed overt hyperthyroidism After 1 year, sTSH normal in half!

20 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...

21 Hyperthyroidism: Treatment
Anti-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


23 Radioiodine and Mortality
Franklyn, 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

24 Hypothyroidism: Epidemiology
Etiology Autoimmune (Hashimoto’s) Iodine deficiency Iatrogenic A. Radioiodine/ surgery B. Drugs (lithium, amiodarone) Pituitary/ hypothalamic disease

25 Hypothyroidism: Prevalence
Population based prevalence of elevated TSH: Author age men women Tunbridge(1977) > % % Bagchi(1990) > % 2.7% Parle(1991) > % % Bauer(1993) > %


27 Billewicz Index*

28 Overt Hypothyroidism in the Elderly
“Classic” features often missing Neuropsychiatric complaints common: depression, weakness, memory loss Other clues: hypercholesterolemia, elevated CK, pleural effusion

29 Subclinical Hypothyroidism: CV Outcomes
Observational studies Total cholesterol unchanged, but higher LDL and lower HDL? What about atherosclerosis? Rotterdam population-based study (Hak, 2000) 1149 women, mean age 70 Subclinical hypo (TSH > 4, nl T4) in 10.8% Aortic atherosclerosis RR = 1.7 (1.1, 2.6) History of MI RR = 2.3 (1.3, 4.0)

30 Meta Analysis of Subclinical Hypothyroidism and CHD
Summary OR 1.65 ( ) P for heterogeneity: 0.12

31 Subclinical Hypothyroidism: Other Outcomes
Observational studies of neuropsychiatric symptoms Conflicting evidence Four small double blinded trials, sTSH > 5-7 Randomized to thyroxine or placebo No significant change in weight, lipids, other laboratory values Psychometric testing: Treated felt better and had better memory scores

32 Subclinical Hypothyroidism: Natural History
Many good studies Spontaneous resolution infrequent Antibodies strongly influence outcome If TPO positive, overt hypothyroidism 5%/yr

33 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)

34 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 TSH fell with T4 tx but no difference in cognitive or psychological function

35 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%

36 Thyroid Nodules: Treatment
Cancer - Histology is important (papillary best) - Surgery and 131I 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 prevent new nodules

37 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)

38 Screening for Subclinical Thyroid Disease
US Preventive Task Force, 1996 “Routine screening is not recommended. Insufficient evidence for high risk patients, including elderly.” ACP, 1998 “It is reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid disease.”

39 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?

40 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

41 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

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