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