Update on the Thyroid

Douglas C. Bauer, MD
UCSF Division of General Internal Medicine

No Disclosures
 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;
4-6 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, 9-24 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

sTSH (mU/L)
< 0.5 0.5 - 5.5 > 5.5
<9 4 16 49
Free T4
9 - 24 536 2024 309
(pmol/L)
> 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, TPO (titer<100, $78)

Similar to anti-microsomal
Most sensitive thyroid autoantibody
Specificity a problem
TSH receptor antibody (absent, $112)
Causes Graves 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: Graves, 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 (Graves 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%
 Crooks 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 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
 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 (Hashimotos)
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, 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)
Meta Analysis of Subclinical Hypothyroidism and CHD

Summary OR
P for heterogeneity: 0.12 1.65 (1.28-2.12)
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
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
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
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 131I 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 doesnt 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.
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.
 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