Update on the ThyroidUpdate on the Thyroid

Douglas C. Bauer, MDDouglas C. Bauer, MD

UCSF Division of General Internal MedicineUCSF Division of General Internal Medicine

No DisclosuresNo Disclosures

CasesCases

• 68 yr old female with new atrial fibrillation 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, and no other findings except TSH=0.04, normal free T4normal free T4

• 79 yr old man with 1 yr of fatigue and 79 yr old man with 1 yr of fatigue and lassitude and no findings except TSH=9.0, lassitude and no findings except TSH=9.0, anti-TPO positiveanti-TPO positive

• 45 yr old women, enlarged thyroid with 45 yr old women, enlarged thyroid with dominant nodule since 1999, FNA benign. dominant nodule since 1999, FNA benign. On T4 suppession ever since, TSH=0.1On T4 suppession ever since, TSH=0.1

Thyroid Tests: sTSHThyroid Tests: sTSH

• Very sensitive to circulating thyroid hormone levelsVery sensitive to circulating thyroid hormone levels

• Excellent correlation with TRH stimulation (sTSH < 0.1)Excellent correlation with TRH stimulation (sTSH < 0.1)

• Requires intact pituitary-hypothalamic axis;Requires intact pituitary-hypothalamic axis;4-6 weeks to equilibrate4-6 weeks to equilibrate

• Falsely low: severe illness, corticosteriods, dopamineFalsely low: severe illness, corticosteriods, dopamine

• Normal range 0.5-4.8 mU/L; $58Normal range 0.5-4.8 mU/L; $58

Thyroid Tests: Free ThyroxineThyroid Tests: Free Thyroxine

• Measures unbound hormoneMeasures unbound hormone

• Replacing “index” assaysReplacing “index” assays

• Gold standard: Equilibrium dialysisGold standard: Equilibrium dialysis

• Other immunoassays: ImprovingOther immunoassays: Improving

• Normal range, 9-24 pmol/L; $64Normal range, 9-24 pmol/L; $64

Are Both sTSH and Free T4 Necessary?Are Both sTSH and Free T4 Necessary?

• American Thyroid Association: YesAmerican Thyroid Association: Yes

• Others recommend sTSH firstOthers recommend sTSH first

• UCSF outpatient dataUCSF outpatient data

– Results when both tests ordered on theResults when both tests ordered on the same specimen (N=3143) same specimen (N=3143)

– Each test classified as low, normal or highEach test classified as low, normal or high

Diagnostic Redundancy of sTSH and Free T4Diagnostic Redundancy of sTSH and Free T4

sTSH (mU/L)sTSH (mU/L)< 0.5< 0.5 0.5 - 5.50.5 - 5.5 > 5.5> 5.5

< 9< 9 44 1616 4949

9 - 249 - 24 536536 20242024 309309

> 24> 24 174174 3030 11

Free T4Free T4

(pmol/L)(pmol/L)

Subclinical Thyroid DiseaseSubclinical Thyroid Disease

• Subclinical hypothyroidismSubclinical hypothyroidism“Abnormally “Abnormally highhigh sensitive TSH and sensitive TSH and normal thyroid hormone levels”normal thyroid hormone levels”

• Subclinical hyperthyroidismSubclinical hyperthyroidism“Abnormally “Abnormally lowlow sensitive TSH and sensitive TSH and normal thyroid hormone levels”normal thyroid hormone levels”

Suggested Testing StrategySuggested Testing Strategy

• If sTSH is If sTSH is normalnormal, STOP, STOP

• If sTSH is If sTSH is lowlow, measure T4, consider T3, measure T4, consider T3

• If sTSH is If sTSH is highhigh, measure T4, consider , measure T4, consider TPO antibodiesTPO antibodies

Thyroid AntibodiesThyroid Antibodies

• Anti-thyroperoxidase, TPO (titer<100, $78)Anti-thyroperoxidase, TPO (titer<100, $78)– Similar to “anti-microsomal”Similar to “anti-microsomal”– Most sensitive thyroid autoantibodyMost sensitive thyroid autoantibody– Specificity a problemSpecificity a problem

• TSH receptor antibody (absent, $112)TSH receptor antibody (absent, $112)– Causes Grave’s diseaseCauses Grave’s disease– Rarely found in normal individualsRarely found in normal individuals

Thyroid ScansThyroid Scans

• Technetium 99 ($450)Technetium 99 ($450)– Low radiation, quickLow radiation, quick– Useful for nodules in some circumstancesUseful for nodules in some circumstances– Useful to determine cause of hyperthyroidismUseful to determine cause of hyperthyroidism

• A. High uptake: Grave’s, toxic noduleA. High uptake: Grave’s, toxic nodule• B. Low uptake: thyroiditis, thyroxine useB. Low uptake: thyroiditis, thyroxine use

Hyperthyroidism: EpidemiologyHyperthyroidism: Epidemiology

• Etiology:Etiology:– IatrogenicIatrogenic

• A. Over replacement (30-50% given rx)A. Over replacement (30-50% given rx)• B. Suppression of CA, goiters, and nodulesB. Suppression of CA, goiters, and nodules

– Autoimmune (Grave’s disease): thyroid Autoimmune (Grave’s disease): thyroid stimulating autoantibodiesstimulating autoantibodies

– Autonomous nodule(s). Occasionally T3Autonomous nodule(s). Occasionally T3– TSH secreting tumorsTSH secreting tumors

Hyperthyroidism: PrevalenceHyperthyroidism: Prevalence

• Population based prevalence of Population based prevalence of suppressed TSH:suppressed TSH:

AuthorAuthor ageage menmen womenwomenBagchi (1990)Bagchi (1990) >55 >55 1.8% 1.8% 2.7%2.7%Falkenberg (1991) >60Falkenberg (1991) >60 1.9%1.9%Parle (1991)Parle (1991) >60 >60 5.5 5.5 6.3%6.3%Bauer (1993)Bauer (1993) >55 >55 5.8%5.8%

Crook’s Index*Crook’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 ElderlyHyperthyroidism in the Elderly

• Weight loss, palpitations, and Weight loss, palpitations, and nervousness nervousness lessless common common

• Tachycardia, exophthalmos, tremor Tachycardia, exophthalmos, tremor lessless common common

• Atrial fibrillation Atrial fibrillation moremore common common

• 8-10% are completely asymptomatic8-10% are completely asymptomatic

Subclinical Hyperthyroidism: Cardiac EffectsSubclinical Hyperthyroidism: Cardiac Effects

• Systolic time intervals shortenedSystolic time intervals shortened– Clinical significance uncertainClinical significance uncertain

• Reduced exercise toleranceReduced exercise tolerance

• Increased incidence of atrial fibrillationIncreased incidence of atrial fibrillation

Swain, 1994Swain, 1994Prospective cohort, N = 2000Prospective cohort, N = 2000RR = 3.1 (1.7, 5.5) if sTSH < 0.1RR = 3.1 (1.7, 5.5) if sTSH < 0.1

Subclinical Hyperthyroidism: Skeletal EffectsSubclinical Hyperthyroidism: Skeletal Effects

• Florid hyperthyroidism causes fracturesFlorid hyperthyroidism causes fractures

• Effect on BMD, bone loss controversialEffect on BMD, bone loss controversial

• Increased fracture risk (Bauer, 2001)Increased fracture risk (Bauer, 2001)- Prospective study, 9407 older women- Prospective study, 9407 older women- TSH < 0.1 vs. normal- TSH < 0.1 vs. normal- Hip fracture: RR = 3.6 (1.0, 12. 9)- Hip fracture: RR = 3.6 (1.0, 12. 9)- Vertebral fracture: RR = 4.5 (1.3, 15.6)- Vertebral fracture: RR = 4.5 (1.3, 15.6)

• Effect of accelerated bone turnover?Effect of accelerated bone turnover?

Subclinical Hyperthyroidism: Natural HistorySubclinical Hyperthyroidism: Natural History

• Exogenous: Well establishedExogenous: Well established

• Endogenous: Little longitudinal dataEndogenous: Little longitudinal data

Parle, 1991Parle, 199150 untreated individuals >6050 untreated individuals >601 developed overt 1 developed overt

hyperthyroidismhyperthyroidism

After 1 year, sTSH normal in half!After 1 year, sTSH normal in half!

Who Should Be Treated?Who Should Be Treated?

• Exogenous (iatrogenic)Exogenous (iatrogenic)–Dose reduction unless contraindicatedDose reduction unless contraindicated

• Endogenous (subclinical)Endogenous (subclinical)–Follow if uncomplicatedFollow if uncomplicated–Consider treatment if atrial fibrillation or Consider treatment if atrial fibrillation or

osteoporosis presentosteoporosis present

• Endogenous (overt)Endogenous (overt)–Rule out thyroiditisRule out thyroiditis–Tx everyone else with beta blocker and...Tx everyone else with beta blocker and...

Hyperthyroidism: TreatmentHyperthyroidism: Treatment

• Anti-thyroid drugs (PTU and methimazole)Anti-thyroid drugs (PTU and methimazole)– Remission: 30-50% after 12-18 moRemission: 30-50% after 12-18 mo– Side effects: rash, fever, arthritis, Side effects: rash, fever, arthritis,

agranulocytosis (all rare)agranulocytosis (all rare)

• RadioiodineRadioiodine– Best treatment for hot nodulesBest treatment for hot nodules– Remission: everyoneRemission: everyone– Side effects: transient thyroiditis (rare), Side effects: transient thyroiditis (rare),

hypothyroid (50%), worsening exophthalmoushypothyroid (50%), worsening exophthalmous

Radioiodine and MortalityRadioiodine and Mortality

• Franklyn, 1998Franklyn, 1998- 7209 hyperthyroid pts, 15 yr follow-up- 7209 hyperthyroid pts, 15 yr follow-up- All cause mortality: 13% higher than - All cause mortality: 13% higher than age and sex matched populationsage and sex matched populations- CV deaths increased, but not cancer- CV deaths increased, but not cancer

• Mechanism unknown, clear dose-responseMechanism unknown, clear dose-response

• Unable to adjust for other potential Unable to adjust for other potential confoundersconfounders

Hypothyroidism: EpidemiologyHypothyroidism: Epidemiology

• EtiologyEtiology–Autoimmune (Hashimoto’s)Autoimmune (Hashimoto’s)– Iodine deficiencyIodine deficiency– IatrogenicIatrogenic

A. Radioiodine/ surgeryA. Radioiodine/ surgery

B. Drugs (lithium, amiodarone)B. Drugs (lithium, amiodarone)–Pituitary/ hypothalamic diseasePituitary/ hypothalamic disease

Hypothyroidism: PrevalenceHypothyroidism: Prevalence

• Population based prevalence of Population based prevalence of elevated TSH:elevated TSH:

AuthorAuthor ageage menmen womenwomenTunbridge(1977)Tunbridge(1977) >65>65 6.0% 6.0% 10.9% 10.9%

Bagchi(1990)Bagchi(1990) >55>55 1.8% 1.8% 2.7% 2.7%

Parle(1991)Parle(1991) >60>60 2.9% 2.9% 11.6% 11.6%Bauer(1993)Bauer(1993) >55>55 5.4% 5.4%

Billewicz Index*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 ElderlyOvert Hypothyroidism in the Elderly

• ““Classic” features often missingClassic” features often missing

• Neuropsychiatric complaints common: Neuropsychiatric complaints common: depression, weakness, memory lossdepression, weakness, memory loss

• Other clues: hypercholesterolemia, Other clues: hypercholesterolemia, elevated CK, pleural effusionelevated CK, pleural effusion

Subclinical Hypothyroidism: CV OutcomesSubclinical Hypothyroidism: CV Outcomes

• Observational studiesObservational studies– Total cholesterol unchanged, but higher LDL Total cholesterol unchanged, but higher LDL

and lower HDL?and lower HDL?

• What about atherosclerosis?What about atherosclerosis?

• Rotterdam population-based study (Hak, 2000)Rotterdam population-based study (Hak, 2000)– 1149 women, mean age 701149 women, mean age 70– Subclinical hypo (TSH > 4, nl T4) in 10.8%Subclinical hypo (TSH > 4, nl T4) in 10.8%– Aortic atherosclerosis RR = 1.7 (1.1, 2.6)Aortic atherosclerosis RR = 1.7 (1.1, 2.6)– History of MI RR = 2.3 (1.3, 4.0)History of MI RR = 2.3 (1.3, 4.0)

Summary OR 1.65 (1.28-2.12) P for heterogeneity: 0.12

Meta Analysis of Subclinical Hypothyroidism and CHDMeta Analysis of Subclinical Hypothyroidism and CHD

Subclinical Hypothyroidism: Other OutcomesSubclinical Hypothyroidism: Other Outcomes

• Observational studies of neuropsychiatric Observational studies of neuropsychiatric symptomssymptoms– Conflicting evidenceConflicting evidence

• Four small double blinded trials, sTSH > 5-7Four small double blinded trials, sTSH > 5-7– Randomized to thyroxine or placeboRandomized to thyroxine or placebo– No significant change in weight, lipids, other No significant change in weight, lipids, other

laboratory valueslaboratory values– Psychometric testing: Treated felt better and Psychometric testing: Treated felt better and

had better memory scoreshad better memory scores

Subclinical Hypothyroidism: Natural HistorySubclinical Hypothyroidism: Natural History

• Many good studiesMany good studies

• Spontaneous resolution infrequentSpontaneous resolution infrequent

• Antibodies strongly influence outcomeAntibodies strongly influence outcome– If TPO positive, overt hypothyroidism If TPO positive, overt hypothyroidism

5%/yr5%/yr

Hypothyroidism: TreatmentHypothyroidism: Treatment

• Replace with thyroxine (T4)Replace with thyroxine (T4)– T3 + T4 benefit unprovenT3 + T4 benefit unproven

• Typical replacement dose 1.6 mcg/kgTypical replacement dose 1.6 mcg/kg–Elderly or CAD: start low (0.025-0.05 Elderly or CAD: start low (0.025-0.05

mg/d), gradually increase dosemg/d), gradually increase dose

• Maintain TSH within the normal rangeMaintain TSH within the normal range–Wait 6 weeks after dose changeWait 6 weeks after dose change

• Monitor yearly (noncompliance, reduced Monitor yearly (noncompliance, reduced T4 clearance)T4 clearance)

What About Treatment of Symptomatic but What About Treatment of Symptomatic but Euthyroid Patients? Forget It.Euthyroid Patients? Forget It.

• Symptoms of hypothyroidism commonSymptoms of hypothyroidism common– Real but not detected by usual tests?Real but not detected by usual tests?

• Double blind RCT (Pollock, 2001)Double blind RCT (Pollock, 2001)– 25 “symptomatic”, 18 “controls”25 “symptomatic”, 18 “controls”– All euthyroidAll euthyroid– 3 mo of T4 (0.1/d) or placebo, cross-over3 mo of T4 (0.1/d) or placebo, cross-over– TSH fell with T4 tx but no difference in TSH fell with T4 tx but no difference in

cognitive or psychological functioncognitive or psychological function

Thyroid Nodules: Epidemiology and EvaluationThyroid Nodules: Epidemiology and Evaluation

• Nodules are common (and cancer is rare)Nodules are common (and cancer is rare)– 90% women over age 60 have one or more 90% women over age 60 have one or more

thyroid nodules at autopsythyroid nodules at autopsy

• Risk factors for cancer: neck irritation, FHRisk factors for cancer: neck irritation, FH

• Evaluation: FNA firstEvaluation: FNA first– 75% benign, 20% suspicious, 5% malignant75% benign, 20% suspicious, 5% malignant– Best centers: false negative 2%Best centers: false negative 2%

false positive 1% false positive 1%

Thyroid Nodules: TreatmentThyroid Nodules: Treatment

• CancerCancer- Histology is important (papillary best)- Histology is important (papillary best)- Surgery and - Surgery and 131131I ablation I ablation - Suppression with T4? TSH = 0.1-0.4- Suppression with T4? TSH = 0.1-0.4

• Benign nodulesBenign nodules- Many shrink spontaneously- Many shrink spontaneously- Meta analysis of T4 suppression - Meta analysis of T4 suppression

Smaller: 26% vs. 12% (NNT=7)Smaller: 26% vs. 12% (NNT=7)Larger: 8% vs. 17% (NNT=11)Larger: 8% vs. 17% (NNT=11)

- T4 doesn’t prevent new nodules- T4 doesn’t prevent new nodules

Screening Cost-effectivenessScreening Cost-effectiveness

• Danese and Sawin, 1995Danese and Sawin, 1995

– Cost-utility analysis, sTSH-based screeningCost-utility analysis, sTSH-based screening

– Modeled progression, symptoms and CADModeled progression, symptoms and CAD

– Screening every 5 year from 35-65: Screening every 5 year from 35-65: $9,223 per QALY in women$9,223 per QALY in women$22,595 per QALY in men $22,595 per QALY in men

– Sensitivity analysis: cost of TSH key ($25)Sensitivity analysis: cost of TSH key ($25)

Screening for Subclinical Thyroid DiseaseScreening for Subclinical Thyroid Disease

• US Preventive Task Force, 1996US Preventive Task Force, 1996“Routine screening is not recommended. “Routine screening is not recommended. Insufficient evidence for high risk patients, Insufficient evidence for high risk patients, including elderly.” including elderly.”

• ACP, 1998ACP, 1998“It is reasonable to screen women older “It is reasonable to screen women older than 50 years of age for unsuspected but than 50 years of age for unsuspected but symptomatic thyroid disease.”symptomatic thyroid disease.”

Screening Cost-effectivenessScreening Cost-effectiveness

• Effects on HDL, fractures not included. Effects on HDL, fractures not included. Cost of testing overestimated ($3/TSH) Cost of testing overestimated ($3/TSH)

• Published analyses Published analyses underestimateunderestimatecost-effectivenesscost-effectiveness

• Other unresolved issues:Other unresolved issues:– Age to start screening?Age to start screening?– Optimal frequency?Optimal frequency?

Summary Take Home PointsSummary Take Home Points

• sTSH is best testsTSH is best test

• Subclinical thyroid disease is common, Subclinical thyroid disease is common, associated with morbidity, and treatableassociated with morbidity, and treatable

• Low threshold to treat subclinical hypoLow threshold to treat subclinical hypo

• Treatment threshold for subclinical hyper Treatment threshold for subclinical hyper less certain less certain

• Screening with sTSH is cost-effectiveScreening with sTSH is cost-effective

CasesCases

• 68 yr old female with new atrial fibrillation 68 yr old female with new atrial fibrillation and no other findings except TSH=0.04, and no other findings except TSH=0.04, normal free T4normal free T4

• 79 yr old man with 1 yr of fatigue and 79 yr old man with 1 yr of fatigue and lassitude and no findings except TSH=9.0, lassitude and no findings except TSH=9.0, anti-TPO positiveanti-TPO positive

• 45 yr old women, enlarged thyroid with 45 yr old women, enlarged thyroid with dominant nodule since 1999, FNA benign. dominant nodule since 1999, FNA benign. On T4 suppession ever since, TSH=0.1On T4 suppession ever since, TSH=0.1