Subclinical HyperthyroidismLow Serum TSH

Normal FT4 and FT3

Undetectable

ng/dL

T SHR eference

Interval

H yperth yroidH yp o-T h yroidF T 4 R eference

In terval

0 .7 1 .8

0.01

0 .1

4 .010

100

1,000

TSHmIU/L

F ree T 49 2 3 pmol/L{

0.4

Adapted from Spencer , C A

Subclinical hyperthyroidismDefinition

Patient DC: History

Generally healthy 74 year woman found to have a TSH of 0.2 mIU/L

Asymptomatic except for insomnia and anxiety

PMH: treated for hypertension with ACE I, previously treated with LT4 for nodules

Fam hx: 2 daughters with thyroid nodules, one s/p thyroidectomy

Soc Hx: retired teacher, plays tennis regularly

Patient DC: Evaluation

Thyroid exam normal except for irregular surface with bilateral 1 cm nodules

No stigmata of hyperthyroidism on PE

TSH level 0.2 mIU/L

Thyroid hormone levels normal

Is she currently taking thyroid

hormone?

All cases of hyper = 2.2% (570)% of cases with SC Hyper = 94% (535)

PREVALENCE LOW TSH (

Subclinical Hyperthyroidism Prevalence

Colorado study: 25,682 subjects

Present in 0.9% of those not taking TH

Present in 21% of those taking TH

NHANES III:

0.7% if criteria was TSH

Subclinical Hyperthyroidism: Iatrogenic:

target rangeHypo HyperEuth

Prevention of Subclinical Hyperthyroidism

Patients on levothyroxine

Monitor therapy

Keep TSH within normal range

Be aware of factors that may change patients dose requirement

Will her TSH remain subnormal?

Subclinical Hyperthyroidism Natural history

First TSHTSH one year later

Normal Low Total0.05-0.5 38 (76%) 12 50

TSH

Subclinical Hyperthyroidism Natural history

2024 patients with endogenous SC hyperF/up year TSH normalized

Year 2 17%Year 5 32%Year 7 36%

Low TSH values may revert to normalNormalization more common with subnormal TSH values

Monitoring of patients with history of low TSH values important

Vadiveloo et al, JCEM: epub, Oct 2010

Patient DC: Evaluation

PE: normal except for irregular thyroid gland, with bilateral 1 cm nodules

TSH level (repeated on several occasions) 0.2-0.3

mIU/L

Thyroid hormone levels normal

Patient DC: Evaluation

RAIU and scan: multiple hyperfunctioning

nodules

with partial suppression of rest of gland

DEXA: bone mineral density normal (T scores in hip and spine -0.5 and -0.9)

ECG: normal

Is the etiology of the SCH important with respect to its natural history?

Subclinical HyperthyroidismEtiology

Differential Diagnoses

Nonthyroidal

illness, psychiatric illness, drugs

Exogenous causes

Unintentional excessive TH replacement therapy

Intentional TSH suppression therapy

Endogenous causes

Graves disease

Multinodular

goiter

Autonomous thyroid nodule

Subclinical Hyperthyroidism Natural history

Diagnosis

TSH 11-36 months later

Became euthyroid

Remained with SC

Became overtly hyperthyroid Total

Graves 5 1 1 7

MNG 0 9 0 9Natural history of subclinical hyperthyroidism depends on the etiology

of the hyperthyroidism: may remit or progress

Woeber, Thyroid 15: 687-691, 2005

Subclinical Hyperthyroidism Natural history

Diagnosis Baseline TSH Progression of SC hyper at 5 yearsSubclinical

Graves 0.02-0.10 9%

MNG 0.02-0.14 21%Autonomous

nodule 0.02-0.10 61%

Natural history of subclinical hyperthyroidism depends on the etiology

Schouten et al, Clin Endo: epub, Nov 2010

Patient DC

Should she receive treatment?

Yes/No

If yes, what treatment?

If no, what monitoring

Subclinical Hyperthyroidism Potential adverse effects

Skeletal effects

Cardiac effects

Mortality

Cognitive effects/Symptoms

Subclinical Hyperthyroidism Potential adverse effects

Is DC at risk for decreased BMD?

Subclinical Hyperthyroidism and FracturesThe Study of Osteoporotic Fractures

-Prospective Cohort Study-686 from Cohort of 9704 women-Age >65 yrs, mean follow-up 6 years-Data Adjusted by Multifactorial Analysis

Bauer et al Annals Int Med 134: 561-568, 2001

0 1 2 3 4 5

HipFracture

SpineFracture

TSH 0.5-5.5

Subclinical Hyperthyroidism and FracturesThe Study of Osteoporotic Fractures

Bauer et al Annals Int Med 134: 561-568, 2001

Relative Risk

TSH

Patient DC

Would treatment improve (protect?) her BMD?

Yes

No

Effect of Treatment on BMD

28 menopausal women with SC hyperthyroidism due to a MNG

TSH

Effect of Treatment of Bone Density Post-menopausal women/non-randomized

90

92

94

96

98

100

102

104

No RAI/hip No RAI/spine RAI/hip RAI/spine

Baseline1 year2 year

Faber et al. Clin Endo 48: 285-290, 1998

P

Effect of Treatment on BMD

16 menopausal women with endogenous SC hyperthyroidism

8 received methimazole

therapy

8 followed without treatment

forearm bone mineral density followed

BMD significantly higher (p

Subclinical Hyperthyroidism Potential adverse effects

Is DC at risk for cardiac events?

0.4-5.0

0.9 1.4 1.9 2.4 2.9 3.4

T

S

H

(

u

U

/

m

l

)

RELATIVE RISK

SUBCLINICAL HYPERTHYROIDISMATRIAL FIBRILLATION

Cappola et al. JAMA 2006;295:1033-1041.

Increased risk of atrial fib for

both TSH

Patient DC

Would treatment decrease her risk of cardiac arrhythmias?

Yes

No

Effect of Treatment on Cardiac Function non-randomized study

Sgarbi et al. JCEM 88: 1672-1677, 2003

n=10 each group Controls

SC hyper before tx

SC hyper after tx

P (before vs after tx)

Atrial premature

beats2.5 86.5 10.5 0.002

Ventricular premature

beats0 8 0 0.003

Subclinical Hyperthyroidism Potential adverse effects

Is DC at risk for increased

mortality?

Subclinical Hyperthyroidism Survival

1191 subjects in Birmingham, UKSingle TSH measurementEnrollment 1988-89, analyzed 1999>60 years old, mean age 70 years509 died during the 10 yrsExclusions: Thyroid Hormone or Antithyroid

Rx

Parle et al Lancet 358: 861,2001

Subclinical hyperthyroidism Survival

Parle J et al Lancet 358: 861,2001

100

80

60

45

Surv

ival

(%)

TSH

5.02.1-5.01.3-2.00.5-1.2

All Causes

2.1(1.2-3.8), 1.8(1.2-2.7)Circulatory

2.3(1.0-5.2), 2.3(1.3-4.0)Cardiovascular

3.3(1.3-8.0), 2.2(1.1-4.4)

Parle et al Lancet 358: 861,2001

Subclinical HyperthyroidismSurvival

Hazard Ratio (95% CI)

2yr

5yr

Cerebrovascular

1.0(0.1-7.7), 2.8(0.9-8.2)Malignancy

2.3(0.8-6.7), 1.7(0.8-3.6)Respiratory

1.6(0.4-7.1), 1.7(0.6-4.7)

SUBCLINICAL HYPERTHYROIDISM ALL CAUSE

MORTALITY

Cappola et al. JAMA 2006;295:1033-1041.

HR for SC hyper = 1.13 (95% CI 0.76-1.70)

Subclinical Hyperthyroidism and Mortality

Meta-analysis All Cause Mortality

Volzke

et al, JCEM 92: 2421- 2429, 2007

Not increased

Haentjens

et al, Eur

J. Endo 159: 329-341, 2008

IncreasedHR 1.41 (95% CI 1.12-

1.79), p=0.004Singh et al, Int

J Cardiol

125: 41- 48, 2008

Not increased

Subclinical Hyperthyroidism and Mortality

Sgarbi et al, Europ. J. Endo 162: 569-577, 2010

1,110 participants followed for 7.5 years

None taking thyroid hormone

74 deaths over the follow-up period

Cause of death documented

Multivariate analysis

Subclinical Hyperthyroidism and Mortality

Mortality HR 95 % CI P

SC hyperthyroid All-cause 3.0 1.5-5.9

Patient DC

Would treatment decrease her mortality?

Yes

No

Subclinical Hyperthyroidism Potential adverse effects

Are DCs symptoms (insomnia and anxiety) due to her SC Hyper?

Subclinical Hyperthyroidism Symptoms

10-15 patients each group

Wayne score (index of

hyperthyroidism)TSH Mean Age

Overt hyperthyroidism -0.3 +/-

2.5

Patient DC

Would treatment change her symptoms?

Yes

No

Effect of Treatment on Quality of Life non-randomized study

Sgarbi et al. JCEM 88: 1672-1677, 2003

n=10 each group Controls

SC hyper before tx

SC hyper after tx

P (before vs after tx)

Wayne index 1.0 12.0 2.0 0.004

TSH 1.5 0.05 1.4 0.002

Patient DC

Would your decision to treat change if

the patient was 45 years old instead of 74?

the patients TSH was

Subclinical hyperthyroidism

Two categories of low TSH

May have implications for treatment

Low, but detectable TSH (0.1-0.4)

Undetectable TSH (

Treatment of Subclinical Hyperthyroidism

Consider treatment

Older patientesp if heart disease,

osteoporosis,symptoms

Observe

Younger patientno risk factors

TSH 0.1-0.5

Treat

Older patient

Observeor treat

Younger patientno risk factors

TSH

Slide Number 1Slide Number 2Patient DC: HistoryPatient DC: EvaluationSlide Number 5Subclinical hyperthyroidism: EtiologySubclinical HyperthyroidismPrevalenceSubclinical Hyperthyroidism: Iatrogenic: target rangePrevention of Subclinical HyperthyroidismPatients on levothyroxineSlide Number 10Subclinical HyperthyroidismNatural historySubclinical HyperthyroidismNatural historyPatient DC: EvaluationPatient DC: EvaluationSlide Number 15Slide Number 16Subclinical HyperthyroidismNatural historySubclinical HyperthyroidismNatural historyPatient DCSubclinical HyperthyroidismPotential adverse effectsSubclinical HyperthyroidismPotential adverse effectsSlide Number 22Slide Number 23Patient DCEffect of Treatment on BMDEffect of Treatment of Bone DensityPost-menopausal women/non-randomizedEffect of Treatment on BMDSubclinical HyperthyroidismPotential adverse effectsSlide Number 29Slide Number 30Patient DCEffect of Treatment on Cardiac Functionnon-randomized studySubclinical HyperthyroidismPotential adverse effectsSubclinical HyperthyroidismSurvivalSubclinical hyperthyroidismSurvivalSlide Number 36SUBCLINICAL HYPERTHYROIDISM ALL CAUSE MORTALITYSubclinical Hyperthyroidism and MortalitySubclinical Hyperthyroidism and MortalitySubclinical Hyperthyroidism and MortalityPatient DCSubclinical HyperthyroidismPotential adverse effectsSubclinical HyperthyroidismSymptomsPatient DCEffect of Treatment on Quality of Lifenon-randomized studyPatient DCSubclinical hyperthyroidismTreatment of Subclinical HyperthyroidismSlide Number 49