هوالطیف

Subclinical thyroid dysfunction Subclinical thyroid dysfunction

Is a common clinical problem

(Hypo > Hyper) Abnormal TSH

Normal T4, FT4, FT4I

Changing TSH Reference LimitsChanging TSH Reference Limits

0

2

4

6

8

10

12

~4.0

0.3-0.4

~5.0

0.5

~10.0

?

2004200420042004

~2.50.3-0.4

RIA1970-85

2nd gen IMA1985-90

3rd gen IMA1990-00

TSH(mIU/L)

National Health & Nutrition Examination Survey National Health & Nutrition Examination Survey NHANES IIINHANES III

0

5

10

15

20

25

30

35

0.30.3 1.01.0 2.02.0 3.03.0 4.04.0

Frequency(%)

No thyroid disease 13,344

95% TSH 0.3-2.5

Mean TSH 1.49

TSH (mIU/L)

Total 17,353 subjectsTotal 17,353 subjects

NHANES IIINHANES III Effect of Age on TSH Effect of Age on TSH

0.0

0.5

1.0

1.5

2.0

2.5

12-1912-19 20-2920-29 30-3930-39 40-4940-49 50-5950-59 60-6960-69 70-7970-79 8080 AvgAvg

Age (yr)

TSH(mIU/L

1.49

28.0 30.9 54.6 85.2 96.58.3 14.413.5 18.1 30.65.5 5.8

0

20

40

60

80

100

NHANES IIINHANES III Positive Correlation of TPOAb and Positive Correlation of TPOAb and TSH TSH

0.10.1 0.40.4 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 4.54.5 55 1010 >20>20

5.7

Subclinical/OvertHypothyroidismTypical TSH Reference Range

SubclinicalHyperthyroidism

TSH (mIU/L)

TP

OA

b (

%)

So What is Normal TSH Range?

• TSH reference range of 0.5-5.0 is considered normal based on results of general cross-sectional population studies

• More recent studies of rigorously screened normal euthyroid volunteers show serum TSH levels 0.5-2.5 mIU/L

• New TSH reference intervals should be established in studies that exclude subsets with goiter, TPOAb, FHx thyroid dis, meds

• Target TSH for T4 treatment is now 0.3-3.0

FT4, FT3

Low TSH

ClinicalHyper

ClinicalHypo

Low FT4

TSHNormalFT4 & FT3

SubclHyper

Normal FT4TPOAb +

SubclHypo

NewTSHrange

UnequivocallyEuthyroid

New Spectrum of Thyroid DysfunctionNew Spectrum of Thyroid Dysfunction

0.010.01 0.10.1 1010 100100

0.50.5 2.52.5

TSH (mIU/L)

Subclinical HypothyroidismSubclinical Hypothyroidism

• Serum TSH >5.0 mIU/L

• Normal FT4 and FT3

• Mild symptoms may be present

Definition :

Subclinical HypothyroidismPrevalence : Whickham Study

1.1 - 9% in 12 studies (1977-2002)

Women 2.7-11.6%; Men 1.9-3.4%;

Elderly women 8.8-11.6%

White, non-Hispanic 4.8%

Black, non-Hispanic 1.6%

Mexican-American 3.9%

75% with TSH = 5-10 mIu/l

Hollowell, 2002; Canaris, 2000; Vanderpump, 1995; Parle, 1991

Subclinical HypothyroidismSubclinical HypothyroidismWhickham Study: Risk of Progression

Annual risk 20-yr cumulative

Positive test (%) incidence (%)TSH N, Ab+ 2.1 27

TSH , Ab– 2.6 33

TSH , Ab+ 4.3 55

Subclinical HypothyroidismSubclinical Hypothyroidism Whickham Study: Follow-UpWhickham Study: Follow-Up

1,877 subjects Lower risk with young age, lower

TSH, Ab neg Prevalence increased in women with

age: 4.5% in <44; 17.4% in >75 Prevalence in men >65 was 6.2%

Subclinical HypothyroidismSubclinical Hypothyroidism Colorado StudyColorado Study

25,862 subjects surveyed Mean age 55 TSH > 5.0 in 9.5% TSH 5.0 -10 in 74% TSH >10 in 26%

Subclinical HypothyroidismSubclinical HypothyroidismCauses

• Autoimmune Thyroiditis

• Subacute Thyroiditis

• Post 131I or Surgery

• Postpartum Thyroiditis

• Medications (ATD,Lithium,I131 )

Potential Side EffectsPotential Side Effects

TC and LDLc Lpa Homocysteine LV diastolic dysfunction Atherosclerosis

5-10 10-15 15-20 20-40 40-60 60-80 >80150

200

250

Low150

200

250

Normal

Colorado StudyColorado StudyMean Cholesterol LevelsMean Cholesterol Levels

P<0.001P<0.001

TSH levels

Colorado StudyColorado StudyMean Cholesterol LevelsMean Cholesterol Levels

150

200

250

Normal 5-10

P<0.003

TSH levels

Rotterdam StudyRotterdam Study

Population study of 7,983

(1990-1993) 1,149 women evaluated for

Lpids, TSH, Aortic calcifications, ECG and MI

Follow-up chart review in 1996

Rotterdam StudyRotterdam Study

Association of MTF with Risk of Atherosclerosis and MIAssociation of MTF with Risk of Atherosclerosis and MI

1.0 1.0

1.7

2.3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Aortic atherosclerosisAortic atherosclerosis Myocardial infarctionMyocardial infarction

** **

Euthyroid

Mild hypothyroidism (TSH >4.0)

Oddsratio

52-year-old woman with mild fatigue and obesity; thyroid exam is normal TSH= 5.6 FT4 = 1.1 TPO= 420Q: Do you Rx with T4?

a. Yesb. No

Case:

Prevent progression to overt hypothyroidism

Reduce TC and CV risk Improve symptoms

Subclinical HypothyroidismSubclinical Hypothyroidism

Why Treat?Why Treat?

RCT, 63 F 34 with SCH Mean TSH 11-14 (range 5-50) Duration of LT4 therapy = 48 wk TC 3.8%, LDL C 8.2% Risk reduction of CAD mortality 17%

Subclinical HypothyroidismSubclinical HypothyroidismBasel StudyBasel Study

Younger pt TSH >5 TPOAb+ cholesterol

Subclinical HypothyroidismSubclinical HypothyroidismFavoring TreatmentFavoring Treatment

■ Goiter■ Symptoms■ Infertility■ Pregnancy

Hypothyroidism:Hypothyroidism:Recommendations for therapyRecommendations for therapy

Thyroxin therapy= Euthyrox®

TPO-Antibodies positive

Elevated TSH

Symptoms, goiter, elevated total or LDL cholesterol, pregnancy,

or ovulatory dysfunction with infertility

TSH 10 mU/L

Check TSH, fT4, TPO-Abobtain lipid profile

TPO-Antibodies negative

Annual follow-up (TSH, fT4)or thyroxine therapy

TSH < 10 mU/L

No symptoms, goiter, elevated total or LDL-C, pregnancy, or

ovulatory dysfunction with infertility

Adapted fromCooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345(4):260-5

Pharmacological Considerationson Thyroid Pharmacological Considerationson Thyroid HormonesHormones

• IIn the normal adultn the normal adult

– 100 µg T4 is secreted by the thyroid daily100 µg T4 is secreted by the thyroid daily– 30 µg T3 is produced daily (80% from peripheral de-iodination of 30 µg T3 is produced daily (80% from peripheral de-iodination of

T4, 20% from thyroid secretion)T4, 20% from thyroid secretion)

• Administration of Levothyroxine sodium closely mimics glandular Administration of Levothyroxine sodium closely mimics glandular secretionsecretion

– Conversion to T3 is appropriately regulated in the tissuesConversion to T3 is appropriately regulated in the tissues– Stable serum T3 concentrations between levothyroxine dosesStable serum T3 concentrations between levothyroxine doses

• Levothyroxine has a long half-life of approximately 7 daysLevothyroxine has a long half-life of approximately 7 days

– Small fluctuations in serum concentrations between dosesSmall fluctuations in serum concentrations between doses

• Levothyroxine is the treatment of choice for the routine Levothyroxine is the treatment of choice for the routine management of hypothyroidismmanagement of hypothyroidism

Initial Dosing of Levothyroxine in Primary Initial Dosing of Levothyroxine in Primary HypothyroidismHypothyroidism

• NewbornsNewborns– 10 - 15 µg/kg/day, i.e. 50 µg/day10 - 15 µg/kg/day, i.e. 50 µg/day

• ChildrenChildren– 4-5 µg/kg/day, i.e. 12.5 - 50 µg/day4-5 µg/kg/day, i.e. 12.5 - 50 µg/day

• Adults:Adults:– approximately 1.6 µg/kg/day (e.g., 100-125 µg/day for a 70 approximately 1.6 µg/kg/day (e.g., 100-125 µg/day for a 70

kg adult) kg adult) – Patients with known coronary disease: up to 25 µg/dayPatients with known coronary disease: up to 25 µg/day

• Older patientsOlder patients– Patients > 60 years with long duration of hypothyroidism:Patients > 60 years with long duration of hypothyroidism:

50 µg/day or less50 µg/day or less– Patients without clinically overt cardiac disease: 50 µg/dayPatients without clinically overt cardiac disease: 50 µg/day

• Treatment may aggravate angina in ~20% of patientsTreatment may aggravate angina in ~20% of patients

Factors That Increase Levothyroxine Factors That Increase Levothyroxine RequirementRequirement

• Pregnancy, estrogen, tamoxifen, raloxifenePregnancy, estrogen, tamoxifen, raloxifene

• Small bowel diseaseSmall bowel disease

• Drugs or dietary supplements that reduce absorptionDrugs or dietary supplements that reduce absorption– Large amounts of fiber, bran, soy proteinLarge amounts of fiber, bran, soy protein– Aluminium- or iron-containing drugs, calcium carbonateAluminium- or iron-containing drugs, calcium carbonate

• Drugs that increase metabolismDrugs that increase metabolism– Rifampin, carbamazepine, phenytoin, phenobarbitalRifampin, carbamazepine, phenytoin, phenobarbital

• Drugs that reduce T4 to T3 conversionDrugs that reduce T4 to T3 conversion– Amiodarone, betablockers, pAmiodarone, betablockers, propylthiouracil, glucocorticoids and iodine ropylthiouracil, glucocorticoids and iodine

containing contrast mediacontaining contrast media

• Others (mechanism not known)Others (mechanism not known)– Sertraline, chloroquine/proguanil, lovastatinSertraline, chloroquine/proguanil, lovastatin

Case: 46-year-old woman with hypothyroidism is on thyroxine (T4) 0.125 mg daily

Q: What do you consider optimal target TSH?

a. 0.1 b. 1.0c. 5.0 d. 10.0

CONCLUSION :

Subclinical thyroid dysfunction is a common (hypo > hyper) clinical problem

Lab TSH reference range should be reset at

0.3-3.0 TSH therapeutic goal should be at 0.3-3.0 Patients with TSH >5 would likely benefit form

T4 Rx TSH >2.5 is associated with a higher risk for

clinical hypothyroidism

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