Clinical Implications of the New TSH Reference Range TSH Reference ranges clinical...Clinical Implications of the New TSH Reference Range ... Limitations of using population reference

Carole Spencer Ph.D., FACB.,Professor of Medicine

Technical Director, USC Endocrine Services LaboratoryUniversity of Southern California

Los Angeles, California

Clinical Implications of the

New TSH Reference Range

AACC Expert Access

8/15/06

USCUNIVERSITY

CALIFORNIAOF SOUTHERN

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101112

TSHmIU/L

1970-85

Changing TSH Reference Ranges Over Three Decades

1985-90

0.3-0.4

~ 5.0

0.3 - 0.4

5 - 6

2nd. generationIMA

1990 - present

4 - 5

3rd. generationIMA

0.3 - 0.4

2.5 - 3.0

0.3 - 0.4

~10.0

?

More sensitive thyroidAntibody tests

Immunometric assays(IMA)

New Guidelines

1st. generationRIA

Why TSH has become the primary thyroid test

Limitations of using population reference ranges for the thyroid tests -TSH has a low index of individuality

Rationale for a TSH lower reference limit of ~ 0.3 mIU/L

Rationale for an empiric TSH upper reference limit of 2.5-3.0 mIU/L

Clinical Rationale for adopting a TSH reference range 0.3-3.0 mIU/L

OUTLINETSH Testing in Ambulatory Patients

(+)

TRH

(-)

T4 T4T3

(+)

TSH

TSH Pituitary

Thyroid

HypothalamusTRH

20%Peripheral Tissues

T4 T380%

100%DIRECT T4

INDIRECT

1100fold

2 fold

undetectable

TSHmIU/L

Hypothyroid Reference Range Hyperthyroid

From: Spencer JCEM 70:453, 1990

1000

100

10

0.1

0.01

The Diagnostic Power of TSH is Due to the TSH/Free T4 Relationship

Free T4

Andersen et al JCEM 87: 1068, 2002

Individuals have a Genetically Controlled Free T4 Set-Point

PopulationReference

Range

Participants

0

2

4

6

8

10

12

Free T4Index

Mild(Subclinical)

Overt(Clinical)

Mild(Subclinical)

Overt(Clinical)

ReferenceRanges

DevelopingHypothyroidism

DevelopingHyperthyroidism

Months / Years

TSH

TSH

FT4

FT4

ReferenceRanges

“overt” hypothyroidism

“overt” hyperthyroidismTSH = 0.05

0

TSHreference range

mIU/L

1000

100

10

1

0.1

0.01

16 20 24

Free T4 Status Does Not Always Indicate the Degree of Thyroid Dysfunction

TSH = 40

“subclinical”hyperthyroidism

“subclinical”hypothyroidism

TSH = <0.01

4 128FT4 reference range From: Spencer JCEM 70:453, 1990

TSH >10

Free T4 Index

Set

Population Reference Range

OvertHyperthyroidism

13.04.5

OvertHypothyroidism

Classification of Overt Disease is Influenced by the FT4 Set-PointFrom Andersen Thyroid 13:1069, 2003

+117%

+25%

-25%

- 60%

ASetpoint 6.0

BSetpoint 11.0

Mild(Subclinical)

Overt(Clinical)

Mild(Subclinical)

Overt(Clinical)

ReferenceRanges

DevelopingHypothyroidism

DevelopingHyperthyroidism

Months / Years

TSH

TSH

FT4

FT4

TSHreference range

TSHreference range







No personal or family history of thyroid dysfunction

No visible or palpable goiter

No medications (except estrogen)

No thyroid autoantibodies -TPOAb or TgAb(measured by sensitive immunoassay)

TSH reference intervals should be established from the 95 %confidence limits of the log-transformed values of at least

120 rigorously screened normal euthyroid volunteers with:

The TSH Reference RangeThyroid 13:36, 2003

NACB Guideline 22

The TSH Normal RangeReference

-2sd -1sd +1sd +2sd

2.5% 2.5%

mean

0.2

0.5

1.0

1.5

1.8

Index ofIndividuality

(IOI)

PopulationReference Rangehas limited utility

when IOI <0.6

PopulationReference Rangehas most utilitywhen IOI > 1.4

TT4FT4

TT3FT3

TSH

Index of Individuality - Is an Index of the Intra-individual versus Between-individual Variability

Browning Clin Chem 32: 962, 1986Andersen et al JCEM 87: 1068, 2002

Free T4 TSH

Multiple Variables Contribute to Between-Individual TSH Variability

Physiologicvariability

GoiterNodules

Autoimmune Thyroid Diseases (AITD)

ThyroidPathology

GeneticDiurnal rhythmSleep patternsCaloric IntakeIodine intake

Seasonal influencesBody Mass Index (BMI)

PopulationReference

Range

12 1115 24 514 19 166 831310

4

3

2

1

Participant #

TSHmIU/L

GroupReference

Range

0.2

2.4

Mean1.3

Mean1.3

The Population Reference Range is a Crude Parameter for Assessing the Thyroid Status of Individuals

In an individual, a TSH change that exceeds 0.75 mIU/L is biologically significant.(NACB Guideline #8. Thyroid 13:18, 2003)

Andersen JCEM 87:1068, 2002NHANES Survey

Hollowell JCEM 87:489, 2002

0.4

4.1







A TSH Lower Reference Limitof 0.3 - 0.4 mIU/L

is supported by methodologicand clinical studies

Framingham Study - Relative Risk of Developing Atrial Fibrillationin > 60-Year Old Individuals (no L-T4 Rx.)

Sawin NEJM 331:1249, 1994

P = 0.04

0.1 - 0.4< 0.1

p< 0.001

P= 0.06

> 5.00

1

2

3

4

RELATIVERISK

TSH mIU/L

0.4 - 5.0

1 2 3 4 5

HipFracture

SpineFracture

TSH 0.5-5.5

Subclinical Hyperthyroidism -The Study of Osteoporotic Fractures

Bauer DC et al AIM 134:561-568, 2001

Relative Risk

TSH <0.1

*

*

TSH 0.1-0.5

*

• Prospective Cohort Study• 686 from Cohort of 9704 women• Age >65 yrs• Data Adjusted by Multifactorial Analysis1. Previous Hyperthyroidism2. Age3. Self-Rated Health4. Estrogen Use5. Thyroid Hormone Use

TSH Upper Reference Limit

(~ 2.5 - 4.5 mIU/L)

is more controversial!







Access2

AdviaCentaur

Architect2000

RocheE170

Immulite2000

VitrosECi

TSH Methods Likely Measure Different TSH Isoforms

0

1

2

3

4

5

6

7

8

9

10

TSHmIU/L

Rawlins et al Clin Chem 50:2338, 2004

5.3 5.64.9

6.15.5

7.9

Lyphocheck Level 2

(mean ± 2sd)

3.9

4.74.1

4.85.4

4.62006 CAP data

0.3-0.4 1.3-1.4 2.5-3.0 10

Reasons for the skew in the TSH upperreference limit include:

The Predicted versus the Population TSH Upper Reference Limit

TSH mIU/L ~ 4-5

• Occult autoimmune thyroid dysfunction

• TSH receptor polymorphisms - TSH sensitivity

• Measurement of bioinactive TSH isoforms

• Euthyroid outliers - inherent TSH lability

% Women

0

5

10

15

20

25

30s 50s 80s

Whickham 1

(N=2779)Colorado 2

(N=25,862)NHANES3

(N=17,353)

1. Tunbridge W, et al. Clin Endocrinol. 1977;7:481-493.2.2. Canaris G,G, Arch Intern Med. 2000;160:526-534.3.3. HollowellJ,J, J ClinJ Clin Endocr Metab. 2002; 87:489-499.

Prevalence of Mild Thyroid Failure (Subclinical Hypothyroidism)in Women in Different Age Groups

Age Group

0

5

10

1514.7

%Prevalence

Thyroidantibodies

Odds Ratio for Overt Hypothyroidism 23.5 6.9 1.1Odds Ratio for Subclinical Hypothyroidism 11.7 4.0 1.5

TPOAb+ TgAb

TPOAbalone

TgAbalone

Hollowell JCEM 87: 489, 2002NHANES - Prevalence of Thyroid Antibodies (n= 17,353)

6.95.7

3.1

The presence of TPO antibodies (TPOAb)

is the primary exclusion criterion for

autoimmune thyroid disease when

establishing TSH reference ranges

However, TPOAb is not always detectedin patients with AITD!

FNA cytologyTPOAbpositive

0

20

40

60

80

100

Hashimoto's Graves'

normal echogenicity (n = 100)diffuse hypoechogenicity (n = 452)

%

3077 Prospective Ultrasound EvaluationsHypoechogenicity Indicative of Autoimmune Thyroid Disease (AITD) in 15%

from: Pedersen Thyroid 10:251, 2000

88.2

14.0

2.0

77.8

10.4

0

66.8

10.2

64.4

2.0

17.6

2.0

HighTSH

LowTSH

TotalAITD

20%

years/decades

5%/year

1

23

4

Activation ofAutoimmune

Process

EnvironmentalFactors/

Pregnancy

GeneticPredisposition

Developing Autoimmune Thyroid Dysfunction

HypoechoicUltrasound Pattern

TPOAbPositivity

TSH Elevation =mild (subclinical)hypothyroidism

High TSH+

Low T4 =overt

hypothyroidism

National Academy of Clinical Biochemistry (NACB) Guidelines:

Occult Thyroid Dysfunction Skews the TSH Upper Limit

Thyroid 13:42, 2003 & www nacb.org

Recommendations: Adopt an Empiric TSH Upper Limit

Ambulatory patients with a serum TSH above 2.5 mIU/L,when confirmed by a repeat TSH measurement made

after 3 weeks, may be in the early stages of thyroid failure,especially if TPOAb is detected.

Association of Clinical Endocrinologists (AACE) Guidelines:

Endocrine Practice 8:457, 2002Proposes the adoption of a TSH reference range of 0.3 - 3.0 mIU/L







- 5

- 4

- 3

- 2

- 1

0

1

2

3

4

201010.2 0.5 2 5 50

TPOAb - positive

TPOAb - negative

Observeddata

Probability ofDeveloping

Hypothyroidismduring 20 years

follow-up

20-Year Follow-up Study of the Whickham CohortVanderpump Clin Endocrinol 43:55, 1995

Serum TSH measured in 1975 (mIU/L)

Growing recognition that even

mild (subclinical) Thyroxine deficiency

in early pregnancy is

detrimental to mother and fetus

New guidelines state that a TSH below 2.5 mIU/Lis optimal for pregnancy.

Mandel et al Thyroid 15:44, 2005

A TSH Upper Reference Limit of 2.5 mIU/L is now ConsideredOptimal for Managing Pregnant Patients.

Casey et al Obstet Gynecol 105:239,2005

10 20 30 40

TSHmIU/L

Weeks Gestation

0.03

1.5

0.5

2.5

3.5

4.5

1st. Trimester 2nd. Trimester 3rd. Trimester

0.4

3.5

1.2

0.4

3.5

1.2

Changes in TSH During Pregnancy

Panesar Ann Clin Biochem 38: 329, 2001Mandel et al Thyroid 15:44, 2005

1st. Trimester TSH Reference Ranges (95% confidence limits)

0.1

1

10

2.3

A = n = 343 (Hong Kong) Panesar Ann Clin Biochem 38:329, 2001

TSHmIU/L

0.01

C = n = 115 (USA) Mestman ITC, 2005

2.7

D = n = 217 (Europe) Stricker AACC, 2006

B = n = 17,298 (USA) Casey Obstet Gynecol 105:239, 2005

Recommended1st. TrimesterTSH Upper Limit

2.5

0.03~ 0.02 ~ 0.02

2.5

0.02

2.8

0.08

A B C D

Question

In the non-pregnant patient,

do mild TSH abnormalities

(TSH > 3.0 mIU/L)

have any clinical significance?

SubclinicalHypothyroidism

(high TSH/normal FT4)

2002 Consensus Conference Reviewed Literature between 1995 and 2002Surks et al JAMA 291:228, 2004

SystemicSymptoms

NeuropsychiaticSymptoms

Systolic Time Intervals

Total CholesterolLDL- Cholesterol

Panel Concluded:

“Few symptoms and little benefitin treating Subclinical Hypothyroidism when TSH is < 10 mIU/L”

• Many studies were based on small numbers of subjects and most werenot double-blinded, placebo-controlled trials.

• SCHO study groups often included individuals with different degrees ofseverity (i.e. subjects with TSH below & above 10 mIU/L were grouped).

• In some studies claiming a lack of a treatment response suboptimal L-T4treatment was employed that failed to lower TSH below 3.0 mIU/L.

• Typically, insensitive parameters (like symptoms & Total Cholesterol)were used to judge the effects of SCHO.

Problems

2002 Subclinical Hypothyroidism (SCHO) Consensus Conference

AtherosclerosisRisk Factors

Atherogeniclipid markers

InsulinResistance

Associationswith SCHO

#SCHO/contr.

Meanage

entry TSH(mean mIU/L)

mean TSH post Rx. L-T4

Michalopoulou, 1998Meier, 2001Kvetny, 2004Dessein, 2004Serter, 2004Monzani, 2004Milionis, 2005Iqbal, 2006

Bakker, 2001Dessein, 2004

Christ-Crain, 2003Kvetny, 2004Tuzcu, 2005

Muller, 2001Canturk, 2003

Monzani, 2004

Lekakis, 1997Taddei, 2003Cikim, 2004

26/3566/963 RCT249/96314/5530/2645/3228/3084/145

47 controls14/55

63/40 RCT249/96377/80

42/6635/30

45/32

28/714/2825/23

-57425939355462

3459

574234

5942

35

513932

> 0.4 (2.8)> 5.0 (12.8)> 2.9 (3.7)> 4.0 (5.1)> 4.0 (6.2)> 3.6 (6.0)> 4.5 (9.9)> 4.0 (5.7)

> 0.2 (1.8)> 4.0 (5.1)

> 5.0 (9.9)> 2.9 (3.7)> 4.2 (7.4)

> 4.0 (16.0)> 4.0 (8.7)

> 3.6 (6.0)

> 2.0 (9.0)> 3.6 (7.7)> 4.5 (8.9)

1.4 (improved)3.1 (improved)

1.4 (improved)1.3 (improved)1.6 (improved)1.0 (improved)

3.1 (no effect)

1.1 (improved)

1.3 (improved)

1.7 (improved)ImpairedEndothelial Function

Inflammation(hsCRP)

HypercoagulationMarkers

IntimaMedia Thickness

AtherogenicLipid Markers

InsulinResistance

Inflammation(hsCRP)

HypercoagulationMarkers

Intima MediaThickness

ImpairedEndothelial Function

SubclinicalHypothyroidism

There is wide between-subject differences in overall cardiovascular risk.Subject selection (SCHO vs control) likely accounts for the variability among studies.

Risk Factor Atherosclerosis

“There is no single level of serum TSH at which clinical action is always either indicated or

contraindicated. The higher the TSH the more compelling is the rationale for treatment”.

“It is important to consider the individual clinical context (e.g. pregnancy, lipid profile, TPO antibodies)”.

Surks et al JAMA 291:228, 2004

Subclinical Thyroid Disease Consensus Panel

3.0 100100.10.01 1.00.3

empiricreference

range

TSH mIU/L

Patients with TSH Outside the Empiric Reference RangeDo Not Necessarily Need Treatment!

hyperthyroidismrisk for

high NPVif TPOAb(-)

risk fo

rhyp

othyr

oidism

Threshold for Treatment Should be Adjusted for Patient-Specific Risk Factors

OvertSubclinicalHypothyroidism

10010Subclinical Hyperthyroid

Normal FT4Overt SubclinicalHyperthyroidism

0.10.01

CardiovascularRisk

CardiovascularRisk

ageTPOAb +

increased lipidsfamily history of CVD

diabetes mellitusinsulin resistance

hypertensionsmoking

3.010.3

EuthyroidHigh NPV

TPOAb-neg

TSH mIU/L

TPOAb Concentration(risk factor for progression)

Decisionto treat is

multifactorial

risk factors forcardiovascular disease

• cardiovascular disease

• atherogenic lipid profile

• hypertension

• diabetes

• insulin resistance(high BMI)

• ?????

Other Factors

• Age

• General health

• Family history

• Compliance

• Patient preferences

• Symptoms

3.00.3

degree of theTSH abnormality

Threshold for Treatment Should be Patient-Specific!

Conclusions

Each individual has their own TSH range that spans ~ 0.75 mIU/L.The population reference range is NOT an individual’s ‘normal range’

95% of individuals in a population free of thyroid disease have TSH in the 0.3 to 2.5 mIU/L range.

New Guidelines recommend that pregnant patients should have TSHbelow 2.5 mIU/L - this is critical in the 1st. trimester.

There is growing data suggesting that mild subclinical hypothyroidism (TSH 3-10 mIU/L) can exaccerbate the risk for cardiovascular disease in susceptible individuals.

The presence of TPOAb increases the risk of progression to overt disease.

Conclusions - Therapy

TSH is a labile hormone and any TSH abnormality should be confirmed before initiating therapy.

There is no TSH level that either indicates or contraindicates the need for L-T4 therapy, although the higher the TSH the more compelling is the rationale to treat with L-T4.

The threshold TSH for initiating therapy should be patient specific.

The threshold for initiating therapy should be lower for patients with a history of cardiovascular disease, older patients, elevated lipids, hypertension, diabetes or planning pregnancy.

Documents

Clinical Implications of the New TSH Reference Range TSH Reference ranges clinical...Clinical Implications of the New TSH Reference Range ... Limitations of using population reference