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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
0123456789
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
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
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
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
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!
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
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
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
- 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.
Recommended