USC AACC Expert Access 7/8/09 - LBM-MG Medicion de hormonas en... · AACC. Expert Access 7/8/09....

Contemporary Issues

in Thyroid Disease Measurements

Carole Spencer MT, Ph.D, FACBProfessor of Medicine

Department of MedicineUniversity of Southern California

AACCExpert Access 7/8/09

UNIVERSITY

OF SOUTHERN

CALIFORNIA

USC

Thyroid Testing Controversies - 2009

• Thyroid autoantibody testing - strengths and pitfalls

• Limitations of free T4 (FT4) immunoassay methodology

• TSH reference range controversy

• Clinical utility of 2nd generation Thyroglobulin (Tg) measurement

DevelopingHypothyroidism

Mild(Subclinical)

Overt(Clinical)

TSH

Mild(Subclinical)

Overt(Clinical)

TSH

Months / Years

FT4

ReferenceRanges

FT4setpoint

FT4setpoint

FT4

DevelopingHyperthyroidism

TSH reference range TSH reference range

0

2

4

6

8

10

12

TSHmIU/L

TSH upper reference limit has contracted over the last 4 decades

1985-90

0.3-0.4

~ 5.0

~ 0.3

5 - 6

2nd gen.IMA

1990-00

4 - 5

3rd gen.IMA

2002-9

2.5-3.0

1970-85

~10.0

RIA

?

More sensitive thyroid antibody

tests

Immunometric assay (IMA)methodology

New Guidelines

~ 0.3 ~ 0.3

National Academy of Clinical Biochemistry Guidelines:Recommends a TSH upper limit of 2.5 mIU/L

Baloch et al. Thyroid 13:42, 2003 & www nacb.org

Professional organizations recommend adopting a TSH upper reference limit between 2.5 and 3.0 mIU/L

Association of Clinical Endocrinologists (AACE) Guidelines:Proposes a TSH reference range of 0.3 - 3.0 mIU/L

Baskin et al. Endocrine Practice 8:457, 2002

Endocrine Society Pregnancy Guidelines:Preconception & 1st trimester - keep TSH below 2.5 mIU/L

2nd and 3rd trimesters - keep TSH below 3.0 mIU/LAbalovich et al. JCEM 92: S1-S47, 2007

0.2

0.4

Andrew et al CCLM 38:1013-9, 2000

TSH Reference Ranges Reported by 30 Laboratories Using the Same Method

6.03.8

0.1

1

10

“Adapted” reference range (60%)

Manufacturer recommended (30%)

Own (10%)

TSHmIU/L

0.1

10

RocheElecsys

Immulite2000

TosohA1A

BayerCentaur

BeckmanAccess

AbbottAxSym

AbbottArchitect

OrthoEci

1 1.07 1.01 0.98 0.95 0.94 0.85 0.79

0.62

TSHmIU/L

0.27

4.2

0.400.34 0.35 0.35

0.49

0.350.30

4.0 3.8

5.5

3.5

4.7 4.9

3.1

TSH Reference Ranges Cited by 9 Different Manufacturers Assays

0.49

0.27

5.5

3.1

population demographics:• ethnicity• age• iodine intake

rigor for excluding:• family history of thyroid disease• thyroid autoimmunity (Abs & US)• goiter or thyroid nodularity (US)

Assay specificity differs.Different assays detect different circulating TSH isoforms,

some of which may not be biologically inactive.

TSH reference limits are calculated from cohorts of subjects

judged to be euthyroid

50

40

30

20

10

0

%

African Americans 3.6Mexican Americans 4.1

Caucasians 4.2

1.0 2.0 3.0 4.0 5.0 6.0 7.00.1

TSH mIU/L

NHANES III - influence of ethnicity and age on TSH reference ranges

Hollowell JCEM 87:4489, 2002

TSH (97.5%) upper limit

�

Age 50-59 4.0

Age 80+ 7.5

�

� �

�

�

�

�

0.10.2

0.30.4

0.60.9

1.42.1

3.14.7

710

1624

3755

30

25

20

15

10

5

%

0

Surks JCEM 92:4575, 2007Atzmon JCEM 94:1251, 2009

Age 20-29 3.5

TSH (97.5%) upper limit

reference range(entire population)

�

0

20

40

60

80

TSH Intervals (mIU/L)

0

20

40

60

80

%Antibody

(b) Men (n = 8267)

0.01 0.1 0.4 1.0 2.0 2.5 3.0 3.5 4.0 5.0 7.5 10 20154.51.5

(a) Women (n = 7821)

%Antibody

*

*

0.1 0.4 1.0 2.0 2.5 3.0 3.5 4.0 5.0 7.5 10 20154.51.5

(n) (20) (26) (193) (2079) (1937) (1310) (838) (478) (267) (188) (106) (72) (184) (54) (41) (8) (33)

(n) (7) (23) (140) (2120) (2136) (1491) (982) (516) (275 (196) (87) (80) (134) (38) (22) (7) (15)

*

*

* * *

*

*

**

**

*

*

**

*

*

*

0.001

0.010.001

TPOAb+ onlyTgAb+ only

** *

* **

*

*

* *

** *

*

**

*

*

*

Both TPOAb+ and TgAb+

Spencer et al JCEM 92:4236, 2007

lowest antibodyprevalence

0.1 2.0

lowest antibodyprevalence

0.1 1.5

TSH Intervals (mIU/L)

NHANES III: TSH versus Thyroid Antibody Prevalence

10

8

6

4

2

00.1 1.0 10

Persani et al JCEM 85:3631-5, 2000

Free T4pmol/L

Paradoxically normal TSH in central hypothyroidism

TSH reference rangemIU/L

Free T4 reference range

In central hypothyroidism TSH isoforms with impaired biologic activity are secreted

reference range

(2.5 - 97.5%)870healthyblood

donors

1010.1

TSH mIU/L

52%

2.90.4Bayerassay

0.4 3.8Elecsysassay

reference range

(2.5 - 97.5%)

Kratzsch Clin Chem 51:1480, 2005

TSH upper limit is influenced by the assay’s specificity for TSH isoforms

453no fam Hx.normal US

no Abs

n = 4212US Blacks

1

2

3

4

NHANES III JCEM 87:489, 2002

n = 4689US Caucasians

TSHmIU/L

Remarkable Consistency in the TSH Lower Limit of Population Studies (0.3 - 0.4 mIU/L)TSH Upper Limit is Influenced by Geography (iodine), Ethnicity (AITD) and Assay (TSH isoforms)

USA (iodine sufficient)

% TPOAbprevalence

(AITD)5.3 14.3

n = 363German Caucasians

d'Herbomez et alClin Chem Lab Med 43:102, 2005

n = 250French Caucasians

n = 150Italian Caucasians

Europe (varying degrees of iodine deficiency)

6.0 7.0 7.0

Volzke (SHIP study) Thyroid 15:279, 2005

0.40.3 0.4 0.30.4

0.3

4.2

3.6 3.5

3.1

3.7

2.4

n = 4298German Caucasians

4.1

• iodine intake• prevalence of AITD• exclusion UZT abnormalities• TSH assay differences

Reported differences in the TSH upper (97.5%) reference limit

VolzkeGerman Ship

study2.1

2.51st. trim. pregnancy Endocrine Society

Endocrine Society2nd/3rd. trimester

pregnancy3.0

AACE guidelines

87654321

African Americans

3.6NHANES

20-29 year olds

7.5NHANES

80 + year olds

from: Volzke Thyroid 15:279, 2005 Hollowell JCEM 87:4489, 2002Abalovich et al JCEM 92: S1-S47, 2007Surks JCEM 92:4575, 2007Atzmon JCEM 94:1251, 2009

4.2NHANES

Caucasians

50-59 year oldsNHANES

3.9/4.0

Mexican Americans

Thyroid tests have narrow within-person variability relative

to the between-person variability -

i.e. a low indexes of individuality (IoI).

Even values within the reference range can be abnormal

for an individual patient .

From: Jensen CCLM 45:1058, 2007Andersen JCEM 87:1068, 2002

Thyroid tests have narrow within-person variabilities relative to their population reference ranges

population reference range

Individual variability (99% CI over 1 year)

ng

/mL

Thyroglobulin, Tg

Individual subjects

0.2

0.5

1

2

5

10

20

50

Free T4 Index

0

50

100

150

Individual subjects

Thyrotropin, TSH5

4

3

2

1

0.3

Individual subjects

PopulationReference

Range

0.4

4.14

3

2

1

TSHmIU/L

TSH in individuals varies over a narrow range (± 0.5 mIU/L over one year)

Hollowell et al JCEM 87:489, 2002

Euthyroid control subjects (monthly specimens over 1 year)

Andersen et al JCEM 87:1068, 2002

1. clinical consequences?

2. subclinical hypothyroid?

3. L-T4 replacement?

L-T4 replacement should be consideredwith regular monitoring of thyroid Fx.

and cardiovascular risk

Mild Subclinical Hypothyroidism (TSH < 10 mIU/L)

Clinical stratification

High background cardiovascular riskDocumented diastolic dysfunctionDiastolic hypertensionAtherosclerotic risk factorsDyslipidemiaDiabetes mellitusSmoker

Low background cardiovascular riskNormal cardiac functionNormal arterial pressureNo atherosclerotic risk factorsNormal lipid profileNormal glucose metabolismNon-smoker

SymptomsGoiterPositive TPOAb or evidence of autoimmune thyroiditis by USPregnancyInfertility

OR AND

No symptomsNo goiterNO positive TPOAb NO US evidence of thyroid disease No pregnancyVery elderly patient

No evidence of benefit for L-T4 replacement.Regular monitoring of thyroid function andcardiovascular risk if L-T4 not prescribed

Biondi & Cooper Endoc Rev 29:76, 2008

• Lab reference range– Defined by values of a reference population: 0.4 - 4.5 mU/L1

– Adopted from guidelines: 0.3 - 3.0 mU/L 2, 3

• Individual’s range

– Much narrower than reference range 4,5

– � 0.5 mIU/L over time 4

• TSH targets for L-T4 treatment of specific conditions

– Preconception (0.3 - 2.5 mIU/L) 6,7

– Pregnancy : 0.01-2.5 mIU/L (1st trimester) upper limit 3.0 (2nd & 3rd trim.) 6,7

– L-T4 replacement for hypothyroidism: 0.5 - 2.5 mIU/L 2,3

– Thyroid cancer (risk-related TSH target): < 0.01 - 0.5 mIU/L 8,9

1 From (NHANES) III. Hollowell JG, et al. JCEM. 87:489,2002 2 Baloch et al. Thyroid 13:33-44, 2003 and 3Baskin et al. Endocrine Practice 8:457, 20024 Andersen et al. JCEM 87:1068, 2002 and 5Jensen et al. Clin Chem Lab Med 45:1058, 20076 Abalovich et al. JCEM 92: S1-S47, 2007 and 7Mandel et al. Thyroid 15: 44-53, 20058 Cooper et al. Thyroid 16:109-42, 20069 Jonklaas et al. Thyroid 16:1229-42, 2006

TSH Ranges Should Be Patient-Specific

free T4 (0.03%)

free T3(0.3%)

BLOOD

THYROID

5’D deiodinaseT4 T3

biologic activity

nucleusPeripheralTissues

80%

20%

100%

Most (> 99%) thyroid hormonein blood is bound to plasma proteins

T3 . TBG

T4 . LPT4 . IgG

T4 . albuminT4 . TTR

T4 . TBG

1970s

1990s

2009

1980s

Clinical LabsFree T4 Estimate

tests

total T4 / TBG estimate

free T4 index (FT4I)

automated FT4 immunoassays

1-step labeledantibody

2-stepdirect

free T4

Reference Labs:Equil. Dialysis/

Tandem Mass Spectrometry

Clinical labs report FT4 estimates not direct FT4 measurements

FT4 immunoassays are binding protein dependent

10

20

30

40

0100 101 102 103 104

pmol/L

FT4 (immunoassay)

10

20

30

025% 50% 100% 200%

FT4 (immunoassay)pmol/L

0

100 101 102 103 104

FT4 (equil.dial)

8,000

6,000

4,000

2,000

pmol/L nmol/L

100 101 102 103 104

total T4

25

0

50

75

100

125

0

4

2

6

8

μg/dL

10

Protein-bound T4 held constant and free T4 increased

10

20

30

025% 50% 100% 200%

FT4 (equil.dial)pmol/L nmol/L

25% 50% 100% 200%

total T4

25

0

50

75

100

125

0

4

2

6

8

10

μg/dL

Free T4 held constant and protein-bound T4 increased

Free T4 immunoassays are binding protein dependent!

Fritz Clin Chem 53:911, 2007

5-FluorouracilHeroin/MethadoneClofibrateNicotinic AcidPerphenazine

hypothyroidismacute/chronic hepatitisHCC/PBCadrenal insufficiencyAIDSangioneurotic edemaacute intermittent porphyria

excess

Estrogens• pregnancy• oral contraceptives

AndrogensAnabolic steroids

GlucocorticoidsL-asparaginase

deficiency

hyperthyroidismnonthyroidal illnessnephrotic syndromemalnutritionacromegalyCushing’s syndrome

Elevated TBG

Sex Steroids

Drugs

Disease

Congenital

Reduced TBG AlbuminTransthyretin (TTR)

FDHTTR-AH

From: Bartelena Horm Res 45:142-7, 1996

nonthyroidal illnessmalnutritioninflammation

pregnancy

Total T4 & Free T4 Changes During Nonthyroidal Illness (NTI)

Severity Recovery

Mortality

Total T4 & FT4(immunoassays)

Direct FT4(equilibrium

dialysis)referencerange

6

8

10

12

14

16

18

FT4 immunoassay #1

FT4 immunoassay #2

Gow et al Clin Chim Acta 152: 325-33, 1985Toldy et al Clin Chim Acta 352: 93-104, 2005

20 25 30 35 40 45 50 55 60

albumin added

FT4 by Equilibrium Dial.

Albumin (g/L) reference range

FT4 (pmol/L)reference

range

Albumin addition to sera from patients with NTI with low albumin

100

+ 50

20 30 40

+ 100

0

- 50

weeks gestation

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

E2

TT4

TBG

% changeversus

preconception

Normal changes in thyroid Indices during gestation

hCG

FT4 (ED + tandem mass spec) 1

TSH 2

1 Kahric-Janicic Thyroid 17:303, 20072 Abalovich et al JCEM 92: S1-S47, 20073 Guven et al. Acta Obstet Gynecol 88:479-82, 20094 Gow et al Clin Chim Acta 152:325-33, 19855 Sapin Clin Lab 50:581, 2004

albumin 3, 4FT4 (immunoassays) 1,5

0

5

10

15

20

25

30

35

40

FT4pmol/L

EL AI

non-pregnant reference range

Free T4 Immunoassays

3rd Trimester Free T4 - Measured by Different Immunoassays

From: Sapin et al Clin Lab 50:581, 2004

% belownon-pregnant

referencerange

62

VD

14

VT

41

GC

45

AD

24

IM

21

AX

48

AC

17

3rd. trimester

24

20

40

60

80

100

120

140

0

160

1Lee et al. AJOG 200:260 e1-e6, 20092 Kahric-Janicic et al. Thyroid 17:303-11, 20073 Guven et al. Acta Obstet Gynecol 88:479-82, 20094 Gow et al Clin Chim Acta 152:325-33, 1985 Non-pregnant reference range (95% CI)

Trimester Related Changes during Pregnancy

* p < 0.05 relative to non-pregnant (NP)

NP 1st 2nd 3rd

Albumin 3,4

**

Total T4 1

NP 1st 2nd 3rd NP 1st 2nd 3rd

Free T4 Index 1FT4 (ref. method)

equil. dial. + TMS 2

NP 1st 2nd 3rd

**

NP 1st 2nd 3rd

FT4 Immunoassay 1,2

ElecsysTosohDade

*

* *

* *

ATD therapy for hyperthyroidism should be adjusted to maintain thematernal free T4 in the upper third of the non-pregnant reference rangefor the assay.

Grade 1Recommendation

FT4

Endocrine Society Guidelines for Pregnancy (Abalovich et al JCEM 92: S1-S47, 2007)

When hypothyroidism is diagnosed before pregnancy, it is recommendedthat the preconception thyroxine dose be adjusted to target a TSH levelnot higher than 2.5 mIU/L prior to pregnancy.


L-T4 dosage should be titrated to rapidly reach and thereafter maintainserum TSH concentrations of less than 2.5 mIU/L in the first trimester (orless than 3 mIU/L in the 2nd and 3rd trimesters) or trimester-specific TSHreference ranges. Thyroid function tests should be remeasured within 30 -40 days.


TSH

TSH


• Thyroid autoantibody testing - strengths and pitfalls- TSH Receptor antibodies (TRAb):- TPOAb, Thyroid Peroxidase antibodies- Thyroglobulin antibodies (TgAb)




TPOAb (U/mL)

WHO 66/387

34

35

10.1

0.3

9.0

12

5.61 *

60 *

Manufacturers cut-offs for positivity using different antibody tests

TRAb (U/L)

WHO 90/672

1.75

no method

no method

1.0

no method

no method

no method

1.0

TgAb (U/mL)

WHO 65/93

115

40

27.8

0.3

4.0

34

4.11 *

60 *

Standard*

Roche Elecsys

DPC Immulite 2000

Tosoh A1A

Kronus

Beckman Access

Abbott Axsym

Abbott Architect

Brahms

* standardization not specified


• Thyroid autoantibody testing - strengths and pitfalls- TSH Receptor antibodies (TRAb):

- TSAb = stimulating (cause Graves’ hyperthyroidism)- TSBAb = block TSH action (rare, hypothyroidism)

- Thyroid Peroxidase antibodies, TPOAb- Thyroglobulin antibodies (TgAb)




Graves’ Hyperthyroidism - Eyes

• Due to retro-orbital inflammation and lymphocyte infiltration.

• Can confirm swelling on CT / MRI

ExopthalmosProptosis

Placenta

Anti-thyroidDrugs (ATD)

ATD

T4 T4

pituitary

hypothalamus

thyroid

TRH

Mother

TSH

Fetus

TRH

TSH

TRAb measurements are 1° used to assess risk of neonatal hyper- or hypothyroidism in the 3rd Trimester of mothers with a history of Graves’ Dz.

TSH Receptor Abs(TRAb) TRAb

block

stimulate

block

stimulate

Predicting Graves’ diseaseremission after

medical treatment

not useful

TSH receptor Ab (TRAb) measurement

Predicting severityand outcome of

Graves’ opthalmopathy

useful

Suspected euthyroidGraves’

opthalmopathy

Determiningetiology of

hyperthyroidism

Neonatal risks - pregnant mothers with active

Graves’ or prior Sx/RAI Rx.)

Ajjan & Weetman Nat Clin Pract Endoc Metab 4:461, 2008


• Thyroid autoantibody testing - strengths and pitfalls- TRAb, TSH Receptor antibodies- Thyroid Peroxidase antibodies, TPOAb

- most sensitive marker for thyroid autoimmunity- Thyroglobulin antibodies (TgAb)




%Prevalence

Odds Ratio for Overt Hypothyroidism 23.5 6.9 1.1

Odds Ratio for Subclinical Hypothyroidism 11.7 4.0 1.5

TPOAb is strongly associated with overt and subclinical hypothyroidism

0

5

10

15

14.7

Thyroidantibodies

TPOAb+ TgAb

TPOAbalone

TgAbalone

6.9

5.7

3.1

NHANES III Survey (n = 17,353)Hollowell JCEM 87: 489, 2002

monocytes(PBMC)

20

40

60

80

0

TPOAb mediate antibody-dependent and complement-dependent cytotoxicities

Rebuffat JCEM 93:929, 2008

HL-60 THP-1

thyroid cell lines

Medium

Irrelevant Ab

TPOAb from patient with AITD

18.8

74.5

11.0

Developing thyroid failure (secondary to Hashimoto’s thyroiditis)

5% /year

hypoechoicultrasound pattern

geneticpredisposition

activation ofautoimmune

process

environmentalfactors

years/decades

TSH elevationsubclinical

hypothyroidism

high TSH + low FT4overt

hypothyroidism

TPOAbabnormality

• Diagnosis of Autoimmune Thyroid Disease

• Risk factor for Autoimmune Thyroid Disease

• Risk factor for thyroid dysfunction during Interferon-alpha, Interleukin-2, Lithium or Amiodarone Rx.

• Risk factor for hypothyroidism in Down’s Syndrome patients

• Risk factor for miscarriage, IVF failure post-partum thyroiditis

Clinical Uses of TPOAb Measurement

NACB Guideline 34

Baloch et al Thyroid 13:49, 2003


• Thyroid autoantibody testing - strengths and pitfalls- TRAb, TSH Receptor antibodies- TPOAb, Thyroid Peroxidase antibodies- Thyroglobulin antibodies (TgAb) - used to assess risk for

TgAb interference with Tg measurements for DTC




TgAb prevalenceDTC ~ 20%General population ~ 10 %

Radioimmunoassay (RIA)

(1973 - present) no resistantdays

Immunometric Assay(IMA)

(1990 - present)

Most laboratories use Tg Immunometric Assay (IMA) methods

yes susceptible

assay class

hours

turn-aroundtime automation

TgAb & HAMAinterferences

RIAMethods

IMAMethods

Tg Tg

TgAb-boundTg

Free Tg

TgAb

TgAb interferes with IMA measurements causing falsely low Tg

1 432 5 6

RIA IMA

SerumTg

ng/mL

13.8 13.2

SerumTg

ng/mL

functional sensitivity estimates

TgAb interference causes falsely low Tg IMA measurements

reference range for TgAb-negative controlsFrom: Spencer et al Nat Clin Pract Endocr Metab 4:223, 2008

10

0.1

1

100

1

10

0.1

100TgAb-positive euthyroid controls

Euthyroid control subjects:• intact thyroid glands• TSH between 0.3 and 3.0 mIU/L

Reporting falsely low Tg values is clinically unacceptable because patients with persistent TgAb have a higher stage of disease

Kim et al JCEM 93:4683-9, 2008Chung et al Clin Endocrinol 57:215, 2002

0

20

40

60

80

multifocal LNmetastases

extrathyroidextension

tumor recurrence

TgAb+TgAb negative

Clinicopathologic factors associatedwith the detection of TgAb

%

Changing TgAb can be used asa surrogate tumor marker

0

10

20

30

40

> 50% declinein TgAb

< 50%declinein TgAb

increasingTgAb

% p

ersi

sten

t dis

ease 37

19

0

Changes in TgAb 6-12 months post Tx.

TgAb Positivity Comparison of Different TgAb Methods

ACC

DYN

KRY

ESO

FLY

KRO

ADV

NID

ELE

TOS

positive*cu t-o ff

* Positive cut-off from normal euthyroid subjects with no TgAb detected by any method

< 2

< 30

< 40

< 40

< 3

< 1

< 1

< 2

< 1

< 40

< 30

FUJ <1:100

1 TgAb method + 2 3 5 8 9 11 12

IMM

Spencer et al JCEM 90:5566, 2005

Mass of thyroid tissue(normal remnant +/- tumor)

• functional sensitivity• reference range• methodology

(IMA vs. RIA)

Tg assay characteristics

SerumThyroglobulin (Tg)

concentration

Thyroid Injury(Sx./ FNAB/ RAI Rx.)

TSH Receptor Stimulation(TSH /hCG/ TSAb)

" SuperSensitive"

"Sensitive" " UltraSensitive"

"HighlySensitive"

Resist using confusing nomenclature!

TSHTg

Restrictions:• Precision to be determined in human serum pools containing

no evidence of Tg antibodies (TgAb)

Baloch et al Thyroid 13: 57-67, 2003

Protocol for determining Tg Assay Functional Sensitivity (FS)

NACB Guidelines 20 & 44

Definition: FS = Tg value that can be measured with 20% between-run CV(1:1 CRM-457 standardization)

• Precision should be determined across a time-span that relates tothe use of the measurement in clinical practice (6 - 12 months)

• This time-span should involve the use of more than 2 reagent lotsand 2 instrument calibrations

40

10

serum Tg(ng/mL)

1:1 CRM-457 standardization

Tg Assay Sensitivity - generational nomenclature

50

3

euthyroid reference range

1st generation functional sensitivity

mean~ 13.0

1

0.5

1

0.1

0.01

2nd generation functional sensitivity0.1

0.05some current assays

most current assays

3rd generation functional sensitivity0.01

0.005future assays

1 432 5 6

RIA IMA

SerumTg

ng/mL

10

0.1

12.2 12.010.1

7.5

methodclass

method#

1

10-fold functional sensitivitydifferences between assays

Spencer et al Nat Clin Pract Endocr Metab 4:223, 2008

60

8.9 9.1

Below functional sensitivity

0.01

Assays:

1. USC RIA, Los Angeles, CA

2. Esoterix RIA, Calabasas, CA

3. Kronus IRMA, Boise, ID

4. Beckman Access, Fullerton, CA

5. Esoterix ICMA, Calabasas, CA

6. Siemens Immulite, Los Angles, CA

TgAb-negative euthyroid controls

0.5

0.1

2.0

0.5

0.91.0

0.12nd. gen. assay

functionalsensitivity

lymph node recurrence detected

(by ultrasound)

It has become common practice to use recombinant human TSH (rhTSH) stimulation to overcome the insensitivity of the 1st generation Tg assays

7 26 04 83 62 41 2

rhTSH cut-off for a positive test

100

10Serum Tgng/mL

rhTSH-stimulated Tg= 2.7 ng/mL

L-T4 Suppression

basal Tg = 0.3 μg/Lnon-detectable

1st. gen. assayfunctionalsensitivity

2

Tx.

1

+ rhTSHresponse

rhTSH stimulation is used to compensate for Tg assay insensitivity

0.1

10

100

Serum Tgng/mL

Basal Tg(low TSH)

rhTSH-stimulated Tg(after 72-hours)

0.01

below functional sensitivity

1

Disease present in 6%(Kloos, JCEM 2005)

20%Disease present in 1.6%

(Pacini, JCEM 2003)80%

Disease present in 45%(Kloos, JCEM 2005)

2

2nd. generationsensitivity 0.1

0.01

10

100

Tgng/mL

Basal Tg(on L-T4 Rx.)

rhTSH-stimulated Tg(72 hours after rhTSH)

rhTSH cut-off for + response2

2nd generation assays detect responses not undetected by 1st generation assays

below functional sensitivity

rhTSH-stimulated Tg / basal Tg~ 10:1

2/09

1 Haugen et al JCEM 84:3877, 1999

10,000

rhTSH-stim. Tg

µg/L

rhTSH-Tg = 17.6*bTg -12.9r = 0.72, p < 0.0001

1000100101

basal Tg (bTg) µg/mL

2nd. generation functionalsensitivity

0.10.05

0.05

0.1

1

10

serum Tgµg/L

2

0.3%

1.1%

28.9%

69.7%

284 212

2nd. generation functionalsensitivity

analyticalsensitivity

“positive”rhTSH-Tgresponse 1

basalTg

72-hourrhTSH - stimulated Tg

373 patients with basal Tg < 0.1 µg/mL

rhTSH cut-off 1

From: Spencer & LoPresti Nat Clin Pract Endocr Metab 4:223, 2008

Basal Tg correlates with rhTSH-stimulated Tg

0.05

10

100

1,000

0.1

1

2

n=373

Expensive rhTSH tests are merely used to compensate for Tg assay insensitivity. There is growing consensus that rhTSH is unnecessary when a 2nd generation assay is used

(Smallridge JCEM 92:82, 2007, Iervasi Clin Endoc 67:434, 2007, Spencer NCPEM 4:233, 2008)

2nd generation Tg measurement

minimizes the need

for expensive rhTSH stimulation

and maximizes the clinical utility

of serial Tg testing

Contemporary Issues in Thyroid Disease Measurements

• Limitations of free T4 immunoassay methodology


The TSH upper reference limit is assay dependent and less important than evaluating TSH status relative to the patient’s risk

factors for CVD.

FT4 immunoassays binding protein (albumin) dependent. Total T4, free T4 indexes (FT4I) and FT4 reference methods

(ED+TMS) are preferred when evaluating FT4 status in pregnancy and NTI.


• 2nd generation Thyroglobulin (Tg) measurement

Cannot compare absolute values reported by different methodsTRAb: to assess Graves’ mothers for neonatal risksTPOAb: primary marker for thyroid autoimmunityTgAb: surrogate DTC tumor marker & risk for Tg interference

Contemporary Issues in Thyroid Disease Measurements

• Tg assay variability precludes switching methods• 2nd generation assays (functional sensitivity ≤ 0.1 ng/mL) obviate the need for expensive rhTSH stimulated Tg

USC AACC Expert Access 7/8/09 - LBM-MG Medicion de hormonas en... · AACC. Expert Access 7/8/09....

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