Reference Intervals for Children and Adults

Elecsys® Thyroid Tests

TSH, FT4, FT3, T4, T3, T-Uptake, FT4-Index,
Anti-TPO, Anti-Tg, Anti-TSHR, Tg, hCT
cobas e analyzers

COBAS and ELECSYS are trademarks of Roche.

© 2018 Roche

Published by:
Roche Diagnostics International Ltd
CH-6343 Rotkreuz
Switzerland

cobas.com

04640292001
Table of content 1 Introduction

1 Introduction 3 This brochure is an update of the highly valued “Reference At this moment in time, with respect to the standardization
2 Reference population 4 Intervals for Children and Adults – Elecsys® Thyroid Tests” concept, the reference ranges of the currently available thyroid
2.1 Package inserts 4 (material no. 07640292001). In addition to the previous version tests are assay generation independent.
2.1.1 Elecsys® TSH  4 new data for all thyroid tests being currently on the market have
2.1.2 Elecsys® FT4, Elecsys® T3, Elecsys® T4, Elecsys® T-uptake 4 been included. In chapter “3 Statistical Methods” populations and biostatistics
2.1.3 Elecsys® FT3 4 background is described. In subsequent chapters reference
2.1.4 Elecsys® Anti-TPO, Elecsys® Anti-Tg 4 The following updates to the previous version have been made: ranges for various populations for each thyroid parameter is
2.1.5 Elecsys® Anti-TSHR 4 •• For all thyroid tests currently on the market tables with shown. Additionally, reference ranges for in- and outpatients
2.1.6 Elecsys® Tg, Elecsys® Calcitonin 4 reference ranges for different subject groups have been are available in chapter “6 Concentration of Elecsys® TSH,
2.2 Reference population groups 5 included. The previous version is now completed with data for Elecsys® FT4 and Elecsys® FT3 in the serum of euthyroid in- and
2.2.1 Group GEL 5 Elecsys® Anti-TSHR, Elecsys® hCT, Elecsys® Tg II. outpatients”.
2.2.2 Group GL 5 •• Data from the LIFE study (http://life.uni-leipzig.de) have been
2.2.3 Group P 5 added, comprising more than 1,000 children between 3 months A one page overview of all populations can be found at the end
2.2.4 LIFE cohort 6 and 17 years of age and more than 5,300 adults between 18 of the brochure. The overview can be detached and used like a
2.2.5 Local reference studies 6 and 80 years of age. LIFE study data are available for Elecsys® bookmark to support easy orientation.
3 Statistical Methods 7 TSH, Elecsys® FT3, Elecsys® FT4, Elecsys® Anti-Tg, Elecsys® Anti-
3.1 Computation of quantiles 7 TPO, Elecsys® Anti-TSHR and Elecsys® hCT.
3.2 Quantile regression 8 •• The inpatient/outpatient data, previously being published under
3.3 Boxplot 8 the material number 05968810001, have been included to this
3.4 Statistical programming 9 brochure.
4 Terminology  10
4.1 Reference population 10
4.2 Reference range 10
4.3 Confidence interval 10
5 Results and Discussion 11
5.1 Thyrotropin – Elecsys® TSH 11
5.2 Free thyroxin – Elecsys® FT4 14
5.3 Free triiodothyronine – Elecsys® FT3 21
5.4 Thyroxine – Elecsys® T4 27
5.5 Thyroxine-binding capacity – free T4 index (T4/TBI) 31
5.6 Triiodothyronine – Elecsys® T3 36
5.7 Antibodies to thyroid receptor – Elecsys® Anti-TSHR 40
5.8 Antibodies to thyroid peroxidase – Elecsys® Anti-TPO 41
5.9 Antibodies to thyroglobulin – Elecsys® Anti-Tg 43
5.10 Thyroglobulin – Elecsys® Tg 45
5.11 Calcitonin – Elecsys® hCT 46
6 Concentration of Elecsys® TSH, Elecsys® FT4 and Elecsys® FT3  48
in the serum of euthyroid in- and outpatients
7 Conclusion 51
Short description 52
Notes 53
References 54

2 3
2 Reference population 2 Reference population
2.1 Package insert 2.2 Reference population groups

In this brochure the reference range data from the package 2.1.4 Elecsys® Anti-TPO, Elecsys® Anti-Tg 2.2.1 Group GEL The TSH inclusion or exclusion criteria were ensured based on
inserts – chapter 2.1 – as well as additional studies – chapter 2.2 – The reference population tested for Elecsys® Anti-TPO and Newborns, infants, children and adolescents in age the results of a commercially available test (ADVIA Centaur, Bayer,
are summarized. Elecsys® Anti-Tg in 2000/2001 consisted of women and men 0 – 20 years from Erlangen and Leipzig, Germany 2003, Germany).
whose TSH and FT4 concentrations were within the euthyroid 2004, 2007 (Group GEL)
2.1.1 Elecsys® TSH range and the clinical appearance was without any signs for The reference range calculation for the thyroid parameters was The group GL equals GL1. Furthermore, the groups GL2, GL3, GL5
The reference range population tested for Elecsys® TSH in 1996/97 thyroid dysfunction. made using remaining sample material (serum and plasma have been derived from GL1 by applying different inclusion and
consisted of 516 euthyroid women and men measured in Vienna, collected in Erlangen between May and August 2003 and in exclusion criteria. A summary is depicted in the table below.
Tokyo, Paris, Tutzing1. Elecsys® Anti-TPO was measured at clinical sites in Germany and Leipzig between January and June 2006). This combined collective
Austria. is referred to as Group GEL in the brochure. In the subgroup Group GL1
2.1.2 Elecsys® FT4, Elecsys® T3, Elecsys® T4, Elecsys® Erlangen a total of 420 specimens and in the subgroup Leipzig a Blood donors, all men and women: all tested blood donors,
T-uptake, FT4-index 2.1.5 Elecsys® Anti-TSHR total of 1,004 specimens of newborns, children and adolescents of no in- and exclusion criteria
The clinical study was conducted in late 1997/early 1998 to The reference population tested for Elecsys® Anti-TSHR assay both sexes and in the age of 0 and <20 was included. Depending Group GL2
introduce a revised Elecsys® T4 test and to validate the reference consisted of 436 apparently healthy individuals, 210 patients with on the parameter between 53 – 473 specimens in each of the GEL
Inclusion criteria: normal thyroid ultrasound (volume and structure),
ranges of the assays, which were established in 1995/1996 at the thyroid diseases without diagnosis of Graves’ disease, and 102 subgroups are shown. ADVIA Centaur TSH within reference range >0.35 and <5.5 µIU/mL
time of the introduction of the Elecsys® systems or have been patients with untreated Graves’ disease2.
adopted from the previous tests – the Enzymun-Test parameters. The exclusion and inclusion criteria for both groups were similarly Group GL3
2.1.6 Elecsys Tg, Elecsys Calcitonin
® ®
applied: no previous or acute thyroid disorder, no in intensive Inclusion and exclusion criteria according to Guideline 22 of the
The reference population, which is the basis for the information in The reference population tested for Elecsys® TgII assay consisted care, no post-operative care, no family history of thyroid disorder National Academy of Clinical Biochemistry (NACB), USA 2002 –
Recommendations on determining reference intervals of TSH 3
the current package inserts, consisted of women and men between of 478 healthy Caucasian subjects (224 females, 254 males). (Erlangen), no endocrine disorders or severe non-endocrine Inclusion criteria: no visible or palpable goiter (ultrasound normal,
25 and 60 years of age, whose serum samples were measured in Measurements were done in Germany. diseases that may influence the Thyroid function (Leipzig). structure and volume of thyroid normal), Elecsys ® Anti-TPO (<34 IU/
routine tests in clinical centers in Belgium, Japan and Germany. mL) and Elecsys ® Anti-Tg (<115 IU/mL) determined from Elecsys ®
results. Exclusion criteria: subjects with personal or family history of
The groups consisted of blood donors in addition to hospital The reference population tested for Elecsys® Calcitonin The general presence of autoantibodies was not an exclusion thyroid dysfunction, no medications (except contraceptives).
inpatients and outpatients. The TSH results were within the normal assay consisted of 355 German apparently healthy subjects criterion. Measurements were taken for Elecsys® TSH, Elecsys®
range for the respective routine method for all specimens. No (193 females, 162 male) and 364 US apparently healthy subjects FT4, Elecsys® FT3, Elecsys® T3, Elecsys® T4, Elecsys® T-uptake, Group GL5
information was available on any medication taken by the subjects. (180 female, 184 male). Elecsys® Anti-TPO and Elecsys® Anti-Tg. The fT4-index was Inclusion and exclusion criteria according to Guideline 33 of the NACB,
No information on possible pregnancies was available in the determined from the T4 and T-uptake (TBI) ratio. USA 2002 – Recommendations on determining reference intervals of
Anti-TPO and Anti-Tg. 3 Inclusion criteria: only male samples, non-
female groups. The number of samples, which varied from 370 to smoker, ADVIA Centaur TSH within range >0.5 and <2.0 µIU/mL, age
2,526, depending on the test parameter, is given in the tables of 2.2.2 Group GL <30 years, normal thyroid ultrasound (volume and structure), no non-
the corresponding chapters on the individual tests. Adults, Leipzig, Germany 2003 and 2004 thyroid autoimmune diseases (e.g. lupus erythemathodes or diabetes).
Elecsys ® Anti-TPO (<34 IU/mL) and Elecsys ® Anti-Tg (<115 IU/mL).
To determine the reference ranges of thyroid parameters, in Exclusion criteria: subjects with personal or family history of thyroid
Measurements were taken for Elecsys® FT4, Elecsys® T3, Elecsys® 2003/2004, at the “Universitätsklinikum Leipzig“, Germany, serum dysfunction excluded.
T4 and Elecsys® T-uptake. The FT4 index was determined by the specimens were used from a total of 870 blood donors between
ratio of T4 and T-uptake results. the ages of 18 and 60 years. 2.2.3 Group P
Pregnant women in their 1st, 2nd and 3rd trimester of
Reference population USA for T4 and FT4-index: Specimens The following information is available for these specimens: pregnancy
from 275 serum and plasma samples from healthy test subjects age, sex, height, weight, personal and family history of thyroid The group consists of 957 samples of healthy, pregnant women
with Elecsys® TSH concentrations within 0.27 to 4.2 μIU/mL and disorders, contraceptive use and cigarette use. Measurement from Essen (436) and 521 samples of healthy, pregnant women
Elecsys® FT4 values within the range of 12.0 to 22.0 pmol/L. results are available for: thyroid volume and structure, blood (<40 years) from Hamburg with a normal pregnancy without
pressure, heart rate, blood count, lipid metabolism parameters, known complications.
2.1.3 Elecsys® FT3 protein, albumin and the thyroid parameters including
The reference population tested for Elecsys® FT3, Cat. no. autoantibodies. Exclusion criteria for this group were: A known or supposed
03051986 (generation taken from the market by now), in 2004 thyroid dysfunction or history, substitution of thyroid hormones,
consisted of the group GHH – please see chapter 2.2. Elecsys® FT3 concentrations <3 pmol/L and Elecsys® FT4
concentrations >22 pmol/L. Samples with Elecsys® TSH
concentrations outside a range of 0.1 to 10 μIU/mL were excluded
in both groups.

4 5
 3 Statistical methods
3.1 Computation of quantiles

2.2.4 LIFE cohort LIFE child (Age: 3 month to >18 years) Quantiles are suitable methods to describe the scattering of Instruction to compute reference ranges
Adults and children, Leipzig, Germany 2011 – 2016 Elecsys ® TSH, Elecsys ® FT4, Elecsys ® FT3, Elecsys ® Calcitonin data. The clinical and laboratory standards institute (CLSI) Generally, reference ranges have to be computed for the
The life study is a project of the university Leipzig (www.life. Inclusion criteria: Elecsys ® Anti-TPO <34 IU/mL, Elecsys ® Anti-TSHR guidelines recommend the calculation of the 2.5 % and 97.5 % population of interest. In most cases this corresponds to an
<1.75 IU/mL, Elecsys ® Anti-TG <115 IU/mL, no thyroid disease, thyroid
uni-leipzig.de). Goal of the study is to investigate diseases of ultrasound normal, no medication except for vitamin D supplemen- quantiles for reference ranges (also called reference intervals), apparently healthy population. The correct inclusion and exclusion
the civilized population like depression, diabetes, allergy etc. For tation and contraceptives, no known endocrine disease, no reported see CLSI C28-A3c5. criteria have to be chosen thoughtfully. The size of the population
this purpose, as many information as possible about the health stationary stay in hospital should be at least 120 samples to calculate the central 95 %
and environment of the general population is collected. Adults Elecsys ® Anti-TPO and Elecsys ® Anti-Tg interval with confidence level of 90 for the 2.5 % and 97.5 quantile.

10
Inclusion criteria: no thyroid disease, thyroid ultrasound normal, no
are invited once to fill out a questionnaire and undergo physical medication except for vitamin D supplementation and contraceptives, With higher number of well-chosen samples, the estimation of the
examination while children are invited several times to participate no known endocrine disease, no reported stationary stay in hospital reference ranges improves.

concentration of the analyte

8
in the study and follow up their development over time. Elecsys ® Anti-TSHR
97.5 % Quantil
Inclusion criteria: Elecsys ® Anti-TPO <34 IU/mL, Elecsys ® Anti-TG <115 One possible way to compute quantiles is the following
IU/mL, no thyroid disease, thyroid ultrasound normal, no medication
The data of the LIFE study have been provided to Roche (see also figure 2):

6
except for vitamin D supplementation and contraceptives, no known
Diagnostics to determine reference ranges. Inclusion/exclusion endocrine disease, no reported stationary stay in hospital 1. Healthy population containing n measured values
criteria for adults and children differ, therefore, they are split into 50 % Quantil 2. Sort measured values in increasing order

4
two groups. As children might have participated more than once, 2.2.5 Local reference ranges 3. Apply the following formula: n (number of measured samples) ×
they have been considered to be apparently thyroid healthy only if Local reference ranges for Elecsys® FT3, partly also for Elecsys® 2.5 % Quantil percentile = position in list

2
the inclusion criteria have been fulfilled at every visit. TSH, Elecsys® FT4 were determined in clinical centers in Norway,
Austria, Thailand and Germany, which have kindly been provided Measured value

0
LIFE adult (Age: <18 to >81 years) 0 100 200 300 Sample no. (pIU/mL)
to us for publication.
number of sample 1 1.18
Elecsys ® TSH, Elecsys ® FT4, Elecsys ® FT3
Inclusion criteria: no known thyroid disease, Elecsys ® Anti-TPO <34 IU/ Group N 2 1.24
mL and Elecsys ® Anti-TSHR <1.75 IU/mL, no medication with T4, iodine Figure 1: Graphical illustration of the determination of quantiles. The measured 2.5 th percentile
Combined population, n = 604, Molde and Sandefjord, Norway. 3 1.27
substitution, thyreostatic drugs, T3/T4 compounds samples are presented in ascending order. The vertical lines describe the 2.5 %, 50 % (0.025 ×120 = 3)
Inclusion criteria: TSH concentrations between 0.3 – 3.6 mIU/L [results 4 1.29
Exclusion criteria: albumin measuring results out of reference range and 97.5 % quantile, respectively.
(adults 39.7 – 49.4 g/L measured on Clinical Chemistry module on published by Bjoro et. al. 2000 “Health Study of Nord-Trondelag”4 and 5 1.33
cobas ® 6000/8000 FT4 concentrations between 11 – 22 pmol/L. This FT4 reference range
6 1.34
has been used in Norway for the Elecsys ® method since 1998. For some The central 95 % reference range corresponds to the 2.5 % and N ×percentile =
Elecsys ® Anti-TPO and Elecsys ® Anti-Tg specimens, the criterion Anti-TPO negative was applied. However Anti- … …
Inclucion criteria: no known thyroid disease, no medication with T4, 97.5 % quantiles. Figure 1 illustrates the distribution of measured position in list
TPO measurements are not available for all samples. The same is true 114 4.61
iodine substitution, thyreostatic drugs, T3/T4 compounds for age information. In Sandefjord there were 237 outpatients; in Molde results from a routine cohort. Looking at the area around the 2.5 %
Exclusion criteria: albumin measuring results out of reference range 115 4.76
the 367 test subjects were approx. 30 % outpatients and 70 % inpatients. and 97.5 % quantile, there are only a few measured values. The
(adults 39.7 – 49.4 g/L measured on Clinical Chemistry module on 116 5.13
cobas ® 6000/8000 fewer data points are found at the outer ends, the less reliable is 97.5 th percentile
Group GHH 117 5.20 (0.975 ×120 = 117)
Elecsys ® Anti-TSHR
the biostatistics computation.
Hamburg, Germany, population for Elecsys ® FT3 and Elecsys ® FT4, 118 5.31
Inclusion criteria: no known thyroid disease, Elecsys ® Anti-TPO <34 IU/ 119 5.44
n=5,366 specimens came from a large commercial community
mL, Elecsys ® Anti-TG <115 IU/mL, no medication with T4, iodine substi- The recommendation of CLSI C28-A3c is the use of the
laboratory. Inclusion criteria: TSH concentration from 1– 3 mIU/L, no 120 5.45
tution, thyreostatic drugs, T3/T4 compounds
Exclusion criteria: albumin measuring results out of reference range
other information on the patients was analyzed. This corresponds to 95 % reference range. For every laboratory it is very highly
a so called “routine collective” as it has been also used for earlier recommended to determine own reference ranges.
(adults 39.7 – 49.4 g/L measured on Clinical Chemistry module on
reference interval determinations.
cobas ® 6000/8000 Figure 2: exemplary table for computing quantiles. The 2.5 % quantile corresponds
The following criteria have been applied to LIFE adult patients to to sample number on position 3 if n = 120 samples (0.025 × 120), 97.5 % quantile
Group A
additionally filter for increased BMI: corresponds to sample number on position 117 if n = 120 samples (0.975 ×120). In
All healthy, male, female patients (BMI >30 and increased waist to hip Vienna, Austria, population for Elecsys ® FT3, Elecsys ® FT4 and Elecsys ® this example the 95 % reference interval ranges from 1.27 – 5.20 µIU/mL.
ratio, female ≥0.85, male ≥0.9). Body mass index (BMI) was calculated TSH. Specimens from 127 clinically characterized euthyroid patients
using the formula: BMI = weight [kg] / height 2 [m]2. were used. Inclusion criteria: no history of thyroid medication, thyroid
Waist-Hip ratio was calculated using the formula: waist [cm]/hip [cm]. palpation negative, TSH concentrations within the reference range of
the routine method.

Group Thailand
Thailand, population for Elecsys ® T3. n=967 specimens from euthyroid
subjects. No other information on the subjects was given.

6 7
3 Statistical methods 3 Statistical methods
3.2 Quantile regression 3.4 Statistical Programming

If reference ranges for target variables are influenced by >20 Quantiles were computed with the statistical programming Minor changes in results to the previous version of the brochure
Results
covariates like age or sex, quantile regression is an appropriate 20 >20 µIU/mL
language R (version 3.2.1), particulary the function quantile “Reference Intervals for Children and Adults” (material no.
method for calculation. Goal of the quantile regression is the (type=4). 04640292001) might appear due to the use of different software
evaluation of the correlation between covariate and target variable versions or different calculation software. Former computations

Elecsys TSH [µlU/mL]

for a given quantile. 15
Women Quantile regression was computed with the function gcrq() with the software SAS were done with the version 9.1 (or 9.1.3).
from the R package quantregGrowth in R. Similar analyses are Actual computations were done with the version 9.3. New
Quantile regression is a nonparametric method to estimate Men described by Kristin Rieger et al. 2016.6 analyses were done with the statistical programming language
10
covariate dependent quantiles. Hence no distributional properties R (version 3.2.1). This change can lead to differences in the
have to be verified. For the quantile regression the same quantiles computation because R and SAS use different methods to
like recommended by the CLSI C28-A3c are computed (2.5 %, 5 97.5% quantile
calculate quantiles and confidence intervals.
97.5 % quantile).
50% quantile
For LIFE child the quantile regression has been computed for 0 2.5% quantile
every parameter over the age from 3 months to 20 years and age 0 10 20 30 40 50 60 70
Age [years]
segmentation has been performed out of this computation.

Figure 3: Exemplary quantile regression graphic in which the dependency of TSH

in terms of age is depicted.

3.3 Boxplot
Boxplot is a graphical way to describe the distribution of one 6
Mean

parameter. The illustration shows different robust measures of

dispersion. 50 % of the data are represented in a box defined by
the 25 % and 75 % quantile. In addition, the location of the median 4
whisker (1.5 times the distance from 25 –75 % quantile or maximum result)
is described.
2 75% of all measurements
The interquartile range (IQR) is defined as the difference of the 50% (median) of all measurements (yellow cross is mean)
25% of all measurements
75 % quantile minus 25 % quantile. The above whisker is computed
as follows: 75 % quantile plus 1.5 ×IQR. And accordingly the 0 whisker (1.5 times the distance from 25 –75 % quantile or minimum result)

below whisker is computed by 25 % quantile minus 1.5 ×IQR. Both

Figure 4: Description of boxplot.
whiskers do not always end at exact that length, but at the nearest
value inside the 1.5 ×IQR limits.

Boxplots are very suitable methods to compare different groups

with each other indicating the median, 25 % and 75 % quantile and
the whiskers and thereby visualizing differences at a glance.

8 9
4 Terminology 5 Results and Discusscion
5.1 Thyrotropin, Thyroid stimulating hormone – TSH

Reference population/reference group: Frequency Reference interval (corresponds in this case to the 95% central range) 3 rd generation TSH tests (defined with functional The tables 1 to 4 below describe the TSH reference ranges
Random samples from the population of asymptomatic patients. sensitivity of 0.01 – 0.02 mIU/L) are used as first line determined in different studies for: 1. adults, separated into male
The reference population provides the basis for determining parameters to identify thyroid dysfunction. Even very and female and age, 2. pregnant women, separated into the
reference intervals. The reference population is also called slight changes in the concentrations of the free thyroid 3 trimesters and 3. children, separated by age. For children two
reference group. hormones bring about much greater opposite changes separated tables have been created as the number of children
in the TSH level. Accordingly, TSH is a very sensitive and in the GEL group has been too low to compute the confidence
Reference ranges/reference intervals/reference values/ min max
specific parameter for assessing thyroid function and is interval with 95 % confidence level. The applied confidence level
Concentration
expected values: 2.5% 50% (median) 97.5% of the analyte particularly suitable for early detection or exclusion of was set to 90 %. For all other groups confidence levels have been
In accordance with IFCC recommendations, the reference intervals quantile quantile quantile disorders in the central regulating circuit between the set to 95 %.
or reference ranges are the non-parametrically estimated 2.5 % hypothalamus, pituitary and thyroid7-11.
and 97.5 % quantiles (= percentiles) of the reference population. Confidence interval Confidence interval Confidence interval

The 2.5 % quantile designates the value for which 2.5 % of the Figure 5: Description of reference range
data are smaller or equal than this value; the 97.5 % quantile
designates the value for which 97.5 % of the data are smaller The tables in this brochure are structured as illustrated in figure 5.
or equal than the quantile value. Occasionally, the reference
values are also called reference limits because they bracket the Confidence interval Confidence interval Confidence interval

reference range. Reference ranges are furthermmore sometimes 95p CI low 95p CI 95p CI low 95p CI 95p CI low
95p CI
Year of
2.5% 50% 97.5% high N

also referred to as 95 % central range (e.g. 2.5 % of all data are

(2.5% high (2.5% (50% high (50% (97.5% publ.
quant. quant. quant. (97.5%
quant.) quant.) quant.) quant.) quant.)

below and above this range). Elecsys assay -

package insert

Group 1

Elecsys® package inserts contain the term expected values instead

Group 2

of reference values or reference intervals.

...

Confidence interval (CI): 2.5% 50% (median) 97.5%

Concentration
of the analyte

In the given context, the range around the estimated quantile, quantile quantile quantile

which includes the true value of the quantile with a given

Confidence interval Confidence interval Confidence interval
coverage probability. The confidence interval decreases in size as
the sample size increases. Figure 5 shows the position of the 95 % Figure 6: The investigated group is described in the first column. In the last two
confidence intervals of the 2.5 %, the 50 % (median) and 97.5 % columns the size of the group (N) and the year of publication are stated. Column
quantile. 2 – 4 describe the 2.5 % quantile with the lower and upper confidence interval (CI).
Column 5 – 7 describe the median 50 % quantile with the lower and upper CI. Column
8 – 10 describe the 97.5 % quantile with the lower and upper CI.
Coverage probability:
Probability (typically a value of 95 % is selected if possible) that
the true quantile value is covered by the confidence interval.
Samples that are too small lead to insufficient coverage
probabilities. Note that the IFCC recommends at least n = 120
to compute confidence intervals with 90 % coverage probability.

10 11
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
1 2
  TSH quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   TSH quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
µIU/mL µIU/mL
Elecsys ® TSH – 0.27 4.2 516 96/97 Pregnant Women
package insert 1st Trimester 0.21 0.33 0.48 1.37 1.48 1.61 3.99 4.59 5.80 418 2004
Group GL1 0.21 0.30 0.37 1.25 1.31 1.35 3.35 3.69 4.32 869 2004 2nd Trimester 0.21 0.35 0.41 1.38 1.52 1.60 3.61 4.10 4.80 369 2004
(all blood donors)
3rd Trimester 0.11 0.21 0.29 1.32 1.42 1.59 2.78 3.15 7.08 170 2004
L1 Males all 0.24 0.30 0.40 1.21 1.25 1.32 3.01 3.18 4.32 445 2004
L1 Males 20 – 39 y 0.29 0.46 0.58 1.32 1.42 1.55 3.04 3.25 4.66 286 2004
L1 Males 40 – 69 y 0.18 0.21 0.30 0.87 0.96 1.07 2.09 2.52 4.32 150 2004 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
low high low high low high Year
L1 Females all 0.12 0.30 0.39 1.31 1.38 1.47 3.54 3.94 7.18 424 2004 (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
3
L1 Females 20 – 39 y 0.10 0.44 0.58 1.35 1.46 1.58 3.36 3.63 6.15 269 2004   TSH quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L1 Females 40 – 69 y 0.05 0.16 0.37 1.01 1.21 1.37 2.86 3.94 66.8 128 2004 µIU/mL
L1 Females 0.10 0.39 0.60 1.34 1.46 1.59 3.36 3.82 11.2 236 2004 Group GEL Children,
with contracept. Adolescents
L1 Females with 0.10 0.52 0.62 1.38 1.51 1.60 3.49 5.09 11.2 181 2004 0 – 6 Days 0.11 0.70 4.62 3.51 4.41 5.55 8.49 15.2 27.0 103 2007
contracept. 20 – 39 y >6 Days ≤3 Months 0.09 0.72 5.81 2.88 3.72 4.79 5.79 11.0 20.9 119 2007
L1 Females with 0.30 0.30 0.37 0.75 1.20 1.59 2.68 2.88 2.88 33 2004 >3 ≤12 Months 0.08 0.73 7.03 2.43 3.19 4.21 4.16 8.35 16.8 123 2007
contracept. 40 – 69 y
>1 ≤6 Years 0.06 0.70 8.52 1.89 2.58 3.50 2.75 5.97 13.0 346 2007
L1 Females 0.05 0.16 0.37 1.18 1.30 1.42 3.22 4.25 66.8 187 2004
w/o contracept >6 ≤11 Years 0.04 0.60 9.02 1.53 2.14 2.99 2.07 4.84 11.3 265 2007
L1 Females w/o 0.05 0.22 0.60 1.18 1.36 1.67 2.80 3.05 4.47 87 2004 >11 ≤20 Years 0.03 0.51 8.89 1.30 1.86 2.66 1.75 4.30 10.6 471 2007
contracept. 20 – 39 y
L1 Females w/o 0.05 0.14 0.37 1.01 1.27 1.42 3.22 4.25 66.8 95 2004
contracept. 40 – 69 y 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year
Group GL2 (TSH + 0.54 0.60 0.65 1.36 1.44 1.52 3.35 3.69 4.32 631 2004 (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
4
SD-Sono NAD)   TSH quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L2 Males 0.52 0.58 0.64 1.29 1.37 1.46 3.04 3.44 4.66 332 2004 µIU/mL
L2 Females 0.51 0.63 0.72 1.40 1.52 1.64 3.49 3.82 5.29 299 2004 LIFE Child
Group GL3 org 0.29 0.40 0.47 1.29 1.36 1.44 3.14 3.77 4.47 447 2004 >3 ≤12 Months 0.85 1.02 1.27 2.94 3.24 3.48 5.92 6.75 8.07 90 2016
(NACB crit. for TSH)
>1 ≤6 Years 0.87 1.09 1.20 2.51 2.70 2.85 5.57 6.07 6.80 200 2016
L3 Males 0.20 0.36 0.46 1.24 1.34 1.43 3.01 3.44 5.12 274 2004
>6 ≤11 Years 1.04 1.13 1.24 2.29 2.41 2.61 4.95 5.34 5.82 250 2016
L3 Females 0.12 0.44 0.63 1.30 1.42 1.59 3.14 3.94 5.29 173 2004
>11 ≤20 Years 0.97 1.01 1.12 2.06 2.25 2.42 4.58 5.09 5.39 208 2016
LIFE Adults 0.41 0.45 0.47 1.46 1.49 1.51 3.77 3.91 4.09 5,482 2013
all male patients 0.38 0.41 0.46 1.40 1.43 1.47 3.59 3.74 3.98 3,169 2013
(sd healthy)
male <40 years 0.49 0.81 0.98 1.78 1.92 2.08 3.92 4.33 6.17 156 2013 The selection of inclusion and exclusion criteria clearly influences >20
male ≥40 and 0.39 0.45 0.48 1.39 1.42 1.46 3.47 3.67 3.86 2,322 2013 the width of the range. This is also reflected by the different Results
20 >20 µIU/mL
<70 years groups GL1, GL2, GL3, LIFE adult and LIFE child. In general:
male ≥70 years 0.22 0.31 0.38 1.27 1.35 1.42 3.30 3.83 4.49 691 2013 the stricter the inclusion and exclusion criteria, the slimmer the

Elecsys TSH [µlU/mL]

all female patients 0.46 0.48 0.54 1.52 1.55 1.60 3.88 4.13 4.30 2,313 2013 reference range. 15
(sd healthy) Women
female <40 years 0.16 0.50 0.86 1.73 1.91 2.23 4.57 5.10 7.25 155 2013
The TSH reference ranges show a clear age dependency Men
female ≥40 and 0.48 0.54 0.58 1.53 1.57 1.62 3.86 4.07 4.31 1,760 2013 (see figure 7). 10
<70 years
female ≥70 years 0.20 0.28 0.43 1.27 1.38 1.44 3.06 3.45 3.86 398 2013
Over trimester 1 to 3, pregnant women show a tendency in
Results from 5 97.5% quantile
various locations
the upper limits towards lower TSH concentrations. As also
recommended in the guidelines from the American Thyroid
Group A 0.3 1.5 3.3 128 2003 50% quantile
(euthyroid indiv.) Association, a trimester specific reference range for TSH shall be
0 2.5% quantile
Group N (HUNT 0.30 3.60 70,000 2000 applied.12
0 10 20 30 40 50 60 70
Study) females Age [years]
Group N (HUNT 0.30 3.40 2000 The group LIFE adult did not reveal any dependencies on BMI
Study) males Figure 7: Containing data from GL1 and GEL, shows measured data for children
nor >30 neither >35 with a hip/waist ratio according the WHO.
and adults from birth to 70 years of age using separate symbols to distinguish
Furthermore, the reference ranges determined for healthy between male and female. The TSH concentration is high in the first days after
non-smokers, healthy former smokers and healthy smokers are birth and continuously decreases with age. This emphasizes the importance of
comparable to each other. age-specific reference ranges for TSH.

12 13
5 Results and Discusscion 95p CI
low
(2.5 % 2.5 %
95p CI
high
(2.5 %
95p CI
low
(50 % 50 %
95p CI
high
(50 %
95p CI
low
(97.5 % 97.5 %
95p CI
high
(97.5 %
Year
of

5.2 Free thyroxin – FT4

5
  FT4 quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
pmol/L
Elecsys ® FT4 – 12 22 801 1998
package insert
Group GL1 12.3 12.7 13.0 16.0 16.2 16.5 20.4 20.8 21.4 870 2004
(all blood donors)
L1 Males all 12.8 13.1 13.4 16.7 16.9 17.2 20.8 21.3 22.2 445 2004
L1 Males 20 – 39 y 12.9 13.4 14.0 16.9 17.2 17.5 20.7 21.3 23.0 286 2004
L1 Males 40 – 69 y 10.3 12.5 13.2 15.8 16.2 16.8 19.9 21.2 22.2 150 2004
L1 Females all 11.5 12.3 12.7 15.4 15.6 15.9 20.0 20.2 21.0 425 2004
The determination of free T4 has the advantage of being The tables 5 to 12 below describe the Elecsys® FT4 reference L1 Females 20 – 39 y 11.7 12.4 12.9 15.4 15.7 16.0 19.9 20.4 21.7 270 2004
independent of changes in the concentrations and ranges determined in different studies for: 1. adults, separated L1 Females 40 – 69 y 8.24 11.5 13.3 15.2 15.6 15.9 18.9 19.6 21.0 128 2004
binding properties of the binding proteins; additional into male and female and age, 2. pregnant women, separated into L1 Females 11.5 12.4 12.8 15.3 15.6 16.0 19.6 20.0 21.7 236 2004
determination of a binding parameter (T‑uptake, TBG) is the 3 trimesters and 3. children, separated by age. For children with contracept.
therefore unnecessary. Free T4 is a useful tool in clinical two separated tables have been created as the number of children L1 Females with 11.5 12.4 12.8 15.3 15.7 16.1 19.4 19.9 21.7 181 2004
routine diagnostics for the assessment of the thyroid in the GEL group has been too low to compute the confidence contracept. 20 – 39 y
status. It should be measured together with TSH if thyroid interval with 95 % confidence level. The applied confidence level L1 Females with 12.3 12.3 13.2 14.1 14.9 16.1 17.1 19.0 19.0 33 2004
contracept. 40 – 69 y
disorders are suspected and is also suitable for monitoring was set to 90 %. For all other groups confidence levels have been
thyrosuppressive therapy.13 set to 95 %. L1 Females 8.24 11.7 13.3 15.4 15.7 15.9 20.0 20.4 28.6 188 2004
w/o contracept
L1 Females w/o 11.7 13.0 13.6 15.3 15.7 16.7 20.0 20.5 28.6 88 2004
contracept. 20 – 39 y
L1 Females w/o 8.24 9.30 13.4 15.3 15.7 16.0 19.0 20.1 21.0 95 2004
contracept. 40 – 69 y
Group GL2 (TSH + 12.3 12.8 13.0 15.9 16.2 16.5 20.2 20.7 21.4 632 2004
SD-Sono NAD)
L2 Males 12.7 13.1 13.4 16.7 17.0 17.3 20.4 21.3 23.0 332 2004
L2 Females 11.5 12.3 12.8 15.3 15.6 15.8 19.6 20.1 20.8 300 2004
Group GL3 org 12.2 12.8 13.0 15.9 16.2 16.6 20.2 20.4 21.5 448 2004
(NACB crit. for TSH)
L3 Males 10.3 12.9 13.2 16.7 17.0 17.4 20.4 21.4 24.7 274 2004
L3 Females 9.30 12.2 12.8 15.3 15.5 15.8 19.2 20.0 20.7 174 2004
LIFE Adults 11.8 11.9 12.1 15.6 15.7 15.7 19.9 20.1 20.3 5,476 2013
all male patients 11.8 12.0 12.2 15.7 15.8 15.9 19.9 20.2 20.5 3,169 2013
(sd healthy)
male <40 years 9.56 12.9 13.82 16.0 16.2 16.6 19.9 21.4 22.5 156 2013
male ≥40 and 11.7 11.9 12.2 15.7 15.8 15.9 19.8 20.2 20.5 2,323 2013
<70 years
male ≥70 years 11.6 12.1 12.3 15.7 15.8 16.0 19.8 20.2 21.0 690 2013
all female patients 11.7 11.8 12.0 15.4 15.5 15.6 19.5 20.0 20.3 2,307 2013
(sd healthy)
female <40 years 10.6 11.2 11.9 14.7 15.2 15.7 18.9 19.9 21.2 155 2013
female ≥40 and 11.6 11.8 12.0 15.3 15.4 15.5 19.5 19.8 20.4 1,754 2013
<70 years
female ≥70 years 11.6 12.2 12.7 15.9 16.1 16.3 19.5 20.2 23.2 398 2013
Results from
various locations
Group A 9.75 21.3 127 2003
(euthyroid indiv.)
Group GHH 11.2 11.4 11.5 15.7 21.7 22.0 22.4 5,365 2004
(routine samples)

14 15
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
9
6
  FT4 quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   FT4 quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.

pmol/L ng/dL
Pregnant Women Elecsys ® FT4 – 0.93 1.71 801 1998
package insert
1 Trimester
st
11.8 12.1 12.4 15.1 15.4 15.7 19.2 19.6 21.4 418 2004
Group GL1 0.95 0.99 1.01 1.24 1.26 1.28 1.58 1.62 1.67 870 2004
2nd Trimester 9.18 9.63 10.0 12.6 12.9 13.1 16.1 17.0 18.0 369 2004 (all blood donors)
3rd Trimester 6.95 8.39 9.31 11.6 11.9 12.3 14.8 16.0 17.8 169 2004 L1 Males all 0.99 1.01 1.04 1.30 1.31 1.34 1.62 1.65 1.72 445 2004
L1 Males 20 – 39 y 1.00 1.04 1.09 1.31 1.33 1.36 1.61 1.65 1.79 286 2004
90p CI 90p CI 90p CI 90p CI 90p CI 90p CI L1 Males 40 – 69 y 0.80 0.97 1.02 1.23 1.25 1.30 1.55 1.65 1.72 150 2004
low high low high low high Year L1 Females all 0.89 0.95 0.99 1.20 1.21 1.23 1.55 1.57 1.63 425 2004
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
7 L1 Females 20 – 39 y 0.91 0.97 1.00 1.20 1.22 1.25 1.55 1.58 1.68 270 2004
  FT4 quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L1 Females 40 – 69 y 0.64 0.89 1.03 1.18 1.21 1.24 1.47 1.52 1.63 128 2004
pmol/L
L1 Females 0.90 0.97 0.99 1.19 1.21 1.24 1.52 1.56 1.68 236 2004
Group GEL Children, with contracept.
Adolescents
L1 Females with 0.90 0.97 0.99 1.19 1.22 1.25 1.51 1.55 1.68 181 2004
0 – 6 Days 7.70 11.0 15.8 16.0 17.7 19.6 26.4 32.0 38.9 112 2007 contracept. 20 – 39 y
>6 Days ≤3 Months 7.73 11.5 17.1 15.6 17.4 19.4 22.8 28.3 35.1 111 2007 L1 Females with 0.95 0.95 1.03 1.10 1.16 1.25 1.33 1.48 1.48 33 2004
>3 ≤12 Months 7.75 11.9 18.2 15.3 17.2 19.3 20.3 25.6 32.3 117 2007 contracept. 40 – 69 y
>1 ≤6 Years 7.71 12.3 19.7 14.8 16.9 19.2 17.6 22.8 29.5 344 2007 L1 Females 0.64 0.91 1.03 1.20 1.22 1.24 1.55 1.58 2.22 188 2004
>6 ≤11 Years 7.58 12.5 20.7 14.4 16.6 19.2 16.2 21.5 28.4 263 2007 w/o contracept

>11 ≤20 Years 7.44 12.6 21.3 14.2 16.5 19.1 15.6 21.0 28.2 469 2007 L1 Females w/o 0.91 1.01 1.05 1.19 1.22 1.30 1.55 1.59 2.22 88 2004
contracept. 20 – 39 y
L1 Females w/o 0.64 0.72 1.04 1.18 1.22 1.25 1.47 1.56 1.63 95 2004
95p CI 95p CI 95p CI 95p CI 95p CI 95p CI contracept. 40 – 69 y
low high low high low high Year Group GL2 (TSH + 0.95 0.99 1.01 1.23 1.26 1.28 1.57 1.61 1.67 632 2004
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of SD-Sono NAD)
8
  FT4 quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ. L2 Males 0.99 1.01 1.04 1.30 1.32 1.34 1.59 1.65 1.79 332 2004
pmol/L L2 Females 0.90 0.95 0.99 1.19 1.21 1.23 1.52 1.56 1.62 300 2004
LIFE Child Group GL3 org 0.94 0.99 1.01 1.23 1.26 1.29 1.57 1.59 1.67 448 2004
>3 ≤12 Months 12.6 13.3 13.8 15.9 16.2 16.7 19.2 20.5 21 83 2016 (NACB crit. for TSH)
>1 ≤6 Years 12.9 13.4 13.7 15.9 16.3 16.5 19.6 20.1 20.6 193 2016 L3 Males 0.80 1.00 1.02 1.30 1.32 1.35 1.58 1.67 1.92 274 2004
>6 ≤11 Years 12.4 12.9 13.1 15.7 15.9 16.2 19.3 19.7 20.4 243 2016 L3 Females 0.72 0.94 0.99 1.19 1.20 1.23 1.49 1.56 1.61 174 2004
>11 ≤20 Years 11.2 11.6 12.0 14.9 15.3 15.6 19.3 19.6 20.8 206 2016 LIFE Adults 0.92 0.93 0.94 1.21 1.22 1.22 1.54 1.56 1.58 5,476 2013
all male patients 0.91 0.93 0.95 1.22 1.23 1.24 1.55 1.57 1.59 3,169 2013
(sd healthy)
male <40 years 0.74 1.00 1.07 1.24 1.26 1.29 1.55 1.67 1.75 156 2013
male ≥40 and 0.91 0.93 0.95 1.22 1.22 1.23 1.54 1.57 1.6 2,323 2013
<70 years
male ≥70 years 0.90 0.94 0.95 1.22 1.23 1.24 1.54 1.57 1.63 690 2013
all female patients 0.91 0.92 0.93 1.20 1.20 1.21 1.52 1.55 1.58 2,307 2013
(sd healthy)
female <40 years 0.82 0.87 0.93 1.14 1.18 1.22 1.47 1.54 1.64 155 2013
female ≥40 and 0.90 0.92 0.93 1.19 1.20 1.21 1.51 1.53 1.58 1,754 2013
<70 years
female ≥70 years 0.90 0.95 0.98 1.23 1.25 1.26 1.52 1.57 1.80 398 2013
Results from
various locations
Group A 0.76 1.65 127 2003
(euthyroid indiv.)
Group GHH 0.87 0.89 0.90 1.22 1.69 1.71 1.74 5,365 2004
(routine samples)

16 17
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI The different cohorts show that FT4 is quite stable over the life- Group GL1 − all blood donners (n = 869 : 445 females, 424 males)
low high low high low high Year time and that there are no big differences between male and
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of 100
10 FT4 female reference ranges.
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
Women
ng/dL
Over trimester 1 to 3, pregnant women show decreasing

TSH [µIU/mL] bg
Pregnant Women Men
4.2
reference ranges. As also recommended in the guidelines from
1 Trimester
st
0.92 0.94 0.96 1.17 1.20 1.22 1.49 1.52 1.66 418 2004
the American Thyroid Association, a trimester specific reference 1
2nd Trimester 0.71 0.75 0.78 0.98 1.00 1.02 1.25 1.32 1.40 369 2004
range for FT4 shall be applied.12
3rd Trimester 0.54 0.65 0.72 0.90 0.93 0.95 1.15 1.24 1.38 169 2004
0.1
The group LIFE adult did not reveal any dependencies on BMI
90p CI 90p CI 90p CI 90p CI 90p CI 90p CI nor >30 neither >35 with a hip/waist ratio according the WHO.
0.01
low high low high low high Year Furthermore, the reference ranges determined for healthy
0 5 10 15 20 25 30 35
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of non-smokers, healthy former smokers and healthy smokers are
11 FT4 FT4 [pmol/L]
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
comparable to each other.
ng/dL
Group GEL Children,
Correlation between Elecsys® TSH and Elecsys® FT4 results Group GL2 − TSH+Sono NAD (n = 643 : 338 females, 305 males)
Adolescents
In figure 8, each graph shows the Elecsys® FT4 results for the
0 – 6 Days 0.60 0.86 1.23 1.25 1.38 1.52 2.05 2.49 3.02 112 2007 100
subjects of the individual groups GL1, GL2, GL3, pregnant women
>6 Days ≤3 Months 0.60 0.89 1.33 1.21 1.35 1.51 1.77 2.20 2.72 111 2007
and LIFE adult, respectively, plotted against the Elecsys® TSH results Women
>3 ≤12 Months 0.60 0.92 1.41 1.19 1.33 1.50 1.58 1.99 2.51 117 2007
of the same samples. Samples from male persons are indicated with

TSH [µIU/mL] bg
Men
>1 ≤6 Years 0.60 0.96 1.53 1.15 1.31 1.49 1.37 1.77 2.29 344 2007 4.2
rectangles and from female persons with circles. The dashed lines
>6 ≤11 Years 0.59 0.97 1.61 1.12 1.29 1.49 1.26 1.67 2.20 263 2007 correspond to the 2.5 % and 97.5 % quantiles of the valid reference 1
>11 ≤20 Years 0.58 0.98 1.65 1.10 1.28 1.49 1.21 1.63 2.19 469 2007 intervals as listed in the package inserts. The continuous lines
represent the reference ranges determined in each group which 0.1
95p CI 95p CI 95p CI 95p CI 95p CI 95p CI is also stated in the legends. In these graphs, the dependency of
low high low high low high Year the reference values on the applied inclusion/exclusion criteria as
0.01
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of well as changes in the values during pregnancy becomes apparent.
12 FT4 0 5 10 15 20 25 30 35
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
These results emphasize the importance of applying reference FT4 [pmol/L]
ng/dL ranges adapted to specific cohorts e.g. trimester specific reference
LIFE Child ranges for pregnant women.
>3 ≤12 Months 0.98 1.04 1.07 1.23 1.26 1.30 1.49 1.59 1.63 83 2016
>1 ≤6 Years 1.00 1.04 1.06 1.23 1.26 1.28 1.52 1.56 1.60 193 2016
Pregnant Women (n = 957 : 418 1st trim., 369 2nd trim., 170 3rd trim.) Group GL3 (TSH NACB) (n = 447 : 274 females, 173 males)
>6 ≤11 Years 0.97 1.00 1.02 1.22 1.24 1.26 1.50 1.53 1.58 243 2016
>11 ≤20 Years 0.87 0.90 0.93 1.16 1.19 1.21 1.50 1.53 1.62 206 2016 100 100

Trimester 1 Women

TSH [µIU/mL] bg
TSH [µIU/mL] bg
Trimester 2 Men
4.2 4.2
Trimester 3 1
1

0.1 0.1

0.01 0.01
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
FT4 [pmol/L] FT4 [pmol/L]

Figure 8: Correlation between Elecsys® FT4 and Elecsys® TSH results.

Group LIFE (healthy patients) (n = 5475 : 2,307 females, 3,168 males)

100

Women
TSH [µIU/mL] bg

Men
4.2

0.1

0.01
0 5 10 15 20 25 30 35
FT4 [pmol/L]

18 19
Reference ranges of Elecsys® FT4 under L-thyroxine
supplementation
Status T4
medication
Mean 5 Results and Discusscion
5.3 Free triiodothyronine – FT3
The figure 9 shows Elecsys® FT4 results of LIFE adult patients under
thyroxine treatment filtered for euthyroid TSH (0.27 – 4.2 µIU/mL) 40
N=8367 N=1235
and Anti-TPO negative patients. The results demonstrate a shift for
Elecsys® FT4 measurements towards upper values. Evaluating the
LIFE adult cohort shows a shift of reference ranges for patients
30
under L-thyroxine supplementation to 13.61 – 28.29 pmol/L for

FT4 [pmol/L]
Elecsys® FT4.
22
This finding emphasizes the importance of adapting reference 20
ranges for patients under L-thyroxine supplementation treatment.
12 As for free T4, the determination of free T3 has the The tables 13 to 20 below describe the Elecsys® FT3 reference
10 advantage of being independent of changes in the ranges determined in different studies for: 1. adults, separated
concentrations and binding properties of the binding into male and female and age, 2. pregnant women, separated into
proteins; additional determination of a binding parameter the 3 trimesters and 3. children, separated by age. For children
L-Thyroxine (T-uptake, TBG) is hence unnecessary. Therefore, free two separated tables have been created as the number of children
supplementation T3 is a useful tool in clinical routine diagnostics for the in the GEL group has been too low to compute the confidence
assessment of the thyroid status. Free T3 measurements interval with 95 % confidence level. The applied confidence level
support the differential diagnosis of thyroid disorders, are was set to 90 %. For all other groups confidence levels have been
Figure 9: Filter – Distribution of FT4 [pmol/L] in patients under L-thyroxine
needed to distinguish different forms of hyperthyroidism, set to 95 %.
supplementation and euthyroid TSH.
and to identify patients with T3 thyrotoxicosis.13-15

20 21
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
13 FT3 14 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
pmol/L pmol/L
Elecsys ® FT3 – 3.1 6.8 5,366 2004 Pregnant Women
package insert 1st Trimester 3.60 3.78 3.87 4.74 4.80 4.87 5.84 5.97 6.22 416 2004
Group GL1 3.67 3.89 3.99 5.02 5.10 5.15 6.54 6.66 7.00 870 2004 2nd Trimester 3.08 3.21 3.28 4.02 4.09 4.18 5.25 5.45 5.75 368 2004
(all blood donors)
3rd Trimester 2.44 3.09 3.19 3.80 3.90 3.99 4.73 5.03 6.36 169 2004
L1 Males all 4.02 4.09 4.29 5.23 5.30 5.36 6.54 6.65 7.21 445 2004
L1 Males 20 – 39 y 4.04 4.36 4.54 5.22 5.29 5.37 6.54 6.74 7.21 286 2004
L1 Males 40 – 69 y 2.52 3.98 4.09 5.17 5.29 5.45 6.24 6.54 9.47 150 2004 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
L1 Females all 3.34 3.71 3.84 4.71 4.76 4.82 6.18 6.70 7.27 425 2004 low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
L1 Females 20 – 39 y 3.13 3.66 3.89 4.72 4.78 4.88 6.10 6.72 7.94 270 2004 15 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L1 Females 40 – 69 y 3.52 3.74 3.97 4.54 4.68 4.81 5.94 6.11 6.85 128 2004 pmol/L
L1 Females 3.18 3.91 4.03 4.74 4.82 4.94 6.20 6.85 9.96 236 2004 Group GEL Children,
with contracept. Adolescents
L1 Females with 3.18 3.91 4.08 4.72 4.80 4.91 6.02 6.31 9.96 181 2004 0 – 6 Days 1.50 2.65 4.69 4.76 5.50 6.36 8.05 9.68 11.6 109 2007
contracept. 20 – 39 y
>6 Days ≤3 Months 1.60 3.00 5.61 4.97 5.82 6.83 7.57 9.28 11.4 106 2007
L1 Females with 3.97 3.97 4.02 4.52 4.82 5.11 5.55 6.85 6.85 33 2004
contracept. 40 – 69 y >3 ≤12 Months 1.68 3.30 6.48 5.12 6.07 7.21 7.19 8.95 11.1 115 2007
L1 Females 3.01 3.55 3.74 4.61 4.70 4.80 6.10 6.37 7.94 188 2004 >1 ≤6 Years 1.76 3.69 7.75 5.19 6.27 7.59 6.64 8.46 10.8 347 2007
w/o contracept >6 ≤11 Years 1.75 3.88 8.59 5.04 6.18 7.58 6.20 8.02 10.4 265 2007
L1 Females w/o 3.01 3.34 3.8 4.63 4.74 4.91 5.67 6.87 7.94 88 2004 >11 ≤20 Years 1.71 3.93 9.03 4.81 5.96 7.39 5.88 7.70 10.1 470 2007
contracept. 20 – 39 y
L1 Females w/o 3.52 3.71 3.92 4.47 4.63 4.77 5.94 6.11 6.37 95 2004
contracept. 40 – 69 y 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
Group GL2 (TSH + 3.67 3.92 4.03 4.99 5.08 5.15 6.54 6.65 7.00 632 2004 low high low high low high Year
SD-Sono NAD) (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
16 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L2 Males 3.85 4.07 4.28 5.21 5.25 5.35 6.54 6.66 7.21 332 2004
pmol/L
L2 Females 3.13 3.80 3.92 4.7 4.75 4.82 6.12 6.31 7.27 300 2004
LIFE Child
Group GL3 org 3.71 3.92 4.07 5.03 5.12 5.19 6.54 6.74 7.21 448 2004
(NACB crit. for TSH) >3 ≤12 Months 4.94 5.19 5.87 6.91 7.01 7.14 8.15 8.46 9.12 76 2016
L3 Males 2.52 4.09 4.28 5.19 5.25 5.36 6.57 6.79 8.46 274 2004 >1 ≤6 Years 4.99 5.30 5.65 6.61 6.72 6.86 8.00 8.25 8.73 195 2016
L3 Females 3.01 3.80 3.89 4.70 4.77 4.85 6.10 6.70 9.96 174 2004 >6 ≤11 Years 5.28 5.42 5.61 6.55 6.67 6.77 7.68 7.93 8.21 244 2016
LIFE Adults 3.90 3.95 3.98 5.01 5.03 5.05 6.26 6.31 6.36 5,478 2013 >11 ≤20 Years 4.37 4.77 4.89 5.91 6.03 6.15 7.29 7.52 7.85 207 2016
all male patients 4.08 4.14 4.19 5.14 5.17 5.20 6.35 6.41 6.50 3,170 2013
(sd healthy)
male <40 years 4.19 4.50 4.67 5.41 5.51 5.57 6.49 6.86 7.88 156 2013
male ≥40 and 4.15 4.23 4.29 5.20 5.23 5.26 6.38 6.44 6.53 2,324 2013
<70 years
male ≥70 years 3.83 3.96 4.04 4.85 4.92 4.97 5.81 5.92 6.10 690 2013
all female patients 3.77 3.84 3.89 4.81 4.84 4.87 5.94 6.03 6.12 2,308 2013
(sd healthy)
female <40 years 3.53 3.96 4.09 4.97 5.07 5.23 6.25 7.07 8.29 155 2013
female ≥40 and 3.79 3.86 3.90 4.83 4.85 4.89 5.94 6.02 6.13 1,755 2013
<70 years
female ≥70 years 3.53 3.64 3.86 4.62 4.67 4.73 5.60 5.80 6.01 398 2013
Results from
various locations
Group A (euthyroid 3.30 6.30 127 2003
indiv. 2003)
Group N, all 2.80 3.10 3.30 6.20 6.30 6.80 604 2003
Group N, 3.00 4.50 6.30 367 2003
SKKL+Molde
Group N, SKKL 3.60 4.80 6.50 237 2003
(outpatients)

22 23
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
17 FT3 18 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
pg/mL pg/mL
Elecsys ® FT3 – 2.04 4.4 5,366 2004 Pregnant Women
package insert 1st Trimester 2.34 2.46 2.52 3.09 3.12 3.17 3.80 3.89 4.05 416 2004
Group GL1 2.39 2.53 2.60 3.27 3.32 3.35 4.26 4.34 4.56 870 2004 2nd Trimester 2.01 2.09 2.14 2.62 2.66 2.72 3.42 3.55 3.74 368 2004
(all blood donors)
3rd Trimester 1.59 2.01 2.08 2.47 2.54 2.60 3.08 3.27 4.14 169 2004
L1 Males all 2.62 2.66 2.79 3.40 3.45 3.49 4.26 4.33 4.69 445 2004
L1 Males 20 – 39 y 2.63 2.84 2.96 3.40 3.44 3.50 4.26 4.39 4.69 286 2004
L1 Males 40 – 69 y 1.64 2.59 2.66 3.37 3.45 3.55 4.06 4.26 6.16 150 2004 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
L1 Females all 2.17 2.42 2.50 3.07 3.10 3.14 4.02 4.36 4.73 425 2004 low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
L1 Females 20 – 39 y 2.04 2.38 2.53 3.07 3.11 3.18 3.97 4.37 5.17 270 2004 19 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L1 Females 40 – 69 y 2.29 2.43 2.58 2.96 3.05 3.13 3.87 3.98 4.46 128 2004 pg/mL
L1 Females 2.07 2.55 2.62 3.09 3.14 3.22 4.04 4.46 6.48 236 2004 Group GEL Children,
with contracept. Adolescents
L1 Females with 2.07 2.55 2.66 3.07 3.12 3.20 3.92 4.11 6.48 181 2004 0 – 6 Days 0.98 1.73 3.05 3.10 3.58 4.14 5.24 6.30 7.58 109 2007
contracept. 20 – 39 y
>6 Days ≤3 Months 1.04 1.95 3.65 3.23 3.79 4.44 4.93 6.04 7.40 106 2007
L1 Females with 2.58 2.58 2.62 2.94 3.14 3.33 3.61 4.46 4.46 33 2004
contracept. 40 – 69 y >3 ≤12 Months 1.10 2.15 4.22 3.33 3.95 4.69 4.68 5.83 7.25 115 2007
L1 Females 1.96 2.31 2.43 3.00 3.06 3.12 3.97 4.15 5.17 188 2004 >1 ≤6 Years 1.15 2.41 5.05 3.38 4.08 4.94 4.33 5.50 7.01 347 2007
w/o contracept >6 ≤11 Years 1.14 2.53 5.59 3.28 4.02 4.93 4.03 5.22 6.76 265 2007
L1 Females w/o 1.96 2.17 2.47 3.01 3.09 3.20 3.69 4.47 5.17 88 2004 >11 ≤20 Years 1.11 2.56 5.88 3.13 3.88 4.81 3.82 5.01 6.56 470 2007
contracept. 20 – 39 y
L1 Females w/o 2.29 2.42 2.55 2.91 3.01 3.11 3.87 3.98 4.15 95 2004
contracept. 40 – 69 y 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
Group GL2 (TSH + 2.39 2.55 2.62 3.25 3.31 3.35 4.26 4.33 4.56 632 2004 low high low high low high Year
SD-Sono NAD) (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
20 FT3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
L2 Males 2.51 2.65 2.79 3.39 3.42 3.48 4.26 4.34 4.69 332 2004
pg/mL
L2 Females 2.04 2.47 2.55 3.06 3.10 3.14 3.98 4.11 4.73 300 2004
LIFE Child
Group GL3 org 2.42 2.55 2.65 3.27 3.33 3.38 4.26 4.39 4.69 448 2004
(NACB crit. for TSH) >3 ≤12 Months 3.21 3.38 3.82 4.50 4.56 4.65 5.30 5.51 5.93 76 2016
L3 Males 1.64 2.66 2.79 3.38 3.42 3.49 4.28 4.42 5.51 274 2004 >1 ≤6 Years 3.25 3.45 3.68 4.30 4.38 4.47 5.21 5.37 5.68 195 2016
L3 Females 1.96 2.47 2.53 3.06 3.10 3.16 3.97 4.36 6.48 174 2004 >6 ≤11 Years 3.44 3.53 3.65 4.27 4.34 4.4 5.00 5.16 5.34 244 2016
LIFE Adults 2.54 2.57 2.59 3.26 3.27 3.29 4.08 4.11 4.14 5,478 2013 >11 ≤20 Years 2.85 3.10 3.18 3.85 3.93 4.01 4.74 4.89 5.11 207 2016
all male patients 2.66 2.70 2.73 3.35 3.37 3.39 4.13 4.17 4.23 3,170 2013
(sd healthy) Establishing values reference ranges for the package insert non-smoker, healthy former smoker and healthy smokers are
male <40 years 2.73 2.93 3.04 3.52 3.59 3.63 4.22 4.47 5.13 156 2013 is based primarily obtained on samples from one commercial comparable to each other.
male ≥40 and 2.70 2.75 2.79 3.39 3.40 3.42 4.15 4.19 4.25 2,324 2013 laboratory. TSH and FT4 levels are found to be in the euthyroid Figure 10 shows all data for children and adults from birth to 70
<70 years range in these samples. The patients often have non-thyroid years using separate symbols to distinguish between male and
male ≥70 years 2.49 2.58 2.63 3.16 3.20 3.24 3.78 3.85 3.97 690 2013 diseases which might influence the thyroid function in general, female. The FT3 concentration decreases continuously with age.
all female patients 2.45 2.5 2.53 3.13 3.15 3.17 3.87 3.93 3.98 2,308 2013 and especially the FT3 level (please see also chapter 6). This may This emphasizes the importance of age-specific reference ranges.
(sd healthy)
explain the differences observed when comparing the reference
female <40 years 2.30 2.58 2.66 3.24 3.30 3.40 4.07 4.60 5.40 155 2013 ranges based on different population groups using the same >13
female ≥40 and 2.47 2.51 2.54 3.14 3.16 3.18 3.87 3.92 3.99 1,755 2013 Results
Elecsys® FT3 method. Beside local differences in iodine intake the 12
>13 µIU/mL
<70 years 11
overall health status of the individuals involved is decisive for the
female ≥70 years 2.30 2.37 2.51 3.01 3.04 3.08 3.65 3.78 3.91 398 2013 10
outcome of the reference intervals.

FT3 [pmol/L]
Results from 9
The FT3 reference ranges show an age dependency. A slight 8
various locations
difference in gender is seen especially for the 2.5 % quantile and 7
Group A (euthyroid 2.15 4.10 127 2003
the median. Males show higher values as compared to women. 6 97.5% quantile
indiv. 2003)
5
Group N, all 1.82 2.02 2.15 4.04 4.10 4.43 604 2003 Pregnant women have lower FT3 concentrations compared to 50% quantile
4
Group N, 1.95 2.93 4.10 367 2003 healthy, non-pregnant women correlated with the gestational 3 2.5% quantile
SKKL+Molde age. As also recommended in the guidelines from the American 2
Group N, SKKL 2.34 3.12 4.23 237 2003 Thyroid Association, a trimester specific reference range for FT3 1
(outpatients) 0
shall be applied.12 Women
The group LIFE adult did not reveal any dependencies on BMI 0 10 20 30 40 50 60 70 Men
nor >30 neither >35 with a hip/waist ratio according the WHO.
Age [years]
Furthermore, the reference ranges determined for healthy

Figure 10: Quantile regression for Elecsys® FT3

24 25
 Correlation between Elecsys® TSH and Elecsys® FT3 results
In figure 11, each graph shows the Elecsys® FT3 results for the
The continuous lines represent the reference ranges determined
in each group which is also stated in the legends. In these 5 Results and Discusscion
5.4 Thyroxine – T4
subjects of the individual groups GL1, GL2, GL3, pregnant women graphs, the dependency of the reference values on the applied
and LIFE adult, respectively, plotted against the Elecsys® TSH inclusion/exclusion criteria as well as changes in the values
results of the same samples. Samples from male persons are during pregnancy becomes apparent. These results emphasize
indicated with rectangles and from female persons with circles. the importance of applying reference ranges adapted to specific
The dashed lines correspond to the 2.5 % and 97.5 % quantiles cohorts e.g. trimester specific reference ranges for pregnant
of the valid reference intervals as listed in the package inserts. women.

Group GL1 − all blood donners (n = 869 : 445 females, 424 males) Pregnant Women (n = 957 : 418 1st trim., 369 2nd trim., 170 3rd trim.)

100 100

Women Trimester 1
To measure thyroid hormones in serum, there are in principle two the free hormone level, and therefore the thyroid function,
different approaches: remains unchanged. This is the case e.g. in pregnancy, during
TSH [µIU/mL] bg

TSH [µIU/mL] bg
Men Trimester 2 •• Measurement of total T3 and T4 (TT3, TT4) treatment with certain medications and in patients with genetic
4.2 4.2
Trimester 3 •• Measurement of free T3 and T4 (FT3 ~0.3 % abnormalities in the binding proteins.
1 1
and FT4 ~0.03 % of the TT3 and TT4, respectively)
If the total thyroid hormones are measured, it is recommended
0.1 0.1
T4 in serum is bound to proteins in over 99.9 %. The major binding to determine the thyroxine-binding capacity to take into account
protein is the thyroxine-binding-globulin (TBG). In much lower influences caused by varying concentrations of binding proteins.
0.01 0.01 frequency transthyretin (TTR) and in low amounts albumin bind The free thyroxine index can be calculated (e.g. measurements of
0 2 4 6 8 10 12 0 2 4 6 8 10 12 thyroid hormones. T3 is also bound to TBG, but with an about TBG and T-uptake).3,16
FT3 [pmol/L] FT3 [pmol/L]
10-fold lower affinity than T4, to albumin and in very low
frequency also to TTR. The tables 21 to 26 below describe the Elecsys® T4 reference
Group GL2 − TSH+Sono NAD (n = 643 : 338 females, 305 males) Group LIFE (healthy patients) (n = 5476 : 2,308 females, 3,168 males)
ranges determined in different studies for: 1. adults, separated
100 100 Changes of the binding protein concentration or binding protein into male and female and age, 2. pregnant women, separated into
Women Women
capacity leads to a change in the total hormone level while the 3 trimesters and 3. children, separated by age.
TSH [µIU/mL] bg

TSH [µIU/mL] bg

Men Men
4.2 4.2

1 1

0.1 0.1

0.01 0.01
0 2 4 6 8 10 12 0 2 4 6 8 10 12
FT3 [pmol/L] FT3 [pmol/L]

Group GL3 (TSH NACB) (n = 447 : 274 females, 173 males)

100

Women
TSH [µIU/mL] bg

Men
4.2

0.1

0.01
0 2 4 6 8 10 12
FT3 [pmol/L]

Figure 11: Correlation between Elecsys® FT3 and Elecsys® TSH results.

26 27
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
21 T4 24 T4
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
Elecsys® T4 – insert 59 154 275 1998 Elecsys® T4 – insert 4.6 12 275 1998
Europe/Japan Europe/Japan
Elecsys® T4 – insert 66 181 2,526 1998 Elecsys® T4 – insert 5.1 14.1 2,526 1998
USA, 99 % centr. USA, 99 % centr.
Group GL1 68.3 71.5 72.7 99.4 101 103 152 158 163 870 2004 Group GL1 5.31 5.56 5.65 7.72 7.84 7.99 11.7 12.2 12.7 870 2004
(all blood donors) (all blood donors)
L1 Males all 65.8 71.6 72.7 93.5 95.9 97.3 125 128 130 445 2004 L1 Males all 5.11 5.56 5.65 7.26 7.45 7.56 9.67 9.91 10.1 445 2004
L1 Males 20 – 39 y 62.6 71.8 73.6 92.2 94.7 96.6 122 125 130 286 2004 L1 Males 20 – 39 y 4.86 5.57 5.72 7.16 7.36 7.51 9.51 9.69 10.1 286 2004
L1 Males 40 – 69 y 52.1 68.4 75.4 95.3 97.4 100 124 129 144 150 2004 L1 Males 40 – 69 y 4.05 5.32 5.86 7.40 7.57 7.80 9.59 10.0 11.2 150 2004
L1 Females all 63.5 71.5 75.6 108 110 114 161 166 192 425 2004 L1 Females all 4.93 5.56 5.88 8.38 8.58 8.86 12.5 12.9 14.9 425 2004
L1 Females 20 – 39 y 70.0 76.2 80.0 113 116 119 160 166 193 270 2004 L1 Females 20 – 39 y 5.44 5.92 6.22 8.79 9.01 9.22 12.4 12.9 15.0 270 2004
L1 Females 40 – 69 y 55.2 63.5 72.5 95.9 99.7 105 143 157 168 128 2004 L1 Females 40 – 69 y 4.29 4.93 5.63 7.45 7.75 8.17 11.1 12.2 10.0 128 2004
L1 Females 70.0 81.8 89.4 121 124 126 166 173 209 236 2004 L1 Females 5.44 6.35 6.94 9.37 9.61 9.82 12.9 13.4 16.3 236 2004
with contracept. with contracept.
L1 Females with 70.0 84.5 91.2 120 123 126 162 172 198 181 2004 L1 Females with 5.44 6.64 7.09 9.34 9.57 9.82 12.6 13.3 15.4 181 2004
contracept. 20 – 39 y contracept. 20 – 39 y
L1 Females with 75.8 75.8 83.7 105 118 135 163 168 168 33 2004 L1 Females with 5.88 5.88 6.50 8.17 9.14 10.5 12.6 13.0 13.0 33 2004
contracept. 40 – 69 y contracept. 40 – 69 y
L1 Females 55.2 68.0 71.5 92.9 95.7 99.0 126 138 170 188 2004 L1 Females 4.29 5.29 5.56 7.21 7.43 7.69 9.80 10.7 13.2 188 2004
w/o contracept w/o contracept
L1 Females w/o 69.1 71.5 76.5 91.7 96.1 103 122 138 161 88 2004 L1 Females w/o 5.37 5.56 5.95 7.12 7.46 7.96 9.45 10.7 12.5 88 2004
contracept. 20 – 39 y contracept. 20 – 39 y
L1 Females w/o 55.2 59.8 70.5 92.1 95.7 101 120 127 139 95 2004 L1 Females w/o 4.29 4.64 5.48 7.16 7.44 7.85 9.36 9.90 10.8 95 2004
contracept. 40 – 69 y contracept. 40 – 69 y
Group GL2 (TSH + 68.3 71.4 73.1 98.4 100 103 152 160 166 632 2004 Group GL2 (TSH + 5.31 5.55 5.68 7.64 7.81 8.01 11.8 12.4 12.9 632 2004
SD-Sono NAD) SD-Sono NAD)
L2 Males 62.6 68.9 72.7 92.1 94.6 96.4 122 124 131 332 2004 L2 Males 4.86 5.35 5.65 7.15 7.35 7.49 9.51 9.64 10.2 332 2004
L2 Females 68.0 71.5 76.5 109 113 116 161 166 175 300 2004 L2 Females 5.29 5.56 5.95 8.48 8.79 9.02 12.5 12.9 13.6 300 2004
Group GL3 org 68.0 69.1 71.8 96.1 98.5 101 150 159 166 448 2004 Group GL3 org 5.29 5.37 5.58 7.47 7.65 7.84 12.7 12.3 12.9 448 2004
(NACB crit. for TSH) (NACB crit. for TSH)
L3 Males 61.8 68.4 71.8 90.6 93.0 96.3 122 125 144 274 2004 L3 Males 4.80 5.31 5.58 7.04 7.23 7.48 9.51 9.71 11.2 274 2004
L3 Females 63.5 71.4 76.5 107 113 118 161 166 173 174 2004 L3 Females 4.93 5.55 5.95 8.32 8.80 9.19 12.5 12.9 13.4 174 2004
Results from Results from
various locations various locations
Group A (euthyroid) 71.0 162 127 2003 Group A (euthyroid) 5.52 12.6 127 2003

95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
22 T4 25 T4
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
Pregnant Women Pregnant Women
1st Trimester 87.9 94.4 96.4 126 130 132 186 191 210 417 2004 1st Trimester 6.83 7.33 7.49 9.80 10.1 10.3 14.4 14.8 16.3 417 2004
2nd Trimester 96.7 102 106 144 147 151 197 208 228 368 2004 2nd Trimester 7.51 7.93 8.23 11.2 11.4 11.8 15.3 16.1 17.7 368 2004
3rd Trimester 81.4 89.5 104 140 145 149 193 202 279 169 2004 3rd Trimester 6.33 6.95 8.06 10.9 11.3 11.6 15.0 15.7 21.7 169 2004

90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
23 T4 26 T4
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
Group GEL Children, Group GEL Children,
Adolescents Adolescents
0 – 6 Days 45.5 64.9 92.6 128 147 170 176 239 323 93 2007 0 – 6 Days 3.54 5.04 7.19 9.94 11.4 13.2 13.7 18.5 25.1 93 2007
>6 Days ≤3 Months 46.8 69.6 104 117 138 161 156 219 309 99 2007 >6 Days ≤3 Months 3.64 5.41 8.04 9.13 10.7 12.5 12.1 17.0 24.0 99 2007
>3 ≤12 Months 47.6 73.0 112 110 131 155 143 206 299 105 2007 >3 ≤12 Months 3.70 5.67 8.68 8.58 10.2 12.1 11.1 16.0 23.2 105 2007
>1 ≤6 Years 47.7 76.6 123 101 122 148 125 189 287 341 2007 >1 ≤6 Years 3.71 5.95 9.53 7.87 9.50 11.5 9.72 14.7 22.3 341 2007
>6 ≤11 Years 46.2 77.1 129 94.9 116 142 113 178 280 264 2007 >6 ≤11 Years 3.59 5.99 9.97 7.38 9.03 11.1 8.75 13.8 21.8 264 2007
>11 ≤20 Years 44.3 76.1 131 90.8 112 139 104 170 277 470 2007 >11 ≤20 Years 3.45 5.91 10.1 7.06 8.73 10.8 8.10 13.2 21.5 470 2007

28 29
 The data of the different cohorts basically confirm the reference
range stated in the package insert. The reference limits are a bit
Correlation between Elecsys® TSH and Elecsys® T4 results
In figure 12, each graph shows the Elecsys® T4 results for the 5 Results and Discusscion
5.5 Thyroxine-binding capacity –
narrower for Elecsys® T4 which reflects local differences and the subjects of the individual groups GL1, GL2, GL3 and pregnant
influence of the inclusion/exclusion criteria for the selection of the women, respectively, plotted against the Elecsys® TSH results of
cohort. The data in the group from Austria (Group A) correspond the same samples. Samples from male persons are indicated with
to those of the group of blood donors.
A clear dependency on the increased TBG concentration caused
rectangles and from female persons with circles. The dashed lines
correspond to the 2.5 % and 97.5 % quantiles of the valid reference Free T4-Index – FT4I (T4/TBI)
by the intake of contraceptives could be observed. Significantly intervals as listed in the package inserts. The continuous lines
higher Elecsys® T4 results were seen in the group of women taking represent the reference ranges determined in each group which is
contraceptives (GL1 females contraceptives) compared to the also stated in the legends. In these graphs, the dependency of the
group of women not taking contraceptives (GL1 females without reference values on the applied inclusion/exclusion criteria as well
contraceptives). The results from the group of women not taking as changes in the values during pregnancy becomes apparent.
contraceptives approximate to those of the group GL1 males. These results emphasize the importance of applying reference As the major part of the total thyroxine is bound to transport thyroxine index (FT4I) from the ratio of total T4 and TBI (thyroxine-
Pregnant women have higher Elecsys® T4 concentrations ranges adapted to specific cohorts e.g. trimester specific proteins (TBG, prealbumin, and albumin), the determination binding index = result of the T-uptake determination) takes into
correlated with the gestational age. reference ranges for pregnant women. of total thyroxine only provides correct information when the account changes in the thyroid hormone carrier proteins and the
thyroxine-binding capacity in serum is normal. The free thyroid thyroxine level.
hormones are in equilibrium with the hormones bound to the
Group GL1 − all blood donners (n = 869 : 445 females, 424 males) Group GL2 − TSH+Sono NAD (n=643 : 338 females, 305 males) carrier proteins. A change in the TBG concentration can lead The tables 27 to 29 below describe the Elecsys® T-uptake and
to elevated or lowered total T4 concentrations being measured the FT4I reference ranges determined in different studies for:
100 100
although the Free T4 concentration is in the euthyroid range. 1. adults, separated into male and female and age, 2. pregnant
Women Women women, separated into the 3 trimesters and 3. children, separated
The performance of a T-uptake or TBC assay provides a measure by age.
TSH [µIU/mL] bg

TSH [µIU/mL] bg

Men Men
4.2 4.2
of the available thyroxine-binding sites. Determination of the free
1 1

0.1 0.1

0.01 0.01
0 50 100 150 200 250 0 50 100 150 200 250
T4 [nmol/L] T4 [nmol/L]

Group GL3 (TSH NACB) (n=447 : 274 females, 173 males) Pregnant Women (n=957 : 418 1st trim., 369 2nd trim., 170 3rd trim.)

100 100

Women Trimester 1
TSH [µIU/mL] bg

TSH [µIU/mL] bg

Men Trimester 2
4.2 4.2
Trimester 3
1 1

0.1 0.1

0.01 0.01
0 50 100 150 200 250 0 50 100 150 200 250
T4 [nmol/L] T4 [nmol/L]

Figure 12: Correlation between Elecsys® T4 and Elecsys® TSH results.

30 31
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
27 T-uptake 29 T-uptake
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
TBI TBI
Elecsys® T-uptake 0.8 1 1.30 974 1998 Group GEL Children,
– insert Europe/ Adolescents
Japan 0 – 6 Days 0.64 0.81 1.03 0.97 1.02 1.07 1.04 1.20 1.39 60 2007
Elecsys® T-uptake 0.78 1.39 275 1998 >6 Days ≤3 Months 0.62 0.81 1.06 0.95 1.01 1.07 1.02 1.21 1.43 64 2007
– insert USA, 99 %
centr. >3 ≤12 Months 0.61 0.81 1.08 0.94 1.00 1.07 1.01 1.21 1.45 88 2007
Group GL1 0.80 0.81 0.84 0.99 0.99 1.00 1.22 1.23 1.25 870 2004 >1 ≤6 Years 0.59 0.81 1.12 0.93 1.00 1.07 0.99 1.22 1.49 335 2007
(all blood donors) >6 ≤11 Years 0.57 0.81 1.15 0.92 0.99 1.07 0.97 1.22 1.53 253 2007
L1 Males all 0.77 0.80 0.82 0.96 0.96 0.97 1.06 1.08 1.09 445 2004 >11 ≤20 Years 0.56 0.81 1.17 0.92 0.99 1.07 0.96 1.22 1.56 462 2007
L1 Males 20 – 39 y 0.77 0.80 0.83 0.96 0.97 0.97 1.05 1.07 1.09 286 2004
L1 Males 40 – 69 y 0.70 0.85 0.85 0.95 0.97 0.99 1.07 1.09 1.18 150 2004
L1 Females all 0.75 0.85 0.87 1.04 1.05 1.07 1.25 1.26 1.30 425 2004
The data provided from the different groups basically confirm The data provided from the different groups basically confirm the
L1 Females 20 – 39 y 0.75 0.84 0.90 1.06 1.08 1.11 1.25 1.27 1.32 270 2004
the reference interval currently given in the Elecsys® T-Uptake reference intervals calculated for the FT4-index from T4 and TBI
L1 Females 40 – 69 y 0.56 0.84 0.87 0.99 1.01 1.03 1.19 1.22 1.31 128 2004
package insert. (T4/TBI) currently given in the Elecsys® T-Uptake package insert.
L1 Females 0.80 0.94 0.96 1.11 1.12 1.13 1.26 1.27 1.32 236 2004
with contracept.
L1 Females with 0.80 0.94 0.96 1.11 1.12 1.14 1.26 1.27 1.32 181 2004
Looking at the group of women with and without taking Looking at the group of women with and without taking
contracept. 20 – 39 y contraceptives, a dependency on the increased TBG concentration contraceptives, a dependency on the increased TBG concentration
L1 Females with 0.95 0.95 1.00 1.07 1.09 1.13 1.25 1.31 1.31 33 2004 caused by the intake of contraceptives could be observed for caused by the intake of contraceptives could also be observed
contracept. 40 – 69 y T-uptake. for FT4I.
L1 Females 0.56 0.81 0.84 0.98 0.99 1.00 1.13 1.16 1.34 188 2004
w/o contracept The median value of 1.0 TBI which was set arbitrarily for a group As expected FT4-index concentrations are decreasing with
L1 Females w/o 0.73 0.81 0.85 0.98 0.99 1.00 1.12 1.16 1.34 88 2004 of healthy subjects (women without taking contraceptives) was gestational age. The median values in the 1st, 2nd and 3rd trimester
contracept. 20 – 39 y
confirmed in all groups evaluated. show highly significant (p<0.05) differences.
L1 Females w/o 0.56 0.81 0.86 0.96 0.98 1.00 1.11 1.16 1.20 95 2004
contracept. 40 – 69 y
As expected T-uptake concentrations are increasing with
Group GL2 (TSH + 0.77 0.81 0.84 0.99 1.00 1.01 1.23 1.25 1.27 632 2004
SD-Sono NAD) gestational age. The median values in the 1st, 2nd and 3rd
L2 Males 0.76 0.80 0.82 0.96 0.97 0.98 1.06 1.08 1.09 332 2004 trimester differ highly significant (p<0.05) between each other.
L2 Females 0.73 0.86 0.90 1.05 1.07 1.09 1.25 1.27 1.32 300 2004
The table 30 to 35 below describe the FT4I determined from total
Group GL3 org 0.77 0.81 0.83 0.98 0.99 1.00 1.22 1.25 1.27 448 2004
(NACB crit. for TSH) T4 and TBI (thyroxine-binding index = result of the T-uptake
L3 Males 0.70 0.80 0.82 0.96 0.97 0.98 1.07 1.09 1.18 274 2004 determination) in different studies for 1. adults, separated into
L3 Females 0.73 0.84 0.90 1.05 1.08 1.10 1.25 1.27 1.34 174 2004 male and female and age, 2. pregnant women, separated into the
3 trimester and 3. children, separated by age.

95p CI 95p CI 95p CI 95p CI 95p CI 95p CI

low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
28 T-uptake
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
TBI
Pregnant Women
1st Trimester 0.91 0.96 0.98 1.10 1.11 1.12 1.29 1.31 1.35 415 2004
2nd Trimester 1.06 1.17 1.18 1.32 1.33 1.34 1.46 1.48 1.51 369 2004
3rd Trimester 0.84 1.28 1.28 1.39 1.41 1.42 1.50 1.52 1.55 169 2004

32 33
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
30 FT4I (T4/TBI) 33 FT4I (T4/TBI)
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
FT4 Index – Insert 62.0 164 825 1998 FT4 Index – Insert 4.8 12.7 825 1998
Europe/Japan Europe/Japan
FT4 Index – Insert 57.0 147 275 1998 FT4 Index – USA, 4.4 11.4 275 1998
USA, 99 % centr. 99 % centr.
Group GL1 68.6 72.2 74.4 101 102 103 145 147 154 870 2004 Group GL1 5.33 5.61 5.78 7.85 7.94 8.03 11.2 11.5 12.0 870 2004
(all blood donors) (all blood donors)
L1 Males all 67.6 72.2 74.4 97.7 99.4 101 135 138 152 445 2004 L1 Males all 5.25 5.61 5.78 7.59 7.72 7.87 10.5 10.7 11.8 445 2004
L1 Males 20 – 39 y 67.1 73.0 75.8 97.8 98.7 101 132 136 152 286 2004 L1 Males 20 – 39 y 5.21 5.67 5.89 7.52 7.67 7.86 10.3 10.5 11.8 286 2004
L1 Males 40 – 69 y 58.5 68.7 76.1 96.7 101 104 135 145 153 150 2004 L1 Males 40 – 69 y 4.54 5.34 5.91 7.51 7.83 8.08 10.5 11.2 11.9 150 2004
L1 Females all 66.0 72.9 76.3 103 105 107 147 154 176 425 2004 L1 Females all 5.13 5.66 5.93 8.00 8.17 8.30 11.4 12.0 13.7 425 2004
L1 Females 20 – 39 y 70.7 76.4 80.1 103 106 108 146 154 191 270 2004 L1 Females 20 – 39 y 5.49 5.94 6.22 8.03 8.20 8.41 11.4 12.0 14.9 270 2004
L1 Females 40 – 69 y 48.0 66.0 74.3 97.5 101 106 131 142 165 128 2004 L1 Females 40 – 69 y 3.73 5.13 5.77 7.58 7.85 8.25 10.2 11.0 12.8 128 2004
L1 Females L1 Females
71.8 79.7 82.9 107 109 112 148 156 204 236 2004 5.50 6.19 6.44 8.35 8.46 8.70 11.5 12.1 15.8 236 2004
with contracept. with contracept.
L1 Females with L1 Females with
74.6 81.8 83.4 106 109 112 146 154 204 181 2004 5.79 6.36 6.48 8.26 8.46 8.72 11.4 12.0 15.8 181 2004
contracept. 20 – 39 y contracept. 20 – 39 y
L1 Females with L1 Females with
70.8 70.8 79.7 95.1 108 121 137 148 148 33 2004 5.50 5.50 6.19 7.39 8.41 9.37 10.7 11.5 11.5 33 2004
contracept. 40 – 69 y contracept. 40 – 69 y
L1 Females 48.0 66.1 72.9 96.0 98.7 102 134 148 173 188 2004 L1 Females 3.73 5.13 5.66 7.46 7.67 7.91 10.4 11.5 13.5 188 2004
w/o contracept w/o contracept
L1 Females w/o 70.1 72.9 76.8 93.8 98.4 103 125 148 173 88 2004 L1 Females w/o 5.45 5.66 5.96 7.28 7.64 8.00 9.73 11.5 13.5 88 2004
contracept. 20 – 39 y contracept. 20 – 39 y
L1 Females w/o 48.0 60.8 70.9 94.0 98.9 105 125 142 165 95 2004 L1 Females w/o 3.73 4.72 5.51 7.30 7.68 8.16 9.67 11.0 12.8 95 2004
contracept. 40 – 69 y contracept. 40 – 69 y
Group GL2 (TSH + 58.7 72.2 74.6 99.6 102 102 143 147 154 632 2004 Group GL2 (TSH + 5.34 5.61 5.79 7.74 7.89 7.99 11.1 11.4 12.0 632 2004
SD-Sono NAD) SD-Sono NAD)
L2 Males 67.1 71.8 73.8 96.5 98.1 101 134 137 153 332 2004 L2 Males 5.21 5.58 5.74 7.49 7.62 7.84 10.4 10.7 11.9 332 2004
L2 Females 66.0 74.4 76.9 103 105 107 146 150 176 300 2004 L2 Females 5.13 5.78 5.98 7.96 8.11 8.29 11.3 11.6 13.7 300 2004
Group GL3 org 68.0 71.8 73.5 97.7 100 102 137 147 154 448 2004 Group GL3 org 5.25 5.58 5.71 7.59 7.74 7.94 10.7 11.4 12.0 448 2004
(NACB crit. for TSH) (NACB crit. for TSH)
L3 Males 64.0 70.3 73.0 95.5 97.5 100 133 137 161 274 2004 L3 Males 4.98 5.46 5.67 7.42 7.57 7.77 10.4 10.7 12.5 274 2004
L3 Females 60.8 72.9 76.9 100 103 107 146 153 176 174 2004 L3 Females 4.72 5.66 5.98 7.79 8.01 8.29 11.4 11.9 13.7 174 2004

95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
31 FT4I (T4/TBI) 34 FT4I (T4/TBI)
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
Pregnant Women Pregnant Women
1st Trimester 79.6 83.2 85.9 113 116 118 158 166 176 414 2004 1st Trimester 6.18 6.46 6.68 8.78 9.02 9.20 12.3 12.9 13.7 414 2004
2nd Trimester 71.7 75.8 78.5 109 112 115 153 159 184 368 2004 2nd Trimester 5.57 5.89 6.10 8.48 8.71 8.91 11.9 12.4 14.3 368 2004
3rd Trimester 55.4 65.8 69.6 101 103 107 142 160 199 168 2004 3rd Trimester 4.30 5.11 5.41 7.82 7.98 8.31 11.0 12.4 15.5 168 2004

90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI 90p CI
low high low high low high Year low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
32 FT4I (T4/TBI) 35 FT4I (T4/TBI)
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L µg/dL
Group GEL Children, Group GEL Children,
Adolescents Adolescents
0 – 6 Days 43.1 65.3 98.9 119 131 146 178 268 403 53 2007 0 – 6 Days 3.35 5.08 7.69 9.21 10.2 11.3 13.9 20.8 31.3 53 2007
>6 Days ≤3 Months 43.7 70.5 114 113 127 143 145 232 372 55 2007 >6 Days ≤3 Months 3.39 5.48 8.85 8.76 9.87 11.1 11.2 18.0 28.9 55 2007
>3 ≤12 Months 43.8 73.1 122 110 125 142 130 216 357 81 2007 >3 ≤12 Months 3.41 5.68 9.48 8.53 9.70 11.0 10.1 16.8 27.8 81 2007
>1 ≤6 Years 43.3 76.3 134 105 121 139 110 193 337 330 2007 >1 ≤6 Years 3.36 5.93 10.4 8.13 9.37 10.8 8.55 15.0 26.2 330 2007
>6 ≤11 Years 41.8 76.8 141 100 117 136 98.2 179 326 249 2007 >6 ≤11 Years 3.25 5.97 11.0 7.78 9.06 10.5 7.63 13.9 25.4 249 2007
>11 ≤20 Years 40.1 76.1 144 96.5 113 133 90.7 170 320 455 2007 >11 ≤20 Years 3.12 5.91 11.2 7.49 8.79 10.3 7.05 13.2 24.9 455 2007

34 35
5 Results and Discusscion 36 T3
95p CI
low
(2.5 % 2.5 %
95p CI
high
(2.5 %
95p CI
low
(50 % 50 %
95p CI
high
(50 %
95p CI
low
(97.5 % 97.5 %
95p CI
high
(97.5 %
Year
of

5.6 Triiodothyronine – T3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L
Elecsys® T3 – 1.3 3.1 514 1996
package insert
Group GL1 1.17 1.23 1.28 1.75 1.77 1.81 2.70 2.80 2.90 870 2004
(all blood donors)
L1 Males all 1.17 1.28 1.31 1.68 1.72 1.75 2.24 2.29 2.47 445 2004
L1 Males 20 – 39 y 1.24 1.30 1.35 1.65 1.69 1.74 2.20 2.29 2.34 286 2004
L1 Males 40 – 69 y 0.90 1.17 1.31 1.70 1.73 1.81 2.20 2.42 3.36 150 2004
L1 Females all 1.11 1.20 1.26 1.82 1.88 1.94 2.84 2.92 3.44 425 2004
Please see also 5.4 Thyroxine – T4 L1 Females 20 – 39 y 1.08 1.20 1.28 1.90 1.97 2.03 2.81 2.90 3.50 270 2004
L1 Females 40 – 69 y 0.98 1.17 1.28 1.58 1.64 1.76 2.37 2.70 3.26 128 2004
The tables 36 to 41 below describe the Elecsys T3 reference
® L1 Females 1.20 1.33 1.48 2.06 2.12 2.19 2.89 3.26 4.00 236 2004
with contracept.
ranges determined in different studies for: 1. adults, separated
L1 Females with 1.20 1.33 1.48 2.06 2.14 2.20 2.81 2.92 3.96 181 2004
into male and female and age, 2. pregnant women, separated into contracept. 20 – 39 y
the 3 trimesters and 3. children, separated by age. L1 Females with 1.42 1.42 1.55 1.84 1.99 2.21 2.70 3.26 3.26 33 2004
contracept. 40 – 69 y
L1 Females 0.98 1.13 1.19 1.58 1.62 1.66 2.25 2.79 2.92 188 2004
w/o contracept
L1 Females w/o 1.06 1.11 1.24 1.59 1.66 1.73 2.12 2.84 2.92 88 2004
contracept. 20 – 39 y
L1 Females w/o 0.98 1.14 1.23 1.50 1.57 1.64 2.20 2.40 2.77 95 2004
contracept. 40 – 69 y
Group GL2 (TSH + 1.13 1.24 1.28 1.75 1.79 1.83 2.70 2.81 2.99 632 2004
SD-Sono NAD)
L2 Males 1.13 1.28 1.31 1.66 1.72 1.75 2.23 2.29 2.51 332 2004
L2 Females 1.08 1.23 1.28 1.85 1.92 1.99 2.88 2.97 3.50 300 2004
Group GL3 org 1.14 1.26 1.30 1.73 1.77 1.81 2.66 2.75 2.97 448 2004
(NACB crit. for TSH)
L3 Males 0.89 1.28 1.31 1.65 1.70 1.75 2.21 2.29 2.66 274 2004
L3 Females 1.06 1.23 1.30 1.85 1.94 2.01 2.88 2.97 3.96 174 2004
Results from
various locations
Group A (euthyroid) 1.17 1.81 2.73 126 2003
Thailand 1999 0.93 1.59 2.72 967 1999

95p CI 95p CI 95p CI 95p CI 95p CI 95p CI

low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
37 T3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L
Pregnant Women
1st Trimester 1.52 1.61 1.66 2.18 2.24 2.28 3.28 3.53 3.91 415 2004
2nd Trimester 1.83 1.98 2.15 2.77 2.84 2.91 3.79 4.03 4.40 368 2004
3rd Trimester 1.87 2.08 2.21 3.00 3.10 3.18 3.93 4.02 5.01 169 2004

90p CI 90p CI 90p CI 90p CI 90p CI 90p CI

low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
38 T3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
nmol/L
Group GEL Children,
Adolescents
0 – 6 Days 0.92 1.12 1.35 2.05 2.43 2.90 3.32 4.43 5.89 100 2007
>6 Days ≤3 Months 1.00 1.23 1.52 2.09 2.54 3.08 3.07 4.22 5.81 95 2007
>3 ≤12 Months 1.05 1.32 1.66 2.11 2.60 3.20 2.88 4.07 5.74 101 2007
>1 ≤6 Years 1.09 1.42 1.84 2.07 2.61 3.28 2.59 3.80 5.58 342 2007
>6 ≤11 Years 1.07 1.43 1.91 1.94 2.49 3.20 2.34 3.55 5.37 267 2007
>11 ≤20 Years 1.02 1.40 1.92 1.81 2.35 3.05 2.15 3.34 5.18 473 2007

36 37
 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI The data of the different cohorts basically confirm the reference Correlation between Elecsys® TSH and Elecsys® T3 results
low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of range stated in the package insert. The reference limits are a bit In figure 13, each graph shows the Elecsys® T3 results for the
39 T3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ. narrower for T3 which reflects local differences and the influence subjects of the individual groups GL1, GL2, GL3 and pregnant
ng/mL of the inclusion/exclusion criteria for the selection of the cohort. women, respectively, plotted against the Elecsys® TSH results of
Elecsys® T3 – 0.8 2.0 514 1996 the same samples. Samples from male persons are indicated with
package insert The cohort from Thailand shows a clear decrease of values for the rectangles and from female persons with circles. The dashed lines
Group GL1 0.76 0.8 0.83 1.14 1.15 1.18 1.76 1.82 1.89 870 2004 lower reference range (2.5 % quantile) and the median. correspond to the 2.5 % and 97.5 % quantiles of the valid reference
(all blood donors)
intervals as listed in the package inserts. The continuous lines
L1 Males all 0.76 0.83 0.85 1.09 1.12 1.14 1.46 1.49 1.61 445 2004
A dependency on the increased TBG concentration caused by represent the reference ranges determined in each group which is
L1 Males 20 – 39 y 0.81 0.85 0.88 1.07 1.10 1.13 1.43 1.49 1.52 286 2004 the intake of contraceptives could be observed. Significantly also stated in the legends. In these graphs, the dependency of the
L1 Males 40 – 69 y 0.59 0.76 0.85 1.11 1.13 1.18 1.43 1.58 2.19 150 2004 higher Elecsys® T3 results were seen in the group of women reference values on the applied inclusion/exclusion criteria as well
L1 Females all 0.72 0.78 0.82 1.18 1.22 1.26 1.85 1.90 2.24 425 2004 taking contraceptives (GL1 females contraceptives) compared as changes in the values during pregnancy becomes apparent.
L1 Females 20 – 39 y 0.70 0.78 0.83 1.24 1.28 1.32 1.83 1.89 2.28 270 2004 to the group of women not taking contraceptives (GL1 without These results emphasize the importance of applying reference
L1 Females 40 – 69 y 0.64 0.76 0.83 1.03 1.07 1.15 1.54 1.76 2.12 128 2004 contraceptives). The results from the group of women not taking ranges adapted to specific cohorts e.g. trimester specific
L1 Females 0.78 0.87 0.96 1.34 1.38 1.43 1.88 2.12 2.60 236 2004 contraceptives approximate to those of the group GL1 males. reference ranges for pregnant women.
with contracept.
Pregnant women have higher Elecsys® T3 concentrations
L1 Females with 0.78 0.87 0.96 1.34 1.39 1.43 1.83 1.90 2.58 181 2004
contracept. 20 – 39 y correlated with the gestational age.
L1 Females with 0.92 0.92 1.01 1.20 1.30 1.44 1.76 2.12 2.12 33 2004
contracept. 40 – 69 y
Group GL1 − all blood donners (n = 869 : 445 females, 424 males) Group GL2 − TSH+Sono NAD (n=643 : 338 females, 305 males)
L1 Females 0.64 0.74 0.77 1.03 1.05 1.08 1.46 1.82 1.90 188 2004
w/o contracept 100 100
L1 Females w/o 0.69 0.72 0.81 1.04 1.08 1.13 1.38 1.85 1.90 88 2004
contracept. 20 – 39 y Women Women

TSH [µIU/mL] bg

TSH [µIU/mL] bg
L1 Females w/o 0.64 0.74 0.80 0.98 1.02 1.07 1.43 1.56 1.80 95 2004 Men Men
4.2 4.2
contracept. 40 – 69 y
Group GL2 (TSH + 0.74 0.81 0.83 1.14 1.17 1.19 1.76 1.83 1.95 632 2004 1 1
SD-Sono NAD)
L2 Males 0.74 0.83 0.85 1.08 1.12 1.14 1.45 1.49 1.63 332 2004
0.1 0.1
L2 Females 0.70 0.80 0.83 1.20 1.25 1.30 1.87 1.93 2.28 300 2004
Group GL3 org 0.74 0.82 0.85 1.13 1.15 1.18 1.73 1.79 1.93 448 2004
(NACB crit. for TSH) 0.01 0.01
L3 Males 0.58 0.83 0.85 1.07 1.11 1.14 1.44 1.49 1.73 274 2004 0 1 2 3 4 5 0 1 2 3 4 5
T3 [nmol/L] T3 [nmol/L]
L3 Females 0.69 0.80 0.85 1.20 1.26 1.31 1.87 1.93 2.58 174 2004
Results from
Group GL3 (TSH NACB) (n=447 : 274 females, 173 males) Pregnant Women (n=957 : 418 1st trim., 369 2nd trim., 170 3rd trim.)
various locations
Group A (euthyroid) 0.76 1.18 1.78 126 2003 100 100
Thailand 1999 0.61 1.04 1.77 967 1999
Women Trimester 1

TSH [µIU/mL] bg

TSH [µIU/mL] bg
95p CI 95p CI 95p CI 95p CI 95p CI 95p CI Men Trimester 2
4.2 4.2
low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of Trimester 3
40 T3 1 1
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
ng/mL
0.1 0.1
Pregnant Women
1 Trimester
st
0.99 1.05 1.08 1.42 1.46 1.48 2.14 2.30 2.55 415 2004
2nd Trimester 1.19 1.29 1.40 1.80 1.85 1.89 2.47 2.62 2.86 368 2004 0.01 0.01
3rd Trimester 1.22 1.35 1.44 1.95 2.02 2.07 2.56 2.62 3.26 169 2004 0 1 2 3 4 5 0 1 2 3 4 5
T3 [nmol/L] T3 [nmol/L]
90p CI 90p CI 90p CI 90p CI 90p CI 90p CI Figure 13: Correlation between Elecsys® T3 and Elecsys® TSH results.
low high low high low high Year
(2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
41 T3
  quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
ng/mL
Group GEL Children,
Adolescents
0 – 6 Days 0.60 0.73 0.88 1.33 1.59 1.89 2.16 2.88 3.84 100 2007
>6 Days ≤3 Months 0.65 0.80 0.99 1.36 1.65 2.00 2.00 2.75 3.78 95 2007
>3 ≤12 Months 0.68 0.86 1.08 1.37 1.69 2.09 1.88 2.65 3.74 101 2007
>1 ≤6 Years 0.71 0.92 1.20 1.35 1.70 2.14 1.69 2.48 3.63 342 2007
>6 ≤11 Years 0.69 0.93 1.25 1.27 1.62 2.08 1.53 2.31 3.50 267 2007
>11 ≤20 Years 0.66 0.91 1.25 1.18 1.53 1.99 1.40 2.18 3.37 473 2007

38 39
5 Results and Discusscion 5 Results and Discusscion
5.7 Antibodies to TSH receptor – Anti-TSHR 5.8 Antibodies to thyroid peroxidase – Anti-TPO

Hyperthyroidism in Graves’ disease (autoimmune hyperthyroidism) toxic nodular goiter.20,21 Because the aim of treatment for Elevated serum titers of antibodies to TPO are found in several The determination of Elecsys® Anti-TPO together with Elecsys®
is typically caused by autoantibodies to the thyroid stimulating Graves’ disease may differ from the treatment of other forms of forms of thyroiditis caused by autoimmunity.31,32 TSH is recommended:
hormone receptor (TSHR), and measurement of these TSHR thyrotoxicosis, an initial TRAb determination is clearly of value. •• for the detection of suspected dysfunction, especially regarding
antibodies (TRAb) can be useful in disease diagnosis and •• monitoring the therapy of Graves’ disease patients and High Anti-TPO titers are found in up to 90 % of patients with the long-term risk of the development of a thyroid disease
management.3,12,15-17 prediction of relapse, thereby constituting an important chronic Hashimoto’s thyroiditis. In Graves’ disease, 70 % of the •• during and after pregnancy
decision-making aid in treatment management. TRAb levels patients have an elevated titer.32-34 Although the sensitivity of •• to clarify subclinical hypothyroidism
TRAb can be classified as stimulating, blocking or neutral tend to fall during antithyroid drug therapy for Graves’ disease. the diagnostic procedure can be increased by simultaneously
depending on their mechanism of action. Despite having actions Low levels or the absence of TRAb after a course of drug determining other thyroid antibodies (Elecsys® Anti-Tg, Elecsys® The tables 44 to 47 below describe the Elecsys® Anti-TPO
similar to TSH, TSHR stimulating antibodies are not subject to treatment may indicate disease remission, and therefore the Anti-TSHR), a negative finding does not rule out the possibility reference ranges determined in different studies for: 1. adults,
the negative feedback mechanisms associated with TSH, leading withdrawal of therapy can be considered.22-24 of an autoimmune disease. The magnitude of the antibody titer separated into male and female and age, 2. pregnant women,
to prolonged activation of the TSHR. This results in the elevated •• TRAb measurement during the last trimester of pregnancy. does not correlate with the clinical activity of the disease.33-35 separated into the 3 trimesters and 3. children, separated by
thyroid hormone levels and clinical thyrotoxic state associated Because TRAb are IgG‑class antibodies, they cross the Initially elevated titers can become negative after lengthy periods age. For children two separated tables have been created as the
with Graves’ disease.18,19 placenta and can cause neonatal thyroid disease. The of illness or during remission. If antibodies reappear following number of children in the GEL group has been too low to compute
measurement of TRAb during pregnancy in patients with a remission, then a relapse is probable.54 the confidence interval with 95 % confidence level. The applied
Indications for TRAb determination include: history of thyroid disease is therefore important in assessing confidence level was set to 90 %. For all other groups confidence
•• the detection or exclusion of autoimmune hyperthyroidism the risk of thyroid disease in the neonate.25,26 levels have been set to 95 %.
and its differentiation from disseminated autonomy of the
thyroid gland. The presence of TRAb indicates that the patient’s The tables 42 and 43 below describe the Elecsys® Anti-TSHR
thyrotoxicosis is of autoimmune etiology rather than due to results determined for the LIFE adult and child group.

95p CI 95p CI 95p CI 95p CI high Year 95p CI 95p CI 95p CI 95p CI Year
low (50 % 50 % high (50 % low (97.5 % 97.5 % (97.5 % of low (50 % 50 % high (50 % low (95 % 95 % high (95 % of
42 Anti-TSHR 44 Anti-TPO
  quant.) quant. quant.) quant.) quant. quant.) N publ.   quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/L IU/mL
Elecsys ® Anti-TSHR package 1.22 436 2013 Elecsys ® Anti-TPO package 34.00 208 2000
insert insert
LIFE Adults 0.90 0.90 0.90 1.30 1.36 1.44 4,314 2013 Group GL1 (all blood donors) 13.7 14.1 14.7 92.5 186 287 870 2004
all male patients (sd healthy) 0.90 0.90 0.90 1.33 1.40 1.51 2,572 2013 L1 Males all 13.0 13.5 14.1 32.9 37.1 63.4 445 2004
male <40 years 0.90 0.90 0.90 1.06 1.10 1.83 125 2013 L1 Females all 14.3 14.9 15.7 227 312 422 425 2004
male ≥40 and <70 years 0.90 0.90 0.90 1.33 1.40 1.51 1,889 2013 Group GL2 (TSH + SD-Sono 13.3 14.0 14.6 62.3 167 297 632 2004
male ≥70 years 0.90 0.90 0.90 1.27 1.48 1.71 558 2013 NAD)
all female patients (sd healthy) 0.90 0.90 0.90 1.18 1.26 1.38 1,742 2013 L2 Males 12.8 13.4 14.1 31.7 37.0 63.4 332 2004
female <40 years 0.90 0.90 0.90 0.95 1.07 1.84 118 2013 L2 Females 13.7 14.7 15.4 194 308 426 300 2004
female ≥40 and <70 years 0.90 0.90 0.90 1.15 1.21 1.33 1,308 2013 Group GL5 (NACB crit. for a-TPO) 11.5 12.6 14.5 23.8 28.2 32.7 80 2004
female ≥70 years 0.90 0.90 0.90 1.30 1.51 2.69 316 2013 90 % cent.
LIFE Adults 10.3 10.5 10.7 76.0 85.8 97.7 6,080 2013
95p CI 95p CI 95p CI 95p CI high Year all male patients (sd healthy) 10.0 10.2 10.5 42.2 48.1 62.6 3,418 2013
low (50 % 50 % high (50 % low (97.5 % 97.5 % (97.5 % of
43 Anti-TSHR male <40 years 8.60 9.45 10.2 29.7 93.1 388 168 2013
  quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/L male ≥40 and <70 years 10.30 10.50 10.7 43.9 52.4 68.9 2,515 2013
LIFE Child male ≥70 years 9.00 9.50 9.98 30.3 38.4 46.9 735 2013
>3 ≤12 Months <0.3 <0.3 <0.3 <0.3 0.94 1.00 19 2016 all female patients (sd healthy) 10.6 10.9 11.2 111 137 173 2,662 2013
>1 ≤6 Years <0.3 <0.3 <0.3 <0.3 0.97 1.07 143 2016 female <40 years 9.30 10.4 11.6 89.4 304 384 173 2013
>6 ≤11 Years <0.3 <0.3 <0.3 0.92 1.02 1.14 170 2016 female ≥40 and <70 years 10.9 11.2 11.6 115 146 187 2,044 2013
>11 ≤20 Years <0.3 <0.3 <0.3 0.98 1.05 1.25 145 2016 female ≥70 years 9.10 9.60 10.10 54.9 78.7 125 445 2013

The upper limits of Elecsys® Anti-TSHR for the cohort of healthy in the study described in the package insert by calculating
individuals described in the Elecsys® Anti-TSHR package insert is the receiver operating characteristic (ROC) curve. The results
1.22 IU/L (97.5th percentile). The optimal cutoff of 1.75 IU/L with a generated in both studies are comparable and did not reveal
sensitivity of 96 % and a specificity of 99 % has been determined impact of age and gender.

40 41
 45 Anti-TPO
 
95p CI
low (50 %
quant.)
50 %
quant.
95p CI
high (50 %
quant.)
95p CI
low (95 %
quant.)
95 %
quant.
95p CI
high (95 %
quant.) N
Year
of
publ.
5 Results and Discusscion
Pregnant Women
IU/mL
5.9 Antibodies to thyroglobulin – Anti-Tg
1 Trimester
st
10.8 11.3 11.8 47.0 64.4 119 410 2004
2nd Trimester 9.98 10.5 11.4 30.1 50.8 101 362 2004
3rd Trimester 12.4 13.3 14.6 40.0 123 171 165 2004

90p CI 90p CI 90p CI 90p CI high Year

low (50 % 50 % high (50 % low (97.5 % 97.5 % (97.5 % of
46 Anti-TPO
  quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/mL
The Elecsys® Anti-Tg assay is used in monitoring the course of This includes cases of suspected autoimmune thyroiditis of
Group GEL Children, Adolescents
Hashimoto’s thyroiditis and for the differential diagnosis: unknown origin with negative Anti‑TPO test results34,42 and to
0 – 6 Days <5.0 <5.0 5.1 28 117 269 54 2007
•• cases of suspected autoimmune thyroiditis of unknown origin distinguish Hashimoto’s thyroiditis from nontoxic nodular goiter or
>6 Days ≤3 Months <5.0 5.9 8.0 29 47 158 57 2007
with negative Anti-TPO test results from other forms of thyroiditis.39
>3 ≤12 Months <5.0 5.1 5.6 29 32 52 72 2007
•• Graves’ disease without lymphocytic infiltration
>1 ≤6 Years <5.0 <5.0 <5.0 13 13 16 327 2007 •• to rule out interference by Tg-autoantibodies in the Tg test Anti‑Tg has also been reported as a useful surrogate diagnostic
>6 ≤11 Years 7.4 8.1 8.8 17 18 26 247 2007 marker for differentiated thyroid cancer when serum Tg is
>11 ≤20 Years 6.9 7.4 8.1 20 26 36 457 2007 Elevated serum concentrations of antibodies against Tg are negative43 and for ruling out interference by Tg autoantibodies
found in subjects with autoimmunity-based thyroiditis.37,38 High when measuring serum Tg using a Tg test.45,56
95p CI 95p CI 95p CI 95p CI Year concentrations of Anti‑Tg together with Anti‑TPO are present
low (50 % 50 % high (50 % low (95 % 95 % high (95 % of
47 Anti-TPO in most patients with chronic lymphocytic-infiltrative thyroiditis The tables 48 to 51 below describe the Elecsys® Anti-Tg reference
  quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/mL
(Hashimoto’s disease).38 The frequency of thyroglobulin antibodies ranges determined in different studies for: 1. adults, separated into
is approximately 50 – 80 % in subjects with autoimmune-thyroiditis, male and female and age, 2. pregnant women, separated into the
LIFE Child 6.05 11.67
including Hashimoto’s disease, and approximately 30 – 50 % in 3 trimesters and 3. children, separated by age. For children two
>3 ≤12 Months 5.69 8.79 6.87 11.4 12.4 14.5 83 2016
individuals with Graves’ disease.38-41 The Anti‑Tg assay can also separated tables have been created as the number of children in
>1 ≤6 Years 8.05 8.65 9.60 16.3 18.1 20.9 190 2016
provide useful information for: the GEL group has been too low to compute the confidence interval
>6 ≤11 Years 8.01 8.72 9.20 17.3 19.8 24.3 257 2016
•• monitoring the course of Hashimoto’s thyroiditis with 95 % confidence level. The applied confidence level was set to
>11 ≤20 Years 8.22 8.22 9.70 16.7 26.5 58.6 216 2016 •• differential diagnosis 90 %. For all other groups confidence levels have been set to 95 %.

The selection of inclusion and exclusion criteria clearly influences The cutoff published by EQALIS is the lowest with a 95 % quantile 95p CI 95p CI 95p CI 95p CI Year
low (50 % 50 % high (50 % low (94 % 94 % high (94 % of
the cutoff levels. The non-selected group of blood donors limit of 19 IU/mL. 48 Anti-Tg
  quant.) quant. quant.) quant.) quant. quant.) N publ.
(GL1), group GL2 and LIFE adult show significant higher values. IU/mL
These results are caused by the group of women, who showed In pregnant women the Elecsys® Anti-TPO concentrations
Elecsys ® Anti-Tg package insert 115 392 2001
essentially higher values. are slightly higher in the 3rd trimester. There is no significant
Group GL1 (all blood donors) 17.2 17.6 18.2 313 400 455 870 2004
difference between the three trimesters.
L1 Males all 16.2 16.7 17.3 36.6 67.3 188 445 2004
The group GL5 selected according to the NACB criteria for
L1 Females all 18.1 18.9 20.3 443 492 623 425 2004
the reference interval determination of Elecsys® Anti-TPO and
Elecsys® Anti-Tg (e.g. only males <30 years) show with 28.1 IU/ Group GL2 (TSH + SD-Sono 16.4 16.9 17.6 218 350 415 632 2004
NAD)
mL a lower cutoff as compared to that of Elecsys® Anti-TPO. The
L2 Males 15.7 16.3 16.9 33.7 72.0 248 332 2004
cutoff of 34 IU/mL currently stated in the package insert (mat.
L2 Females 17.2 18.2 19.2 402 436 531 300 2004
No.: 06368590 190 V4.0 and 07026935 190 v1.0 status June 2018)
Group GL5 (NACB crit. for a-TPO) 18.6 23.7 25.0 25.0 33.5 98.1 80 2004
is close to the upper limit of the 95 % confidence interval of 32.68
90 % cent.
IU/mL in the GL5 cohort.
LIFE Adults 17.6 17.8 18.0 172 200 245 5,047 2013
all male patients (sd healthy) 16.7 17.0 17.3 57.5 66.7 87.7 2,863 2013
male <40 years 17.8 19.6 21.4 76.8 175 388 145 2013
male ≥40 and <70 years 16.9 17.2 17.6 57.7 70.1 106 2,110 2013
male ≥70 years 15.3 15.9 16.3 29.4 38.0 63.7 608 2013
all female patients (sd healthy) 18.7 19.1 19.5 331 385 412 2,184 2013
female <40 years 18.0 19.8 21.4 221 369 555 139 2013
female ≥40 and <70 years 19.0 19.5 20.0 340 397 422 1,667 2013
female ≥70 years 16.6 17.5 18.0 141 273 415 378 2013

42 43
 49 Anti-Tg
 
95p CI
low (50 %
quant.)
50 %
quant.
95p CI
high (50 %
quant.)
95p CI
low (94 %
quant.)
94 %
quant.
95p CI
high (94 %
quant.) N
Year
of
publ.
5 Results and Discusscion
Pregnant Women
IU/mL
5.10 Thyroglobulin – Tg
1 Trimester
st
18.1 18.7 19.8 333 398 511 418 2004
2nd Trimester 16.0 16.5 17.4 85.2 139 195 369 2004
3rd Trimester 17.0 17.4 17.9 37.2 62.1 370 170 2004

90p CI 90p CI 90p CI 90p CI high Year

low (50 % 50 % high (50 % low (97.5 % 97.5 % (97.5 % of
50 Anti-Tg
  quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/mL
Synthesis of T3 and T4 from Thyroglobulin (Tg) is regulated by The main application of Tg testing is the post-operative follow-up
Group GEL Children, Adolescents
TSH, intrathyroidal iodine levels and the presence of thyroid- of patients with differentiated thyroid carcinoma (DTC). A global
0 – 6 Days <10.0 13 24.6 97.6 134 295 57 2007
stimulating immunoglobulins. During synthesis of Tg by the rise in the prevalence of DTC has resulted in higher numbers of
>6 Days ≤3 Months 14.6 23 33.3 125 146 182 83 2007
thyrocytes and the transport of Tg to the follicles, small quantities thyroidectomized patients who require lifelong monitoring for
>3 ≤12 Months <10.0 13 17.0 103 130 180 91 2007
of the protein can pass into the bloodstream. Accordingly, persistent or recurrent disease.48,49 As the thyroid gland is the only
>1 ≤6 Years 11.8 13 12.9 27.0 38 57.1 337 2007 low concentrations of Tg can be found in the blood of healthy known source of Tg, the serum Tg level will drop to a very low or
>6 ≤11 Years 12.3 13 13.7 29.7 37 77.1 253 2007 individuals not suffering from thyroid diseases.46 undetectable concentration after total or near-total thyroidectomy
>11 ≤20 Years 13.4 14 14.6 37.8 64 191 463 2007 and successful radioiodine ablation of the residual thyroid
Elevated Tg concentrations have been reported in many tissue. Detectable levels of serum Tg after total thyroidectomy
95p CI 95p CI 95p CI 95p CI Year different thyroid conditions such as Hashimoto’s disease, are indicative of persistent or recurrent DTC. As a consequence
low (50 % 50 % high (50 % low (94 % 94 % high (94 % of
51 Anti-Tg Graves’ disease, thyroid adenoma, and thyroid carcinoma. The significantly increasing Tg levels are interpreted as a sign of
  quant.) quant. quant.) quant.) quant. quant.) N publ.
IU/mL
determination of Tg can also be helpful to distinguish between recurrence of the disease.50-56 In patients who have undergone a
subacute thyroiditis and factitious thyrotoxicosis. In cases of partial thyroidectomy Tg levels will still be measurable depending
LIFE Child
congenital hypothyroidism the determination of Tg can be used to on how much tissue is remaining after surgery.
>3 ≤12 Months 12.8 14.1 15.7 19.4 21.9 26.2 22.0 2016
differentiate between the complete absence of the thyroid gland
>1 ≤6 Years 15.3 16.1 17.7 24.4 27.3 30.0 160 2016
and thyroid hypoplasia or other pathological conditions.13,47,48 The table 52 below describes the Elecsys® Tg results determined
>6 ≤11 Years 15.6 16.3 17.3 25.2 29.7 45.9 197 2016
in the MCE study.
>11 ≤20 Years 15.2 16.5 17.6 33.3 71.7 104 170 2016

The non-selected group of blood donors, GL1, the group GL2 and In pregnant women the Elecsys® Anti-Tg concentrations are 95p CI 95p CI 95p CI 95p CI 95p CI 95p CI
low high low high low high Year
the group LIFE adult show significant higher values compared significantly higher in the 1st trimester as compared to the 2nd (2.5 % 2.5 % (2.5 % (50 % 50 % (50 % (97.5 % 97.5 % (97.5 % of
52 Tg
to GL5. These results are caused by the group of women, which and 3rd trimester. The results for the 2nd and the 3rd trimester are   quant.) quant. quant.) quant.) quant. quant.) quant.) quant. quant.) N publ.
showed essentially higher values compared to the group of males. nearly identical. ng/mL
Elecsys ® Tg 3.5 77 478 2012
Group GL5 was selected according to the NACB criteria for package insert
the reference interval determination of Elecsys® Anti-TPO and
Elecsys® Anti-Tg (e.g. only males <30 years). GL5 shows for
Elecsys® Anti-Tg with 33 IU/mL clearly a lower cutoff as compared
to that of Elecsys® Anti-Tg package insert (115 IU/mL). This cutoff
is still not covered by the upper limit of the 95 % quantile in the
group GL5 (98 IU/mL). This finding reflects the influence of cohort
selection.

44 45
5 Results and Discusscion
5.11 Calcitonin – hCT

Calcitonin is metabolized in the liver and kidney and regulated by with thyroid nodules.61 Moderately elevated calcitonin levels can The table 54 below describes the hCT results determined for
serum calcium levels. Physiologically hCT has effects on calcium be falsely positive for either technical reasons or the presence children in the LIFE child study.
and phosphorus metabolism. It is an inhibitor of bone resorption of other rare pathological conditions (i.e. other neuroendocrine
to prevent bone loss at times of calcium stress (e.g. pregnancy, tumors, hyperparathyroidism, renal failure etc.). Therefore, the 95p CI 95p CI 95p CI 95p CI high Year
low (50 % 50 % high (50 % low (97.5 % 97.5 % (97.5 % of
lactation and growth).57,58 European Panel of Experts recommends that subjects with 54 hCT
  quant.) quant. quant.) quant.) quant. quant.) N publ.
elevated basal calcitonin undergo a stimulation test, either by pg/mL
The most prominent clinical syndrome associated with a injection of pentagastrin or a rapid infusion of calcium. Most
LIFE Child female
disordered hypersecretion of hCT is the medullary thyroid MTCs respond with a significant increase of hCT levels upon
>3 ≤12 Months 7.07 10.7 13.9 20.6 26.3 27.8 23 2016
carcinoma (MTC), a tumor of the calcitonin secreting cells of the stimulation.62,63
>1 ≤6 Years 2.55 3.07 3.98 7.08 8.68 11.0 70 2016
thyroid, which comprises 5 – 10 % of all thyroid cancers. 75 – 80 %
>6 ≤11 Years 1.97 2.29 2.66 5.84 7.42 8.12 97 2016
of cases occur sporadically and the remainder as an autosomal The table 53 below describes the hCT results determined in the
dominant trait. MTC Management Guidelines were developed MCE study for Calcitonin. >11 ≤20 Years 0.99 2.01 3.96 6.53 70 2016
by the American Thyroid Association and recommend calcitonin LIFE Child male
measurements in the risk stratification / selection of treatment The serum Elecsys® hCT levels for adult men are significantly >3 ≤12 Months 8.65 10.6 14.0 51.5 26.6 28.4 37 2016
in inherited MTC and in the evaluation and treatment post higher compared to adult women whereas smoking may lead to >1 ≤6 Years 3.33 4.12 5.54 8.59 13.0 22.7 76 2016
thyroidectomy.59,60 These recommendations were endorsed by the an additional increase in serum calcitonin levels. These finding >6 ≤11 Years 3.31 4.01 4.71 7.38 9.81 12.1 101 2016
European Thyroid Association and extended by an European Panel correlate with the literature.64-66 >11 ≤20 Years 0.67 1.12 2.06 2.14 4.11 5.45 76 2016
of Experts to routine measurement of serum calcitonin in patients

95p CI 95p CI 95p CI 95p CI high Year Elecsys® hCT results for LIFE child female and male do not show
low (95 % 95 % high (95 % low (97.5 % 97.5 % (97.5 % of
53 hCT significant differences from each other. In general, the Elecsys®
  quant.) quant. quant.) quant.) quant. quant.) N publ.
pg/mL
hCT levels are relatively high in infants, decline rapidly and are
relatively stable from childhood (about the age of 11) through
Elecsys ® hCT package insert 5.17 6.40 9.82 193 2013
female adult life.
female smoker 5.91 6.81 7.49 5.91 7.49 7.49 27 2013
female non-smoker 3.16 3.84 6.37 3.58 4.30 6.75 142 2013
Elecsys ® hCT package insert 8.31 9.52 14.3 162 2013
male
male smoker 8.31 8.47 10.9 8.31 10.9 10.9 29 2013
male non-smoker 6.73 7.72 14.3 7.22 9.52 14.32 102 2013

46 47
 6 Concentrations of Elecsys® TSH, Elecsys® FT4
and Elecsys® FT3 in the serum of euthyroid
inpatients and outpatients

A key issue for clinicians is the extent to which they General determinants 2. Serum Elecsys® FT4 determinants •• HD
can reliably apply the algorithms of thyroid laboratory Factors that lower TSH levels comprise acute illness (infection The group distribution of Elecsys® FT4 concentrations (Figure 15) Individual drugs can affect thyroid hormone concentrations
diagnostics to inpatients and outpatients with a broad etc), severe (preterminal) disease progression (like sepsis), shows a clear decrease in ICU patients, but also a trend towards in these polymedicated patients. Thus beta-blockers such as
spectrum of nonendocrine disease. The aim of this article surgery, fasting, and smoking. Other factors are mainly lower values in RF patients compared to the HD, DM, and RD propranolol, that decrease the peripheral conversion of T4 to
is to identify the laboratory diagnostic characteristics that pharmacologic: dopamine, heparin, calcium channel blockers, and groups. T3, may account for the higher FT4 levels in some patients in
need to be taken into account when excluding thyroid nonsteroidal antiinflammatory drugs (NSAIDs). this group.
dysfunction in intensive care unit (ICU) patients and in

30
patients with heart disease (HD), rheumatic disease (RD), Cirrhosis of the liver and hypercholesterolemia can increase TSH •• RF

FT4 [pmol/L]
type 2 diabetes mellitus (DM), and renal failure (RF). values, as can stress and the menopause. Drugs with a similar Chronic RF decreases FT3 and FT4 concentrations, accounting

20
We present and compare the general and group-specific effect include lithium, beta-blockers, and opioids. for the trend towards lower levels in this group. An increase in

10
determinants of serum thyroid-stimulating hormone FT4 is observed after hemodialysis, which may be associated
(TSH), free thyroxine (FT4) and free triidiothyronine (FT3) Group-specific determinants with heparin administration.

5
0
concentrations observed in a Leipzig University Hospital •• ICU
ICU HD RD DM RF
study in 120 patients selected per specified disease and Euthyroid sick syndrome (abnormal thyroid function results 3. Serum Elecsys® FT3 determinants
also as recorded in the literature. in a nonthyroid illness setting) is common in ICU patients. The group distribution of FT3 concentrations (Figure 16) shows
Figure 15: Boxplots showing Elecsys® FT4 results in different patient groups.
Lifethreatening illness is associated with central down- a clear decrease in ICU patients.
1. Serum Elecsys® TSH determinants regulation of TSH with a simultaneous decrease in FT3 and, In all groups, the expected number of data points for a more or
The group distribution of TSH concentrations (Figure 14) shows above all in the final stages, in FT4. less relevant number of Elecsys® FT4 results exceeded the 97.5 %

10
clearly lower values in ICU and RD patients than quantile in blood donors, namely 22 pmol/L. The increase was

FT3 [pmol/L]

8
in the other groups. •• RD seen mainly in the ICU, HD, and KI groups. In addition, values

6
Glucocorticoids and NSAIDs lower basal TSH levels, no doubt varied widely in ICU and RF patients. Possible determinants of FT4
7

4
accounting for the tendency towards lower values in this group. values in the individual groups include:
6

2
5
TSH [µlU/mL]

0
•• DM General determinants
4

ICU HD RD DM RF
TSH levels were little changed. Relatively high levels, Diseases associated with increased FT4 levels comprise anorexia
3

Figure 16: Boxplots showing Elecsys FT3 results in different patient groups.
®
2

approaching 5 mU/L, can be found in individual patients, nervosa, decompensated cirrhosis of the liver, and acute
1

possibly associated with hypercholesterolemia. psychiatric illness. Drugs with a similar effect include beta- Values also tended to be lower in the RF group than in patients
0

ICU HD RD DM RF blockers, heparin, aspirin/NSAIDs, and also furosemide, which with HD, RD, or DM. Individual HD sera showed a tendency
•• RF blocks the binding of T4 to plasma proteins. towards decreased concentrations. Possible determinants of FT3
Figure 14: Boxplots showing Elecsys TSH results in different patient groups.
®
The effect of dialysis on TSH is disputed, but levels may values in the individual groups include:
increase in some cases. Decreased serum FT4 values have been observed in response
Median concentrations differed only slightly in the HD, DM, and to drugs such as fenclofenac, furosemide, lithium, propranolol, General determinants
RF groups. Possible determinants of Elecsys® TSH concentrations phenobarbital, phenylbutazone, and phenytoin. Factors lowering FT3 concentrations comprise acute illness (like
in the individual groups include: infection), severe (preterminal) disease progression (like sepsis),
Group-specific determinants advancing age, chronic RF, and surgery. Drugs with a similar effect
•• ICU include glucocorticoids and beta-blockers.
Euthyroid sick syndrome is a common cause of low FT4 levels
in patients with life-threatening or critical illness. Central Aspirin/NSAIDs increase FT3 by displacing the hormone from its
downregulation of TSH leads to a decrease in FT3 and, above binding to plasma proteins. Posttraumatic stress may also increase
all in the final stages, in FT4. FT3 levels.

48 49
 7 Conclusion

Group-specific determinants 1 In most critically ill patients, e.g. after major surgery or with This brochure provides a rather complete survey of results on In 2007, a new study in Leipzig, Germany, was performed to
•• ICU severe infection, TSH and FT3 levels were decreased, as also the reference intervals of the Elecsys® thyroid parameters. update and complete the children reference range values. The
Euthyroid sick syndrome is a common cause of low FT3 levels were FT4 levels in the more serious cases (euthyroid sick The data evaluated embrace the time-span from launch of brochure has been updated accordingly.
in patients with life-threatening or critical illness. Central syndrome). the Elecsys® systems in 1996 until 2016.
downregulation of TSH leads to a decrease in FT3 and, above 2 In HD patients TSH and FT4 concentrations were normal, with In the group of in- and outpatients described in chapter 6,
all in the final stages, in FT4. FT3 tending to be lower in individual cases, presumably because This is an overview on the performed studies: the influence of non-thyroidal disease and drugs has been
drug-induced (beta-blockers). •• 1996: Elecsys® TSH, Elecsys® T3 investigated also reflecting that certain conditions may have an
•• HD 3 In RD patients, standard synthetic glucocorticoid and NSAID •• 1998: Elecsys® FT4, Elecsys® T4, Elecsys® Tuptake impact on the TSH, FT4 and FT3 results.
Individual drugs can affect thyroid hormone concentrations therapy no doubt accounted for the decreased serum TSH •• 2000/2001: Elecsys® Anti-Tg, Elecsys® Anti-TPO
in these polymedicated patients. Thus beta-blockers such as concentrations in some cases. •• 2003: Elecsys® FT3 In 2016, new reference range studies for most of the Elecsys®
propranolol, that decrease the peripheral conversion of T4 to 4 In DM patients, almost all thyroid hormone parameters were •• 2003: additional reference ranges for adults, children and thyroid parameters have been initiated in the context of the LIFE
T3, may account for the lower FT3 levels in some patients in in the reference range. Hypercholesterolemia may explain the pregnant women for Elecsys® TSH, Elecsys® FT4, Elecsys® FT3, study (http://life.uni-leipzig.de) in Leipzig, Germany. The studies
this group. slight increase in TSH values in rare cases. Elecsys® T4, Elecsys® T3, Elecsys® Anti-TPO, Elecsys® Anti-Tg, supported another investigation whether there might have been
5 Some RF patients exhibited decreased FT3 or FT4 values with Elecsys® Tuptake any significant shifts in the ranges obtained earlier. The results
•• RF normal TSH concentrations. •• 2007: extension of data for children according to the in 2003 confirmed – as already in the studies performed in 2003 and
Chronic RF lowers free hormone levels. 6 A clear number of patients from all groups exhibited FT4 investigated thyroid parameters 2007 – a remarkable stability of the reference intervals for the
concentrations exceeding the upper reference range •• 2012: Elecsys® Tg Elecsys® thyroid parameters during the course of time, also
4. Summary (97.5 % quantile). •• 2013: Elecsys® hCT ruling out reference shifts due to generation changes for
Pathological concentrations of thyroid parameters TSH, FT4 and •• 2016: additional reference ranges for adults and children for Elecsys® FT3 and Elecsys® FT4 assays.
FT3 in the serum of nonthyroid patients generally indicate overt In most cases, diagnostic algorithms based on serum TSH, Elecsys® TSH, Elecsys® FT4, Elecsys® FT3, Elecsys® Anti-TSHR,
or subclinical thyroid dysfunction. However, patients’ underlying FT3 and FT4 determination can be relied on to exclude thyroid Elecsys® Anti-TPO, Elecsys® Anti-Tg, Elecsys® hCT In the LIFE child cohort, reference ranges for children show quite
disease and/or drug treatments, as well as other factors both disease in inpatients and outpatients with a broad spectrum dramatic changes in the levels of the most thyroid parameters
preanalytical and analytical, can also produce pathological TSH, of nonendocrine disease. However, specific illness-related In 2004, with the launch of the Elecsys FT3® II, the first reference during early childhood. This has been already shown and reported
FT4 and FT3 concentrations without signifying thyroid dysfunction. determinants of the individual hormone concentrations must be interval brochure has been published. In addition, a new reference in the previous studies for children in Erlangen and Leipzig,
In addition, it should be borne in mind that reference ranges are taken into consideration when interpreting laboratory values. range study was initiated for all Elecsys® thyroid parameters to Germany. Therefore, reporting of age related reference ranges for
determined using the 2.5 % and 97.5 % quantile of the hormone investigate whether there might have been any significant shifts at least TSH, FT3, T3 and hCT are highly recommended.
concentrations in euthyroid subjects. Given this statistical in the ranges obtained earlier. A further goal was to characterize
background, tests on the sera of 100 euthyroid individuals will in great detail the most important influencing factors on thyroid With the data generated in the LIFE adult cohort, reference ranges
yield 2 – 3 samples with levels above or below the reference range. Acknowledgement: parameters. Allowing for minor changes in the estimated for a broader age range up to 80 years is available, now. Age
We studied the distribution of thyroid hormone concentrations in We would like to thank the following for their valuable input: reference values due to the particular compositions of the dependency could be observed especially for TSH and FT3 which
Prof. Dr. J. Kratzsch and T. Kussmaul, Institute of Laboratory Medicine, Clinical Chemistry and
severely ill but clinically euthyroid patients in an ICU, and in patients Molecular Diagnostics (Head: Prof. Dr. Joachim Thiery), Leipzig University Hospital, Liebigstr. 27,
respective reference groups, we observed a remarkable stability of leads to the recommendation of applying age specific reference
with HD, RD, DM, and RF. The results can be summarized as follows: D-04103 Leipzig the reference intervals of the Elecsys® thyroid parameters during ranges to patients.
the course of time. In fact, there are only very few cases where the
55 established reference value of the package insert was not covered The LIFE adult cohort allowed the computation of reference
TSH (µIU/mL) FT4 (pmol/L) FT3 (pmol/L)
Patient group Median Quantile Median Quantile Median Quantile by the confidence interval of the newly calculated quantile. ranges for the common group of patients under L-thyroxine
2.5 – 97.5 2.5 – 97.5 2.5 – 97.5
supplementation pointing out the effect of this medication on
With a cohort of pregnant women additional statements could reference ranges.
ICU (n=111) 0.80 0.05 – 3.33 15.8 6.19 – 22.75 3.13 1.34 – 5.56
be made on the ranges for all thyroid parameters according to
HD (n=100) 1.20 0.41 – 3.21 17.3 13.91 – 22.42 4.80 2.73 – 6.48
trimesters. The ranges, especially those for thyroid autoantibodies, In general, laboratories should check the reference ranges for
RD (n=99) 1.01 0.20 – 3.13 17.1 13.12 – 21.63 4.81 3.46 – 6.23
must be assessed under consideration of the information available transferability. This reference interval brochure for adults, children
DM (n=109) 1.41 0.30 – 3.97 16.9 12.91 – 23.42 4.57 3.73 – 5.88
on the pregnant women. and pregnant women shall support a more precise and accurate
RF (n=112) 1.40 0.20 – 3.35 16.1 11.30 – 22.80 4.02 2.62 – 5.32 diagnosis of thyroid conditions, enabling laboratories to apply
In the very well characterized group of blood donors from group specific reference intervals to offer high diagnostic value to
Leipzig, Germany, age and sex of the subjects have been identified their customers and patients.
as the most important influencing factors. Within the females,
the use of oral contraceptives was another decisive influencing
factor of the values.

50 51
Short description Notes

Detailed description can be found in chapter. LIFE Adult

apparently healthy adults, Leipzig, Germany 2013.
Group GEL
Newborns, infants, children and adolescents in age 0 – 20 years, LIFE Child
Erlangen and Leipzig, Germany 2003, 2004, 2007. apparently healthy children, Leipzig, Germany 2016.

Group GL1 Group N

Blood donors, men and women, no exclusion criteria. apparently healthy adults, Molde and Sandefjord, Norway 200067.
Adults Leipzig, Germany 2003, 2004.
Group GHH
Group GL2 apparently healthy adults, Hamburg, Germany 2003.
Normal thyroid ultrasound (volume and structure), ADVIA Centaur
TSH within reference range. Adults Leipzig, Germany 2003, 2004. Group A
apparently healthy adults, Vienna, Austria 2003.
Group GL3
Inclusion and exclusion criteria according to Guideline 22 of the Thailand
National Academy of Clinical Biochemistry (NACB), USA 2002.3 apparently healthy adults, Thailand 1999.
Adults Leipzig, Germany 2003, 2004.

Group GL5
Inclusion and exclusion criteria according to Guideline 33
of the NACB, USA 20023. Adults Leipzig, Germany 2003, 2004.

Group P
Apparently healthy women in the 1st, 2nd and 3rd trimester of
pregnancy without complication. Essen and Hamburg, Germany.

52 53
References
49 Davies, L., Welch, HG. (2014). Current thyroid cancer trends in the United States.
1 Ebert, C. et al. (1998). Elecsys® TSH, FT4, T4, T-uptake, FT3 and T3 Clinical results 26 Quadbeck, B., Hoermann, R., Roggenbuck, U. et al. (2005). Sensitive thyrotropin
JAMA Otolaryngol Head Neck Surg. 140(4), 317-22.
of a multicenter study. Wien Klin Wochenschr. 110, Suppl 3, 27-40. and thyrotropin-receptor antibody determinations one month after discontinuation
of antithyroid drug treatment as predictors of relapse in Graves’ disease. Thyroid 15, 50 Spencer, C., LoPresti, J., Fatemi, S. (2014). How sensitive (second-generation)
2 Hermsen et al. (2009). Technical evaluation of the first fully automated assay for the 1047-1054. thyroglobulin measurement is changing paradigms for monitoring patients
detection of TSH receptor autoantibodies. Clinica Chimica Acta 401, 84-89.
with differentiated thyroid cancer, in the absence or presence of thyroglobulin
27 Okamoto, Y., Tanigawa, SI., Ishikawa, K. et al. (2006). TSH receptor antibody
3 Demers, LM., Spencer, CA. (2002). National Academy of Clinical Biochemistry autoantibodies. Curr Opin Endocrinol Diabetes Obes 21(5), 394-404.
measurements and prediction of remission in Graves’ disease patients treated with
(NACB): Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. minimum maintenance doses of antithyroid drugs. Endocr J 53(4), 467-472. 51 Pacini, F., Schlumberger, M., Dralle, H. et al. (2006). European consensus for the
4 Bjoro, T., Holmen, Y., Krüger, O., Midthjell, K., Hundstad, KD., Schreiner, T. et al. management of patients with differentiated thyroid carcinoma of the follicular
28 Zöphel, K., Wunderlich, G., Kopprasch, C. et al. (2003). Predictive value of
(2000). Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase epithelium. Eur J Endocrinol 154, 787-803.
thyrotropin receptor antibodies using the second generation TRAb human assay after
antibodies in a large, unselected population. The Health Study of Nord-Trondelag radioiodine treatment in Graves’ disease. Nuklearmedizin 42, 63-70. 52 Cooper, DS., Doherty, GM., Haugen, BR. et al. (2009). Revised American Thyroid
(HUNT). Eur J Endocrin 143, 639-647.
Association Management Guidelines for Patients with Thyroid Nodules and
29 Barbesino, G., Tomer, Y. (2013). Clinical Utility of TSH Receptor Antibodies.
5 www.CLSI.org Differentiated Thyroid Cancer. Thyroid 19(11), 1-48.
J Clin Endocrinol Metab 98, 2247-2255.
6 Rieger, Kristin, M. V. (2016). Referenzintervalle für eisenabhängige Blutparameter 53 Pitoia, F., Ward, L., Wohllk, N. et al. (2009). Recommendations of the Latin
30 Kamijo, K. (2007). TSH-receptor antibodies determined by the first, second and third
bei Kindern und Jugendlichen:Ergebnisse einer populationsgestützten Kohortenstudie American Thyroid Society on diagnosis and management of differentiated thyroid
generation assays and thyroid-stimulating antibody in pregnant patients with Graves’
(LIFE Child). J Lab Med, 31-41. cancer. Arq Bras Endocrinol Metab 53(7), 884-897.
disease. Endocr J 54(4), 619-624.
7 Wu, AHB. (2006). Tietz Clinical Guide To Laboratory Tests. Saunders Elsevier, 54 Mazzaferri, EL., Robbins, RJ., Spencer, CA. et al. (2003). A Consensus Report of the
31 Suzuki, K., Kawashima, A., Yoshihara, A. et al. (2011). Role of thyroglobulin
Philadelphia, 4th edition, section II, 1040-1043. Role of Serum Thyroglobulin as a Monitoring Method for Low-Risk Patients with
on negative feedback autoregulation of thyroid follicular function and growth.
Papillary Thyroid Carcinoma. J Clin Endocrinol Metab 88, 1433-1441.
8 Surks, MI., Chopra, IJ., Mariash, CN. et al. (1990). American Thyroid Association J Endocrinol 209, 169-174.
Guidelines for the Use of Laboratory Tests in Thyroid Disorders. JAMA 263, 55 Zucchelli, G., Iervasi, A., Ferdeghini, M. et al. (2009). Serum thyroglobulin
32 Effraimidis, G., Wiersinga, WM. (2014). Autoimmune thyroid disease: old and new
1529-1532. measurement in the follow-up of patients treated for differentiated thyroid cancer.
players. Eur J Endocrinol 170(6), 241-252.
Q J Nucl Med Mol Imaging 53, 482-489.
9 Keffer, JH. (1996). Preanalytical Considerations in Testing Thyroid Function. Volpé, R. (1997). Rational Use of Thyroid Function Tests. Crit Rev Clin Lab Sci
33 
Clin Chem 42(1), 125-135. 56 Elisei, R., Pinchera, A. (2012). Advances in the follow-up of differentiated or
34(5), 405-438.
medullary thyroid cancer. A Nat Rev Endocrinol 8, 466-475.
10 Ladenson, PW. (1996). Optimal laboratory testing for diagnosis and monitoring of 34 F
 eldt-Rasmussen, U. (1996). Analytical and clinical performance goals for testing
thyroid nodules, goiter and thyroid cancer. Clin Chem 42(1), 183-187. 57 Inzerillo, AM., Zaidi, M., Huang, CL. (2004). Calcitonin: physiological actions and
autoantibodies to thyroperoxidase, thyroglobulin, and thyrotropin receptor. Clin Chem
clinical applications. J Pediatr Endocrinol Metab 17(7), 931-940.
11 Nicoloff, JT., Spencer, CA. (1990). The use and misuse of the sensitive thyrotropin 42(1), 160-163.
assays. 58 Austin, LA., Heath, H. (1981). 3rd Calcitonin: physiology and pathophysiology.
35 Utiger, RD. (1991). The pathogenesis of autoimmune thyroid disease.
J Clin Endocr Metab 71, 553-558. New Engl J Med 304(5), 269-278.
N Eng J Med 325, 278-279.
12 Alexander, E.K. et al. (2017). Guidelines of the American Thyroid Association for the 59 Kloos, RT., Eng, C., Evans, DB. et al. (2009). Medullary thyroid cancer: management
36 Schott, M., Eckstein, A., Willenberg, HS. et al. (2007). Improved prediction of
diagnosis and management of thyroid disease during pregnancy and the postpartum. guidelines of the American Thyroid Association. Thyroid 19(6), 565-612.
relapse of Graves’ thyrotoxicosis by combined determination of TSH receptor and
www.thyroid.org. thyroperoxidase antibodies. Horm Metab Res 39(1), 56-61. 60 Wells, SA. Jr., Asa, SL., Dralle, H. et al. (2015). Revised American Thyroid
13 Kronenberg, HM., Melmed, S., Polonsky, KS. et al. (2011). Williams Textbook of Association guidelines for the management of medullary thyroid carcinoma.
37 Ruf, J., Ferrand, M., Durand-Gorde, JM. et al. (1993). Significance of thyroglobulin
Endocrinology. Saunders Elsevier, Philadelphia, 12th edition, chapter 10, 301-311. Thyroid 25(6), 567-610.
antibodies cross-reactive with thyroperoxidase (TGPO antibodies) in individual
14 Wu, AHB. (2006). Tietz Clinical Guide To Laboratory Tests. Saunders Elsevier, patients and immunized mice. Clin Exp Immunol 92(1), 65-72. 61 Elisei, R., Romei, C. (2013). Calcitonin estimation in patients with nodular goiter
Philadelphia, 4th edition, , section II, 1076-1077. and its significance for early detection of MTC: European comments to the guidelines
38 Thomas, L. (1998). Thyroid function. Thyroglobulin antibodies. In: Thomas L (ed.).
of the American Thyroid Association. Thyroid Res 6, Suppl 1, 2.
15 Brent, GA. (2010). Thyroid Function Testing. Springer, Berlin, 1st edition, chapter 5, Deutsch: Labor und Diagnose. TH-Books, Frankfurt. 5th edition 1998:1043. English:
86-88. Clinical Laboratory Diagnosis. 1st edition:1021. 62 Kratzsch, J., Petzold, A., Raue, F. et al. (2011). Basal and stimulated calcitonin and
procalcitonin by various assays in patients with and without medullary thyroid
16 Zigman, JM., Cohen, SE., Garber, JR. (2003). Impact of Thyroxine-Binding Globulin 39 Slatosky, J., Shipton, B., Wahba, H. (2000). Thyroiditis: differential diagnosis and
cancer. Clin Chem 3, 467-474.
in Thyroid Hormone Economy During Pregnancy. Thyroid 13(12), 1169-1175. management. Am Fam Physician 61(4), 1047-1052.
63 Kudo, T., Miyauchi, A., Ito, Y. et al. (2011). Serum calcitonin levels with calcium
17 McIntosh, RS., Asghar, MS., Weetman, AP. (1997). The antibody response in human 40 Garber, JR., Cobin, RH., Gharib, H. et al. (2012). Clinical practice guidelines for
loading tests before and after total thyroidectomy in patients with thyroid diseases
autoimmune thyroid disease. Clin Sci 92, 529-541. hypothyroidism in adults: cosponsored by the American Association of Clinical
other than medullary thyroid carcinoma. Endocr J 58(3), 217-221.
Endocrinologists and The American Thyroid Association. Thyroid 22(12),
18 Schott, M., Seißler, J., Scherbaum WA. (2006). Diagnostic testing for autoimmune 1200-1235. 64 Mitchell, DM., Jüppner, H. (2010). Regulation of calcium homeostasis and bone
thyroid diseases. J Lab Med. 34(4), 254-257. metabolism in the fetus and neonate. Curr Opin Endocrinol Diabetes Obes 17,
41 Iddah, MA., Macharia, BN. (2013). Autoimmune thyroid disorders.
19 
Feldt-Rasmussen, U. (1996). Analytical and clinical performance goals for testing 25-30.
ISRN Endocrinol 509764.
autoantibodies 65 Machens, A., Hoffmann, F., Sekulla, C. et al. (2009). Importance of genderspecific
to thyroperoxidase, thyroglobulin, and thyrotropin receptor. Clin Chem 42(1), 42 Lazarus, J., Brown, RS., Daumerie, C. et al. (2014). European Thyroid Association
calcitonin thresholds in screening for occult sporadic medullary thyroid cancer.
160-163. guidelines for the management of subclinical hypothyroidism in pregnancy and in
Endocr Relat Cancer 16, 1291-1298.
children. Eur Thyroid J 3, 76-94.
20 Farid, NR., Szkudlinski, MW. (2004). Minireview: structural and functional 66 D’Herbomez, M., Caron, P., Bauters, C. et al. (2007). Reference range of serum
evolution of the thyrotropin receptor. Endocrinology 145(9), 4048-4057. 43 Nam, HY., Paeng, JC., Chung, JK. et al. (2014). Monitoring differentiated thyroid
calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette
cancer patients with negative serum thyroglobulin. Diagnostic implication of TSH-
21 Rapoport, B., Chazenbalk, GD., Jaume, JC. et al. (1998). The thyrotropin (TSH) smoking. Eur J Endocrinol 157(6), 749-755.
stimulated antithyroglobulin antibody. Nuklearmedizin 53(2), 32-38.
receptor: interaction with TSH and autoantibodies. Endocrine Reviews 19(6), 67 Bjoro, T., Holmen, Y., Krüger, O., Midthjell, K., Hundstad, KD., Schreiner, T. et al.
673-716. 44 Spencer, CA., Takeuchi, M., Kazarosyan, M. et al. (1998). Serum Thyroglobulin
(2000). Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase
Antibodies: Prevalence, Influence on Serum Thyroglobulin Measurement, and
22 Michalek, K., Morshed, SA., Latif, R. et al. (2009). TSH receptor autoantibodies. antibodies in a large, unselected population. The Health Study of Nord-Trondelag
Prognostic Significance in Patients with Differentiated Thyroid Carcinoma. J Clin
Autoimmun Rev. 9(2), 113-116. (HUNT). Eur J Endocrin 143, 639–647.
Endocrin Metabol 83(4), 1121-1127.
23 Chiamolera, MI., Wondisford, FE. (2009). Minireview: Thyrotropin-releasing 45 Spencer, C. (2001). International Thyroid Testing Guidelines. National Academy of
hormone and the thyroid hormone feedback mechanism. Endocrinology 150, Clinical Biochemistry, Section 3E,11-14.
1091-1096.
46 De Vijlder, JJM., Ris-Stalpers, C., Vulsma, T. (1999). On the origin of circulating
24 Paunkovic, J., Paunkovic, N. (2006). Does autoantibody-negative Graves’ disease thyroglobulin. Eur J Endocrinol 140(1), 7-8.
exist?
A second evaluation of the clinical diagnosis. Horm Metab Res 38, 53-56. 47 Torréns, JI., Burch, HB. (2001). Serum thyroglobulin measurement. Utility in clinical
practice. Endocrinol Metab Clin North Am 30(2), 429-467.
25 Sturniolo, G., Gagliano, E., Tonante, A. et al. (2013). Toxic multinodular goitre.
Personal case histories and literature review. G Chir 34(9-10), 257-259. 48 Pacini, F., Pinchera, A. (1999). Serum and tissue thyroglobulin measurement:
Clinical applications in thyroid disease. Biochemie 81, 463-467.

54 55