Reference Intervals for Children and Adults

Transcription

1 for Children and Adults TSH, FT4, FT3, T4, T3, T-Uptake, FT4-index, Anti-TPO, Anti-Tg, Tg Elecsys systems /20 MODULAR ANALYTICS E70 cobas e 4 and cobas e 60 analysers

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3 Contents Page Introduction 4 2 Summary Subjects, Materials and Methods 6 3. Description of the reference population Newborns, infants, children and adolescents 0 20 years, / Adults (20 69 years), Leipzig, Germany, 2003/ Pregnant women, Essen and Hamburg, Germany, Reference population mentioned in the package inserts, 995/96 up to Local reference intervals, groups for ft3, partly also for TSH and ft Analytical methods Statistical evaluation, Terminology 9 4 Results and Discussion Cross-parameter results and explanations on the following chapters Thyrotropin, Thyroid stimulating hormone TSH Free thyroxine ft Free triiodothyronine ft Total triiodothyronine T Total thyroxine T Thyroxine-binding capacity or TBC, T-uptake / Free T4-index ft4i (T4/TBI) Antibodies to thyroid peroxidase anti-tpo Antibodies to thyroglobulin anti-tg Thyroglobulin Tg Conclusion 48 6 References 49 Significant additions or changes are indicated by a change bar in the margin. 3

4 Introduction The introduction of a new Elecsys FT3 test in the year 2003 was an opportunity to retest reference intervals for all of the thyroid tests that Roche offers for the Elecsys /20/ MODULAR ANALYTICS E70 automated immunoassay analyzer for children and adults in order to close some of the gaps that have appeared due to product improvements. This applies especially to the values for children, adolescents, and pregnant women. In this context, the reference values given in the product package inserts have been summarized together with the newly determined values and others from laboratories in different countries. All available information on the composition of the population groups is given. Explanations for some the differences found can be valued in the light of this information. The latest discussions on the diagnosis and treatment of subclinical thyroid disorders prompted us to analyze the adult population in particular. In this context we have looked into the necessity of having different reference ranges for different patient groups. To update and complete the reference range values for children a new study was performed in. 2 Summary Reference ranges for all Elecsys thyroid parameters are available for the following groups: characterized as clinically healthy with respect to thyroid disorders. A dependency on age, sex, thyroid volume and density, body mass index, thyroglobulin, albumin and contraceptives was tested in the adult group and, if noticeable, identified. This group was evaluated in three steps: Additional reference groups used by clinical centers or commercial labs in various - patients and for hypo- and hyperthyroid patients for ft3 and ft4 are available. All groups are described in greater detail in chapter 3., analytical methods in chapter 3.2, and the statistical methods used in chapter 3.3. Chapters show the individual on potentially influencing factors for all thyroid tests. 4

5 rently available Elecsys thyroid tests have not been changed since launch. The refer- current respective reference groups and continue to be valid. This is due to the fact from the well characterized Leipzig data. Differences to the reference intervals listed in the Elecsys package inserts and those provided by clinical centers and commercial labs are most likely due to the differing composition of the reference groups see chapter 3.. An analysis in the adult group using multivariate methods to account for the factors age and sex as well as age and contraceptives, gave the following results for the below listed parameters: Using alle data the multivariate analysis assesses in how far the combined effect of the factors age, gender, medication take influence on the assay result. Even if there is no such connection, the univariate statistics may well exhibit a statistically significant difference for individual group comparisons. The following overview shows the effects of influencing factors on the concentration of the thyroid test parameters in the various groups evaluated by univariate analysis. Legend: = significantly depressed TSH ft4 ft3 T3 T4 T-upt. ft4i A-TPO A-Tg Tg Sex m. vs. f. Age 20 up to 69 years Males vs y. Females vs y. Contraceptives w vs. w/o TBG Albumin Obesity, BMI Pregnancy 2nd trim. vs. st trim. 3rd trim. vs. 2nd trim. Reference groups NACB (GL3/4/5) vs. all GL2 TSH+Sono NAD vs. all

6 3 Subjects, Materials and Methods 3. Description of reference population groups information is summarized below. In addition to the populations tested for the latest groups mentioned in the package inserts of the respective test parameters. 3.. Newborns, infants, children and adolescents 0-20 years Erlangen and Leipzig, 2003// The reference range calculation for the thyroid parameters was made using remaining Group GEL in the brochure. In the subgroup Erlangen a total of 420 specimen and in the subgroup Leipzig a total of 04 specimen of newborns, children and adolescents of both sexes between the ages of 0 and > 20 was included. Depending on the parameter between The exclusion and inclusion criteria for both groups were similarly applied: The general presence of autoantibodies was not an exclusion criterion Adults Leipzig, To determine the reference ranges of all thyroid parameters, in 2003/, at the Information is available for these specimens as to: Age, sex, height, weight, personal and family history of thyroid disorders, contraceptive use and cigarette use. Measurement results are available for: Thyroid volume and structure, blood pressure, heart rate, blood count, lipid metabolism parameters, protein, albumin and all thyroid parameters including autoantibodies and thyroglobulin. - The following groups were formed assessment for all thyroid test parameters Group GL: Blood donors, all men and women: all tested blood donors no exclusions Group GL2: within reference range. Group GL3: - 2 others labotatory parameter covered except for the autoantibodies! Additionally for thyroglobulin: Group GL4: excluded.

7 Additionally for antibodies to thyroid peroxidase and thyroglobulin: Group GL5: Number of individuals of the reference population tested Group P: Women in their st, 2nd and 3rd trimester of pregnancy. pregnancy without known complications. Exclusion criteria for this group were: A known or supposed thyroid dysfunction or history, substitution of thyroid hormones, concentrations outside a range of 0. to µiu/ml were excluded in both groups. from Erlangen, adults, children from Leipzig and pregnant women from Essen and tested. The data shown in the table provide the basis for the data in the figures depicting the age-dependency for the individual thyroid tests. FT3 FT4 T3 T4 A-TG TG A-TPO TSH TUP FTI n n n n n n n n n n Male 0 6 Days Days 3 Months Months Years Years Years Years Years Years Years Years Female 0 6 Days Days 3 Months Months Years Years Years Years Years Years Years Years Total 0 6 Days Days 3 Months Months Years Years Years Years Years Years Years Years Table 7

8 3..4 Reference population given for the data in the package inserts ft4, T3, T4, T-uptake, ft4-index 2000 / 200 Description of the reference population used as the basis of the reference interval given in the package inserts for the Elecsys thyroid parameters see below: introduction of the Elecsys systems or in some cases adopted from the previous tests the Enzymun-Test parameters. The reference population which is the basis for the information in the current package samples were measured in routine tests in clinical centers in Belgium, Japan and The groups consisted of blood donors in addition to hospital inpatients and outpa- for all specimens. No information was available on any medication taken by the test meter, is given in the tables in the chapters on the individual tests. Measurements were taken for ft4, T3, T4 and T-uptake. The ft4 index was determined from the T4 and T-uptake ratio. within 0.27 to 4.2 µiu/ml and free T4 values within 2.0 to 23.0 pmol/l. clinical appearance was without any signs for thyroid dysfunction. for ft3, partly also for Local reference intervals which have kindly been provided to us for publication. Group N: Molde and Sandefjord, Norway: inclusion 2 and ft4 concentrations between 22 pmol/l. This ft4 reference interval has been used in Norway for the Group GHH: Hamburg, Germany, samples came from a large commercial community laboratory. The criterion for patients was analyzed. This corresponds to a so called routine collective as was also used for earlier reference interval determinations. Group GHD: Heidelberg, Germany, Routine samples. Reference range based on personal communication. Group A: Vienna, Austria, clinically characterized euthyroid patients were used. The main criteria were: no history reference range of the routine method. 8

9 Group SE: Helsingborg/Boras and Västeras, Sweden, Inclusion criteria for this group were: no family history of thyroid disorder, no goiter, Thailand: was given. 3.2 Analytical methods To determine the reference intervals, the Roche Electro-ChemiLuminescence Immuno- A were used on the Elecsys 20 and the MODULAR ANALYTICS E70 immunoassay control guidelines. test is a 3 rd 20 The measurement methodology for the samples taken from children and adults in Erlangen and Leipzig in 2003 and as well as for the samples taken from pregnant The clinical-chemical laboratory parameters were measured with the Roche Diagnostics tests. The normal thyroid echo was classified as homogeneous. If the echo pattern was not homogeneous, showing small lesions or distinct abnormalities in the echo texture of the nodules. height Statistical methods Assay data: sources, Leipzig and Erlangen, have been combined. A Wilcoxon rank sum test to evaluate the statistical significance of differences in assay results between the two centers was found statistically significant different. Boxplots to investigate the relevance of the observed differences have been generated, too. It has been decided that the situation observed for these two study centers reflect the real world target population very well. As a

10 3.3 Statistical methods functions. 23,24 A linear model utilizing non-integer powers of the explanatory variable age extreme values are smoothed out. When surveying the whole age span of the thyroidal assays the largest amount of variation takes place at the infant and early stages of adoles- reference values. 3,4 tion of respective confidence limits is recommended. In this broschure two approaches Comparison of clinical groups: For the evaluation of the significance of the differences in assay results between clinically - test has been used. Multivariate methods: Multivariate methods have been used to investigate the combined influence of age and taking contraceptives on the test results. In particular the situation corresponds to a treatment effect is the block-treatment-interaction. The generalized linear model ap- do not take contraceptives, and the true impact of contraceptives on the result level of the test parameters has been assessed. The combined influence of age and gender on the assay results has also been investigated by means of multivariate methods. Again the situation corresponds to a randomized The generalized linear model approach thus corrects for the effects of an age-dependent result level of the test. For a statistical evaluation of the pregnancy data, the differences between the trimesters - difference between means does not include zero.

11 Terminology Reference population / reference group: Random sample from the population of asymptomatic patient specimens. The reference population provides the basis for determining reference intervals. The reference population is also called reference group. Reference intervals / reference range / reference values / expected values: In accordance with IFCC recommendations, the reference intervals or reference ranges are the called reference limits because they bracket the reference range. Reference ranges are Elecsys package inserts contain the term expected values instead of reference values or reference intervals. Confidence interval: interval decreases in size as the sample size increases. Figure shows the position of the Coverage probability: insufficient coverage probabilities. Note that the IFCC recommends at least n = 20. Frequency Reference interval (corresponds in this case to the 95% central range) min max 2.5% quantile 50% quantile 97.5% quantile Concentration of the analyte Confidence interval Confidence interval Confidence interval Figure

12 4 Results and Discussion 4. Cross-parameter results For the Leipzig blood donor group, the scatter plots of figure 2 show the age-dependent concentration or body mass index. Information on a correlation between the concentration in the thyroid tests and other parameters not described here is given in the individual chapters on the tests. 53 All blood donors - Leipzig 60 All blood donors - Leipzig Albumin [g/l] Tthyroid volume [ml] Pearson s r = Age [Years ] Age [Years ] Thyroxin binding globulin (TBG) [mg/l] All blood donors - Leipzig Thyroxin binding globulin (TBG) [mg/l] Females Age [Years ] Age [Years ] Females Males With contraceptives W/o contraceptives Figure 2 Explanation on the following chapters The following details apply to each of the parameters tested: Each figure shows an age-dependent representation of the individual data of the Erlangen and Leipzig reference group for children, adolescents and young grown-ups groups of children, youths, and adults. 2

13 4.2 Thyrotropin, Thyroidstimulating- combination with ft4 concentrations in the reference range, which are associated with a subclinical thyroid hyper- or hypofunction is in various studies described as being approx. therapeutic measures is still open. separately. 8 Marginally significant differences were found in the group of women which did or did not The selection of inclusion and exclusion criteria influences the width of the range 3

14 4.2 Thyrotropin, Thyroidstimulating- The so determined reference ranges correspond to those obtained in 2000 in a multicenter concentrations in the reference range of another method. 7 included except for the autoantibodies and the patient history on personal and familiar thyroid disorders shows correspondingly low limit values. There is no significant differ- Over trimester to 3, pregnant women show a tendency in the upper limits towards lower Figure 3 TSH (µlu/ml) age male female Figure 3 4

15 4.2 Thyrotropin, Thyroidstimulating- 95p CI low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% µiu/ml µiu/ml µiu/ml µiu/ml µiu/ml µiu/ml µiu/ml µiu/ml µiu/ml Elecsys TSH package insert / 97 Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Females with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 org (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ. Results from various locations Group A (euthyroid indiv.) Group GHD (routine samples) Group N (HUNT Study) females Group N (HUNT Study) males Group SE (EQALIS) Table 2 Applying the given inclusion and exclusion criteria, the ranges for the groups from various locations in different countries that were available for evaluation correspond Free thyroxin ft4 are identified separately. also for ft4. These differences were also found in the present studies for the different groups. The publications are reporting er values as well as lower values for males compared to those of women. For ft4 the reference interval currently given in the Elecsys FT4 package insert is basically males into account. eters were included except for the autoantibodies and the patient history on personal and familial thyroid disorders shows correspondingly narrowed reference limits.

16 4.3 Free thyroxin ft4 There is no significant difference between the groups from Leipzig. No significant differences were found in the group of women which did or did not take As expected, pregnant women have lower ft4 concentrations correlated with the gesta- between each other. low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l Elecsys FT4 package insert Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ. Results from various locations Group A (euthyroid indiv. 2003) Group GHD (routine samples) Group GHH (routine samples) Group SE (EQALIS) Males Group SE (EQALIS) Females Table 3a SI units Applying the given inclusion and exclusion criteria, the ranges for the groups from various locations in different countries that were available for evaluation correspond be observed

17 4.3 Free thyroxin ft4 low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% ng/dl ng/dl ng/dl ng/dl ng/dl ng/dl ng/dl ng/dl ng/dl Elecsys FT4 package insert Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ. Results from various locations Group A (euthyroid indiv. 2003) Group GHD (routine samples) Group GHH (routine samples) Group SE (EQALIS) Males Group SE (EQALIS) Females Table 3b conventional units 7

18 4.3 Free thyroxin ft4 Figure 4 The dependency of the ft4 concentration levels on sex is statistically significant for all age groups. ft4 (pmol/l) age male female Figure 4 Women: central range is identified by grey areas. The continuous lines and the white areas corre- The dependency of the reference values on the applied inclusion/exclusion criteria 8

19 4.3 Free thyroxin ft4 0 0 Group GL - all blood donors (n = 870: 445 males, 425 females ) 0 Group GL2 - TSH+Sono NAD (n = 632: 332 males, 300 females ) Ref. interval Ref. interval , 0. 0, 0. 0, , ft4 [pmol/l] Ref. interval ft4 [pmol/l] Ref. interval Group GL3 - (TSH-NACB) (n = 447: 274 males, 73 females ) Pregnant women ( st trim. n = 47, 2nd trim. n = 368, 3rd trim. 69) 0 Ref. interval GL 0. c - lines GL Figure ft4 [pmol/l] Ref. interval ft4 [pmol/l] - lines GL Leipzig Blood Donors - ft4 versus Group GL 30 Females ft4 [pmol/l] 5 ft4 [pmol/l] 5 Pearson s r = Pearson s r = Frauen Females Males TBG [mg/l] With contraceptives W/o contraceptives Figure 6

20 4.4 Free triiodothyronine ft3 Establishing values in reference range studies is based primarily on samples obtained from be in the euthyroid range in these samples. The patients often have non-thyroid diseases which might influence the thyroid function in general, and especially the ft3 level. This may explain the differences observed when comparing the reference ranges based on different population groups using the same ft3 method. Beside local differences in iodine intake the overall health status of the individuals involved is decisive for the outcome of the reference intervals. Due to the new assay formulation in 2003 reference ranges for the Elecsys FT3 were established based on reference population selected by differing criteria. The width is differing for these ranges see tables 4a and 4b. are identified separately. Results of routine samples from community labs located in various regions and results from following characterized patient groups are also listed in the tables: dialysis patients and NTI patients. low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l pmol/l Group GHH (routine samples), ins Group GHD (Dialysis patients), insert MCE, NTI patients, insert Adults years Group GL (all blood donors) _ins. final L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ. Results from various locations Group A (euthyroid indiv. 2003) Group GHD (routine samples) Group N, all Group N, SKKL+Molde Group N, SKKL (outpatients) Table 4a: SI units

21 4.4 Free triiodothyronine ft3 cant and non significant differences between the sex groups. In our study differences Slightly er values were seen in the group of women which did take contraceptives As expected, pregnant women have lower ft3 concentrations correlated with the gesta- between each other. Applying the given inclusion and exclusion criteria, the ranges for the groups from various locations in different countries that were available for evaluation correspond Local differences as well as differences caused by the composition of the groups can be observed. low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% pg/ml pg/ml pg/ml pg/ml pg/ml pg/ml pg/ml pg/ml pg/ml Group GHH (routine samples), ins Group GHD (Dialysis patients), insert MCE, NTI patients, insert Adults years Group GL (all blood donors) _ins. final L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ. Results from various locations Group A (euthyroid indiv. 2003) Group GHD (routine samples) Group N, all Group N, SKKL+Molde Group N, SKKL (outpatients) Table 4b: conventionell units

22 4.4 Free triiodothyronine ft3 Figure 7 The dependency of the ft3 concentration levels on sex is statistically significant for all age groups. ft3 (pmol/l) age male female Figure 7 Women: central range is identified by grey areas. The continuous lines and the white areas corre- 22

23 4.4 Free triiodothyronine ft3 The dependency of the reference values on the applied inclusion/exclusion criteria 0 Group GL - all blood donors (n = 870: 445 males, 425 females ) 0 0 Group GL2 - TSH+Sono NAD (n = 632: 332 males, 300 females ) Ref. interval Ref. interval , ft3 [pmol/l] Ref. interval Group GL3 - (TSH-NACB) (n = 447: 274 males, 73 females ) , ft3 [pmol/l] Ref. interval Pregnant women ( st trim. n = 46, 2nd trim. n = 368, 3rd trim. 69) 0 Ref. interval all 0. 0, lines GL 0. 0, 0.0 0, ft3 [pmol/l] Ref. interval , ft3 [pmol/l]- lines GL Figure 8 Leipzig Blood Donors - Group GL 2 Females Elecsys FT3 [pmol/l] Elecsys FT3 [pmol/l] Females Males TBG [mg/l] With contraceptives W/o contraceptives Figure 9 23

24 The total thyroid hormone levels, T3 and T4, are more commonly influenced as a result of -fold lower. abnormalities in binding proteins are influencing the concentration level of the measurements. The composition of the reference population is therefore decisive for the outcome of the reference intervals. For triiodothyronine the reference interval currently given in the Elecsys T3 package insert reference values for females. The reference limits are also narrower for T3. Furthermore the ranges are slightly shifted downwards in comparison to the reference range for the group given in the current insert. Local differences or differences caused by the composition of the reference groups can be are identified separately. Results of routine samples from community labs located in various regions are also listed in the tables. Results from investigations in Thailand show clearly decreased values for the lower low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l Elecsys T3 package insert Elecsys T3 package insert Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years Results from various locations n Year of publ. Group A (euthyroid indiv. 2003) Group GHD (routine s. < 50 y) Group GHD (routine s. > 50 y) Thailand Table 5a: SI units 24

25 Significant differences between males and females in group of blood donors from Leipzig, ceptives could be observed. Significantly er T3 values were seen in the group of women which did take contraceptives compared to the group of women which did not contraceptives approximate those of the group of men. The dependency of the T3 concentration levels on the intake of contraceptives is statistically significant for all age groups. Women in er ages have slightly lower values than young women. These As expected, pregnant women have er T3 concentrations correlated with the gesta- between each other. low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% ng/ml ng/ml ng/ml ng/ml ng/ml ng/ml ng/ml ng/ml ng/ml Elecsys T3 package insert Elecsys T3 package insert Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years Results from various locations n Year of publ. Group A (euthyroid indiv. 2003) Group GHD (routine s. < 50 y) Group GHD (routine s. > 50 y) Thailand Table 5b: conventional units

26 Figure - The T3 concentrations in the first days after birth decrease continuously. T3 (nmol/l) age male female Figure

27 Women: central range is identified by grey areas. The continuous lines and the white areas corre- The dependency of the reference values on the applied inclusion/exclusion criteria 0 Group GL - all blood donors (n = 870: 445 males, 425 females ) 0 Group GL2 - TSH+Sono NAD (n = 632: 332 males, 300 females ) Ref. interval Ref. interval , T3 [nmol/l] Ref. interval Group GL3 - (TSH-NACB) (n = 447: 274 males, 73 females ) 0, ,5 0.5, , , , T3 [nmol/l] Ref. interval Pregnant women ( st trim. n = 47, 2nd trim. n = 368, 3rd trim. 69) 0 Ref. interval all 0. 0, c - lines GL 0. 0, 0.0 0, ,5.5, , , ,5 5 T3 [nmol/l] Ref. interval , T3 [nmol/l]- lines GL Figure 27

28 Leipzig Blood Donors T3 versus compared to those of men. Among the group of women further increased values were caused by the contraceptives taken. For the correlation presented in the scatter plots the No relevant dependency of T3 on albumin was observed see lower scatter plot in Figure Group GL 50 Females Elecsys T3 [nmol/l x ] Elecsys T3 [nmol/l x ] Pearson s r = Pearson s r = Females Males TBG [mg/l] With contraceptives W/o contraceptives 50 Pearson s r = Pearson s r = Elecsys T3 [nmol/l x ] Elecsys T3 [nmol/l x ] Albumin [g/l] Figure 2 28

29 endogenous effects, the status of the binding proteins must also be taken into account in the assessment of the thyroid hormone concentration in serum. As described already for T3 the total thyroid hormone levels, T3 and T4, are more commonly influenced as a result of binding protein variances than result from true therapy, as well as genetic abnormalities in binding proteins are influencing the concentration level of the measurements. The composition of the reference population is therefore decisive for the outcome of the reference intervals. It is furthermore recommended to determine the throxine-binding capacity to take influences caused by varying concentrations of binding protein into 2, are identified separately. Results of a clinical center in Austria are also listed in the tables. For thyroxine the reference interval currently given in the Elecsys T4 package insert is Europe and Japan were found in the group of women taking contraceptives also. There is no significant difference between the median values of the different groups of blood donors from Leipzig evaluated. The ranges are again closer compared to those of the currently described groups. The data in the group from Austria correspond to those of the group of blood donors. Significant differences between males and females in group of blood donors from Leipzig In our study males show significantly lower values as compared to women, when the total women which did not take contraceptives approximate those of the group of men. The dependency of the T4 concentration levels on the intake of contraceptives is statistically by the intake of contraceptives could be observed also for T4. and 3rd trimester.

30 Figure 3 T4 (nmol/l) age male female Figure 3 low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l nmol/l ng/ml Elecsys T4 insert Europe / Japan Elecsys T4 insert USA 99% centr Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years Results from various locations Group A (euthyr. Prob. 2003) T4 Table 6a, SI Units n Year of publ. 30

31 low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% µg/dl µg/dl µg/dl µg/dl µg/dl µg/dl µg/dl µg/dl µg/dl Elecsys T4 insert Europe / Japan Elecsys T4 insert USA 99% centr Adults years Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years Results from various locations Group A (euthyr. Prob. 2003) T4 Table 6b, Conventional Units n Year of publ. 3

32 Women: central range is identified by grey areas. The continuous lines and the white areas corre- The dependency of the reference values on the applied inclusion/exclusion criteria 0 Group GL - all blood donors (n = 870: 445 males, 425 females ) 0 Group GL2 - TSH+Sono NAD (n = 632: 332 males, 300 females ) Ref. interval Ref. interval T4 [nmol/l] Ref. interval Group GL3- (TSH-NACB) (n = 447: 274 males, 73 females ) T4 [nmol/l] Ref. interval Pregnant women ( st trim. n = 47, 2nd trim. n = 368, 3rd trim. 69) 0 Ref. interval , - lines GL 0. 0, 0.0 0, T4 [nmol/l] Ref. interval , T4 [nmol/l]- lines GL Figure 4 32

33 Leipzig Blood Donors Albumin explains the er values of women compared to those of men. Among the group of women further increased values were caused by the contraceptives taken. No relevant dependency of T4 on albumin was observed in the group investigated see 2 Group GL 2 Females Elecsys T4 [nmol/l] Elecsys T4 [nmol/l] Pearsons r = Pearson s r = Females Males Elecsys T4 [nmol/l] TBG [mg/l] Elecsys T4 [nmol/l] With contraceptives W/o contraceptives Albumin [g/l] Figure Thyroxine-binding capacity - Free T4-Index ft4i when the thyroxine-binding capacity in serum is normal. The free thyroid hormones are concentration can lead to elevated or lowered total T4 concentrations being measured although the free T4 concentration is in the euthyroid range. The performance of a T-uptake or TBC assay provides a measure of the available thyroxine-binding sites. changes in the thyroid hormone carrier proteins and the thyroxine level. separately. The data basically confirm the reference interval currently given in the Elecsys T-Uptake new results. 33

34 4.7 Thyroxine-binding capacity - Free T4-Index ft4i There is no significant difference between the median values of the different groups of narrower as compared to those of the described groups. in the evaluation. The results from the group of women which did not take contraceptives approximate those of the group of men. The dependency of the T-uptake concentration levels on the intake of contraceptives is statistically significant for all age groups. A could be observed also for T-uptake. As expected T-uptake concentrations are increasing with gestational age. The median other. Figure 6 - The dependency of the T-uptake concentration levels on sex is statistically significant for all age groups. The median T-uptake concentration levels of children are nearly constant over all age groups. Table 7. T-uptake (TBI) age male female Figure 6: T-uptake 34

35 4.7 Thyroxine-binding capacity - Free T4-Index ft4i Figure 7 trations in the first years of age decrease continuously up to approx. 40 years of age. ft4-index (nmol/l) age male female Figure 7: ft4-index T-uptake Elecsys T-Uptake Insert Europe/Japan Elecsys T-Uptake Insert USA 99% centr. Adults years low (2.5% 2.5% (2.5% 95 p CI low 50% median 95p CI low (97.5% 97.5% (97.5% TBI TBI TBI TBI TBI TBI TBI TBI TBI Group GL (all blood donors) L Males all L Males y L Males y L Females all L Females y L Females y L Fem. with contracept. L Fem. with contracept y L Fem. with contracept y L Fem. w/o contracept. L Fem. w/o contracept y L Fem. w/o contracept y Group GL2 (TSH+SD Sono NAD) L2 Males L2 Females Group GL3 (NACB crit. for TSH) L4 Males L4 Females Group P (Pregnancy) st Trimester 2nd Trimester 3rd Trimester Group GEL Children, Adolescents 0 6 Days 6 Days 3 Months 3 2 Months 6 Years 6 Years 20 Years n Year of publ Table 7