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© Borgis - Postępy Nauk Medycznych 4/2018, s. 206-210 | DOI: 10.25121/PNM.2018.31.4.206
Zenon Jakubowski1, Monika Zagorska1, *Marlena Robakowska2, Grzegorz Krzykowski3, Krzysztof Sworczak1, Miroslawa Szczepanska-Konkel1, Anna Tyranska-Fobke4, Daniel Slezak4, Przemyslaw Zuratynski4, Jakub Kraszewski5, Marzena Domanska-Sadynica6
Method of establishing reference intervals of thyroid profile parameters
Metoda wyznaczania przedziałów referencyjnych parametrów profilu tarczycowego
1Faculty of Health, Medical University of Gdansk, Poland
2Department of Public Health and Social Medicine, Faculty of Health Sciences with Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Poland
3Institute of Informatics, University of Gdansk, Poland
4Emergency Medicine Workshop, Faculty of Health Sciences with Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Poland
5University Clinical Center, Gdansk, Poland
6Alliance for Innovation, Warsaw, Poland
Streszczenie
Wstęp. W ostatnich latach coraz częściej zwraca się uwagę na to, że stosowane w laboratoriach przedziały referencyjne nie spełniają oczekiwań lekarzy endokrynologów. Problem ten ma duże znaczenie w odniesieniu do parametrów profilu tarczycowego. Zdaniem niektórych specjalistów z zakresu endokrynologii, wykorzystywane obecnie przedziały referencyjne dla tych parametrów zostały określone dla zbyt szerokich grup.
Cel pracy. Celem niniejszego badania była próba wyznaczenia wewnętrznych przedziałów referencyjnych, uwzględniających specyfikę populacji pacjentów i podstawowych parametrów profilu tarczycowego: TSH, fT4 i fT3.
Materiał i metody. Analizą objęto wyniki oznaczeń stężeń TSH, fT4 i fT3 w surowicy wykonanych w Centralnym Laboratorium Klinicznym Uniwersyteckiego Centrum Medycyny Laboratoryjnej Uniwersyteckiego Centrum Klinicznego (UCML UCK) w Gdańsku, w przedziale czasu od 8 października 2010 roku do 26 października 2011 roku. Analizowano wyniki badań osób w wieku powyżej 16 lat, bez dodatkowych ograniczeń populacyjnych.
Wyniki. Wejściowa baza danych liczyła 67 430 zarejestrowanych obserwacji pomiarowych. Po zastosowaniu wszystkich kryteriów wykluczenia do analiz zakwalifikowano łącznie 16 480 obserwacji pomiarowych dla 9726 pacjentów. Grupa badanych obejmowała 6619 (68,0%) kobiet i 3107 (32,0%) mężczyzn. Poniżej 40. r.ż. było 2134 (32,2%) kobiet i 1008 (22,4%) mężczyzn. U 8252 osób oznaczono stężenie TSH w surowicy. Wśród nich 5547 osób stanowiły kobiety (32,83% poniżej i 67,17% powyżej 40. r.ż.), a 2705 mężczyźni (23,51% poniżej i 76,49% powyżej 40. r.ż.). Oznaczenie stężenia fT4 wykonano u 4916 osób: 3565 kobiet (35,57% poniżej i 64,43% powyżej 40. r.ż.) i 1351 mężczyzn (21,76% poniżej i 78,24% powyżej 40. r.ż.). Oznaczenie stężenia fT3 wykonano u 3312 osób: 2337 kobiet (27,86% poniżej i 72,14% powyżej 40. r.ż.) i 975 mężczyzn (20% poniżej i 80% powyżej 40. r.ż.).
Wnioski. Górna i dolna wartość zakresu referencyjnego dla TSH dla pełnego odniesienia (bez rozróżnienia na płeć i wiek) wyniosła odpowiednio 3,78 i 0,43 μIU/ml. Zakres referencyjny sugerowany przez producenta odczynnika w zestawach używane w Centralnym Laboratorium Klinicznym profilu tarczycy wahają się od 0,35 do 4,94 μIU/ml. Zakres odniesienia TSH w surowicy jest niższy niż wartości końcowe sugerowane przez producenta zestawu odczynników.
Na podstawie wyników testu całej grupy odniesienia, dolny i górny zakres wartości referencyjnych swobodnych frakcji tarczycy wyniosły 11,13 i 15,87 pmol/L (fT4), a także 2,92 i 5,41 pmol/L (fT3). Referencyjne zakresy sugerowane przez producenta wyniosły od 9,01 do 19,05 pmol/L (fT4) i od 2,63 do 5,70 pmol/L (fT3) w surowicy.
Summary
Introduction. In recent years, attention has been paid to the fact that the reference intervals applied in laboratories do not meet endocrinologists’ expectations. This problem is of great importance with regard to thyroid profile parameters. According to some endocrinologists, the currently used reference ranges for these parameters have been defined for too wide groups.
Aim. The purpose of this study is the attempt to determine internal reference intervals of the basic thyroid profile parameters: TSH, fT4 and fT3 taking into account the specificity patients’ population.
Material and methods. The analysis covers test results of TSH, fT4 and fT3 levels in serum collected by the Central Clinical Laboratory of the Laboratory Medicine Center of the University Clinical Center in Gdansk (UCML UCK). Only tests results collected in the period from 8 October 2010 to 26 October 2011 were taken into account. Moreover, only results of patients aged over 16 years with no additional population limits were considered relevant.
Results. The initial amount of data reached 67 430 registered test observations. After the application of all exclusion criteria, there were 16 480 test observations for 9726 patients in total to be considered in the analysis. The group under research included 6619 (68.0%) female patients and 3107 (32.0%) male patients. There were 2134 (32.2%) women under the age of 40 and 1008 (22.4%) men under the age of 40. TSH level in serum was estimated in 8252 individuals. Within this group, there were 5547 women (32.83% under the age of 40 and 67.17% aged over 40 years) and 2705 men (23.51% under the age of 40 and 76.49% aged over 40 years). FT4 level estimation was performed in 4916 patients: in 3565 women (35.57% under the age of 40 and 64.43% aged over 40 years) and 1351 men (21.76% under the age of 40 and 78.24% aged over 40 years). FT3 level was estimated in 3312 individuals: 2337 women (27.86% under the age of 40 and 72.14% aged over 40 years) and 975 men (20% under the age of 40 and 80% aged over 40 years).
Conclusions. Upper and poured value of referential scope for TSH for the full reference (without distinguishing to the sex and the age) took out appropriately 3.78 and 0.43 μIU/ml. Range referential suggested by the producer of reagent in sets used in the Central clinical laboratory setting of the profile of the thyroid gland are hesitating from 0.35 to 4.94 μIU/ml. The TSH range of reference in serum is lower than final values suggested by the producer of the set of reagents.
Based on test results of the entire reference group, amounted to the bottom and upper scope of free ratable values of the faction of the thyroid gland 11.13 and 15.87 pmol/L (fT4), as well as 2.92 and 5.41 pmol/L (fT3). Referential scopes suggested by the producer took out from 9.01 to 19.05 pmol/L (fT4) and from 2.63 to 5.70 pmol/L (fT3) in serum.
Introduction
In recent years, attention has been paid to the fact that the reference intervals applied in laboratories do not meet endocrinologists’ expectations. This problem is of great importance with regard to thyroid profile parameters. According to some endocrinologists, the currently used reference ranges for these parameters have been defined for too wide groups.
For example, the reference groups involved in the process of determining reference ranges included patients with subclinical hypothyroidism (1-4). This subclinical dysfunction is characterized by an elevated level of thyroid stimulating hormone (TSH) in serum as well as by free thyroxine (fT4) and free triiodothyronine (fT3) levels close to reference range ends. These factors disturb the process of determining reference ranges. Results of population-based studies have confirmed that subclinical hypothyroidism has been observed in 10% of the population (5). Early diagnosed subclinical hypothyroidism becomes more important because this dysfunction is one of the risk factors of the development of hypothyroidism, cardiovascular disorders, lipid disorders, miscarriage, depression, and other pathological conditions (6). Therefore, it has been more and more frequently emphasized that the upper TSH reference range end should be lowered. In a majority of laboratories, the reference range end currently oscillates between 4.0-5.0 μIU/mL (1-4, 7).
For many years, the need to define credible reference systems has been the reason of attempts to define reference ranges of laboratory test results in hospital population. According to the guidelines of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), clinical laboratories ought to verify the reference ranges that are used by these laboratories (8). Such procedure aims at the identification of population-specific deviations of laboratory test results. However, due to the considerably time-consuming and expensive nature of such activities, the establishment of internal reference intervals according to the IFCC guidelines exceeds the capacity of most laboratories. Alternatives are: the application of reference ranges described in literature, using reference ranges recommended by manufacturers of laboratory reagent kits, and “borrowing” reference range values from other laboratories. Nevertheless, such procedure involves a risk of disturbing factors such as the characteristics of the particular target population, equipment factors and methodological factors. The above mentioned conditions justify the need of searching new, more cost-efficient and accessible methods of establishing internal reference ranges.
Aim
The purpose of this study is the attempt to determine internal reference intervals of the basic thyroid profile parameters: TSH, fT4 and fT3 taking into account the specificity patients’ population.
The structure of the study involves the model of retrospective analysis of thyroid profile parameter test results collected in the database of the Central Clinical Laboratory of the University Clinical Center in Gdansk.
Material and methods
The analysis covers test results of TSH, fT4 and fT3 levels in serum collected by the Central Clinical Laboratory of the Laboratory Medicine Center of the University Clinical Center in Gdansk (UCML UCK). Only tests results collected in the period from 8 October 2010 to 26 October 2011 were taken into account. Moreover, only results of patients aged over 16 years with no additional population limits were considered relevant.
A series of exclusion criteria was applied to filter the information from the database. The first exclusion criterion was a missing PESEL (i.e. the unique 11-digit personal identification number of Polish citizens). PESEL enables clear identification of patients and provides date of birth and gender required for the purpose of the analysis.
Another exclusion criterion was that the pre-analytical phase of the diagnostic process (involving i.e. preparation of individuals before collecting the sample, sample collection, transportation and storage of the biological material) was performed exclusively in the University Clinical Center (UCK) in order to ensure compliance of procedures.
Test results of patients of UCK departments and clinics with specializations posing risk of falsifying the established reference ranges (endocrinology and maternity clinics and medical practices, as well as intensive care units) were also rejected. The remaining exclusion criteria were as follows: patients participated in the multi-center public health research (9), level values were beyond the valid Central Clinical Laboratory (10), the same parameter was tested twice or more frequently within the analyzed period, and, simultaneously, there was a positive test result for thyroglobulin, thyroid peroxidase and thyrotropin hormone receptor antibodies.
Ethics
The study protocol has been approved by the Local Bioethics Committee of the Medical University of Gdansk. Due to the character of the analyzed data (results of routine laboratory tests collected due to various reasons) and the aggregate, retrospective character of the analysis, individual patient’s consent was not required.
Laboratory estimation methods
In the Central Clinical Laboratory, the CMIA method (Abbott Laboratories Poland) was applied for quantitative determination of TSH, fT4 and fT3 in serum. The reference ranges recommended by the reagent kit producer for the specific parameters, obtained by means of AxSYM Ultrasensitive hTSH II and AxSYM Free T4 estimation results in healthy individuals are the following: 0.35-4.94 μIU/mL for TSH (99% confidence interval, a group of 549 patients), 9.01-19.05 pmol/L for fT4 (99% confidence interval, a group of 411individuals) and 2.63-5.7 pmol/L for fT3 (95% confidence interval, a group of 436 patients) (10).
Statistical analysis
Distribution normality of the results of the analyzed parameters was tested by means of the Cramer-von Mises normality test. Descriptive statistics such as mean and median were calculated for the groups under research. A non-parametric method was applied to establish the reference ranges of all the analyzed parameters. The Q 2.5 and Q 97.5 quantile values were adopted as the upper and the low end respectively. The data was calculated by means of Statistica 10.0 and the R 2.15.0 statistical computing package.
Results
The initial amount of data reached 67 430 registered test observations. After the application of all exclusion criteria, there were 16 480 test observations for 9726 patients in total to be considered in the analysis. The group under research included 6619 (68.0%) female patients and 3107 (32.0%) male patients. There were 2134 (32.2%) women under the age of 40 and 1008 (22.4%) men under the age of 40. TSH level in serum was estimated in 8252 individuals. Within this group, there were 5547 women (32.83% under the age of 40 and 67.17% aged over 40 years) and 2705 men (23.51% under the age of 40 and 76.49% aged over 40 years). FT4 level estimation was performed in 4916 patients: in 3565 women (35.57% under the age of 40 and 64.43% aged over 40 years) and 1351 men (21.76% under the age of 40 and 78.24% aged over 40 years). FT3 level was estimated in 3312 individuals: 2337 women (27.86% under the age of 40 and 72.14% aged over 40 years) and 975 men (20% under the age of 40 and 80% aged over 40 years).

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Piśmiennictwo
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2. Brabant G, Beck-Peccoz P, Jarzab B et al.: Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol 2006; 154(5): 633-637.
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8. Solberg H: Establishment and use of reference values. [In:] Burtis C, Ashwood E, Bruns D (eds.): Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. Saunders, St. Louis 2006: 425-448.
9. Zdrojewski T, Wyrzykowski B, Szczech R et al.; Steering Committees of the Programmes NATPOL PLUS; SMS; Polish 400-Cities Project: Epidemiology and prevention of arterial hypertension in Poland. Blood Press 2005; 2 (suppl.): 10-16.
10. Standardowa procedura operacyjna oznaczania stężenia TSH/FT4/FT3 w surowicy Abbott Laboratories: ref. 7K62 49-4654/R03 B7K62. Pref. 7K65 49-0272/R3B7K65P.
11. Kokot F: Diagnostyka różnicowa objawów chorobowych. PZWL, Warszawa 2007.
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16. Hamilton TE, Davis S, Onstad L et al.: Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab 2008; 93(4): 1224-1230.
otrzymano: 2018-07-05
zaakceptowano do druku: 2018-07-26

Adres do korespondencji:
*Marlena Robakowska
Department of Public Health and Social Medicine Faculty of Health Sciences with Institute of Maritime and Tropical Medicine Medical University of Gdansk
42A Zwyciestwa Av., 80-210 Gdansk, Poland
Phone: +48 (58) 3492045
E-mail: marlena.robakowska@gumed.edu.pl

Postępy Nauk Medycznych 4/2018
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