Reference interval by the indirect approach of serum thyrotropin (TSH) in a Mediterranean adult population and the association with age and gender
Abstract
Background
The serum concentration of thyrotropin (TSH) represents a first-line test in diagnostic algorithms. The estimation of TSH reference intervals (RIs) is still a matter of debate due to the high prevalence of subclinical disease making difficult the definition of truly healthy subjects. The aim of this study was to estimate TSH RIs in healthy subjects and to evaluate the effect of age and gender on TSH concentration.
Methods
Forty-four thousand one hundred and fifty-six TSH data were collected between July 2012 and April 2018 at the Department of Laboratory Medicine, University-Hospital, Palermo. Common and sex-specific RIs were estimated by Arzideh’s indirect method after exclusion of individuals younger than 15 years, subjects with repeated TSH tests and with abnormal free thyroxine (fT4), free triiodothyronine (fT3) or anti-thyroid-peroxidase antibodies. The combined effect of age and gender on TSH values was evaluated.
Results
RIs estimated in the selected individuals (n = 22602) were, respectively, 0.18–3.54 mIU/L (general), 0.19–3.23 mIU/L (men) and 0.18–3.94 mIU/L (women). Women showed significantly higher median TSH than men (1.46 vs. 1.39 mIU/L; p < 0.0001). Both in men and in women, median TSH decreased along with age; however, although up to 60 years in both men and women showed similar values, afterwards women showed constantly higher TSH than men. Accordingly, statistical analysis showed a significant interaction between gender and age (p = 0.001), suggesting that the effect of age on TSH is different between genders.
Conclusions
Our findings suggest that the indirect method, with appropriate cleaning of data, could be useful to define TSH RIs.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid 2011;21:5–11.10.1089/thy.2010.0092Search in Google Scholar PubMed PubMed Central
2. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007;92:4575–82.10.1210/jc.2007-1499Search in Google Scholar PubMed
3. d’Herbomez M, Jarrige V, Darte C. Reference intervals for serum thyrotropin (TSH) and free thyroxine (FT4) in adults using the Access Immunoassay System. Clin Chem Lab Med 2005;43:102–5.10.1515/CCLM.2005.017Search in Google Scholar PubMed
4. Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab 2010;95:496–502.10.1210/jc.2009-1845Search in Google Scholar PubMed
5. Grasbeck R, Saris NE. Establishment and use of normal values. Scand J Clin Lab Invest 1969;26:62–3.Search in Google Scholar
6. IFCC, CLSI, EP28-A3c Document. Defining, establishing, and verifying reference intervals in the clinical laboratory: approved guideline, 3rd ed., vol. 28, No. 30. Wayne, PA: CLSI, 2010.Search in Google Scholar
7. Sunderman Jr FW. Current concepts of “normal values,” “reference values,” and “discrimination values” in clinical chemistry. Clin Chem 1975;21:1873–7.10.1093/clinchem/21.13.1873Search in Google Scholar
8. Grasbeck R. The evolution of the reference value concept. Clin Chem Lab Med 2004;42:692–7.10.1515/CCLM.2004.118Search in Google Scholar PubMed
9. Katayev A, Balciza C, Seccombe DW. Establishing reference intervals for clinical laboratory test results; is there a better way? Am J Clin Pathol 2010;133:175–7.10.1309/AJCPN5BMTSF1CDYPSearch in Google Scholar PubMed
10. Grossi E, Colombo R, Cavuto S, Franzini C. The REALAB project: a new method for the formulation of reference intervals based on current data. Clin Chem 2005;51:1232–40.10.1373/clinchem.2005.047787Search in Google Scholar PubMed
11. Henny J, Vassault A, Boursier G, Vukasovic I, Brguljan PM, Lohmander M, et al. Recommendation for the review of biological reference intervals in medical laboratories. Clin Chem Lab Med 2016;54:1893–900.10.1515/cclm-2016-0793Search in Google Scholar PubMed
12. Agnello L, Bellia C, Lo Sasso B, Pivetti A, Muratore M, Scazzone C, et al. Establishing the upper reference limit of Galectin-3 in healthy blood donors. Biochem Med (Zagreb) 2017;27:030709.10.11613/BM.2017.030709Search in Google Scholar PubMed PubMed Central
13. Bellia C, Zaninotto M, Cosma C, Agnello L, Lo Sasso B, Bivona G, et al. Definition of the upper reference limit of glycated albumin in blood donors from Italy. Clin Chem Lab Med 2017;56:120–5.10.1515/cclm-2017-0179Search in Google Scholar
14. Bivona G, Agnello L, Ciaccio M. Vitamin D and immunomodulation: is it time to change the reference values? Ann Clin Lab Sci 2017;47:508–10.Search in Google Scholar
15. Haeckel R, Wosniok W, Arzideh F, Zierk J, Gurr E, Streichert T. Critical comments to a recent EFLM recommendation for the review of reference intervals. Clin Chem Lab Med 2017;55:341–7.10.1515/cclm-2016-1112Search in Google Scholar
16. Ritchie RF, Palomaki G. Selecting clinically relevant populations for reference intervals. Clin Chem Lab Med 2004;42:702–9.10.1515/CCLM.2004.120Search in Google Scholar
17. Wang Y, Zhang YX, Zhou YL, Xia J. Establishment of reference intervals for serum thyroid-stimulating hormone, free and total thyroxine, and free and total triiodothyronine for the Beckman Coulter DxI-800 analyzers by indirect method using data obtained from Chinese population in Zhejiang Province, China. J Clin Lab Anal 2017;31:e22069.10.1002/jcla.22069Search in Google Scholar
18. Pryce SD. Level of haemoglobin in whole blood and red blood cells, and proposed convention for defining normality. Lancet 1960;ii:233–6.10.1016/S0140-6736(60)91480-XSearch in Google Scholar
19. Hoffmann R G. Statistics in the practice of medicine. J Am Med Assoc 1963;185:964–73.10.1001/jama.1963.03060110068020Search in Google Scholar PubMed
20. Arzideh F, Wosniok W, Gurr E, Hinsch W, Schumann G, Weinstock N, et al. A plea for intra-laboratory reference limits. Part 2. A bimodal retrospective concept for determining reference limits from intra-laboratory databases demonstrated by catalytic activity concentrations of enzymes. Clin Chem Lab Med 2007;45:1043–57.10.1515/CCLM.2007.250Search in Google Scholar PubMed
21. Arzideh F, Wosniok W, Haeckel R. Reference limits of plasma and serum creatinine concentrations from intra-laboratory data bases of several German and Italian medical centres: Comparison between direct and indirect procedures. Clin Chim Acta 2010;411:215–21.10.1016/j.cca.2009.11.006Search in Google Scholar PubMed
22. Arzideh F, Brandhorst G, Gurr E, Hinsch W, Hoff T, Roggenbuck L, et al. An improved indirect approach for determining reference limits from intra-laboratory data bases exemplified by concentrations of electrolytes. J Lab Med 2009;33:52–66.10.1515/JLM.2009.015Search in Google Scholar
23. Jones GR, Haeckel R, Loh TP, Sikaris K, Streichert T, Katayev A, et al. IFCC Committee on Reference Intervals and Decision Limits. Indirect methods for reference interval determination – review and recommendations. Clin Chem Lab Med 2018;57:20–9.10.1515/cclm-2018-0073Search in Google Scholar PubMed
24. Tozzoli R, D’Aurizio F, Metus P, Steffan A, Mazzon C, Bagnasco M. Reference intervals for thyrotropin in an area of Northern Italy: the Pordenone Thyroid Study (TRIPP). J Endocrinol Invest 2018;41:985–94.10.1007/s40618-018-0825-0Search in Google Scholar PubMed
25. Arzideh F, Wosniok W, Haeckel R. Indirect reference intervals of plasma and serum thyrotropin (TSH) concentrations from intra-laboratory data bases from several German and Italian medical centres. Clin Chem Lab Med 2011;49:659–64.10.1515/CCLM.2011.114Search in Google Scholar PubMed
26. Friis-Hansen L, Hilsted L. Reference intervals for thyrotropin and thyroid hormones for healthy adults based on the NOBIDA material and determined using a Modular E170. Clin Chem Lab Med 2008;46:1305–12.10.1515/CCLM.2008.258Search in Google Scholar PubMed
27. Dhatt GS, Griffin G, Agarwal MM. Thyroid hormone reference intervals in an ambulatory Arab population on the Abbot Architect i2000 immunoassay analyzer. Clin Chim Acta 2006;364:226–9.10.1016/j.cccn.2005.07.003Search in Google Scholar PubMed
28. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab 2005;90:5489–96.10.1210/jc.2005-0170Search in Google Scholar PubMed
29. Hollowell JG, Stehling NW, Flanders WE. Serum TSH, T4 and anthyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87: 489–99.10.1210/jcem.87.2.8182Search in Google Scholar PubMed
30. Ehrenkranz J, Bach PR, Snow GL, Schneider A, Lee JL, Ilstrup S, et al. Circadian and circannual rhythms in thyroid hormones: determining the TSH and free T4 reference intervals based upon time of day, age, and sex. Thyroid 2015;25:954–61.10.1089/thy.2014.0589Search in Google Scholar PubMed
31. Cai J, Fang Y, Jing D, Xu S, Ming J, Gao B, et al. Reference intervals of thyroid hormones in a previously iodine-deficient but presently more than adequate area of western China: a population-based survey. Endocr J 2016;63:381–8.10.1507/endocrj.EJ15-0574Search in Google Scholar PubMed
32. Sriphrapradang C, Pavarangkoon S, Jongjaroenprasert W, Chailurkit LO, Ongphiphadhanakul B, Aekplakorn W. Reference ranges of serum TSH, FT4 and thyroid autoantibodies in the Thai population: the national health examination survey. Clin Endocrinol 2014;80:751–6.10.1111/cen.12371Search in Google Scholar PubMed
33. Amouzegar A, Delshad H, Mehran L, Tohidi M, Khafaji F, Aziz F. Reference limits of thyrotropin (TSH) and free thyroxine (FT4) in thyroperoxidase positive and negative subjects: a population based study. J Endocrinol Invest 2013;36:950–4.Search in Google Scholar
34. Schalin-Jäntti C, Tanner P, Välimäki MJ, Hämäläinen E. Serum TSH reference interval in healthy Finnish adults using the Abbott Architect 2000i analyzer. Scand J Clin Lab Invest 2011;71:344–9.10.3109/00365513.2011.568630Search in Google Scholar PubMed
35. Demers LM, Spencer CA. Laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003;58:138–40.10.1046/j.1365-2265.2003.01681.xSearch in Google Scholar PubMed
36. O’Leary PC, Feddema PH, Michelangeli VP, Leedman PJ, Chew GT, Knuiman M, et al. Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study. Clin Endocrinol (Oxf) 2006;64:97–104.10.1111/j.1365-2265.2005.02424.xSearch in Google Scholar PubMed
37. Milinković N, Ignjatović S, Žarković M, Jovičić S, Radosavljević B, Singh S, et al. Indirect estimation of age-related reference limits of thyroid parameters: a cross-sectional study of outpatients’ results. Scand J Clin Lab Invest 2014;74:378–84.10.3109/00365513.2014.898324Search in Google Scholar PubMed
38. Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 2009;94:1251–4.10.1210/jc.2008-2325Search in Google Scholar PubMed PubMed Central
39. van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab 2005;90:6403–9.10.1210/jc.2005-0872Search in Google Scholar PubMed
40. Magri F, Muzzoni B, Cravello L, Fioravanti M, Busconi L, Camozzi D, et al. Thyroid function in physiological aging and in centenarians: possible relationships with some nutritional markers. Metabolism 2002;51:105–9.10.1053/meta.2002.28968Search in Google Scholar PubMed
41. Clerico A, Trenti T, Aloe R, Dittadi R, Rizzardi S, Migliardi M, et al. A multicenter study for the evaluation of the reference interval for TSH in Italy (ELAS TSH Italian Study). Clin Chem Lab Med. 2018;57:259–67.10.1515/cclm-2018-0541Search in Google Scholar PubMed
42. Bagnasco M, Moleti M, Regalbuto C, Tonacchera M, Olivieri A. Iodoprofilassi 11 anni dopo: progressi e prospettive. L’Endocrinologo 2017;18:54–6.10.1007/s40619-017-0309-zSearch in Google Scholar
43. van de Ven AC, Netea-Maier RT, Smit JW, Kusters R, van der Stappen JW, Pronk-Admiraal CJ, et al. Thyrotropin versus age relation as an indicator of historical iodine intake. Thyroid 2015;25:629–34.10.1089/thy.2014.0574Search in Google Scholar PubMed
©2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Blood biomarkers in neurology: “a call to arms” for laboratory professionals
- Reviews
- Diagnostic accuracy of glycated hemoglobin for gestational diabetes mellitus: a systematic review and meta-analysis
- Laboratory medicine: health evaluation in elite athletes
- Prostate cancer screening: guidelines review and laboratory issues
- Opinion Papers
- Extra-analytical sources of uncertainty: which ones really matter?
- Benefits and harms of wellness initiatives
- Genetics and Molecular Diagnostics
- Analytical and clinical validation of a novel amplicon-based NGS assay for the evaluation of circulating tumor DNA in metastatic colorectal cancer patients
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical practices for routine coagulation tests in European laboratories. A collaborative study from the European Organisation for External Quality Assurance Providers in Laboratory Medicine (EQALM)
- Preanalytical robustness of blood collection tubes with RNA stabilizers
- Continual improvement of the pre-analytical process in a public health laboratory with quality indicators-based risk management
- Comparison of six commercial serum exosome isolation methods suitable for clinical laboratories. Effect in cytokine analysis
- A multicenter study to evaluate harmonization of assays for N-terminal propeptide of type I procollagen (PINP): a report from the IFCC-IOF Joint Committee for Bone Metabolism
- Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches
- Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury
- Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis
- Reference Values and Biological Variations
- Reference interval by the indirect approach of serum thyrotropin (TSH) in a Mediterranean adult population and the association with age and gender
- Next-generation reference intervals for pediatric hematology
- Hematology and Coagulation
- Preliminary evaluation of a new flow cytometry method for the routine hematology workflow
- Diabetes
- Trueness assessment of HbA1c routine assays: are processed EQA materials up to the job?
- Infectious Diseases
- Utility of procalcitonin for differentiating cryptogenic organising pneumonia from community-acquired pneumonia
- A high C-reactive protein/procalcitonin ratio predicts Mycoplasma pneumoniae infection
- Letters to the Editor
- Evaluation of reference change values for a hs-cTnI immunoassay using both plasma samples of healthy subjects and patients and quality control samples
- Outlier removal methods for skewed data: impact on age-specific high-sensitive cardiac troponin T 99th percentiles
- Comparison of precision and operational performances across six immunochemistry analyzers
- Evaluation of the possible interference of abiraterone therapy on testosterone immunoassay
- Erroneous thyroid and steroid hormones profile due to anti-streptavidin antibodies
- Reference values for 24,25-dihydroxyvitamin D and the 25-hydroxyvitamin D/24,25-dihydroxyvitamin D ratio
- Pre-analytical error in a hematology laboratory: an avoidable cause of compromised quality in reporting
- Stability of tubular damage markers epidermal growth factor and heparin-binding EGF-like growth factor in urine
- Blood from heparin tubes is an acceptable alternative to assess hematocrit determination
Articles in the same Issue
- Frontmatter
- Editorial
- Blood biomarkers in neurology: “a call to arms” for laboratory professionals
- Reviews
- Diagnostic accuracy of glycated hemoglobin for gestational diabetes mellitus: a systematic review and meta-analysis
- Laboratory medicine: health evaluation in elite athletes
- Prostate cancer screening: guidelines review and laboratory issues
- Opinion Papers
- Extra-analytical sources of uncertainty: which ones really matter?
- Benefits and harms of wellness initiatives
- Genetics and Molecular Diagnostics
- Analytical and clinical validation of a novel amplicon-based NGS assay for the evaluation of circulating tumor DNA in metastatic colorectal cancer patients
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical practices for routine coagulation tests in European laboratories. A collaborative study from the European Organisation for External Quality Assurance Providers in Laboratory Medicine (EQALM)
- Preanalytical robustness of blood collection tubes with RNA stabilizers
- Continual improvement of the pre-analytical process in a public health laboratory with quality indicators-based risk management
- Comparison of six commercial serum exosome isolation methods suitable for clinical laboratories. Effect in cytokine analysis
- A multicenter study to evaluate harmonization of assays for N-terminal propeptide of type I procollagen (PINP): a report from the IFCC-IOF Joint Committee for Bone Metabolism
- Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches
- Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury
- Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis
- Reference Values and Biological Variations
- Reference interval by the indirect approach of serum thyrotropin (TSH) in a Mediterranean adult population and the association with age and gender
- Next-generation reference intervals for pediatric hematology
- Hematology and Coagulation
- Preliminary evaluation of a new flow cytometry method for the routine hematology workflow
- Diabetes
- Trueness assessment of HbA1c routine assays: are processed EQA materials up to the job?
- Infectious Diseases
- Utility of procalcitonin for differentiating cryptogenic organising pneumonia from community-acquired pneumonia
- A high C-reactive protein/procalcitonin ratio predicts Mycoplasma pneumoniae infection
- Letters to the Editor
- Evaluation of reference change values for a hs-cTnI immunoassay using both plasma samples of healthy subjects and patients and quality control samples
- Outlier removal methods for skewed data: impact on age-specific high-sensitive cardiac troponin T 99th percentiles
- Comparison of precision and operational performances across six immunochemistry analyzers
- Evaluation of the possible interference of abiraterone therapy on testosterone immunoassay
- Erroneous thyroid and steroid hormones profile due to anti-streptavidin antibodies
- Reference values for 24,25-dihydroxyvitamin D and the 25-hydroxyvitamin D/24,25-dihydroxyvitamin D ratio
- Pre-analytical error in a hematology laboratory: an avoidable cause of compromised quality in reporting
- Stability of tubular damage markers epidermal growth factor and heparin-binding EGF-like growth factor in urine
- Blood from heparin tubes is an acceptable alternative to assess hematocrit determination