Thyroid-stimulating Hormone Reference Intervals Research Articles

Reference intervals for thyroid function from the fifth to seventh day of life in twin-pregnancy preterm neonates: an 8-year retrospective study.

The immature and developing hypothalamic-pituitary-thyroid axis leads to different levels of thyroid function in twin neonates, including free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) levels. No reference intervals for twins have been established until now. To compensate for this lack, we collected data and established this standard across different gestational ages (GAs) and sexes. A total of 273 pairs of neonates admitted to the NICU in Southeast China from 2015 to 2022 were included. Each pair was divided into Neonate A (relatively heavy birth weight (BW)) and Neonate B (relatively light BW). Their thyroid functions were analyzed to establish reference intervals and comparisons were made stratified by GA and sex. The FT3, FT4, and TSH reference intervals in twin neonates with a GA of 26-36 weeks were as follows: Neonate A and B: 3.59 ± 0.99 and 3.57 ± 1.00 pmol/L; Neonate A and B: 17.03 ± 5.16 and 16.77 ± 5.29 pmol/L; and Neonate A and B: 4.097 ± 3.688 and 4.674 ± 4.850 mlU/L, respectively. There were significant differences between serum FT3 and FT4 reference intervals and GA (p < 0.05). The serum FT3 and FT4 reference intervals for male neonates were lower than those for female neonates in the 29-32-week group (p < 0.05). This was the first study, to our knowledge, to establish reference intervals for thyroid function in twin neonates from the fifth to seventh day of life, which will be beneficial for the diagnosis and management of congenital hypothyroidism.

Should we depend on reference intervals from manufacturer package inserts? Comparing TSH and FT4 reference intervals from four manufacturers with results from modern indirect methods and the direct method.

Correct interpretation of thyroid function tests relies on correct reference intervals (RIs) for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). ISO15189 mandates periodic verification of RIs, but laboratories struggle with cost-effective approaches. We investigated whether indirect methods (utilizing historical laboratory data) could replace the direct approach (utilizing healthy reference individuals) and compared results with manufacturer-provided RIs for TSH and FT4. We collected historical data (2008-2022) from 13 Dutch laboratories to re-establish RIs by employing indirect methods, TMC (for TSH) and refineR (for FT4). Laboratories used common automated platforms (Roche, Abbott, Beckman or Siemens). Indirect RIs (IRIs) were determined perlaboratory per year and clustered per manufacturer (>1.000.000 data points per manufacturer). Direct RIs (DRIs) were established in 125 healthy individuals per platform. TSH IRIs remained robust over the years for all manufacturers. FT4 IRIs proved robust for three manufacturers (Roche, Beckman and Siemens), but the IRI upper reference limit (URL) of Abbott showed a decrease of 2 pmol/L from 2015. Comparison of the IRIs and DRIs for TSH and FT4 showed close agreement using adequate age-stratification. Manufacturer-provided RIs, notably Abbott, Roche and Beckman exhibited inappropriate URLs (overall difference of 0.5-1.0 µIU/mL) for TSH. For FT4, the URLs provided by Roche, Abbott and Siemens were overestimated by 1.5-3.5 pmol/L. These results underscore the importance of RI verification as manufacturer-provided RIs are often incorrect and RIs may not be robust. Indirect methods offercost-effective alternatives for laboratory-specific or platform-specific verification of RIs.

Establishment of Reference Interval of Thyroid Hormones and Autoantibodies: A Cross-sectional Study

Introduction: The accurate diagnosis of thyroid disease relies on the sensitivity and specificity of laboratory tests, which require specific reference intervals. Thyroid hormone levels can be influenced by factors such as age, gender, iodine intake and geographical region. Therefore, it is recommended for clinical laboratories to establish their own reference intervals. Aim: To establish reference intervals for Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Anti-thyroglobulin antibody (anti-TG), and Anti-Thyroid Peroxidase Antibody (antiTPO) in males and and females. Materials and Methods: A cross-sectional study was conducted in the Department of Biochemistry, Amrita Institute of Medical Sciences (AIMS), Kochi, India, from December 2021 to July 2022. The study included 217 apparently healthy subjects aged between 18 years and 60 years. TSH, FT4, anti-TPO, and anti-TG levels were analysed to establish reference values for males and females in the two age groups: 18-40 years and 41-60 years. Reference intervals for thyroid parameters were expressed as mean±Standard Deviation (SD), median, 2.5th and 97.5th percentiles. The Mann-Whitney U test was used to assess the statistical significance of thyroid parameters between gender and age groups. Results: The mean age in the female population was 38.24±11.64 years, while in the male population, it was 39.24±10.98 years. The reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO in females were determined as 0.80-4.12 μIU/mL, 0.99- 1.57 ngm/mL, &lt;85.33 IU/mL and &lt;45.13 IU/mL, respectively. In males, the reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO were determined as 0.51-5.09 μIU/mL, 1.03-1.79 ng/mL, &lt;87.09 IU/mL and &lt;33.88 IU/mL, respectively. There was a significant difference in anti-TPO (p-value=0.017) in males between the two age groups. A significant difference was also observed in FT4 (p-value=0.010) and anti-TPO (p-value=0.034) between males and females. Conclusion: The study successfully established reference intervals and cut-off values for TSH, FT4, anti-TG, and antiTPO. It was found that anti-TPO levels decrease significantly with age progression. Additionally, the reference interval for TSH was wider in the 41-60 years age group compared to the younger age group.

B-123 Utilization of Five Data Mining Algorithms Combined with Simplified Preprocessing to Establish Reference Intervals of Thyroid Related Hormones for Nonelderly Adults

Abstract Background Despite the extensive research on data mining algorithms, there is still a lack of a standard protocol to evaluate the performance of the existing algorithms. Therefore, the study aims to provide a novel procedure that combines data mining algorithms and simplified preprocessing to establish reference intervals (RIs), with the performance of five algorithms assessed objectively as well. Methods The Test data set and the Reference data set are the two data sets derived from the population undergoing a physical examination. After the thyroid-related hormone including thyroid stimulating hormone (TSH), free triiodo-thyronine (FT3), total triiodo-thyronine (TT3), free thyroxine(FT4), and total thyroxine (TT4) were measured by an ADVIA Centaur XP chemiluminescence immunoassay analyzer, five data algorithms were used to calculated RIs. Hoffmann, Bhattacharya, Expectation Maximum (EM), kosmic, and refineR algorithms combined with two-step data preprocessing respectively were implemented in the Test data set to establish RIs for thyroid-related hormones. The first step is to conduct a random sampling strategy to balance the ratio of sex and age, and the second step is to identify the outliers of variables in each subgroup by the Tukey method. Algorithm-calculated RIs were compared with the standard RIs calculated by transformed parametric method from the Reference data set in which reference individuals were selected following strict inclusion and exclusion criteria. RIs partition were comprehensively determined by the multiple linear regression and variance component analysis. Objective assessment of the methods is implemented by the bias ratio (BR) matrix, of which the BR threshold was set to 0.375. Results The levels of the all five thyroid-related hormones are significantly different in sex, with the male having lower TSH and higher FT3, FT4, TT3, and TT4 compared to the female. Further analysis indicates the establishment of sex-specific RIs for FT3 and FT4. Standard RIs derived from the Reference data set by transformed parametric method are 0.801–4.221 μIU/L for TSH, 2.58–3.82 pg/mL for FT3, 0.98–1.53 ng/dL for FT4, 0.80–1.38 ng/mL for TT3, 5.46–10.05 g/dL for TT4, respectively. There is a high consistency between TSH RIs established by the EM algorithm and the standard TSH RIs (BR = 0.063), although EM algorithms seems to perform poor on other hormones with the BR higher than 0.375. RIs calculated by Hoffmann, Bhattacharya, and refineR methods for free and total triiodo-thyronine, free and total thyroxine respectively are close and matched the standard RIs. Conclusion An effective approach for objectively evaluating the performance of the algorithm based on the BR matrix is established. EM algorithm combined with simplified preprocessing can handle data with significant skewness, but its performance is limited in other scenarios. The other four algorithms perform well for data with Gaussian or near-Gaussian distribution. Using the appropriate algorithm based on the data distribution characteristics is recommended.

A-338 TSH Reference Range in the First Trimester in a Iodine Sufficient Population of Pregnant Women Attended by the Public Health System in Curitiba South of Brazil

Abstract Background Thyroid diseases are common among women of reproductive age, and the serum concentration of thyroid-stimulating hormone (TSH) is the most used index to assess thyroid function during pregnancy. Changes in thyroid function during pregnancy can have a clinical impact on a woman's health and pregnancy outcome, as well as interfere with fetal health and child development. An adequate thyroid function is essential for normal intrauterine development. When comparing the levels of TSH between pregnant and non-pregnant women, TSH levels are lower in pregnancy, mainly in the first trimester, with gradual increase during pregnancy. Although some guidelines propose fixed TSH reference values in pregnancy according to the gestational trimester, the main recommendation is to carry out a study of their local population due to the significant variation in TSH reference range levels in different populations and different assays. Therefore, it is necessary to determine values of a reference interval for TSH for the local population of pregnant women. This study aims to determine the normal reference range of TSH in the first trimester of gestation in the public health system pregnant women from Curitiba. Methods This is an ongoing prospective cohort study, with the population sample from the pregnant women using the public health system, with age &amp;gt;18 years old in Curitiba, South of Brazil. 383 pregnant women were invited to participate. After evaluate the exclusion criteria (gestational age more than 13 weeks, twin pregnancy, thyroid disease, iodine ingestion, identification of the samples in the laboratory), 225 pregnant women had the TSH measured by chemiluminescent immunoassay on Atellica IM Analyzer (Siemens Healthineers), as well as the TPO-ab presence, FreeT4 and Total T4. The 2.5, 50 end 97,5 TSH percentiles were estimated for the normal pregnant population. Results The mean gestational age was 8,6 weeks (standard deviation 2.33). From 225 pregnant women, 22 (9.8%) had TPO-ab positive. The 2.5 and 97.5 percentiles of TSH were 0.12 and 5.28 μIU/mL after using de exclusion criteria. The populational iodine status was sufficient. In the TPO-ab positive population was found a higher level of TSH. The proportion of TPO-ab positive was significantly higher in the population with TSH &amp;gt;2.5 μIU/mL. Conclusions This preliminary data shows the TSH reference range with levels higher than other regions, reinforcing to do not use fixed values of TSH from other populations to evaluate the thyroid function in pregnancy. Comparing to the laboratory reference for non-pregnant adult (0.48 to 5.60 μIU/mL), the recommended reduction of 0.5 μIU/mL on upper limit and 0.4 μIU/mL on the lower limit found similar values to our findings.

B-159 Data Mining With the Bhattacharya Method as a Tool for Reference Interval Determination in Populations With Thyroid Disorders

Abstract Background Establishing a precise reference interval (RI) is crucial for laboratory diagnosis, population studies, and aiding physicians in patient follow-up treatment. Data mining and Bhattacharya analysis can be an efficient and cost-effective way to determine RIs for thyroid disorders based on large datasets. Bhattacharya analysis is a simple resolution method that detects distributions into Gaussian components. Unlike traditional reference interval studies using parametric or non-parametric statistics, Bhattacharya analysis does not exclude results from an “unhealthy” population before analysis. This study aimed to define the RI for thyroid-stimulating hormone (TSH) and free thyroxine (fT4) from three distinct regions in São Paulo, Brazil, using the Bhattacharya method. Methods The study was a 20-month retrospective analysis of a large laboratory database in São Paulo from February/2021 to September/2022. Individuals aged 21 or older with available TSH or fT4 results were selected, including only outpatient results. Three groups from different regions (R1, R2, R3) were studied and the indirect Bhattacharya method was used to determine each region’s RI values. The midpoint, upper and lower reference limits (URL and LRL), were calculated, and a data plot was created using Microsoft Excel. One-way ANOVA was used for multiple group comparisons and results with *P &amp;lt; 0.01 were considered statistically significant. Results A total of 234 903 TSH and fT4 records were obtained. The three groups showed significant differences in their mean age and TSH and fT4 results (P &amp;lt; 0.001). The mean age was 49.41 ± 16.9 for R1, 46.9 ± 9.6 for R2, and 53 ± 16 years old for R3. The average TSH value for all three regions was 2.44 µIU/mL (SD 0.18, CV 7.2%), and the average fT4 value was 1.17 ng/dL (SD 0.06, CV 4.7%). The central bin was selected for the best data distribution and close to the average or median for each group. The derived RIs for R1, R2, and R3 were compared for consideration of a common RI. Other criteria, such as the best bin size and at least four bins for the graph curve, were also applied. Altogether, Bhattacharya’s analysis identified the following estimates from all collection points for TSH and fT4: TSH Average LRL 0.43 µIU/mL (SD 0.07, CV 16.6%)/TSH Average URL 6.45 µIU/mL (SD 0.85, CV 13.1%)/TSH Average Range 6.03 µIU/mL (SD 0.88, CV 14.6%)/fT4 Average LRL 0.82 ng/dL (SD 0.07, CV 8.1%)/fT4 Average URL 1.47 ng/dL (SD 0.07, CV 4.4%)/fT4 Average Range 0.65 ng/dL (SD 0.02, CV 3.5%). 9.7% of individuals in R3 had results outside the accepted RIs for TSH and fT4, compared to R2 as a standard population with the lowest possibility of relevant thyroid disorders. Conclusion Bhattacharya’s non-parametric method could be useful to determine reference values and laboratory analysis of populations with distinct characteristics. The study highlights the importance of choosing the correct control group in comparison studies, and the potential bias in unifying distinct regions to determine RIs. The low cost of data mining makes it possible for nearby laboratories to perform similar studies using the Bhattacharya method to establish RI results suitable for specific patient populations.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. None.

Thyroid Hormone Reference Intervals among Healthy Individuals In Lanzhou, China.

The common reference intervals (RIs) for thyroid hormones currently used in China are provided by equipment manufacturers. This study aimed to establish thyroid hormone RIs in the population of Lanzhou, a city in the subplateau region of northwest China, and compare them with previous reports and manufacturer-provided values. In total, 3,123 individuals (1,680 men, 1,443 women) from Lanzhou, an iodine-adequate area of China, perceived as healthy were selected. The Abbott Architect analyzer was used to determine the serum concentration of thyroid hormones. The 95% RI was estimated using the 2.5th and 97.5th percentiles as the lower and upper reference limits, respectively. The serum levels of thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), antithyroglobulin (ATG) antibody, and antithyroid peroxidase (ATPO) antibody levels were significantly correlated with sex (P<0.05). TSH, total thyroxine (TT4), and ATPO levels were significantly correlated with age (P<0.05). The serum levels of TSH, ATG, and ATPO in men were significantly lower than in women; in contrast, the serum TT3 level was significantly higher in men than in women (P<0.05). Serum TSH, TT3, TT4, and ATG levels differed across age groups (P<0.05), but no such variation was observed for ATG levels (P>0.05). The established RIs of TSH, ATG, and ATPO in this study differed between sexes (P<0.05). The thyroid hormone RIs established herein were inconsistent with the manufacturer-provided values. The RIs of thyroid hormones in the healthy population of Lanzhou were inconsistent with those in the manufacturer's manual. Validated sex-specific values are required for diagnosing thyroid diseases.

Neonatal reference intervals for thyroid stimulating hormone and free thyroxine assayed on a Siemens Atellica® IM analyzer: a cross sectional study

BackgroundDeriving population specific reference intervals (RIs) or at the very least verifying any RI before adoption is good laboratory practice. Siemens has provided RIs for thyroid stimulating hormone (TSH) and free thyroxine (FT4) determined on their Atellica® IM analyzer for all age groups except the neonatal age group which provides a challenge for laboratories that intend to use it to screen for congenital hypothyroidism (CH) and other thyroid disorders in neonates. We set out to determine RIs for TSH and FT4 using data obtained from neonates undergoing routine screening for CH at the Aga Khan University Hospital, Nairobi, Kenya.MethodologyTSH and FT4 data for neonates aged 30 days and below were extracted from the hospital management information system for the period March 2020 to June 2021. A single episode of testing for the same neonate was included provided both TSH and FT4 were done on the same sample. RI determination was performed using a non-parametric approach.ResultsA total of 1243 testing episodes from 1218 neonates had both TSH and FT4 results. A single set of test results from each neonate was used to derive RIs. Both TSH and FT4 declined with increase in age with a more marked decline seen in the first 7 days of life. There was a positive correlation between logFT4 and logTSH (rs (1216) = 0.189, p = < 0.001). We derived TSH RIs for the age groups 2–4 days (0.403–7.942 µIU/mL) and 5–7 days (0.418–6.319 µIU/mL), and sex specific RIs for males (0.609–7.557 µIU/mL) and females (0.420–6.189 µIU/mL) aged 8–30 days. For FT4, separate RIs were derived for the age groups 2–4 days (1.19–2.59 ng/dL), 5–7 days (1.21–2.29 ng/dL) and 8–30 days (1.02–2.01 ng/dL).ConclusionOur neonatal RIs for TSH and FT4 are different from those published or recommended by Siemens. The RIs will serve as a guide for the interpretation of thyroid function tests in neonates from sub-Saharan Africa where routine screening for congenital hypothyroidism using serum samples is done on the Siemens Atellica® IM analyzer.

Reference Intervals for Thyroid Hormones and Thyroid Volume in Children Aged 7 ~ 13 Years from Iodine-Sufficient Areas in Tianjin, China.

Reference intervals (RIs) for serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) suitable for local children are urgently needed in northern China. The reference interval for thyroid volume (Tvol) in Chinese children also differed greatly from that recommended by the WHO. This study aimed to establish TSH, FT3, FT4, and Tvol RIs suitable for children in northern China. A total of 1070 children aged 7 ~ 13 were recruited from iodine nutrition-sufficient areas in Tianjin, China, from 2016 to 2021. Four hundred fifty-eight children aged 7 ~ 13years, and 815 children aged 8 ~ 10years were eventually included to study RIs for the thyroid hormones and Tvol. RIs for thyroid hormones were established in accordance with the Clinical Laboratory Standards Institute (CLSI) document C28-A3 guidelines. Quantile regression was used to analyze the influencing factors of Tvol. RIs for TSH, FT3, and FT4 were 1.23 (1.14 ~ 1.32) to 6.18 (5.92 ~ 7.26) mIU/L, 5.43 (5.29 ~ 5.52) to 7.89 (7.66 ~ 7.98) pmol/L, and 13.09 (12.85 ~ 13.73) to 22.22 (21.61 ~ 22.51) pmol/L. There was no need to establish RIs by age and gender. Our RIs could increase the prevalence of subclinical hyperthyroidism (P < 0.001) and reduce the prevalence of subclinical hypothyroidism (P < 0.001). Body surface area (BSA) and age are correlated with the 97th percentile of Tvol (both P < 0.001). Our reference interval could increase the goiter rate in children from 2.97 to 4.96% (P = 0.007). The thyroid hormones' reference intervals suitable for local children should be established. In addition, BSA and age should be considered when establishing Tvol reference interval.

Indirect Estimation of the Pediatric Reference Intervals for Thyroid Function Tests in Public Health Laboratory.

Reference intervals (RI) are an essential section of the information that medical laboratories present to clinicians to facilitate the management process of the patient. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) are the most valuable and cost-effective parameters of thyroid functions. According to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), Clinical and Laboratory Standards Institute (CLSI), and American Thyroid Association (ATA), every laboratory should determine own RI on own population and method. In this study we aim to evaluate the pediatric reference intervals in a public health laboratory. The results of TSH, fT4, and fT3 from pediatric patients (aged: 0 - 18 years) were included in our study. These results were stored in our laboratory information system. TSH, fT4, and fT3 are measured in Abbott Architect i2000 (Abbott Diagnostics, Abbott Park, IL, USA) chemiluminescent microparticle immunoassay analyzer. RI study was conducted according to CLSI EP28-A3 guidelines. Results were evaluated with MedCalc ver. 19.2.1 (MedCalc Software Ltd., Ostend, Belgium), and Minitab 19.2 (Minitab Statistical Software, AppOnFly Inc., San Fransisco, CA, USA). The final study included 483 samples. Study sample consisted of 288 girls and 195 boys. Our reference intervals for TSH, fT4 and fT3 were found as 0.74 - 4.11 mIU/L, 0.80 - 1.42 ng/dL, and 2.40 - 4.38 pg/mL, respectively. Reference intervals were compatible with expected values in the insert sheets, except for fT3. Laboratories should implement their reference intervals based on CLSI C28-A3 guidelines.

Reference intervals for thyroid hormones for the elderly population and their influence on the diagnosis of subclinical hypothyroidism.

This study aims to establish reference intervals (RIs) for thyroid hormones in the elderly population and analyze their influence on the prevalence of subclinical hypothyroidism. Thyroid hormone records of subjects who underwent routine health checkup at our hospital between 2018 and 2020 were analyzed. Thyroid stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine (FT3), and free thyroxine (FT4) levels were compared between young and elderly subjects. Thresholds of these thyroid hormones were established for elderly subjects. A total of 22,207 subjects were included. Of them, 2,254 (10.15%) were aged ≥ 65 years. Elderly subjects had higher TSH, and lower FT3 and FT4 levels when compared with young subjects. In the elderly group, the RIs for TSH, FT3 and FT4 were 0.55-5.14 mIU/L, 3.68-5.47 pmol/L, and 12.00-19.87 pmol/L, respectively. The age and sex specific RIs for TSH were 0.56-5.07 mIU/L for men and 0.51-5.25 mIU/L for women. With whole-group RIs and age and sex-specific RIs for elderly people, the prevalence of subclinical hypothyroidism was 9.83% and 6.29% (p < 0.001), respectively. Elderly individuals had higher TSH levels than young individuals. Our study indicated that establishing specific RIs for elderly individuals is needed. This has implications for the diagnosis and management of subclinical hypothyroidism in the elderly population.

Laboratory policies and practices for thyroid function tests in Croatia: survey on behalf of Working Group for Laboratory Endocrinology of the Croatian Society of Medical Biochemistry and Laboratory Medicine.

IntroductionLaboratory plays important part in screening, diagnosis, and management of thyroid disorders. The aim of this study was to estimate current laboratory preanalytical, analytical and postanalytical practices and policies in Croatia.Materials and methodsWorking Group for Laboratory Endocrinology of the Croatian Society of Medical Biochemistry and Laboratory Medicine designed a questionnaire with 27 questions and statements regarding practices and protocols in measuring thyroid function tests. The survey was sent to 111 medical biochemistry laboratories participating in external quality assurance scheme for thyroid hormones organized by Croatian Centre for Quality Assessment in Laboratory Medicine. Data is presented as absolute numbers and proportions.ResultsFifty-three participants returned the questionnaire. Response rate varied depending on question, yielding a total survey response rate of 46-48%. All respondents perform thyroid stimulating hormone (TSH). From all other thyroid tests, most performed is free thyroxine (37/53) and least TSH-stimulating immunoglobulin (1/53). Laboratories are using nine different immunoassay methods. One tenth of laboratories is verifying manufacturer’s declared limit of quantification for TSH and one third is verifying implemented reference intervals for all performed tests. Most of laboratories (91%) adopt the manufacturer’s reference interval for adult population. Reference intervals for TSH are reported with different percentiles (90, 95 or 99 percentiles).ConclusionThis survey showed current practices and policies in Croatian laboratories regarding thyroid testing. The results identified some critical spots and will serve as a foundation in creating national guidelines in order to harmonize laboratory procedures in thyroid testing in Croatia.

Adult and neonate TSH blood spot reference intervals.

Background: Neonatal congenital hypothyroidism screening is performed by measuring thyroid-stimulating hormone (TSH) in a dried blood spot (DBS) sample, whereas acquired hypothyroidism uses serum TSH. There is no established DBS TSH reference interval, but knowing this is useful, as some patients cannot tolerate venepuncture, so DBS collection is seen as an acceptable alternative. The aim of this study was to establish DBS TSH reference intervals in adults and neonates (day 5-8), and determine the relationship between serum and DBS TSH.Methods: Euthyroid adults, not on thyroid medication and with a normal haematocrit, were selected. If they had a paired lithium heparin sample, DBS were prepared by spotting 50µL of whole blood onto filter paper. Dried blood spot TSH was measured using the PerkinElmer Neonatal hTSH kit on the GSP instrument and serum using the Abbott Architect assay. The relationship between DBS and serum TSH was analysed using Passing-Bablok regression and the adult DBS TSH reference interval calculated using transformed data. The neonatal reference interval was calculated from screening results using the non-parametric method.Results: Overall, 109 adult samples were included in the study (61 female). The Passing-Bablok regression was: DBS TSH = 0.68 × serum TSH + 0.07, and reference interval was 0.49-3.07 mU/L. The neonatal DBS reference interval was 0.40-4.10 mU/L from 8351 results.Conclusion: This study derived adult and neonate TSH DBS reference intervals using the GSP analyser and established the relationship between serum and DBS TSH. Knowing this information will allow for improved interpretation of DBS TSH results.

Accurate interpretation of thyroid dysfunction during pregnancy: should we continue to use published guidelines instead of population-based gestation-specific reference intervals for the thyroid-stimulating hormone (TSH)?

BackgroundConsidering the changes in thyroid physiology associated with pregnancy and poor outcomes related to abnormal maternal thyroid function, international guidelines recommend using population-based trimester-specific reference intervals (RIs) for thyroid testing. If these RIs are not available in the laboratory, implementing recommended fixed cut-off values globally is still controversial. To address this issue, we aimed to establish appropriate RI of thyroid-stimulating hormone (TSH) in pregnant Turkish women for our laboratory and compare the prevalence of thyroid dysfunction based on the established and recommended criteria.MethodsOf 2638 pregnant women, 1777 women followed in the obstetric outpatient were enrolled in the reference interval study after applying exclusion criteria related to medical and prenatal history. A retrospective study was conducted by collecting data from July 2016 to March 2019. Serum TSH was measured by UniCel DxI 800 Immunoassay System (Beckman Coulter Inc., Brea, CA, USA). The study design relied on two approaches in order to classify pregnant women: trimester-specific and subgroup-specific; the latter involved dividing each trimester into two subgroups: T1a, T1b, T2a, T2b, T3a, T3b. The lower and upper limits of the RIs were derived by the parametric method after normalizing the data distribution using the modified Box-Cox power transformation method.ResultsThe lowest TSH value was detected at 8-12 weeks in early pregnancy, and the median value of TSH in the T1b subgroup was significantly lower than the T1a subgroup (P < 0.05). TSH levels showed a gradual trend of increase along with the pregnancy and increased significantly in the T2a, T2b, and T3b subgroups compared to the preceding subgroups (P < 0.05). Compared to the diagnostic criteria recommended by American Thyroid Association (ATA), the prevalence of thyroid dysfunction was significantly different from the established trimester- and subgroup-specific RIs throughout the pregnancy (P < 0.001).ConclusionsWe conclude that establishing gestation- and laboratory-specific RIs, especially for TSH, is essential for diagnosing thyroid disorders in pregnancy, and the recommended universal cut-off values, which may contribute to the risk of a misdiagnosis or a missed diagnosis, should be taken with caution in the clinical setting. However, regarding the fluctuation of thyroid function tests throughout pregnancy, trimester-specific RIs are insufficient, and implementing split phases is required.

Reference intervals for thyroid-stimulating hormone, free thyroxine, free triiodothyronine, and total triiodothyronine in the Lebanese adult population.

For a better assessment of thyroid function, each laboratory should establish its own reference intervals (RI). In Lebanon, no previous study has been conducted to establish the reference values for thyroid function tests. This cross-sectional study included 301 volunteers aged between 18 and 65 years (65.8% women, 34.2% men), free from any thyroid pathology and any condition that could affect thyroid function tests. The reference intervals of thyroid-stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), and total T3 (TT3) were measured on the Roche Cobas e411 machine. 39 subjects tested positive for thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TGAb), were excluded from the study. There was an increase in the 2.5th percentile for the TSH compared to the value provided by the manufacturer (from 0.27 to 0.53 mlU/L) as well as a decrease in the 97.5th percentile for the FT4, TT3, and FT3 (respectively, from 22 to 19.78 pmol/L for FT4, from 3.1 to 2.71nmol/L for TT3, and from 6.80 to 6.10 pmol/L for FT3). Higher TT3 and FT3 values were noted in men compared to women (respectively, p = 0.068 and p < 0.0001). An age decrease in FT4 and FT3 was also observed (respectively, p = 0.045 and p < 0.0001). The established RI of thyroid function tests for the Lebanese population were significantly different from the values recommended by the manufacturer (Roche Diagnostics). Changing our RI values will allow a more accurate diagnosis of thyroid dysfunction.

Establishment of Reference Intervals for Thyroid-Associated Hormones Using refineR Algorithm in Chinese Population at High-Altitude Areas

ObjectivesDiagnosis of thyroid disease among individuals dwelling at high altitude remains a challenge. Reference intervals (RIs) for thyroid-associated hormones among Tibetans living at various high altitudes were established to improve diagnosis.MethodsOne thousand two hundred eighty-one subjects were randomly recruited from Nyingchi, Shigatse/Lhasa, and Ali of Tibet. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured by the Cobas e601 electrochemiluminescence analyzer. We used multiple linear regression and variance component analysis to assess the effect of sex, age, and altitude on hormones. RIs were established by refineR algorithm and compared with those provided by the manufacturer.ResultsSerum TSH was significantly lower in males than in females, while FT3 and FT4 were higher in males. Both FT3 and FT4 decreased with increasing age. FT3 increased with altitude, while TSH and FT4 were less influenced by altitude. The RI for TSH was 0.764–5.784 μIU/ml, while for FT4, the RIs were 12.36–19.38 pmol/L in females and 14.84–20.18 pmol/L in males. The RIs for FT3 at Nyingchi, Shigatse/Lhasa, and Ali in females were 4.09–4.98, 4.31–5.45, and 4.82–5.58 pmol/L, while in males, the values were 4.82–5.41, 4.88–5.95, and 5.26–6.06 pmol/L, respectively. The obtained RIs for TSH and FT4 were generally higher, while that for FT3 was narrower than the RIs provided by Cobas.ConclusionsSpecific RIs were established for thyroid-associated hormones among Tibetans, which were significantly different from those provided by the manufacturer.

Reference Interval of Thyroxine and Thyroid Stimulating Hormone in Cord Blood in Tertiary Care Hospital, Kerala

Introduction: Even though Congenital hypothyroidism (CH) is one of the most common causes of preventable mental retardation, diagnosis at birth is difficult due to absent or delayed clinical manifestations, owing to the transplacental transfer of maternal thyroid hormones. Delayed diagnosis and treatment can cause irreversible damage to the developing brain. The occurrence of cognitive dysfunction due to CH has reduced significantly in countries where Newborn Screening (NBS) is routinely practiced. Cord blood screening is considered to be an effective method to diagnose congenital hypothyroidism. Aim: To establish reference interval for thyroxine (T3 and T4) and Thyroid Stimulating Hormone (TSH) in cord blood Medical College, Thrissur. Materials and Methods: In the present cross-sectional observational hospital based study, the cord blood samples from 252 deliveries collected over a period of three months from May 2011 at in Government Medical College, Thrissur, Kerala, India. A 5 mL of cord blood samples were collected in a plain non vacuum tube with clot activator from umbilical cord incised 15-20 cm at the time of birth. T3, T4 and TSH was estimated by Enzyme Linked Immuno-sorbent Assay (ELISA) using kits of ELISA reader and Washer. Normality check done by visual inspection of histogram, Q-Q plot, box plot and Kolmogorov-Smirnov test. Results: In total of 153 cord blood samples considered, and final analysis was done on 151 samples (69 males and 82 females) after excluding the samples of babies delivered by Lower Segment Cesarean Section (LSCS). The gestational age was mean 38.48 weeks and mean age of mothers was 24.22 years. More than 90% of the values for TSH is less than 12 mIU/mL and 90% of T4 values is less than 20 µg/dL. Reference interval determined by non parametric ascending rank order. Reference interval established is 0.63-17.033 mIU/L and 9.45-27.173 for TSH and T4 respectively, lower than those reported from studies in other parts of India. The mean value of TSH was 5.084 mIU/L and 87.5% of babies are having TSH values &lt;10 mIU/L. Conclusion: The study was conducted to establish reference intervals for cord blood TSH, T4 and T3 and confirms to the use of cut off values for the screening of CH for TSH as &gt;20 mIU/L.

Mild Anemia May Affect Thyroid Function in Pregnant Chinese Women During the First Trimester.

BackgroundPregnant women are often susceptible to anemia, which can damage the thyroid gland. However, compared with moderate and severe anemia, less attention has been paid to mild anemia. The purpose of this study was to evaluate the effect of mild anemia on the thyroid function in pregnant women during the first trimester.MethodsA total of 1,761 women in the first trimester of their pregnancy were enrolled from Shenyang, China, and divided into mild anemia and normal control groups based on their hemoglobin levels. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels were compared between the two groups.ResultsThe TSH levels of pregnant women with mild anemia were higher than those of pregnant women without mild anemia (p < 0.05). Normal control women were selected to set new reference intervals for TSH, FT3, and FT4 levels during the first trimester, which were 0.11–4.13 mIU/l, 3.45–5.47 pmol/l, and 7.96–16.54 pmol/l, respectively. The upper limit of TSH 4.13 mU/l is close to the upper limit 4.0 mU/l recommended in the 2017 American Thyroid Association (ATA) guidelines, indicating that exclusion of mild anemia may reduce the difference in reference values from different regions. Mild anemia was related to 4.40 times odds of abnormally TSH levels (95% CI: 2.84, 6.76) and 5.87 increased odds of abnormal FT3 (95% CI: 3.89, 8.85). The proportion of hypothyroidism and subclinical hypothyroidism in patients with mild anemia was higher than that in those without anemia (0.6% vs. 0, p = 0.009; 12.1% vs. 1.9%, p < 0.001). Mild anemia was related to 7.61 times increased odds of subclinical hypothyroidism (95% CI: 4.53, 12.90).ConclusionsMild anemia may affect thyroid function during the first trimester, which highlights the importance of excluding mild anemia confounding when establishing a locally derived specific reference interval for early pregnancy.

Preterm to term infant postmenstrual age reference intervals for thyroid-stimulating hormone and free thyroxine.

Infants born preterm are affected by a hypothalamic-pituitary-thyroid axis that is immature and still developing as they progress closer to corrected term gestation. Multiple risk factors place preterm infants at risk for a hypothyroid state. However, there is variability in thyroid-stimulating hormone cutoff values and limited data on free thyroxine reference intervals to guide clinicians. 1584 thyroid-stimulating hormone and 1576 free thyroxine laboratory samples that were originally collected to screen hospitalized infants for delayed-onset of hypothyroidism were retrospectively evaluated from a group of 1087 infants who ranged in postmenstrual age from 25 to 43 weeks gestation at the time of laboratory sample collection. Median thyroid hormone values and reference intervals were established using R and the mixtools package. Thyroid-stimulating hormone reference intervals remained similar across gestational ages from 0.340-9.681 µIU/mL in 25-27 6/7-week infants to 1.090-7.627 µIU/mL in 40-43-weeks infants. For the same age groups, free thyroxine reference intervals increased from 0.42-0.91 ng/dL to 0.87-1.32 ng/dL. The reference intervals identified suggest that infants <31 weeks gestation have a higher thyroid-stimulating hormone and lower free thyroxine level at baseline than previously anticipated. The increasing free thyroxine values in preterm to term infants indicate a maturing hypothalamic-pituitary-thyroid axis. Clinicians need thyroid hormone reference intervals that also vary by postmenstrual age to aid the evaluation of sick preterm infants who are at risk of a delayed hypothyroidism diagnosis that can be missed on the initial newborn screen. This study provides one of the largest samples of thyroid-stimulating hormone and free thyroxine data to establish reference intervals in preterm infants. Clinicians may utilize the identified postmenstrual age-based reference intervals to inform follow-up thyroid testing in preterm infants at several weeks postnatal age.