Defining Trimester-Specific Reference Intervals for Thyroid Hormones: Insights from a Bulgarian Monocenter Study.

Background and Objectives: Pregnancy introduces various interfering factors that, alongside individual variations, impact the assessment of thyroid function tests. This underscores the necessity of defining trimester-specific reference intervals for thyroid-stimulating hormone (TSH) levels. Differences in population characteristics, including ethnicity, socio-economic factors, iodine prophylaxis, and obesity, emphasize the need to establish trimester-specific TSH ranges for women of reproductive age in the respective region or center. The aim of the present study was to establish first- and second-trimester-specific reference intervals for TSH and free thyroxine (FT4) in a relevant pregnant population. Materials and Methods: A retrospective monocenter analysis utilized the electronic database of Ob/Gyn Hospital "Dr. Shterev", Sofia, Bulgaria. The analysis involved data from 497 pregnant and 250 non-pregnant women, all without evidence of thyroid dysfunction or a family history thereof, no indication of taking medication interfering with thyroid function, no evidence of levothyroxine treatment, and no history of sterility treatment. To establish the limits of the TSH reference range, the percentile method was applied using a bootstrapping procedure following the recommendations of the International Federation of Clinical Chemistry (IFCC). Results: Trimester-specific reference intervals for TSH and FT4 in our center were established as follows: first trimester-0.38-2.91 mU/L, FT4-12.18-19.48 pmol/L; second trimester-0.72-4.22 mIU/L and 9.64-17.39 pmol/L, respectively. We also established the normal reference range for the non-pregnant control group, which is similar to that applicable in our laboratory. Conclusions: Our results differ from the fixed limits recommended by the American Thyroid Association, European Thyroid Association, and Endocrine Society Guidelines. Following the relevant established intervals would significantly impact timely diagnosis and therapy requirements for a substantial proportion of pregnant women.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Agreement between routinely used immunoassays for thyroid function testing in non-pregnant and pregnant adults.

OBJECTIVE: Thyroid function tests are common biochemical analyses, and agreement between the routinely used immunoassays is important for diagnosis and monitoring of thyroid disease. Efforts are continuously made to align the biochemical assays, and we aimed to evaluate the agreement between immunoassays used in a clinical laboratory setting among non-pregnant and pregnant adults. DESIGN: Cross-sectional study. PARTICIPANTS: Serum samples were obtained from 192 blood donors (non-pregnant adults) and from 86 pregnant women in the North Denmark Region with no known thyroid disease. MEASUREMENTS: Each sample was used for measurement of thyroid-stimulating hormone (TSH) with the routinely used automatic immunoassays in the regional Departments of Clinical Biochemistry (Alinity, Abbott Laboratories, Cobas, Roche Diagnostics, and Atellica, Siemens Healthineers) and reported as the median with 95% confidence interval (95% CI). RESULTS: In nonpregnant adults, the level of TSH was higher with Cobas and Atellica than with Alinity as reflected by median (Alinity: 1.39 mIU/L (95% CI: 1.30-1.51 mIU/L); Cobas: 1.57 mIU/L (95% CI: 1.48-1.75 mIU/L); Atellica: 1.74 mIU/L (95% CI: 1.61-1.83 mIU/L)). Similarly, a trend was seen towards higher median TSH with Cobas than with Alinity among pregnant women (Alinity: 1.90 mIU/L (95% CI: 1.37-2.82 mIU/L); Cobas: 2.33 mIU/L (95% CI: 1.69-3.62 mIU/L)). CONCLUSION: Results of thyroid function tests obtained with different immunoassays were not interchangeable when evaluated among pregnant and non-pregnant adults. The distinct differences are relevant for clinical decision making and emphasize the necessity of clinical laboratory information when different assays are used for diagnosis and monitoring of patients with thyroid disease.

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.

OBJECTIVES: 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. METHODS: 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 per laboratory per year and clustered per manufacturer (>1.000.000 data points per manufacturer). Direct RIs (DRIs) were established in 125 healthy individuals per platform. RESULTS: 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. CONCLUSIONS: These results underscore the importance of RI verification as manufacturer-provided RIs are often incorrect and RIs may not be robust. Indirect methods offer cost-effective alternatives for laboratory-specific or platform-specific verification of RIs.

Establishment of reference intervals for fT3, fT4, and TSH levels in Japanese children and adolescents.

The present study aimed to establish new reference intervals (RIs) for serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in Japanese children and adolescents aged 4 to 19 years. A total of 2,036 (1,611 girls, 425 boys) participants were included over a 17-year period; they all tested negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonography. RIs were determined by nonparametric methods. The results showed that serum fT3 was significantly higher in the 4-15-year-olds than in the 19-year-olds. The serum fT4 was significantly higher in the 4-10-year-olds than in the 19-year-olds. The serum TSH was significantly higher in the 4-12-year-olds than in the 19-year-olds. All of them gradually decreased with age to approximate the adult levels. The upper limit of TSH was lower in those aged 13 to 19 years than in adults. The differences were examined by sex. The serum fT3 was significantly higher in boys than in girls between the ages of 11 and 19 years. The serum fT4 was significantly higher in boys than in girls between the ages of 16 and 19 years. There did not seem to be any sex difference in those under 10 years of age. In conclusion, serum fT3, fT4, and TSH levels in children and adolescents differ from those in adults. It is important to evaluate thyroid function using the new RIs that are appropriate for chronological age.

First Estimation of Reference Intervals for Thyroid-Stimulating Hormone and Thyroid Hormones in Slovenian Population.

For thyroid function estimation and clinical decision making, use of appropriate reference intervals for thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) is crucial. For each laboratory, establishment of own reference intervals is advised. For the first Slovenian estimation of reference intervals for thyroid hormones a large group of 1722 healthy individuals without thyroid disease was established retrospectively. Hormone analyses were performed on automated analyser Advia Centaur XP Immunoassay System (Siemens Healthineers), which reference intervals for TSH, fT4 and fT3 were 0.55-4.78 mIU/L, 11.5-22.7 pmol/L, and 3.5-6.5 pmol/L, respectively. Statistical analysis followed non-parametric percentile method. Our laboratory reference intervals for TSH, fT4 and fT3 are mostly narrower than intervals given by manufacturer. Median value, lower and upper limit for TSH, fT4 and fT3 were 1.98 (0.59-4.23) mIU/L, 14.5 (11.3-18.8) pmol/L and 4.82 (3.79-6.05) pmol/L, respectively. Most likely, an inclusion of a high number of healthy individuals without thyroid disease was a reason for such results.

Seasonal Changes of Thyroid Function Parameters in Women of Reproductive Age Between 2012 and 2018: A Retrospective, Observational, Single-Center Study.

Background: Thyroid function can be influenced by external stimuli such as light and temperature. However, it is currently unknown whether there is seasonal variation of thyroid function in women of reproductive age. Adequate thyroid function in reproductive-aged women is necessary for optimal fetal-maternal outcomes. Therefore, this study aims to evaluate the seasonal changes in levels of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and TSH index (TSHI) in women of reproductive age. Methods: A large retrospective study was conducted that included women aged 20-49 years who visited our outpatient or checkup center between 2012 and 2018. Thyroid function was measured using the automated immunochemiluminescent assay kit. Subjects with overt thyroid dysfunction, pregnancy, thyroid disease, cancer, and severe infectious or psychological disease were excluded. Seasonal differences of thyroid function were analyzed using the Kruskal-Wallis test or the analysis of means with transformed ranks. Spearman's correlation was performed to evaluate the association between thyroid function parameters and age. A subset of 181 subjects was included in the longitudinal analyses. Differences in thyroid function between summer and winter were analyzed using the Wilcoxon signed-rank test. Results: A total of 48,990 women with a median age of 39 years were included. The prevalence of subclinical hypothyroidism was lower in summer but higher in winter (5.6% vs. 7.0%, p < 0.05). The TSH, FT3, and FT4 levels and TSHI reached a peak in winter, while they declined to trough in summer. The TSH concentrations (r = 0.044, p < 0.001) and TSHI (r = 0.025, p < 0.001) were positively correlated with age, whereas FT3 (r = -0.073, p < 0.001) and FT4 (r = -0.059, p < 0.001) were negatively correlated with age. The associations of thyroid parameters with age were similar between subjects with positive thyroid peroxidase antibody (TPOAb) and those with negative TPOAb. In the matched longitudinal analysis of 181 subjects, no differences were detected in the thyroid parameters between summer and winter. Conclusions: This retrospective single-center study showed that thyroid hormone levels and central sensitivity to thyroid hormones are influenced by age and seasonal fluctuations among women of reproductive age, while their impact on reproductive health remains to be elucidated in future studies.

Common Pitfalls in the Interpretation of Endocrine Tests.

Endocrine tests are the cornerstone of diagnosing multiple diseases that primary care physicians are frequently faced with. Some of these tests can be affected by situations that affect the proper interpretation, leading to incorrect diagnoses and unnecessary treatment, such as the interference of biotin with thyroid function test, falsely elevated prolactin values in presence of macroprolactinemia or falsely normal due to the "hook effect" in macroprolactinomas. Recognizing these situations is essential for the clinician to make an adequate interpretation of these tests as well as an accurate diagnosis that guarantees the best outcomes for the patient.

Establishing paediatric reference intervals for thyroid function tests in Croatian population on the Abbott Architect i2000.

INTRODUCTION: Evaluation of thyroid function is often requested and therefore defining paediatric reference intervals (RIs) is of vital importance. Currently, there is a distinct lack of paediatric RIs for thyroid function tests in Croatia. Thus, we established RIs for thyroid stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3) and free thyroxine (FT4) in the Croatian paediatric population. MATERIALS AND METHODS: Reference intervals were calculated from 397 apparently healthy children, aged from 2 days to < 19 years. Serum samples were analysed for thyroid function tests on the Abbott Architect i2000. Age- and sex-specific 95% RIs with 90% confidence intervals were established according to Clinical and Laboratory Standards Institute guidelines. To express the magnitude of sex and age variation, standard deviation ratio (SDR) was calculated using two-level nested ANOVA. The criterion for considering partitioning reference values was set to SDR > 0.3. RESULTS: All thyroid function tests required age partitioning, confirmed by SDR above 0.3. There was no need for sex partitioning, confirmed by SDR below 0.3. Still, FT3 was partitioned due to visually noticeable sex related difference for the oldest group (12 years to < 19 years). CONCLUSION: This is the first study to establish RIs for thyroid function tests in the Croatian paediatric population. We propose RIs for widely used Abbott platform, thus giving laboratories method- and population-specific paediatric RIs for thyroid function tests that should improve clinical test interpretation.

Relationship of TSH Levels with Cardiometabolic Risk Factors in US Youth and Reference Percentiles for Thyroid Function.

CONTEXT: Thyroid hormones play an important role in metabolic homeostasis, and higher levels have been associated with cardiometabolic risk. OBJECTIVE: To examine the association of cardiometabolic risk factors with TSH levels in US youth. METHODS: Cross-sectional study of youth aged 12 to 18 years without known thyroid abnormalities from 5 National Health and Nutrition Examination Survey cycles (n = 2818) representing 15.4 million US children. Subclinical hypothyroidism (SH) was defined as thyrotropin (TSH) levels of 4.5 to 10 mIU/L. Assessed cardiometabolic risk factors include abdominal obesity (waist circumference >90th percentile), hypertriglyceridemia (triglyceride ≥130 mg/dL), low high-density lipoprotein cholesterol (<40 mg/dL), elevated blood pressure (systolic and diastolic blood pressure ≥90th percentile), hyperglycemia (fasting blood glucose ≥100 mg/dL, or known diabetes), insulin resistance (homeostatic model for insulin resistance > 3.16), and elevated alanine transferase (≥ 50 for boys and ≥44 U/L for girls). Age and sex- specific percentiles for thyroid parameters were calculated. RESULTS: In this cohort of youth (51.3% male), 31.2% had overweight/obesity. The prevalence of SH was 2.0% (95% CI 1.2-3.1). The median TSH levels were higher in youth with overweight/obesity (P < 0.001). Adjusting for age, sex, race/ethnicity, and obesity, youth with TSH in the fourth quantile had higher odds of abdominal obesity (OR 2.53 [1.43-4.46], P = .002), insulin resistance (OR 2.82 [1.42-5.57], P = .003), and ≥2 cardiometabolic risk factors (CMRF) (OR 2.20 [1.23-3.95], P = .009). CONCLUSION: The prevalence of SH is low in US youth. The higher odds of insulin resistance and cardiometabolic risk factors in youth with TSH levels >75th percentile requires further study.

Testing, Monitoring, and Treatment of Thyroid Dysfunction in Pregnancy.

Both hyperthyroidism and hypothyroidism can have adverse effects in pregnancy. The most common causes of thyrotoxicosis in pregnancy are gestational transient thyrotoxicosis and Graves' disease. It is important to distinguish between these entities as treatment options differ. Women of reproductive age who are diagnosed with Graves' disease should be counseled regarding the impact of treatment options on a potential pregnancy. Although the absolute risk is small, antithyroid medications can have teratogenic effects. Propylthiouracil appears to have less severe teratogenicity compared to methimazole and is therefore favored during the first trimester if a medication is needed. Women should be advised to delay pregnancy for at least 6 months following radioactive iodine to minimize potential adverse effects from radiation and ensure normal thyroid hormone levels prior to conception. As thyroid hormone is critical for normal fetal development, hypothyroidism is associated with adverse obstetric and child neurodevelopmental outcomes. Women with overt hypothyroidism should be treated with levothyroxine (LT4) to a thyrotropin (thyroid-stimulating hormone; TSH) goal of <2.5 mIU/L. There is mounting evidence for associations of maternal hypothyroxinemia and subclinical hypothyroidism with pregnancy loss, preterm labor, and lower scores on child cognitive assessment. Although there is minimal risk of LT4 treatment to keep TSH within the pregnancy-specific reference range, treatment of mild maternal thyroid hypofunction remains controversial, given the lack of clinical trials showing improved outcomes with LT4 treatment.

Newborn Screening for Congenital Hypothyroidism: the Benefit of Using Differential TSH Cutoffs in a 2-Screen Program.

CONTEXT: Analysis of a 2-screen program for congenital hypothyroidism (CH) was performed using differential dried-blood spot thyrotropin (bTSH) cutoffs of 10 mU/L at first screening (all infants) and 5 mU/L at second screening (selected infants). OBJECTIVES: This work aimed to characterize CH infants identified by the second screening and compare infants with bTSH of 5.0 to 9.9 and 10 mU/L or greater on second screening. DESIGN AND PATIENTS: Maternal and neonatal clinical features were retrospectively analyzed for 119 CH babies detected on the second screen in the Lombardy region of Italy, 2007 to 2014. RESULTS: Fifty-two (43.7%) of the 119 CH neonates showed bTSH values ranging from 5.0 to 9.9 mU/L at the second screening (low bTSH group) and 67 (56.3%) bTSH of 10.0 mU/L or greater (high bTSH group). The frequency of thyroid dysgenesis and eutopic gland was similar in both groups, as was the frequency of permanent and transient CH. Moreover, a high frequency of extrathyroidal malformations was found in both groups. The percentage of preterm infants (57.7% vs 23.9%, P < .001) and infants admitted to the neonatal intensive care unit (50.0% vs 17.9%, P < .001) was significantly higher in the low vs the high bTSH group. In addition, maternal treatment with glucocorticoids in pregnancy was significantly more frequent in the low bTSH group than in the high bTSH group (11.5% vs 1.5%, P = .042), as well as maternal hypothyroidism and/or goiter (26.9% vs 10.4%, P = .036). CONCLUSIONS: This study has demonstrated that a lower TSH cutoff at the second screening can detect additional cases of CH and that a second bTSH cutoff of 5.0 mU/L is appropriate for identifying preterm newborns and babies with associated risk factors.

Interpretation of thyroid function tests during pregnancy.

Thyroid hormones are crucial for normal pregnancy and fetal development. Large physiological changes occur during pregnancy, posing challenges for the correct interpretation of thyroid function tests. TSH concentrations are the principal first test to rule out thyroid disease taking into account trimester-specific reference ranges. Free T4 (FT4) measurements by immuno-assays may be subject to interference by endogenous and exogenous factors. The relevance of measuring free T3 (FT3) during pregnancy is unclear. Thyroid autoimmunity is well-reflected by the presence of antibodies against TPO. TPO-antibody positivity is associated with an increased risk of adverse pregnancy outcomes.

Pediatric reference values of TSH should be personalized according to BMI and ethnicity.

OBJECTIVE: The need for personalization of the reference values of thyroid function tests has been previously suggested. We aimed at determining TSH reference values in a large cohort of children according to age, sex, BMI, and ethnicity. DESIGN: A population-based cohort study. METHODS: The study cohort included 75 549 healthy children aged 5-18 years. Data analyzed included age, gender, TSH, FT4 levels, BMI and ethnicity. Multivariate logistic regression analysis examined the associations between the study parameters. RESULTS: TSH in the Jewish population is lower than in the non-Jewish population (median: 2.1 IU/L (IQR: 1.5) vs 2.2 IU/L (IQR: 1.5), P < 0.0001). TSH is significantly affected by BMI for children defined as underweight, normal weight, overweight or obese, levels increased as weight diverged from the normal range (median levels: 2.1 IU/L (IQR: 1.4), 2.0 IU/L (IQR: 1.3), 2.1 IU/L (IQR: 1.4), 2.4 (IQR: 1.5), respectively, P < 0.001). The 2.5 percentile is affected by gender and BMI (P < 0.02 and P < 0.001, respectively), while the 97.5 percentile is affected by ethnic origin and BMI (P < 0.001 for both). New TSH reference intervals (RI) adjusted according to BMI and ethnicity are suggested. Comparison of the old and new RI demonstrate the significance of RI personalization: 25.1% of the children with TSH levels above the old RI are within the new RI, while 2.3% of the children who were in the old RI are below the new RI. CONCLUSIONS: TSH reference values in children are affected by BMI and ethnicity. Reference values should be individualized accordingly to improve future clinical decision-making and treatment.

Optimization and validation of patient-based real-time quality control procedure using moving average and average of normals with multi-rules for TT3, TT4, FT3, FT3, and TSH on three analyzers.

BACKGROUND: We have designed a patient-based real-time quality control (PBRTQC) procedure to detect analytical shifts and review analytical trends of measurement procedures. METHODS: All the nine months' patient results of total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) measured by three identical analyzers were divided into three groups according to the source of inpatient patients, outpatient patients, and healthy people. The data in each group were truncated by optimized Box-Plot method and normalized by Box-Cox method if necessary. The z-score charts of internal quality control (IQC) samples' results and PBRTQC data were drawn by IQC levels and groups, respectively. The analytical shifts and analytical trends were detected by multi-rules of 2-2S rules and moving average rules. The performances of PBRTQC were compared with the BIQC in which IQC samples were measurand only once per day at the beginning of the analytical batch. Twelve quality control cases were listed to validate the performances. RESULTS: All the five analytes presented normal distributions when the parameter n of Box-Plot method was 1.2. The percentages of excluded data ranged from 2.9% to 11.6%. 31 and 14 rejections triggered in PBRTQC and BIQC, respectively. 96.8% of the shift rejections in PBRTQC were trend-related shifts and calibration-related shifts, while the proportion was 85.7% in BIQC but 78.6% of the shift rejections in TSH. 25.7% and 8.6% of 105 calibration events which caused analytical shifts were detected by PBRTQC and BIQC, respectively. However, the performance of PBRTQC was not well in TSH because of its large coefficient of variation. CONCLUSIONS: The optimized PBRTQC is high efficiency than BIQC in detecting analytical shifts, trends, and calibration events. The PBRTQC can be used as a low-cost supplementary procedure to IQC every day, especially at the end of the analytical batch on that day when the within-individual biological variation of analyte is not larger than its coefficient of variation in IQC. Further optimization and validation of PBRTQC are still needed.

Relationship between Thyroid and Kidney Function: Analysis from the Korea National Health and Nutrition Examination Survey Between 2013 and 2015.

INTRODUCTION: Thyroid function is evaluated by thyroid stimulating hormone (TSH) and free thyroxine (fT4). Although many studies have indicated an intimate relationship between thyroid hormones and kidney functions, reports about the simultaneous evaluation of TSH and fT4 are rare. OBJECTIVE: We aimed to analyze the association between TSH and kidney function, with emphasis on a potential nonlinear relationship, and identify an independent relationship between fT4 and kidney function. METHODS: We reviewed the data of 7,061 subjects in the Korea National Health and Nutrition Examination Surveys who were randomly subsampled for thyroid function evaluation between 2013 and 2015. A total of 5,578 subjects were included in the final analysis, after excluding people <18 years old, and those with a short fasting time, abnormal fT4 levels, and thyroid disease or related medications. Creatinine-based estimated glomerular filtration rate (eGFR) was used to define kidney function. RESULTS: A 1 mmol/L increase of logarithmic TSH was associated with decreased eGFR (ß: -1.8; 95% CI -2.3 to -1.2; p < 0.001), according to multivariate linear regression analysis. On the multivariate generalized additive model plot, TSH demonstrated an L-shaped relationship with eGFR, showing a steeper slope for 0-4 mIU/L of TSH. A 1 µg/dL increase of fT4 was also associated with decreased eGFR (ß: -7.0; 95% CI -0.94 to -4.7; p < 0.001) on the multivariate linear regression analysis; this association was reversed after adjusting for age. On the mediation analysis, the indirect effect via age and direct effect per 1 µg/dL increase of fT4 on eGFR was 9.9 (8.1 to 11.7, p < 0.001) and -7.1 (-9.3 to -4.8, p < 0.001), respectively. CONCLUSIONS: Increased TSH was associated with decreased eGFR, particularly in the reference range. The direct effect of increased fT4 was decreased eGFR, which may be affected indirectly by age.

Pitfalls in the assessment of gestational transient thyrotoxicosis.

Gestational transient thyrotoxicosis (GTT) is associated with direct stimulation of the maternal thyroid gland by human chorionic gonadotropin (hCG). It is characterized by slightly higher thyroid hormone and lower thyroid-stimulating hormone (TSH) levels in early pregnancy and mild or no symptoms. While GTT must be distinguished from Graves' disease (GD), which is associated with maternal and fetal complications, treated GD and new-onset GD in pregnancy are occasionally challenging to distinguish. Evaluating serum hCG levels and TSH receptor antibody (TRAb) titers can help, but the results are not irrefutable due to pregnancy-related immunosuppression. Moreover, GTT can follow unusual clinical courses in relation to some pregnancy complications. Excessive hCG production can cause severe GTT symptoms in patients with hyperemesis gravidarum, trophoblastic disease, or multiple pregnancies. Thyrotoxicosis can emerge beyond the second trimester in patients with gestational diabetes mellitus and mirror syndrome, because of delayed elevations in the hCG levels. Detailed knowledge about GTT is necessary for correct diagnoses and its appropriate management. This review focuses on the diagnosis of GTT, and, particularly, its differentiation from GD, and unusual clinical conditions associated with GTT that require comprehensive management.