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Abstract 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.

The IFCC Committee for Standardization of Thyroid Function Tests intended to standardize free thyroxine (FT ) immunoassays. We developed a Système International d'Unités traceable conventional reference measurement procedure (RMP) based on equilibrium dialysis and mass spectrometry. We describe here the latest studies intended to recalibrate against the RMP and supply a proof of concept, which should allow continued standardization efforts. We used the RMP to target the standardization and reference interval (RI) panels, which were also measured by 13 manufacturers. We validated the suitability of the recalibrated results to meet specifications for bias (3.3%) and total error (8.0%) determined from biological variation. However, because these specifications were stringent, we expanded them to 10% and 13%, respectively. The results for the RI panel were reported as if the assays were recalibrated. We estimated all but 1 RI using parametric statistical procedures and hypothesized that the RI determined by the RMP was suitable for use by the recalibrated assays. Twelve of 13 recalibrated assays had a bias, meeting the 10% specification with 95% confidence; for 7 assays, this applied even for the 3.3% specification. Only 1 assay met the 13% total error specification. Recalibration reduced the CV of the assay means for the standardization panel from 13% to 5%. The proof-of-concept study confirmed our hypothesis regarding the RI but within constraints. Recalibration to the RMP significantly reduced the FT immunoassays' bias, so that the RI determined by the RMP was suitable for common use within a margin of 12.5%.

Abstract 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.

ContextThyroid function testing often uses thyrotropin (TSH) measurement first, followed by reflex testing for free thyroxine (T4) if TSH is outside the reference range. The utility of different TSH cutoffs for reflex testing is unknown.ObjectiveTo examine different TSH cutoffs for reflex free T4 testing.Design, Setting, and PatientsWe analyzed concurrent TSH and free T4 results from 120,403 individuals from a single laboratory in Western Australia (clinical cohort) and 4568 Busselton Health Study participants (community cohort).ResultsIn the clinical cohort, restricting free T4 measurement to individuals with TSH <0.3 or >5.0 mU/L resulted in a 22% reduction in free T4 testing compared with a TSH reference range of 0.4 to 4.0 mU/L; using TSH cutoffs of 0.2 and 6.0 mU/L resulted in a 34% reduction in free T4 testing. In the community cohort, the corresponding effect was less: 3.3% and 4.8% reduction in free T4 testing. In the clinical cohort, using TSH cutoffs of 0.2 and 6.0 mU/L, elevated free T4 would go undetected in 4.2% of individuals with TSH levels of 0.2 to 0.4 mU/L. In most, free T4 was marginally elevated and unlikely to indicate clinically relevant hyperthyroidism. Low free T4 would go undetected in 2.5% of individuals with TSH levels of 4 to 6 mU/L; in 94%, free T4 was marginally reduced and unlikely to indicate clinically relevant hypothyroidism.ConclusionsSetting TSH cutoffs at 0.1 to 0.2 mU/L less than and 1 to 2 mU/L greater than the reference range for reflex testing of free T4 would reduce the need for free T4 testing, with minimal effect on case finding.A “TSH first” strategy is common in thyroid function testing. We found that using wider TSH cutoffs (outside reference range limits) to trigger free T4 testing is more efficient and cost-effective.

The work of the Expert Group was published as IARC Technical Publication No. 46.1 The objective of this Expert Group was not evaluation of the thyroid examination programmes that were implemented after the past nuclear accidents, or recommendations related to thyroid health monitoring activities currently in progress. Since the Chernobyl accident in 1986 in Ukraine, the guidelines for overall preparedness and response to nuclear emergencies have evolved2 and have contributed to the implementation of successful countermeasures against radiation exposure from nuclear accidents and associated potential adverse health effects.3 In view of the established association of thyroid cancer risk with radiation exposure, particularly during childhood and adolescence, appropriate preparedness and response regarding thyroid cancer-related issues are crucial. Because thyroid cancer has a large reservoir of subclinical disease in the population,4 population thyroid screening identifies cancers that would have developed into clinical cases as well as those that would not have been diagnosed if the screening had not taken place or would not have caused symptoms or death during the patient's lifetime. In the context of overdiagnosis and low disease-specific mortality,7 recommendations have been developed by professional organisations to avoid thyroid ultrasonography screening in low-risk, asymptomatic adult populations.8 The Expert Group agrees with this view for populations, of all ages, affected by nuclear accidents, because screening the affected asymptomatic populations irrespective of risk levels (ie, thyroid radiation dose) is also expected to result in the issues related to overdiagnosis without clear public health benefits. [...]we express our gratitude to the Ministry of the Environment, Japan, for their financial support of the project and to the Nuclear Safety Research Association of Japan for managing the grant.

The study aims to establish trimester-specific reference ranges for serum iodine (SI) in Chinese pregnant women and explore its associations with maternal and infantile thyroid function. Apparently healthy pregnant women were enrolled during their first antenatal visit. Fasting venous and spot urine samples were collected for determining serum and urinary iodine (UI) levels by a validated inductively coupled plasma mass spectrometry. Serum free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), and neonatal TSH levels were tested by electro-chemiluminescent assay. The reference ranges of SI were established by percentile method and reported as 2.5–97.5%. ROC analysis was applied to compare the discriminative ability of SI, UI, and UI to urinary creatine ratio (UI /UCr) in early pregnancy for various thyroid conditions. The trimester-specific reference ranges of SI for Chinese pregnant women were 60.91–114.53 μg/L for the first trimester (T1, n = 1029), 54.57–103.42 μg/L for the second trimester (T2, n = 379), and 52.03–110.40 μg/L for the third trimester (T3, n = 455). Maternal SI at T1 but not UI and UI/UCr was significantly correlated with FT3 (r = 0.393, P < 0.001), FT4 (r = 0.637, P < 0.001), and TSH (r = −0.299, P<0.001). Maternal SI change% from T1 to T2 (but not SI change% from T1 to T3) had marginal correlation with neonatal TSH (r=−0.106, P=0.046). ROC analysis showed that maternal SI at T1 had better predictability for several thyroid conditions than UIC and UI/UCr.

Abstract Context Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. Objective To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. Design, Setting, and Participants Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and ≤5 mIU/L) and normal prolactin levels (≤20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). Main Outcome Measures TSH and prolactin. Results Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, interquartile range: (1.54, 2.61); severe male factor: TSH 1.66 mIU/L, interquartile range: (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH ≥2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Conclusions Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI. In women with no known thyroid disease and TSH levels within the normal range, we demonstrate an association between TSH levels >2.5 mIU/L and the diagnosis of UI.

Laboratory testing of serum thyroid-stimulating hormone (TSH) is an essential tool for the diagnosis and management of various thyroid disorders whose collective prevalence lies between 4% and 8%. However, between-assay discrepancies in TSH results limit the application of clinical practice guidelines. We performed a method comparison study with 40 sera to assess the result comparability and performance attributes of 16 immunoassays. Thirteen of 16 assays gave mean results within 10% of the overall mean. The difference between the most extreme means was 39%. Assay-specific biases could be eliminated by recalibration to the overall mean. After recalibration of singlicate results, all assays showed results within the biological total error goal (22.8%), except for 1 result in each of 4 assays. For a sample with a TSH concentration of 0.016 mIU/L, 6 assays either did not report results or demonstrated CVs >20%. Within-run and total imprecision ranged from 1.5% to 5.5% and 2.5% to 7.7%, respectively. Most assays were able to match the internal QC targets within 5%. Within-run drifts and shifts were observed. Harmonization of TSH measurements would be particularly beneficial for 3 of the 16 examined assays. These data demonstrate that harmonization may be accomplished by establishing calibration traceability to the overall mean values for a panel of patient samples. However, the full impact of the approach must be further explored with a wider range of samples. Although a majority of assays showed excellent quality of performance, some would benefit from improved within-run stability.

Graves' disease (GD) is an autoimmune disorder characterized by activation of the TSH receptor by stimulatory autoantibodies (TSH Receptor Antibodies, or TRAbs), leading to unregulated thyroid hormone production. Diagnosis is largely based on the typical clinical picture and laboratory thyroid panel. Establishment of elevated serum levels of TRAbs by competitive binding assay or cell-binding assay has its unique role in diagnosis and management of GD, especially in the differential diagnosis, therapy selection, prognostication, evaluation of thyroid function during pregnancy, peri-conceptional and neonatal thyroid workup, and in certain special situation. Inclusion of TRAbs in GD diagnostic algorithm can improve cost-effectiveness of GD management. The current best practice guidelines were developed to provide evidence-based recommendations in the use of TRABs in GD management for healthcare providers in South Asia. A panel of endocrinologists with minimum 10 years of clinical experience in thyroid disorders reviewed existing literature and their quality, and after deliberation and discussion, developed 21 recommendations surrounding the best practices surrounding the role of TRAbs in GD management.

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 (β: –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 (β: –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.