OBJECTIVE:Obesity, particularly excess visceral adipose tissue (VAT), may accelerate biological aging; however, few studies have examined this in middle-aged adults. We investigated associations between dual-energy X-ray absorptiometry (DXA)-derived VAT and two biomarkers of biological aging-phenotypic age acceleration (PhenoAgeAccel) and leukocyte telomere length (LTL)-in 4799 participants (2614 females, aged 45-69 years) from the Busselton Healthy Ageing Study. METHODS:Whole-body DXA (GE Lunar) quantified VAT mass. Phenotypic age was estimated from chronological age and nine biomarkers. In a subsample of 1221 participants, LTL was measured as the telomeric DNA to single-copy gene (T/S) ratio. Sex-stratified linear regressions assessed associations, adjusting for chronological age and lifestyle factors. RESULTS:Mean ± SD VAT mass was 1677 ± 873 g in males and 882 ± 598 g in females. Higher VAT was associated with greater PhenoAgeAccel in both sexes; each 1-SD increase in VAT corresponds to 1.397 (95% CI 1.197, 1.596) and 1.919 (1.738, 2.099) years higher PhenoAgeAccel in males and females, respectively. In females only, higher VAT was associated with shorter LTL (-0.041 [-0.069, -0.013] per 1 SD). Associations mostly remained significant after adjustment for anthropometric and other DXA-derived adiposity measures. CONCLUSIONS:VAT may represent a specific marker of accelerated biological aging, independent of lifestyle and adiposity measures.

Context: Subclinical thyroid dysfunction (ScTD) comprising subclinical hypothyroidism (SHypo) and subclinical hyperthyroidism (SHyper) has been associated with increased risk for cardiovascular events. Objective: To assess associations between ScTD and cardiovascular risk factors (cvRFs) according to age and sex. Design and setting: Pooled individual participant data analysis of large prospective cohort studies from the Thyroid Studies Collaboration. Participants: Aged 18 to 103 years with SHypo (TSH >4.50 mU/l, normal fT4) and SHyper (TSH <0.45 mU/l, normal fT4) vs. euthyroid (TSH 0.45-4.50 mU/l). Interventions: None as this is an observational study. Main outcome measures: cvRFs, i.e. blood pressure, lipid levels, hs-CRP. Results: Of 69,006 participants (mean age 62 years, 55% women, 25% current smokers) from 16 international cohorts, 3,748 (5.4%) had SHypo and 3,428 (5.0%) had SHyper. In both women and men, systolic and diastolic BP were similar regardless of thyroid status. Exceptions were lower diastolic BP in women with SHyper compared to euthyroids (adjusted mean difference [aMD] -1.3 mmHg, 95%CI -2.0 to -0.5), and lower systolic BP in men with SHyper compared to euthyroids (aMD -3.1 mmHg, 95%CI -4.8 to-1.4). In both women and men, lipid levels (total, HDL, LDL cholesterol, triglycerides) and hs-CRP were similar regardless of thyroid status. The only exception were women with SHyper who had a lower LDL cholesterol compared to euthyroids (aMD -0.17 mmol/l, 95%CI -0.29 to -0.05). Conclusions: Participants with ScTD and euthyroids have similar cvRFs and differences are arguably too small to explain the increased cardiovascular risk in ScTD observed in previous studies.

BACKGROUND:Limited data are available on the association of body composition and lung function in middle-aged adults. We investigated the cross-sectional and longitudinal associations in participants of the Busselton Healthy Ageing Study. METHODS:At baseline (n = 4857, aged 46-70 years) and 6-year follow-up (n = 3436), body mass index (BMI), fat and lean mass index (FMI and LMI) and abdominal visceral adipose tissue (VAT) using dual-energy x-ray absorptiometry (DXA), forced expiratory volume in one second (FEV1 % predicted) and forced vital capacity (FVC % predicted) were assessed. Relationships were examined using linear regression, adjusted for age, lifestyle factors and comorbidities. RESULTS:At baseline, the reduction in FEV1 % and FVC% for each additional 1 kg/m2 of FMI was twice greater than that of BMI (men: 1.5-1.9 vs 0.4-0.7; women: 1.0-1.2 vs 0.3-0.5); in contrast each additional 1 kg/m2 of LMI was associated with 1.3-1.6 units increment in FEV1 % and FVC%. In the longitudinal analysis, ∆FEV1 % and ∆FVC% per 1 kg/m2 increment in ∆FMI were -2.2 and -2.3 in men and -1.0 and -1.1 in women, in comparison with -1.8 and -1.9 in men and -0.8 and -0.9 in women for ∆BMI. The range of change in LMI over time was narrow, and ∆LMI had little impact on ∆FEV1 % and ∆FVC%. Higher baseline VAT and greater increase over time were associated with lower lung function, but not totally independent of FMI. CONCLUSION:In middle-aged adults, increased fat mass is a driver for lung function deterioration, whereas higher baseline lean mass may have a protective effect.

BACKGROUND:Thyroid peroxidase antibody (TPOAb) positivity is the most important risk factor for hypothyroidism and determines thyroid function follow-up during pregnancy. TPOAb positivity is usually defined by manufacturer cut-offs which typically derived from non-pregnant populations. However, as a state of immune tolerance, pregnancy can affect TPOAb concentrations. To improve the understanding of clinical relevance of TPOAb concentrations during pregnancy, we investigated the association of TPOAbs with maternal thyroid function. METHODS:We performed an individual participant data meta-analysis embedded in the Consortium on Thyroid and Pregnancy. Participants with multiple gestations, pre-existing thyroid disease, thyroid (interfering) medication usage, or conception by in vitro fertilization were excluded. We used mixed effects regression models to assess the association of TPOAb percentiles calculated in each cohort with maternal thyroid function. RESULTS:The study population comprised 62,634 pregnant women from 24 cohorts. As compared to TPOAb percentiles ≤80, there were progressively higher mean thyroid stimulating hormone (TSH) concentrations across TPOAb percentiles ≥89, with corresponding mean differences ranging from +0.11 SD (95 % confidence interval [CI] +0.04 SD, +0.19 SD) at the 89th percentile to +1.04 SD (95 % CI + 0.96 SD, 1.11 SD) at the 100th percentile. Higher TPOAb percentiles were associated with progressively lower mean free thyroxine (FT4) concentrations across TPOAb percentiles ≥91, with corresponding mean differences ranging from -0.08 SD (95 % CI -0.16 SD, -0.01 SD) at the 91st percentile to -0.48 SD (95 % CI -0.56 SD, -0.4 SD) at the 100th percentile. From the 89th TPOAb percentile upwards, there were progressively higher risks of TSH >4.0 mU/L, with absolute risks of 2.4 %, 4.0 %, and 28.1 % in cases of ≤80th, 89th, and 100th TPOAb percentiles, respectively. Higher TPOAb percentiles were also associated with lower thyroidal response to human chorionic gonadotropin stimulation and higher risks of overt and subclinical hypothyroidism. In 19 of the included cohorts, there were 0.4-6.3 % of pregnant women with TPOAb concentrations lower than the positivity cut-offs but larger than or equal to the 89th-percentile concentrations. The associations of TPOAbs with TSH and with FT4 were most apparent during early pregnancy (P for interaction <0.001 for both TSH and FT4). CONCLUSIONS:During pregnancy, TPOAbs were dose-dependently associated with TSH, FT4, and the risk of abnormal thyroid function. With concentrations below currently used positivity cut-offs, TPOAbs could be associated with lower maternal thyroid function, which indicates clinically relevant thyroid autoimmunity. These findings implicates that high normal TPOAb concentrations upon first assessment in pregnancy may warrant active follow-up.

BACKGROUND:DXA-measured visceral adipose tissue (VAT) is associated with development of metabolic syndrome in middle-aged adults, but its association with incident cardiovascular disease (CVD) has not been studied. We evaluated the longitudinal association of baseline VATDXA with incident CVD events within the Busselton Healthy Ageing study. METHODS:Participants (n = 4866, 54 % female, aged 46-70 years, ∼99 % white) were assessed for VATDXA and were followed up longitudinally for a median of 7.9 years. Outcome measures were time to incident CVD or coronary heart disease (CHD) events (defined as non-fatal hospitalisations or death). Sex-stratified associations were examined using Cox proportional hazards models adjusting for baseline age, lifestyle factors and prior CVD. RESULTS:Mean baseline VATDXA mass was 1678±877 g and 882±600 g in males and females respectively. Incident CVD and CHD events were recorded for 332 (6.8 %) and 245 (5.0 %) study participants. There was a near-linear increase in risk for CVD and CHD events with VATDXA in both sexes. After covariate adjustment each standard deviation (SD) increment in VATDXA was associated with a hazard ratio [95 % confidence interval] for incident CVD in males and females of 1.26 [1.11-1.44] and 1.30 [1.10-1.55] respectively, and a hazard ratio for CHD of 1.28 [1.11-1.49] and 1.40 [1.14-1.72] respectively. However, VATDXA was no longer independently associated with CVD events once adjusted for BMI and waist circumference. CONCLUSION:VATDXA has utility for identifying middle-aged adults at greater risk for incident CVD and CHD but further studies are needed to determine if VATDXA can improve risk discrimination beyond anthropometric measures.

BACKGROUND:Pregnancy is a state of increased metabolic demand that necessitates major changes in endocrine physiology. Gestational thyroid dysfunction and gestational diabetes are common endocrine conditions of pregnancy that frequently coincide. Although the effects of thyroid hormones on glucose metabolism are well documented, important knowledge gaps remain in terms of the extent and clinical relevance of these effects during pregnancy. The aim of this meta-analysis is to assess the association of thyroid function test results with gestational diabetes and markers of glucose metabolism. METHODS:In this systematic review and individual participant data meta-analysis, we searched Ovid MEDLINE, EMBASE, and Web of Science from database inception to Dec 12, 2024, for prospective population-based cohort studies with individual patient data on thyroid function, gestational diabetes, and measures of glucose homoeostasis during pregnancy. Furthermore, open invitations to join the Consortium on Thyroid and Pregnancy were issued to identify unpublished datasets. We excluded participants with multiple pregnancies; pre-existing thyroid disease or diabetes; current use of medications that could affect thyroid or glucose levels; or a history of infertility treatment, miscarriage, or stillbirth. Exposures were maternal gestational concentrations of thyroid-stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), and total T3; thyroperoxidase antibody positivity; thyroglobulin antibody positivity; and thyroid disease entities (ie, subclinical hypothyroidism, overt and subclinical hyperthyroidism, and isolated hypothyroxinaemia), which were defined according to current guidelines. The primary outcome was presence of gestational diabetes as defined in individual cohorts. Individual participant data were analysed using generalised linear mixed-effects regression models adjusting for maternal age, BMI, smoking status, parity, ethnicity, fetal sex, and gestational age at blood sampling. We preregistered our study protocol with PROSPERO (CRD42022371927). FINDINGS:We identified 638 published studies with our systematic search, of which 21 studies based on 17 cohorts met inclusion criteria; 11 of these prospective cohort studies provided individual participant data, and data from an additional 14 cohorts were added via personal contacts and open invitations, resulting in a study population of 63 548 participants from 25 cohorts after exclusions. Of the 52 632 participants in 17 cohorts with TPOAb measurements available to define thyroid disease entities, 1687 (3·2%) of these participants had subclinical hypothyroidism, 1153 (2·2%) had isolated hypothyroxinaemia, and 2958 (4·7%) had gestational diabetes. Compared with euthyroidism, isolated hypothyroxinaemia was associated with a higher risk of gestational diabetes (absolute risk 6·5% [72 of 1113] for isolated hypothyroxinaemia vs 3·5% [1555 of 44 787] for euthyroidism; adjusted odds ratio [aOR] 1·52 [95% CI 1·17-1·98], p=0·0017; 45 900 participants). A lower FT4 concentration was associated with a higher risk of gestational diabetes (non-linear, p<0·0001). A higher risk of gestational diabetes was found both with a higher FT3 concentration (aOR 1·18 [95%CI 1·10-1·28], p<0·0001) and with a higher FT3-to-FT4 ratio (non-linear; p<0·0001). No evidence was found of associations of TSH, thyroid antibodies, or other thyroid function test abnormalities with gestational diabetes. I2 statistics for the primary analyses ranged from 0-43%, indicating low to moderate heterogeneity. The funnel plot for overt hyperthyroidism indicated a possibility for publication bias (p=0·049), but funnel plots for all other variables did not. INTERPRETATION:A lower FT4 concentration and isolated hypothyroxinaemia during pregnancy are associated with a higher risk of gestational diabetes. Our results challenge the long-standing notion that subclinical hypothyroidism or thyroid autoimmunity are risk factors for gestational diabetes and support both the risk profile for gestational thyroid dysfunction and ongoing efforts on optimisation of treatment targets for pregnant people taking levothyroxine. Follow-up studies are required to establish to what extent levothyroxine initiation or dose adjustments can affect insulin resistance and antihyperglycaemic therapies during pregnancy. FUNDING:The Netherlands Organization for Scientific Research, ZonMw, and the EU Horizon 2020 Program.

Genome-wide association studies (GWAS) relevant to osteoporosis have identified hundreds of loci; however, understanding how these variants influence the phenotype is complicated because most reside in non-coding DNA sequence that serves as transcriptional enhancers and repressors. To advance knowledge on these regulatory elements in osteoclasts (OCs), we performed Micro-C analysis, which informs on the genome topology of these cells and integrated the results with transcriptome and GWAS data to further define loci linked to BMD. Using blood cells isolated from 4 healthy participants aged 31-61 yr, we cultured OC in vitro and generated a Micro-C chromatin conformation capture dataset. We characterized chromatin loops (CLs) in OC from among more than 69 million chromatin interactions identified in the genome. Of the CL identified in OC, >16 000 were unique compared to precursor cells. When sentinel single nucleotide polymorphisms from osteoporosis and bone-related GWAS and those in linkage disequilibrium at r 2 > 0.6 were mapped to CL for OC, 12 588 of these variants were observed within chromatin contact regions. Notable in differential gene ontology enrichment analyses of the topology data for OC and precursors were pathways regulating pluripotency of stem cells, Wnt signaling, nucleotide-binding oligomerization domain (NOD)-like receptor signaling and chemokine signaling. These data, in combination with other 3D genome architecture and epigenetic data (eg, histone modifications and chromatin accessibility), will be useful in modeling to predict genome-wide, which enhancers regulate which genes in OC. This data will therefore also be informative for resolving GWAS hits. In conclusion, we have generated a high-resolution genome topology dataset for human OC and have used this to identify CLs relevant to studies of the genetics of osteoporosis. This data will serve as a powerful resource to inform future functional studies of OC biology.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

BACKGROUND AND AIMS:DXA-measured visceral adipose tissue (VATDXA) is associated with adverse cardiometabolic risk profiles in cross-sectional studies, but longitudinal associations have not been investigated. We examined the longitudinal associations of baseline and change in VATDXA with future cardiometabolic risk in Australian participants of the Busselton Healthy Ageing study. METHODS AND RESULTS:We studied 3569 participants (54.7% female, aged 46-70 years) with data on VATDXA (GE Lunar Prodigy) and cardiometabolic risk factors at baseline and 6 years follow-up. The associations were examined using logistic and linear regression models, adjusting for baseline age and lifestyle factors. Mean baseline VATDXA mass was 1653 ± 880 g and 855 ± 580 g, and mean change in VATDXA +99 ± 500 g and +58 ± 312 g in males and females, respectively. Among all participants, 182 males (11.3%) and 197 females (10.1%) developed incident metabolic syndrome (MetS). Baseline VATDXA was associated with incident MetS with an adjusted odds ratio of 2.53 (95% CI: 2.03, 3.15) in males and 2.78 (2.30, 3.36) in females per SD increment. There was a graded positive association between longitudinal change in VATDXA and MetS severity z score in both sexes adjusted for baseline VAT (P < 0.001). All the above associations remained significant after further adjustment for baseline or change in BMI, waist circumference or waist-to-hip ratio in respective models (all P < 0.001). CONCLUSIONS:Higher baseline and greater longitudinal increase in VATDXA are independently associated with raised cardiometabolic risk over time, and may serve as useful markers for identifying middle-aged individuals at increased cardiometabolic risk.

CONTEXT:Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE:To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS:We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS:The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION:This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

OBJECTIVE:Hypothyroidism is a common endocrine condition usually managed with levothyroxine (LT4). However, controversy remains around the use of liothyronine (LT3). We aimed to investigate the practices of Australian endocrinologists when managing patients with hypothyroidism, their use of LT3 + LT4 combination therapy and use of thyroid hormones in euthyroid patients.DESIGN AND PARTICIPANTS:Members of the Endocrine Society of Australia (ESA) were invited to participate in an online questionnaire.MEASUREMENTS:We analysed questionnaires that had complete demographic data.RESULTS:Eighty-seven questionnaires fulfilled the criteria. LT4 was used as first line treatment for hypothyroidism by all respondents. Only 45% reported that their patients were dispensed the brand of LT4 that they recommend. LT3 (alone or in combination) was prescribed by 44% in their clinical practice. Although 49% of respondents would consider LT3 + LT4 in patients with normal TSH who had ongoing symptoms of hypothyroidism, the inability of LT4 to restore normal physiology was ranked the least likely explanation for persistent symptoms and only 32% would consider it for themselves if they were diagnosed with hypothyroidism. The majority (55%), in accordance with evidence, would not prescribe thyroid hormone to euthyroid individuals but 39% would consider use in euthyroid female infertility with high levels of thyroid antibodies and 11% in euthyroid patients with a simple goitre growing over time. LT4 use in pregnancy was variable among members.CONCLUSIONS:Australian endocrinologists mostly follow international guidelines when prescribing thyroid hormone therapy and many prescribe combination LT3 and LT4 therapy, particularly for patients who remain symptomatic on LT4 monotherapy. Prescribing practices are largely similar to other countries who have completed similar questionnaires.

CONTEXT:Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto disease (HD), which often run in the same family. AITD etiology is incompletely understood: Genetic factors may account for up to 75% of phenotypic variance, whereas epigenetic effects (including DNA methylation [DNAm]) may contribute to the remaining variance (eg, why some individuals develop GD and others HD). OBJECTIVE:This work aimed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) comparing GD to HD. METHODS:Whole-blood DNAm was measured across the genome using the Infinium MethylationEPIC array in 32 Australian patients with GD and 30 with HD (discovery cohort) and 32 Danish patients with GD and 32 with HD (replication cohort). Linear mixed models were used to test for differences in quantile-normalized β values of DNAm between GD and HD and data were later meta-analyzed. Comb-p software was used to identify DMRs. RESULTS:We identified epigenome-wide significant differences (P < 9E-8) and replicated (P < .05) 2 DMPs between GD and HD (cg06315208 within MDC1 and cg00049440 within KLF9). We identified and replicated a DMR within CUTA (5 CpGs at 6p21.32). We also identified 64 DMPs and 137 DMRs in the meta-analysis. CONCLUSION:Our study reveals differences in DNAm between GD and HD, which may help explain why some people develop GD and others HD and provide a link to environmental risk factors. Additional research is needed to advance understanding of the role of DNAm in AITD and investigate its prognostic and therapeutic potential.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity >= 2, BMI >= 40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

BACKGROUND:Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. METHODS:We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. RESULTS:The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. CONCLUSION:We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Context Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations.Methods We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines.Results The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches.Conclusion Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Background. Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion. This study shows the importance of examining patient’s family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister’s unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Objectives Osteoarthritis (OA) is a joint disease with a heritable component. Genetic loci identified via genome-wide association studies (GWAS) account for an estimated 26.3% of the disease trait variance in humans. Currently, there is no method for predicting the onset or progression of OA. We describe the first use of the Collaborative Cross (CC), a powerful genetic resource, to investigate knee OA in mice, with follow-up targeted multi-omics analysis of homologous regions of the human genome. Methods We histologically screened 275 mice for knee OA and conducted quantitative trait locus (QTL) mapping in the complete cohort (> 8 months) and the younger onset sub-cohort (8–12 months). Multi-omic analysis of human genetic datasets was conducted to investigate significant loci. Results We observed a range of OA phenotypes. QTL mapping identified a genome-wide significant locus on mouse chromosome 19 containing Glis3 , the human equivalent of which has been identified as associated with OA in recent GWAS. Mapping the younger onset sub-cohort identified a genome-wide significant locus on chromosome 17. Multi-omic analysis of the homologous region of the human genome (6p21.32) indicated the presence of pleiotropic effects on the expression of the HLA − DPB2 gene and knee OA development risk, potentially mediated through the effects on DNA methylation. Conclusions The significant associations at the 6p21.32 locus in human datasets highlight the value of the CC model of spontaneous OA that we have developed and lend support for an immune role in the disease. Our results in mice also add to the accumulating evidence of a role for Glis3 in OA.