Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were re-examined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (OR 3.39 [95% CI 1.57-7.33], p < 0.05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed re-examination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

Identification of iodotyrosines as novel substrates for the thyroid hormone transporter MCT8.

Background Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is currently unknown if MCT8, like other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods In this study, we aimed to identify such substrates by applying LC-MS-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates was validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared to controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared to control cells. This effect was largely blocked in the presence of T3 (IC50: 2.5±1.5 µM) or T4 (IC50: 5.8±1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50%-reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine in. However, studies in human fibroblasts showed a 1.5-1.9-times higher glutamate uptake in control fibroblasts compared to fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro, and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines in vivo.

Clinical and Histopathological Risk Factors for Radioactive Iodine Refractory Follicular and Oncocytic Thyroid Carcinoma.

INTRODUCTION: Risk factors for radioactive iodine (RAI)-refractory disease in follicular (FTC) and oncocytic thyroid carcinoma (OTC) are unknown. Therefore, the aim of this study is to identify clinical and histopathological risk factors for RAI-refractory disease in FTC and OTC patients, facilitated by an extensive histopathological revision. METHODS: All adult FTC and OTC patients treated at Erasmus MC (the Netherlands) between 2000 and 2016 were retrospectively included. 2015 ATA Guidelines were used to define RAI-refractory disease. An extensive histopathological revision was performed applying the 2022 WHO Classification using Palga: Dutch Pathology Databank. Logistic regression was used to identify risk factors for RAI-refractory disease, stratified for histological subtype. RESULTS: Ninety FTC and 52 OTC patients were included, of which 14 FTC (15.6%) and 22 OTC (42.3%) developed RAI-refractory disease over a follow-up time of 8.5 years. RAI-refractory disease occurred in OTC after fewer cycles than in FTC (2.0 [IQR: 1.0-2.0] vs 2.5 [IQR: 2.0-3.75]), and it substantially decreased the 10-year disease specific survival, especially in OTC (46.4%; FTC 85.7%). In FTC, risk factors were higher age at diagnosis, pT3/pT4-stage, N1-stage, widely invasive tumors and extra-thyroidal extension. N1-stage and M1-stage were the strongest risk factors in OTC, rather than histopathological characteristics of the primary tumor. CONCLUSION: To our knowledge, this is the first study that correlates clinical and histopathological risk factors with RAI-refractory disease in FTC and OTC, facilitated by a histopathological revision. In FTC, risk factors for RAI-refractory disease were foremost histopathological characteristics of the primary tumor, whereas in OTC presentation with lymph node and distant metastasis was associated with RAI-refractory disease. Our data can help clinical decision making, particularly in patients at risk for RAI-refractory disease.

Management of Postthyroidectomy Hypoparathyroidism and Its Effect on Hypocalcemia-Related Complications: A Meta-Analysis.

OBJECTIVE: The aim of this Meta-analysis is to evaluate the impact of different treatment strategies for early postoperative hypoparathyroidism on hypocalcemia-related complications and long-term hypoparathyroidism. DATA SOURCES: Embase.com, MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and the top 100 references of Google Scholar were searched to September 20, 2022. REVIEW METHODS: Articles reporting on adult patients who underwent total thyroidectomy which specified a treatment strategy for postthyroidectomy hypoparathyroidism were included. Random effect models were applied to obtain pooled proportions and 95% confidence intervals. Primary outcome was the occurrence of major hypocalcemia-related complications. Secondary outcome was long-term hypoparathyroidism. RESULTS: Sixty-six studies comprising 67 treatment protocols and 51,096 patients were included in this Meta-analysis. In 8 protocols (3806 patients), routine calcium and/or active vitamin D medication was given to all patients directly after thyroidectomy. In 49 protocols (44,012 patients), calcium and/or active vitamin D medication was only given to patients with biochemically proven postthyroidectomy hypoparathyroidism. In 10 protocols (3278 patients), calcium and/or active vitamin D supplementation was only initiated in case of clinical symptoms of hypocalcemia. No patient had a major complication due to postoperative hypocalcemia. The pooled proportion of long-term hypoparathyroidism was 2.4% (95% confidence interval, 1.9-3.0). There was no significant difference in the incidence of long-term hypoparathyroidism between the 3 supplementation groups. CONCLUSIONS: All treatment strategies for postoperative hypocalcemia prevent major complications of hypocalcemia. The early postoperative treatment protocol for postthyroidectomy hypoparathyroidism does not seem to influence recovery of parathyroid function in the long term.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

Comparison of two different TSH-receptor antibody assays: A clinical practice study.

Background: Graves' disease (GD) is caused by the production of TSH-receptor (TSHR) stimulating auto-antibodies. Over the years various TSHR-antibody (TRAb) detection assays have been developed. Most clinical laboratories use competitive TSH-binding inhibitory immunoglobulin (TBII) assays, which measure the total amount of stimulating and blocking auto-antibodies. Selective detection of TSHR stimulating auto-antibodies (TSI) was previously only possible with functional cell-based bioassays. However, more recently an automated bridge-based binding assay to more specifically measure TSI has become available. The aim of our study was to compare the third-generation automated competitive immunoassay (TBII) with the automated bridge immunoassay (TSI) in clinical practice in an academic thyroid expert center. Methods: A retrospective study in 356 patients with Graves' disease, Graves orbitopathy (GO), and other (thyroid) disease treated in an academic thyroid center was performed. All samples were analyzed for TBII and TSI. For both assays, sensitivity, specificity, positive predictive value (PVV), negative predictive value (NPV) and diagnostic odds ratios were calculated using different cut-offs for negativity. Results: Using the provided cut-off, the overall sensitivity appeared similar between TBII and TSI, but TSI showed higher overall specificity, PPV, NPV and diagnostic odds ratio. Using two or three times the cut-off for negativity resulted in a decrease in sensitivity, but an increase in specificity and PPV, which was most pronounced for the TBII-assay. Analysis in a subgroup of newly diagnosed treatment naïve GD/GO patients also revealed overall favorable results for the TSI-assay. Increasing the cut-off for negativity resulted in increased specificity for both assays, with similar results using two or three times the cut-off. Most patients with concordant positive results for TBII and TSI suffered from GD or GD + GO (n = 110, 95.6 %), while patients negative for both TBII and TSI mostly suffered from other (thyroid) disease (n = 143, 77.3 %). From patients with positive TBII but negative TSI only 42.1 % had GD/GO (n = 16), whereas 57.9 % (n = 22) had other (thyroid) disease. In contrast, 88.9 % of patients with positive TSI but negative TBII had GD/GO (n = 16), whereas 11.1 % (n = 2) had other (thyroid) disease. Conclusion: In our academic thyroid center, the diagnostic performance of the TSI-assay outperformed the TBII-assay. Using a higher cut-off value for negativity can be helpful in assessing clinical relevance.

Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice.

Background: Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes. Methods: We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways. Results: Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO1 inhibition, Xpg -/- and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence. Conclusions: Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.

A symptom-based algorithm for calcium management after thyroid surgery: a prospective multicenter study.

Objective: Evidence-based treatment guidelines for the management of postthyroidectomy hypocalcemia are absent. The aim of this study was to evaluate a newly developed symptom-based treatment algorithm including a protocolized attempt to phase out supplementation. Methods: In a prospective multicenter study, patients were treated according to the new algorithm and compared to a historical cohort of patients treated with a biochemically based approach. The primary outcome was the proportion of patients receiving calcium and/or alfacalcidol supplementation. Secondary outcomes were calcium-related complications and predictors for supplementation. Results: One hundred thirty-four patients were included prospectively, and compared to 392 historical patients. The new algorithm significantly reduced the proportion of patients treated with calcium and/or alfacalcidol during the first postoperative year (odds ratio (OR): 0.36 (95% CI: 0.23-0.54), P < 0.001), and persistently at 12 months follow-up (OR: 0.51 (95% CI: 0.28-0.90), P < 0.05). No severe calcium-related complications occurred, even though calcium-related visits to the emergency department and readmissions increased (OR: 11.5 (95% CI: 4.51-29.3), P <0.001) and (OR: 3.46 (95% CI: 1.58-7.57), P < 0.05), respectively. The proportional change in pre- to postoperative parathyroid hormone (PTH) was an independent predictor for supplementation (OR: 1.04 (95% CI: 1.02-1.07), P < 0.05). Conclusions: Symptom-based management of postthyroidectomy hypocalcemia and a protocolized attempt to phase out supplementation safely reduced the proportion of patients receiving supplementation, although the number of calcium-related hospital visits increased. For the future, we envision a more individualized treatment approach for patients at risk for delayed symptomatic hypocalcemia, including the proportional change in pre- to post- operative PTH.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

Association of gestational thyroid function and thyroid peroxidase antibody positivity with postpartum depression: a prospective cohort study and systematic literature review with meta-analysis.

IMPORTANCE: Postpartum depression (PPD) has a major impact on maternal and offspring well-being, with multiple possible risk factors: Studies on the association of thyroid peroxidase antibody (TPOAb) positivity and thyroid function with PPD provide heterogeneous results. OBJECTIVE: To study the association of thyroid function and TPOAb positivity with PPD. DESIGN: We assessed the association of TPOAb and thyroid function with PPD in a population-based prospective cohort study and performed a systematic literature review and meta-analysis. METHODS: We measured thyroid stimulating hormone (TSH), free thyroxine (FT4), and TPOAb between 9- and 17-week gestation. Postpartum depression was assessed with Edinburgh Postpartum Depression Scale at 2-month postpartum and Brief Symptom Inventory at 2-, 6-, and 36-month postpartum. Additionally, we performed a systematic literature review and meta-analysis assessing this association. RESULTS: In the present study, there was no association of thyroid function with PPD (TSH: odds ratio [OR] 0.83, 95% CI 0.58-1.19, P = .32; FT4: OR 0.99, 95% CI 0.95-1.05, P = .86) or TPOAb positivity with PPD (OR 0.79, 95% CI 0.47-1.33, P = .37). An impaired thyroidal response to human chorionic gonadotropin (hCG), a surrogate marker for TPOAb positivity, was associated with a lower risk of PPD (P for interaction TSH = 0.04; FT4 = 0.06). Our systematic review and meta-analysis included 3 articles that were combined with the present study. There was no statistically significant association of TPOAb positivity with PPD (OR 1.93, 95% CI 0.91-4.10, P = .08), but the results were heterogeneous (I2 = 79%). CONCLUSIONS AND RELEVANCE: There was no significant association of TPOAb positivity, TSH, or FT4 with PPD. Our systematic review and meta-analysis revealed high heterogeneity of the current literature. Although TPOAb-positive women should be monitored for postpartum thyroiditis, our findings do not support routinely screening for PPD.

Parent Perspectives on Complex Needs in Patients With MCT8 Deficiency: An International, Prospective, Registry Study.

CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare neurodevelopmental and metabolic disorder, with daily care posing a heavy burden on caregivers. A comprehensive overview of these complex needs and daily care challenges is lacking. DESIGN: We established an international prospective registry to systemically capture data from parents and physicians caring for patients with MCT8 deficiency. Parent-reported data on complex needs and daily care challenges were extracted. RESULTS: Between July 17, 2018, and May 16, 2022, 51 patients were registered. Difficulties in daily life care were mostly related to feeding and nutritional status (17/33 patients), limited motor skills (12/33 patients), and sleeping (11/33 patients). Dietary advice was provided for 11/36 patients. Two of 32 patients were under care of a cardiologist. Common difficulties in the diagnostic trajectory included late diagnosis (20/35 patients) and visiting a multitude of specialists (15/35 patients). Median diagnostic delay was significantly shorter in patients born in or after 2017 vs before 2017 (8 vs 19 months, P < .0001). CONCLUSIONS: Feeding and sleeping problems and limited motor skills mostly contribute to difficulties in daily care. The majority of patients did not receive professional dietary advice, although being underweight is a key disease feature, strongly linked with poor survival. Despite sudden death being a prominent cause of death, potentially related to the cardiovascular abnormalities frequently observed, patients were hardly seen by cardiologists. These findings can directly improve patient-centered multidisciplinary care and define patient-centered outcome measures for intervention studies in patients with MCT8 deficiency.

Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

OBJECTIVE: Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS: We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS: We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION: The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Preferences of patients, clinicians, and healthy controls for the management of a Bethesda III thyroid nodule.

BACKGROUND: Active surveillance is propagated as an alternative for hemithyroidectomy in the management of Bethesda III thyroid nodules. METHODS: A cross-sectional survey questioned respondents on their willingness to accept risks related to active surveillance and hemithyroidectomy. RESULTS: In case of active surveillance, respondents (129 patients, 46 clinicians, and 66 healthy controls) were willing to accept a risk of 10%-15% for thyroid cancer and 15% for needing more extensive surgery in the future. Respondents were willing to accept a risk of 22.5%-30% for hypothyroidism after hemithyroidectomy. Patients and controls were willing to accept a higher risk on permanent voice changes compared with clinicians (10% vs. 3%, p < 0.001). CONCLUSION: Real-life risks associated which active surveillance and hemithyroidectomy for Bethesda III nodules are equivalent or less than the risks people are willing to accept. Clinicians accepted less risk for permanent voice changes.

Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice.

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3'-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.

Epigenome-Wide Association Study Reveals CpG Sites Associated with Thyroid Function and Regulatory Effects on KLF9.

Background: Thyroid hormones play a key role in differentiation and metabolism and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation. Methods: We carried out a fixed-effect meta-analysis of epigenome-wide association study (EWAS) of blood DNA methylation sites from 8 cohorts from the ThyroidOmics Consortium, incorporating up to 7073 participants of both European and African ancestry, implementing a discovery and replication stage. Statistical analyses were conducted using normalized beta CpG values as dependent and log-transformed thyrotropin (TSH), free thyroxine, and free triiodothyronine levels, respectively, as independent variable in a linear model. The replicated findings were correlated with gene expression levels in whole blood and tested for causal influence of TSH and free thyroxine by two-sample Mendelian randomization (MR). Results: Epigenome-wide significant associations (p-value <1.1E-7) of three CpGs for free thyroxine, five for free triiodothyronine, and two for TSH concentrations were discovered and replicated (combined p-values = 1.5E-9 to 4.3E-28). The associations included CpG sites annotated to KLF9 (cg00049440) and DOT1L (cg04173586) that overlap with all three traits, consistent with hypothalamic-pituitary-thyroid axis physiology. Significant associations were also found for CpGs in FKBP5 for free thyroxine, and at CSNK1D/LINCO1970 and LRRC8D for free triiodothyronine. MR analyses supported a causal effect of thyroid status on DNA methylation of KLF9. DNA methylation of cg00049440 in KLF9 was inversely correlated with KLF9 gene expression in blood. The CpG at CSNK1D/LINC01970 overlapped with thyroid hormone receptor alpha binding peaks in liver cells. The total additive heritability of the methylation levels of the six significant CpG sites was between 25% and 57%. Significant methylation QTLs were identified for CpGs at KLF9, FKBP5, LRRC8D, and CSNK1D/LINC01970. Conclusions: We report novel associations between TSH, thyroid hormones, and blood-based DNA methylation. This study advances our understanding of thyroid hormone action particularly related to KLF9 and serves as a proof-of-concept that integrations of EWAS with other -omics data can provide a valuable tool for unraveling thyroid hormone signaling in humans by complementing and feeding classical in vitro and animal studies.

Asymmetrical Transport of Thyroxine Across Human Term Placenta.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Evaluating Disease-specific Survival Prediction of Risk Stratification and TNM Systems in Differentiated Thyroid Cancer.

BACKGROUND: Many countries have national guidelines for the management of differentiated thyroid cancer (DTC), including a risk stratification system to predict recurrence of disease. Studies whether these guidelines could also have relevance, beyond their original design, in predicting survival are lacking. Additionally, no studies evaluated these international guidelines in the same population, nor compared them with the TNM system. Therefore, we investigated the prognostic value of 6 stratification systems used by 10 international guidelines, and the TNM system with respect to predicting disease-specific survival (DSS). METHODS: We retrospectively studied adult patients with DTC from a Dutch university hospital. Patients were classified using the risk classification described in the British, Dutch, French, Italian, Polish, Spanish, European Society of Medical Oncology, European Thyroid Association, the 2009 and 2015 American Thyroid Association (ATA) guidelines, and the latest TNM system. DSS was analyzed using the Kaplan-Meier method, and the statistical model performance using the C-index, Akaike information criterion, Bayesian information criterion, and proportion of variance explained. RESULTS: We included 857 patients with DTC (79% papillary thyroid cancer, 21% follicular thyroid cancer). Median follow-up was 9 years, and 67 (7.8%) died because of DTC. The Dutch guideline had the worst statistical model performance, whereas the 2009 ATA/2014 British guideline had the best. However, the (adapted) TNM system outperformed all stratification systems. CONCLUSIONS: In a European population of patients with DTC, of 10 international guidelines using 6 risk of recurrence stratification systems and 1 mortality-based stratification system, our optimized age-adjusted TNM system (8th edition) outperformed all other systems.

Thyroid Hormone Transporters in Pregnancy and Fetal Development.

Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis.