Deiodinase Activity Research Articles

Impact of peripheral thyroid hormone balance on liver fat: insights from the NutriAct trial.

Hypothyroidism has been proposed as a potential contributor to steatotic liver disease (SLD), but existing data shows conflicting results in euthyroid subjects. Therefore, we investigated the association between thyroid function and intrahepatic lipids (IHLs) during a 36-month randomized controlled trial evaluating a diet known to reduce liver fat. 502 eligible subjects (aged 50-80 years, ≥1 risk factor for unhealthy aging) were randomly assigned to either follow a diet rich in unsaturated fatty acids, plant protein, and fiber (intervention group, IG), or dietary recommendations of the German Nutrition Society (control group, CG). Serum levels of thyroid hormones (THs) as well as IHLs, defined via magnetic resonance spectroscopy, were measured within an euthyroid subgroup without significant alcohol consumption at baseline (n = 332) and after 12 months (n = 243). A ratio of T3/T4 was used to assess whole-body deiodinase activity. Estimates of glucose and lipid metabolism were analyzed. Only fT3 and T3/T4 ratios showed a significant positive correlation with IHL at baseline. We observed a significant decline in fT3, T3, fT3/fT4 ratio, and T3/T4 ratio in CG and IG after 12 months without significant differences between groups. TSH, fT4, and T4 remained stable. A larger improvement of IHL during dietary intervention was seen in those subjects with a lower decline in T3 concentrations. Altered TH balance indicates a possible compensatory upregulation of whole-body TH activity in subjects with increased liver fat. This might be also relevant during the improvement of hepatic steatosis.

Relationship between serum thyroid hormone and IL-1β levels and postmortem tissue deiodinase activity in critically ill patients

Objective: This study investigated the relationship between serum thyroid hormones and IL-1β levels and postmortem tissue deiodinase activity in critically ill patients. Methods: Serum thyroid hormones and IL-1β were measured on the 5th, 15th, and last day of 80 critically ill patients. Forty of these patients were non-survived, and liver and skeletal muscle were harvested to analyze deiodinase activity. Results: Serum TSH, T4, and T3 were decreased, and rT3 and IL-1β were increased in non-survivors. From day 5 to the last day, serum TSH, T4, and T3 levels increased, and rT3 and IL-1β levels decreased with time in survivors, while serum TSH, T4, and T3 levels decreased or remained unchanged, and rT3 and IL-1β increased in non-survivors. On the last day, liver D1 activity was in a negative correlation with serum rT3 and IL-1β, while liver and skeletal muscle D3 activities were in a positive correlation. Conclusion: Serum thyroid hormones and IL-1β are correlated with postmortem deiodinase activity in critically ill patients.

Supplementation with selenium and coenzyme Q10 in an elderly Swedish population low in selenium — positive effects on thyroid hormones, cardiovascular mortality, and quality of life

BackgroundSelenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL).MethodsFree T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses.ResultsIn the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group.ConclusionsSupplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency.Trial registrationThis study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

Alteration in kynurenine pathway metabolites in young women with autoimmune thyroiditis

The kynurenine pathway (KP) of tryptophan degradation includes several compounds that reveal immunomodulatory properties. The present study aimed to investigate the alteration in KP metabolites in young women with autoimmune thyroiditis (AIT) and their associations with thyroid function. The thyroid function tests, antithyroid antibodies measurement and ultrasonography of the thyroid gland have been performed in 57 young women with AIT and 38 age-matched healthy controls. The serum levels of tryptophan, kynurenine (KYN) and its metabolites were determined, and the activity of KP enzymes was calculated indirectly as product-to-substrate ratios. KP was activated and dysregulated in AIT, along with significantly elevated levels of KYN and anthranilic acid (AA), at the expense of the reduction of kynurenic acid (KYNA), which was reflected by the increase in the AA/KYNA ratio (p < 0.001). In univariate and multiple regression analyses, peripheral deiodinase (SPINA-GD) activity in AIT was positively associated with KYNA, AA, and quinolinic acid (QA). The merger of AA, AA/KYNA ratio, QA and SPINA-GD exhibited the highest sensitivity and specificity to predict AIT (p < 0.001) in receiver operating characteristic (ROC) analysis. In conclusion, the serum KYN metabolite profile is dysregulated in young women with AIT and could serve as a new predictor of AIT risk.

Takotsubo syndrome outcomes predicted by thyroid hormone signature: insights from cluster analysis of a multicentre registry

Recently, abnormal thyroid function was shown to be common in patients with Takotsubo syndrome (TTS), being classified into "endocrine-type" and "stress-type" responses. The aim of this study was to investigate the association between thyroid homeostasis and TTS in a larger international registry. In total 288 patients with TTS were enrolled through the GEIST multicentre registry from Germany, Italy and Spain. Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at admission. Data were collected both retrospectively and prospectively from 2017 onwards. Primary endpoints included in-hospital and all-cause fatality, determined by cluster analysis using an unsupervised machine learning algorithm (k-medoids). Three clusters were identified, classifying TTS with low (TSLT), high (TSHT) and normal (TSNT) thyroid output, based on TSH and FT4 levels in relation to the median thyroid's secretory capacity (SPINA-GT). Although TSH and FT4 concentrations were similar among survivors and non-survivors, these clusters were significantly associated with patient outcomes. In the longitudinal Kaplan-Meier analysis including in- and out-of-hospital survival, the prognosis related to concentrations of TSH, FT4, and FT3 as well as SPINA-GT, deiodinase activity (SPINA-GD) and clusters. Patients in the TSHT cluster and with cardiogenic shock had a lower initial left ventricular ejection fraction (LVEF). This study suggests that thyroid hormones may impact the evolution and prognosis of TTS. The findings indicate that thyroid-derived biomarkers may help identify high-risk patients and pave the way for novel personalized and preventive therapeutic options. This research was not funded by any public, commercial, or not-for-profit agencies.

Urine Se concentration poorly predicts plasma Se concentration at sub-district scales in Zimbabwe, limiting its value as a biomarker of population Se status.

The current study investigated the value of urine selenium (Se) concentration as a biomarker of population Se status in rural sub-Saharan Africa. Urine and plasma Se concentrations were measured among children aged 6-59 months (n = 608) and women of reproductive age (WRA, n = 781) living in rural Zimbabwe (Murehwa, Shamva, and Mutasa districts) and participating in a pilot national micronutrient survey. Selenium concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS), and urine concentrations were corrected for hydration status. The median (Q1, Q3) urine Se concentrations were 8.4 μg/L (5.3, 13.5) and 10.5 μg/L (6.5, 15.2) in children and WRA, respectively. There was moderate evidence for a relationship between urine Se concentration and plasma Se concentration in children (p = 0.0236) and WRA (p = < 0.0001), but the relationship had poor predictive value. Using previously defined thresholds for optimal activity of iodothyronine deiodinase (IDI), there was an association between deficiency when indicated by plasma Se concentrations and urine Se concentrations among WRA, but not among children. Urine Se concentration poorly predicted plasma Se concentration at sub-district scales in Zimbabwe, limiting its value as a biomarker of population Se status in this context. Further research is warranted at wider spatial scales to determine the value of urine Se as a biomarker when there is greater heterogeneity in Se exposure.

Effect of Radioiodine Treatment on Quality of Life in Patients with Subclinical Hyperthyroidism: A Prospective Controlled Study.

Study aim was to evaluate thyroid-related QoL in patients with subclinical hyperthyroidism mostly due to toxic nodular goitre undergoing RIT, compared to a control group of euthyroid subjects. Study design was monocentric, prospective, controlled. Fifty control subjects were enrolled and 51 RIT patients. Most subjects were examined at least twice at an interval of 6 months, with visits immediately before and 6 months after treatment in the RIT group. QoL was estimated with the ThyPRO questionnaire, using its composite scale as primary outcome. Treatment effect was the mean adjusted difference (MAD) between groups over time, using repeated? measures mixed? effects models. TSH concentrations were lower in the RIT group prior to treatment and recovered thereafter slightly above the level of the control group. Correspondingly, QoL improved significantly after 6 months from a worse level in the RIT group, compared to controls (MAD -10.3 [95% CI -14.9, -5.7], p<0.001). QoL improvements were strong for general items, but less pronounced for the hyperthyroid domain. Compared to controls, thyroid volume, thyroid functional capacity (SPINA-GT) and deiodinase activity (SPINA-GD) were significantly reduced in the RIT group. Patients with subclinical hyperthyroidism improve both biochemically and in their QoL after RIT, compared to controls. QoL assessment should have a wider role in clinical practice to complement biochemical tests and help with treatment decisions.

Clinical characteristics and outcomes of an exogenous thyrotoxicosis epidemic in prison

IntroductionAn outbreak of exogenous thyrotoxicosis is an uncommon cause of thyrotoxicosis. This study aimed to investigate the characteristics and outcomes of exogenous thyrotoxicosis and electrolyte imbalance in a prison during...

Exploring the association between triglyceride-glucose index and thyroid function

BackgroundThyroid dysfunction is associated with abnormal glucose-insulin homeostasis, and the triglyceride-glucose (TyG) index has been recommended as a convenient surrogate of insulin resistance (IR). This study aimed to investigate the relationship between TyG and thyroid function in the US population.Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2012 in a cross-sectional manner. Aside from conventional thyroid parameters, our study evaluated the central sensitivity to thyroid hormones (THs) using the thyroid feedback quantile-based index (TFQI), thyrotropin resistance index (TT4RI), and thyrotropin index (TSHI). To evaluate peripheral sensitivity to THs, we calculated the ratio of free triiodothyronine (FT3) to free thyroxine (FT4) and the sum activity of peripheral deiodinases (SPINA-GD). In the 1848 adults, multivariable linear regression, subgroup, and interaction analyses were employed to estimate the association between TyG and thyroid parameters. The nonlinear relationship was addressed by smooth curve fittings and generalized additive models.ResultsAfter adjusting covariates, we demonstrated a significant negative association between TyG and FT4 (β = − 0.57, p < 0.001), and a positive relationship between TyG and thyroid-stimulating hormone (β = 0.34, p = 0.037), as well as TgAb (β = 17.06, p = 0.005). Subgroup analysis indicated that the association between TyG and TgAb was more pronounced in the female subjects (β = 32.39, p < 0.001, p for interaction = 0.021). We also confirmed an inverse correlation between TyG and central sensitivity to THs, as assessed by TSHI and TT4RI (βTSHI = 0.12, p < 0.001; βTT4RI = 2.54, p = 0.023). In terms of peripheral sensitivity to THs, we found a significant positive correlation between TyG and FT3/FT4 (β = 0.03, p = 0.004), and SPINA-GD (β = 2.93, p = 0.004).ConclusionThe present study established a noteworthy association between TyG and thyroid parameters, indicating a strong link between IR and thyroid dysfunction. Further investigations are warranted to validate these results.

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

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. 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. 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. 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.

SAT477 Consumptive Hypothyroidism In A Patient With Plasma Cell Neoplasm

Abstract Disclosure: G. Sidhu: None. I. Madahar: None. A. Haider: None. J. Giordano: None. Introduction: Thyroxine (T4) is converted into metabolically active form triiodothyronine (T3) by deiodinase enzyme 1 &amp; 2 (D1 &amp; D2). Deiodinase 3 converts T4 and T3 into metabolically inactive form reverse T3 (rT3)&amp; di-iodothyronine (T2) . Consumptive hypothyroidism syndrome (CHS) is a very rare form of hypothyroidism seen in patients with neoplasms, which express high levels of D3 enzyme. Case: 68-year-old female withhistory of Multiple Myeloma (MM), POEMS, hyperlipidemia and hypothyroidism was admitted with acute kidney injury, cirrhosis of unclear etiology, large volume ascites and anasarca. She weighed 92 kg on admission. She was complaint with her 50 mcg of levothyroxine and on admission her TSH was 7.14 (N: 0.43-3.55 uIU/ml), Free T4 (FT4): &amp;lt;0.42 (N: 0.7-1.25 ng/dl), total T4 (TT4): 2.6 (N: 4.8-11.7 ug/dl), total T3 (TT3): &amp;lt;20 (N: 80-200 ng/dl). Oral LT4 was switched to IV form due to underlying concerns of malabsorption from anasarca. rT3 was noted to be 40 (N: 8-25 ng/dl). Despite escalated intravenous levothyroxine doses for seven days her FT4, FT3 continued to remain undetectable So her LT4 dose was increased to 75 mcg IV daily initially and eventually to 100 mcg IV daily and 125 mcg daily. On 10th day of hospitalization, after her IV LT4 dose was increased to 200 mcg daily, (almost 2.5 mcg/kg/day) her FT4 levels became detectable, 0.50, rT3: 68 and TT3: &amp;lt;20 and TT4: 3.1. Since her rT3 levels were noted to rise after increasing the dose of LT4, liothyronine (LT3) 5 mcg BID was added to her regimen. PET scan showed small sclerotic bone lesions suspicious for active malignancy. Chromogranin A was elevated 313 (N: &amp;lt;311 ng/ml). IR guided biopsy of scapular sclerotic lesion was done and specimen was sent University of Chicago to measure DI-3 activity in the specimen Pathology results were suggestive of plasma cell neoplasm but unfortunately deiodinase activity could not be quantified. Patient developed hepato-renal syndrome during hospitalization and her family decided to pursue hospice care. Discussion: Critical care illness thyroid disease is also associated with increased DI-3 activity and increases rT3, however T4 and TSH are also low in the setting of critical care illness, and most patient do not require supraphysiologic T4 replacements. The presence of D3 in normal tissues such as the brain &amp; placenta has been hypothesized to protect tissues from the effects of excessive thyroid hormone. However, aberrant expression of the enzyme can lead to severe hypothyroidism from inactivation of both endogenously produced and exogenously administered thyroid hormone. Previously this rare syndrome was described in association with massive hemangiomas in children and in a single case of a hemangioendothelioma in an adult. However case reports in adults have been described in nonvascular tumors who required supraphysiologic doses of levothyroxine prior to the resection of a large malignant solitary fibrous tumor. Presentation Date: Saturday, June 17, 2023

FRI475 The Impact Of Suppression Of Androgen Signaling On Thyroid Hormone Homeostasis In Prostate Cancer Patients

Abstract Disclosure: K. David: None. G. Devos: None. W. Devlies: None. N. Narinx: None. L. Antonio: None. L. Deboel: None. D. Schollaert: None. D.M. Vanderschueren: None. F.A. Claessens: None. S. Joniau: None. B. Decallonne: None. Next to the classical androgen deprivation therapy (ADT) with GnRH-(ant)agonists, androgen receptor signaling inhibitors (ARSIs) such as apalutamide (APA) have become available for the treatment of prostate cancer (PC) patients in the last years. Hypothyroidism was more frequent in APA-treated patients compared to placebo in the SPARTAN trial (NCT01946204) (8.1% vs 2%). We collected serum of PC patients included in a RCT (ARNEO; NCT03080116) before and after 12 weeks of neo-adjuvant ADT (GnRH-antagonist degarelix (DGX) with APA or placebo). We aimed to explore changes in thyroid homeostasis under deep androgen suppression with combined GnRH-antagonist and ARSI. Of the 88 patients ending the trial, 1 was excluded because of history of hypothyroidism for which he received levothyroxine. 43 and 44 patients were included in the DGX+placebo and DGX+APA group, respectively. Mean age was 66.3y. Sex steroid levels measured by LC-MS/MS decreased significantly to castrate range with median testosterone 10.5 ng/dL and estradiol 3.6 ng/L. TSH levels increased in both treatment groups, but more pronounced in the DGX+APA group (DGX+placebo before: 1.18 mIU/L and after: 1.33 mIU/L, p 0.0351 vs. DGX+APA before: 1.07 mIU/L and after: 1.87 mIU/L, p &amp;lt;0.0001; difference between groups after treatment: p &amp;lt;0.0001). Free T4 and total T4 levels decreased in the DGX+APA group, but remained unaltered in the DGX+placebo group (free T4 after: 16.53 vs 13.87 pmol/L, p&amp;lt;0.0001 and total T4 after: 8.77 vs. 7.78 µg/dL, p 0.0055). Total T3 and free T3 increased in the DGX+APA group, and again did not differ after treatment in the DGX+placebo group. (free T3 after: 5.03 vs 5.41 pmol/L, p 0.0066 and total T3 after: 132.30 vs 149.50 ng/dL, p 0.0003). As a result, the total and free T3/T4 ratio increased in the DGX+APA group with 32% and 35%, respectively. Reverse T3 decreased in both treatment arms, but greater in the DGX+APA group (19.55 vs 14.20 ng/dL, p 0.0157). Thyroxine binding globulin (TBG) increased in both treatment arms, with 6.9% and 8.4%, respectively. In conclusion, interference with androgen signaling alters thyroid homeostasis in PC patients, and is most pronounced under deep androgen suppression with combined GnRH-antagonist and ARSI therapy. The increase in T3 and decrease in rT3 may indicate additional effects of ARSI on deiodinase activity. Longer follow-up trials are needed to confirm these findings and assess the clinical implications of these changes in thyroid homeostasis. Presentation: Friday, June 16, 2023

Understanding the Roles of Selenium on Thyroid Hormone-Induced Thermogenesis in Adipose Tissue.

Brown adipose tissue (BAT) and white adipose tissue (WAT) are known to regulate lipid metabolism. A lower amount of BAT compared to WAT, along with adipose tissue dysfunction, can result in obesity. Studies have shown that selenium supplementation protects against adipocyte dysfunction, decreases WAT triglycerides, and increases BAT triiodothyronine (T3). In this review, we discuss the relationship between selenium and lipid metabolism regulation through selenoprotein deiodinases and the role of deiodinases and thyroid hormones in the induction of adipose tissue thermogenesis. Upon 22 studies included in our review, we found that studies investigating the relationship between selenium and deiodinases demonstrated that selenium supplementation affects the iodothyronine deiodinase 2 (DIO2) protein and the expression of its associated gene, DIO2, proportionally. However, its effect on DIO1 is inconsistent while its effect on DIO3 activity is not detected. Studies have shown that the activity of deiodinases especially DIO2 protein and DIO2 gene expression is increased along with other browning markers upon white adipose tissue browning induction. Studies showed that thermogenesis is stimulated by the thyroid hormone T3 as its activity is correlated to the expression of other thermogenesis markers. A proposed mechanism of thermogenesis induction in selenium supplementation is by autophagy control. However, more studies are needed to establish the role of T3 and autophagy in adipose tissue thermogenesis, especially, since some studies have shown that thermogenesis can function even when T3 activity is lacking and studies related to autophagy in adipose tissue thermogenesis have contradictory results.

Associations of metal mixtures with thyroid function and potential interactions with iodine status: results from a cross-sectional study in MEWHC.

Few studies are available on associations between metal mixture exposures and disrupted thyroid hormone homeostasis; particularly, the role of iodine status was ignored. Here, we aimed to explore the cross-sectional relationship of blood cell metals with thyroid homeostasis and explore the potential modifying effect of iodine status. Among 328 workers from the manganese-exposed workers healthy cohort (MEWHC), we detected thyroid function parameters: thyroid stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total tetraiodothyronine (TT4), free tetraiodothyronine (FT4) as well as calculated sum activity of peripheral deiodinases (GD) and thyroid's secretory capacity (GT). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure 22 metal concentrations in blood cells. Based on the consistent results of least absolute shrinkage and selection operator (LASSO) and Bayesian kernel machine regression (BKMR) analyses, there were significant positive associations between copper and TSH (β = 2.016), iron and FT4 (β = 0.403), titanium and GD (β = 0.142), nickel and GD (β = 0.057), and negative associations between copper and FT4 (β = - 0.226), selenium and GD (β = - 0.332), among the participants. Interestingly, we observed an inverted-U shape relationship between magnesium and FT4. Furthermore, we found a synergistic effect between arsenic and copper on the TSH level, while antagonistic effects between nickel and copper as well as nickel and selenium on the TSH level. We observed a modified effect of iodine status on association between strontium and GD (Pinteraction = 0.026). It suggests metal mixture exposures can alter thyroid homeostasis among the occupational population, and deiodinase activity had a modified effect on association between strontium and GD. Validation of these associations and elucidation of underlying mechanisms require further researches in the future.

Temporary hypothyroidism in severe crush syndrome: a potential novel entity.

Thyroid hormone synthesis is a complex process in the human body. Although the thyroid gland is essential for thyroid hormone synthesis, skeletal muscles also have crucial roles in thyroid hormone metabolism due to the deiodinase activities of the muscle cells. Hypothyroidism-related myopathy is a well-known entity. However, systemic effects of acute myopathies, such as rhabdomyolysis, on thyroid hormone metabolism have not to date been fully clarified. Fifty-three earthquake victims were evaluated retrospectively. We investigated the thyroid function tests (TFTs) among patients with creatine kinase (CK) levels higher than 10.000 U/L at admission. Fifteen patients had CK levels higher than 10.000 U/L and 12 of them had data of TFTs, including thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) during hospitalization. These patients were evaluated. TSH levels were increased in all seven patients who required HD due to severe crush syndrome. Decreased FT4 levels were detected in 71.4% of them. None of the five non-HD patients had increased TSH levels or reduced FT4 levels. During follow-up, all patients survived. Renal and thyroid functions were normalized during follow-up without thyroxin replacement in patients with no prior history of hypothyroidism. Moreover, TFTs were normalized in two patients with history of hypothyroidism under thyroxine treatment without dose adjustments. In severe forms of crush syndrome, temporary hypothyroidism might be seen. The exact mechanism underlying this entity is not well-known. Further clinical and experimental trials should be conducted to illuminate the mechanism of disrupted thyroid hormonogenesis in crush syndrome victims.

Effects of Perfluorooctane Sulfonate on Cerebellar Cells via Inhibition of Type 2 Iodothyronine Deiodinase Activity.

Perfluorooctane sulfonate (PFOS) has been used in a wide variety of industrial and commercial products. The adverse effects of PFOS on the developing brain are becoming of a great concern. However, the molecular mechanisms of PFOS on brain development have not yet been clarified. We investigated the effect of early-life exposure to PFOS on brain development and the mechanism involved. We investigated the change in thyroid hormone (TH)-induced dendrite arborization of Purkinje cells in the primary culture of newborn rat cerebellum. We further examined the mechanism of PFOS on TH signaling by reporter gene assay, quantitative RT-PCR, and type 2 iodothyronine deiodinase (D2) assay. As low as 10-7 M PFOS suppressed thyroxine (T4)-, but not triiodothyronine (T3)-induced dendrite arborization of Purkinje cells. Reporter gene assay showed that PFOS did not affect TRα1- and TRβ1-mediated transcription in CV-1 cells. RT-PCR showed that PFOS suppressed D2 mRNA expression in the absence of T4 in primary cerebellar cells. D2 activity was also suppressed by PFOS in C6 glioma-derived cells. These results indicate that early-life exposure of PFOS disrupts TH-mediated cerebellar development possibly through the disruption of D2 activity and/or mRNA expression, which may cause cerebellar dysfunction.

WPŁYW INFEKCJI SARS-CoV-2 NA FUNKCJĘ TARCZYCY – PATOMECHANIZM I IMPLIKACJE KLINICZNE

The SARS-CoV-2 virus is the pathogenic agent of the COVID-19 disease, which pandemic had caused 6.8 million deaths worldwide by February 2023. In the course of the disease, involvement of the thyroid gland is observed. The pathomechanism of damage to the thyroid gland is bidirectional – direct cytotoxicity of the virus and the indirect effect of a cytokine storm. Circulating pro-inflammatory cytokines lead to deiodinase activity dysregulation, resulting in changes in plasma concentrations of TSH, fT3, and fT4. These hormone abnormalities are observed in about 16% of patients during COVID-19 and may also result from the treatment itself – systemic corticosteroids. Dysregulation of the immune system also leads to autoinflammatory thyroid diseases. It seems crucial to monitor thyroid hormones to detect subclinical forms of thyroiditis early. This paper presents the prevalence and potential pathomechanism of thyroid disorders observed during SARS-CoV-2 infection – subacute thyroiditis, low T3 syndrome, Graves-Basedow disease, and Hashimoto’s disease.

Thyroid disrupting effects of multiple metals exposure: Comprehensive investigation from the thyroid parenchyma to hormonal function in a prospective cohort study

This study aimed to investigate the thyroid disrupting effects of multiple metals exposure with comprehensive investigation from the thyroid parenchyma to hormonal function. In this prospective cohort study of in-service staff of the Baoding Power Supply, we found that arsenic was negatively associated with total thyroxine (TT4) [βAs = −0.075, 95% confidence interval (CI): −0.129, −0.020, Padj = 0.04]. Similarly, selenium was negatively correlated with TT4 (βSe = −0.134, 95% CI: −0.211, −0.058, Padj < 0.01) and peripheral deiodinase activity (GT) (βSe = −0.133, 95% CI: −0.210, −0.056, Padj = 0.01). With respect to strontium, there were positive associations of strontium with thyroid-stimulating hormone (βSr = 0.263, 95% CI: 0.112, 0.414, Padj = 0.01), and negative associations of strontium with TT4 (βSr = −0.099, 95% CI: −0.150, −0.048, Padj < 0.01) and GT (βSr = −0.102, 95% CI: −0.153, −0.050, Padj < 0.01). We also observed negative associations of metal mixtures with TT4 and GT and potential interactions. Increased risks of thyroid nodule associated with aluminum, cobalt and nickel were also observed. Our findings suggest that multiple metals exposure leads to a multi-pronged assault to thyroid from the thyroid parenchyma to hormonal function. Future large-scale prospective cohort studies of general population and experimental studies were warranted.

The role of transducin β-like 1 X-linked receptor 1 (TBL1XR1) in thyroid hormone metabolism and action in mice.

Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.

Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone

Chronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination.Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6–15.6% in CFS versus 0.9–2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) μg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3.We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.