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Context Many patients with hypothyroidism receive suboptimal treatment that may affect hospital outcomes. Objective This work aimed to identify differences in hospital outcomes between patients with and without hypothyroidism. Methods A retrospective cohort study, using the propensity score-based fine stratification method to balance covariates, was conducted using a large, US-based, commercial claims database from January 1, 2008 to December 31, 2015. Participants included patients aged 64 years and younger who had a thyrotropin (TSH) level collected before a hospital admission. Covariates included age, sex, US region, type of admission, year of admission, and comorbidities. Exposure included clinical hypothyroidism, which was divided into 4 subgroups based on prehospitalization TSH level: low (TSH 10.00 mIU/L). Main outcome measures included length of stay (LOS), in-hospital mortality, and readmission outcomes. Results A total of 43 478 patients were included in the final study population, of whom 8873 had a diagnosis of hypothyroidism. Those with a high prehospitalization TSH level had an LOS that was 1.2 days longer (95% CI, 1.1-1.3; P = .003), a 49% higher risk of 30-day readmission (relative risk [RR] 1.49; 95% CI, 1.20-1.85; P Conclusion The results suggest suboptimal treatment of hypothyroidism is associated with worse hospital outcomes, including longer LOS and higher rate of readmission.

OBJECTIVE: Patient-centered studies have shown that several patients on thyroid hormone replacement therapy for hypothyroidism exhibit persistent symptoms, including “brain fog.” Here, we aimed to determine which of these specific symptoms are associated with brain fog, identify patient-reported factors that modify these symptoms, and identify patient concerns related to brain fog not included in thyroid-specific questionnaires. METHODS: A survey on brain fog symptoms adapted from thyroid-specific patient-reported outcome was distributed online. Textual data analysis was performed to identify common areas of concern from open-ended survey responses. RESULTS: A total of 5170 participants reporting brain fog while being treated for hypothyroidism were included in the analysis. Of these, 2409 (46.6%) participants reported symptom onset prior to the diagnosis of hypothyroidism, and 4096 (79.2%) participants experienced brain fog symptoms frequently. Of the symptoms listed, participants associated fatigue and forgetfulness most frequently with brain fog. More rest was the most common factor provided for improving symptoms. The textual data analysis identified areas of concern that are not often included in thyroid-specific quality of life questionnaires, including a focus on the diagnosis of hypothyroidism, the types and doses of medications, and the patient-doctor relationship. CONCLUSION: Brain fog in patients treated for hypothyroidism was associated most frequently with fatigue and cognitive symptoms. Several additional areas of patient concern were found to be associated with brain fog, which are not typically addressed in thyroid-specific questionnaires.

Background: L-triiodothyronine (LT3) has been increasingly used in combination with levothyroxine in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical triiodothyronine (T3) peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics (PK) of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) incidence of adverse events, and (iv) exploratory analysis of the sleep patterns after LT3, PZL, or placebo (PB) administration. Methods: Twelve healthy volunteers 18–50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose PB-controlled, crossover study to compare PZL against LT3 or PB. Subjects were admitted three separate times to receive a randomly assigned capsule containing PB, 50 μg LT3, or 50 μg PZL, and were observed for 48 hours. A 2-week washout period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a T(max) at 2 hours and return to basal levels by 24–36 hours. PZL-derived serum T3 levels exhibited ∼30% lower C(max) that was 1 hour delayed and extended into a plateau that lasted up to 6 hours. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded ½ of C(max). Thyrotropin levels were similarly reduced in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 PK. PZL is on track to provide hypothyroid patients with stable levels of serum T3.

Background: Illness severity in patients infected with COVID-19 is variable. Methods: Here, we conducted an observational, longitudinal, and prospective cohort study to investigate serum thyroid hormone (TH) levels in adult COVID-19 patients, admitted between June and August 2020, and to determine whether they reflect the severity or mortality associated with the disease. Results: Two hundred forty-five patients [median age: 62 (49-75) years] were stratified into non-critical (181) and critically ill (64) groups. Fifty-eight patients (23.6%) were admitted to the intensive care unit, and 41 (16.7%) died. Sixteen (6.5%) exhibited isolated low levels of free triiodothyronine (fT3). fT3 levels were lower in critically ill compared with non-critical patients [fT3: 2.82 (2.46-3.29) pg/mL vs. 3.09 (2.67-3.63) pg/mL, p = 0.007]. Serum reverse triiodothyronine (rT3) was mostly elevated but less so in critically ill compared with non-critical patients [rT3: 0.36 (0.28-0.56) ng/mL vs. 0.51 (0.31-0.67) ng/mL, p = 0.001]. The univariate logistic regression revealed correlation between in-hospital mortality and serum fT3 levels (odds ratio [OR]: 0.47; 95% confidence interval [CI 0.29-0.74]; p = 0.0019), rT3 levels (OR: 0.09; [CI 0.01-0.49]; p = 0.006) and the product fT3 × rT3 (OR: 0.47; [CI 0.28-0.74]; p = 0.0026). Serum thyrotropin, free thyroxine, and fT3/rT3 values were not significantly associated with mortality and severity of the disease. A serum cutoff level of fT3 (≤2.6 pg/mL) and rT3 (≤0.38 ng/mL) was associated with 3.46 and 5.94 OR of mortality, respectively. We found three COVID-19 mortality predictors using the area under the receiver operating characteristic (ROC) curve (AUC score): serum fT3 (AUC = 0.66), rT3 (AUC = 0.64), and the product of serum fT3 × rT3 (AUC = 0.70). Non-thyroidal illness syndrome (fT3 < 2.0 pg/mL) was associated with a 7.05 OR of mortality ([CI 1.78-28.3], p = 0.005) and the product rT3 × fT3 ≤ 1.29 with an 8.08 OR of mortality ([CI 3.14-24.2], p < 0.0001). Conclusions: This prospective study reports data on the largest number of hospitalized moderate-to-severe COVID-19 patients and correlates serum TH levels with illness severity, mortality, and other biomarkers to critical illness. The data revealed the importance of early assessment of thyroid function in hospitalized patients with COVID-19, given the good prognostic value of serum fT3, rT3, and fT3 × rT3 product. Further studies are necessary to confirm these observations.

Context Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. Objective This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. Methods This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. Results The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. Conclusion In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1–5 (P1–P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p, Whether thyroid hormones affect gene expression via DNA methylation is not well known. Here the authors show that type 2 deiodinase (D2) converts T4 to produce T3, which prevents DNA methylation of discrete areas in the neonatal liver. In the absence of D2, DNA methylation occurs and is associated with reduced chromatin accessibility in promoters and enhancers and affects gene expression.

PURPOSE The development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non–small-cell lung cancer (NSCLC) who had a functional thyroid. MATERIALS AND METHODS Thyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases. RESULTS Upon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels. CONCLUSION An off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. Here we report the presence of C-terminal suPAR fragment, D2D3, in patients with diabetic nephropathy. D2D3-positive human sera inhibited glucose-stimulated insulin release in human islets and were associated with patients requiring insulin therapy. D2D3 transgenic mice presented kidney disease and diabetes marked by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β-cell mass, and high fasting glucose. D2D3 fragment dysregulated glucose-induced cytoskeletal dynamics, impaired maturation and trafficking of insulin granules, and inhibited bioenergetics of β-cells in culture. An anti-uPAR antibody restored β-cell function in D2D3 transgenic mice. We show that the D2D3 fragment injures the kidney and pancreas, offering a unique dual therapeutic approach for kidney diseases and insulin-dependent diabetes.SummaryProteolytic suPAR fragment, D2D3, simultaneously injures two organs, the kidney and pancreas, thus causing a dual organ disease.

In the 1970s, treatment with thyroid extract was superseded by levothyroxine, a synthetic l form of tetraiodothyronine. Since then, no major innovation has emerged for the treatment of hypothyroidism. The biochemical definition of subclinical hypothyroidism is a matter of debate. Indiscriminate screening for hypothyroidism has led to overdiagnosis and treatment initiation at lower serum levels of thyroid-stimulating hormone (TSH) than previously. Adverse health effects have been documented in individuals with hypothyroidism or hyperthyroidism, and these adverse effects can affect health-related quality of life (QOL). Levothyroxine substitution improves, but does not always normalize, QOL, especially for individuals with mild hypothyroidism. However, neither studies combining levothyroxine and liothyronine (the synthetic form of tri-iodothyronine) nor the use of desiccated thyroid extract have shown robust improvements in patient satisfaction. Future studies should focus not only on a better understanding of an individual’s TSH set point (the innate narrow physiological range of serum concentration of TSH in an individual, before the onset of hypothyroidism) and alternative thyroid hormone combinations and formulations, but also on autoimmunity and comorbidities unrelated to hypothyroidism as drivers of patient dissatisfaction. Attention to the long-term health consequences of hypothyroidism, beyond QOL, and the risks of overtreatment is imperative.

Adaptive thermogenesis in small mammals and infants takes place in brown adipose tissue (BAT). Heat is produced via uncoupling protein 1 (UCP1)-mediated uncoupling between oxidation of energy substrates and adenosine 5′-triphosphate synthesis. Thyroid hormone (TH) signaling plays a role in this process. The deiodinases activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3) (D2) or inactivate T4 and T3 to 3,3,5′-triiodothyronine and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 × UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (embryonic days 16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, including Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA sequencing, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by more than 1.5-fold, 36 of which play a role in metabolic/thermogenic processes. BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22 °C) and in the cold (4 °C). They also defend their core temperature more effectively and do not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in the BAT transcriptome.

Introduction: The number of non-cardiac major surgeries carried out has significantly increased in recent years to around 200 million procedures carried out annually. Approximately 30% of patients submitted to non-cardiac surgery present some form of cardiovascular comorbidity. In emergency situations, with less surgery planning time and greater clinical severity, the risks become even more significant. The aim of this study is to determine the incidence and clinical outcomes in patients with cardiovascular disease submitted to non-cardiac surgical procedures in a single cardiovascular referral center. Methods: This is a prospective cohort study of patients with cardiovascular disease submitted to non-cardiovascular surgery. All procedures were carried out by the same surgeon, between January 2006 and January 2018. Results: 240 patients included were elderly, 154 were male (64%), 8 patients presented two diagnoses. Of the resulting 248 procedures carried out, 230 were emergency (92.8%). From the data obtained it was possible to estimate the day from which the occurrence of mortality is less probable in the postoperative phase. Conclusion: Our research evaluated the epidemiological profile of the surgeries and we were able to estimate the survival and delimit the period of greatest risk of mortality in these patients. The high rate of acute mesenteric ischemia was notable, a serious and frequently fatal condition.

Context The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. Objective Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. Methods Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. Results In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (n = 79), Thr/Ala (n = 119), and Ala/Ala (n = 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. Conclusion Here we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.

Introduction Many patients in the US with hypothyroidism receive suboptimal treatment with thyroid hormone. Sustained off-target TSH levels have been shown to cause serious harm to patients, including increased risk of cardiovascular disease and excess mortality over time. Suboptimal treatment may also impact hospital outcomes. The primary objective of the study was to identify differences in hospital outcomes between patients with and without hypothyroidism. Methods This is a retrospective cohort study that utilized the propensity score-based fine stratification method to balance covariates. Patient data was extracted from a large, US-based, IBM MarketScan® Commercial Claims and Encounters Database from January 1, 2008 to December 31, 2015. Participants included patients 64 years and younger who had commercial insurance and a thyrotropin (TSH) level collected prior to a medical or surgical hospital admission. Covariates included age, sex, US region, type of admission (medical vs surgical), year of admission, and co-morbidities. The primary exposure was defined as clinical hypothyroidism, which was divided into 4 subgroups based on pre-hospitalization TSH level: low (TSH 10.00 mIU/L). Non-hypothyroidism was the non-exposure (control). The primary outcomes were length of stay (LOS), in-hospital mortality, and readmission outcomes following medical and surgical admission. Results A total of 46,235 patients were included in the final study population, of whom 9,394 had a diagnosis of hypothyroidism. Those with a high pre-hospitalization TSH level had a LOS that was 1.2 days longer (95% CI [1.1–1.3]; p = 0.001), a 41% higher risk of 30-day readmission (RR 1.41, 95% CI [1.13–1.75]; p = 0.002), and 33% higher rate of 90-day readmission (RR 1.33, 95% CI [1.13–1.56]; p Conclusions Suboptimal treatment of hypothyroidism appears to be associated with worse hospital outcomes, including longer LOS and higher rate of readmission. Public health strategies designed to deliver appropriate, consistent outpatient treatment of hypothyroidism are needed to improve hospital outcomes in those patients with off-target TSH levels. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m.

Levothyroxine monotherapy has been the standard of care for treatment of hypothyroidism for more than 40 years. However, patients treated with levothyroxine have relatively lower serum tri-iodothyronine (T(3)) concentrations than the general population, and symptoms of hypothyroidism persist for some patients despite normalisation of thyroidstimulating hormone (TSH) concentrations. The understanding that maintenance of normal T(3) concentrations is the priority for the thyroid axis has redirected the clinical focus to serum T(3) concentrations in patients with hypothyroidism. This Personal View explores whether it is currently feasible to identify patients who could be considered for liothyronine supplementation in combination with levothyroxine. Genetic profiling stands out as a potential future tool to identify patients who do not respond well to levothyroxine due to suboptimal peripheral thyroxine (T(4)) activation. Moreover, new slow-release liothyronine preparations are being developed to be trialled in these symptomatic patients, in an attempt to restore T(3) concentrations and provide conclusive results for the use of T(4) plus T(3) combination therapy.

Background: Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves’ disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3'-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease. Methods: To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used. Surface plasmon resonance (SPR), co-immunoprecipitation and Proximity Ligation Assay (PLA) were used for the interaction studies. Findings: Healthy podocytes expressed D3 as the predominant deiodinase isoform. Upon podocyte injury, levels of DIO3 transcript and D3 protein were dramatically reduced both in vitro and in the LPS mouse model of podocyte damage. D3 was no longer directed to the cell membrane, it accumulated in the Golgi and nucleus instead. Further, depleting D3 from the mouse podocytes resulted in foot process effacement and proteinuria. Treatment of mouse podocytes with T3 phenocopied the absence of D3 and elicited activation of αvβ3 integrin signaling, which led to podocyte injury. We also confirmed presence of an active thyroid stimulating hormone receptor (TSH-R) on mouse podocytes, engagement and activation of which resulted in podocyte injury. Interpretation: The study provided a mechanistic insight into how D3-αvβ3 integrin interaction can minimize T3-dependent integrin activation, illustrating how D3 could act as a renoprotective thyrostat in podocytes. Further, injury caused by binding of TSH-R with TSH-R antibody, as found in patients with Graves’ disease, explained a plausible link between thyroid disorder and NS. Funding: Funding support from American Thyroid Association (ATA) to NJT (ATA-2018-050.R1). Declaration of Interest: Jochen Reiser has patents on novel strategies for kidney therapeutics and stands to gain royalties from their commercialization. He is the co-founder of Walden Biosciences (Cambridge, MA, USA), a biotechnology company in which he has financial interest, including stock. Other authors have nothing to disclose and there are no competing or conflicting interests. Ethical Approval: All animal experiments were carried out according to the NIH’s Guide for the Care and Use of Experimental Animals (National Academies Press, 2011), and approved by the Institutional Animal Care and Use Committee (IACUC) at Rush University (Chicago, Illinois, USA). Human biopsy kidney sections from healthy donors and patients with FSGS, DN and MCD were procured in accordance with guidelines on human research and with approval of the Institutional Review Board of Rush University Medical Center (Chicago, Illinois, USA).

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.

A number of mechanisms modify thyroid hormone (TH) signaling at the cellular level. To restore TH signaling in patients with hypothyroidism or in patients with the syndrome of TH resistance, it is necessary to quantify the action of THs in a tissue-specific manner. The development of biomarkers that are tissue-specific and respond to TH is a significant first step toward understanding and possibly modifying TH signaling in health and disease states.

Introduction The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients. Objective To explore the impact of calorie exposure on NTIS over time in critically ill patients. Methods Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio. Results Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1. Conclusions Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.

Background A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein. Methods Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. Results The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH. Conclusions EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.

Background: Liothyronine (LT3) has limited short-term clinical applications, all of which aim at suppressing thyrotropin (TSH) secretion. A more controversial application is chronic administration along with levothyroxine in the treatment of hypothyroidism. Long-term treatment with LT3 is complicated by its unique pharmacokinetics that result in a substantial triiodothyronine (T3) peak in the blood three to four hours after oral dosing. This is a significant problem, given that T3 levels in the blood are normally stable, varying by

Introduction Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. Methodology Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. Results Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). Conclusions As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.

Deiodinases modify the biological activity of thyroid hormone (TH) molecules, ie, they may activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3), or they may inactivate T3 to 3,3′-diiodo-L-thyronine (T2) or T4 to reverse triiodothyronine (rT3). Although evidence of deiodination of T4 to T3 has been available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP), and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.

Purpose Both undertreatment and overtreatment of hypothyroidism with thyroid hormone are associated with adverse clinical outcomes. Disparities in the treatment of hypothyroidism may lead to a higher risk of adverse outcomes for certain sociodemographic groups. Our objectives were to identify sociodemographic disparities between those with treated and untreated hypothyroidism, and between those who were adequately and inadequately treated. Methods This is a cross-sectional study of a representative sample of US adults aged 20 years and older with hypothyroidism (n = 698). The main measures were age, gender, race/ethnicity, education, income, and health care access differences among those with treated and untreated hypothyroidism. Results Of those with hypothyroidism, women were more likely than men to be taking thyroid hormone (odds ratio [OR] 2.66 [95% confidence interval (CI) 1.42–4.99]), as were older participants (45–69 years old vs 20–44 years old: OR 7.25 [95% CI 4.15–12.67]; 70 years of age and older: OR 11.00 [95% CI 5.30–22.79]). Health care access was strongly associated with thyroid hormone use (OR 14.32, 95% CI 3.63–56.58). Hispanic race/ethnicity was associated with inadequate treatment compared with non-Hispanic whites (OR 2.42, 95% CI: 1.14–5.14). Main Conclusions Male gender, younger age, and lack of health care access were associated with untreated hypothyroidism, and Hispanic race was associated with inadequate treatment of hypothyroidism. Clinicians should be aware of these sociodemographic disparities in the hypothyroid population and consider strategies to improve treatment of hypothyroidism in men, younger adults, Hispanics, and those without routine health care access.

Context Treatment with levothyroxine (LT4) that normalize serum thyrotropin (TSH) is expected to restore lipid metabolism. Objective To assess statin utilization in LT4-treated patients through an observational drug utilization study. Methods Three sites were involved: (1) 10 723 outpatients placed on LT4 during 2006-2019 identified from the Clinical Research Data Warehouse of the University of Chicago; (2) ~1.4 million LT4 prescriptions prepared by primary care physicians during January-December 2018, identified from the IQVIA™ database of medical prescriptions in Brazil; (30 ~5.4 million patient interviews during 2009-2019, including ~0.32 million patients on LT4, identified from the Fleury Group database in Brazil. Results On site 1, initiation of therapy with LT4 increased the frequency of statin utilization (19.1% vs 24.6%), which occurred ~1.5 years later (median 76 weeks) and, among those patients that were on statins, increased intensity of treatment by 33%, despite normalization of serum TSH levels; on site 2, after matching for sex and age, the frequency of statins prescription was higher for those patients using LT4: females, 2.1 vs 3.4% (odds ratio [OR] 1.656 [1.639-1.673]); males, 3.1 vs 4.4% (OR 1.435 [1.409-1.462]); and, on site 3, after matching for sex and age, the frequency of statin utilization was higher in those patients using LT4: females, 10 vs 18% (OR 2.02 [2.00-2.04]); males, 15 vs 25% (OR 1.92 [1.88-1.96]); all P values were Conclusion Prescription and utilization of statins were higher in patients taking LT4. The reasons for this association should be addressed in future studies.

Introduction: Before the availability of levothyroxine (LT4), patients were treated with desiccated thyroid extract (DTE). When switching from DTE to LT4, despite adequate dosing based on serum TSH levels, some patients still feel unwell with fatigue, mental fogginess, weight gain etc. A recent randomized, crossed over study between DTE vs. LT4 conducted in our department showed that once-daily DTE caused modest weight loss and possible improvement in mental health scores without appreciable adverse effects; also, nearly half of the study patients preferred DTE over LT4. A few studies have shown that LT4/T3 combination had beneficial effects in improving quality of life relative to LT4 alone. Furthermore, it has been reported that patients with CC genotype in the deiodinase type 2 polymorphism responded more favorably with LT4/T3 combination than T4 monotherapy. Hypothesis: This study investigated the efficacy and effectiveness of DTE vs. LT4/T3 combination vs. LT4 monotherapy in hypothyroid patients based on genotypic differences of deiodinase type 2. Methodology: This was a prospective, randomized, double-blind, crossover study. 75 subjects completed the study. There were 3 arms: DTE, LT4+T3 combination, and LT4 alone. Each subject was randomly allocated to one of these 3 arms for 12 weeks randomly. The study was powered to detect the primary outcome. The primary endpoint was post-treatment score on the 36-point thyroid symptom questionnaire. Secondary endpoints were weight, general health questionnaire, the Beck depression inventory, Wechsler Memory testing, lipid panels and thyroid function tests. Analysis was performed with a linear mixed model using subject as a random factor and group as a fixed effect. Results: There was no significant difference between the 3 arms on the thyroid symptom questionnaire (p=.32), and the secondary outcomes showed no between group differences. Auditory memory index (p=.008), and visual working memory index (p=.02) were higher in the Hashimoto’s than non-Hashimoto’s group. There was no significant primary or secondary outcome difference among various genotypes of deiodinase 2. There was no relationship between Hashimoto’s vs. non-Hashimoto’s based on genotypes or likelihood of carrying Thr92AlaD2 polymorphism. Though there was no statistically significant preference for any treatment, numerically more patients with Hashimoto’s preferred DTE and LT4/T3 combination than LT4-monotherapy. Conclusions: There was no significant difference between hypothyroid patients taking DTE vs. LT4/T3 combination vs. LT4 monotherapy. Numerically, Hashimoto’s patients tended to prefer DTE and LT4/T3 combination. Also, there was no observed relationship between Hashimoto’s and polymorphism. Further studies with more patients may be needed.

More than a billion people worldwide are at risk of iodine deficiency (ID), with well-known consequences for development of the central nervous system. Furthermore, ID has also been associated with dyslipidemia and obesity in humans. To further understand the metabolic consequences of ID, here we kept 8-week-old C57/Bl6 mice at thermoneutrality (~28°C) while feeding them on a low iodine diet (LID). When compared with mice kept on control diet (LID + 0.71 μg/g iodine), the LID mice exhibited marked reduction in T4 and elevated plasma TSH, without changes in plasma T3 levels. LID mice grew normally, and had normal oxygen consumption, ambulatory activity, and heart expression of T3-responsive gene, confirming systemic euthyroidism. However, LID mice exhibited ~5% lower respiratory quotient (RQ), which reflected a ~2.3-fold higher contribution of fat to energy expenditure. LID mice also presented increased circulating levels of nonesterified fatty acids, ~60% smaller fat depots, and increased hepatic glycogen content, all indicative of accelerated lipolysis. LID mice responded much less to forced mobilization of energy substrates (50% food restriction for 3 days or starvation during 36 hours) because of limited size of the adipose depots. A 4-day treatment with T4 restored plasma T4 and TSH levels in LID mice and normalized RQ. We conclude that ID accelerates lipolysis and fatty acid oxidation, without affecting systemic thyroid hormone signaling. It is conceivable that the elevated plasma TSH levels trigger these changes by directly activating lipolysis in the adipose tissues.