bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Expression to Guide Glucocorticoid Replacement in Autoimmune Addison’s Disease
Authors: Sævik Åse Bjorvatn , Wolff Anette , Björnsdottir Sigridur , Simunkova Katerina , Hynne Martha S , Dolan David , Bratland Eirik , Knappskog Per , Methlie Paal , Carlsen Siri , Isaksson Magnus , Bensing Sophie , Kämpe Olle , Husebye Eystein Sverre , Løvås Kristian , Øksnes Marianne
Published: May 2021

Objective: Deciding the optimal doses of glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD) is impeded by the lack of reliable biomarkers. This frequently results in over-treatment, with alarming and persistent side-effects, or under-replacement, which could be fatal. There is a need to think new in the quest for robust biomarkers to optimize GC replacement in AAD at an individual level.

Aim: We aimed to identify genes that are consistently up- or down-regulated in patients with AAD in response to different GC replacement doses. This information can be used to establish novel biomarkers to guide GC treatment in AAD.

Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. To verify the results, we performed real-time PCR to compare gene expression levels of three of the highly differentially expressed genes (FKBP5, MMP9, and DSIPI) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.

Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression.

Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.
A Tale of Two Therapies- A Comparison of Armour Thyroid and Levothyroxine
Authors: Shah Meghna , Proumen Rachael , Sunkara Akhila , Acharya Runa , Patel Amy
Published: May 2021

Treatment of hypothyroidism is predominantly with levothyroxine due to its ability to generate stable T3 levels and its long half-life. Many patients report continued hypothyroid symptoms despite normal TSH values on levothyroxine and request to switch to desiccated animal thyroid extract. Desiccated thyroid extract is less used for fear of side effects and risks. There are only a handful of studies available comparing desiccated animal thyroid extract to levothyroxine. We conducted a retrospective study on 250 hypothyroid patients over the age of 18 who presented to our clinic from 2008-2018. We excluded patients who had a history of thyroid cancer and documented non-adherence. We analyzed 125 patients on levothyroxine (males=43, females=82) and 125 patients who were on levothyroxine but chose to switch to Armour Thyroid (males=7, females=118). We examined the following variables; when comparisons of proportions were made between the two groups, N-1 chi square test was used to determine significance.

1. Reason for change to Armour Thyroid from levothyroxine: Top reasons were fatigue (n=51/125, 40.8%), inability to lose weight (n=32/125, 25.6%), mental fog (n=8/125, 6.4%), hair loss (n=8/125, 6.4%) and desire for a natural product (n=7/125, 5.6%)

2. Percentage of patients complaining of fatigue/weight gain in euthyroid state: 16/125 (12.8%) of patients on Armour Thyroid and 29/125 (23.2%) of patients on levothyroxine had complaints of fatigue and weight gain with a normal TSH. This 10.4% difference was significant (p value=0.033, 95% CI 0.84% to 19.8%).

3. Presence of side effects: 24/125 (19.2%) patients on Armour Thyroid discontinued it before 6 months. The top reasons were no improvement of symptoms (n=9/24, 37.5%), palpitations (n=5/24, 20.8%), worsening anxiety (n=3/24, 12.5%), cost (n=2/24, 8.33%), and loss of appetite (n=2/24, 8.33%). 5/125 (4.00%) patients on levothyroxine chose to discontinue it before 6 months. The reasons included presence of palpitations (n=3/5, 60.0%), hair loss (n=1/5, 20.0%), and gluten intolerance (n=1/5, 20.0%). A total of 11/125 (8.8%) had adverse effects from Armour Thyroid while 4/125 (3.2%) of patients on levothyroxine had adverse effects to the medication. The difference of 5.6% leaned toward clinical significance and trended toward being statistically significant (p value=0.06, CI -0.4842% to 12.1677%).

Our research shows that patients generally feel better on Armour Thyroid compared to levothyroxine. Armour Thyroid is an effective medication to use for patients who remain symptomatic on levothyroxine and should be considered as a viable option in clinical practice. However, our study also indicated that patients may have more adverse effects on Armour Thyroid when compared to levothyroxine and further studies are needed comparing the two medications. Limitations of our study include the retrospective nature of the study and the sample size.
Clinical Implication of TSH Screening in Venous Thromboembolism Patients
Authors: Dejhansathit Siroj , Mejia Ana Marcella Rivas , Nugent Kenneth
Published: May 2021

Background: Venous thromboembolism (VTE) that have significant morbidity and mortality for patients in the community and hospital. A recent meta-analysis found a significantly increased risk of incidence VTE among patients with hyperthyroidism compared to patients without hyperthyroidism. To our knowledge, no study has attempted to explore whether screening for TSH levels in VTE patients leads to a diagnosis of undiagnosed thyroid dysfunction as VTE could be the first presenting symptom. Method: We conducted a retrospective cohort study and analyzed data of all patients treated at University Medical Center, Lubbock, Texas in 18-85 years of age with a diagnosis of DVT and/or PE in 2019. Qualitative chart review to identify cases of clinically significant TSH screening in VTE patients that leads to thyroid dysfunction diagnosis. Associations between variables tested using Student’s t-test, chi-square, and Fisher’s exact test. Results: Of total of 533 participants with diagnosis of VTE in 2019, 85 participants were included in the study. Seven participants (8.24%) were found to have high TSH level (>4.2 mIU/mL). None of them was found to have low level of TSH. Participants in high TSH group were more likely to be female (71.43%) and Caucasian (71.43%). In high TSH group patients tended to have both PE and DVT diagnosis at the same admission (71.43%). Weight and BMI were significance higher than those with normal TSH level. Segna et al conducted a prospective multicenter cohort study on association between thyroid dysfunction and venous thromboembolism. The study measure thyroid hormones and thrombophilic biomarkers at 1 year after the acute VTE and follow for the recurrent VTE (rVTE). They found that after 20.8 months of follow-up, 9% developed rVTE. However, none of them was found in subclinical hyperthyroidism group. Furthermore, in their multi-variate analyses, the hazard ratio for rVTE was 0.80 (95%CI 0.23-2.81) subclinical hyperthyroidism compared with euthyroid participants. They concluded that subclinical hyperthyroidism may be associated with lower rVTE risks. Similarly, with Liviu study found hyperthyroidism was not associated with an increased risk of VTE. Qualitative chart review in our patients with high TSH resulted that none of them had history of tobacco use. One participant was on birth control pills with the history of cervical carcinoma. Conclusion:The association of thyroid dysfunction and the development of VTE is debated on the literature review. In our study we found multiple patients with high TSH level (8.24%) in VTE patients with no prior history of thyroid dysfunction. TSH could play an important role in hypercoagulable state. Subclinical hypothyroidism and/or hypothyroidism may induce a prothrombotic event. However, larger cohort studies with higher prevalence of high TSH participants are needed to prove a relationship between TSH level and VTE events.
Evaluation of the Optimal Thyroxine Levels for Thyroxine Hormone Replacement in Patients With Central Hypothyroidism
Authors: Lee Ka Fai , So Hay Man , Mak Wai Han
Published: May 2021

Introduction: Central hypothyroidism results from pituitary or hypothalamic dysfunction. The evaluation of the adequacy of thyroxine replacement is difficult, due to the loss of thyrotropin (TSH) as an accurate feedback marker. This study aim to explore the potential metabolic and clinical effects of different free T4 (fT4) replacement targets in patients with central hypothyroidism. Method: This was a single center, prospective open-label crossover-like trial of 51 patients (mean age 56±12.9 years, 27 male) with hypopituitarism with multiple hormonal deficiencies including central hypothyroidism after excluding those with primary thyroid diseases, high risk for cardiovascular diseases (CVD) and known CVD. Dosage of levothyroxine (L-T4) was titrated to a targeted lower, middle and upper fT4 tertile and maintained for 24 weeks before assessment. Anthropometric and physiological measurements, metabolic and peripheral tissue markers, cognitive and quality of life assessments (SF-36 and Hong Kong Montreal Cognitive Assessment-5 [HK-MoCA-5]) were compared before and after each fT4 tertile change. This was followed by another 24-week cycle of L-T4 dosage adjustment to achieve fT4 in another tertile, with the same assessment as above. Results: We demonstrated that raising fT4 target from lower to upper tertile within the normal reference range resulted in significant decrease in body mass index (27.1±6.0 vs 25.7±5.6 kg/m2, P<0.01), waist circumference (89.5±12.7 vs 86.4±12.1 cm, p<0.01), diastolic blood pressure (79.1±12.9 vs 74.5±12.9 mmHg, p<0.05) and low density lipoprotein cholesterol (3.94±0.88 vs 2.90±0.71 mmol/L, p<0.01), apart from expected significant effect on tissue markers such as increased sex-hormone binding globulin (SHBG), increased ferritin and reduced creatinine kinase (CPK). The occurrence of metabolic syndrome (48.2% vs 29.0%, p <0.05) was significantly reduced with increasing fT4 from middle to upper tertile, without significant effect on glycemic indexes, heart rate, SF-36 and HK-MoCA-5. Conclusion: In this study, we demonstrated that raising fT4 target to the upper tertile of normal resulted in a favourable improvement in various metabolic indexes without a significant increase in adverse effects over a period of 48 weeks.
High Prevalence of Anti Thyroid Antibodies in an Albanian Cohort of Patients
Authors: Minxuri Dorina , Mitre Anila , Bino Silva , Toska Ina , Mulla Ina
Published: May 2021

Introduction: Albania is classified as iodine deficient region and endemic goiter in this country has been a concern for public health. A salt iodization program has been implemented in Albania since 2008. Most of regions still remain with a mild or moderate iodine deficiency there are no studies on prevalence of thyroid autoimmune disorders. The purpose of this study was to assess thyroid function and the presence of thyroid antibodies in subjects that were not previously diagnosed or treated for thyroid disorders. Methods: This is a cross-sectional study performed in a cohort of patients in Albania during a 2 year period (january 2018-january 2020). We assessed the prevalence of thyroid function disorders and presence of thyroid antibodies in 5047 subjects (81% females and 19% males). Individuals previously diagnosed or treated for thyroid disease were excluded from the study. TSH, Free T4, total T3, Anti TPO(thyroid peroxidase) and anti TG (thyroglobulin) were measured with electrochemiluminescence method with Cobas 6000 Roche Diagnostics. We calculated the frequency of thyroid antibodies and the abnormal thyroid function. Statistical analysis was performed to see if there was a difference between individuals with positive antibodies and those negative for antibodies. Results: 91 % (4596) of subjects resulted euthyroid. We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.48% and hypothyroidism 1.69%). The rates of subclinical hypothyroidism and hyperthyroidism were 5.5% and 1.4% respectively. The prevalence of positive thyroid antibodies, at least one of them was 28% in females and 14% in males (2:1 ratio). 97.3 % of subjects who testet negative for antibodies had normal thyroid function compared to 73.5% in antibodies positive group. There was a significant difference for subclinical hypothyroidism and other thyroid disorders between antibodies positive group and antibodies negative group (p value <0.0000119% of individuals(from 5047 examined) had normal thyroid function and resulted positive for anti TPO or anti TG. Conclusions: Undiagnosed biochemical thyroid dysfunctions were common in subjects living in a mild to moderate iodine-deficient area especially subclinical hypothyroidism. TSH level correlated well with the presence of antibodies resulting in significant difference in thyroid function between 2 groups. We found a high prevalence (19%) of thyroid antibodies in euthyroid subjects. TPO antibodies in euthyroid subjects can be used to identify subjects with increased risk for hypothyroidism such as women who are pregnant (to predict first trimester or postpartum thyroid dysfunction), patients with other autoimmune diseases, subjects on drugs like amiodarone or relatives of patients with autoimmune thyroid diseases.
Patterns of Body Weight Changes in Patients With Hypothyroidism, a Retrospective Study From Basrah, Southern Iraq
Authors: Alidrisi Haider A , Odhaib Samih Abed , Altemimi Mahmood Thamer , Alibrahim Nassar Taha , Alhamza Ali Hussain , Almomin Ammar , Zaboon Ibrahim , Nwayyir Hussein Ali , Hussein Ibrahim Hani , Imran Husam Jihad , Alzajaji Qusay Baqer , Budair Ahmed Sabah , Hamza Muqdam Ali , Mansour Abbas Ali
Published: May 2021

Background: Weight gain is one of the most important hypothyroidism-related concerns among patients with hypothyroidism. However, not as expected, thyroxine replacement does not necessarily result in body weight (BWT) reduction among those patients. The study aimed to assess the patterns of BWT changes through time in patients with hypothyroidism. Method: A retrospective database study from Faiha Specialized Diabetes, Endocrine, and Metabolism Center. A total of 346 adult patients with hypothyroidism, 192 newly diagnosed and 154 known, who had 1 visit every 3 months, 5 visits per one year. From those patients, 116 new and 69 known had completd 9 visits per two years. Each visit involved thyroid-stimulating hormone (TSH) and BWT measurements. Patients with chronic liver or renal disease, diabetes mellitus, thyroid cancer, or other malignancies, pregnancy, and on steroid or hormonal therapies were excluded. The patients were further subdivided based on average TSH levels into controlled (TSH≤4.2 μIU/mL) and uncontrolled TSH>4.2 μIU/mL. Repeated measures ANOVA with a Greenhouse-Geisser correction and Post hoc tests using the Bonferroni correction were used to evaluate BWT changes through the study. Results: Both newly diagnosed and known hypothyroidism, over one and two years, in patients with average TSH>4.2 μIU/mL, BWT increased significantly through visits. For newly diagnosed over one year, (F(2.41, 321.60) = 3.28, p = 0.03), and mean BWT increase = 1.4 ± 0.38 kg from 3rd to 12th month visits, (p = 0.004). For newly diagnosed over two years, (F(3.10, 263.89) = 9.08, P < 0.0005), mean BWT increase = 3.02 ± 0.77 kg from 3rd to 24th month visits, (p = 0.007). And for known hypothyroidism over one year, (F(2.56, 187.47) = 7.11, p = 0.0003), mean BWT increase = 1.97 ± 0.64 kg at 12th month visit, and over two years, (F(2.35, 77.56) = 4.67, P = 0.009), mean BWT increase = 3.78 ± 1.26 kg at 24th month visit. While in all other patients with average TSH≤4.2 μIU/mL, the BWT changed non-significantly through visits. For newly diagnosed patients over one year and two years (p = 0.10, 0.34 respectively), and known patients over one year and two years (p = 0.47, 0.34 respectively). Conclusion: In contrary to what is believed, adequate treatment with thyroxine does not associate with weight reduction. Instead, either the patient kept on the same weight or continued to gain more weight.
A Higher Cutoff for TSI Would Better Predict Recurrence in Patients With Graves’ Disease?
Authors: Fontes Rosita , Negri Maurício Massucati , Marui Suemi , Gomes Dalva Margareth Valente , Schrank Yolanda , Castelar Pinheiro Maria Fernanda Miguens , Fragoso Perozo Andrea Faria Dutra , Araujo Paula Bruna Mattos Coelho
Published: May 2021

Introduction: GD is an autoimmune disease mediated by immunoglobulins (Igs) that activate TSH receptor (rTSH). Relapse after withdrawal of antithyroid drugs (ATD) can reach 60%. Measurement of TSH receptor antibodies (TRAb) and thyroid stimulating immunoglobulin (TSI) could be an indirect indicator of GD activity. TRAb assays measures thyroid-stimulating, thyroid-blocking and neutral Igs; TSI assays measures only stimulating Igs. Objetive: Evaluate, prospectively, autoimmunity before and after ATD therapy for thyrotoxicosis through TSI measurement. Methods: Patients were evaluated at the first visit and at the time of ATD withdrawal. TSH, thyroid hormones, TPO antibody, thyroglobulin antibody, and TRAb were measured using eletrochemiluminescent assays Roche Diagnostics; TSI was determined by chemiluminescent assay Siemens Diagnostics. According to manufacturers, TRAb < 1.75 IU/L and TSI < 0.55 IU/L were negative. Results: Sixty-seven patients mean age 45,7±2,45 years, 65 women, were evaluated: 50 at the first visit, 40 (80%) with GD, and 10 (20%) with toxic multinodular goiter (TMNG). TSI diagnostic sensitivity (Sen%) and specificity (Spe%) to diagnose GD were 90% and 100% respectively, similar to that of TRAb, of 89% and 100%. Thirty-six patients were evaluated for recurrence after suspension of ATD (19 of them also had the initial assessment): 21 (58.3%) did not present recurrence in an mean period of 9.5±2.1 months (3-18); and 15 (41.7%) relapsed in 4.4±2.6 months (2-12). In 10/21 patients who did not relapse, and whose TRAb was negative, TSI was positive at low levels, which was responsible for the low Spe% of this test. Assessing possible other cutoff points for the TSI in the recurrence assessment, an adjustment to 1.4 (TSI <1.4 IU/L = negative) raised the Spe% to 86%. Conclusions: In this group, TSI and TRAb were equivalent for GD diagnosis. Many clinical factors have been suggested and TRAb measurement is known to be useful for predicting GD relapse because of the active pathogenic role of TRAb. For predicting recurrence, with the proposed cutoff point proposed by the kit manufacturer for TSI, a better sensitivity was obtained when compared with TRAb (93% versus 67%), despite very low specificity (38%); by raising the cutting point to 1.4 specificity could be increased to 86% without reduced sensitivity. A larger sample in needed to support a higher TSI cutoff point in the clinical routine for the assessment of GD recurrence after ATD.
Abnormal Thyroid Function Is Associated With Lymphopenia in Bacterial Sepsis and COVID-19
Authors: Grondman Inge , de Nooijer Aline H , Antonakos Nikolaos , Janssen Nico A F , Mouktaroudi Maria , Leventogiannis Konstantinos , Medici Marco , Smit Johannes W A , Van Herwaarden Antonius E , Jaeger Martin , Netea Mihai G , Giamarellos-Bourboulis Evangelos J , Netea-Maier Romana T
Published: May 2021

Background: Lymphopenia is a key feature of immune dysfunction in bacterial sepsis and COVID-19 patients and is associated with poor clinical outcomes, but the cause is largely unknown. These severely ill patients may also present with thyroid function abnormalities, so-called non-thyroidal illness syndrome (NTIS), and several studies have suggested that TSH, thyroxin (T4) and triiodothyronine (T3) play a crucial role in the homeostatic regulation and function of lymphocyte populations.

Aim: The purpose of this study was to test the hypothesis that abnormal thyroid function correlates with lymphopenia in severly ill patients with bacterial sepsis or COVID-19.

Methods: Retrospective analysis of absolute lymphocyte counts and circulating TSH, T4, FT4, T3, albumin and inflammatory biomarkers was performed in two independent cohorts of bacterial sepsis (n=224) and hospitalized COVID-19 patients (n=35).

Results: Only T3 correlated (rho=0.252, p-value: <0.001) with lymphocyte counts in the bacterial sepsis population and lower concentrations were found in severe lymphopenic compared to non-lympopenic patients (p-value: <0.001; n=56 per group). Severe lymphopenic COVID-19 patients (n=17) showed significantly lower plasma concentrations of TSH, T4, FT4 and T3 (p-value: 0.026, <0.001, 0.001, <0.001, respectively) compared to patients withouth lymphopenia (n=18), and demonstrated significantly increased values of the inflammatory parameters IL-6, C-reactive protein and ferritin (p-value: <0.001, 0.023, and 0.008, respectively). Remarkable, after one week follow-up, the majority of (12/15) COVID-19 patients showed quantitative recovery of their lymphocyte numbers, while TSH and thyroid hormones remained mainly disturbed.

Conclusions: Abnormal thyroid function correlates with low lymphocyte counts in severe sepsis and COVID-19 patients, but future studies need to establish whether a causal relationship is involved.
Characterization of Thyroid Disease Prevalence Among Transgender and Gender-Diverse Patients
Authors: Christensen John David , Davidge-Pitts Caroline , Castro M Regina , Caraballo Pedro
Published: May 2021

Objective: Transgender and gender-diverse individuals are at risk of insufficient treatment of endocrine diseases due to a number of barriers to care. There are currently no data evaluating the prevalence of thyroid disease in this population, and it is unknown if gender-affirming hormone therapy affects treatment of thyroid disease in these individuals. Methods: Utilizing a registry of 676 patients over 18 years of age who were seen in our Transgender and Intersex Specialty Care Clinic from 2015-2019, we identified 554 individuals seeking medical therapy for gender dysphoria/incongruence. Of these, 56 patients were taking thyroid hormone or antithyroid medications or had a coded diagnosis of thyroid disease; 2 were excluded as they were receiving thyroid hormone as adjunctive therapy for refractory depression. 54 patients were therefore analyzed with respect to thyroid disease (TD+), and compared to those 498 patients without thyroid disease (TD-) with regard to average vital signs, demographics, and presence of common comorbidities. Results: Fifty percent of our TD+ patients were recorded female sex at birth, and 98% were Caucasian. TD+ patients were much more likely to have essential hypertension (OR 5.99), to use tobacco (OR 2.23), and to be overweight or obese (OR 2.16) than TD- patients. Due to the evolving natural history of disease, some TD+ patients belonged to multiple categories: 48 patients, 26 trans feminine and 21 trans masculine, had hypothyroidism, of whom 41 had overt hypothyroidism and 2 patients had subacute thyroiditis that progressed to the hypothyroid phase of illness. 5 patients (3 trans masculine and 2 trans feminine) demonstrated hyperthyroidism, 4 of whom had Graves’ Disease. 2 patients had multinodular goiter, both trans masculine. 2 patients had thyroid malignancies, both trans feminine, of whom one had proven follicular thyroid carcinoma and the other had unspecified thyroid malignancy. Among hypothyroid patients, there was a slight non-significant trend toward increased thyroid hormone requirements while receiving treatment with estradiol or testosterone. Conclusion: To our knowledge, this represents the first attempt to characterize the prevalence of various thyroid disease states in the gender diverse population. Our data corresponded to a prevalence of hypothyroidism of approximately 8.7%, which is higher than previously published estimates of 3-5% in the general population. Whether this represents actual increased prevalence or assessment bias is uncertain. It is important for all health professionals who care for gender diverse people to identify and appropriately treat thyroid disease, and to monitor thyroid function closely if gender-affirming hormone therapy is initiated.
Managing Thyroid Nodules in Qatar During the COVID19 Pandemic
Authors: Alamer Zaina , Karuppasamy Gowri , Alsaud Arwa , Jaber Tania , Farghaly Hanan , Rohani Zaina Seros , Zirie Mahmoud A , Naem Emad
Published: May 2021

Background: The Coronavirus disease 2019 (COVID-19) pandemic impacted health care systems in all countries, including Qatar. Hamad Medical Corporation (HMC); In compliance with recommendations, suspended all non-urgent procedures, including thyroid fine needle aspiration biopsies (FNAB). Thyroid nodules are second most common cause of referral to HMC endocrine clinic. FNABs are gold standard to differentiate benign from malignant nodules.1- 2

Methods: Our approach includes a teleconsultation to obtain patient’s history and risk factors. Reviewing neck ultrasound (US), obtaining a calcitonin level if indicated, considering comorbidities associated with a high risk of COVID-19 morbidity and mortality.3

Results: We developed a pathway triaging thyroid (FNAB) to:1-Urgent: patients at higher risk of aggressive thyroid malignancy. Benefits of early detection and treatment outweigh the risk of COVID-19 exposure.4 FNAB should not be delayed.2-Semi-urgent: patients at low risk for COVID-19 and high suspicion thyroid nodules, but no evidence that early detection improves survival2, FNAB may be delayed up to 12 months.3-Non-urgent: patients with asymptomatic nodules that have low or intermediate suspicion US pattern.2 Also, includes nodules with ATA high suspicion US pattern in pregnant women and patients at high risk for COVID-19. The risks outweigh the benefits. FNAB should be delayed until outbreak is controlled.4 When urgent FNAB is indicated, safety of patients and medical staff needs to be addressed.5 We recommend testing patient for COVID-19 before FNAB, utilizing US guidance with rapid on-site adequacy evaluation in all cases. Cervical lymph node FNAB with TG washout should be done if indicated. The patient should wear a mask. All medical staff involved should wear personal protective equipment (PPE). The operator should wear N95 mask and face shield. The patient should be informed about cytopathology results via telemedicine.

Conclusion: Triaging thyroid (FNAB) during the COVID-19 pandemic should be based on nodule characteristics and risk of COVID-19 morbidity and mortality. Our group recommends deferring FNAB for asymptomatic patients.4FNAB should not be delayed in selected patients who benefit from early detection and intervention.

Table1: Triage of Thyroid fine needle aspiration biopsies (FNAB). ATA: American thyroid association. US: ultrasound.
Telehealth for Endocrinology: Effect on Utilization in Non-Pandemic Care
Authors: Williams Alexander , Walsh Colin , Griffith Michelle
Published: May 2021

Telehealth (TH) usage increased exponentially with the COVID-19 pandemic, aided by more permissive policies. Prior to the pandemic, policy makers and payers expressed concern that telehealth might lead to over-utilization of services. This contributed to a limited reimbursement environment. To assess evidence for this concern, we studied real-world TH at an academic medical center and hypothesized that TH would not increase utilization. We compared pre-pandemic utilization in a retrospective cohort of adult endocrinology patients with either TH (synchronous audio-visual visits) or conventional visits (CV) between 11/1/2017 - 3/16/2020. We focused on a pre-pandemic cohort to reflect usual practice. TH patients (i.e., 1+ TH visit with endocrinology in the study period) were identified using billing modifiers in EHR-derived data. CV patients were matched for provider and primary diagnosis, then selected from EHR-derived data in a 1:3 ratio. A minority of providers were performing TH visits pre-pandemic. Matching was performed to eliminate confounding from individual practice variation and to assure ability to compare patients with similar diagnoses. The majority of TH encounters in our practice during the study were clinic-to-clinic, with patients at a TH-enabled remote clinic. 75 TH and 225 CV patients were identified. 77% (55) of TH and 72% (163) of CV patients were female. The mean age was 45.2 (SD 12.4) and 49.6 (SD 16.7) years, respectively. Among TH patients, 68% (51) were white and 12% (9) were black with no statistically significant demographic differences between groups. The most common TH primary diagnoses were DM (33 patients) and thyroid disease (33 patients). Other TH diagnoses included pituitary/adrenal conditions, hyperparathyroidism, PCOS, and hypogonadism. TH patients had median follow-up of 21 months (IQR 13-25) and CV patients 18 months (IQR 11-25), p=0.613. TH patients had a range of 1 to 9 TH encounters during this time (median 2, IQR 1-3). Median TH visits per month were 0.20 (IQR 0.11-0.3). Looking at all endocrine encounters, TH patients had a median of 0.24 (IQR 0.015-0.36) encounters per month. CV patients had median of 0.20 encounters per month (IQR 0.11-0.37). Total encounters per month did not vary significantly between groups (p=0.0512, Wilcoxon rank-sum test). Patients with primary thyroid diagnoses had similar frequencies of TSH testing with TH median 4 tests (IQR 2-7); CV median 3 tests (IQR 1-5), p=0.057. A1c testing frequency was similar in patients with primary diagnosis of DM. TH patients had median 2 tests (IQR 1-3.5); CV median 3 (IQR 1-5), p=0.8012. In conclusion, TH was not associated with higher utilization of visits or lab testing in a small study of a pre-pandemic telehealth program. Coupled with larger scale and replicative studies, these findings might inform policy making and support continuation of telehealth in the post-pandemic environment.
Incidence of Venous Thromboembolic Events in Patients With Endogenous Cushing Syndrome
Authors: Subbu Karthik , Tariq Zunera , Erickson Dana Z , Bancos Irina , Donegan Diane
Published: May 2021

Background: Hypercortisolemia is a hypercoagulable state associated with increased risk of venous thromboembolic events (VTE). The reported incidence of VTE in patients with ACTH-dependent or independent Cushing Syndrome (CS) is variable, ranging from 3 to 14%. Our aim was to assess the incidence of clinically significant VTE among patients with endogenous CS and to identify risk factors for the development of VTE.

Methods: We conducted a single center retrospective longitudinal study of adult patients diagnosed with endogenous CS between 2010 and 2020. Patients with a known prothrombotic disease (e.g. Factor V Leiden), insufficient data, or non-neoplastic hypercortisolism were excluded. Data collected included patient demographics, presenting symptoms, biochemical and radiological workup, treatment details, and incidence of clinically significant VTE.

Results: A total of 114 patients (mean age of 45.55 ± 14.78 years, 79.8% women) followed for mean of 3.26 ± 2.9 years were included. Of the 114 patients, 58 (50.9%) had Cushing disease (CD), 40 (35.1%) had CS due to adrenal adenoma/hyperplasia, 6 (3.5%) had adrenocortical carcinoma (ACC), and 10 (8.8%) had ectopic Cushing syndrome (eCS). The overall incidence of VTE at any time point was 14/114 (12.3%); 11 (79%) VTEs were associated with presence of an additional VTE risk factor (8 surgery and 3 malignancy). Prior to any intervention for CS, 3 of 114 (2.6%) patients had a VTE. Surgery for CS (adrenalectomy, transsphenoidal surgery, tumor resection) was performed in 97 patients (85.1%) whereas 17 were treated medically (n=10), died before treatment (n=1) or observed (n=6). VTE occurred in 2 patients receiving medical therapy for CS. The post-operative incidence of VTE was 9 (9.3%; 4 in CD, 1 in adrenal CS, 3 in ACC, and 1 in eCS). VTE occurred ≤ 3-month post-operative in 4 patients (44.4%). Among the 5 patients in whom VTE occurred >3 months post-operative, 3 had recurrent metastatic ACC with hypercortisolemia and 2 were in remission (1 with CS and 1 with eCS). The median time from surgery to VTE occurrence was 315 days (8-1006). Compared to those who did not develop VTE, those who developed VTE had higher mean 24-hour urine free cortisol (4663.6 vs 558.21 mcg/dL; n = 100, P < 0.0001) and mean 1 mg overnight dexamethasone suppression test (36.3 vs 11.8 mcg/dL; n = 69, P = 0.0003), but similar mean late-night salivary cortisol (0.591 vs 0.790 ng/dL, n = 84, P = 0.71) at diagnosis of CS.

Discussion: Among those with CS, the overall incidence of VTE was 12.3% and the majority of VTE were provoked (surgery, malignancy). Moreover, VTE was more likely in those with higher UFC and 1 mg overnight dexamethasone suppression test in our cohort. This suggests that in patients with CS who have an active malignancy, severe CS or those undergoing a surgical procedure may be at increased risk of VTE. Future studies should investigate the optimal type and duration of the VTE prophylaxis.
Monitoring Thyroid Function Tests in Patients With Type 1 Diabetes Mellitus: Adherence to Recommended Guidelines and Comparison of Practice Patterns in a Health Care System
Authors: Cui Ling , Walsh Madeleine , Potluri Sai Deepika , Suleman Nawar , Schroeder Pamela
Published: May 2021

Approximately 1.7 million people in the U.S. have type 1 diabetes mellitus. Autoimmune thyroid disease occurs in 17 to 30% of patients with type 1 diabetes. The American Diabetes Association recommends that thyroid function be assessed at diagnosis of type 1 diabetes and repeated every 1 to 2 years thereafter or sooner if clinically indicated. With Centricity, our former electronic medical records (EMR) system, an EMR aid automatically imported key diabetes metrics including the TSH test. Our new EMR system, MedConnect, does not have an EMR aid that imports these metrics. We hypothesized that the screening rate for thyroid dysfunction in type 1 diabetic patients would be higher with the previous EMR system than with the new EMR system. We also hypothesized that the screening rate in patients followed by an endocrinologist would be higher than in those followed by a primary care physician.

Methods: We compared practice patterns with Centricity (from June 1, 2013, to May 30, 2016) versus MedConnect (from January 1, 2017, to December 31, 2019) in both primary care and endocrinology clinics. A total of 502 patients (271 Centricity, 231 MedConnect) were identified by chart review with age ≥18 years and ICD 9/10 codes for type 1 diabetes mellitus in outpatient clinics in our multicenter system.

Results: Baseline TSH was done in 253 of 271 (93.4%) Centricity patients and in 181 of 231 (78.4%) MedConnect patients. The odds of baseline TSH with Centricity was 3.88 times higher compared to MedConnect (OR = 3.88, 95% CI=2.19,6.88). Of the 214 patients with normal baseline TSH, 135 (63.1%) had repeat TSH done in 1-2 years; and of the 136 MedConnect patients with normal baseline TSH, 86 (63.2%) had repeat TSH done in 1-2 years. Of 434 patients with baseline TSH, 81 (18.6%) had abnormal TSH. Of these patients, 67 (82.7%) had hypothyroidism, 1 (1.2%) had hyperthyroidism, 8 (9.8%) had subclinical hypothyroidism, and 5 (6.1%) had subclinical hyperthyroidism. Of the total 502 patients, 380 (75.7%) were followed by an endocrinologist and 122 (24.3%) were followed by a primary care provider. Among patients followed by an endocrinologist, 348 (91.6%) had a baseline TSH result. Only 86 of 122 (70.5 %) patients followed by a primary care physician had a baseline TSH. Endocrinologists had 4.6 times higher odds of TSH screening at baseline compared with primary care physicians (p <0.0001).

Conclusion: Thyroid function was not assessed at baseline in all patients with type 1 diabetes mellitus and was not followed at the recommended intervals per the guidelines. Higher screening rates were seen with an EMR aid. Endocrinologists screened significantly more patients than primary care physicians. Education of providers regarding the guidelines is needed, and addition of an EMR aid may help to improve detecting thyroid dysfunction in patients with type 1 diabetes mellitus.
Aggressive Thyroid Cancer is Associated With Suppressor Circulating Immunophenotype
Authors: Kotwal Anupam , Bornschlegl Svetlana , Gustafson Michael , Dietz Allan , Delivanis Danae Anastasia , Ryder Mabel M
Published: May 2021

Introduction: The influence of the immune system on follicular cell-derived thyroid cancer behavior has been suggested by various studies but this information has not been comprehensively translated into a prediction for thyroid cancer prognosis. We aimed to identify circulating immune cell profiles associated with thyroid cancer prognosis. This information would be a significant advance in the field of thyroid cancer management. Methods: We performed a single-center prospective cohort study of 32 follicular-cell derived thyroid cancer patients enrolled at the time of initial or subsequent surgery. We performed peripheral blood multi-parameter flow cytometry and collected relevant clinicopathologic, biochemical and radiologic data. We classified patients based on the AJCC TNM cancer stage, American Thyroid Association (ATA) initial risk of recurrence, and status of disease during follow-up. Results: On initial immunophenotyping, patients with aggressive/advanced thyroid cancer (ATA high risk vs. intermediate/low risk; AJCC stage 3/4 vs. 1/2; recurrence or distant metastases vs. no evidence of disease during follow-up) demonstrated increased circulating monocytes and granulocytes but decreased all lymphocytes, T cells (specifically CD4+ and gamma delta) and natural killer (NK) T-like cells. Further immunophenotyping revealed that aggressive/advanced thyroid cancer had increased circulating CD4+CD45+RO effector memory but decreased CD4+CD45+RA central memory T cells and increased regulatory T cells. Stage 3/4 thyroid cancer patients additionally had increased circulating CD33+HLADR- myeloid-derived suppressor cells (MDSCs) as compared to stage1/2. Conclusions: Aggressive thyroid cancer at presentation (AJCC stage, ATA risk category) or during follow-up (distant metastases) is characterized by a circulating immunophenotype comprising of increased immune suppressor cells (regulatory T cells, MDSCs, effector memory T cells) but decreased immune activator cells (CD4+ T cells, gamma delta T cells, NK T-like cells, central memory T cells) as compared to less aggressive thyroid cancer. This circulating immunophenotype may serve as a biomarker for cancer prognosis and guide the selection and development of novel immunotherapies for advanced thyroid cancer.
Low Protein Expression of ATRX and ZNRF3 as a Novel Prognostic Marker of Adult Adrenocortical Carcinoma
Authors: Brondani Vânia Balderrama , Lacombe Amanda Meneses Ferreira , Mariani Beatriz Marinho , Montenegro Luciana Ribeiro , Cauduro Ibere Soares , Neto João Evangelista Bezerra , Mendonca Berenice Bilharinho , Almeida Madson Q , Zerbini Maria Claudia Nogueira , Villares Fragoso Maria Candida Barisson
Published: May 2021

Adrenocortical carcinoma (ACC) is a rare malignant neoplasia that is usually associated with a dismal prognosis. ACC overall survival (OS) depends on the particular biology of the tumor. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Aim: To evaluate ATRX and ZNRF3 protein expression in a large cohort of adults with ACC followed at a single tertiary referral center to establish the prognostic value of these genes. Methods: Two pathologists analyzed immunohistochemically-stained slides for ATRX and ZNRF3 (blinded assessment) proteins using tissue microarrays comprising tissue samples from 82 ACC (kappa 0.854; P<0.001). Cohort: female 76.8%; median age 38.2 (15.3–85.4) years; 67.5% of patients presented with hypercortisolism; ENSAT stage 1, 11.12%; 2, 44.44%; 3 and 4: (44.44%). The median follow-up time was 39.58 (1.4–406.8) months; 39 patients died during this period. Low protein expression was defined as follows: ATRX, when < 25% of tumor cells were immunoreacted; ZNRF3, when a score < 3 (extension + intensity) was established. Results: Low ATRX protein expression was positively associated with the age at diagnosis (P< 0.001), and it was negatively correlated with tumor size (P=0.020) and with Weiss score (P=0.033). Low ZNRF3 protein expression correlated negatively with tumor weight (P=0.026), with tumor size (P= 0.005), and with Weiss score (P=0.002). Regarding OS, the low protein expression of ATRX and ZNRF3 was associated with a decrease of OS (P=0.045 and P=0.012, respectively). The Cox model for ATRX protein expression showed a HR of 0.521 (95% CI 0.273–0.997; P=0.049); for ZNRF3 expression, HR = 0.441 (95% CI 0.229–0.852; P=0.015). The combined protein expression of both genes was also associated with a decrease in OS in this cohort (P=0.02). The high ATRX and ZNRF3 protein expressions were positively associated with optimistic recurrence-free survival (P=0.027, P=0.005, respectively). Conclusion: The knowledge of tumor biology is an important step to deliver personalized medicine, affording the opportunity to design better clinical approaches and targeted therapies. This study brought pan-genomic studies closer to clinical practice with an easily accessible tool for stratifying patients with ACC. We demonstrated that low levels of protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC.
Circulating Tumour Cells and MicroRNA in Thyroid Cancer - a Systematic Review
Authors: Bappayya Shaneel , Clydesdale Hamish , Tsao Simon
Published: May 2021

Background: Thyroid cancer (TC) is the most common endocrine malignancy worldwide. Currently available circulating biomarkers such as thyroglobulin and calcitonin present severe limitations to the diagnosis and management of often difficult-to-diagnose lesions. There is increasing interest in the utility of circulating tumour cells (CTCs) and microRNAs to diagnose and optimise the management of patients with TC.

Methods: In this study, we undertake a systematic review to gain a better understanding of the utility of CTCs and microRNAs in the diagnosis and management of patients with TC. A systematic review of the literature was performed by searching electronic bibliographic databases MEDLINE, EMBASE, SCOPUS and Web of Science. Studies which measured CTCs or microRNA levels in peripheral blood from TC patients were included. Review articles, conference abstracts, and foreign language papers were excluded.

Results: There were 238 records screened for inclusion. Full texts of 47 articles were reviewed and included for qualitative analysis.

CTCs demonstrated value in disease monitoring by distinguishing between disease recurrence and remission in patients with papillary thyroid cancer (PTC) and differentiated thyroid cancer (DTC). Higher CTC counts were associated with poorer progression free survival. This is consistent with CTC studies in other cancers such as breast and colorectal.

A total of 31 microRNA biomarker candidates were investigated in studies reviewed. Circulating miR-222, miR-221 and miR-146b were most commonly increased in patients with PTC compared to benign nodules and healthy controls, and were associated with poorer prognostic factors including extrathyroidal invasion and metastatic lymph nodes. Circulating miR-222-3p and miR-17-5p demonstrated discriminatory power between medullary thyroid cancer (MTC) and benign nodules and healthy controls.

Conclusion: CTCs demonstrate a promising avenue for disease monitoring and detection of local and distant recurrence in patients with DTC. Several microRNA candidates demonstrate value in diagnosis of PTC and MTC. There is a large degree of heterogeneity in studies assessing the

utility of microRNA biomarker candidates. Further studies are warranted to ascertain the value of circulating microRNA in disease monitoring and prognosis.
Comparison of Diagnostic Performance in Thyroid Nodules on US: Deep Convolutional Neural Network Models vs Endocrinologists With Various Experiences
Authors: Kang Sunyoung , Lee Eunjung , Kim Yoo Hyung , Kwon Seul Ki , Jung Kyong Yeun , Park Young Joo , Park Do Joon , Cho Sun Wook , Kwak Jin Young
Published: May 2021

Objectives: To diagnose thyroid cancer, ultrasonography is a primary tool, but diagnostic accuracy varies according to the proficiency of clinicians. The aim of this study was to compare diagnostic performance between deep convolutional neural network (CNN) models and endocrinologist with various experiences. Methods: Patients who underwent fine needle aspiration at endocrinology department in Seoul National University Hospital, between April 2014 and June 2019, were reviewed. Among them, thyroid nodules which were pathologically confirmed by surgery and maximal diameter greater than 1cm were included. Ultrasonography images of thyroid nodules were reviewed by 13 endocrinologists with various experiences: 0 month (E0, n=8), 1 year (E1, n=2), and >5 years (E5, n=3). Results: Of total 451 thyroid nodules, 66.5% was diagnosed as cancer and 83.7% was papillary thyroid cancer (PTC). Sensitivity and specificity of CNN were 85.3% and 63.6%, respectively, and its area under the curve (AUC) was 0.855. Compared to CNN, mean accuracy of E0 group was significantly lower (Accuracy 68.7% vs 78.0%, P <0.001), and after CNN-assistance, that of E0 was significantly improved (68.7% [before] vs 73.93% [after], P = 0.008). E1 and E5 groups showed similar diagnostic performance to CNN, and CNN-assistance did not change it. Next, subgroup analysis was performed according to the histologic subtypes. AUC of CNN in PTC (0.925) was much higher than that of other cancers including FTC (0.529). Interestingly, CNN-assistance significantly improved diagnostic performance for PTC not only in beginners (E0), but also a subset of experienced endocrinologist (E1 and E5). Conclusions: CNN has good diagnostic performance in the diagnosis of PTC. Endocrinologist with lower experience in ultrasonography, CNN-assistance is beneficial for improving diagnostic performance especially in PTC.