bluuebunny/crossref_metadata_2025 huggingface dataset:
OR07-6 Disrupting DNA-binding Domain Dimerization In The Androgen Receptor In Mice Results In a Partial Androgen Insensitivity Model
Authors: Claessens Frank , Libert Claude , Palvimo Jorma , El Kharraz Sarah
Published: November 2022

The androgen receptor (AR) plays a crucial role in the development and maintenance of the male phenotype, as shown in patients with androgen insensitivity syndrome (AIS). The AR is a nuclear receptor that needs to homodimerize to execute its role as transcription factor. Dimerization can occur through three different modes: via the DNA-binding domain (DBD), via the ligand-binding domain and via an interaction between the LBD and the aminoterminal domain. Dimerization via the DBD is very well known and occurs through the D-box located in the second zinc finger. DBD dimerization is generally accepted for all steroid receptors, but some of them show that D-box mutations do not inactivate them completely. However, for the AR, no monomeric transactivation capacity was described yet. To study the role of D-box independent activity of the AR, we introduced a double point mutation in the D-box that is predicted to disrupt DBD dimerization (ARDmon). These two point mutations were found in separate patients suffering from partial AIS. In vitro studies with this mutant suggest that the remaining activity depends on the androgen response element under investigation. We show that ligand binding was not affected by the D-box mutation. Furthermore, BioID assays indicated no changes in coregulatory interactions. When introducing the corresponding mutation in mice, this led to a phenotype that is intermediate between global ARKO and wild type (WT) males. Based on their anogenital distance (AGD) and the absence of nipples at early age, the ARDmon/Y mice were identified as males. Follow-up of their AGD and body weight, however, revealed clear differences with both WT males and females. Furthermore, hypospadias was observed in the ARDmon/Y mice. Testes were smaller in size compared to the WT males and first analysis showed almost no expression of well-known AR regulated genes. Reminiscent structures of the epididymis were found.

In summary, the ARDmon mouse model shows an intermediate AIS phenotype. Via orchidectomy in combination with androgen replacement therapy, we will now investigate remaining androgen responses in the ARDmon/Y mice and elucidate response elements on which the AR can act in a D-box independent way. Additionally, we generated the first rodent PAIS model with a genetic cause of hypospadias.

Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.
OR26-1 Alternative Polyadenylation as a Therapeutic Vulnerability in Prostate Cancer
Authors: Dehm Scott , Miller Jeffery , Munro Sarah , Van Etten Jamie , Tietz Kiel
Published: November 2022

Prostate cancer is the second leading cause of male cancer death in the United States. While localized disease can be cured by radiation or surgery, metastatic prostate cancer presents a clinical challenge. Metastatic prostate cancer can initially be controlled by endocrine therapies that target the androgen receptor (AR), however, these tumors will inevitably develop resistance. This stage of the disease, termed castration-resistant prostate cancer (CRPC), is responsible for the majority of prostate cancer-specific deaths. Truncated AR variant (AR-V) proteins are broadly enriched in CRPC cell lines and clinical samples, and can function as ligand-independent, constitutively active transcription factors. We found that blocking an alternative poly(A) site located in AR intron 3 reduced expression of multiple AR-V mRNA and protein species and increased expression of full-length (FL) AR mRNA and protein in 22Rv1 and LNCaP95 CRPC cells. We found the cleavage and polyadenylation specificity factor (CPSF) component, CPSF1, regulates selection of this alternative poly(A) site based on the finding that knockdown of CPSF1 also reduced expression of AR-Vs and increased expression of FL-AR in 22Rv1 and LNCaP95 cells. Further, knockdown of CPSF1 inhibited growth of these CRPC cell lines, as well as androgen-dependent LNCaP cells. To define how CPSF1 regulates alternative polyadenylation of AR and to determine novel pathways that are manipulated by CPSF1 in prostate cancer, we identified CPSF1-dependent gene expression using RNA-seq and CPSF1-dependent poly(A) site usage using poly(A)-ClickSeq (PAC-Seq). Gene set enrichment analysis of RNA-seq data revealed the Glycolysis Hallmark gene was positively regulated by CPSF1, and nominated multiple differentially-expressed genes encoding regulators of glycolysis as CPSF1 targets. These results highlight AR independent pathways that are also regulated by CPSF1 in prostate cancer. We are currently integrating RNA-Seq and PAC-seq datasets to define novel CPSF1 regulated pathways that can be targeted therapeutically in prostate cancer. This research will determine trans-acting factors and cis-regulatory elements that drive alternative polyadenylation of AR mRNA transcripts to promote CRPC progression. This research will also identify AR independent targets of CPSF1 that could be exploited for development of new therapies for CRPC.

Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.
OR26-3 USP19 Deubiquitinating Enzyme Functions as a Novel Co-Chaperone of Hsp90 to Regulate Glucocorticoid Receptor Levels
Authors: Bedard Nathalie , Coyne Erin , Huynh Julie , Jacq Xavier , Rozycka Ewelina , Schorova Lenka , Young Jason , Wing Simon
Published: November 2022

Ubiquitin specific protease 19 (USP19) is a deubiquitinating enzyme involved in metabolism. Its expression is upregulated in skeletal muscle in many conditions of muscle wasting. Genetic inactivation of USP19 (USP19KO) in mice protects from muscle atrophy and diet induced obesity and insulin resistance. We previously reported that the protection against muscle atrophy in USP19KO is due at least in part to reduction in muscle glucocorticoid receptor (GR) levels and signaling. Here, we report that USP19KO mice show > 50% decrease in GR protein level in multiple tissues with no observed changes in GR mRNA levels. Overexpression of the endoplasmic reticulum or cytosol-localized isoforms of USP19 in cells resulted in increased GR protein levels, while knockdown by siRNA or knockout by CRISPR-Cas9 resulted in decreased GR protein levels. Intriguingly, GR was not more ubiquitinated in the absence of USP19. Furthermore, expression of a catalytically inactive form of USP19 also increased GR protein levels and exposure of cells to a small molecule inhibitor of USP19 enzymatic activity had no effects on levels of GR. Deletion analysis revealed that the N-terminal CS domains of USP19, which are structurally similar to the p23 co-chaperone of HSP90, were required for increasing levels of GR. Since HSP90 is known to regulate GR folding and stability, this suggested that USP19 may function as a p23 like co-chaperone. Indeed, overexpression of USP19 not only increased GR levels, but translocation to the nucleus and transcriptional activity of a reporter gene. Using a novel BRET assay, we observed that USP19 interacts indirectly with GR through binding with HSP90. This interaction with HSP90 is critically dependent on the CS2 domain of USP19 and can be competed by expression of the p23 co-chaperone of HSP90. We have therefore identified a novel co-chaperone-like mechanism through which USP19 regulates GR protein stability independent of its catalytic activity. Targeting the interaction of USP19 with the GR-HSP90 complex could be a strategy to decrease GR levels, reduce glucocorticoid signalling and prevent muscle atrophy.

Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
PSUN66 Statin Intake as a Cause of Decreased Steroid Hormone Secretion
Authors: Mostovaya Maria , Kalinchenko Svetlana , Vorslov Leonid
Published: November 2022

Materials and methods

The study enrolled 2 men aged 58 years (history of acute cerebral circulation disorder at 47 and 57 years) and 64 years (history of acute myocardial infarction at 62 years), who complained of shortness of breath, daytime sleepiness, decreased libido, weakened erections, increased blood pressure. Both patients had been taking atorvastatin 10 mg for more than three months.

We used high-performance liquid chromatography (HPLC) to determine steroid hormones in saliva: Agilent 1200 chromatograph, AB Sciex 3200 MD mass spectrometer (Sciex, USA). Saliva was collected in a Salivette container.

A significant decrease in pregnenolone levels of 440.0 pg/ml and 300 pg/ml, respectively, was detected in the saliva analyses). The norm for pregnenolone was 575-665 pg/ml.

Conclusion

Statins lead to decreased pregnenolone secretion, most likely due to inhibition of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methyl glutaryl-CoA to mevalonate, a cholesterol precursor. The decrease in cholesterol synthesis leads to a decrease in pregnenolone and a decrease in steroid hormone secretion, both in the adrenal glands and gonads, which clinically manifests as hypogonadism and adrenal fatigue. All patients taking statins should have their salivary steroid profile evaluated. If statins cannot be withdrawn, hormone replacement therapy with sex hormones is necessary.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
LBSAT238 Teprotumumab Reduces Orbital Fat And Muscle Volume In Patients With Thyroid Eye Disease
Authors: Ugradar Shoaib
Published: November 2022

Teprotumumab, a novel IGF-1R antibody has been shown to reduce proptosis in patients with thyroid eye disease (TED) in 2 randomized controlled trials. At present, it is unclear whether the reduction in proptosis is related to a decrease in extraocular muscle or orbital fat tissue. In this prospective longitudinal study, we reviewed the changes to orbital fat and muscle, and compared them, in consecutive patients with TED, who had completed treatment with teprotumumab (8 infusions). The primary outcome was change in orbital fat and muscle volume within 6 weeks of starting and completing therapy. Secondary outcome measures included change in proptosis and the clinical activity score (CAS). All patients had either CT or MRI with ≤ 1 mm slice thickness. Three-dimensional volumetric analysis of the orbital fat and muscle volume was performed using the previously validated 3D image analysis software, MIMICS (Materialise, Leuven, Belgium). Hounsfield units of fat and muscle were defined manually. All extraocular muscle tissue and fat between the orbital septum (eyelid) and the orbital outlet of the optic canal was included. A 3D model created by voxel addition was expressed in millimeters cubed. Segmentation and measurements were performed independently by two graders to review repeatability and observer variability. In line with previous clinical trials, the orbit with the most proptosis was defined as the study orbit and the contralateral orbit was designated the fellow orbit. Twenty-one patients (15 females and 6 males) met the inclusion criteria. Mean (SD) age was 55 (16), while mean (SD) duration of TED was 71 (46) months. There was a reduction of 3 mm in both; study and fellow orbits following treatment (p < 0. 01 for both). Compared to baseline, there was a mean (SD) CAS reduction of 4 (1) in the study orbit and 2.4 (1.1) in the fellow orbit (p < 0. 01 for both). Following therapy, mean (SD) reduction in muscle tissue was 1691 mm3 (1358) in the study orbit and 1714 mm3 (1927) in the fellow orbit (p < 0. 01 when compared to baseline for each). The mean (SD) reduction of fat volume was 1382 mm3 (1318) in the study orbit and 933 mm3 (1699) in the fellow orbit (p < 0. 01 when compared to baseline for each). There was no difference between fat and muscle reduction for the study orbit (p = 0.4) or fellow orbit (p = 0.2). There was a significant correlation between a reduction in proptosis and reduction in orbital soft tissue (fat and muscle) volume. The results of this study suggest that following treatment with teprotumumab, there is a significant decrease in orbital fat and muscle volume. This reduction in soft tissue volume likely drives the reduction in proptosis.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT244 Prospective, Blinded, Multicenter Head-to-head Clinical Comparison Of Two "TSI" Assays In Patients With Autoimmune Thyroid Disease
Authors: Lupo Mark Armin , Kahaly George Jean
Published: November 2022

Objective

This study evaluated the clinical performance of the thyrotropin receptor Antibody (TSHR-Ab) bridge assay (Siemens TSI assay) versus the cell-based bioassay for the measurement of thyroid stimulating immunoglobulins (TSI, Quidel) (in patients with autoimmune thyroid disease (AITD).

Methods

Two-hundred two subjects (median age 54 years, 162 female, 80%), with well-documented thyroid disorders and controls were prospectively enrolled in a consecutive, unselected manner. Antibody measurements were performed using the Bridge (Siemens Immulite) and stimulating (TSAb or TSI) and blocking (TBAb) TSHR-Ab cell-based bioassays (Quidel Thyretain) each according to the manufacturers’ specfications. The testing laboratories were blinded to any clinical data.

Results

The three assays were negative in controls (n=10), patients with euthyroid nodular disease (n=11) and non-autoimmune thyrotoxicosis (n=21). In patients with Graves’ disease (GD), independent of disease duration or activity, TSHR-Ab positivity was present in 70/113 (62%) and 88 (78%) for the Bridge and TSAb bioassay, respectively (p<0. 001). Concordant positive results in the Bridge and TSAb bioassay were noted only in 67/88 (76%) patients with GD and TSAb positivity. Of these 21 discordant findings of TSAb positive and Bridge negative patients, four were new diagnosis of untreated overt Graves’ hyperthyroidism. Nine patients were euthyroid on low dose methimazole - two of these nine were taken off methimazole shortly after enrollment and remain in remission however the other seven required anti-thyroid drug (ATD) for at least 12 months post-enrollment. Three patients were euthyroid without treatment (follow-up data not available). Four had subclinical hyperthyroidism due to GD and one with GD and subsequent spontaneous hypothyroidism had moderate Graves’ orbitopathy (GO). Patients with GO were TSHR-Ab positive in 23/25 (92%) and 20 (80%) in the TSAb bioassay and Bridge assays, respectively (p<0. 001). In 160 patients with AITD, TBAb were present in 32 (20%), HT 11/27 (41%) and GD 21/133 (16%). 28/32 (88%) of the TBAb positive samples were also Bridge assay positive but TSAb bioassay negative.

Conclusions

Thyroid Stimulating Immunoglobulin (TSI or TSAb) is the key clinical biomarker for GD. We found that the TSAb functional bioassay was more sensitive than the Bridge TSH-R-Ab test not only in cases of subclinical GD but also new overt GD hyperthyroidism, as well as in euthyroid patients on low dose ATD which impacts decisions regarding discontinuing therapy. TSAb was also a better biomarker in patients with GO. In patients with AITD and TSAb negative, the Bridge assay was positive in the presence of blocking TSHR-Ab measured in a TBAb bioassay.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT291 Familial Papillary Thyroid Carcinoma
Authors: Arora Gunjan
Published: November 2022

Introduction

Familial papillary thyroid carcinoma is a rare entity; however, it must be considered if a strong family history of non medullary thyroid carcinoma is noted. As this cancer presents earlier and with more aggressive features with each subsequent generation, a targeted diagnostic and management approach should be utilized.

Case Presentation

A 26 year old female presented to the PCP after sustaining head trauma while kickboxing. During the visit, she requested for thyroid evaluation due to a strong family history of thyroid cancer in her mother, maternal aunt, maternal uncle and maternal grandfather. She reported that her mother was diagnosed with thyroid cancer at the age of 40 years; however, she was unaware of further details. She denied any personal history of cancer or exposure to radiation. An extensive review of systems was negative. TSH was within the normal range 2.65 uIU/ml (0.40 - 4. 0). Thyroid ultrasound showed a 1.1 cm nodule in the right thyroid lobe with microcalcifications suspicious for malignancy. Fine needle aspiration cytology of the nodule confirmed papillary thyroid carcinoma. A preoperative CT neck and soft tissue was negative for cervical lymphadenopathy per size criteria. She underwent a total thyroidectomy with neck dissection. Surgical pathology report showed 1.8 cm right thyroid lobe papillary carcinoma and 13 lymph nodes positive for metastatic carcinoma, the largest measuring 0.4 cm. Post-operatively, she underwent radio-active iodide therapy and was started on Levothyroxine supplementation. She was closely monitored with serial thyroid function tests, thyroglobulin levels and thyroid ultrasound examinations. Tempus XT positive for BRAF and FOXP1. Approximately one year after the surgery, serum thyroglobulin levels started to plateau. A surveillance thyroid ultrasound was concerning for left lobe thyroid tissue remnant/cancer. Thus, a radio-active iodine total body scan was planned to locate the remnant thyroid tissue followed by biopsy and excision in case of recurrent cancer.

Discussion

Papillary thyroid cancer runs in families and becomes more aggressive with each subsequent generation. The American Thyroid Association guidelines detail that screening with thyroid ultrasound should be considered in families with three or more family members affected by familial non medullary thyroid cancer. In addition, certain mutations such as the BRAF mutation are associated with aggressive clinicopathological characteristics and high tumor recurrence. There is limited data available on the FOXP1; however, it may also be linked to an aggressive course. Therefore, screening ultrasound should be offered in such patients and FNAC samples should be sent for genetic analysis to help formulate an appropriate treatment plan. These patients benefit from receiving early screening, more intensive management and frequent follow up.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT313 Hashimoto Encephalitis Presenting With Stroke-like Symptoms In An Adult Male
Authors: Canales Shellsea Portillo , Loria Gloriana Madrigal , Sanchez Valenzuela Maria C , Fernandez Felix Daniel A , Castano Yennifer Gil , Sharma Sapna , Arias Morales Carlos E
Published: November 2022

Hashimoto encephalopathy (HE) is a term used to describe an encephalopathy of presumed autoimmune origin characterized by high titers of antithyroid peroxidase antibodies, an essential feature of this disorder. Pertinent laboratory findings include an elevated serum level of antithyroid peroxidase antibody (TPOAb) and/or antithyroglobulin antibody (TgAb) and negative autoimmune markers of encephalitis in cerebrospinal fluid (CSF). The analysis of CSF may show increased cellularity due to lymphocytic pleocytosis. However, there is no clear relationship between the severity of neurologic symptoms and the type or serum concentration of antibodies. Approximately two-thirds of patients of HE will experience seizures. Patients can present with a recurrence/remission or a diffuse, progressive pattern characterized by slowly progressive cognitive impairment with dementia, confusion, or hallucinations. We present a rare case of Hashimoto's encephalopathy associated with hyperthyroidism in a 61-year-old man evaluated for left facial droop and right upper extremity weakness, successfully treated with corticosteroids and methimazole. We conclude that the diagnosis of HE should be suspected early and be on the differential in patients who present with encephalopathy, which workup shows positive anti-thyroid antibodies and CSF with lymphocytosis. Treatment for meningitis or other life-threatening conditions should never be postponed, as HE is a diagnosis of exclusion that usually requires an extensive laboratory and diagnostic workup. Early diagnosis has an excellent outcome once treatment is started as it is a steroid-responsive encephalopathy associated with autoimmune thyroiditis.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP453 A Lady Changes from Hypothyroid to Hyperthyroid State during Pregnancy
Authors: Ho Cheuk Wah
Published: November 2022

A 34-year-old lady presented to the Endocrine Clinic in 2021 initially for hypothyroidism complicated pregnancy. She volunteered history of Graves’ disease at age 11 and went into remission after taking anti-thyroid medication for 1-2 years. She did not have family history of thyroid disease. She was found to have hypothyroidism during pre-pregnancy check-up in 2017 and started thyroxine (LT4) replacement. The anti-thyroid peroxidase antibody was elevated to 358 (< 35) kIU/l. She had first pregnancy in early 2018 and LT4 was increased to 128 microgram daily which was reduced to 50 microgram daily after delivery. Before the second pregnancy, her TSH was decreasing. The family doctor reduced LT4 to 25 microgram 5 days per week. The TFT just before the patient became pregnant showed TSH 0. 08 (0.35-3.8)mIU/l, fT4 15 (9.5-18.1) pmol/l. At 8th week of pregnancy, her TSH became undetectable, while fT4 was 20.8 (11.8-25.7)pmol/l. At 17th week, her fT4 further increased to 19.9 (10.1-19.4) pmol/l and fT3 was 7.3 (3.25-5.2)pmol/l. TSH remained undetectable. Clinically, she complained of palpitation. She had goiter but no thyroid bruit. Her pulse rate was 118 bpm. LT4 was stopped. She was suspected to have relapse of thyrotoxicosis. Anti-TSH receptor antibody was raised to 3.3 (<1. 0) IU/l. The thyroid stimulating immunoglobulin (TSI) was raised to 155% above baseline activity (nl<140%). At 22th week, her fT4 remained elevated at fT4 19.1 (9.2-17.44), fT3 7.6 (3. 03-4.75) pmol/l. Carbimazole was started at 5mg daily for 2 weeks then 5mg alternate day. At 28th week, her fT4 was still elevated fT4 17.7 (9.2-17.4), fT3 6.9 (3. 03-4.75) pmol/l. She was also noted to have poor maternal weight gain from 61kg pre-pregnancy to 62.4kg at 22th week. She had nausea and vomited once per week. She had iron deficiency anaemia requiring iron supplement. Carbimazole was increased again to 5mg daily for 3 weeks then tailed down to 5mg alternate day. At 33th week, her anti-TSH receptor antibody level reduced to 1.9. At 36th week of gestation, her fT4 level came down to mid normal range 14.1 (9.2-17.4)pmol/l. She delivered at 40th week uneventfully. There are a number of clinical challenges. Usually, the dose of thyroxine is increased by 30% in early pregnancy with TSH aim of 0.5-2. 0mIU/l. But in this patient, the TSH was already low before pregnancy and then became undetectable so LT4 was not increased. Gestational thyrotoxicosis is a differential diagnosis but seldom persisted towards second trimester and TSI is expected to be normal in such case. Graves’ disease usually becomes quiescent during pregnancy due to immunosuppression or haemodilution of autoimmune antibodies. Changing from hypothyroidism to hyperthyroidism is a rare phenomenon. It is related to the concentration and the affinity of anti-thyroid stimulating antibodies and blocking antibodies. The outcome depends on which antibodies predominate.

Presentation: No date and time listed
ODP586 Analysis of Adrenal Vein Sampling (AVS) Success: A Retrospective Study of Primary Aldosteronism Patients at the National University of Malaysia (UKM) Medical Center
Authors: Azizan Elena Aisha , Sukor Norlela , Zakaria Rozman , Nazri Syed Mohammed , Khadijah Siti
Published: November 2022

Currently, the gold standard for identifying a unilateral Primary Aldosteronism (PA) is adrenal vein sampling (AVS), an invasive and technically challenging procedure. In this study, we aim to identify the clinical-laboratory characteristics associated with successful AVS, and clinical parameters associated with PA patients that had successful AVS (on 1st, 2nd, or 3rd attempt), or had rejected further attempts after a failed AVS attempt.100 records of AVS from eighty-three AVS patients conducted between 2015 and 2020 at the National University of Malaysia (UKM) Medical Centre, Kuala Lumpur, Malaysia were analysed retrospectively. Of the 83 PA patients studied, 47 were performed on men and 36 were on women. Variables significantly associated with patients who booked for a further attempt of AVS was having a serum aldosterone of <300pg/ml compared to those who rejected further attempts. There was also a trend for those who rejected further attempts to have a shorter duration of hypertension. Over one third of patient's have a failed AVS on 1st attempt and more than half do not wish to reattempt this invasive procedure. A biomarker for those that achieve complete cure should be identified to give incentives to the PA patients to proceed with AVS.

Presentation: No date and time listed
ODP466 Case of Sporadic Medullary Thyroid Cancer Detected by Serum Calcitonin Measurement
Authors: Juneau Andrea Kate , McMullen Kyle , Uwaifo Gabriel
Published: November 2022

Introduction

Thyroid nodules are common and their prevalence has increased with more widespread neck sonography. While most thyroid nodules are benign their evaluation and surveillance is centered around identifying nodules that harbor malignant growths. While secular trends suggest progressively increasing prevalence of thyroid cancer, it is largely an indolent generally curable disease. Medullary thyroid cancer (MTC) is comparatively rare (3-5% of all thyroid cancer) and significantly more virulent than the common papillary thyroid cancer. Guidelines regarding screening for potential MTC remain controversial. We describe the case of a patient with sporadic MTC detected by routine serum calcitonin measurement. Clinical case; The patient is a 52 yr old Caucasian man referred after a serendipitous finding of thyroid calcifications found on Neck and Chest CT done for radiculopathy evaluation. He had no neck symptoms and no anomalies on clinical neck examination nor history of radiation exposure nor relevant family neoplastic history. The neck ultrasound showed a multinodular goiter with a dominant hypoechoic 1.4 cm nodule in the right hemi-thyroid with microcalcifications (TIRADS 5). The nodule biopsy showed pauci-cellular specimen with abundant colloid and the patient had opted for repeat serial sonography rather repeat biopsy because of his unpleasant experience with the first biopsy. Routine initial endocrine evaluation included thyroid function tests (normal) and a random serum calcitonin; 267 (n; <15pg/ml). This degree of elevation was confirmed on repeated measures. A calcitonin stimulation test with calcium gluconate showed a peak stimulated calcitonin of 786 pg/ml. Total thyroidectomy and central neck dissection, confirmed a diagnosis of MTC (T1a N1a Mx). Only one of six sampled neck lymph nodes showed metastatic disease. RET mutation testing was -ve and 4 months post surgery his calcitonin is 97pg/ml with no radiologic evidence of any residual or recurrent disease.

Discussion

The patient's clinical presentation is typical of sporadic MTC (found serendipitously) which while uncommon is more prevalent than familial MTC and has a significantly more virulent clinical course than the much more prevalent classic papillary thyroid cancer. It also has significantly less cure potential and greater morbidity and mortality risk making early detection and aggressive management even more vital. Despite not being included in many guidelines for standard evaluation of thyroid nodules the random calcitonin obtained in the patient was central to the prompt and correct diagnosis of the patient.

Conclusions

Despite the limitations and caveats to its interpretation, our case highlights the potential utility of routine serum calcitonin measurement as part of the routine screening work up of thyroid nodules even in so called "low risk" clinical presentations with no clinical flags suggestive of possible familial MTC or MEN 2.

Presentation: No date and time listed
ODP468 Checkpoint Inhibitor Immunotherapy- related Thyroid Disorders and Iodine Contrast Studies
Authors: Borges Espinosa Luis , Dicenso Daniela , Rodriguez Valentina
Published: November 2022

Introduction

Checkpoint Inhibitor Immunotherapy (CII) has been linked to multiple endocrinopathies. Thyroid dysfunction is more frequently associated with anti-PD-1 and anti-PD-L1 monoclonal antibody use, yet there are no good predictors for the development of thyroid complications after immunotherapy treatment. Iodinated contrast studies have been related to the development of thyroid dysfunction, and are frequently used in the oncology patient population for surveillance of malignancy and response to treatment.

Methodology and Results

We conducted a retrospective observational study to identify any potential association between the development of thyroid dysfunction and exposure to iodinated contrast studies in patients receiving CII. A chart review was conducted from 2012-2020. Data analysis was performed using Chi-square. Using ICD codes, 236 patients with new thyroid dysfunction after initiation of CII, and no alternative etiology for the thyroid dysfunction, were included. Out of these, 162 (68.6%) patients developed hypothyroidism, 71 (30%) developed thyrotoxicosis initially and subsequently developed hypothyroidism, and 3 (1.27%) developed hyperthyroidism. Of the total patients who developed thyroid dysfunction following CII, 145 vs.91 patients received ≥3 contrast studies, (p. 0. 0004).

Discussion

These findings suggest that there is an association with the use of three or more iodinated contrast studies and the development of thyroid dysfunction in patients receiving CII. More research is needed to identify additional predictors that could be utilized in clinical practice for earlier detection of patients at risk of developing CII related thyroid dysfunction.

Conclusion

Thyroid dysfunction following the use of CII, namely anti-PD-1 and anti-PD-L1 therapies, remains prevalent; however, it has been difficult to identify who is most at risk for this complication. This is the first study examining exposure to iodinated contrast and its potential contribution to CII thyroid endocrinopathy, and it warrants further investigation.

Presentation: No date and time listed
ODP596 Central Adrenal Insufficiency After Intra-Articular Triamcinolone Injection In A Patient On Dolutegravir And Cobicistat Boosted Darunavir
Authors: Chen Ying , Wong Beatrice Y , Shah Sejal
Published: November 2022

Background

Central adrenal insufficiency from drug-drug interaction between steroids and HIV anti-retroviral medications is a well-documented phenomenon in the literature, but in clinical practice making this diagnosis can prove challenging.

Clinical Case

58-year-old woman with well-controlled HIV on dolutegravir and cobicistat/darunavir, type 2 diabetes mellitus, and chronic kidney disease presented to our emergency department with 3 days of polyuria, polydipsia, headaches, nausea, and decreased appetite. She also noticed that her glucose readings have been much higher than usual. 5 days prior to presentation, she received a 40 mg triamcinolone acetonide injection into her right subacromial bursa for chronic shoulder pain. For diabetes, she had been on the same dosage of weekly dulaglutide with good control. Initial laboratory evaluation revealed elevated serum glucose of 763 mg/dl (70 - 140 mg/dL) without an elevated anion gap, sodium of 124 mEq/L (135 - 145 mEq/L) and potassium of 5.9 mmol/L (3.6 - 5.2 mmol/L). Morning cortisol was sent as part of the workup for hyponatremia and returned low at 1.2 ug/dL (4 - 20 ug/dL). A 250 mcg cosyntropin stimulation test was performed, with baseline cortisol at 1.3 ug/dL and one-hour post-stimulation cortisol of 8.8 ug/dL. Pre-stimulation ACTH was < 5. 0 pg/mL (10 - 60 pg/mL). A synthetic glucocorticoid panel were sent on the 11th day after her injection and detected triamcinolone acetonide at 3.3 mcg/dL (cutoff: 0.1 mcg/dL) in urine and 0.85 mcg/dL (cutoff: 0.1 mcg/dL) in serum. She was diagnosed with iatrogenic adrenal insufficiency from intra-articular triamcinolone injection, the effect of which had been potentiated by her HIV medications cobicistat and dolutegravir (both CYP3A4 inhibitors). She was started on hydrocortisone and experienced improvement in appetite and fatigue. A plasma renin activity assay was elevated at 7.66 ng/mL/h (0.25 - 5.82 ng/ml/h) with 15 ng/dL of aldosterone (3 - 16 ng/dL). While awaiting the ACTH result, we discussed the possibility of primary adrenal insufficiency given persistent hyponatremia despite improved glucose control. However, given recent normal cross-sectional abdominal imaging, the history of steroid exposure, and lack of opportunistic infections in the past, central adrenal insufficiency remained the leading diagnosis. Further workup, including urine anion gap, eventually determined the cause of her hyponatremia to be a type 4 RTA likely related to her longstanding history of diabetes. The patient was discharged home on hydrocortisone with plan for repeat stimulation test in 6 weeks.

Conclusion

1. Keep primary adrenal insufficiency in mind in a patient with HIV who presents with hyponatremia and low cortisol. 2. Steroid injections carry risks of significant hyperglycemia and iatrogenic adrenal insufficiency in patients receiving cobicistat and integrase inhibitor.

Presentation: No date and time listed
ODP490 Levothyroxine Dosing Based on BMI and Different Causes of Hypothyroidism
Authors: Darquea Andres , Izquierdo Roberto , Huang Danning , Greenfield Margaret
Published: November 2022

While several approaches can be used when initiating levothyroxine therapy, it is commonly stated that total levothyroxine dose can be calculated as a function of the person's body weight. 1.6 mcg/kg of body weight. But studies have suggested that other factors must be assessed when trying to calculate a total daily dose. The cause of a patient's hypothyroidism may have an effect on their actual replacement needs. It is not the same to consider a patient with postsurgical hypothyroidism who has had all thyroid tissue completely removed versus Hashimoto's or Radioactive Iodine ablation where some thyroid function may be preserved. It is also important to consider a patient's ideal body weight as studies have shown that ideal body weight rather than actual body weight may be more useful in determining a patient's ultimate levothyroxine requirements. As the prevalence of obesity is increasing in the United States and worldwide, factors such as BMI may start playing a more important role when deciding initiation dosage in these patients. We conducted a retrospective chart review with a total of 260 hypothyroid patients on levothyroxine and with two stable TSH values on the same dose. We divided the patient into three BMI categories. <= 24.9, 25-29.9 and >=30. Patients with BMI <= 24.9 had a levothyroxine mean (SD) dose of 1.5 MCG/KG (0.63), those with a BMI 25-29.9: 1.3MCG/KG (0.44), and those with a BMI >=30: 1.1MCG/KG (0.45). P Value <0. 001. When further subdivided into the cause of hypothyroidism (Hashimoto's, post surgical and radioactive iodine), the effects of BMI on levothyroxine dose seem to also be affected. In postsurgical hypothyroidism, patients with BMI <= 24.9 had a levothyroxine mean (SD) dose of 1.8 MCG/KG (0.47), BMI 25-29.9: 1.5MCG/KG (0.21) and BMI >=30: 1.4MCG/KG (0.38). P Value <0. 001. Patients with Hashimoto's with BMI <= 24.9 had a levothyroxine mean (SD) dose of 1.3 MCG/KG (0.65), BMI 25-29.9: 1.1MCG/KG (0.50) and BMI >=30: 0.9MCG/KG (0.44). P Value <0. 001. In patients with hypothyroidism due to radioactive iodine therapy, the levothyroxine dose for those with BMI <= 24. was 1.4 MCG/KG, BMI 25-29.9: 1.2MCG/KG (0.53) and BMI >=30: 1.2MCG/KG (0.39). P Value 0.883 These results suggest that when initiating levothyroxine therapy, a starting dose of 1.6 MCG/KG is not adequate for all patients and that BMI and cause of hypothyroidism should be considered before making this decision.

Presentation: No date and time listed
ODP500 Nephrotic syndrome as a cause of worsening hypothyroidism due to Hashimoto's thyroiditis
Authors: Thewjitcharoen Yotsapon , Nakasatien Soontaree , Butadej Siriwan , Veerasomboonsin Veekij , Himathongkam Thep
Published: November 2022

Background

Thyroid function has been reported to worsen when urinary protein levels increase from the loss of protein-bound thyroid hormones, such as thyroxine-binding globulin, transthyretin, and albumin, into the urine. In patients with previously undiagnosed Hashimoto's thyroiditis, subclinical hypothyroidism and overt hypothyroidism might develop at the onset of nephrotic syndrome. Here, we present an interesting case of Hashimoto's thyroiditis aggravated by newly developed nephrotic syndrome. Clinical case: A 43-year-old woman with no known underlying disease presented with generalized edema and weight gain of 5 kgs over 2 months. Physical examination revealed slightly enlarged thyroid goiter and pitting pedal edema. Thyroid function tests revealed hypothyroidism (FT4 0.71 ng/dL; reference range 0.93-1.70 ng/dL, TSH 8.32 uIU/mL; reference range 0.27-4.20 uIU/mL). Anti-thyroid peroxidase was negative but anti-thyroglobulin was positive. Thyroid ultrasound showed diffused heterogeneous parenchymal echotexture at both thyroid lobes, compatible with Hashimoto's thyroiditis. Subsequent investigations showed nephrotic range proteinuria (urine protein/creatinine ratio 7.5 grams), low serum albumin 2. 0 g/dL, and hypercholesterolemia 421 mg/dL. Viral infections including HIV, hepatitis B and C were negative. Kidney biopsy showed the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membrane, confirming membranous glomerulonephritis as a cause of nephrotic syndrome. Further investigations did not show potential secondary causes of membranous glomerulonephritis. Oral prednisolone and cyclosporin was given to treat nephrotic syndrome and levothyroxine 350 µg/week was initiated to treat hypothyroidism. Over the next 6 months, nephrotic syndrome went into remission and thyroid function tests showed stabilization. During a 3-year follow-up period, patient is still in stable condition with levothyroxine 450 µg/week.

Conclusion

Nephrotic syndrome may trigger the onset of hypothyroidism or aggravate preexisting hypothyroidism, with subsequent increase in thyroid hormone requirements. Careful history taking and physical examination are necessary when evaluating the patients with new-onset hypothyroidism or patients with worsening hypothyroidism. The diagnostic workup of patients with increasing requirements of thyroid replacement therapy should not be concentrated on the digestive system alone.

Presentation: No date and time listed
ODP509 Proof-of-concept, Multicenter, Open-Label Phase 2a Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease
Authors: Janes Jonathan , Kahaly George , Liang Su , Tedeschi Philip
Published: November 2022

In thyroid eye disease (TED), immunoglobulin G (IgG) autoantibodies target thyrotropin receptors (TSHR) on the thyroid gland causing Graves’ disease. These TSHR-Ab also bind to the TSHR on orbital fibrocytes, inducing inflammation and hyaluronan production, resulting in extraocular muscle swelling and orbital fat expansion, causing the clinical manifestations of TED. Batoclimab (IMVT-1401) is a selective, fully human monoclonal antibody with high affinity for the IgG binding site on the neonatal Fc receptor (FcRn). Normally, the half-life of IgG is extended by FcRn-mediated recycling from lysosomal degradation. By competitively binding to the IgG binding site on FcRn, batoclimab blocks FcRn-mediated recycling of IgG, resulting in increased elimination and decreased levels of IgG. Batoclimab thus has the potential to provide clinical benefit for TED patients by reducing the level of pathogenic IgG anti-TSHR-Ab.

In this open-label, multicenter, phase 2a study (NCT03922321), subjects with anti-TSHR-Ab positive, moderate-to-severe TED with a clinical activity score (CAS) ≥4 received weekly subcutaneous (SC) injections of batoclimab for six weeks (680 mg for two weeks followed by 340 mg for four weeks). Subjects were monitored for up to an additional 11 weeks. Safety and tolerability were assessed throughout the study. Pharmacodynamic changes in serum IgG and anti-TSHR-Ab were monitored weekly. Clinical efficacy was assessed weekly by response rate for proptosis (≥2 mm reduction in study eye without a deterioration in the other eye). The study eye was defined as the eye with greater proptosis at baseline. CAS response was defined as having a CAS score of 0 or 1.

Seven subjects enrolled and completed this study (baseline mean [SD] age 56.7 [14.9] years, CAS 5.4 [1.1], proptosis 23.1 [3.3] mm). Serum IgG and anti-TSHR-Ab were reduced by a mean (SD) of 64.8% (17.7) and 56.7% (33.6), respectively at Week 6 compared to baseline. Similar reductions were also observed with each IgG subclass. Three of seven subjects were proptosis responders and four subjects were CAS responders. Three of seven subjects were joint responders for both proptosis and CAS. All adverse events (AEs) were mild to moderate in severity and no participant reported serious AEs or discontinuation due to AE. The most common AEs were increased lacrimation, fatigue, and dizziness (n=2 for each).There was a reversible reduction in serum albumin while on treatment which returned to normal levels in all subjects by the end of the study.

In conclusion, batoclimab reduced serum IgG and especially the pathogenic anti-TSHR-Ab with an acceptable tolerability profile. Approximately half of study subjects demonstrated improvement in ophthalmologic assessments with six weeks of treatment. Together, these results support further evaluation of SC batoclimab as a therapeutic option for patients with TED.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP533 Graves’ Ophthalmopathy in the Setting of Primary Hypothyroidism
Authors: Alajmi Sarah , Alshehri Sara , Ekhzaimy Aishah
Published: November 2022

Background

Graves’ ophthalmopathy (GO) is commonly associated with hyperthyroidism secondary to Graves’ disease (GD). Although rare, there have been case reports of it occurring in patients who are hypothyroid with underlying Hashimoto's thyroiditis (HT), as well as in euthyroid patients. It is thought that the mechanism behind developing GO in these patients is due to the presence of stimulating thyrotropin receptor antibodies (TRAB). Below we describe a case of GO developing in a patient who has hypothyroidism secondary to HT.

Clinical Case

A 53 years-old female non-smoker, known to have primary hypothyroidism (Hashimoto's thyroiditis) diagnosed at the age of 39 years, on levothyroxine 75 mcg/day. Presented to our endocrine clinic complaining of diplopia and periorbital swelling for the past 5 months. The diplopia occurs on left gaze while both eyes are open, it resolves with closure of either eye. No history of ocular surgeries, injections, or trauma. No previous hyperthyroid state or radioactive iodine therapy. On physical examination there was no goiter, bruit, palpable lymphadenopathy, tremor, or pretibial myxedema. Ophthalmic examination showed left sided upper and lower eyelid swelling, limited abduction with diplopia and mild punctate keratopathy. Laboratory investigation revealed TSH 3.6 mIU/L (0.250 - 5), T4 14.6 pmol/L (11.5 - 22.7), positive thyroid peroxidase antibody 173.9 units (> 100 units positive) and positive thyroid stimulating immunoglobulin 500IU/ml (Normal < 140). On ultrasound the thyroid gland was small and heterogeneous. MRI orbits demonstrated bilateral ocular proptosis with intraocular muscles enlargement particularly the medial, inferior, superior rectus as well as the levator palpebrae superioris muscles. Our impression was active moderate-severe isolated GO with aBackground of HT, clinically and biochemically euthyroid on levothyroxine. The patient was referred to an ophthalmologist and was started on a course of high dose oral prednisone tapered over 3 months. She reported a 50% improvement in her symptoms after the first month of therapy. Patient was then started and maintained on selenium 100 mcg oral twice daily with lubricating eyedrops. During her last clinic visit she had stable thyroid eye disease and there was no need for further medical or surgical intervention.

Conclusion

GO can occur in patients with HT due to the development of stimulating TRAB targeting thyrotropin receptors expressed on orbital fibroblasts. The incidence varies between studies from 2-7.5%. Awareness of this clinical presentation is important, as early detection and treatment can prevent visual complications. To date there are no clear guidelines on how to treat GO with underlying HT. Treating our patient with high dose steroids extrapolated from treating GO secondary to GD showed significant improvement in her symptoms.

Presentation: No date and time listed
ODP535 Thyrotoxic Periodic Paralysis (TPP) in A Young African American Male: Post Exercise
Authors: Agu Chinyere , Tan Zimri , Cobbs Ronald
Published: November 2022

Thyrotoxic periodic paralysis (TPP) is a rare fatal disorder with hypokalemia as the hallmark feature associated with thyrotoxicosis. Compared with existing studies that TPP is prevalent among younger men of Asian descent, this study intends to complement this area of study by addressing aspects currently not fully covered involving the existence of TPP among men of African descent. This study documents the case of a 37year old African American Man with no previous history of hyperthyroidism who presented with sudden onset lower extremity paralysis and hypokalemia. It is particularly important to note that while majority of patients with TPP have preexisting hyperthyroidism, our patient presented with no history of overactive thyroid. The finding of this work fills a gap in literature highlighting the importance of separating Familial Hypokalemic periodic paralysis (FPP) and TPP at its earliest detection. We find strong and robust evidence suggesting that patients may be easily termed FPP in view of its similarity to TPP thereby leading to a delay in the diagnosis and treatment. TPP has been linked with genetic mutations in specific ion channels (calcium channels and KIR) and increased Na-K ATPase pump activity. This leads to a massive intracellular shift in potassium causing hypokalemia under the influence of excess thyroid hormone. We find that both TPP and FPP have similar clinical presentations and same precipitants hence the need for a high index of suspicion in patients with hypokalemia and sudden onset paralysis with no history of hyperthyroidism to prevent lethal complications. Our results suggest that prompt correction of hypokalemia and treatment of hyperthyroidism is key in resolving attacks and preventing lethal complications.

Presentation: No date and time listed