bluuebunny/crossref_metadata_2025 huggingface dataset:
RF03 | PMON286 Engineering Steroid Receptors to Respond to Chemicals of Choice
Authors: Claessens Frank , Eerlings Roy , Gupta Purvi , Lee Xiao Yin , Kharraz Sarah E , Jacquemyn Maarten , Vandewinkel Bram , Munter Sofie D , Nguyen Tien , Handle Florian , Smeets Elien , Moris Lisa , Devlies Wout , Voordeckers Karin , Gorkovskiy Anton , Henckaerts Els , Daelemans Dirk , Verstrepen Kevin J , Voet Arnout , Helsen Christine
Published: November 2022

In synthetic biology, small molecules are commonly used for altering gene expression through the (in)activation of gene switches. Current switches, however, have a narrow species range, are non-titratable, or use non-inert inducers which evoke important side effects. Universal gene switches (XRs) that have dynamic ranges without interference with the host cell physiology will overcome these limitations. Ideal starting points for developing such XRs are the steroid receptors (SRs). The SRs are frequently applied as regulator domain or gene switch in organisms in which they are not naturally expressed, like microbes and plants. Several SRs, such as the estrogen receptor alpha (ERα), have been redesigned to respond to synthetic effectors but these variants require inducer amounts that are detrimental to the host or affect endogenous SRs.

By combining in silico modelling with directed evolution in the yeast Saccharomyces cerevisiae, we developed a platform and strategy for evolving SRs towards a chemical of choice. Validation of this method was achieved by first evolving the ERα to employ tamoxifen as an agonist, yielding the preTERRA variant. Subsequently, activation by estradiol was removed, rendering a tamoxifen receptor (TERRA). We show that TERRA gets activated by subtoxic tamoxifen amounts while remaining insensitive for physiological estradiol levels. Further evaluation demonstrated TERRA to be transferable to mammalian cells. Ongoing research aims at converting the TERRA receptor into a regulatory domain for controlling nuclear translocation of Cre recombinases and Cas9 proteins in both cell lines and mouse models.

The same platform was employed for adapting ERα towards the plasticizer Bisphenol A. This yielded an ERα variant that is no longer inducible by estradiol but is responsive to lower concentrations of Bisphenol in yeast. The transferal to cell lines will provide us with an additional regulatory domain. The ability to engineer any SR towards a synthetic ligand of choice not only expands the synthetic biology toolbox but can find applications in landscaping SR-related drug resistance and ligand-inducibility.

Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF03 | PMON287 Examining the role of Constitutive Androstane Receptor during Imidacloprid exposure
Authors: Sen Anushna , Goforth Madison , Cooper Kerry , Anakk Sayeepriyadarshini
Published: November 2022

Imidacloprid (IMI) is a neonicotinoid pesticide used for pest control and seed treatments. It mimics nicotine and selectively targets insect nicotinic acetylcholine receptors to induce paralysis and death. Popularly used worldwide, IMI residue is readily detectable in crops, the environment, and human samples. Gastrointestinal symptoms in patients as well as defective gut barrier and hepatoxicity in animal models have been reported subsequent to IMI exposure. However, the mechanism underlying IMI toxicity in mammals is unclear. Pesticide exposure frequently activates xenobiotic nuclear receptors, like constitutive androstane receptor (CAR), to induce detoxification phase I and phase II genes. We found that IMI exposure in wild-type (WT) mice induced hepatic expression of Cyp2b10, a bona fide target of CAR. This data led us to investigate the role of CAR in alleviating IMI toxicity. We dosed wild-type (WT) and Car-/- mice with 50mg/kg BW IMI, twice daily for 21 days and collected serum, liver, and intestine tissues. The absence of CAR resulted in a three-fold increased accumulation of IMI within the liver as well as a 6% increase in body weight. Intriguingly, IMI exposure resulted in hepatic inflammatory pockets in WT mice but did not induce serum liver injury markers (ALT and AST) in either WT or Car-/- mice. We quantified the expression of genes involved in detoxification and oxidative stress within the liver and ileum using qRT-PCR. We found Car-/-mice had significantly blunted expression of Cyp-P450 enzymes in the ileum. To compare gut function, we measured organ coefficient and examined ileal histology using Alcian Blue/PAS staining. We found the absence of CAR altered small intestine (SI) morphology independent of IMI exposure suggesting a basal role of CAR in maintaining overall SI morphology. Car-/-mice also exhibited increased SI weight and length and shorter villi height. AB-PAS staining showed IMI reduced ileal mucin production in WT mice but not Car-/- mice. To further examine CAR's role in the xenobiotic metabolism in the ileum, we will compare microbial diversity and bile acid pools with and without IMI exposure. Our results suggest IMI is not overtly toxic, but the absence of xenobiotic nuclear receptor CAR allows increased accumulation of IMI in the liver and disrupts the structure and Cyp gene expression in the intestine.

Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF03 | PMON303 Serum 25-Hydroxyvitamin D Concentration Significantly Decreases in COVID-19 Patients With Pneumonia During the First 48 Hours After Hospital Admission
Authors: Smaha Juraj , KuÅma Martin , Nachtmann Samuel , Jackuliak Peter , Max Filip , Tibenskã Elena , Binkley Neil , Payer Juraj
Published: November 2022

Objectives

Although 25(OH)D is generally considered the best marker for assessing vitamin D body stores, its role as a marker during acute illness is less well established. Indeed, acute inflammatory insult may reduce circulating 25(OH)D. The objective was to examine serum 25(OH)D levels during the evolution of acute COVID-19 pneumonia.

Material and methods: This pilot study was undertaken as a prospective cohort study. Patients with severe COVID-19, defined as clinical signs of pneumonia and respiratory rate > 30 breaths/minute or severe respiratory distress or oxygen saturation < 90% on room air, were admitted to the internal medicine department between 1 November and 31 December. Blood samples were taken on admission (day 0) and every 24 hours for the subsequent four days (days 1-4). Patients were not supplemented with vitamin D preparations during the monitoring period. All patients received 6 milligrams of dexamethasone daily during the monitoring period.

Results

22 patients (6 females, 16 males; median age 60.6 years) were included. On admission, 59% of patients were 25(OH)D sufficient (>30 ng/ml), and 41% of patients had 25(OH)D inadequacy (<30 ng/ml) according to the existing guidelines. A significant fall in mean 25(OH)D concentration from admission to day 2 (first 48 h) was observed (30,7 ng/ml vs. 26,4 ng/ml; p<0.0001). No subsequent significant fall in 25(OH)D concentration was observed between day 2 and 3 (26, 4 ng/ml vs. 25,9 ng/ml; p=0.2300) and day 3 and day 4 (25,8 ng/ml vs. 25,9 ng/ml; p=0.7026). The absolute 25(OH)D change between hospital admission and day 4 was 4.8 ng/mL (p<0.0001) and was not associated with mortality or the need for high flow oxygen (p=0.2113 and p=0.6467, respectively). On day 4, the number of patients with 25(OH)D inadequacy (<30 ng/ml) increased by 18% (p=0.0180).

Conclusions

Serum concentration of 25(OH)D decreases significantly during the first 48 hours after hospital admission in acutely ill COVID-19 patients and should be therefore interpreted with caution. Whether low 25(OH)D in COVID-19 reflects tissue level vitamin D deficiency or represents only a laboratory phenomenon remains to be elucidated in prospective randomized trials of vitamin D supplementation.

Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF15 | PMON291 Crystal Structures of Androgen DNA Binding Domain Interacting with its Response Elements (C3(1) ARE and MMTV-GRE)
Authors: Claessens Frank , Yin Lee Xiao , Helsen Christine , Voet Arnout
Published: November 2022

Prostate cancer (PCa) is the second leading cancer in the world in men. The major therapeutic target in advanced PCa is the ligand-binding pocket (LBP) of the androgen receptor (AR). The anti-androgens used to treat cancer are binding to this domain and compete with the natural agonist. Over time the cancer grows resistant towards this therapy. Nevertheless, the cancer still typically depends on the AR, indicating other sites of the AR may still serve as drug targets. The DNA binding domain (DBD) is a likely good therapeutic target as it is involved in essential processes such AR dimerization, translocation to the nucleus and binding to the androgen response elements (AREs). However the structure and the DNA binding interactions with AREs are not fully explored yet. Only one crystal structure (pdb: 1R4I) is available. In this structure, the DBD is bound to an artificial direct repeat DNA sequences (ADR3), resulting in an unexpected dimeric head-to-head arrangement. A better understanding on how the AR recognizes and binds to different native DNA sequences which are mainly organized as semi inverted repeats is crucial for rational drug design. Here, we performed protein crystallography of the DBD in complex with various natural ARE sequences, including the mouse mammary tumour virus (MMTV-GRE) motif. Surprisingly, this latter element is still able to be activated by a dimerization deficient AR.

Our first crystal structures were hallmarked by a high degree of disorder and appeared to bind both in a head-to-head as a head-to-tail fashion. Rational engineering of the DNA duplexes used for crystallography yielded well diffracting crystals for two different complexes. These two structures were diffracted to a range of 2 to 2.7 Å. Both structures with natural sequences appeared to bind in the head-to-head arrangement including the MMTV-GRE which consist out of semi inverted repeat DNA, whereas the C3(1)ARE contains the canonical fully inverted repeats. The structure reveals a slightly bend arrangement from the previously reported structure. The displacement is most visible at the DNA recognition helix bound to the half site and the so-called lever arm, which positions this helix in this region with a RMSD difference of 1.3 A. This indicates that the structural conformation changes of the protein is driven towards improved DNA-base pair recognition. Indeed the protein is able to make an additional set of non-covalent interactions with the base pairs of MMTV-GRE, leading to higher affinity. Both these extra interactions and conformational change lead to a higher affinity binding of protein-DNA, which seems to overcome the barrier introduced by the dimerization breaking mutations. This interaction surface could be a druggable site for structure-based drug design in the future, targeting AR-DBD dimerization.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBODP100 A Rare Case Of Pembrolizumab Induced Graves’ Disease
Authors: Alqaisi Sura , Rahman Ali
Published: November 2022

Cancer immunotherapies have recently changed the therapeutic armamentarium of anti-cancer treatments, particularly for melanoma and cancers of the kidneys, lungs, and colon. Immune checkpoint inhibitors (ICPis) act on various immune checkpoints. Of them, anti-PD-1 antibodies (such as pembrolizumab) are monoclonal antibodies that act against programmed cell death 1 protein. However, by counteracting the regulators of adaptive immunity, this class of drugs may cause immune-related adverse events that involve multiple organs and endocrine glands, such as the thyroid gland. The symptoms of thyroid dysfunction usually present during the first weeks of ICPis therapy. In the current report, we present a case of a 50-year-old male who presented to the emergency department complaining of fever, chills, nausea, and vomiting for one week. The patient had a history of colon cancer with lymph node metastasis status post tumor resection and colostomy. He began Keytruda® (pembrolizumab) treatment after tumor resection, and the presenting symptoms appeared after receiving the first immunotherapy infusion. His medical history was significant for psoriasis and rheumatoid arthritis. The patient's history was unremarkable for thyroid diseases, and he did not receive thyroid medications with no previous exposure to intravenous contrast media, over-the-counter iodine preparations, or biotin. At the emergency department, the patient had a temperature of 101.4°F, a heart rate of 110 bpm, and blood pressure of 130/70 mm Hg. On examination, tenderness was indicated upon palpating the anterior part of the neck. The patient was treated with intravenous fluids, steroids, beta-blockers, and broad-spectrum antibiotics. A workup for sepsis was requested, and it revealed negative blood culture and urine culture results. His laboratory indices demonstrated a suppressed level of TSH (0. 01 mIU/mL) and elevated Free T4 (3.16 ng/dl). Still, his TSH level reported at the Oncology clinic before Keytruda administration was (0.9 mIU/mL), and Free T4 was (1.7 ng/dl). Thyroid ultrasound revealed a heterogeneous thyroid gland consistent with thyroiditis. Antibody testing showed positive thyroid antithyroglobulin antibodies and elevated thyroid-stimulating antibodies (TSI). A radioactive iodine uptake test was ordered, revealing increased contrast uptake. These findings suggested that the cause of thyroid dysfunction was Graves’ disease. The patient was started on Methimazole 20mg per day and discharged home after scheduling an outpatient follow-up appointment with the endocrinologist. This case is one of the rare cases of thyrotoxicosis attributable to Graves’ disease related to pembrolizumab therapy. To the best of our knowledge, two studies in the literature reported three cases of ICPi-induced thyrotoxicosis with thyroid antibody positivity following anti-PD-1 antibody therapy.

Presentation: No date and time listed
LBSAT247 Factors Guiding Successful Treatment Discontinuation In Levothyroxine Replacement Therapy Overuse: Short And Long-term Observation Data Of 802 Subjects.
Authors: Livadas Sarantis , Androulakis I , Kollias A , Paparodis R D , Angelopoulos N , Boniakos A , Askitis D , Anagnostis P , Duntas L
Published: November 2022

Background

Levothyroxine (LT4-Rx) is one of the most commonly prescribed drugs worldwide and the vast majority of patients receive long-term treatment. However, in a recent study of LT4-Rx withdrawal in 291 subjects, it was found that 60% of those remained biochemically euthyroid two months after LT4-Rx discontinuation1.

Aim of the study

A prospective clinical cohort follow-up study was carried out to address this issue. We registered all patients presented in our clinical practice who were not on LT4-Rx for a solid diagnosis of hypothyroidism and abruptly discontinued treatment. All subjects underwent weight, height, TSH, TPO, Tg-Abs and free T4 measurement and thyroid ultrasound on enrolment, 2-4 months later, and at the end of follow up. A TSH value of ≥4.5IU/mL was considered as underlying hypothyroidism.

Results

We enrolled 802 consecutive subjects (83% females) aged 48±16 (range 18-84 years) with 8.8±7.3 years on LT4-Rx. The treatment indications and corresponding percentage for LT4-Rx were classified as a nodule(s) (35%), indefinite (25%), post-partum (7%) and Hashimoto's (33%); 48% of subjects were part of Group A and long-term follow-up up to 5 years was achieved in the remaining. Among the entire cohort, n=182 subjects became hypothyroid, while the remaining n=620 remained euthyroid off LT4-Rx (23 vs. 77%, p<0. 001). On subgroup analysis, 40% of subjects comprising Group A became hypothyroid, whereas the corresponding value for Group B was 7%. In Group A, the reason for LT4-Rx, LT4 dose, LT4 dose/BMI, TSH levels and the presence of increased thyroid autoantibodies titers (ATA) were significantly different in those who became hypothyroid, whereas only the reason for LT4-Rx differed in Group B. Subjects with a diagnosis of nodules, negative ATA, lower TSH values and lower LT4 dose during treatment had significantly lower probability to become hypothyroid. Furthermore, in Group A, 14.8% became hypothyroid with baseline TSH>3IU/mL vs. 5.2% with baseline TSH<3IU/mL (p<0. 001); the corresponding values for Group B were 22.2% vs. 8.8%, (p<0. 001), respectively.

Conclusions

These findings suggest considerable overuse of thyroxine therapy. In cases of uncertainty, the existence of nodules, a low-normal TSH value, a relatively small T4 dose, and the absence of ATA are strong predictors of euthyroidism, and accordingly a treatment discontinuation trial is recommended. Furthermore, if hypothyroidism does not ensue 2-4 months post-treatment discontinuation, the likelihood to develop hypothyroidism in the long term is minimal.1. Livadas S, et al. Thyroid 2018.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT292 A Rare Case Of Co-existent Grave's Disease Complicated By Non Medullary Thyroid Carcinoma And Primary Hyperparathyroidism In A Young Male
Authors: Arora Gunjan , Patel Toral
Published: November 2022

Introduction

The relationship between medullary thyroid carcinoma and parathyroid adenoma is well recognized and has been described in connection with MEN syndromes; however, co-existing Grave's disease with underlying non medullary thyroid carcinoma and primary hyperparathyroidism remains a rare phenomenon. The basis of this entity remains yet to be deciphered. With this case we wish to highlight that synchronous abnormalities of thyroid and parathyroid should always be considered and further testing to evaluate for underlying genetic abnormalities should be offered on a case by case basis. In addition, since both Grave's disease and hyperparathyroidism contribute to hypercalcemia, their interplay must be considered in interpretation of serum calcium and parathyroid function.

Case presentation

A 44 year old male with no significant medical history presented to the PCP with chest pain and dyspnea on exertion. EKG showed sinus tachycardia. Labs showed Calcium 11.1 mg/dl (8.6 - 10.3), Albumin 4 g/dl (3.5 - 5.7), TSH <0. 010 uIU/ml (0.27 - 4.20), Free T4 3.71 ng/dl (0.5 - 1.6). Repeat labs confirmed these findings. Additional tests included: PTH 105.9 pg/ml (12 - 88), Ionized calcium 6.4 mg/dl (4.5-5.4), TPO antibody positive and TSI antibody positive. Propranolol was started and Endocrinology was consulted. Thyroid ultrasound showed hyperechoic gland and 24 hour radio-active Iodine uptake was abnormally increased to 67.8% (8 - 33%), consistent with Grave's disease. Options for treatment were discussed. Decision was made to start Methimazole to achieve euthyroid state followed by repeat PTH (104.1 pg/ml) and Calcium (calcium 10.6 mg/dL) testing. Due to persistent hypercalcemia with inappropriately elevated PTH, surgical intervention was planned. Pre-operative localization studies were ordered: thyroid ultrasound showed two hypoechoic thyroid nodules in the superior right thyroid lobe and inferior left thyroid lobe, and sestamibi scan did not show any focus of increased activity to suggest a parathyroid adenoma. Total thyroidectomy with parathyroid exploration was planned. Surgical pathology was consistent with three foci of papillary thyroid carcinoma measuring 5 mm, 3 mm and 1 mm in size in the right thyroid lobe and right inferior parathyroid adenoma. Post-operatively, thyroid hormonal supplementation was initiated and thyroid and parathyroid function panel normalized.

Discussion

Our patient had concurrent non medullary thyroid carcinoma and primary hyperparathyroidism. Concurrent thyroid carcinoma should always be considered in patients presenting with parathyroid abnormalities, and a complete pre-surgical screening evaluation must be done. Genetic testing should be considered. And since hyperthyroidism and hyperparathyroidism both can lead to hypercalcemia, their interplay must be considered in interpretation of serum calcium and parathyroid function.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT310 A Rare Disease Engulfing Thyroid And Masquerading As Common Thyroid Disorders
Authors: Myint Myat Su Mon , Pinero-Pilona Antonio
Published: November 2022

Introduction

– Langerhans cell histiocytosis (LCH) is a rare clonal disorder caused by the CD207+ Langerhans cells derived from the myeloid origin. We present a case of LCH where it mimicked Hashimoto's and Riedel's thyroiditis and completely infiltrated the thyroid gland.

Case description

– A 54-year-old female was initially diagnosed with hypothyroidism, goiter, and bilateral parotid and submandibular glands enlargement. CT imaging revealed a diffuse goiter which imposed infraglottic airway narrowing and a suspicious left inferior thyroid nodule. Biopsy revealed atypia of undetermined significance. GSC showed a 50% suspicion of malignancy with a negative BRAF. Follow up imaging revealed increased infiltrative masses within the salivary glands, enlarging thyroid gland, and increased infiltration of the superior component of the right thyroid lobe into the submandibular space. A core needle biopsy revealed a background of acute and chronic inflammation without evidence of malignancy. Sjogren's, sarcoidosis and IgG4 diseases were ruled out. She was then referred to us after a myriad of work up. She had a diffusely enlarged goiter with a crusted area of skin over the thyroid gland and significant bilateral parotid swelling. We repeated a thyroid ultrasound which revealed diffusely enlarged and heterogeneous thyroid glands with pseudo-nodules and 3 suspicious nodules greater than 1cm on right and left lobes. She also had prominent reactive lymphadenopathy. Her submandibular glands were hypoechoic, avascular, markedly enlarged and abnormal appearing. She underwent total thyroidectomy. Pathology revealed proliferation of histiocytes, few islands of lymphoid tissue, and eosinophilic micro abscesses without any identifiable thyroid parenchyma in the entire resected specimens. Immunohistochemistry confirmed the diagnosis of Langerhans Cell Histiocytosis with atypical features. BRAF (V600E/V600K) mutation was again not detected. Flow cytometry showed no evidence of neoplastic myeloid blast population. She was referred to an oncologist for further management of LCH.

Discussion

– Our patient had a remarkably diffuse goiter with a sonographic appearance mimicking Hashimoto's thyroiditis or Riedel's thyroiditis. Initial thyroid FNA failed to reveal LCH. The diagnosis was reached only after total thyroidectomy. Treatment depends on single or multi-system involvement, presence or absence of risk organ involvement, and presence or absence of BRAF mutation.

Conclusion

In the cases of infiltrated thyroid diseases, Langerhans cell histiocytosis should be on the differential diagnosis, especially if there is concomitant infiltrative process in other organs. The sonographic finding can mimic Hashimoto's or Riedel's thyroiditis which may lead to misdiagnosis and treatment delay.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP448 A Case of Lithium-Induced Silent Thyroiditis
Authors: Dawahir Wafa , Gilden Janice , Moid Alvia , Trendafilova Victoria
Published: November 2022

Background

Lithium is a drug used in the management of psychiatric condition such as acute mania and bipolar disorder. Lithium is generally known to decrease thyroid hormone synthesis and release, causing hypothyroidism and thyromegaly. Much less commonly, lithium can cause elevated thyroid function tests; we describe such a case.

Clinical Case

A 21-year-old man with bipolar disorder and polysubstance abuse, presented with acute mania and was started on Lithium. Baseline TSH was 1.42 [0.358-3.74 µIU/mL], but one week after starting Lithium, TSH was 0.1 uIU/mL [0.358 - 3.74 µIU/mL] with free T4 of 0.95 [0.76-1.46 ng/dL]. Three weeks later, TSH was 0. 01 µIU/mL [0.358 - 3.74 µIU/mL], FT4 1.52 ng/dL [0.76 - 1.46 ng/dL], FT3 6.16 pg/mL [ 2.18 - 3.98 pg/mL], total T3 221 ng/dL [76–181 ng/dL]. Six weeks after starting Lithium, TSH remained suppressed at <0. 005 µIU/mL [0.358 - 3.74 µIU/mL], FT4 1.66 ng/dL [0.76 - 1.46 ng/dL], FT3 6.21 pg/mL [ 2.18 - 3.98 pg/mL]. During this time the patient's only complaint was tremor, with no other symptoms of hyperthyroidism. Physical exam showed mild tachycardia, with no evidence of thyroid eye disease, and the thyroid gland was normal size and nontender. TSI was negative with normal thyroglobulin and iodine levels, negative thyroglobulin and peroxidase antibodies. Lithium was in the therapeutic range. Thyroid US was normal without thyromegaly, normal echogenicity and color flow and without nodules or masses. I-123 thyroid uptake and scan showed low uptake and no nodules. The patient was diagnosed with Lithium-induced silent thyroiditis. He was treated with propranolol 10 mg PO BID for tremors, which was stopped later, due to bradycardia and dizziness. Due to persistent suppression of TSH and elevated FT4 and FT3 eight weeks after initiation of Lithium, this was discontinued, and Depakote was started.

Conclusion

Prior studies have shown that Lithium-induced thyrotoxicosis occurs in 2.7 cases/per 1000 person-years, with Lithium-associated Graves’ disease in 1.4 cases/1000 person-years, and silent thyroiditis only in 1.3 cases/per 1000 person-years. Although rare, our case highlights the importance of considering silent thyroiditis in patients treated with lithium and hyperthyroidism. References: K. K. Miller and G. H. Daniels, Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clinical Endocrinology 2001; 55, 501-508Kibirige et al. Spectrum of lithium induced thyroid abnormalities: a current perspective. Thyroid Research 2013; 6: 3

Presentation: No date and time listed
ODP449 A Case of Malignant Struma Ovarii
Authors: Alhusseini Maha , Daher Mona , Mehanna Reem
Published: November 2022

A 45 year old female presented to the ER with pelvic pain. Ultrasound of the uterus revealed a left ovarian 8 cm dermoid cyst. She underwent a unilateral salpingo-hysterectomy. During the operation, no high risk features were seen including no ascites or adhesions. Final pathology revealed a 2.2 cm papillary thyroid cancer with no other worrisome features (no angio-invasion or lymphatic invasion). A diagnosis of malignant struma ovarii was made, and the patient was referred to endocrinology for further work up. A neck US was performed revealed a benign looking, partially cystic, 0.8 cm right thyroid nodule. An FNA attempted came back non-diagnostic. Thyroid functions and baseline thyroglobulin were normal. The clinical dilemna that came up was how to approach the thyroid gland status since in the majority of thyroid cancer cases, the thyroid gland is removed. On review of over 200 cases reported in the literature of localized malignant struma ovarii, the majority of the cases were treated with pelvic surgery alone, and the thyroid gland was left in place. There is no available data that removing the thyroid gland in these patients decreases the risk of recurrence of thyroid cancer. Given the lack of any high risk features in our patient, it was decided not to pursue further adjuvant treatment and to continue surveillance with a repeat of thyroglobulin level in 6 months.

Presentation: No date and time listed
ODP459 Adiposity Rebound in Japanese Patients with Congenital Hypothyroidism Detected by Neonatal Screening
Authors: Nakayama Kanako , Kaneko Naoya , Hishimura Nozomi , Yamaguchi Takeshi , Ishizu Katsura , Tajima Toshihiro , Nagasaki Keisuke , Nakamura Akie
Published: November 2022

Background

More than 40 years have passed since the introduction of newborn screening programs (NBS) for congenital hypothyroidism (CH), and there have been many reports on the long-term outcome of CH identified by NBS. There are some reports that CH is associated with early adiposity rebound and adult obesity. On the other hand, the association between AR and CH has not been revealed in Japan.

Objective

The aim of this study was to evaluate the timing of AR in individuals with CH detected by NBS in our institution, furthermore, to find out the risk factors of early AR in CH individuals.

Patients and Methods

The study included 212 CH children (105 female/107 males) who were ten years of age or older as of September 2021. We retrospectively collected height and weight data from one to ten years of age, and the timing of AR was visually determined. We examined the association between the AR age and the severity of hypothyroidism at NBS and at the first visit.

Results

The median AR age was 5.6 years for boys and 6.2 years for girls, which was unexpectedly not unexpectedly younger than that of the general Japanese population reported by Koyama (4.8 ± 1.4 years for boys, 4.7 ± 1.5 years for girls). Data from 115 patients (107 males, 105 females) whose physique data between the age of 15 and 18 were available showed that body mass index (BMI) was 21.1±3.2 kg/m2 for males and 20.6±2.7 kg/m2 for females, positively correlated with AR age, and not significantly different from BMI at 15-19 years of age (21.1±3.6 for males and 20.2±2.2 for females) in the 2019 National Nutrition and Health Survey (p=0.790, p=0.619). NBS-FT4 was slightly positively correlated to AR age (r=0.234, p=0. 0315). We found that the AR age may be earlier and adult BMI may be higher in CH patients without ossification of the distal femoral epiphyseal nucleus at first evaluation.

Discussion

Severe fetal hypothyroidism may cause an absence of mineralization of the distal femoral epiphyses in the neonatal period. Our results indicate that severe fetal hypothyroidism, even if diagnosed and treated at neonatal, contributes to the development of adult obesity.

Conclusion

The AR age and BMI at 15-18 years of CH are not significantly different from the general population. However, severe fetal hypothyroidism could result in adult obesity.

Presentation: No date and time listed
ODP462 Amiodarone Induced Thyrotoxicosis-Treatment Challenges
Authors: Firak Gabriela , Gabriely Ilan , Leu James , Zahedpour Sara , Magaji Vasudev , Singh Vinita , Sherpa Chheki , Shrestha Bishow
Published: November 2022

Amiodarone induced thyrotoxicosis (AIT) presents a diagnostic and treatment challenge. Importantly, uncontrolled thyrotoxicosis can be associated with significant morbidity and mortality. The following presentation depicts a case of AIT with persistent thyrotoxicosis despite optimal and prolonged medical therapy. The case was complicated by patient's high-risk cardiovascular profile postponing definitive therapy with thyroidectomy. Patient was a 58-year-old female with past medical history of coronary artery disease, severe systolic heart failure, atrial fibrillation, and ventricular tachycardia maintained on amiodarone therapy since 2019, who was noted to have abnormal thyroid function labs in 2021 with TSH of 0. 04 uIU/mL (0.45-5.3), free T3 of 4.6 pg/mL (2.2-4.1) and free T4 of 2.7 ng/dL (0.58-1.64) indicative of hyperthyroidism. Her evaluation included negative family history of thyroid disorder, negative thyroid antibody profile, as well as a thyroid ultrasound that demonstrated no thyroid enlargement, no nodules and normal vascularity. At the time of initial evaluation, patient was suffering from episodes of atrial fibrillation with rapid ventricular response. Patient was diagnosed with AIT (presumably type 1). Amiodarone was discontinued and patient was initiated on methimazole 10 mg twice daily. Unfortunately, three weeks after initiation of methimazole treatment, patient's clinical status deteriorated and she was hospitalized for multifactorial shock requiring multidisciplinary approach and vasopressor/ionotropic support. At that time her free T4 had risen to >5.6 ng/dL and free T3 peaked at 6.17 pg/mL. The most probable diagnosis was AIT type 2 and her medical therapy was augmented to methimazole 20 mg three times daily and prednisone 50 mg daily. After clinical stabilization, she was discharged home on this regimen. Unfortunately, her thyroid function tests remained persistently elevated for almost three months despite maximum medical therapy. At that point, patient was referred for thyroidectomy despite severe cardiomyopathy and high-risk surgical profile. Fortunately, her thyroid function tests began to improve prior to planned surgery and medical therapy was successfully de-escalated, precluding the need for surgical intervention. While most cases of AIT can be successfully treated with medical therapy, refractory cases can present a clinical challenge, especially in patients at high risk for thyroidectomy. Weighing the risks and benefits of each treatment plan requires a multi-disciplinary approach and close communication with all parties involved.

Presentation: No date and time listed
ODP464 Association between preoperative vitamin D insufficiency and postoperative symptomatic hypocalcemia in patients with thyroid cancer
Authors: Ram Hong A , Choi Wonsuk , Park Ji Yong , Yoon Jee Hee , Kim Hee Kyung , Kang Ho-Cheol
Published: November 2022

Background

It is controversial whether vitamin D insufficiency (VDI) increases the risk of postoperative hypocalcemia and decreases the predictive power of parathyroid hormone (PTH) for postoperative hypocalcemia in patients undergoing total thyroidectomy (TT). Here, we investigated the role of VDI in the development of postoperative symptomatic hypocalcemia and assessed its effect on the predictive power of PTH as a marker for postoperative symptomatic hypocalcemia in thyroid cancer patients who underwent TT plus central compartment neck dissection (CCND).

Methods

All consecutive differentiated thyroid cancer patients who underwent TT plus CCND between January 2017 and December 2020 at a single tertiary referral hospital were retrospectively reviewed. Patients were divided into two groups according to their preoperative 25-hydroxyvitamin D (25(OH)D) levels (< 20 vs. ≥ 20 ng/ml). Postoperative symptomatic hypocalcemia was defined as ionized calcium < 2.2 mEq/l on postoperative day 1 and positive symptoms or signs of hypocalcemia. The effects of exposure on postoperative symptomatic hypocalcemia were analyzed using a multivariate logistic regression model.

Results

The incidence of postoperative symptomatic hypocalcemia was comparable between patients with and without VDI (P= 0.252). Preoperative VDI was not associated with the development of postoperative symptomatic hypocalcemia (OR = 1. 07, 95% CI 0.73 to 1.56, P= 0.744). Postoperative hypoparathyroidism (iPTH < 15 pg/ml) was associated with the development of postoperative symptomatic hypocalcemia in both VDI and non-VDI patients (OR = 6.78, 95% CI 3.88 to 11.85, P< 0. 001 and OR = 9.68, 95% CI 3.86 to 24.28, P< 0. 001, respectively).

Conclusions

VDI did not predict postoperative symptomatic hypocalcemia after TT plus CCND in thyroid cancer patients and did not influence the predictive power of postoperative PTH for postoperative symptomatic hypocalcemia. Therefore, prophylactic calcium and vitamin D supplementation in patients with VDI should be carefully considered in thyroid cancer patients.

Presentation: No date and time listed
ODP475 Developing suppurative thyroiditis
Authors: Katwal Dilasha , Aziz Shima , Lequerica Joe , Steinberg Helmut
Published: November 2022

Suppurative thyroiditis is rare and associated with significant mortality. A high level of suspicion and aggressive management is needed to reduce the risk of serious outcomes. A 67-year-old male with a medical history including diabetes type 2, cognitive impairment, and ESRD presented with decreased appetite and lethargy for a few days. He presented with fever, tachycardia, and hypertension. There was a non-tender fullness around the anterior neck region. Initial laboratory tests revealed leukocytosis to 24K/uL, lactic acid of 5. 0 mmol/L, ESR 100 mm/hr, CRP 419 ng/dl, and blood culture was positive for gram-positive cocci in clusters for which he was started on iv vancomycin and piperacillin/tazobactam. CT scan on admission showed a probable inflammatory process in the neck originating from the thyroid bed, concerning acute thyroiditis and developing abscess/abscesses vs. very atypical presentation of thyroid cancer. Thyroid ultrasound showed diffuse thyroid enlargement with heterogeneous echogenicity. Repeat CT obtained due to apparent thyroid enlargement with erythema and tenderness on examination and fever on day 7 showed extensive heterogeneous thyroid enlargement with ill-defined margins to the adjacent soft tissue structures. A modified barium swallow revealed severe oropharyngeal dysphagia leading to thyroid fine-needle aspiration of both thyroid lobes by interventional radiology and subsequent urgent incision and drainage (I&D) of the right neck and thyroid biopsy under general anesthesia by ENT. I&D showed purulent drainage from the thyroid. Cultures were positive for MRSA. Surgical pathology reported a necrotic muscle and abscess and fragment of thyroid tissue. Thyroid function tests (TFTs) on admission revealed a TSH 0.31 mcIU/ml (reference: 0.30 - 5. 0 mcIU/ml) and a free T4 of 2.21 ng/dl (reference: 0.76- 1.46 ng/dl) and repeat TFTs with a TSH of 0.30 mcIU/mL, free T4 of 1.87 ng/dL, free T3 of 2.15 pg/ml (reference: 2.18- 3.98 pg/ml), consistent with sick euthyroid syndrome. TPO and TSI were negative. Subsequently, the patient's fever resolved, and the neck swelling improved. He continued IV vancomycin for a month. TFTs six weeks later showed an elevated TSH of 13.10 mcIU/ml and normal free T4 of 1. 03 ng/dl.

Conclusion

MRSA suppurative thyroiditis is rare, and its diagnosis may be delayed due to its indolent course, especially in immunocompromised patients. Therefore, a high index of clinical suspicion is needed for this endocrine emergency in a patient presenting with fever and neck swelling. While an early FNA of the thyroid is likely to aid in diagnosing thyroid infection, TFTs may be variable and not helpful.

Presentation: No date and time listed
ODP481 Frequency and outcomes of reporting Bethesda class III thyroid cytopathology- An integrated health network's experience
Authors: Dantey Kossivi , Hasan Farhad , Tipu Ali , Verma Tanvi
Published: November 2022

Introduction

Indeterminate thyroid nodule cytologic diagnosis causes anxiety and confusion to the patient and typically results in additional intervention including thyroid surgery. This increases risk of harm and cost of healthcare. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends that cytologists attempt to limit reporting 'indeterminate' [Bethesda III (B-III)] category when interpreting thyroid fine needle aspiration (FNA) specimens, and that all effort be made to limit this diagnosis to less or equal to 7% of all thyroid FNA cases. B-III encompasses follicular lesion of undetermined significance (FLUS) and atypia of undetermined significance (AUS). Because we noted a high reporting of B-III cases at our institution, we aim to review the cytologic interpretation of thyroid FNAs, specifically, the rate of indeterminate cytologic diagnoses. Our second aim is to assess the outcomes of nodules labeled as B-III category.

Methods

We reviewed the electronic medical records of adults who underwent FNA of thyroid nodules at Allegheny Health Network between January 1, 2016 and December 31, 2019.

Results

700 patient records were reviewed, out of which 167 records were excluded (non-thyroid FNA or no relevant records). Meaningful records were available for 725 thyroid nodules biopsied during the study period (533 patient records). Mean age in our sample was 54.7±13.9 years and female-to-male ratio was 4: 1. Percent reporting of diagnostic categories based on Bethesda system were as follows: non-diagnostic/unsatisfactory (B-I) 8%; benign (B-II) 52%; FLUS/AUS (B-III) 28%; FN/SFN (B-IV) 6.2%; suspicious for malignancy (B-V)2.3%; and malignant (B-VI) 3.2%. Out of 28% reported as B-III, 73% were FLUS and 27% were AUS. Results of molecular diagnostic testing (ThyGeNEXT-ThyraMIR; Interpace Diagnostics®) were available for 95/203 of B-III category cases, of which 76% were labeled as very likely benign (probability of malignancy ≤5%) and 15% had low to moderate (10-40%) probability of malignancy. Only 9/95 (9%) had a ≥ 45% probability of malignancy. Four cases out of the 9 above cases were confirmed malignant and 1 was 'indeterminate' on surgical pathology. One in four of all B-III category nodules (n=52) underwent partial or total thyroidectomy, of which 32 were reported as benign, 18 malignant, one NIFTP, and one indeterminate by final surgical pathology.

Conclusion

We observed higher than recommended (28%) rate of B-III thyroid cytology at our institution. Most of these nodules underwent further interventions (molecular testing and/or thyroidectomy) where the majority were determined to be benign. All efforts should be made to decrease this rate with the ultimate goal of improving patient care, decrease unnecessary intervention, and reduce healthcare cost.

Presentation: No date and time listed
ODP486 Hypothyroidism And Its Relation To Clinical Outcome In Covid-19 Inpatients
Authors: Rech Carolina Leães , Viel Jessica , Camboim Isadora , dos Santos Lersch Andressa Gabriela , Lima Julia Fernanda Pereira
Published: November 2022

Thyroid dysfunction associated with Coronavirus infection (COVID-19) such as thyroiditis and sick euthyroid syndrome have been reported in recent studies, but the role of hypothyroidism in disease progression and severity remains uncertain. Our aim was to assess the frequency of hypothyroidism and its relationship with clinical outcome in patients hospitalized for COVID-19. The study was retrospective and observational with a cohort of 966 patients hospitalized for COVID-19 infection from February to August 2021, separated into two groups, with and without previous hypothyroidism, and compared in relation to the following variables: age, index of body mass (BMI), type of care, gender, initial hospitalization sector, comorbidities, requirement mechanical ventilation (MV), oxygen supplementation (O2), levothyroxine dose, thyrostimulating hormone (TSH) and free thyroxine (T4L) levels, total length of hospital stay and death. Of the 966 patients evaluated, 87 (9%) had hypothyroidism prior to hospital admission. Patients with hypothyroidism were on average 6.5 years older and had a significantly greater mean age than those without hypothyroidism. The outcome of death was evidenced in 38% of the total sample, with no statistically significant difference between the groups. In uni and multivariate analysis groups matched for sex, age and comorbidities, only older age (increase of 1.8% for each year) and the need for mechanical ventilation (increase of 9.5 times) were associated with a higher risk of death,with no impact of hypothyroidism in requirement mechanical ventilation, oxygen supplementation (O2), total length of hospital stay and death.

Presentation: No date and time listed
ODP487 Iatrogenic Thyroid Storm Treated with Plasmapheresis
Authors: Alam Mustafa , Abdelrahim Baha , Alam Mariam , Hosam Horani Mohamed
Published: November 2022

Presentation: A 25-year-old man presented to the ED with intentional multi-drug overdose onset 9PM on the night prior to admission. PMHx is significant for seizures, hypothyroidism, resting tremors, and smoking. The patient expressed frustration over his persistent hand tremors with depressed mood and took 25 tablets of 500mg Keppra, 30-40 tablets of 150 mcg Levothyroxine, and 25 tablets of 10mg propranolol. The patient denied any chest pain, SOB, nausea, vomiting, lightheadedness, fever, focal weakness, numbness or tingling, prior SI, rash, dysuria, or bleeding. Hospital Course: Vitals were T: 37 Celsius, HR: 92 BPM, 135/87 BP, RR: 18, and SpO2: 93%. Initial EKG showed sinus rhythm with 80 heart rate. The physical exam was significant for profuse diaphoresis and generalized tremors. There were no ST or T wave abnormalities indicating ischemia. The patient had a lab workup that was significant for a TSH of 0. 006, FT4 of >5, FT3 of 7. 09, and T4 of 22.77, after which he was placed on plasmapheresis. The FT4 trended downward to 2.56 after plasmapheresis. The patient experienced transient elevations in creatine kinase and bilirubin, but lab workup was otherwise unremarkable. The patient met admission criteria for inpatient psychiatry and discharged to a psych facility.

Discussion

Given the 7-day half-life of Levothyroxine, plasmapheresis was considered the best option to prevent fatal thyroid storm. This case also demonstrates the importance of how a multi-drug overdose can present more benign presentation with stable vitals. In this case, the effects of propranolol masked the initial symptoms of hyperthyroidism and decreased FT3 levels, indicating the importance to conduct a thorough history to manage polypharmacy drug overdoses. This case highlights plasmapheresis as an effective treatment modality for thyroid storm.

Presentation: No date and time listed
ODP496 Methimazole Induced Agranulocytosis Despite Minimal Intermittent Therapy
Authors: Uddin Ashraf , Gardner Michael
Published: November 2022

Introduction

Anti-thyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of Graves Disease. Agranulocytosis is a rare but lethal adverse effect of anti-thyroid medications. Here we discuss a case that highlights the importance of monitoring not only in the early stages of therapy, but also low dosing of therapy, intermittent therapy and even missing doses/discontinuation of therapy.

Case History

A 65 year-old male with past medical history of end-stage renal disease on peritoneal dialysis who presented to the hospital with syncope, ventricular tachycardia, tremulousness, weight loss of 22 pounds over 2 weeks was subsequently diagnosed with pericardial effusion with tamponade as well as hyperthyroidism. Suppressed TSH of < 0. 005 µIU/mL, Free T4 = 4.5 ng/dL, FT3 8.4 pg/ml, Negative TSI and TPO antibodies. He was started on methimazole 30 mg daily which he received 2 doses prior to discharge as well as beta-blocker therapy. He was re-admitted 1 week later for hypotension, nausea, vomiting and reportedly not taking any medications due to the vomiting right after last discharge supported by his hyperthyroidism being unchanged with a TSH of <0. 005 µIU/mL, free T4 4.21, Free T3 5.8 pg/ml. He was restarted on methimazole 3 days into admission. He received 4 days total of 30 mg daily and was discharged on methimazole 20 mg bid. He was re-admitted 8 days later, during which time again he had nausea and vomiting resulting in not taking methimazole for 1 week prior to admission, maximally 1 day of therapy. At this 3rd admission he was found to have evidence of agranulocytosis with a WBC count of 0.97×10^9 and absolute granulocyte count of 0. 06×10^9. Methimazole was held, he was started on propranolol 60 q6 and cholestyramine 4g bid. Hematology Oncology consultation indicated there would be little benefit from granulocyte colony stimulating factor therapy in medication induced agranulocytosis. He was monitored inpatient for recovery of he neutrophil count. He began to improve after 3 days of monitoring and was discharged. Repeat blood counts 3 months later showed full normalization. Further work-up revealed the etiology of his hyperthyroidism as likely a sub-acute/viral thyroiditis with thyroid I-123 uptake scan at 0.8% at 4, 6, and 24 hours. His hyperthyroidism also resolved over a total of 3 months and his beta-blocker and cholestyramine were discontinued.

Discussion

This case demonstrates that agranulocytosis is not a dose dependent side effect and can occur with as little as 7 days of therapy that are not even sequentially given. It also may support what very few case reports have demonstrated that even discontinuation of therapy may incite agranulocytosis as a side effect. It helps prescribers inform frequency of surveillance and selection of therapy in hyperthyroidism management.

Presentation: No date and time listed