bluuebunny/crossref_metadata_2025 huggingface dataset:
RF03 | PMON296 Insulin-induced AKR1C3 Metabolizes Classical and 11-oxygenated Androgens in a Model of PCOS Adipocytes
Authors: Mesaros Clementina , Paulukinas Ryan , Penning Trevor
Published: November 2022

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. These patients commonly develop hyperandrogenism and this androgen excess (AE) is believed to drive the syndrome. PCOS women also characteristically develop insulin resistance (IR), which correlates with AE in PCOS women. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the conversion of peripheral androgens and is induced by insulin in adipocytes. Classically, AKR1C3 converts Δ4-androstene-3,17-dione (4AD) to testosterone (T) and 5α-androstane-3,17-dione (5AD) to 5α-dihydrotestosterone (DHT). As a result, androgen conversion in adipocytes may contribute to the AE of PCOS women. Additionally, the 11-oxygenated androgens of adrenal origin were reported as the dominant androgens of PCOS and may be an alternative source of AE. AKR1C3 can also convert 11-ketoandrostene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-ketoandrostane-3,17-dione (11K-5AD) to 11-ketodihydrotestosterone (11K-DHT). T, DHT, 11K-T and 11K-DHT are potent agonists for the androgen receptor (AR). Therefore, overexpression of AKR1C3 by insulin could increase AR activation through production of both classical and 11-keto potent androgens. We hypothesize that AKR1C3 induced by insulin will produce 11K-T and 11K-DHT in a model of PCOS adipocytes. We developed a stable-isotope-dilution liquid chromatography high resolution mass spectrometric assay (SID-LC-HRMS) for the quantification of both classical and 11-oxygenated androgens in differentiated Simpson-Golabi-Behmel Syndrome adipocytes. Cells were treated with 4AD, 11K-4AD, or 11β-hydroxy-androstene-3,17-dione (11β-OH-4AD), the adrenal precursor to 11K-4AD. Androgens were derivatized with Girard P to enhance sensitivity and specificity. Analyte peaks were quantified using calibration curves of analyte to internal standard ratios versus pg of authentic standard. Our data suggests that 11β-OH-4AD is converted to 11K-4AD, which is then converted by insulin-induced AKR1C3 to 11K-T. The conversion of 11K-4AD to 11K-T was AKR1C3 dependent since a panel of AKR1C3 inhibitors blocked 11K-T formation. We found that 11K-T is deactivated to 11β-hydroxy-testosterone (11β-OH-T) and 11K-4AD can be back converted to 11β-OH-4AD by 11β-hydroxy steroid dehydrogenase type 1 (HSD11B1). This suggests that HSD11B1 protects the AR from overactivation by converting potent 11-keto androgens to their less potent 11β-hydroxy counterparts. Both classical and 11-oxygenated androgens may be sources of AE in PCOS by their intracrine formation in adipocytes. Our work elucidates the role of AKR1C3 in the formation of both classical and 11-keto potent androgens in a model of PCOS adipocytes and supports AKR1C3 as a potential therapeutic target in mitigating the AE of PCOS.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP436 Adrenal Insufficiency After Combined Treatment of Itraconazole and Triamcinolone
Authors: Sajan Alen , Mandhan Akash , Wong Beatrice , Abraham Smita , Stefan Simona
Published: November 2022

Introduction

Adrenal insufficiency (AI) has been reported due to the use of budesonide and itraconazole. We report an unusual presentation of adrenal insufficiency from the use of triamcinolone and itraconazole.

Clinical Case

46-year-old man with a history of NASH and alcoholic cirrhosis requiring liver transplant presented to ER with two weeks of progressive lower extremity weakness. He reported difficulty climbing stairs and getting up from a chair. He denied anorexia, nausea, vomiting, abdominal pain, or lightheadedness. He was treated with itraconazole for diffuse histoplasmosis for over one year and received one dose of intra-articular triamcinolone 40mg for shoulder pain 2 weeks prior to the hospital admission. Physical exam was significant for proximal weakness, ecchymoses on upper and lower bilateral extremities, mild truncal obesity, but no violaceous striae, moon facies, dorsocervical fat pad or supraclavicular fullness. Laboratory evaluation was notable for sodium 129 mEq/L (n: 135-145), potassium 5.9 mEq/dl (n: 3.5-5), albumin 2.9 g/dl (n: 3.5-5) and glucose 345 mg/dl (n: 70-140), ACTH of 6 pg/ml (6-20) AM cortisol of <1 ug/dl (n: 4-20), aldosterone <1 ng/dl (n: 3-16), and plasma renin activity (PRA)20.54 ng/mL/h (n: 0.25-5.82). Serum cortisol increased to 3.4 ug/dl at 60 minutes of cosyntropin stimulation test, consistent with adrenal insufficiency. Synthetic glucocorticoid panel detected triamcinolone. Patient was discharged on hydrocortisone and fludrocortisone with marked clinical improvement. Abdominal MRI 3 months after admission did not show any adrenal involvement by histoplasmosis. Fludrocortisone was slowly titrated off and only hydrocortisone continued. Repeat evaluation 6 months after last triamcinolone injection demonstrated recovery of HPA axis with peak cosyntropin stimulation cortisol level 16.3 ug/dL (assay by Abbott Alinity) and recovery of renin/angiotensin/aldosterone axis (AM aldosterone 7 ng/dl, renin 2 ng/ml/h). Repeat synthetic glucocorticoid testing confirmed clearance of triamcinolone.

Conclusion

Itraconazole is CYP3A inhibitor that has been shown to decrease the metabolism and clearance of different corticosteroids. While our patient's lab results supported a diagnosis of AI, it was unclear if the etiology was primary (PAI) or central AI (CAI). The Na+, K+, aldosterone and PRA levels support a diagnosis of PAI; whereas the suppressed ACTH level supports CAI. We believe that our patient had an atypical presentation of both PAI due to histoplasmosis and CAI due to itraconazole/triamcinolone. This confounding picture can potentially be explained by an underlying PAI that may have been masked and exacerbated by the HPA axis suppression of the itraconazole/triamcinolone combination.

Presentation: No date and time listed
LBODP092 Proposal Of Indication For Completion Thyroidectomy In Follicular Thyroid Carcinoma Using TERT Promoter Mutational Status
Authors: Park Hyunju , Heo Jung , Ki Chang-Seok , Shin Jung Hee , Oh Young Lyun , Son Young I , Kim Jee Soo , Kim Sun Wook , Chung Jae Hoon , Kim Tae Young , Kim Tae Hyuk , Kim Jung-Han
Published: November 2022

Background

Stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to solve the dilemma of definite characterization of follicular thyroid carcinoma (FTC). However, which patients will be candidates for completion thyroidectomy has been controversial. The aim of this study is to clarify the selection criteria for completion thyroidectomy using TERT promoter mutation.

Methods

A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the WHO 2017 classifications were calculated.

Results

Of the 87 patients, 8 patients (9.2%) had initial distant metastasis, and 15 patients (17.2%) had persistent disease or developed structural recurrence. Threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT it was 4cm. Cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification were significantly different only in patients with WT-TERT (P = 0. 001, P = 0. 019, and P = 0. 005, respectively).

Conclusions

The data suggested that 2 cm may be a critical threshold diameter for deciding completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can be a game changer for selecting candidates for completion thyroidectomy.

Presentation: No date and time listed
LBODP103 Ectopic Thyroid Tissue In A Pediatric Patient After Total Thyroidectomy
Authors: Gurnurkar Shilpa , Vyas Neha , Seekford Jennifer Leigh
Published: November 2022

Introduction

Ectopic thyroid tissue is defined as any functional thyroid tissue outside the normal anatomical location. It is rare and occurs with a frequency of 1 in 100,000-300,000. Most commonly, it is located along the normal track of thyroid development along the floor of the primitive gut to the pre-tracheal region of the neck; however, rarely it has been found in other areas. Malignancy is very rare in ectopic thyroid tissue (<1%) and when it occurs, papillary carcinoma is the most common type. Maki et al have reported multiple cases of lateral neck ectopic thyroid tissue in the presence of an orthotopic thyroid gland in the adult population. Only 2 pediatric cases have been reported in the literature so far.

Clinical Case

A 11-year-old male presented with concerns of morbid obesity and a neck swelling. He endorsed a previous history of thyroid nodules measuring over 2 cm that were being monitored by his previous endocrinologist. On exam, he was noted to have a goiter. Labs were obtained which indicated normal thyroid function tests (TSH 3. 040 uIU/mL, nl 0.45-4.5 uIU/mL and free T4 0.96 ng/dL, nl 0.93-1.6 ng/dL) and negative anti thyroid antibodies (TPO antibody <9 IU/mL, nl 0-26 IU/mL and thyroglobulin ab <1 IU/mL, nl 0. 0-0.9 IU/mL). His previous medical records revealed that a FNA was completed 2 years prior which was reported as benign. A repeat thyroid ultrasound revealed a multinodular goiter with 5 nodules measuring 3.3 x1.5×1.3cm and 5×6×5mm in the right lobe and 7×6×4cm, 2.4×2.1×1.8cm, and 5×6×5cm in the left lobe. After reviewing different management approaches, the family preferred thyroidectomy. He was referred to general surgery and subsequently underwent total thyroidectomy. Post-operatively, he was started on levothyroxine and calcium carbonate supplementation. The calcium supplementation was subsequently weaned and discontinued. Final pathology was reported as benign. Unfortunately, he was lost to follow up and presented to his primary care provider 6 months post-operatively with continued weight gain and a right sided neck mass. Labs obtained showed an elevated TSH (9.820 uIU/mL, nl 0.45-4.5 uIU/mL) and normal free T4 (1. 07 ng/dL, nl 0.93-1.6 ng/dL). Ultrasound of the neck revealed a 2.5 cm heterogeneous nodule in the right neck adjacent to the thyroid bed, concerning for recurrent/residual disease. FNA was completed and was consistent with normal appearing thyroid tissue. Ultrasound monitoring will continue to assess for change in size and need, if any for surgical removal in the future.

Discussion

Ectopic thyroid tissue with an orthotopic thyroid is a very rare finding in the pediatric population. Ectopic thyroid tissue outside of the thyroglossal duct is rare as well. We present an 11-year-old male who underwent thyroidectomy for multiple large thyroid nodules and subsequently developed a new neck mass diagnosed as ectopic thyroid tissue.

Presentation: No date and time listed
ODP583 Screening for Pheochromocytoma in a Cohort of Patients with Takotsubo Cardiomyopathy: New insights on Prevalence and Screening Tests Reliability Surrounding the Acute Cardiac Event
Authors: Bitton Yoel , Bourdeau Isabelle , Gagnon Nadia , Legault Jonathan , Mansour Samer , Guay-Gagnon Martin
Published: November 2022

Background

According to Takotsubo cardiomyopathy (TCM) diagnostic criteria, pheochromocytoma and paraganglioma (PPGL) should be excluded as secondary causes. However, it is unclear whether PPGL screening in the setting of acute TCM is reliable. We aimed to assess the prevalence of PPGL and the reliability of PPGL screening in a cohort of patients with TCM. Method: We retrospectively reviewed data from patients admitted in a tertiary hospital between August 2012 and January 2021 with a diagnosis of TCM proven by typical echocardiography findings and no acute occlusion on coronarography, who were screened for PPGL by plasma metanephrines/normetanephrines (M/NM). If the first screening was positive, a second plasma M/NM sample was used for confirmation. Time between TCM diagnosis and PPGL screening was collected.

Results

Among 64 patients identified with TCM, 42 underwent plasma M/NM screening. 81. 0% were female, and the mean age was 67.4 ± 9.9 years old. Ten patients (23.8%) had a positive result. Of those, 8 patients had a weakly positive result (1-2×upper limit of normal [ULN]) and 2 had a strongly positive result (>2×ULN). Of those 10 patients, 6 underwent a second screening: 5 had a normal result and 1 had a weakly positive result (plasma NM 1. 06×ULN). This patient underwent a third screening that was negative. In addition, an abdominal CT showed normal adrenal glands, and their chromogranin A levels were normal. Four patients had a positive initial PPGL screening, but they did not undergo a second screening: 3 died of causes unrelated to TCM before a second plasma M/NM sample was taken and one patient was lost to follow-up (his plasma NM was weakly positive at 1.29×ULN). They all had an abdominal CT that showed normal adrenal glands. Average time between TCM diagnosis and PPGL screening in all patients and in patients with a positive initial screening was 4.57 ± 3.91 and 3.38 ± 2.12 days, respectively. A linear regression model suggested an inverse relationship between plasma M/NM and time between TCM diagnosis and screening, with R2 = 0.2275.

Conclusion

TCM occurring as the initial presentation of PPGL is rare. All patients with a positive screening ended up being false positives in our study. The ratio of false positive results when screening for PPGL in the setting of acute TCM seems to be higher than in the general population, which could be explained by a hyperadrenergic state. It is unclear whether a shorter delay between TCM diagnosis and PPGL screening may be associated with more false positives. More research is needed to determine what is the optimal timing for PPGL screening in acute TCM and if higher cut-offs should be used to minimize false positive results.

Presentation: No date and time listed
LBSAT311 Rhabdomyolysis: A Rare Presentation Of Hashimoto Thyroiditis In An Adolescent Boy
Authors: Saroufim Rita , Eugster Erica A
Published: November 2022

Introduction

Hashimoto thyroiditis is the most common cause of hypothyroidism and is associated with a wide range of clinical presentations in children and adolescents. Hypothyroidism-induced rhabdomyolysis without precipitating factors is extremely rare, particularly in pediatric patients. We describe a previously healthy adolescent boy who came to our institution with vague symptoms and was found to have rhabdomyolysis secondary to hypothyroidism due to Hashimoto thyroiditis.

Clinical Case

A 16 year old boy presented to the emergency department at Riley Hospital for Children due to a two week history of bilateral eye and lip swelling. Additional symptoms included fatigue, sleepiness, slowing of speech, decreased attention span and weight gain. He was not on any medications and had no history of allergies. There was no family history of endocrine or neuromuscular disorders. Physical exam revealed a height of 177 cm (75th tile), weight of 118.4 kg (99th %tile) and BMI at the 99th %tile. Exam was significant for slow generalized movements, facial edema, and delayed deep tendon reflexes in all extremities. The thyroid gland was normal. Laboratory evaluation revealed Creatinine-1.46 mg/dL (0.3-1.2), ALT-88 Units/L (7-52), AST-254 Units/L (13-39), TSH-32.2 mcU/mL (0.4-4.2), fT4 <0.2 ng/dL (0.6-1.5) and CK 20,500 Units/L (30-223). Thyroid peroxidase antibody was elevated at 686.1 IU/mL. A renal and bladder ultrasound showed trace intra-abdominal ascites and decreased echogenicity of the bilateral psoas muscles favoring edema and consistent with rhabdomyolysis. He received IV hydration and was started on levothyroxine 25 mcg daily that was increased over a 10 month period to achieve euthyroidism. Genetic testing for rhabdomyolysis revealed two variants of unknown significance. Acyl carnitine and carnitine profiles were normal ruling out a metabolic myopathy. His symptoms improved significantly after treatment with levothyroxine although his CK levels plateaued around 1,000 Units/L. Liver and kidney function normalized during follow up.

Conclusion

Rhabdomyolysis is a rare but serious complication of hypothyroidism, the pathogenesis of which is unclear. Proposed hypotheses include impaired mitochondrial oxidative metabolism, decreased muscle carnitine and switching of muscle fibers from fast-twitching type II to slow-twitching type I due to thyroxine deficiency ultimately leading to myolysis and release of intracellular muscle contents into the circulation. It is important for clinicians to have a high index of suspicion for hypothyroidism in children who present with muscle weakness and high creatinine kinase levels. The etiology of the disproportionately mild elevation of TSH in the setting of an unmeasurable free T4 and severe clinical hypothyroidism in our patient remains a mystery.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP447 A Case of Hidden Grave's After Total Thyroidectomy
Authors: Baghel Annavi , Ortega Lucy
Published: November 2022

Introduction

A Sub-sternal goiter is a condition where there is an abnormal enlargement of thyroid gland that extends into the chest. The most commonly accepted definition is when >50% of the volume of a goiter extends into the thoracic inlet. We present an interesting case of a Sub-sternal goiter emerging as a cause of Grave's disease, years after Total Thyroidectomy.

Clinical Case

The Patient is a 75 year old female with PMH of endometrial cancer, who initially underwent total thyroidectomy due to Thyromegaly causing dysphagia, and was started on Levothyroxine therapy after surgery. Three years later, a sub-sternal mass, was incidentally found via CT chest, which measured 3.7cm in largest diameter. Nuclear Medicine uptake and scan confirmed thyroid origin of this mass with an increased uptake but no percentage uptake was provided. Patient's Thyroid functions tests remained within normal range on levothyroxine. But over the next 2 years,the patient needed declining doses of LT4, then became euthyroid, off of levothyroxine and eventually became hyperthyroid, with positive Thyroid stimulating immunoglobulin. She also developed symptoms of tremors and tachycardia, and developed Atrial fibrillation as well. Noophthalmopathyor dermopathy was found on exam. Repeat CT chest showed the sub-sternal goiter had increased to a partially calcified mass of 5.6 cm. NM uptake scan showed 38.6%, at 24 hour, generalized uptake of this mass. Radioactive Iodine Ablation was performed with 30.1mCi and she subsequently became hypothyroid again until 1 year ago when she had episodes of A-fib again, and was found with TSH of 0. 09(0.45-5.33mIU/L) and FT40.9 (0.6- 1.2 ng/dl) and free T3 of 6.4 (pg/dl), off of levothyroxine. NM uptake and scan was repeated which indicated recurrence of Grave's disease from the same source. The Patient chose to initiate Methimazole therapy while contemplating surgical resection.

Clinical Lesson: This is a unique case of Sub-sternal goiter, presenting as grave's disease, years after total thyroidectomy. This case emphasizes on the importance of identifying and treating sub-sternal goiter, as it can cause severe Grave's disease and thyrotoxicosis. Especially in this case, since Grave's caused by this sub-sternal goiter was recurrent after Radioactive iodine ablation.

Presentation: No date and time listed
ODP451 A Case of Papillary Thyroid Cancer Presenting with Marantic Endocarditis and Recurrent Stroke
Authors: Karuppasamy Gowri , Elhadd Tarik
Published: November 2022

Marantic endocarditis or non-bacterial thrombotic endocarditis (NBTE) is characterized by the presence of vegetations on cardiac valves, which consist of fibrin and platelet aggregates and are devoid of inflammation or bacteria. The hypercoagulable state associated with malignancy is well known to be associated with NBTE. Here we report a rare case of Papillary Thyroid Cancer presenting with Marantic Endocarditis and Recurrent Stroke. A 52-year-old lady, with medical background of hypertension, presented to the Emergency Department with history of sudden onset of difficulty in speaking for 3 days. On examination she had slurred speech and tongue deviation to the right side. Neurological examination was otherwise normal. Imaging revealed left frontal, right frontal and left cerebellar infarcts. Transthoracic Echocardiogram showed a large, highly mobile vegetation 18 mm in size, attached to the posterior mitral valve leaflet as well as severe Mitral Regurgitation. She was diagnosed as a case of Cardioembolic ischemic stroke due to endocarditis. She completed a course of empiric antibiotic therapy. However, her blood cultures and fungal culture revealed no growth. After 5 years, she again presented to the hospital with acute stroke. Trans esophageal Echocardiography now revealed multiple filamentous vegetations on the atrial surface of mitral valve, largest measuring 20 mm×4 mm. Her inflammatory markers were negative and 3 sets of blood cultures were again negative. A question was raised, as to whether the filamentous masses represent prolapsing ruptured chordae tendinae rather than vegetations. FDG PET-CT scan was thus performed and revealed: Left thyroid lobe focal uptake seen with an FDG-avid left parajugular lymph node. Ultrasound neck was then performed, which showed bilateral thyroid nodules with high suspicion ultrasound pattern per American Thyroid Association: ill-defined nodule seen in the lower pole measuring 8×8×7 mm with multiple foci of macrocalcification. Thyroid function tests were normal. Ultrasound guided thyroid fine needle aspiration (FNA) biopsy of the left thyroid nodule was performed. The cytology report was consistent with papillary thyroid carcinoma. She is planned for total thyroidectomy, after undergoing mitral valve replacement surgery. This case illustrates one of the paraneoplastic syndromes associated with thyroid cancer. A hypercoagulable state has been observed in several types of thyroid cancer, although the pathogenesis has not been well studied. The etiology of cancer-associated coagulopathy is complex, related to an imbalance in the hemostatic system and abnormal levels of coagulation factors. Further studies on the occurrence of thrombosis in different types of thyroid cancer would help to inform clinical practice in the management of thyroid cancer, including the need for anticoagulation in certain situations.

Presentation: No date and time listed
ODP465 BRAF V600 and NRAS Q61 mutations in thyroid fine-needle aspiration (FNA) with indeterminate cytology in Argentina
Authors: Repetto Esteban M , Fernandez Lucia , Lambertini Roberto , Jaen Ana Del Valle , Vega Veronica Ruda , Moldes Sofia , Aranda Claudio , Faure Eduardo , Oneto Adriana
Published: November 2022

It is known that thyroid cancer initiation and progression occurs because of gradual accumulation of genetic and epigenetic alterations at cell level. Many mutations associated with this disease have been reported to be present in genes encoding proteins in the mitogen-activated protein kinase (MAPK) signaling pathway, specifically BRAF and RAS genes, as well as in the PI3K/Akt signaling pathway, among others. In particular, molecular alterations in follicular cells in the BRAF or NRAS genes have been reported to be associated with the process of carcinogenesis. Previously we found BRAF and NRAS mutations are observed in a significant number of papillary and follicular thyroid carcinomas in our population, respectively. In this study, we tested the diagnostic performance of BRAF and NRAS mutation in thyroid carcinoma in fine-needle aspiration (FNA) specimens with indeterminate cytology. In total, residual material from 73 FNA samples was used (n= 16, Bethesda III; n=48, Bethesda IV and n=9 Bethesda V). BRAF codon 600 mutation and NRAS codon 61 mutations were investigated using qPCR and melting curve analysis was carried out. Diagnosis of malignancy was confirmed by histology on paired surgical specimen in 54 cases.

Results

In the cytologically indeterminate categories, 9.6% of specimens were BRAF V600 mutated: 1 of 16 were subcategorized as atypia of undetermined significance or follicular lesion of undetermined significance (6.3%); 2 of 48 as follicular neoplasm or suspicious for follicular neoplasm (4.1%); and 4 of 9 as suspicious for malignancy (44.4%). NRAS Q61 mutation was found in 4 patients (2 with Bethesda IV and 2 with cytology V). The BRAF V600 mutations were associated with carcinoma in 100% of cases (n = 7), whereas only 75% (n = 3) of the nodules with NRAS were associated with carcinoma. BRAF V600 and NRAS Q61 mutations had high specificity in predicting malignant carcinoma (96.8%); the sensitivity was 43.5% with a positive predictive value of 90.9% and a negative predictive value of 69.8%. In specific categories of indeterminate cytology, the pre-test risk of malignancy was 38%, 33% and 88% while the post molecular test risk of malignancy was 100%, 75% and 100% respectively.

Conclusions

BRAF V600 and NRAS Q61 molecular test in residual FNA samples improve diagnostic accuracy of the cytology analysis in our population and may help to better select patients for avoid inadequate or unnecessary surgeries.

Presentation: No date and time listed
ODP474 Critical Analysis of the Thyroid Cytopathologic Diagnosis of Atypia of Undetermined Significance and Associated Clinical Outcomes
Authors: LaRoe Matthew , Godfrey Sean , Kalia-Reynolds Shelly , Sheth Krupa , Yesaulava Mila , Demirtas Esra , Drake Almond
Published: November 2022

Introduction

FNA is the optimal test for classifying concerning thyroid nodules. Approximately 15-30% of FNAs are indeterminate, representing diagnostic challenge with intra- and inter-observer variability among cytologists. The Bethesda System (BS) for cytopathology was created in 2007 to standardize thyroid cytology with corresponding malignancy risk. Our goal is to identify the incidence of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/ FLUS) and the percent of malignant AUS/FLUS cases at our institution.

Methods

Chart review of 3068 adult patients with FNA performed from 2003 to 2015 was completed, with attention to reports considered "indeterminant". BS for reporting thyroid cytology was not in use at our institution during that time. Cytopathology reports were evaluated for key descriptors concerning for AUS, FLUS, or follicular neoplasm.

Results

461 cytology reports included language consistent with possible "indeterminate" cytology. These reports were reviewed with our institution's cytopathologist and retrospectively assigned an equivalent BS category. 241 cases were consistent with BS category III (7.86% of all thyroid nodule FNAs done during this time period). Molecular marker studies were not being performed at our institution on indeterminate thyroid cytology specimens during this time period. Of the patients who had indeterminate cytology consistent with BS category III, 66.3% (160/241) went for surgery. The malignancy rate was 27.5% (44/160) in the BS category III group.

Conclusion

Our data demonstrated that category III nodules in some practice settings may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration. Molecular marker testing on indeterminate thyroid cytology specimens has been shown to be helpful in determining cases for surgery and is now being utilized at our institution.

Presentation: No date and time listed
ODP476 Does Levothyroxine Intake at Breakfast Matter for Patients With Hypothyroidism? A Meta- Analysis of Randomized Control Trials
Authors: Cheng Ce , Sun Chenyu , Rizwan Tehlil , Ramanathan Shrungavi , Pendergrass Merri
Published: November 2022

The American Thyroid Association recommends taking levothyroxine consistently, "either 60 minutes before breakfast or at bedtime." However, clinicians typically opt to recommend taking levothyroxine on an empty stomach, rather than offering the option of bedtime or with breakfast. Many patients find it cumbersome to take levothyroxine in the morning without food. A meta-analysis was performed to evaluate the effects of taking levothyroxine (LT4) before breakfast (BB) vs. with breakfast (AB) on thyroid function tests in our included four clinical trials. Four randomized controlled trials involving 243 patients were retrieved from PubMed, according to established inclusion criteria. The Standard Mean Difference (SMD) of thyroid-stimulating hormone (TSH), free T4 (FT4), and free or total T3 (F/TT3) with their 95% confidence intervals between AB vs. BB were calculated. Random effect or fixed-effect model was used based on heterogeneity significance. Then a subgroup analysis of liquid levothyroxine and tablet levothyroxine was performed. Sensitivity analysis and publication bias detection were performed. All statistical analysis was performed using RevMan software (v5.4; Cochrane library) and R Core Team (2016, Vienna, Austria), and all p-values were two-tailed, and the significance level was 0. 05. No statistically significant differences of TSH (Mean 1.45-3.74 vs. 1.26-3. 00, SMD 0.25; 95% CI: -0. 06, 0.56; p=0.11, I2=65%), FT4 (Mean 1. 03-1.35 vs. 1. 02-1.24, SMD 0.14; 95% CI: -0.33,0.62; p=0.55, I2=78%), and F/TT3 (SMD -0. 06; 95% CI: -0.28,0.15; p=0.57, I2=0%) between AB vs. BB were found. The subgroup analysis showed that no statistically significant difference of TSH between AB vs. BB when patient took liquid form of levothyroxine (1.45-2.59 vs. 1.26–3. 00; SMD=0. 03; 95% CI: -0.21, 0.27; p=0.81, I2=0%). Although TSH was significantly higher with AB vs. BB when patient took tablet form of levothyroxine (2.89-3.74 vs. 1.54 -1.9; SMD=0.64; 95% CI: 0.24, 0.103; p=0. 001, I2=49%), TSH was within normal limits in both groups. This meta-analysis demonstrates that TSH of patients taking levothyroxine with breakfast is non-inferior to those taking it before breakfast. Although AB group taking levothyroxine by tablet has a significantly higher TSH level than the BB group, both groups have well-controlled levels. Limitations of this study include limited sample size and number of studies. It also was unable to differentiate patients with hypothyroidism from benign or malignant diseases. We also were not able to assess adherence to the prescribed regimen. Patient satisfaction and adherence with treatment may be improved by letting patients know to take LT4 consistently at a time of their choice.

Presentation: No date and time listed
ODP479 Equilibrium Dialysis ID-LC/MS/MS Procedure for Routine Measurement of Free Thyroxine in Serum
Authors: Zhang Li , Ribera Ashley , D’Zio Zachary , Sugahara Otoe , Tse Cindy , Danilenko Uliana , Hubert Vesper
Published: November 2022

Free thyroxine (FT4) test is essential for diagnosis of thyroid diseases. Most FT4 tests used in patient care are immunoassays (IAs). However, concerns about the accuracy of FT4 IAs have been raised in the clinical laboratory community. Reference measurement procedure (RMP) for FT4 based on well-defined equilibrium dialysis (ED) of serum has been established and are well recognized. While FT4 RMP is highly accurate and precise, it is not intended for routine clinical use. Our aim is to develop an ED-based FT4 assay that is traceable to the RMP and suitable for routine measurements such as investigations in epidemiologic studies. The described assay is based on ED-LC-MS/MS. FT4 in serum was isolated from protein-bound T4 in serum according to the CLSI C45-A guideline. FT4 levels achieved equilibrium in a commercially available micro-ED plate after 18 hours. The dialysate was collected and spiked with internal standard (13 C 6 -T4). The IRMM-468 certified primary reference material (JRC, Belgium) of T4 was used for assay calibration. FT4 in dialysate was extracted with ISOLUTE-96-well C18 SPE plates (Biotage) before LC-MS/MS analysis. T4 could be resolved from Triiodothyronine (T3), reverse triiodothyronine (rT3), and other interferences in the dialysate on a C18 UPLC column with an elution time of less than 8 min. Selective reaction monitoring in positive electrospray ionization mode was used for detection. The measuring range covered 1-100 pg/mL of FT4. The assay sensitivity allowed detection of 0.5 pg/mL FT4, which is sufficient for detection of FT4 in normal and hypothyroid patient samples. The difference of this method to the CDC FT4 RMP was within ±5%. The imprecision of the routine assay, evaluated over four different days, was less than 10% CV. The slopes of calibration curves in dialysate matrix and water were comparable with each other indicating no significant matrix effect on FT4 quantification. The use of micro-ED plates in combination with an automated liquid handling system allows for effective automation of the procedure. The stability of T4 calibrator stock and working solutions were confirmed at various conditions. Currently, a comprehensive comparison study is underway between the newly developed routine method and the CDC FT4 RMP. The described routine FT4 assay can significantly improve throughput. The sensitivity, precision, and accuracy are suitable for routine FT4 measurements in clinical laboratories and conducting large epidemiologic studies. Applying this FT4 routine method to generate population data will support the use of standardized FT4 measurements and to address data needs on FT4 in general population.

Presentation: No date and time listed
ODP482 Graves Orbitopathy Secondary to Alemtuzumab Infusion for Multiple Sclerosis
Authors: Alam Mustafa , Abdelrahim Baha , Hosam Horani Mohamed
Published: November 2022

Presentation: This is a 51-year-old male with a history of Graves disease who presented to the ED with worsening proptosis and 10/10 eye pain. He reported being unable to shut his eyes, photophobia, decreased vision, and extreme eye sensitivity to touch. He was initially diagnosed with Graves disease 3 months ago, after which he was started on Methimazole 15mg 3x a day. Patient has a history of multiple sclerosis treated with an Alemtuzumab infusion 6 months ago. He additionally reports a history of depression, smoking, and alcoholism. Hospital Course: The patient presented with stable vitals signs with T: 36.5 C, HR: 97, BP: 117/68, O2 Sat 98% on RA. Physical exam was notable for Va: 20/100 OD, 20/200 OD with near card Sc. The R pupil was dilated Nr OU. EOM exam was notable for restricted ductions in all fields of gaze OU. IP was 20 mmHg OD and 22mmHg OS with Toponen 95%. Significant Proptosis OS more than OD with resistance to retropulsion. Bilateral conjunctival erythema with clouded corneas. Labs were significant for Hgb 12.2, MCV 80, Plt 342, ANC 12.1, Creatinine 0.69, albumin 2.8, Alk Phos 158, CK 41, FT4 0.53, TSH 0.318, and FT3 1.63. An US of the thyroid was significant for thyromegaly and a 5mm right thyroid nodule. A CT Orbit/Sella was significant for thyroid associated orbitopathy with greater exophthalmos on the left and maxillary sinusitis. The patient received 1000mg Rituximab infusion and IV Decadron every 4 hours with referral for possible thyroidectomy, orbital decompression as per ophthalmology, and continued multiple sclerosis management as per neurology.

Discussion

This complex case highlights worsening Graves orbitopathy as a rare side effect of Alemtuzumab. This orbitopathy persisted despite high dose methimazole. Urgent IV Decadron with orbital decompression should be considered in the acute setting with thyroidectomy for symptom resolution.

Presentation: No date and time listed
ODP485 Hyperthyroidism with Concurrent Thyroid Cancer: Causal Relation or Incidental Association?
Authors: Calin Cristiana , Ioana Dumitriu Roxana , Florentina Burcea Iulia , Poiana Catalina
Published: November 2022

Introduction

Thyrotoxicosis caused by Graves’disease (GD),toxic multinodular goiter (TMG) andtoxic adenoma (TA) can be associated with thyroid carcinoma; furthermore, tumors arisen in hyperthyroid tissue show an aggressive behavior (1).

Objective

To determine the incidence of thyroid carcinoma in thyrotoxic patients who underwent thyroidectomy and to analyzethe relationship between thyroid cancer, hyperthyroidism and outcomes of hyperthyroid versus euthyroid patients.

Materials and Methods

We retrospectively studied 304 consecutive hyperthyroid patients who underwent total thyroidectomy, presented in our institute between 2016 and 2021. The indications for surgery were GD (n=167, 3 of them were classified as Bethesda V on the basis of fine needle aspiration biopsy cytological examination prior to surgery), TMG (n=117) and TA (n=20).

Results

The incidence ofthyroid carcinoma in hyperthyroid patients was 18.1% (n=55) and was more common in patients with TMG (19.7%) and GD (18.6%), than in those with TA (5%). According to the post-surgical histological examination 41 patients were diagnosed with papillary thyroid carcinoma (92.7%), 2 patients were diagnosed with follicular thyroid carcinoma (3.6%), 1 patient with undifferentiated thyroid carcinoma (1.8%), and another patient with medullary thyroid carcinoma (1.8%). Papillary thyroid microcarcinoma accounted for 58.2% of all histological types. Lymph node involvement was found in 22% of the patients with GD, in 13% of those with TMG, and in none of those with TA. Distant metastases were found in 2 patients with GD and in other 2 patients with TMG. Compared with a similar group of 120 euthyroid patients who underwent surgery for thyroid cancer during the same time period, the patients with hyperthyroidism have a 3.4 times greater risk for developing lymphovascular metastases compared to euthyroid subjects (23.6% vs 8.3%, p=. 008).

Conclusion

Our study showed that thyroid cancers in hyperthyroid patients have an aggressive behaviour, with a worse prognosis than euthyroid patients. A carefully evaluation of all patients with hyperthyroidism is needed to exclude the presence of concurrent malignancy. Routine thyroid ultrasonographic (US) scans and US-guided FNAB should be considered for complete evaluation of hyperthyroid patients. Reference: Medas F, Erdas E, Canu GL, Longheu A, Pisano G, Tuveri M, Calò PG. Does hyperthyroidism worsen prognosis of thyroid carcinoma? A retrospective analysis on 2820 consecutive thyroidectomies. J Otolaryngol Head Neck Surg.2018 Jan 22;47(1): 6.

Presentation: No date and time listed
ODP491 Levothyroxine Withdrawal Presenting as Myxedema Madness
Authors: Trusty Rhonda-Kaye , Bagar Darin , Kirupakaran Johnathan , Adoulphous Ifediba Nwachukwu , Rodriguez Giovanna , Bahtiyar Gul
Published: November 2022

Introduction

Myxedema coma, a medical emergency, refers to severe hypothyroidism which can be precipitated by several factors including acute infection, myocardial infarction, and hypothermia. Rarely, patients may present with myxedema psychosis which manifests as suicidal ideations, hallucinations and or delusions.

Case Presentation

A 60-year-old woman with a history of hypertension, hypothyroidism, anxiety disorder and heroin abuse on methadone 50 mg every day presented to the hospital with acute onset of altered mental status. Per the patient, she called 911 for "cardiac arrest and talking about dead bodies". Upon presentation, the patient was hypertensive, 184/124mmHg. Physical exam was notable for active hallucinations. She was alert and oriented to person and place, with an unsteady gait. Laboratory examination was remarkable for hyponatremia 131 mmol/L (137-147 mmol/L). She received workup for acute encephalopathy and ED physicians determined that if the workup was negative, she should be evaluated by Psychiatry. Infectious processes and drug intoxication/overdose were ruled out. Psychiatry determined that the patient's psychosis was due to an organic etiology. Follow-up laboratory showed TSH 155 ulU/mL (0.350-4.80 ulU/mL), free thyroxine 4 < 0.1 ng/dL (0.90-1.8 ng/dL) and thyroid peroxidase antibody 460 IU/ml (<34.9). While in the ICU, she became bradycardic, heart rate 25 bpm, and hypoxic, O2 saturation ∼ 75%. She was placed on nasal cannula with improved oxygenation. Later she experienced two seizures lasting approximately 1 minute. The patient received stress dose steroids intravenously every 8 hours and levothyroxine intravenously. Adrenal insufficiency workup was within normal limits. On hospital day 3, her mental status improved and she was transitioned to oral levothyroxine. The patient was transferred to the medical floor for further care. Upon questioning, she reported she stopped taking her levothyroxine for approximately 6 months. Her delusions decreased and later resolved on hospital day 10. She was discharged home with 100 mcg oral levothyroxine and outpatient follow-up with Endocrinology.

Conclusion

Our patient presented with a rare manifestation of severe hypothyroidism, myxedema madness. The relationship between psychosis and thyroid dysfunction has long been documented. In the same period, there has only been a few reported cases of myxedema madness in literature, generally reported in Psychiatric journals. This is surprising, given that these are endocrinological emergencies. Importantly, patients with an acute presentation of psychosis, should be tested for thyroid abnormalities, as this is reversible. In our patient's case, she had no previous documented psychiatric history. It is reasonable therefore to conclude that, herlikely myxedema madness resulted from prolonged thyroid replacement non-compliance.

Presentation: No date and time listed
ODP495 Medullary Thyroid Cancer Outcome in a Tertiary Care Centre in Atlantic Canada
Authors: Rajaraman Kye , Devereaux Emily , Rajaraman Murali , Imran Syed
Published: November 2022

Background

Medullary thyroid carcinoma (MTC) constitutes around 1-2% of all thyroid cancer with a paucity of published data. Distinctively, MTC has a strong genetic component with oncogene mutations. For AJCC stages I, II, III, and IV, 5-year overall survival (OS) rates are 100, 90, 86.5 and 55.5%. The aims of this study are to report outcomes of the MTC patient cohort managed at a single tertiary cancer centre and specifically that of the subset of patients who have a biochemically incomplete response to primary surgical management.

Objectives

Explore the incidence and outcome of MTC including demographics, stage, genetic mutation status, dynamic risk stratification (DRS), and OS rate. Compare the outcome of MTC patients found to have low detectable post-op calcitonin (POC) levels (10-200 pg/ml=Grp B)) with those who have undetectable (< 10 pg/ml=Grp A) and significantly high-level POC levels (>200 pg/ml=Grp C).

Methods

Patients with MTC were identified from the Interdisciplinary Thyroid Oncology Clinic (ITOC) prospective database. Data was extracted and completed with a chart review.

Results

35 cases with MTC were identified from 1570 cases. 21/35 were males. The diagnosis was made between 1988 and 2019 with a median age at diagnosis of 50 years (range=15 to 77) and a median follow-up of 8 years. Distribution (and 5-year OS, p=0.515) across Stages I, II, III, IV were 23% (100%), 14% (100%), 17% (100%) and 32% (90%) respectively with 14% unknown. 10 (29%) tested positive for RET gene mutations. Post-operative DRS response to initial treatment for 29 cases found 48%, 35%, and 17% were classified into excellent (E=undetectable calcitonin), biochemical incomplete (B=only detectable calcitonin), or structural incomplete (S=structural disease present) respectively. The 29 cases with available POC and DRS were divided into Groups A, B, and C based on POC levels as above. The final status at last follow up for Grp A was 13/14 (93%) with E and 1 (7%) with S, for Grp B 6/9 (67%) with B, 3/9 (33%) with S, and for Grp C 6/6 (100%) with S. The DRS for Grp A, B and C was 100% E, 89% B and 11% S, and 33% B and 67% S. The 5-year OS for Grp A, B, C was 100%, 89%, 100% (p=0.223) respectively.

Conclusion

This cohort of MTC cases failed to show significant differences in OS by stage and POC levels but did exhibit a higher rate of genetic mutations (29%) than those from other regions of Canada. Additionally, a biochemically incomplete response with a POC level above 200 pg/ml was highly suggestive of progressive structural disease as final outcome. This study will provide the template for a national survey of MTC in Canada facilitating analysis of a larger dataset.

Presentation: No date and time listed
ODP497 Multifocal Papillary Thyroid Carcinoma with Anaplastic Dedifferentiation
Authors: Jacinto Jorg Jurgen N , Isidro Maria Jocelyn C
Published: November 2022

A 71-year old male with a two-year history of progressively enlarging right thyroid mass presented with hemoptysis. Chest CT scan showed multiple pulmonary nodules and enlarged right thyroid mass with intrathoracic extension. A fine needle biopsy of the right thyroid mass showed atypia of undetermined significance. Patient underwent total thyroidectomy and complete resection of the intrathoracic component. Histopathology reported multifocal Papillary thyroid carcinoma, right lobe, encapsulated follicular variant (9cm) with extensive and vascular invasion. There was also invasion of the left thyroid lobe, follicular variant, infiltrative (0.6 cm) and conventional (0.6 cm). Extrathyroidal extension to skeletal muscle and lymphovascular invasion was present. The tumor showed areas with more solid growth patterns and some ball-like clustering. Consequently, immunostaining was done which showed the following results: positive for cytokeratin, thyroglobulin and TTF-1 consistent with papillary morphology. The more solid areas with significant nuclear pleomorphism, necrosis and increased mitotic activity (atypical forms) support the focal progression to an anaplastic carcinoma. The final histologic reading showed multifocal papillary thyroid carcinoma with focal (20%) progression to undifferentiated (anaplastic) thyroid carcinoma. Two weeks postoperatively, he developed a 4cm×2cm manubrium mass. There were also several metastases on the brain, pancreas, liver and bones seen on FDG PET scan. One month postoperatively, TSH was 15 uIU/mL Thyroglobulin >500 uIU/mL, anti-thyroglobulin <0.20 ng/dl. Due to the widespread metastases even involving the brain, the multidisciplinary team decided to start treatment with Lenvatinib and check for BRAF V600E gene mutation for a more definitive treatment. He was started on Levothyroxine. He also underwent 27 cycles of radiation therapy to the manubrium mass and was given Denosumab 120mg subcutaneously to stabilize the bone and provide pain relief. BRAF gene mutation analysis result came back negative in two weeks. Close monitoring of his sensorium was done. However, he deteriorated clinically and he succumbed to sudden cardiac death two months after.

Presentation: No date and time listed