bluuebunny/crossref_metadata_2025_split huggingface dataset:
LBODP008 Gene Therapy For Congenital Adrenal Hyperplasia With AAV Vectors Into Fibroblasts, IPS Cells And Model Mice
Authors: Naiki Yasuhiro , Miyado Mami , Horikawa Reiko , Katsumata Noriyuki , Takada Shuji , Akutsu Hidenori , Onodera Masafumi , Fukami Maki 
Published: November 2022

Abstract

Background
Congenital adrenal hyperplasia (CAH) is due to defects of steroid synthetic enzymes, which includes microsomal and mitochondrial P450s. Microsomal P450s include 21-hydroxylase and 17α-hydroxylase/17-lyase. 21-hydroxylase deficiency (21-OHD), in which CYP21A2 is mutated or deleted, is the most common cause of CAH and results in underproduction of glucocorticoids and mineralocorticoids, and overproduction of androgens. 11β-hydroxylase deficiency (11β-OHD), which is a defect of a mitochondrial P450, is the second common cause of CAH. Patients with CAH are treated with oral steroid supplementation, but optimal control of blood steroid levels remains difficult. Thus, new therapeutic approaches are still needed. Intravenous adeno-associated virus (AAV)-mediated administration of human CYP21A2 into adult 21-OHD patients has been reported at the ENDO 2021 meeting. In this study, we examined the effects of induction of causative genes with an AAV vector into fibroblasts from patients and iPS cells and adrenal glands of model mice.

Methods
Fibroblasts from CAH patients were subjected to primary culture. The cells were infected with a serotype-2 AAV vector (AAV2) containing defected genes and cultured in steroid substrate-containing medium for 24 hours. We measured steroid metabolites in the medium by liquid chromatography tandem mass spectrometry and evaluated gene expressions by RT-PCR. In addition, iPS cells were established from fibroblasts of 11β-OHD and differentiated into adrenocortical cells with retinoic acid and cAMP. They were infected with a serotype-9 AAV vector (AAV9) containing CYP11B1 cDNA. Steroid metabolites in the culture medium were measured and gene expressions were evaluated by RT-PCR. 11β-OHD model mice were made by a gene-editing method. We injected AAV9 containing Cyp11b1 cDNA into the adrenal gland and measured serum DOC and corticosterone levels before and every 4 weeks after injection.

Results
AAV2 infected fibroblasts from 21-OHD and 17α-hydroxylase/17-lyase deficiency can metabolite steroid precursors but failed to convert DOC to corticosterone in 11β-OHD. Differentiation into adrenocortical cells from iPS cells of 11β-OHD was confirmed by expression of CYP21A2. AAV9 gene induction of adrenal cortical cells successfully induced 11β-hydroxylase activity. 11β-OHD mice also showed improved steroid synthesis after AAV9 adrenal induction.

Conclusion
These results indicate that extra-adrenal induction of CYP21A2 may ameliorate steroid metabolism in 21-OHD patients. In contrast, 11β-OHD needs AAV9 adrenal induction to treat the steroid abnormality. Our results suggest that specific gene therapeutic strategies are needed to be adapted for each type of CAH.
Presentation: No date and time listed
PSAT037 The Unlikely Suspect - A New Diagnosis of Autoimmune Addison's Disease in an 80-year old Lady
Authors: Carroll Dylan , Sharma Pranjali 
Published: November 2022

Abstract

Introduction
Hyponatremia is a common cause of hospitalization in older adults. Addison's disease (AD), an uncommon cause of hyponatremia, is primary adrenal insufficiency (AI) caused by autoimmune adrenalitis, infections, adrenal hemorrhage, or infiltration. Autoimmune adrenalitis is an uncommon cause of AD after age 60 years. We report an 80 year old patient with hyponatremia who was ultimately diagnosed with autoimmune AD.

Case report
An 80 year-old lady with steroid-controlled asthma, presented to the ER with weakness, imbalance, nausea and vomiting two weeks after a urinary tract infection. Her blood pressure was 96/64 mm Hg with otherwise normal vital signs and unremarkable general examination. Laboratory evaluation revealed hyponatremia (Na 120 mmol/L), hyperkalemia (K 5.7 mmol/L) and acute kidney injury (creatinine 1.2 mg/dl, GFR 43 ml/min/m). Hyperkalemia resolved with intravenous fluids, insulin and dextrose therapy (K 4.7 mmol/L). However, hyponatremia persisted (Na 120-123 mmol/L) despite fluid restriction, normal saline, and salt tablets. Additionally, patient remained hypotensive with blood pressure between 90/40-120/60 mm Hg. Due to concern for AI from prior steroid use, morning cortisol was measured and was low (4.63 mcg/dl). Concurrent ACTH level was elevated (252 pg/ml, range 7.2-63.3 pg/ml). Cosyntropin stimulation test done during hospitalization was abnormal (4.5 mcg/d→6.7 mcg/dl→8 mcg/dl) confirming AD.
At outpatient consultation with endocrinology, patient reported nausea and vomiting for 18 months prior to hospitalization, 50 lbs weight loss, weakness, short-term memory loss, and dizziness attributed to vertigo. Symptoms worsened a month prior to patient's hospitalization. Repeat cosyntropin stimulation test remained abnormal (8.5 mcg/dl→9.6 mcg/dl→10 mcg/dl). CAT scan of the abdomen with adrenal protocol was unremarkable for adrenal masses, hemorrhage, infiltration, or metastasis. Surprisingly, 21-hydroxylase antibody testing was positive confirming autoimmune AD. The patient has been on hydrocortisone 15 mg in AM + 5 mg in PM and fludrocortisone 0.1 mg daily for one year now with improvement in symptoms.

Discussion
Medications, poor diet, and diabetes are common causes of hyponatremia in the elderly. AD, an uncommon cause of hyponatremia, should be considered in a hospitalized hyponatremic elderly patient. Non-specificity of AD symptoms makes the diagnosis in this age group difficult, often causing delay in appropriate management.
Autoimmune AD is characterized by the presence of 21-hydroxylase antibodies. Data on autoimmune AD incidence in the elderly is limited due to rarity. Our patient's autoimmune AD was likely masked due to steroid use for asthma. During COVID-19 pandemic, masking, and social distancing decreased the patient's steroid needs and unmasked AD after the UTI. Our case highlights the importance of considering autoimmune AD as a cause of AI even in the elderly.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT041 A Rare Case of Severe Cyclical Cushing Syndrome Due to Ectopic ACTH Secretion by Appendiceal Carcinoid
Authors: Sidra Fnu , Hamidi Oksana , Nwariaku Ohwofiemu , Mirfakhraee Sasan , Jia Liwei , Polanco Patricio 
Published: November 2022

Abstract
Cushing syndrome (CS) secondary to ectopic ACTH secretion (EAS) is rare and accounts for 10% of CS with majority being bronchial or gut neuroendocrine tumors (NETs) and squamous cell lung cancer. There are only a few case reports of EAS due to appendiceal carcinoid.
A 24-year-old woman was referred to endocrinology for 60-pound weight gain, acne, hirsutism, generalized weakness, heat intolerance, and hot flashes. She had secondary amenorrhea for 6 months prior to presentation. Family history was significant for bronchial carcinoid in mother. On examination, she had moon facies, wide purple striae on abdomen, hirsutism, dorsocervical and supraclavicular fat pads. She had normal blood pressure. Her laboratory workup showed potassium 3.2 mmol/L (N, 3.5-5.3), urine free cortisol (UFC) 539 mcg/24 hours (N&lt;50), ACTH 54 pg/ml (N, 6-50) and post 1-mg dexamethasone suppression test cortisol 8.8 mcg/dL. CT abdomen revealed a 3-cm enhancing appendiceal mass, enlarged periappendiceal mesenteric lymph nodes and a 4-cm enhancing right hepatic lobe lesion. Ga-68 Dotatate PET/CT confirmed increased radiotracer uptake in appendiceal mass, lymph nodes and hepatic mass. On liver biopsy, pathology showed well differentiated NET Grade 1 and positive ACTH stain. Repeat UFC was 65 mcg/24 hrs and serum cortisol went down to &lt;1 mcg/dL indicating severe cyclical CS. She was referred to surgical oncology for opinion on debulking surgery. Her genetic testing was negative. She was started on Lanreotide. Given severe cyclical CS with extensive tumor burden, she underwent robotic bilateral adrenalectomy with a plan for cytoreductive surgery once she is on physiologic doses of steroids.
Appendiceal NET causing Ectopic CS is exceedingly rare. In 20 years’ experience at NIH, there was only one case of appendiceal NET reported. First reported case was in 1971, when CS was cured by resection of an appendiceal carcinoid incidentally detected on laparotomy for adrenalectomy. There are 3 additional case reports in literature of appendiceal carcinoid with ectopic CS. Management can be challenging particularly in patients with metastatic disease. Medical therapy should be individualized, and adrenalectomy should be considered early in patients with uncontrolled CS due to EAS.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT045 Spontaneous Adrenal Hemorrhage with Partial Adrenal Insufficiency in a Patient Anticoagulated with Apixaban for Antiphospholipid Syndrome
Authors: Hu Jiun-Ruey , Tan Jiawei 
Published: November 2022

Abstract

Background
Addison's disease secondary to adrenal hemorrhage is a rare complication of antiphospholipid syndrome (APLS). Anticoagulation with a direct oral anticoagulant (DOAC) might increase the risk of adrenal hemorrhage. We report a patient who developed bilateral adrenal hemorrhage after starting apixaban for deep venous thrombosis (DVT) and pulmonary embolism (PE) in the setting of latent APLS.

Clinical Case
A 45-year-old man without significant past medical history presented with a left lower extremity DVT and PE. He had no personal or family history of previous trauma, bleeding or clotting events. He was discharged on apixaban. Three days later he was readmitted with bilateral flank pain. Computerized tomography (CT) imaging showed bilateral adrenal gland edema. He was hemodynamically stable. Due to persistent right flank pain and concern for ileus, CT was repeated and revealed findings concerning for adrenal hemorrhage. He subsequently complained of asthenia. Further testing revealed a reduced morning cortisol of 1.4 ug/dL (reference: 6.0 - 18.4 ug/dL) and an elevated morning ACTH of 149 pg/mL (7.2-63.3 pg/mL). Plasma dehydroepiandrosterone sulphate (DHEA-S) was reduced at 39 mcg/dL (70 - 495 mcg/dL), and epinephrine and norepinephrine were undetectable. Morning plasma aldosterone was undetectable and renin activity was 0.76 ng/mL/h (0.25 - 5.82 ng/mL/h). He was started on stress dose steroids and discharged on maintenance hydrocortisone without reinitiating anticoagulation.
Two weeks later, he re-presented with a right lower extremity DVT. An APLS panel revealed elevated anti-beta2 glycoprotein 1 IgG and anti-cardiolipin IgG. Laboratory work-up for other causes of thrombosis, including inherited and acquired thrombophilias, anatomical vascular obstruction, paroxysmal nocturnal hemoglobinuria (PNH), heparin-induced thrombocytopenia (HIT), and myeloproliferative neoplasms (MPN), was unrevealing. Warfarin was started with an international normalized ratio (INR) target range of 2-3. Hydrocortisone was continued at a total daily dose of 30mg. Since discharge, his morning cortisol levels have been low at 4.4-4.9 ug/dL and ACTH has remained high at 92-137 pg/mL, but aldosterone has been variable at &lt;1 to 9 ng/dL, and renin has been normal at 0.35 ng/mL/h. This suggests what transpired had been microthrombi-associated intra-adrenal hemorrhage involving the zona fasciculata with sparing of the glomerulosa.

Conclusion
This case highlights DOAC-associated adrenal hemorrhage in a patient with underlying APLS, an under-appreciated complication. The extent to which the various layers of the adrenal gland are affected may vary. Since guidelines on the management of patients with partial adrenal insufficiency are lacking, further reporting is needed on long term outcomes and adrenal function of these patients.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT055 ACTH-Dependent or ACTH-Independent: The Importance of a Reliable ACTH Assay in Solving a Case of Cushing Syndrome
Authors: Duro Teodor , Lovato Christina 
Published: November 2022

Abstract

Background
Reliable laboratory assays are of paramount importance in the field of endocrinology, as our ability to make diagnoses and recommend the appropriate treatment, rely heavily on them.

Clinical Case
A 36-year-old woman presented to our clinic with a history of a 30-pound weight gain over the course of a year and hypertension that was sub-optimally controlled on two antihypertensive medications. On physical exam she exhibited facial plethora, moon facies, central obesity, dorsocervical fat pad, and reddish abdominal striae. Laboratory data revealed a 24 hr urine free cortisol 277 mcg/24 h (n ≤ 45 mcg/24 h), 8 am cortisol after 1 mg dexamethasone suppression test 19.2 mcg/dL (cut-off &lt;1.8 mcg/dL) with a dexamethasone level 179 ng/dL (n 140-295 ng/dL). Serum DHEAS &lt;15 mcg/dL (n 35-430 mcg/dL) which was suggestive of an adrenal source of cortisol. CT scan of the adrenals revealed a 3.0×2.3 cm right adrenal nodule, 14 HU, relative washout of 58%, absolute washout of 68%, consistent with an adenoma. However, plasma ACTH was 20 pg/mL (n 0-46 pg/mL) which was suggestive of an ACTH-dependent etiology. Repeat ACTH levels through our local lab ranged between 17-27 pg/mL. An MRI of the brain was obtained which showed a normal pituitary gland without evidence of an adenoma.
Due to the discrepancy between the clinical picture and the ACTH levels, the patient's case was discussed with the medical director of our local lab. It was decided to obtain another sample for ACTH which was tested for heterophile antibodies but did not yield any meaningful results. The patient denied being on any supplements that could interfere with the ACTH assay. The sample was then sent out to an outside lab with a plasma ACTH level &lt;1 pg/mL (n 7.2-63 pg/mL), which was consistent with the patient's clinical presentation of an adrenal source of cortisol excess. Further investigation revealed that our local lab used a Siemens Immulite assay which was likely detecting interference, whereas the outside lab used the Roche Elecsys assay. In previous studies, the Roche assay has highly correlated with intact ACTH that has been measured by HPLC-MS/MS. The patient was started on ketoconazole and has been referred for right adrenalectomy.

Clinical Lessons
Heterophile antibodies and ACTH fragments are common culprits of ACTH immunoassay interference, but they can be difficult to detect if there is not a high index of suspicion. Erroneous laboratory results can lead clinicians to perform unnecessary procedures and delay patient care. This case highlights the importance of a reliable plasma ACTH assay to inform clinical judgment.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT085 Monoclonal Cortisol Immunoassay Cut Off Point to Diagnose Adrenal Insufficiency (AI)
Authors: Cortez Samuel , McNerney Kyle , Arbelaez Ana Maria 
Published: November 2022

Abstract

Objective
Adrenal Insufficiency (AI) is diagnosed when the peak cortisol level after a cosyntropin stimulation test is &lt;18 mg/dL using a standard reference (e.g. polyclonal antibody (pAb) immunoassay). However, in most laboratories the polyclonal assay is being replaced by a specific monoclonal antibody (mAb) immunoassay which yields lower cortisol levels, leading to the over diagnosis of AI and unnecessary steroid use.

Methods/Study Population
We obtained blood samples from 36 patients undergoing 1 mcg cosyntropin stimulation tests for diagnosis of AI. Samples were analyzed using pAb immunoassay (Abbott Architect Cortisol), mAb immunoassay (Roche Elecsys Cortisol II), and mass spectrometry (MS). AI was diagnosed if serum cortisol level was &lt;18 using the pAb immunoassay. Measurements by MS and mAb immunoassay were individually used in simple logistic regression models to predict AI. For each model, we calculated a cortisol level corresponding to a 50% probability (median) of AI and used the delta method to determine the standard error and 95% confidence interval of the median. We used receiver operator characteristic (ROC) curve, area under the curve, sensitivity, and specificity to evaluate the potential of the median values as thresholds for each predictor.

Results
The ROC curve model indicated an area under the curve of 0.997 with a median value of 11.2 mcg/dL for the mAb immunoassay. This provides a sensitivity of 95%, specificity of 95%, positive predictive value of 95%, and negative predictive value of 94%. This new value has a Kappa coefficient of 0.89 when compared to the pAb immunoassay. When using all the data points throughout the stimulation test, data showed a mean difference in cortisol level between the mAb immunoassay and the pAb immunoassay of 5.12 mcg/dL (p-value &lt;0.01) at any point during the test.

Discussion/Significance
New and highly specific mAb immunoassays are being used more widely but yield lower cortisol results. This reflects the need for further studies to determine new cut off points for highly specific cortisol immunoassays. A cut off level of 11.2 mcg/dL for the mAb immunoassay would provide a sensitivity of 95% and specificity of 95%.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
RF33 | PSUN02 Presentation, Management, and Outcomes of Urinary Bladder Paraganglioma: Results from a Multi-center Study
Authors: Yu Kai , Yu Kai , Ebbehoj Andreas Ladefoged , Obeid Hiba , Vaidya Anand , Else Tobias , Wachtel Heather , Main Ailsa Maria , Sondergaard Esben , Christensen Louise Lehmann , Juhlin Christofer , Calissendorff Jan , Cohen Debbie , Bennett Bonita , Andersen Marianne Skovsager , Larsson Catharina , Almeida Madson Q , Boorjian Stephen A , Young William F , Bancos Irina 
Published: November 2022

Abstract

Context and Objectives
Urinary bladder paraganglioma (UBPGL) is rare. We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL.

Methods
We conducted a multi-center study of consecutive patients with pathologically-confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality.

Results
110 patients (56, 51% women) were diagnosed with UBPGL at a median age of 50 years (IQR, 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after initial diagnosis. Development of metachronous metastases was associated with younger age (Hazard ratio, HR 0.97, 95%CI 0.94-0.99), UBPGL size (HR of 1.69, 95%CI of 1.31-2.17), and a higher degree of catecholamine excess (HR of 5.48, 95%CI of 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR of 20.80, 95%CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality.

Conclusions
Only a minority of patients were diagnosed before biopsy/surgery, reflecting the need of better diagnostic strategies. All patients with UBPGL should be monitored life-long for development of recurrence and metastases.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.
LBSAT230 Daily Variation In Serum Calcifediol In Japanese And Non-japanese Adults
Authors: Ashfaq Akhtar , Strugnell Stephen A , Tabash Samir , Bishop Charles W 
Published: November 2022

Abstract
Circadian rhythm and 24-hour intra-subject variation in serum calcifediol (25-hydroxyvitamin D3) in the absence of vitamin D supplementation or treatment are poorly studied in healthy adults of any race. To address this dearth of information, a single-center, open-label study was completed in the US to evaluate both of these parameters in 67 male and female (balanced for gender) first generation Japanese (n=35) and non-Japanese (n=32) subjects, aged between 18 and 55 years. "First generation" was defined as: born in Japan; had 2 Japanese biological parents and 4 Japanese biological grandparents; had lived outside of Japan for less than 5 years; and, had made no significant changes in lifestyle, including diet, since leaving Japan. "Non-Japanese" was defined as: not of Japanese or Asian descent; and, parents and grandparents were not born in Japan or in any Asian countries. Enrolled subjects had a body mass index within 18. 0 to 30. 0 kg/m2 (inclusive) and body weight not less than 50 kg. The body weight for non-Japanese subjects was 9% to 17% higher than that of Japanese subjects (60.3 to 92.9 kg versus 51.2 to 84.9 kg). Exclusion criteria included consumption of a vitamin D supplement within the previous 28 days, consumption of grapefruit or oranges, alcohol, medications or tobacco within the previous 72 hours, and participation in strenuous physical activity within the previous 72 hours. Subjects were housed in a Phase 1 unit for 2 days where they received only standardized diets. Blood samples were collected on the second day at 0, 2, 4, 6, 8, 10, 12, 16 and 24 hours for determination of serum calcifediol by LC/MS/MS (mean accuracy: 0.37%; mean precision: 3. 07%) at Syneos Laboratories (Quebec, Canada). For all subjects, mean serum calcifediol levels ranged from 20.90 to 22.24 ng/mL over the 24-hour collection period with an average inter-subject variation (SD) of 6.79 ng/mL. A circadian rhythm was not evident either in the total population or in the racial subgroups. Mean intra-subject variation over 24 hours was 1. 08 ng/mL (SD; range: 0.27-3.22) or 5. 05% (CV; range: 2.36-14.81). Differences in 24-hour intra-subject variation between races were not significant (P&gt;0. 05). These data support the conclusions that: (1) clinically meaningful circadian rhythms in serum calcifediol are absent in healthy first generation Japanese and non-Japanese adults living in the US; (2) the mean diurnal variation in serum calcifediol is small (approximately 5%); and (3) vitamin D therapies may appropriately be considered "physiological" if they raise serum total 25-hydroxyvitamin D after each dose only within the bounds of normal diurnal variation thereby allowing gradual adaptation to repletion.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.