bluuebunny/crossref_metadata_2025 huggingface dataset:
RF21 | PSAT77 ROLE OF THE TRANSCRIPTION FACTOR HHEX IN INNER ADRENAL CORTEX HOMEOSTASIS AND RESPONSE TO PROGESTERONE SIGNALING
Authors: Dumontet Typhanie , Basham Kaitlin , Lerario Antonio , Bothou Christina , Brixius Bjoern , Turcu Adina F , Beuschlein Felix , Hammer Gary D
Published: November 2022

Congenital adrenal hyperplasia (CAH) is a set of defects in cortisol synthesis due to mutations in genes encoding steroidogenic enzymes. Consequently, the loss of glucocorticoid-mediated negative feedback on the HPA axis leads to chronically elevated ACTH (Adrenocorticotropin Hormone) secretion. The sustained ACTH elevation, in turn, stimulates proliferation and hypertrophy of the adrenal cortex and leads to overproduction of androgens.

To study the complexity of the ACTH-responsive cell population in the adrenal cortex, we performed single-cell RNA sequencing of the steroidogenic lineage in the adult mouse adrenal. We identified the transcription factor HHEX as a gene with restricted expression in the ACTH-responsive zona fasciculata. Although the role of HHEX in adrenal biology is completely unknown, a meta-analysis identified a germ-line variant of uncertain significance near the gene HHEX associated with increased DHEAS (adrenal-specific androgen) in human serum samples, which led us to hypothesize that HHEX contributes to the unique function of the ACTH-responsive inner cortex.

To investigate the mechanisms by which HHEX controls adrenal differentiation and homeostasis, we generated genetically modified mice harboring a deletion of the Hhex gene in the adrenal cortex. Hhex KO mice exhibited progressive adrenomegaly by 15 weeks of age, accompanied by hypertrophy prominent in the inner cortex and disruption of the endothelial organization. Expression of the transcription factor Nr5a1/Sf-1 and steroidogenic enzymes involved in corticosterone production were significantly upregulated at 6 weeks old, prior to adenomegaly, suggesting a precocious increase in cell production of glucocorticoids. For insights into the signaling pathways controlled by HHEX, we analyzed global transcriptional changes during loss of Hhex and found dramatic downregulation of members of the membranous progesterone receptor family (PAQR). PAQR signaling has been implicated in the downregulation of cAMP, a primary mediator of ACTH signaling, and thereby could, in part, drive the increase in steroidogenesis in Hhex KO mice.

These findings suggest that the inner cortex contains a progesterone-responsive cell population in which HHEX provides additional fine-tuning of ACTH-driven cAMP signaling by progesterone and derivatives. Since we observed an increase in Hhex expression in a mouse model of CAH, experiments are now ongoing to assess the implication of HHEX and autocrine progesterone signaling in contributing to the hypertrophy and steroidogenic phenotype observed in CAH.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.
RF21 | PSAT90 Lineage Tracing Sonic Hedgehog-Expressing Cells in Adrenal Glands in Post-Weaning Mice
Authors: Laprocina Kari , Zheng Huifei Sophia , Kang Yuan , Huang Chen-Che Jeff
Published: November 2022

The Sonic Hedgehog (Shh) gene expressed in the subcapsular cortical region of the adrenal gland has been found to play a role in adrenal gland development. The Shh(+) cell population at the fetal stages contributes to different cortical layers in the adrenal gland. However, the (1) capability of these cells after weaning and (2) how soon they can renew the adrenal cortex in the postnatal stages is not fully understood. Here, we conducted a lineage tracing experiment to track Shh(+) cells and cells descended from them in post-weaning mice to ultimately better understand the processes of adrenal cortex renewal and remodeling over time in young adult mice.

This experiment used the NuTRAP; Shh-Cre-ERT2 mice as the Shh-reporter mouse model. This tamoxifen-inducible mouse model allows us to specifically target and label Shh-expressing cells and all descendant cells with green fluorescence. Tamoxifen was given at postnatal days (P) 22, P24, and P26 to enable the Cre recombinase activity driven by the Shh promoter. Adrenal glands were then analyzed after two and four months. This lineage tracing experiment found that Shh(+) cells and their descendant cells reached the margin of the Cyp2f2(+) cortical zone in 2 months and the cortical-medullary boundary in 4 months. This finding indicates that the Shh(+) cell population in post-weaning mice can proliferate, differentiate, and eventually renew the entire adrenal cortex over a four-month period of time.

Understanding the adrenal cortex's renewal rate helps us design our follow-up study to test the capability of Shh(+) cells in adult mice at different ages and how their potency changes overtime at the 'omic' level. Because this NuTRAP;Shh-Cre-ERT2 mouse model also allows us to isolate cell-type-specific DNA/RNA, we can further decipher the underlying gene/pathways which control this progenitor cell population of the adrenal gland cortex.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.
RF33 | PSAT92 Glucocorticoid Excess Alters Metabolic Rate in Male and Female C57BL/6J Mice
Authors: Tsintzas Kostas , Heaselgrave Samuel , Heising Silke , Morgan Stuart , Kabli Ali , Doig Craig , Morton Nicholas , Lavery Gareth
Published: November 2022

Introduction

Glucocorticoids are vital for regulating metabolic processes, as well as use in medical treatments. However glucocorticoid excess is known to cause negative metabolic effects including hyperglycaemia, muscle atrophy and fat accumulation, ultimately leading to Cushing's Syndrome. The effect on energy metabolism and metabolic rate remains undefined and merits investigation in both male and female mice.

Methods

24 male and 24 female C57BL/6J mice were randomly assigned to a corticosterone (100mg/L, approximately 300µg/day) or a vehicle control group. Mice were treated ad libitum via drinking water for 3 weeks, whilst being fed a standard chow diet. Mice were placed into a TSE Phenomaster system for the final week of treatment for indirect calorimetry assessment.

Results

Corticosterone treatment resulted in a typical phenotype of glucocorticoid excess, however female mice experienced significantly greater fat accumulation and bodyweight gain compared to males. Females treated with corticosterone exhibited increased energy expenditure (EE, 25±5.9%), oxygen consumption (21.7±10.0%) and carbon dioxide production (36.4±14.3%) during the day compared to controls, but males did not. However, corticosterone did significantly elevate the respiratory exchange ratio (RER) towards 1 in both males (10.7±5.7%) and females (11.8±7.0%) during the day. At night, when mice are naturally more active and EE increases, female corticosterone mice no longer had elevated EE, oxygen consumption and carbon dioxide production compared to controls. However, RER remained elevated in females (7.6%±4.8%) and moderately so in males (3.2±2.6%), staying close to or exceeding 1 in both. Corticosterone treated mice were hyperphagic and polydipsic throughout, eating and drinking significantly more than controls during both night and day, with intake peaking at night. Subsequent metabolomic analysis of tissue samples (skeletal muscle, liver, gonadal fat) revealed significant treatment and sex differences.

Conclusion

and further investigation: These findings provide further insights into the metabolic consequences of glucocorticoid excess in male and female mice. Whilst energy metabolism and metabolic rate are altered in both (especially during the day), the metabolic effects of glucocorticoid excess might be exaggerated in females. Further investigation will determine whether these changes are driven simply by increased animal activity, increased feeding and drinking or another mechanism. Additionally, we will determine whether 11β-HSD1 KO prevents these changes, as it does with other negative metabolic effects associated with glucocorticoid excess.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:06 p.m. - 1:11 p.m.
LBODP016 Lithocholic Acid Induced 25-hydroxyvitamin D-1alpha Hydroxylase (cyp27b1) Expression And Activities In Vitro And In Vivo
Authors: Lam Chung Yan , Yu Wenxuan , Kong Tsz Hung , Wong Man-Sau
Published: November 2022

Our previous study reported that oleanolic acid, a natural agonist for bile acid membrane receptor Takeda G protein coupled receptor 5 (TGR5), could exert bone protective effects, increase circulating 1, 25(OH)2D3 level and induce renal CYP27B1 expression and activities. However, it is unclear if bile acids, as the endogenous agonist of bile acid receptors, could regulate CYP27B1 expression and activities in kidney and bone tissues. The present study aimed to characterize the effects of lithocholic acid (LCA), a secondary bile acid, on CYP27B1 expression and activities in vitro using human proximal tubule (HKC-8) and osteosarcoma (MG-63) and in vivo using mature (6-month-old) male C57BL/6 mice. HKC-8 and MG-63 cells were treated with either LCA (10-10 to 10-5 M), PTH (10-7M), or its vehicle for 4 hours. For MG-63 cells, LCA significantly induced CYP27B1 protein expression at 10-10 and 10-9M (P<0. 001) and CYP27B1 mRNA expression at 10-9M (P<0. 001). For HKC-8 cells, LCA significantly induced CYP27B1 protein expression at 10-10 to 10-6M (P<0. 01) and CYP27B1 mRNA expression at 10-10M (P<0. 001). In addition, LCA significantly induced CYP27B1 activity in MG-63 cells (10-10M) (P<0. 05) and in HKC-8 cells (10-6M) (P<0. 01). For the in vivo study, male C57BL/6 mice were fed with 25mg/kg LCA or its vehicle for three consecutive days and sacrificed 5 hours after the last gavage. Serum, kidney, and iliac crests were collected for subsequent analysis. LCA significantly induced circulating 1,25(OH)2D3 levels (P<0. 01) and CYP27B1 protein expression in both kidney and iliac crests in mice (P <0. 05). In addition, the time-dependent change (2, 5, 8 hours) in serum 1,25(OH)2D3 levels were determined upon feeding the male mice with a single dose of 25mg/kg LCA. LCA significantly increased serum 1,25(OH)2D3 levels in male mice at 2 and 5 hours (P <0. 01 and P <0. 05, respectively), and serum 1,25(OH)2D3 levels returned to basal level by 8 hours. LCA significantly increased CYP27B1 protein expression in kidney in mice at 8 hours after treatment (vs. control group, P<0. 05). In summary, our results showed that LCA significantly induced circulating 1,25(OH)2D3 levels, possibly by its actions to induce CYP27B1 expressions and activities in renal and extra-renal (bone) tissues. The study indicated that bile acids and other TGR5 ligands might play an important role in the regulation of vitamin D metabolism.

Presentation: No date and time listed
LBODP017 Unusual Presentation Of Brown Tumors In Tertiary Hyperparathyroidism: A Case-based Review
Authors: ALShehri Sara Mohammed , AlAshgar Lolwah , AlShaygy Ibrahim , AlBoukai Ahmad , Neel Mona Ali Fouda
Published: November 2022

Brown tumor (BT) is a rare non-neoplastic skeletal manifestation of untreated tertiary hyperparathyroidism (THPT) that is associated with renal osteodystrophy in patients with End-Stage Renal Disease (ESRD). Nearly half of patients with ESRD have Osteitis Fibrosa Cystica (OFC) of varying severity, which is the most common form of renal osteodystrophy. BT represents the extreme form of OFC. As a result of frequent monitoring of bone profile and the expansion of pharmacological therapy, the disease is increasingly being diagnosed in its early stages; however, some are still seen at an advanced stage. Depending on the tumor size, the management will range from a conservative approach with supportive parathyroidectomy to a comprehensive surgical removal. Here, we report a rare case of an extensive BT of the pelvis in a patient with ESRD and THPT who was also found to have coincidental papillary thyroid cancer following total thyroidectomy and parathyroidectomy with a postoperative complication of hungry bone syndrome. She then underwent prophylactic intramedullary nail fixation for an impending fracture in the right femur. This case report highlights the importance of considering BT as a differential diagnosis of lytic bone lesions and that measuring serum calcium, phosphorus, and parathyroid hormone as part of the initial evaluation is essential to identify the correct diagnosis. Multidisciplinary team approach with frequent follow-up is crucial to allow early diagnosis and prevent unnecessary surgical interventions.

Presentation: No date and time listed
LBODP021 Multifactorial Hypercalcemia
Authors: Ramachandran Aishwarya , Win Kyaw Zin , Ramachandran Akshaya
Published: November 2022

Hypercalcemia (ca) has been described in many patients (pt) with granulomatous diseases. We present a pt with persistent hyperca from a combination of primary hyperparathyroidism (PHPT) and elevated 1,25 dihydroxyvitamin (OH2) D levels from reactivated tuberculosis (TB). An 82-year-old woman with a past medical history of Waldenström's macroglobulinemia and TB presented to hospital for imbalance and fatigue. Examination was unremarkable. Labs were notable for newly elevated ca of 14.8 mg/dl. After 200 mg of subcutaneous calcitonin on day 1, ca levels transiently improved but worsened by day 3. Calcitonin 200 mg twice daily was given for 2 days. Cinacalcet 60 mg daily was started for persistently elevated ca, which was then increased to twice daily. Two days later, cinacalcet was increased to 90 mg twice daily. Laboratory work-up revealed parathyroid hormone (PTH) to be inappropriately normal (45 pg/ml with concurrent ca levels of 14.8 mg/dl). Serum vitamin D levels were normal. Sestamibi scan showed bilateral PT adenoma for which she underwent parathyroidectomy. Pathology showed PT hyperplasia. Post-surgical PTH levels were down to 15 pg/ml but calcium levels remained elevated at 14 mg/dl, for which pamidronate 30 mg was given. Further work up showed elevated 1,25 OH2 D levels at 278 pg/ml and repeat levels were 261 pg/ml. Dexamethasone 6 mg daily was started while the pt was worked up for etiologies of elevated 1,25 OH2 D levels, with no improvement. PTHrP, SPEP and UPEP with IFE, quantiferon, and thyroid functions tests were normal. Radiology was unremarkable. AntiTB, and antifungal agents were empirically started. The latter was discontinued upon negative cultures.1,25 OH2 D levels improved with antiTB drugs continuation. Dexamethasone was tapered and pt completed antiTB treatment with normalization of ca levels (despite negative TB culture which resulted after the 1,25 OH2 D levels improved). PHPT is the most common cause of hyperca whereas malignancy is the most common cause of non PTH mediated hyperca in hospitalized patients. In our pt, ca remained elevated despite appropriate treatment of PHPT, suggesting other causes for hyperca. Although our pt fit the demographic for neoplasia, elevated 1,25 OH2 D levels indicated non-neoplastic etiology. Improvement in 1,25 OH2 D and ca levels following initiation of antiTB drugs supported mycobacterial infection reactivation as the most likely etiology, especially given pt's history of TB. In pts with granulomatous diseases, activated macrophages convert 25 OH D to 1,25 OH2 D without the usual regulation by PTH, ca and phosphorous that control renal 1-alpha hydroxylase activity. Common etiologies of 1,25 OH2 D include sarcoidosis, mycobacterial infections, and lymphoma. The presence of concurrent PTH and non PTH mediated etiology of hyperca makes this case an interesting one and showcases that multifactorial etiologies of hyperca can coexist.

Presentation: No date and time listed
LBSAT127 An Underrecognized Entity: Hypercalcemia Induced PRES
Authors: Sari Esra , Batch Jennifer Tania , Sultan Senan
Published: November 2022

Introduction

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that can present with headaches, focal neurological deficits, altered mental status, and seizures. Common etiologies are uncontrolled hypertension, preeclampsia/eclampsia, and chemotherapeutic agents. Hereby, we present a patient with status epilepticus secondary to PRES induced by hypercalcemia due to primary hyperparathyroidism.

Clinical Case

A 59-year-old Caucasian female with history of T2DM, GERD, gout, and bowel resection for an incarcerated abdominal hernia three weeks ago presented to the emergency department due to seizure-like movements. She had no history of seizures. Initial vitals showed HR of 96 bpm, BP of 148/67 mmHg, RR of 20 rpm, Temperature of 97.7F, and a BMI of 31.5 kg/m2. Physical exam revealed the presence of abdominal wound-vac and tonic-clonic movements that failed to improve with lorazepam, midazolam, and levetiracetam; hence she was intubated for airway protection and started on propofol. Lumbar puncture performed in the ED was unremarkable. Laboratory studies were pertinent for acute kidney injury (AKI) with a serum creatinine of 1.78 mg/dL, lactic acid of 6.1 mmol/L, and serum calcium of 14.5 mg/dL (8.7-10.4) with albumin of 4.2 g/dL. AKI and lactic acidosis rapidly improved with IV fluids. CT-head without contrast was negative for any acute pathologies. MRI-brain showed abnormal subcortical FLAIR signals within the bilateral parietal and occipital lobes with corresponding diffusion restriction in bilateral occipital lobes consistent with PRES. Continuous EEG (cEEG) showed ongoing epileptiform activity with an intermittent suppression pattern. Hypercalcemia workup revealed inappropriately normal intact-PTH of 45.9 pg/mL (10. 0-66. 0), PTHrP <2pmol/L, and 25-(OH)-Vitamin-D3 level of 34 ng/mL (30. 0-100. 0). Paraproteinemia work-up was negative. Thyroid ultrasound demonstrated an incidental nodule in the external aspect of the inferior right lobe measuring 6×3×3mm suggestive of parathyroid gland enlargement. Hypercalcemia was successfully treated with aggressive IV fluids and zoledronic acid. Repeat cEEG showed resolution of epileptiform discharges. She was successfully extubated without recurrence of seizures. She was determined to have hypercalcemia induced PRES secondary to primary hyperparathyroidism. Given the significant elevation of calcium and associated neurological symptoms, she met the surgical criteria and was discharged with outpatient parathyroidectomy plan.

Conclusion

PRES secondary to severe hypercalcemia has been described in the literature, albeit rarely. The exact pathophysiology is unclear but thought to be due to vasospasm based on cerebral angiogram studies. Early recognition of hypercalcemia as a culprit for PRES along with prompt treatment is crucial to treat life-threatening complications of PRES.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT141 Bone Health In Patients With Adrenal Disorders
Authors: Dogra Prerna , Šambula Lana , Zhang Catherine D , Thangamuthu Karthik , Nathani Rohit , Kastelan Darko , Ambroziak Urszula , Genere Natalia , Delivanis Danae , Bancos Irina
Published: November 2022

Introduction

Limited data suggest low bone density in patients with adrenal adenomas. However, most studies are retrospective, single-center, and none were conducted in the United States. We aimed to determine the impact of cortisol and aldosterone excess on bone density.

Methods

We conducted a preliminary analysis of data from our multicenter, prospective observational study of adult patients with adrenocortical hormone excess and referent subjects without adrenal disorders (January 2019 - March 2022). Patients were diagnosed with non-functioning adenomas (NFA), adenomas with mild autonomous cortisol secretion, MACS (defined as cortisol following an overnight 1-mg dexamethasone suppression test (DST)>1.8 mcg/dL), adrenal or pituitary Cushing syndrome (CS), primary aldosteronism (PA), and concomitant PA-MACS. Referent subjects were patients undergoing cross-sectional imaging for reasons other than adrenal disease. All participants were interviewed about their bone health, and had bone density measurements at the spine, hips, and/or radius. Bone disease was defined as osteopenia (T-score -1.1 to -2.4), or osteoporosis (T-score < -2.5).

Results

A total of 417 participants included 156 referent subjects (88, 56% women, median age 65, range 2-95 years) and 261 patients (190, 73% women, median age 59, range 21-88 years). Patients were diagnosed with NFA (51, 19%), PA (46, 17%), MACS (122, 47%), PA-MACS (12, 5%), and CS (30,12%). When compared to referent subjects, sex- and age-adjusted analysis demonstrated an increased prevalence of bone disease only in patients with CS (OR 4.8, 95%CI 1.7-13), but not in other adrenal disorders. After excluding patients with CS, those with post-DST cortisol >5 mcg/dL demonstrated a higher prevalence of bone disease when compared to patients with post-DST cortisol between 1.8-5 mcg/dL (OR 2.8, 95%CI 1.2-6.5) and those with post-DST cortisol <1.8 mcg/dL (OR 2.7, 95% CI 1.1-6.7). Patients with MACS and post-DST cortisol between 1.8-5 mcg/dL did not demonstrate increased sex and age-adjusted prevalence of bone disease compared to those with post-DST <1.8 mcg/dL or referent subjects. However, using post-DST cortisol as a continuous variable, we found that after adjusting for sex and age, the risk of bone disease in patients increased by 13% (OR 1.13, 95%CI 1.6-1.2) for every 1 mcg/dL increase in post-DST cortisol.

Conclusions

The prevalence of osteopenia and osteoporosis increases proportional to the increase in post-DST cortisol concentrations. Patients with CS, and those with MACS and post-DST cortisol > 5mcg/dL have the highest prevalence of bone disease.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP077 Adipopenia is associated with low bone mass in community-dwelling non-underweight adults, independent of sarcopenia
Authors: Lee Seunghyun , Ko Kyoungmyoung , Shin Sungjae , Park Hye Sun , Hong Namki , Rhee Yumie
Published: November 2022

The interaction between fat, muscle, and bone mass is complex. Although sarcopenia and underweight are well-established risk factors for osteoporosis, the association between low body fat percent (adipopenia) and low bone mass in non-underweight adults remains unclear. In Korean National Health and Nutrition Examination Survey dataset 2008-2011, we analyzed individuals aged 50 or older with body mass index (BMI)≥18.5 kg/m 2 . Appendicular skeletal muscle mass (ASMM) and body fat percent were measured using dual-energy x-ray absorptiometry. Sarcopenia was defined as ASMM/height 2 <7. 0 kg/m 2 and <5.4 kg/m 2 in men and women, respectively. Subjects were grouped into adipopenia (<17% in men and <30% in women; 1 standard deviation below the mean of the study population with round down to integer value), normal, or obesity (>30% in men and >40% in women) according to body fat percent. Osteoporosis was defined as T-score≤ -2.5 at the lumbar spine, femoral neck, or total hip. Among 5830 subjects (women 50.2%, mean age 63.9±8.5 years), 793 subjects had adipopenia (13.6%). The adipopenia group had a higher prevalence of osteoporosis (31%) compared to normal (21%) or obesity groups (27%; p<0. 001). Body fat percent showed a positive association with bone mineral density at all sites after adjustment for age, sex, height, and lean mass. In the multivariable logistic model, the presence of adipopenia was associated with 61% elevated odds of osteoporosis (adjusted odds ratio [aOR] 1.61, p<0. 001), independent of sarcopenia (aOR 1.71, p<0. 001), age, sex, height, and covariates, which remained robust in sensitivity analysis with sex-specific lowest 20% quantile thresholds (roughly <18.4% in men; <31.5% in women). In conclusion, adipopenia was associated with osteoporosis independent of sarcopenia in non-underweight adults, which merits further investigation.

Presentation: No date and time listed
ODP122 Recurrent Episodes of Hypercalcemia due to Disseminated Mycobacterium Avium Complex Infection-related Immune Reconstitution Inflammatory Syndrome
Authors: Downs Ian , Donangelo Ines
Published: November 2022

Introduction

Immune reconstitution inflammatory syndrome (IRIS) may occur in patients with acquired immunodeficiency syndrome (AIDS) following initiation of antiretroviral therapy (ART) due to exacerbation of preexisting infectious process, such as disseminated mycobacterium avium complex (dMAC). This type of inflammatory process may be associated with granuloma formation and 1,25(OH) 2 vitamin D-mediated hypercalcemia. Hypercalcemia typically is controlled with a single dose of intravenous bisphosphonate or a two to four-week course of glucocorticoid, in addition to antibiotics for dMAC and ART. Here we present a case of IRIS-associated hypercalcemia related to dMAC resistant to intravenous bisphosphonate therapy and an extended glucocorticoid course.

Case presentation

A 30-year-old man with AIDS with CD4 count 4 cells/mm^3 (441-2,156) was admitted with subacute fevers, chills, and cough one month after starting ART. Cultures drawn during admission were positive for MAC and he was started on therapy for dMAC with ethambutol and azithromycin. Seven months after starting ART, he was readmitted with weakness and fatigue and found to have calcium 13.5 mg/dL (8.6-10.4), albumin 3.9 g/dL (3.9-5. 0), creatinine 1.40 mg/dL (0.6-1.3), CD4 count 80 cells/mm3. Further workup revealed intact PTH 2 pg/mL (11-51), 25-OH vitamin D 38 ng/mL (20-50), 1,25(OH) 2 vitamin D 171 pg/mL (19.9-79.3), PTHrP < 2. 0 pmol/L (0. 0-2.3), suggestive of PTH-independent hypercalcemia mediated by 1,25(OH) 2 vitamin D. CT scan of the chest showed multiple cavitary lesions, ground glass nodularity, and diffuse lymphadenopathy. He was treated with intravenous fluids, zoledronic acid 4mg, and continued ART and antibiotics for MAC. On discharge calcium was 9.5 mg/dL. He had recurrence of 1,25(OH) 2 vitamin D-mediated hypercalcemia (calcium 13.6mg/dL) 11 months after starting ART, which was controlled with intravenous fluid and prednisone 60mg tapered over 6 weeks. He then had recurrence of hypercalcemia 13 and 16 months after starting ART, each resolved with intravenous fluids and repeat prolonged prednisone courses. Testing for other infectious causes of granulomatous disease including Cryptococcus, Histoplasma, Mycoplasma tuberculosis was negative during multiple presentations. At 13 months, his CD4 count was 214 cells/mm^3 and repeat CT scan of the chest showed improvement in size of cavitary nodule and ground glass nodularity.

Conclusion

IRIS related to dMAC is an uncommon cause of 1,25(OH)2 vitamin D-mediated hypercalcemia. Multiple recurrences of hypercalcemia and the need for extended courses of glucocorticoid despite improvement of underlying infectious process has not previously been reported.

Presentation: No date and time listed
ODP124 Sickle Cell Bone Disease and Response to Intravenous Bisphosphonates in Children
Authors: Todd Alexander R , Grimbly Chelsey , Ward Leanne M , Grimbly Chelsey , Escagedo Patricia Diaz , Jaremko Jacob L , Bruce Aisha , Alos Nathalie , Robinson Marie-Eve , Konji Victor N , Page Marika , Simpson Ewurabena , Pastore Yves D , Girgis Rose
Published: November 2022

Purpose

To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with Sickle Cell Disease (SCD).

Methods

We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA).

Results

Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises or stroke attributed to IV bisphosphonate therapy. Bone mineral apparent density Z-score increased at the lumbar spine (N=14, mean change +0.6, SD 0.4) and total body less head (N=14, mean change +0.5, SD 0.4) after IV bisphosphonate therapy (mean 1.5 years, SD 0.8).

Conclusion

Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.

Presentation: No date and time listed
ODP566 Success of CME at Improving Knowledge, Competence and Confidence Related to Guideline-Based Diagnosis and Management of Acromegaly
Authors: Carothers Ann , Larkin Amy , Maeglin John
Published: November 2022

Introduction

We sought to determine if a series of online continuing medical education (CME) activities could improve knowledge, competence and confidence of primary care physicians (PCPs) and endocrinologists (endos) related to guideline-based diagnosis and management of patients with acromegaly.

Methods

The effect of two (2) separate online, 30-minute, CME-certified roundtable discussions among 3 faculty were analyzed to determine efficacy. The activities posted December 16, 2020, and May 19, 2021, and data were collected for 3 months for each activity.

Results

Overall, 42% and 30% of PCP learners and 20% and 43% of endo learners improved their knowledge/competence.

Conclusions

This study demonstrates the success of 2 online, 30-minute roundtable discussions on improving knowledge, competence, and confidence of both PCPs, and endocrinologists regarding guideline-based diagnosis and management of acromegaly, with gaps identified for future education.

Presentation: No date and time listed
ODP588 A Rare Case Of Infantile Transient Psuedohypoparathyrodism
Authors: Hathi Deep , Baidya Arjun , Tarenia Silima Subhasnigdha , Das Niladri , Gaikwad Prashant Manohar , Pathak Yashaswi , Banerjee Abhirup , Chatterjee Mounam , goswami Soumik , Sengupta Nilanjan
Published: November 2022

Background

Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders in which resistance to parathyroid hormone (PTH) in the proximal renal tubules leads to hypocalcemia, hyperphosphatemia, and impaired 1,25(OH)2 vitamin D production.

Clinical Case

A 2-month-old child presented with history of recurrent focal seizures since last 10 days. During the first episode, the child was treated with anti- convulsant by paediatrician. Five days later she again developed focal seizures, this time the child was evaluated and serum calcium was 5.6 mg/dl (normal, 8.6-10.2 mg/dl), phosphorus 7.5 mg/dL (normal, 4. 0-7. 0 mg/dL), and magnesium 2. 0 mg/dL (normal 1.8-2.4 mg/dL). In view of symptomatic hypocalcemia, she was treated with I. V. 10% calcium gluconate and oral calcifediol (800 IU/day). The child was seizure free but still had hypocalcemia - serum calcium-6.8 mg/dl, hence the child was evaluated further- serum PTH was 561 pg/mL (normal, 9-91 pg/mL), 25-hydroxyvitamin D was 54.1 ng/mL (normal, 5-60 ng/mL), 1,25 Vit D-6.28 pg/mL (normal, 19.9-79.3pg/mL), TSH-2.69 μUI/mL (normal, 0.35-8. 00 μUI/mL), FT4 was 1.2 ug/dL (normal, 0.9-1.8 ug/dL). Physical examination was unremarkable, and there were no stigmata of AHO, rachitic rosary, or congenital malformations. EEG was normal and CT brain did not show any intraventricular haemorrhage or basal ganglia calcification. Consistent with hypocalcaemia, hyperphosphatemia, high serum PTH levels, and lack of stigmata of AHO, we considered PHP type Ib. Her parents refused further examinations, so PTH infusion and molecular analysis of the GNAS gene could not be performed. The child was discharged in good clinical condition on calcitriol 0.25 ug/day and calcium (elemental calcium 625 mg/day) supplementation. He had no further seizures and normal serum electrolyte levels till 9 months of age. European Pseudohypoparathyroidism Network (EuroPHP Network) has recently proposed a new classification system to cover all disorders of the PTH pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for these disorders. iPPSDs can be further divided into subtypes: iPPSD1 to iPPSD6. A minimum of one major criterion is mandatory for the clinical diagnosis of iPPSD. Applying iPPSD criteria to this case, one can observe that they all had persistent hypocalcemia and PTH resistance but no other major or minor criteria. Nevertheless, we speculate whether neonatal transient pseudohypoparathyroidism (ntPHP) could be included among iPPSDs, specifically in the group of unknown molecular defects.

Conclusion

To the best of our knowledge, this is the second report in which the new classification of iPPSD has been applied and the child has been diagnosed a case of ntPHP.

Presentation: No date and time listed
ODP592 Delay in Diagnosis of Adult with Familial Hypophosphatasia
Authors: Choe Chlarles , Mao Jimmy , Woods Gina , Rodriguez Arianna
Published: November 2022

Background

Familial Hypophosphatasia (HPP) is a rare genetic disorder characterized by defecitve bone and/or teeth mineralization in the presence of low alkaline phosphatase activity due to loss-of-function mutations in the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene. HPP typically presents in middle age with a mild phenotype.

Case Presentation

A 43-year-old woman with PMH undifferentiated connective tissue disease and GERD referred to endocrinology clinic. She was previously diagnosed with schleroderma and was treated with prednisone and hydroxychloroquine without symptom improvement. Symptoms included: progressing bone, joint, and muslce pain; unsteady gait; proximal muscle weakness; fatigue; early loss of deciduous teeth; loss of teeth mineralization; history of finger and toe fractures from repetitive stress.

Family History: Mother: ongoing joint/muscle pain as well as tooth loss. Daughter: failure to thrive, kyphosis, orthopedic problems, required leg casting for 1 year.

Physical Exam: unrevealing (limited due to video visits).

Significant Laboratory/Imaging Findings: Serum alkaline phosphatase (ALP): 16 U/L (ref. 35-140 U/L)Vitamin B6: 235.3 nmol/L (ref. 20-125 nmol/UL)Calcium: 9.3 mg/dL (ref. 8.5-10.6 mg/dL).Dual energy X-ray absorptiometry (DXA): normal bone mass for age.Genetic testing: one heterozygous pathogenic variant in ALPL, c.318G>C (p.CIn106His).

Treatment Course: Genetic testing consistent with a diagnosis of familial HPP, specifically juvenile onset. Initiated on Asfotase-alfa, an alkaline phosphatase enzyme replacement therapy.

Screening prior to treatment: Renal ultrasonography without ectopic calcificationOpthalmology exam without calficiations identified

Discussion

HPP should be suspected in patients with defective mineralization of bone and/or teeth in the setting of an unexplained low serum ALP activity and elevated Vitamin B6 level. Non-specific symptoms such as bone, joint, and muscle pain are common presenting symptoms in adults with HPP. Treatment with asfotase-alfa may be considered for adults with symptom onset in childhood, including early loss of deciduous teeth. Early diagnosis and treatment may improve overall quality of life. At this time, there are no guidelines for selecting adult patients for treatment with alfoterase-alfa. Further studies are needed to evaluate the benefits of enzyme replacement therapy among adults with HPP.

Presentation: No date and time listed
ODP652 Challenges in the Management of Hypocalcemia in a Patient with Advanced Stage of Parotid Gland Adenocarcinoma
Authors: Go Hannah R , Alba Rebecca
Published: November 2022

Background

Derangements of calcium metabolism are common in patients with cancer. 1 Unlike hypercalcemia which is well-recognized, little is known about hypocalcemia of malignancy. 2 In fact, there were only 2 studies published to date that investigated its incidence among cancer patients. 2,3 Clinical Case: A 40-year-old male consulted an ENT specialist for a 2×2 cm left parotid mass of 3 years duration. There was no fever, cough, night sweats or significant weight loss. Histological analysis of the mass revealed parotid gland adenocarcinoma. Tumor metastases to lung and spine were seen on PET CT scan. Consequently, he received 18 cycles of chemotherapy and 10 sessions of radiotherapy without surgery because of the advanced stage. He initially exhibited good response with the treatment. A year after,he developed shortness of breath, numbness of hands with seizure episode. Chest x-ray showed pleural effusion and osteoblastic changes while cranial CT scan revealed brain metastasis. Bone scintigraphywas evident for multiple osseous metastases. He underwent stereotactic brain surgery, and thoracentesis with pleural fluid analysis consistent with malignancy. Biochemical tests were remarkable for hypocalcemia (0.99, n>1.12 mmol/L, normomagnesemia (0.89, n>0.74 mmol/L), low vitamin D (11.6, n>30 ng/mL), elevated phosphate (1.73; n: <1.49 mg/dL), and elevated intact PTH which eventually dropped (157.7 to 9, n>15 pg/mL). Ultrasound of the neck revealed diffuse thyroid calcifications. Despite oral calcium supplementation (14.4 grams elemental calcium),calcium infusion (1.35 mg/kg/hour elemental calcium) and vitamin D supplementation (6000 IU cholecalciferol and 0.5 mg calcitriol daily), he remained hypocalcemic. His condition eventually worsened, and he succumbed to death in due course despite aggressive measures provided.

Conclusion

To our knowledge, this is the first case illustrating the therapeutic challenge in addressing an intractable hypocalcemia in the setting of an advanced parotid carcinoma inour country. Reference: (1)Carl Blomqvist. A Hospital Survey of Hypocalcemia in Patients with Malignant Disease. Acta Med Scand. 1986;220. (2) Schattner et al. Hypocalcaemia of Malignancy. The Netherlands Journal of Medicine. July 2016, Vol. 74, No. 6. (3) Goncalves. Hypocalcemia in cancer patients: An exploratory Study. Porto Biomed. J. (2019) 4: 4

Presentation: No date and time listed
PSAT223 A Delayed Diagnosis of Oncogenic Osteomalacia Presenting with Bone Pain, Muscle Weakness and Elevated Alkaline Phosphatase
Authors: Gastelum Alheli Arce , Mao Jimmy J , Woods Gina N
Published: November 2022

Background

Tumor-induced osteomalacia (TIO) is a rare bone disease caused by excess production of FGF23 by a phosphaturic mesenchymal tumor, resulting in severe hypophosphatemia, bone demineralization, insufficiency fractures, bone pain and muscle weakness. The Fibroblast Growth Factor-23 (FGF23) is a phosphaturic hormone produced by osteocytes, whose primary effect is to decrease serum phosphate by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption (via diminished 1,25D production).

Clinical case

A 65-year-old male was referred to endocrinology clinic for a second opinion due to severe rib pain and elevated alkaline phosphatase levels. His first endocrinologist diagnosed Paget's disease of the bone based on symptoms of rib pain, an elevated alkaline phosphatase level, and abnormal Tc99 bone scintigraphy demonstrating uptake in multiple areas, including bilateral humeri, ribs, knees, ankles, and L4 vertebral body. He received 5 mg IV zoledronate for treatment of Paget's disease, and immediately post-infusion reported worsening of severe rib pain. Upon presentation to our institution, he reported ongoing severe rib pain and bilateral knee pain. On exam, he had extreme difficulty rising from a seated position. Laboratories revealed calcium 9.0 mg/dL, albumin 5.0 g/dL, alkaline phosphatase 116 U/L, 25D 43 ng/dL, PTH 66 pg/mL and serum phosphorous 1.5 mg/dL. Tubular Reabsorption of Phosphate (TRP) was 59%, based on a spot second morning void with corresponding fasting morning blood draw. 1,25D was 13 pg/mL (19-79 pg/mL). Intact FGF23 was 346 pg/mL (<59 pg/nL). CT revealed bilateral tibial plateau insufficiency fractures. When asked if he noticed any "lumps or bumps", the patient reported a lump under his left second toe. MRI showed a 1.8 cm soft tissue mass.

A GA68-DOTA-TATE PET CT revealed a 2.3 cm soft tissue mass plantar to the 2nd left proximal phalanx with intense activity mass (SUVmax 39.8). This mass was surgically excised. Post-operative FGF23 levels were as follows: 38 pg/mL → 15 pg/mL → <14 pg/mL.

Within 14 days, the patient's ability to rise from a seated position was markedly improved. His severe rib pain persisted for three weeks but was significantly improved by six weeks post-op. Despite treatment with 1 mcg calcitriol daily and 5000 IU vitamin D daily, he developed evidence of post-operative hungry bone syndrome with calcium 8.3 mg/dL, PTH 64 pg/mL, and alk phos 157 U/L.

Conclusion

Tumor-induced osteomalacia is a rare but treatable condition, presenting with severe hypophosphatemia, bone pain, bone demineralization, insufficiency fractures, and muscle weakness. Due to the nonspecific nature of the presenting symptoms, delays in diagnosis are common. Serum phosphorous should be obtained in all patients presenting with unexplained elevations in alkaline phosphatase.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBODP027 Detection Of Metabolic Syndrome In Adolescent With Explainable Artificial Intelligence: Which Place For Mean Blood Pressure?
Authors: Benmohammed Karima , Masry Zeina A , Omri Nabil , Zerhouni Noureddine , Valensi Paul
Published: November 2022

Metabolic syndrome (MetS) definition in adolescents is complicated by the physiologic evolution with age and sexual maturation of the components of this syndrome. While screening for MetS in youth should be useful to assess current complications and prevent future ones, it is not simple in clinical practice due to the number of different definitions of MetS in adolescents, which are generally based for most of them on percentiles. The aim of this study was to check the validity of artificial intelligence (AI)-based scores in screening for MetS in adolescents, using new parameters identified with AI techniques and without using percentiles. This study included 1,086 adolescents (559 girls and 527 boys) aged 12 to 18 with BMI 21.2±3.9 kg/m2. All had anthropometric measurements taken and had blood tests. Mean blood pressure (MBP), and triglyceride glucose index (TyG) were calculated. AI techniques are characterized by their black-box nature. Explainable AI methods are used to extract the learned function. "Gini importance" techniques were tested and used to build new scores for the detection of MetS among children and adolescents. We used 2007 IDF and Cook definitions of MetS to test the validity of these scores. MetS prevalence was 0.9% and 2.2% according to IDF and Cook definitions, respectively. The most accurate AI scores (S-IDF, S-Cook) for the detection of MetS according to these definitions include age, waist circumference, MBP and TyG index: S-IDF= - 0.52×age + 0.48×WC - 0.51×TyG + 0.27×MBP; S-Cook= - 0.52×age + 0.48×WC - 0.51×TyG + 0.29×MBP. With cut-off levels of 51.35/51. 06, these AI scores offer AUC 0.91/0.93, specificity 81%/75%, and sensitivity 90%/100% for MetS detection. Furthermore, with a cut-off point of 92 mmHg, MBP alone offers a better specificity 85%/83% and sensitivity 80%/88%, AUC 0.89, than TyG index alone (100%/46% for specificity, 30%/88% for sensitivity) to detect MetS based on IDF and Cook definitions, and slightly lower performance than AI-scores. MBP was associated with the occurrence of type 2 diabetes (T2D) and cardiovascular disease among the general population; cardiovascular disease and cardiovascular mortality among patients with T2D; and a discriminatory ability as strong as for SBP and DBP in predicting T2D. However, we did not find in the literature similar studies in the pediatric population. TyG index has been assessed mainly in adults and in a few studies in adolescents, and recently proposed as an alternative marker of insulin resistance and a marker of high risk for diabetes and cardiovascular complications or events in both adult and pediatric populations. In this study, AI techniques have proven their ability to extract knowledge from data and come up with new scores based on simplified criteria in adolescents. It allowed us to reveal the MBP as a simple alternative marker for MetS screening in adolescents.

Presentation: No date and time listed
LBODP028 Identifying Biomarkers For Predicting Response To Mineralocorticoid Receptor Antagonist Treatment In Heart Failure
Authors: Karthigan Nikshay , Lockwood Siobhan , White Anthony , Yang Jun , Young Morag Jennifer
Published: November 2022

Despite significant improvements to patient care, heart failure (HF) remains a major public health burden. Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisation and improve survival in patients with HF with reduced ejection fraction (HFrEF) but the widespread use of MRAs is limited by adverse effects including hyperkalaemia. The use of biomarkers to guide therapy may enable earlier treatment or minimise side effects from unnecessary therapies. We have previously described mineralocorticoid receptor responsive genes in monocytes/macrophages and hypothesised that response to MRAs can be detected in this cell population. Therefore, we aimed to identify biomarkers for predicting response to MRAs to facilitate personalised treatment of HF. Microarray-based transcriptome profiling was performed on monocytes obtained from six patients with HFrEF, before and after three months of MRA treatment. Three patients demonstrated improvement in left ventricular ejection fraction (LVEF) after 12 months of MRA treatment (Group 1), whereas the other three patients exhibited minimal functional response to MRAs (Group 2). To visualise sample similarity, multidimensional scaling (MDS) was employed which revealed distinct separation of males from females. To understand the changes in monocyte gene expression following MRA treatment, differential expression analysis was performed. Paired analysis of Group 1 samples (before vs after MRA treatment) identified 319 unique differentially expressed genes (DEGs) with an estimated fold-change ≥ 2 and q-value < 0. 05; 1 upregulated, 318 downregulated, and paired analysis of Group 2 identified 1 unique DEG. RT-qPCR was used validate top DEGs implicated in cardiovascular pathophysiology which confirmed downregulation of 12 of the top DEGs in Group 1. Additionally, cluster of differentiation (CD) encoding genes CD14, CD163, and CD68 were upregulated in Group 1 but downregulated in Group 2. Additional differential expression analyses were also performed by stratifying patients according to additional metrics of functional response including change in B-type natriuretic peptide (BNP). However, these analyses did not identify statistically significant DEGs. Our results indicate MRA treatment can significantly alter the human monocyte transcriptomic profile. Further research is needed to establish the utility of these DEGs as biomarkers for early prediction of MRA treatment-response in patients with HF, and to define sex-specific differences.

Presentation: No date and time listed