bluuebunny/crossref_metadata_2025 huggingface dataset:
PSAT342 Hypothyroidism After Use Of Immune Checkpoint Inhibitor Therapy In Patient With Graves’ Disease
Authors: Sharma Rajeev
Published: November 2022

Background

Immune checkpoint inhibitors (ICIs) are commonly used for many cancers. Thyroid gland involvement is the commonest endocrine toxicity seen with this class of drugs. Most common thyroid dysfunction is thyroiditis followed by hypothyroidism with some cases of recovery. There are rare case reports of Graves’ disease induced by ICIs. However, we report a patient with pre-existing Graves’ disease who developed hypothyroidism after immunotherapy.

Clinical Case

66-year-old man with metastatic squamous cell carcinoma of lung was referred to endocrine clinic for suppressed TSH. He was diagnosed with metastatic poorly differentiated lung cancer in September 2018. He received cheamotherapy with carboplatin and paclitaxel from October 2018 to January 2019. He was switched to immune checkpoint inhibitors with programmed cell death protein-1 (PD-1) inhibitor pembrolizumab every 3 weeks from February 2019. ICI therapy was stopped in until July 2019 due to immune mediated hepatitis. He was started on high dose steroids. Lung cancer findings remained stable even after stopping ICIs. Prior to starting ICIs his thyroid functions were consistent with hyperthyroidism. He continued to have suppressed TSH until his 6th cycle of pembrolizumab. TSH was found be significantly elevated prior to his 7th infusion. He was referred to endocrinology for further management. Clinically, patient was asymptomatic except for fatigue. Family history was positive for mother with Graves’ disease. Laboratory results on presentation showed significantly elevated TSH, low thyroxine (T4) and triiodothyronine (T3) consistent with diagnosis of primary hypothyroidism. Thyroid stimulating immunoglobulin (TSI) was positive suggesting autoimmune thyroid disease. Thyroid scan showed decreased 24-hour uptake (0.8%). A diagnosis of immune checkpoint inhibitor (ICI) related hypothyroidism was made. He was started on hormonal replacement with levothyroxine 50 mcg daily. Review of previous thyroid blood tests showed suppressed TSH since October 2016, but he was never treated. Thyroid peroxidase (TPO) antibodies were positive in the past. Thyroid sonogram in December 2016 showed a heterogeneous thyroid with no nodules. A radioactive scan in 1/2017 showed normal 24-hour uptake (12%) with no hot or cold nodules. (Fig 1). Since starting levothyroxine, the dose has been adjusted few times and patient has been doing well.

Conclusion

This is a unique case of patient with Graves’ disease who was cured because of immune related adverse event from use of immune-checkpoint inhibitor therapy.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
OR29-3 High-specific-activity Iodine 131 Metaiodobenzylguanidine for the Treatment of Advanced Pheochromocytoma and Paraganglioma: A Real-world Study
Authors: Al-ward Ruaa
Published: November 2022

Introduction

Metastatic pheochromocytomas/paragangliomas (mPPGLs) are rare tumors with limited treatment options. High-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) is the only approved therapy for mPPGLs. We summarized the efficacy and safety profile of HSA 131I-MIBG in patients with mPPGL.

Methods

This is a retrospective cohort study in patients with mPPGL treated with HSA 131I-MIBG on label at a tertiary cancer center. The primary endpoint was radiographic treatment response determined with CT/MRI according to RECIST v1.1 and 123 I-MIBG scan. Secondary endpoints were blood pressure changes and HSA 131I-MIBG related adverse events. We correlated responses with the genetic background as an exploratory endpoint.

Results

Twenty-four patients were treated including 15 men (62%). Median age at the time of treatment was 44 years (range 18–82). Twenty-three patients had distant metastases and one patient had an unresectable primary tumor. Seventeen patients (70%) had hormonally active tumors and 17 patients (70%) were on antihypertensive medications before HSA 131I-MIBG therapy [7 patients on alpha-blockers only and 10 on combination antihypertensive therapy]. Thirteen patients (54%) previously received antineoplastic treatment. Eleven patients (46%) received one dose of HSA 131−I-MIBG, the remaining received two doses. Median duration of follow-up was 15 months (range 2–52). In 23 evaluable patients, radiographic responses included: 2 complete responses (CR), 10 partial responses (PR), 8 stable diseases (SD), 2 mixed responses (MR), and 1 progressive disease (PD) yielding disease control rate (DCR) of 87%. Median time to response was 12.5 months (95% CI, 4.6 to 25.1). Radiographic responses in patients with sporadic disease were [6/11 SD, 3/11 PR, 1/11 MR, 1/11 PR], while the response in patients with a genetic mutation (SDHB, VHL, RET) was [2/12 CR, 7/12 PR, 2/12 SD, 1/12 MR]. In 17 hormonally active tumors, plasma metanephrines normalized in 3(18%), improved by 50% in 5(29%), increased in 4(24%), 4 patients (24%) had no repeat levels and one had stable levels. Blood pressure was evaluable in 22 (92%) patients. Blood pressure normalized in 9 patients (41%) leading to discontinuation of antihypertensive therapy. One patient had an improvement in the blood pressure leading to a reduction of antihypertensive medications. The most common adverse events were grade I/II nausea/vomiting and transient bone marrow suppression. One patient developed premature ovarian failure. Grade III/IV myelosuppression was seen in 3/24 (12%) patients. One patient had fatal pneumonitis, and one patient developed fatal gastrointestinal bleeding a month after treatment with unclear attribution to HSA 131 −I-MIBG.

Conclusions

In mPPGL, HSA 131I-MIBG is associated with high DCR regardless of underlying genetic mutation. Severe adverse events are infrequent but can be fatal.

Presentation: Tuesday, June 14, 2022 10:15 a.m. - 10:30 a.m.
PSUN380 A Case of Sclerosing Epithelioid Fibrosarcoma With Metastases to the Thyroid
Authors: Bisquera Nichole Andrea , Villa Michael
Published: November 2022

Background

Sclerosing Epithelioid Fibrosarcoma (SEF) is a rare form of soft tissue sarcoma, often presenting in the soft tissues of the extremities. This tumor is characterized by slow growth, often with local recurrences and/or distant metastases. First described in 1995, subsequent case reports and case series have demonstrated that metastases are primarily to the lung, pleura and bone, but can occur anywhere. Treatment is primarily by wide excision and adjuvant chemotherapy or radiotherapy. However, treatment of this rare form of sarcoma is often unsatisfactory.

Clinical case

A 36-year-old female, had for 30 years presented with a slowly enlarging mass on the left axilla. She had no constitutional symptoms and had previously been in good health. She was first diagnosed with SEF when she presented with abdominal pain where workup showed elevated Lipase 8,098 U/L (73-393 U/L) and Amylase 976 U/L (25-115 U/L). CT scans showed an ill-defined hypodense focus in the body of the pancreas, with incidental findings of a mixed intensity ovoid lesion in the left erector spinae, and heterogeneously enhancing ovoid masses in the left axilla, left lateral chest wall, left lower lung lobe, and the liver. Biopsy of the left axillary mass showed a round cell sarcoma consistent with Sclerosing Epithelioid Fibrosarcoma. PET scan confirmed widespread metastases to the lungs, pancreas, abdominal wall, left thigh and scalp. She underwent wide excision of the masses in the left axilla, thigh, and scalp. Adjuvant chemotherapy with Doxorubicin and Ifosfamide was then initiated. 6 months after starting treatment, she reported a rapidly enlarging anterior neck mass. She denied tremors, palpitations, any change in weight, heat/cold intolerance, changes in bowel movement, fatigue or muscle weakness. On physical examination there was a 2×2 cm, firm, non-tender, palpable nodule on the right thyroid lobe. Thyroid function tests were as follows: TSH 0.52 uIU/mL (0.55-4.78 uIU/mL), FT4 1.27 ng/dL (0.89-1.76 ng/dL), FT3 2.84 pg/mL (2.30–4.20 pg/mL). On thyroid ultrasound there was a 2.6×1.8×2.4 cm, mixed hypoechoic, solid, lobulated nodule in the upper to middle third of the right thyroid lobe, and a 0.3×0.2×0.3 cm hypoechoic solid nodule in the lower third of the left thyroid lobe. FNAB showed hypercellular smears with atypical round to spindle-shaped cells arranged in singly and loose to crowded clusters. She underwent total thyroidectomy, and histopathologic examination was consistent with a multifocal metastatic Sclerosing Epithelioid Fibrosarcoma. She was subsequently started on Levothyroxine replacement.

Conclusion

This case, to our knowledge, is the first reported case of Sclerosing Epithelioid Fibrosarcoma (SEF) metastatic to the thyroid.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN245 Non-ketotic Hyperglycemic Hemichorea-Hemiballismus Precipitated by Antipsychotics
Authors: Elsherif Ahmed , Jun John
Published: November 2022

Background

Non-ketotic hyperglycemic hemichorea-hemiballimus is a rare complication of uncontrolled diabetes mellitus characterized by sudden, unilateral and involuntary flailing movements. It is associated with basal ganglia lesions contralateral to the side of involuntary movements. We present a case with this complication after the initiation of olanzapine.

Clinical Case

A 44-year-old male with anxiety, depression and diabetes mellitus type 2 with a recent increase of glycohemoglobin from 8.0 to 14.6% over 4 months presented with a 2-week history of worsening involuntary jerky movements of his right upper extremity, which eventually progressed to his right lower extremity. He was on metformin monotherapy for his diabetes initially. Olanzapine had been prescribed in place of quetiapine 2 months prior and then he presented to a different hospital with diabetic ketoacidosis a month later. Insulin therapy was initiated at that time and olanzapine was discontinued about 2 weeks prior to the current presentation. Physical examination showed spontaneous, irregular and involuntary flailing movements in his right upper and lower extremities that subsided during sleep. Laboratory tests revealed a random plasma glucose of 124 mg/dL and a glycohemoglobin of 14.6% but otherwise diagnostic studies including heavy metal screening, C-reactive protein, cerebrospinal fluid analysis and electroencephalogram were unremarkable. A CT of brain showed increased attenuation of the left lateral basal ganglia and caudate nucleus, and an MRI of brain showed increased T1 and T2 signal within the left lateral basal ganglia, and decreased T2 signal in the left caudate nucleus. Along with a consistent carbohydrate diet, a basal-bolus insulin regimen was initiated and adjusted to optimize glycemic control between 80 to 150 mg/dL. Clonazepam and Quetiapine were prescribed for his motor symptoms. Over the span of 3 months, his motor symptoms gradually improved, his insulin requirements decreased, and eventually excellent glycemic control was achieved with metformin alone.

Conclusion

This case highlights a unique presentation of hemichorea-hemiballismus as a rare complication of uncontrolled diabetes mellitus precipitated by olanzapine, an atypical antipsychotic with a higher risk of metabolic adverse effects.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN247 Unique Presentation of MODY Type 5
Authors: Bella Sama , Elhamdani Rawan , Benhamed Nesreen
Published: November 2022

A 46-year-old female with a past medical history significant for a blind vaginal birth defect that required vaginal reconstructive surgery with a partial hysterectomy at 15 years old and Type 2 Diabetes diagnosed at 44 years old. The patient was started on Sitagliptin, metformin 500 mg BID, and glimepiride 2 mg, but she remained poorly controlled with A1C 12.5%. Liver enzymes were elevated with the following values on the liver panel: AST 63 U/L Alt113 U/L bilirubin total 1.0 U/L direct bilirubin 0.3 U/L Alkaline phosphatase 642 U/L. Abdominal ultrasound and serology for chronic liver disease were unremarkable; enhanced MRI of the abdomen showed no abnormalities in the liver and pancreas. CT-guided liver biopsy was performed and pathology revealed diabetic hepatosclerosis. Ultimately, the patient was referred for endocrinology evaluation for poorly controlled diabetes mellites. Blood work was negative for GAD antibodies 65 and anti-pancreatic islet cell antibodies. C peptide level was within normal limits. The patient was not compliant with medications; her A1C continues to range between 11.5 and 8.5 so she was started on subcutaneous insulin.

A few years later, the patient presented to the ED for generalized weakness, anorexia, and unintentional weight loss of approximately 40 pounds with a BMI of 17 kg/m2. Bloodwork revealed glucose was 222 mg/dl, and glycated hemoglobin (A1C) was 15.4%, with no acute metabolic disorder (no ketosis). Biochemical analysis reported triglycerides of 174 mg/dL, total cholesterol of 280 mg/dL, HDL of 82 mg/dL, aspartate aminotransferase of 75 U/L, alanine aminotransferase of 117 U/L. alkaline phosphatases 190U/L, Potassium 3.1mEq/L, and magnesium 1.3mEq/L

Her electrolytes failed to correct despite adequate replacement; hence nephrology evaluation was warranted. As a result, 24h urine collection was obtained and revealed a Gitelman pattern with salt wasting, K+ wasting, Mg2+ wasting, and no calcinuria. This raised suspicion for MODY type 5. An enhanced MRI of the abdomen revealed her pancreas was missing the distal body and tail as well as bilateral cystic kidney disease. Genetic testing was pursued and demonstrated mutations in the hepatic nuclear factor 1B (HNF1B) gene which confirmed the MODY type 5 diagnosis.

The patient was discharged on 11 units of insulin degludec at bedtime in addition to insulin aspart 2 units TID; her A1c improved to 8.3% on her most recent follow-up.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN282 Sertraline-Induced Hypoglycemia in a Non-Diabetic Patient
Authors: Zahedpour Anaraki Sara , Vasudev Magaji
Published: November 2022

Background

Sertraline is one of selective serotonin reuptake inhibitors (SSRIs) commonly prescribed for depression. Irrespective of diabetes status, SSRIs can cause glycemic dysregulation.

Clinical Case

74-year-old man with depression was evaluated for hypoglycemia. His depression was managed with sertraline for more than 10 years. He did not have diabetes. Non fasting, laboratory studies done during annual evaluation showed blood glucose of 29 mg/dL but he didn't have any symptom of hunger, sweating, shaking or dizziness. Lab report was initially considered to be an error. Repeat blood glucose was 102 mg/dl. Subsequent labs done 6 months later also reported blood glucose of 27mg/dl. He suffered from a bicycle accident with head laceration in May 2021, his blood glucose on presentation to ED was 38 mg/dL). Follow up labs showed a fasting glucose 86 mg/dL, insulin level 4.2 IU/ml (1.9-23. 0 IU/ml), c-peptide 1.3 ng/ml (0.8-3.5 ng/ml), AM cortisol 22.6 mcg/dL (6.7-22.6 mcg/dl) and hemoglobin A1C 5.3%. Thyroid function test was normal. Sertraline was discontinued and he was on continuous glucose monitoring for 6 months during which there were no hypoglycemic episodes. The exact mechanism of sertraline-induced hypoglycemia remains unclear.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN296 Impact of Diabetes Mellitus on Outcomes of Hospitalizations for SIADH
Authors: Awoyomi Moyosoluwa , Ojemolon Pius , Shaka Hafeez , Koshbin Katayoun , Kwei-Nsoro Robert , Olafimihan Ayobami
Published: November 2022

Introduction

Diabetes mellitus (DM) is known to cause hyponatremia via multiple mechanisms and is often a confounder in the diagnosis of the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, not much is known about the prevalence of DM in patients with SIADH or the effect it has on outcomes of hospitalizations for SIADH.

Method: Data was extracted from the US Nationwide Inpatient Sample (NIS) for 2019. The NIS contains hospital discharge information estimating yearly US hospitalizations. We included hospitalizations with a principal discharge diagnostic code for SIADH using the ICD-10-CM code (E22.2). We excluded hospitalizations of patients less than 18 years. This cohort was divided based on the secondary diagnosis of diabetes mellitus (DM).

We compared inpatient mortality rates, mean length of hospital stay (LOS), mean hospitalization cost (THC), and rates of septic shock, acute myocardial infarction (AMI), acute respiratory failure (ARF), acute renal failure (AKI), and acute pulmonary edema (PE) between the subgroups. Adjustments were made for age, sex, race, primary payer, median household income by zip code, Charlson Comorbidity Index (CCI), hospital location, bed-size, and teaching status using multivariate regression analysis. Statistical significance was set at a p-value < 0.05.

Results

In 2019, there were 39,110 hospitalizations with SIADH as the reason for the admission. Comorbid DM was prevalent in 25.4% of these admissions. A higher proportion of hospitalizations involved females, with no significant difference between both cohorts (62.3 vs 60.1%, p=0.084). Patients with DM had a higher mean age (73.3±12 vs 72.4±13.8 years, p=0.005), a higher proportion of CCI >2, and a higher proportion of ethnic minorities.

In patients with SIADH, DM was associated with no mortality difference (1.2% vs 0.9%, p=0.317) and no difference in LOS (4.9 vs 5.1 days, p=0.328) despite increased THC (10,873 vs 10,641 US$, p =0.03). Comorbid DM was associated with lower odds of AMI (0.4 vs 0.8%, aOR: 0.315, p=0.002), PE (0.15 vs 0.4%, aOR: 0.22, p=0.012) and ARF (6.8% vs 7.5%, aOR: 0.77, p=0.016), higher odds of AKI (15.9 vs 10.7, aOR: 1.23, p=0.008), with no significant difference in odds of septic shock or CVA.

Conclusions

Comorbid DM was associated with no difference in mortality or LOS despite an association with increased THC and AKI in hospitalizations of patients with SIADH. Notably, DM also appeared to lower the odds of AMI, PE, and ARF in this cohort of patients.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN315 Elevated Serum B12 Levels are Associated with Diabetes
Authors: Anwaar Neelum , Chang Villacreses Maria M , Chiu Ken
Published: November 2022

Background

Vitamin B12 is an essential nutrient found in diverse food sources. Prokaryotic beings are capable of production through de novo aerobic and anaerobic biochemical reactions. It is common wisdom that diabetics, especially those receiving metformin, have vitamin B12 deficiency. However, little is known about the relationship between B12 levels and glucose tolerance.

Methods

A retrospective analysis of vitamin B12 levels and glucose tolerance in a representative U.S. population was performed. Records from the 2011-2014 National Health and Nutrition Examination Survey were reviewed. Individuals over the age of 20 were grouped according to a history of diabetes, Hb A1c levels, and fasting or 2-hour glucose tolerance test results into normal glucose (NG), abnormal glucose tolerance (AGT), and diabetes. A total of 19, 931 individuals were identified. Sample weighted analyses were performed with adjustment for the covariates of age, gender, body mass index, race/ethnicity, education, poverty index, current smoking, current alcohol consumption, family history of diabetes, vitamin B12 intake, and metformin use.

Results

Serum vitamin B12 levels were significantly higher among individuals with diabetes compared to those defined as AGT and NGT patients (496±14, 453±6, and 443±8 pmol/L, mean ± SE respectively, P=0.004). Diabetic individuals taking metformin had significantly lower serum vitamin B12 levels than diabetics not using metformin (445±16 vs. 518±13 pmol/L, P=0.0005). After exclusion of metformin users, diabetic subjects still had significantly higher serum vitamin B12 levels than NGT and AGT individuals (498±15, 456±6, and 445±8 pmol/L, respectively, P=0.006). The frequency of vitamin B12 supplement use was similar among diabetic, NGT, and AGT subjects (31%, 33%, and 31%, respectively, P=0.30). Likewise, the quantity of vitamin B12 supplementation was similar among the groups (233±34, 189±18, 192±24 mcg/day, respectively, P=0.50).

Retrospective analysis found higher serum B12 levels in diabetics compared to individuals with abnormal and normal glucose homeostasis. This novel finding was not secondary to exogenous B12 supplementation in diabetic individuals. Not unexpectedly, in individuals with diabetes, metformin exerted a negative effect on B12 levels. While the causes of elevated B12 in these individuals remain unknown, analysis of the intestinal bacterial flora and metabolome may be warranted.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN329 Non-islet Cell Tumor Hypoglycemia Secondary to Advanced Hepatocellular Carcinoma in a 29-Year-Old Male
Authors: Bao Ginny , Chang Christine , Price Austin , Yin Anthony
Published: November 2022

Summary: Non-islet cell tumor hypoglycemia (NICTH) is a rare, but serious complication that can be seen in most all tumors. It is typically mediated by high levels of an incompletely processed form of insulin-growth factor 2 ("big IGF-2") that is produced by the tumor. We describe a case of a 29-year-old male with history of chronic hepatitis B and advanced stage hepatocellular carcinoma (HCC) who had failed prior chemotherapies. The patient was admitted to the hospital for a liver biopsy, following which he developed severe hypoglycemia, refractory to high dose, continuous dextrose infusion. Evaluation was remarkable for low levels of insulin, proinsulin, C-peptide, and IGF-1, normal cortisol, and an IGF-2: IGF-1 ratio of 8, suggestive of NICTH due to IGF-2, although the patient's hypoglycemia may additionally have been due to worsening, and strikingly extensive tumor invasion of the liver. This patient was unfortunately not considered a surgical candidate; hypoglycemia was ultimately controlled with initiation of high dose corticosteroids and total parenteral nutrition with high amounts of dextrose.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN337 Evaluation of Intensive Behavioral Therapy as a Tool to Combat Obesity in a Rural Outpatient Endocrinology Clinic
Authors: Kabir Purnima , Lewis Chantal , Peñaherrera Carlos A
Published: November 2022

Introduction

The prevalence of obesity in the United States has risen from 30.5% in 2000 to 42.4% in 2018. Given this steep increase and the association of obesity with multiple comorbidities, the focus has now turned to behavioral modifications. In 2011, Medicare began to reimburse providers for intensive behavior therapy (IBT) for obesity.

Background

Medicare beneficiaries with a BMI ≥ 30 kg/ m2 are eligible for IBT. The program at Hamilton Diabetes and Endocrinology Center (HDEC), followed a structure similar to that of the nationwide IBT program. It begins with a nutritional assessment and a personalized lifestyle intervention plan. The program includes 20 visits over a 12-month period. At the six-month point mark, we aim to achieve a target weight loss of 6.6 lbs. A thorough literature review revealed limited data on the outcomes of the program. The purpose of our study is to present data which has shown effectiveness of this program in the rural setting.

Methods

A retrospective cohort study was conducted with data obtained between September 2020 to October 2021. The sample being studied included 96 participants after exclusion of those that were unable to complete the program. The participants were matched based on their baseline demographic characteristics. The outcomes studied were weight in pounds, BMI and HbA1C. Using paired t-tests we compared the change in weight before and after implementation of the program, with BMI and HbA1C as secondary outcomes.

Results

The participants began the IBT program with an initial mean weight of 249.4 lbs. and ended the program with a final mean weight of 244.7 lbs. Comparison of the data using paired t-tests revealed that the change in weight was about 4.7 lbs. (95% confidence interval of 2.9 - 6.6, P <0.001). The change in BMI was 0.8 kg/m2 (95% CI: 0.5–1.1, P <0.001). About 31.25% of our study participants were able to lose more than 6.6 lbs. However, it is pertinent to note that our study was conducted during the time of the pandemic, leading to missed appointments and effects on lifestyle. Despite our limitations, the data revealed a statistically significant difference in weight and BMI at the final visit compared to the initial visit. The HbA1C values were reduced by 0.25%, however this change was not statistically significant (P = 0.185).

Conclusion

Analysis of the IBT program at the HDEC has shown a favorable response. In an ideal world, free of limitations by the pandemic, this program is likely to, achieve an even greater degree of weight loss. This brings about a need for raising awareness within the community. Implementation of IBT programs and promoting lifestyle interventions result in reduction of obesity and therefore lead to an improved quality of life.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN339 Persistent Hypoglycemia and Hyperinsulinism in a Patient With Kabuki Syndrome Type 1.
Authors: Gomez Patricia , Stosic Mariana Nunez
Published: November 2022

Background

Transient neonatal hypoglycemia typically resolves within the first few days of life. Persistence of neonatal hypoglycemia is a more significant finding that warrants further investigation.

Clinical case

A 2-year-old female born at 37 weeks of gestation via C-section due to a history of maternal preeclampsia. Delivery was complicated by meconium aspiration syndrome for which the patient was admitted to the NICU where she had a prolonged course. Patient was initially depressed at birth with APGARs of 3/6/8 at 1, 5 and 10 minutes of life, respectively. During the neonatal period, she had multiple complications including GERD, FTT (G-tube was placed), recurrent UTIs, congenital heart disease (mild RVH and ASD) and hypoglycemia.

Regarding her hypoglycemia, the initial work up was suggestive of hyperinsulinism with a critical sample remarkable for a BG: 57 mg/dl (60-100mg/dl), Insulin level: 8.3 uUm/mL Subsequent glucagon challenge test confirmed hyperinsulinism. She initially required a continuous glucose infusion and Diazoxide was started. She was discharged home on Diazoxide and Diuril. Subsequently, Diazoxide was successfully discontinued at the age of 2 months. A Congenital Hyperinsulinism genetic panel was negative for the most frequent mutations.

At 11 months old, she presented to our clinic due to persistent hypoglycemia when enteral feeds were attempted to be spaced. Patient was started on cornstarch which was discontinued secondary to frequent diarrhea. SolCarb was started with enteral feeds with good tolerance and response, maintaining target blood glucose levels.

On physical examination, she had some dysmorphic features that were suggestive of a syndromic condition: prominent ear lobes, broad and flat nasal bridge, a single prominent tooth at the center of the bottom gum line, long palpebral fissures with upward curvature at the lateral edges, prominent finger pads and neurodevelopmental delay.

Since she had features suggestive of Kabuki syndrome, WES was ordered which was remarkable for a pathogenic mutation in KMT2D (Autosomal dominant, Heterozygous, variant c.5269C>T and p.R1757X).

Conclusion

Persistent hypoglycemia beyond the neonatal period is a rare finding in Kabuki syndrome. In addition, it is a more common finding in Kabuki Syndrome type 2 (Mutations in the KDM6A gene).

Our patient presents a rare case of a 2-year-old female with persistent hypoglycemia and hyperinsulinism secondary to KS1.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN133 Assessment of the Rnf20 Histone Modifier in Regulating Pancreatic Beta-Cell Identity and Function
Authors: Pierre Tanya , Liu Yanping , Bethea Maigen , Hunter Chad
Published: November 2022

Type 1 and Type 2 Diabetes are characterized by a loss of functional pancreatic islet β-cells. With the prevalence of diabetes increasing worldwide, a complete understanding of the gene regulatory mechanisms governing the development and function of insulin-producing β-cells is requisite for improving diabetes therapies. Islet 1 (Isl1) is a LIM-homeodomain class transcription factor (TF) required for the maturation, proliferation, function, and survival of islet cells. In our previous study, we identified Isl1 interactions with the ring finger ubiquitin ligases Ring Finger 20 (Rnf20) and Rnf40 in mouse β-cell extracts, mouse islets, and human islets. Rnf20 and Rnf40, exist as homodimeric or heterodimeric complexes to deposit a mono-ubiquitin epigenetic mark on histone (H)2B (i.e., H2Bub1) and regulate gene transcription as a precursor to active H3K4 trimethylation (H3K4me3) and H3K79 methylation (H3K79me) marks. We demonstrated that Rnf20 and Rnf40 are required for the expression of several important β-cell genes and glucose-stimulated insulin secretion in vitro. Specifically, loss of Rnf20and Rnf40 in MIN6 β-cells resulted in a significant dysregulation of β-cell Slc2a2/Glut2 and MafA expression, target genes which were occupied by Rnf20 and H2Bub1. Additionally, using proximity ligation assay (PLA) in MIN6 β-cells, we demonstrated a robust increase in interactions between Isl1 and Rnf20 under high glucose conditions. Based on this, we hypothesize that Rnf20 and/or Rnf40 are required to establish and maintain β-cell identity in adult islets. To begin addressing this, we disrupted Rnf20/Rnf20 and/or Rnf20/Rnf40 complexes in β-cells via generation of adult inducible Rnf20 β-cell-specific knockout mice. In the adult inducible model, 2 weeks following tamoxifen induction (i.e., by 8 weeks of age) both male and female mice became hyperglycemic and severely glucose intolerant. These 8-week-old Rnf20-deficient mice also had reduced plasma insulin following a glucose challenge yet normal insulin sensitivity. Islet RNA exhibited dysregulated mRNAs encoding islet hormones, glucose-stimulated insulin secretion markers, and β-cell identity markers, including Slc2a2/Glut2, Ucn3, and Hb9 . Our findings of similar phenotypes between Isl1 and Rnf20 adult knockout models, a glucose sensitive interaction between Isl1 and Rnf20, and their occupancy of the Slc2a2/Glut2 locus support mechanisms of Isl1-Rnf driven β-cell regulation.

Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN163 In High Glucose Exposed Endothelial Cells BTK is a Novel Component of the Nuclear Factor-Kappa B Pathway
Authors: Singh Madhu , Badr Heba , Moorjani Sonia , Wong Thomas , Dokun Ayotunde
Published: November 2022

Peripheral artery disease (PAD) is atherosclerotic occlusion of vessels outside the heart and most commonly affects the lower extremities. Diabetes worsens PAD outcomes, but the mechanisms involved are poorly understood. A key component of perfusion recovery in experimental PAD is induction of NFkB signaling in ischemic endothelial cells (EC). We have shown that prolonged exposure of ECs to high glucose before simulated ischemic exposure resulted in impairment of the canonical NFkB pathway through activation of protein kinase C β (PKC β). However, the signaling pathways upstream of PKC β involved in this high glucose induced desensitization of NFkB signaling are not known. We used arrays of antibodies to approximately 100 proteins known to participate in the NFkB pathway to identify the changes in their phosphorylation states in human umbilical vein endothelial cells (HUVEC). Cells grown for three days either in culture medium with normal glucose (NG) or high glucose (HG) were subjected to ischemia for 24 hours (NGI and HGI, respectively). Cell lysates were then incubated with the array of antibodies printed on glass slides and fluorescent signals were digitally recorded and normalized. The change in protein phosphorylation was calculated by dividing the intensity of the phosphorylated spot by the signal intensity of the corresponding non-phosphorylated spot for each protein. Differential expression between samples, were calculated by dividing the phosphorylation ratio of the NGI and HGI with that of the NG and HG controls, respectively. A combination of pathway analyses using bioinformatics tools on 65 modulated phosphorylation sites in HGI (represented by 35 genes) and analysis of differential phosphorylation between NGI and HGI samples suggested involvement of B cell linker/adapter protein (BLNK)/Bruton's tyrosine kinase (BTK). BTK plays a key role in B cell antigen receptor (BCR)-coupled signaling but not known to be expressed in ECs or play a role in EC function. Here we confirmed BTK expression in ECs by immunoblotting. Inhibition of BTK by a specific inhibitor terreic acid or by shRNA mediated knockdown decreased PKCβ-S661 phosphorylation and restored NFkB activation in ECs suggesting a critical role of BLNK/BTK in the EC. Thus, we have identified BLNK/BTK as a potentially new component of the NFkB pathway in ECs that may be a therapeutic target to improve PAD outcomes in diabetes.

Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN333 Divergent Pathways in Liver Triglyceride Storage and Secretion in Partial Lipodystrophy vs. Obesity Associated NAFLD
Authors: Klein Rachael , Viana Gracia , Koh Christopher , Brown Rebecca , Rotman Yaron
Published: November 2022

Background

Partial lipodystrophy (PL) syndromes are characterized by deficiency of subcutaneous fat, increased liver fat and insulin resistance (IR). Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality in both PL and obesity. Hepatic lipid derives from re-esterification of free fatty acids (FFA) from adipose tissue lipolysis and dietary sources, as well as de novo lipogenesis. Hepatic TG can be used for energy by β-oxidation, stored in hepatocytes as lipid droplets or secreted as VLDL. Hepatosteatosis develops when the rate of intrahepatic TG production is greater than the rate of TG disposal (oxidation and secretion). Here we investigate the contributions of insulin resistance and adipose tissue to hepatic steatosis in patients with PL vs non-syndromic, obesity associated NAFLD (NAFLD).

Methods

Single-center retrospective analysis of subjects with NAFLD (N=73) and PL (N=28). Fibroscan Controlled Attenuated Parameter (CAP) was used to estimate liver fat. A1c, β-hydroxybutyrate, and circulating lipids by NMR were measured simultaneously and within 6 months of CAP measurement. Insulin resistance was estimated by HOMA-IR (fasting glucose x insulin ÷ 405) and LP-IR (a lipoprotein-based measure of IR derived from circulating lipid particles).

Results

The PL group was 86% female vs 48% in NAFLD (P<0.001) and younger (43±8 vs. 50±14 years, P<0.03). BMI was lower PL vs NAFLD (27±6 vs 33±6 kg/m2, P<0.0001). Fasting insulin was not statistically different between PL and NAFLD (median 26.4 [interquartile range 21.3,51.2]) vs 31.6 mcU/L [15.1-33.4], P=0.052); however, IR was more severe in PL vs NAFLD based on both HOMA-IR (15.5±16.2 vs 7.6±5.2, P=0.003) and LP-IR (65.1±19.3 vs 58.5±16.7, P=0.03). A1c was higher in PL (7.5±2.1 vs 5.9±0.8%, <0.001). CAP was similar in PL and NAFLD (301±57 vs 320±49 dB/m, P=0.1). CAP correlated with HOMA-IR in both PL (r=0.51, p=0.01) and NAFLD (r=0.44, p=0.003), but for any given HOMA-IR liver fat was lower in PL vs NAFLD. FFA levels were comparable between groups (0.52± 0.28 vs 0.50±0.27 mEq/L, P=0.058). TRLP concentration by NMR was higher in PL compared to NAFLD (240±123 vs165±86 nmol/L, p=0.001) as was β-hydroxybutyrate (162±67 vs 115±58 mmol/L, P=0.004).

Conclusions

Patients with PL have comparable liver fat vs. non-syndromic NAFLD despite worse insulin resistance. To understand the lower liver fat relative to insulin resistance in PL, we examined input, oxidation, and export of lipid from the liver. Surprisingly, despite lower adipose mass in PL vs NAFLD, FFA input to the liver was similar. Hepatic fat oxidation and export, estimated by β-hydroxybutyrate and large VLDL respectively, were both higher in PL. This suggests a shift of fat storage out of the liver into the circulation in PL.

Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN334 Mineralocorticoid receptors mediate diet - induced lipid infiltration of skeletal muscle and insulin resistance
Authors: Habibi Javad , Hulse Jack L , Jia George , Jia Prof Guanghong , Sowers James R , Whaley-Connell Adam
Published: November 2022

Excess blood lipids increase the total intramyocellular (IMC) lipid content and ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscle, which is one of the main targets of insulin whose action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), has been shown to activate mineralocorticoid receptors (MRs) to promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles and mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic lipid accumulation and related insulin resistance in diet-induced obesity. Six week-old C57BL6J mice were fed either a mouse chow diet or WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD - induced in vivo glucose intolerance and improved soleus insulin metabolic signaling (protein kinase B and AMP kinase α pathways). Improved insulin sensitivity was accompanied by increased Glut-4 expression in conjunction with decreased IMC lipid content and reduced free fatty acid (FFA) levels and CD36 expression in soleus skeletal muscle tissue. Related to this, miR-99a was identified to negatively target CD36(www.targetscan.org/vert_72/) and elevated CD36 induced excessive FFA uptake, ectopic lipid accumulation, as well as systemic and tissue insulin resistance. Furthermore, in skeletal muscle cells spironolactone prevented enhanced MR signaling mediated reduction of miR-99a and related increased CD36. These data indicate that inhibition of MR activation with spironolactone reversed diet - induced reduction of miR-99a, thereby reducing CD36 expression, leading to reduced IMC lipid content and improved soleus insulin sensitivity.

Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN376 Incidence of Diabetes Mellitus Following Pancreatic Surgery in Individuals with Multiple Endocrine Neoplasia Type 1
Authors: Else Tobias , Henry Marie-Louise , Koeppe Erika , Osborne Jenae , Wolf Katherine
Published: November 2022

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by hyperparathyroidism, pituitary adenomas, and well-differentiated neuroendocrine tumors of the foregut. Pancreatoduodenal neuroendocrine tumors are often managed via surgical intervention, which increases the risk for new onset, post-operative diabetes mellitus (DM). Current estimates of post-operative DM in MEN1 range between 10-86%. Here, we present a retrospective review of the incidence of DM following pancreatic surgery in individuals with MEN1at a single tertiary care center between 2005-2021.

Patients with a clinical or molecular diagnosis of MEN1 with and without pancreatic surgery were identified via the electronic medical record system. A retrospective chart review collected baseline demographic and clinical data. Individuals with an insulinoma diagnosis were excluded. A diagnosis of DM was defined as a hemoglobin A1c greater than 6.5%, fasting plasma glucose level greater than 126 mg/dl, or a random plasma glucose greater than 200 mg/dl.

One-hundred and eighteens adult patients (66F, 52M) with MEN1 were identified. Radiographic evidence of a pancreatic tumor was demonstrated in 84 (71.2%) patients, of which 49 (41.5%) underwent surgical resection (40 (81.6%) distal pancreatectomy with or without enucleation, 6 (12.2%) Whipple procedure, 2 (4.1%) enucleation, and 1 (2.0%) total pancreatectomy) of a pancreatic neuroendocrine tumor (pNET). All but one individual were included in the post-surgical study cohort as it was unknown if onset of DM preceded operation. Fourteen (28.5%) underwent another subsequent pancreatic surgery. Of the above 48 surgical patients, 3 (6.1%) had a pre-operative diagnosis of diabetes. Within the remaining 45 patients, 31 (68.9%) developed a diagnosis of DM following surgery (mean post-operative onset 4.2 years [range 0.1–16.3]). Of the 69 individuals who did not undergo surgery but did have a diagnosis of MEN1, just 15 (21.7%) developed DM and at an older average age 53.4 [range 14–70] when compared to their surgical cohorts 47.5 [range 27–75].

With 61.2% of patients with resected pNET developing DM compared to their non-operative counterparts (21.7%) (p = 0.25), there is a strong suggestion of morbidity associated with pancreatic surgery secondary to the development of DM. Endocrinologists and surgical teams should be aware of the associated risks and screen accordingly with yearly hemoglobin A1c compared to the standard three-year interval begun at age 45 as suggested by the American Diabetes Association. Additionally, patients should be appropriately educated on the signs/symptoms of DM.

Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF27 | LBSUN361 Understanding The Genetics Of Multiple Endocrine Neoplasia Type 1: The Road Ahead
Authors: Worthy Charlita
Published: November 2022

Background

About 10-30% patients have genotype-negative (GN)-MEN1. Here, we compare our cohort of comprehensively phenotyped GN-MEN1 and genotype-positive (GP)-MEN1 patients. We also investigate somatic mosaicism as a cause of GN-MEN1.

Methods

GN-MEN1 patients showed no mutations in MEN1 or other primary hyperparathyroidism (PHPT) genes (CASR, RET, CDKN1B, CDC73, AIP, GNA11, AP2S1, GCM2) performed per clinical indication. Index patients (first patient in kindred to be diagnosed with MEN1) or probands (first patient in kindred to be evaluated at our center) from kindreds with GP-MEN1 were identified. All patients underwent testing for tumor biomarkers, imaging and evaluation for Zollinger-Ellison syndrome (ZES). Whole exome sequencing was performed on multiple tumors from 13 GN-MEN1 patients. GP-MEN1 patients were also categorized into high-impact (nonsense, frameshift, splice site, whole or partial gene deletion) or low-impact (missense or in-frame indels) mutation-bearing groups.

Results

We identified 43 (31 females, 12 males) patients with GN-MEN1 and 160 (102 index, 58 probands) patients with GP-MEN1 (98 females, 62 males). Among GP-MEN1, 97 had high impact and 34 had low-impact mutations. Mean age at last follow-up was 56 (±14) years for GN-MEN1 and 52 (±16) years for GP-MEN1 patients. Among the GN-MEN1 patients, 38/42 developed PHPT - 3/38 (8%) had recurrent disease. In GP-MEN1, 144/149 developed PHPT - 83/144 (58%) with recurrent disease. Median age of index presentation with PHPT significantly differed between the groups (27.5 years in GP-MEN1 vs 53 years in GN-MEN1 (χ2 (1)=5.5: p <0.05)). 33/42 GN-MEN1 patients had a pituitary adenoma (22/33 functioning - 9/22 prolactinomas; 8/22 GH-secreting). In comparison, 94/145 GP-MEN1 patients developed a pituitary adenoma (51 functioning - 37/51 prolactinomas, no GH-secreting tumors). In the GN-MEN1 group, 12/42 (29%) patients developed a gastro-entero-pancreatic (GEP)-NET. In comparison, 86/130 (66%) patients with GP-MEN1 had a GEP-NET. Somatic variants in MEN1, CDC73 or CDKI were observed in six tumors. However, these mutations were not seen in another tumor/s or germline DNA from the patient. All patients with high-impact mutations had PHPT (63% had recurrent disease), 70% had pituitary tumors (35% with macro-adenomas) and 61% developed GEP-NETs (29% with distant metastases). In comparison, 91% patients with low-impact mutations developed PHPT (41% with recurrent disease), 69% developed pituitary tumors (23% with macro-adenomas) and 65% developed GEP-NETs (35% with distant metastases).

Conclusion

Patients with GP-MEN1 generally experience younger age of onset, greater likelihood of recurrent PHPT and co-occurrence of GEP-NETs in comparison to GN-MEN1. Our findings do not support somatic mosaicism as a cause of GN-MEN1. No apparent correlation in phenotype between high-impact vs. low-impact mutations is noted.

Presentation: Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.
PSAT047 Dual Heterozygous Mutations in CYP21A2 and CYP11B1 in a Case of Nonclassic Congenital Adrenal Hyperplasia
Authors: Frontera Eric , Brown Joshua J , Ghareebian Hagop , Mariash Cary
Published: November 2022

Background

Congenital Adrenal Hyperplasia (CAH) is classically attributed to defective 21-hydroxylase, caused by mutations in CYP21A2, impairing the production of mineralocorticoids and glucocorticoids and subsequently shifting steroidogenesis towards androgen production. This produces a classic constellation of neonatal symptoms, including genital virilization, salt-wasting, and adrenal crisis. A rare cause of CAH is a defect in 11β-hydroxylase from a mutation in CYP11B1, preventing production of cortisol and corticosterone, resulting in hypertension, hypokalemia, and androgen excess. Reports of combined mutations in CYP21A2 and CYP11B1 in the literature and the clinical manifestations of such a case are not well described. Here we present a case report wherein a pair of heterogenous mutations in CYP2A12 and CYP11B1 were detected in a new diagnosis of nonclassic Congenital Adrenal Hyperplasia, including a previously undescribed mutation in CYP11B1.

Clinical Case

The patient is a 30-year-old female who presented to her primary care clinic with teenage-onset irregular menses occurring every 2-3 months. She also reported hirsutism, but never had acne, changes in thirst or urination, or breast discharge. Primary evaluation revealed prolactin of 34.7 ng/mL, prompting a pituitary MRI which revealed a 2×3mm lesion. At this point, referral was made to endocrinology for endocrinological. PCOS was felt to be the top differential for her hirsutism and irregular menses but further workup to rule out CAH revealed a 17-OH-Progesterone of 554 ng/dL and a Testosterone of 83 ng/dL. Subsequently, a 250 mcg cosyntropin test increased 17-OH progesterone to 837 ng/dL and resulted in a cortisol of 24.7 mCg/dL after 60 minutes. Subsequent CAH gene sequencing was performed and revealed a heterogeneous pathogenic CYP21A2 variant (c.332_339 del; p.Gly111Valfs*21) and a heterogeneous previously undescribed variant of undetermined significance in CYP11B1 (c.1123C>T; p.Leu375Phe).

Conclusion

At least 100 mutations of CYP11B1 have been found to cause CAH due to 11β-Hydroxylase deficiency. Our case adds to the growing database of described mutations in CY11B1 and suggests that heterogenous mutations in two different genes may present phenotypically as nonclassic CAH in a potentially epistatic fashion. This enriches earlier conclusions that broader genetic analysis beyond CYP21A2 deletions is needed to identify the genotypes of those with CAH due to the complex diversity of genetic mutations, and ought to remind clinicians to consider it as a diagnosis, particularly in young women whose hyperandrogenism or menstrual irregularities cannot be explained by common endocrinological abnormalities or do not have an appropriate response to traditional treatment.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.