bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-Fasting Hypoglycemia Secondary to Opioid Induced Adrenal Insufficiency: A Case Report
Authors: Kubbar Alaa , Banerji Maryann
Published: May 2021

Background: A patient on chronic methadone therapy presented following a suicide attempt, was noted to have recurrent episodes of non-fasting symptomatic hypoglycemia and was diagnosed with opioid induced adrenal insufficiency (OIAI). Opioid induced endocrinopathies are underappreciated, particularly in the midst of a growing opioid epidemic in the United States. We believe this is the first reported clinical case of OIAI associated with non-fasting hypoglycemia. Clinical Case: A 33-year-old female with history of depression and heroine abuse on methadone therapy presented after a suicide attempt by methadone overdose. Home medications included 170mg of methadone daily for the past 5 years. She was afebrile, heart rate of 68, blood pressure 102/72, respiratory rate of 10, oxygen saturation 92%. On exam she was lethargic with altered mental status and had pinpoint pupils. Labs showed a normal complete blood count and metabolic panel. Urine toxicology was positive for methadone. Clinical picture improved temporarily after Narcan administration however 1 hour later she was confused again, with a fingerstick glucose of 50mg/dL and she was admitted to ICU for monitoring. In the ICU she continued to be lethargic with dizziness, nausea and headaches. She continued to have approximately 4 spontaneous episodes of hypoglycemia per day, despite having a good appetite and increased parenteral glucose administration. Blood pressure continued to be marginal, ranging from 85–100/50–60. There was no obvious source of infection. Urine sulfonylurea screen was negative. Investigations showed a morning cortisol of 2.23 ug/dL. A 250 µg ACTH stimulation test showed an inadequate response. The am basal plasma cortisol was 2.25 ug/dL with 15.28 ug/dL and 15.13 ug/dL at 30 and 60 minutes respectively (6.20–19.40ug/dL). She was diagnosed with hypoglycemia secondary to OIAI. Given the patient’s critical condition she was initially started on stress dose of hydrocortisone 80mg every 8 hours. Attempts to down titrate the methadone dose were unsuccessful. Patient’s symptoms improved and hypoglycemia subsided. She was discharged home on hydrocortisone 10mg qam & 5 mg qpm and she was continued on Methadone 170mg daily. Conclusion: OIAI is an under-recognized clinical entity with potentially serious adverse outcomes. Currently, 3% to 4% of US adults receive long-term opioid treatment. OIAI is present in 9—29% of individuals on chronic opioids. Opioids act through suppression of the HPA axis, primarily at the level of the hypothalamus, mediated through either delta or kappa receptors leading to a decrease in ACTH and cortisol secretion. Management should include decreasing and ideally discontinue opioids, along with glucocorticoid replacement until documented recovery of the HPA axis. Reference: Reference: (1)Donegan, Diane et al. Opioid-Induced Adrenal Insufficiency. Mayo Clin. Proc. 2018 93(7), 937–944.
A Novel GATA3 Variant Causing Familial Hypoparathyroidism, Renal Agenesis and Sensorineural Deafness Presenting With Atypical Symptoms of Chronic Hypocalcaemia
Authors: Gaur Smriti , Page Suzanne , Khizer Mansoor , Rehman Shoib
Published: May 2021

Introduction: Familial hypoparathyroidism is a rare cause of hypocalcaemia. We report a case of long-standing hypocalcaemia secondary to hypoparathyroidism caused by a novel GATA3 variant resulting in multiple organ involvement. Case: A 20 year old girl was referred to our bone metabolic clinic for hypocalcaemia. Her past medical history included Bechet’s disease, epilepsy and depression. She had bilateral sensorineural hearing loss and encephalitis as a child. She underwent right nephrectomy for an atrophic non-functioning kidney at the age of 16. Current medication included hydroxychloroquine, diazepam, oral calcium and cholecalciferol. It was noted that the hypocalcaemia dated back to 8 years, she denied any typical symptoms of hypocalcaemia but she did report visual and auditory hallucinations, fatigue and had low seizure threshold. She sustained recurrent fractures of her arm, elbow and wrist. Initial investigations: Corrected calcium 1.88 (2.20-2.60mmol/L), Phosphate 1.54 (0.80–1.50mmol/L), PTH 1.2 (1.6–6.9pmol/), 25-OH vitamin D 37 (50-120nmol/L). Myeloma screen, thyroid, renal and liver functions were all within the normal reference range. Other bone markers: Serum Procollagen Type 1 Amino Terminal Peptide was mildly raised at 82 (19-69ug/L), CTX 0.42 (0.1-0.5ug/L), 1,25 OH Vitamin D 29 (55-139pmol/L), 24,25-dihydroxyvitamin D was normal with normal 25:24,25 Dihyroxyvitamin D ratio at 18 normal. Bone density was in the normal range for her age. MRI of the brain was normal with no evidence of calcification. There was a family history of hypocalcemia in her estranged father. Subsequent genetic analysis showed a novel likely pathogenic GATA3 missense variant (c.961T>C p.(Cys321Arg). She was started on alfacalcidol and achieved near normocalcemia with adjusted calcium levels of 2.18nmol/L. Conclusion: Pathogenic variants in the GATA3 gene are responsible for Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome. In our patient, a novel missense variant in GATA3, p.(Cys321Arg), has been detected. This variant disrupts one of four conserved cysteine residues within a zinc-finger domain, which is involved in DNA binding and is presumed to have a deleterious effect on protein function. Patients may have longstanding asymptomatic hypocalcaemia with atypical features hence genetic testing is recommended in patient with multi-organ involvement. Alfacalcidol successfully restored calcium homeostasis in this case.
Paget’s Disease of Bone Affecting Site With Orthopedic Hardware
Authors: Serrano Santiago Ivan A , Lucier Jessica , Petak Steven Michael
Published: May 2021

Introduction: Paget’s disease of bone is a focal disorder of accelerated bone remodeling which leads to bone hypertrophy, cortical expansion and abnormal bone architecture. Either a single bone (monostotic) or multiple bones (polyostotic) can be affected. Although it has been suggested to be caused by a chronic slow viral infection of the bone, a cause and effect relationship has not been clearly established. Therefore, the etiology of Paget’s disease remains an uncertain and controversial topic of discussion. Case Description: A 62-year-old African American male with a past medical history of a left tibial fracture presented with worsening left leg pain for the past 6 months. He denied any recent traumatic events, falls or strenuous physical activity. Since the pain started, his ambulation had been significantly affected requiring the use of a cane for gait stability. His left tibial fracture occurred over 20 years ago after landing on another person’s foot while playing basketball. It was surgically treated with intramedullary nailing and metal rod insertion into the canal of the tibia. Since then, he remained an active person with no physical limitations or ailments until the recent developments that brought him to clinic. A left leg CT-Scan ordered for evaluation of the tibial hardware revealed cortical thickening, marrow expansion and coarse trabeculae throughout the majority of the tibia consistent with Paget’s disease. The hardware was intact with no peri-hardware lucency to suggest loosening or infection. His laboratory workup showed a normal alkaline phosphatase level (94 U/L; normal range 40 - 115 U/L) and low 25-OH Vitamin D level of 14. A Radionuclide Bone Scan done for evaluation of location and extent of bone disease resulted in diffusely abnormal uptake present in the left tibia with no other locations of suspicious uptake. After his 25-OH Vitamin D levels were replenished, a dose of Zoledronic acid IV infusion was given with significant improvement of pain several months after. Discussion: Paget’s disease of bone is the second most common bone disease after osteoporosis. Affected skeletal sites develop a disorganized mosaic of woven and lamellar bone more susceptible to deformities and fractures than normal bone. It is often asymptomatic, but classical features include bone pain experienced either at rest or with motion, cutaneous erythema and warmth. The goal of medical therapy is to relieve symptoms and to prevent future complications with high potency bisphosphonates. Although it is well known that Paget’s disease increase the risk of fractures, this case brings up an interesting take about the possibility of fractures managed with hardware placement increasing the risk of Paget’s disease in the involved site.
Persistent Calciphylaxis and Secondary Hyperparathyroidism in End Stage Renal Disease Patient Due to Ectopic Mediastinal Parathyroid Adenoma- A Case Report
Authors: Abdelmasih Randa , Abdelmaseih Ramy , Monsour Elio Paul , Hasan S Mustajab , Vesely Josef James Karl
Published: May 2021

Intruducion: Secondary hyperparathyroidism (SHPT) is prevalent in patients with end-stage renal disease (ESRD) with reported prevalence of 90%. SHPT treatment is usually medical. Although 5% ends up with parathyroidectomy. Indications of parathyroidectomy in ESRD patients include persistent elevation of PTH more than 800, Calcyphylaxis, Osteitis Fibrosa Cystica, and persistent anemia. Among these patients who require surgery, 5–20% present with persistent or recurrent disease and require further re-exploration and excision of parathyroid tissue. We present a case of persistent Calciphylaxis and SHPT in ESRD patient despite Parathyroidectomy which prompted diagnosing an ectopic mediastinal parathyroid adenoma. Case Presentation: 49 year-old male with ESRD for 15 years complicated with SHPT, presented due to worsening Caciphylaxis of bilateral lower extremities despite Cinacalcet, IV sodium thiosulfate, and Phosphate binder. Serum Calcium level was 9.0 mg/dl with corrected levels of 10.2 mg/dl, Phosphorus level of 9.3 with Intact PTH level 1,369 pg/ml. Ultrasound of parathyroid glands was normal. Due to failure of medical treatment, He underwent Total parathyridectomy and left arm parathyroid autograft. Intraoperative PTH level went down to 300 (less than 50%). Calciphylaxis never improved. 5 months later, Parathyroid hormone was elevated 1338 pg/ml, Calcium level 6.9 mg/dl and Phosphorus level 10.0 mg/dl. 99mTc-sestamibi parathyroid scan didn’t show any activity in thyroid gland area and no increased uptake at the autograft area. Although it showed a small focus of persistent activity in substernal area suggestive of ectopic parathyroid tissue. Patient was referred for removal of ectopic adenoma. Discussion: Persistent SHPT is identified as the persistence or recurrence of symptoms, lab abnormalities and radiologic findings within 6 months after parathyroidectomy. Pathophysiology of recurrence is not well studied but one theory suggests that in SHPT, altered Calcium-phosphate hemostasis leads to hyperplasia of parathyroid tissue including ectopic and supernumerary tissue. This aforementioned altered hemostasis continues even after parathyroidectomy and cause hyperplasia and hyperfunction of the residual parathyroid tissue left accidentally by seeding within surgical site or implanted autograft or It can present with ectopic adenoma, even if they were undetected prior to or in the first intervention. Ectopic parathyroid tissue is an uncommon etiology of persistent or recurrent secondary hyperparathyroidism, it is reported in many cases where it was missed at initial workup. Prevalence reported up to 14% in patients with persistent SHPT. It is warranted further investigations to look for ectopic parathyroid tissue in patients with ESRD who present with recurrent or persistent secondary hyperparathyroidism after total parathyroidectomy with reimplantation.
Primary Hyperparathyroidism Presenting With Atrial Fibrillation and Calcified Pericardial Effusion
Authors: Li Francesca , Rogers Rebecca , Rehman Shoib Ur
Published: May 2021

Background: Primary hyperparathyroidism is the most common cause of hypercalcemia and is frequently associated with skeletal and renal complications. It affects the older population and female gender more commonly. Cardiovascular complications due to altered calcium homeostasis are not well recognised or studied but recently cases of calcification of the pericardium, myocardium, valves and dysrhythmias have been reported.

Case: A 47-year old female presented to her GP with atrial fibrillation. Initial blood tests revealed an incidental hypercalcaemia; an adjusted calcium of 2.77 (normal 2.20-2.60mmol/L), raised PTH level of 14.0 (normal 1.6–6.9pmol/L), normal phosphate level and thyroid profile. 25-OH vitamin D level was low 39 (normal 50-120nmol/L). Autoantibody screens and CRP was normal. She was initiated on edoxaban, bisoprolol, and cholecalciferol and treated with a short course doxycycline for a presumed chest infection. There was no history of previous pericarditis but she had long standing hypertension and was obese with BMI of 37kg/m2. Retrospectively patient had sustained a recent wrist fracture and reported classic symptoms of hypercalcemia including fatigue, polydipsia, nocturia, constipation, depression in the endocrinology clinic. Further blood tests found a high C-terminal telopeptide (CTX) level of 0.68 (0.10-0.50ug/L) indicative of high bone turnover.24 urinary calcium/creatinine clearance ratio was 0.0189mmol/mmol (R>0.01 for exclusion of FHH). She was prepped for DC cardioversion and Echocardiogram demonstrated Moderate sized pericardial effusion with some organisation but good biventricular function and dilated LA. Subsequent localisation studies with SPECT CT neck revealed a 9mm parathyroid adenoma along with calcified persistent moderate pericardial effusion putting the patient at risk of pericardial constriction. Patient was referred to the parathyroid surgeon for consideration of urgent parathyroidectomy and will be followed up by the cardiologist to see the impact of normalisation of hypercalcemia on the cardiac complication. It is thought that already established calcification of pericardial effusion is unlikely to resolve but achieving normocalcemia could slow the progression of pericardial calcification and improve bone turnover makers by switching off the excess parathyroid hormone. Patient will be followed up with repeat Echocardiogram post parathyroidectomy to elucidate the effects. Conclusion:Cardiac complications of primary hyperparathyroidism are increasingly becoming more evident with the advent and use of SPECT-CT for localising parathyroid adenomas. Simple screening tests like electrocardiogram may potentially point towards a cardiovascular complication and should be considered routinely in hypercalcaemic patients. Further studies to understand the mechanism of developing cardiac complication in such patients are needed.
Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer
Authors: Balinski Alexander M , Khatter Neil J , Gold Jeffrey M , Pothugunta Krishna S , Garlapaty Vamshi K , Rankin Steven M , Thorburn Christopher A , Abu-khaled Jamal
Published: May 2021

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma.

Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure.

Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case.

Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.
The Influence of Vitamin D Status on the Severity of SARS-CoV-2 Respiratory Infection
Authors: Silva José Diogo , Rouxinol-Dias Ana , Rocha Gustavo Melo , Correia Sara , Almeida Lúcia , Alves Helena , Oliveira Maria João
Published: May 2021

Introduction: The high prevalence of vitamin D (vitD) deficiency in the general population is well recognized. Evidence suggests an immunomodulatory role for vitD in pro-inflammatory conditions, but doubt remains on its association with the severity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) respiratory infection (RI).

Aim: To assess the impact of vitD status on the severity of SARS-CoV-2 RI in adults.

Material and Methods: A cross-sectional study that included adults infected with SARS-CoV-2 until 1/14/2020 was performed. Patients taking calcium, vitD supplementation or antiepileptics, with malabsorptive and/or calcium and phosphate metabolic disorders or stage 4 or 5 chronic kidney disease were excluded. Levels of 25-hydroxyvitamin D (25(OH)D) were obtained at the time of RI diagnosis. The participants were divided into 2 groups, depending on the vitD status (sufficiency and insufficiency [≥20 ng/mL]; deficiency [<20 ng/mL]), and in 3 groups of clinical severity of RI (adapted from the update [14/10/2020] of the standard 004/2020 of the Portuguese Directorate-General for Health): mild/moderate disease (g1); severe disease without bacterial coinfection (g2); severe disease with bacterial coinfection/critical disease (g3). Other factors associated with RI severity were analyzed. A multiple logistic regression model was developed to predict the severity of SARS-CoV-2 RI, considering vitD status as a categorical variable and other variables with statistical significance after univariate analysis.

Results: This study encompassed 71 infected patients with a median age of 68 (p25;p75 = 58;77) years, 40 (56.3%) of which were women. 32 (45.1%) patients integrated g1, 14 (19.7%) g2 and 25 (35.2%) g3. 39 (54.9%) presented vitD deficiency and 32 (45.1%) vitD sufficiency or insufficiency. In the univariate analysis, vitD deficiency, age (>60 years old), male gender, Arterial Hypertension, Diabetes Mellitus, use of angiotensin-II receptor antagonist and reduced levels of ionized serum calcium correlated with the severity of RI. In the multivariate regression model that included these variables, vitD deficiency remained independently correlated with critical/severe disease with bacterial coinfection (g3 vs. g1: OR=9.7; CI95%=[1.7; 56.4]; p=0.011; g3 vs. g2: OR=6.3; CI95%=[1.1–37.0]; p=0.044), with a tendency, albeit not statistically significant, for severe RI without bacterial coinfection (g2 vs g1: OR=1.6; CI95%=[0.3; 7.4]; p=0.581).

Conclusions: An independent association of vitD deficiency with the severity of SARS-CoV-2 RI was found, supporting the anti-inflammatory effects of vitD. It is essential to identify and treat its deficiency in patients prone to adverse outcomes of SARS-CoV-2 RI.
Type 2 Diabetes Clusters Indicate Diabetes Duration Key in Fracture Risk
Authors: Ghatan Sam , Ahmadizar Fariba , Li Ruolin , Medina-Gomez Carolina , Zillikens Maria Carola , Rivadeneira Fernando , Kavousi Maryam , Oei Ling
Published: May 2021

Introduction: Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of developing fractures, despite higher mean BMI and BMD. Recently, clinically-relevant sub-groups of T2DM have been characterised using biomarkers of glycemic metabolism. Aim: Characterise T2DM sub-groups in a population-based setting and test for differences in fracture risk. Methods: A total of 10019 Rotterdam Study participants were available with glycemic and (incident) fracture follow-up. Participants with T2DM (n=1678) were partitioned in subgroups using K-means clustering based on: HOMA-B, HOMA-IR, age of diabetes onset, BMI and waist circumference measurements. Non-vertebral fracture risk was estimated across T2D subgroups using Cox proportional hazard models, adjusted for sex, age, BMI, collection cohort and prevalent T2DM. Results: Four T2D clusters were defined each with relatively-unique clinical characteristics namely, 1) advanced age of onset; 2) decreased insulin sensitivity; 3) beta-cell disfunction; 4) Obesity/high BMI. Individuals with prevalent and incident T2DM (independent of cluster) had lower risk of fracture than non-diabetics (see Forest plot). In contrast, individuals with prevalent T2DM (n=1152) had increased risk of non-vertebral fracture (HR: 2.1, 95%CI: 1.65–2.76), than individuals without T2DM. Conclusion: Despite that partitioning the heterogeneity of T2DM in clinically-meaningful clusters opens the road to tailored prevention and care, our findings with prevalent T2DM indicate that disease duration (likely with inadequate glycemic control) is the main determinant of fracture risk. In line with this contention, the association between T2DM and fracture risk is not causal, as causality requires association with incident cases, as also confirmed by earlier Mendelian randomization studies. Future work, using genetically-determined disease definitions and biomarkers will help unveil clusters of individuals with T2DM at increased risk of fracture.
Volanesorsen, an Antisense Oligonucleotide to Apolipoprotein-CIII, Decreases Triglycerides and Increases Lipoprotein Lipase Activity in Partial Lipodystrophy
Authors: Lightbourne Marissa , Brite Brianna , Startzell Megan S , Kimberley Bruce , Eckel Robert , Brown Rebecca J
Published: May 2021

Partial lipodystrophy syndromes (PL) involve selective deficiency of adipose tissue, with regional deficiency of fat in the lower extremities and preservation or even excess fat in the face and neck. Clinical features typical of PL include severe insulin resistance, diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. Apolipoprotein CIII (Apo-CIII) is elevated in PL, and is thought to contribute to high TG by inhibiting lipoprotein lipase (LPL). However, prior studies of this drug in patients with LPL mutations demonstrated LPL-independent mechanisms of TG-lowering. We hypothesized that Volanesorsen, an antisense oligonucleotide (ASO) to apo-CIII, would decrease apo-CIII, increase LPL activity, and lower TG in PL. We further hypothesized that Volanesorsen would improve insulin resistance and glycemia by directing free fatty acids (FFA) into adipose tissue, rather than ectopic sites (e.g. liver) associated with insulin resistance. Five adults with PL and TG ≥500 mg/dL or TG≥200 with A1c >7.0% were enrolled in a 16-week placebo-controlled, randomized, double blind study of Volanesorsen, 300 mg SC weekly, followed by a 1-year open label extension. Here, we report within-subject effects of Volanesorsen lipids, glycemia and lipolysis, before and after 16 weeks of active drug. From week 0 to week 16, apoC-III decreased from 380 (246, 600) to 75 (26, 232) ng/mL, TG decreased from 503 (330, 1040) to 116 (86, 355) mg/dL; and LPL activity measured in post-heparin plasma utilizing the subject’s serum as activator increased from 22.0±3.0 to 35.5±5.9 nEq/ml/min. Free fatty acid turnover (measured by palmitate tracer studies) decreased from 0.41 (0.35, 0.45) to 0.25 (0.23, 0.29) mg/kg/min. There was no change in A1c (8.4±1.2 to 8.3±0.9%), however there was a decrease in HOMA-IR from 26 (20, 54) to 13 (9, 43) and an increase in peripheral insulin sensitivity (glucose infusion rate during euglycemic hyperinsulinemic clamp, 120 mU/m2/min) from 3.6±2.4 to 4.4±1.5 mg/kgFFM/min and in hepatic insulin sensitivity (% suppression of hepatic glucose production during clamp) from 78±19 to 90±13%. Adverse events include injection site reactions and decreased platelets. Volanesorsen decreased apo-CIII and triglycerides, at least in part through an LPL dependent mechanism, and may improve insulin resistance.
PCSK9 Inhibitors for the Management of Mitotane-Induced Hypercholesterolemia in Adrenocortical Carcinoma
Authors: Aurora John A , Erenler Feyza , Matta Stephany , Lechan Ronald M
Published: May 2021

Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin.

Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range <130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily.

Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane.

References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.
Study of Patients’ Characteristics and Mutual Impact Between Covid-19 and Hyperglycemia at a Community Hospital in Central Brooklyn
Authors: Myint Myat S , Htun Kyaw W , Asfaw Menilik , Chakravartty Eesha , Mukherji Rajat , Kazeem Saka
Published: May 2021

Background: Studies have shown that poorly-controlled hyperglycemia worsens the outcomes in patients with COVID-19 (C-19) and C-19 may damage pancreatic islets via ACE2 receptors causing acute hyperglycemia. The major population we serve at Kingsbrook Jewish Medical Center (KJMC) are underprivileged with many of them having multiple comorbidities. Methods: This is a retrospective study wherein patients, admitted from February 2020 to April 2020 with hyperglycemia, were selected and divided into 2 groups based on presence or absence of C-19. Data include demographics, comorbidities, blood glucose level, serum osmolality, serum bicarbonate, anion gap, acute kidney injury (AKI), serum creatinine, ICU admission, length of stay (LOS) and mortality. Data were analyzed using descriptive study and T-test. Results: 100 patients were included in the C-19 group (CG) and 88 patients were included in the Non C-19 group (NCG). Major comorbidities were similar in both groups including HTN, DM, CKD followed by ESRD. Mean age of patients (years) was 65.68 in CG and 61.17 in NCG. 61% were male in CG and 53.41% were male in NCG. 16% and 9% developed DKA and HHS in CG, and 13.64% and 6.82% developed DKA and HHS in NCG respectively. 15% in CG had combined DKA & HHS and 3.41% had same in NCG. Mean blood glucose level (mg/dl) was 541.6 in CG and 460.0 in NCG (p=0.03). Mean serum osmolality (mOsm/kg) was 335.7 (SD±41.01) in CG and 317.1 (SD±30.54) in NCG (p=0.01). Mean serum bicarbonate (mEq/L) was 17.73 (SD±6.31) in CG and 21.46 (SD±5.94) in NCG (p<0.0001). Mean anion gap was 17.93 (SD±7.6) in CG and 13.10 (SD±7.2) in NCG (p<0.0001). 56% in CG and 37% in NCG developed AKI respectively (p=0.01). Mean serum creatinine (mg/dl) was 4.22 in CG and 1.65 in NCG (p=0.004). 55% of CG were admitted to ICU and 34% of NCG were admitted to ICU (p=0.003). Median LOS (days) in discharged patients was 8 in CG and 5 in NCG (p=0.02). Mortality was 40% in CG and 3.41% in NCG (p<0.0001). 12 patients in CG and 2 patients in NCG developed new-onset diabetes. In the subset of DKA, interestingly, mean age (years) was 61.63 (SD±17.73) in CG and 39.67 in NCG (SD±13.39) (p=0.001). Conclusion: In our study, patients in the CG carry worse laboratory parameters, unfavorable clinical outcomes and strikingly higher mortality. We discovered increased incidence of new-onset diabetes and elderly DKA in CG. In an inner city population like ours, the burden of DM with significant social and health care disparities is quite severe. Diabetic patients with concurrent C-19 infection can have particularly negative outcomes and C-19 possibly damages the pancreatic islets resulting in acute hyperglycemic crisis. Further research on larger population is required. References: (1)https://dx.doi.org/10.1016%2Fj.diabres.2020.108142(2) https://doi.org/10.2337/dc20-0723(3)https://www.nejm.org/doi/full/10.1056/NEJMc2018688
Efficacy of High-Intensity Intermittent Training for Improving Cardio-Metabolic Health in Women With Polycystic Ovary Syndrome
Authors: Patten Rhiannon Kate , McIlvenna Luke Colin , Hiam Danielle S , Moreno-Asso Alba , Stepto Nigel Keith
Published: May 2021

Polycystic ovary syndrome (PCOS) is a common and complex endocrinopathy with significant metabolic and reproductive manifestations, carrying a major health and economic burden. Consistent improvements in clinical outcomes have been reported as a result of exercise training, but shortfalls with exercise prescription are evident. Research suggests that high-intensity intermittent training (HIIT) is feasible, well tolerated and enjoyable for people with or at risk of chronic disease and can address many of the shortfalls and barriers to exercise participation. To investigate the effects of high-intensity exercise on cardio-metabolic health, twenty-four reproductive aged, overweight or obese, sedentary women with PCOS were recruited from the community and randomised to complete either 12 weeks of moderate intensity continuous cycling training (MICT; 60–65% of maximal heart rate [HRmax]; n=11) or HIIT (90–100% HRmax; n=13). All exercise was supervised by an exercise physiologist and completed 3 times per week on a cycle ergometer. Baseline and post-testing measures consisted of peak oxygen consumption (VO2peak) determined by a graded maximal exercise test, body composition by DXA scan and insulin sensitivity determined by euglycaemic-hyperinsulinaemic clamp. Significant improvements in VO2peak were seen after both HIIT (P <0.001) and MICT (P <0.013) with a significant between-group interaction favouring HIIT (P = 0.014). The insulin sensitivity index significantly improved after HIIT (P = 0.009) with no changes observed after MICT (P = 0.860), also resulting in a significant between-group difference favouring HIIT (P = 0.046). No changes were observed for body weight, BMI or fat mass, however, there was a significant increase in percentage of lean mass after HIIT (P = 0.026). The present study is the first to compare current exercise recommendations of moderate and vigorous intensities in women with PCOS. The results of this study provide preliminary validation of HIIT, suggesting that vigorous intensity exercise should be considered in order to improve cardio-metabolic health in women with PCOS.
How Novel is Dapagliflozin?
Authors: Vachhani Shyamsunder , Das Gautam
Published: May 2021

Introduction: Dapagliflozin is one of the novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. Diabetes Ketoacidosis (DKA) is defined by the triad of hyperglycaemia, anion-gap acidosis, and increased plasma ketones. Euglycemic DKA is an uncommon form of ketoacidosis which is characterized by metabolic acidosis with a pH <7.3 and a serum bicarbonate of <18mEq/L, ketosis, and a blood glucose level of <200 mg/dl. This can be caused by SGLT2 inhibitors. Euglycemic diabetes ketoacidosis is a rare complication that occurs in patient taking SGLT2 inhibitors. Here we describe a patient with euglycemic DKA. The incidence of DKA associated with dapagliflozin has been reported to be < 0.1%.

Case Presentation: This 55 years old gentleman has past medical history of obesity, type 2 diabetes (since age of 27 yrs.), hypercholesterolemia, hypertension and osteoarthritis. He recently suffered from myocardial infarction discharged 2 days back and presented to emergency department with central chest pain radiating to both arms in the morning. ECG reported as normal and venous blood gas showed pH- 7.10, pCo2- 3.84, pO2- 5.54, glucose- 10, lactate-1.8, bicarbonate- 8.5, base excess 19.2, anion gap 25. And dapagliflozin was stopped as a part of discharge planning and followed up in our diabetes clinic. Urine dipstick revealed Glucose +2, ketone +4, pH 5. He was diagnosed to be suffering from euglycemic diabetic ketoacidosis & treated as per protocol. When he recovered from DKA his insulin was optimised and dapagliflozin was stopped as a part of discharge planning and was followed up in our diabetes clinic.

Discussion: In patients on dapagliflozin, cases of euglycemic diabetes ketoacidosis are increasingly being reported. Diagnosis of euglycemic diabetes ketoacidosis can be easily missed in the emergency department due to absence of marked hyperglycemia, often leading to delayed diagnosis and treatment. Mechanism of action of dapagliflozin is by selectively inhibiting the transporter protein SGLT2 in the renal proximal, which prevents glucose reabsorption and subsequently induces the elimination of filtered glucose via urine, the process is known as ‘glycuresis’ which reduces the blood glucose levels. SGLT-2 inhibitors should be initiated by a clinician cautiously and only after adequately weighing the risks and benefits of treatment. It is advisable to do urine test on patient taking dapagliflozin on admission which will help diagnose euglycemic DKA early. To prevent this potentially dangerous complication, patients taking SGLT2 inhibitors who become ill should discontinue the medication, undergo ketone evaluation, and start basal insulin, if ketones are positive. In addition, patients should be educated to stop their SGLT2 inhibitor at least 1 week prior to elective procedures.
A Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonist in Kidney Transplant Recipients With Type 2 Diabetes
Authors: Sato Tetsuhiko , Ohara Emi , Ozone Chikafumi , Okazaki Mikako , Fuse Sachiho , Sasaki Rie , Azuma Yoshinori
Published: May 2021

Diabetic kidney disease (DKD), a devastating complication of diabetes, is one of the leading causes of end stage kidney disease (ESKD). Kidney transplantation provides superior outcomes for ESKD patients with type 2 diabetes, giving opportunities to be free from dialysis, but needs lifetime immunosuppressive medications to avoid graft kidney rejection. Post-transplant hyperglycemia, however, remains to be unsolved, because immunosuppressive agents, including glucocorticoids and calcineurin inhibitors, may result in impaired insulin secretion and sensitivity. Safe and promising anti-diabetic strategy is long-awaited among kidney transplant recipients (KTRs) with type 2 diabetes. Enormous evidence has accumulated that Glucagon-like peptide 1 (GLP-1) receptor agonists have potential to maintain kidney function as well as improve glucose tolerance in patients with DKD. The present study was designed to elucidate the association between GLP-1 receptor agonist use and better graft kidney function in KTRs with type 2 diabetes. Among KTRs with type 2 diabetes between 2012 and 2019, 73 with GLP-1 receptor agonist use and 73 without GLP-1 receptor use were identified in our center. After propensity matching, 50 KTRs were newly initiated with GLP-1 receptor agonist use or other antidiabetic medications. Baseline characteristics were well-balanced in the 2 groups. KTRs with GLP-1 receptor agonist use had greater kidney function 12 months after initiation of GLP-1 receptor agonists, compared to their counterpart KTRs without GLP-1 receptor agonists, according to estimated glomerular filtration ratio (p=0.01). Interestingly, transient decrease of body mass index was observed in KTRs with GLP-1 receptor agonist use during the 12 months. All GLP-1 receptor agonist-initiated KTRs were followed up through December 31, 2019. In conclusion, GLP-1 receptor agonist treatment was associated with better graft kidney function in KTRs with type 2 diabetes. Pharmacological GLP-1 receptor activation showed favorable tolerability and may alleviate graft kidney damage in KTRs with type 2 diabetes.
Clinical Practice Gap Analysis of CKD in T2D From Identification to Diagnosis to Management
Authors: Larkin Amy , Hanley Kelly , Le Anne
Published: May 2021

Understanding clinical practice gaps in the identification, diagnosis and management of CKD in patients with T2D can inform development of tools to improve physician practices. A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their knowledge, attitudes, and confidence with regard to CKD in T2D. The CME-certified activity was available online to physicians across the globe without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from February 26, 2020, to April 20, 2020. 241 diabetologists/endocrinologists completed the full assessment. Physicians demonstrated gaps in the following areas: Assessment to diagnose kidney disease stage: 47% gap Evidence-based strategies to delay progression of CKD in patients with diabetes: 72% gap SGLT2 inhibitors CVOT data comparisons: 73% gap Results from CREDENCE trial: 43% gap Mechanism of cardiorenal syndrome: 95% gap Link between diabetes, kidney disease, and the cardiorenal syndrome: 42% gap Fibrosis as a component of progression of CKD: 61% gap Knowledge of billing procedure for CKD screening: 64% gap Comparison of safety profiles for approved MRAs: 45% gap Differences in emerging MRAs compared to traditional MRAs: 53% gap Clinical trial data for emerging MRA: 32% gap When asked about satisfaction with current treatment approaches for managing CKD in patients with T2D, 9% selected very satisfied, 75% selected moderately-mostly satisfied, and 17% slightly-not satisfied. This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to identification, screening, diagnosis, and management of CKD in patients with T2D. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.
Development of the University of Colorado Endocrine ECHO Program
Authors: Lorton Eleanor , Coluzzi Alexandra , Maurer Laura , Pitzer Lauren , Saxon David
Published: May 2021

Background: The Extension for Community Health Outcomes (ECHO) model aims to improve rural community healthcare by providing specialist-lead telementoring for primary care providers (PCPs) in a didactic and discussion-based format.1 There is a notable shortage of endocrinologists in Colorado, particularly in rural and frontier counties. Best estimate is that 14 of 64 Colorado counties have at least one practicing endocrinologist. Here we describe the development and initial experience with an endocrine-specific ECHO program.

Methods: Grant-funding was obtained to develop a longitudinal endocrine ECHO program to support PCPs who care for a large proportion of patients with Medicaid insurance. Program development occurred with input from endocrinologists, primary care physicians, and ECHO Colorado staff. Program participation results in continuous medical education credit. PCP recruitment occurred through listserv emails sent to various Colorado-based medical organizations. Endocrinologists provided weekly hour-long sessions focused on 5 main topic domains: diabetes, obesity/lipids, thyroid disorders, reproductive and adrenal disorders, and bone/calcium disorders.

Results: Our endocrine ECHO program started in August 2020 and consisted of 30 weekly sessions (i.e. 9 diabetes, 8 obesity/lipids, 3 thyroid disorders, 5 reproductive and adrenal disorders, 4 bone/calcium disorders, and 1 pseudo-endocrine disorders). A total of 65 clinicians registered for the ECHO series. Sessions were designed by academic endocrinologists and fellows-in-training at the University of Colorado. During block 1 (diabetes block) there were 45 participants of which 12% practice in rural or frontier designated areas, 80% serve patients with Medicaid, and 42% primarily care for an underserved population. Matched pre/post-surveys asking about PCPs’ confidence with each ECHO session were obtained and final results are currently pending completion of the full series in March 2021. Survey data will inform future iterations of this program which is slated to run annually for at least 3 years.

Conclusion: Access to endocrinologists is often a scarce resource for rural communities and underserved populations. The ECHO model can serve as a means to provide longitudinal education and support for PCPs across a range of endocrine topics. Here we describe our initial experience with a 30-week endocrine ECHO program in Colorado and highlight future directions of this program.
Perfect Timing: Associations Between Dietary Timing, Eating Intervals and Metabolic Health
Authors: Ali Marriam , Knutson Kristen , Reutrakul Sirimon
Published: May 2021

Background: Metabolic disorders are on the rise resulting in an increased need for novel interventions to combat this growing concern. One such intervention is time-restricted eating, which consolidates caloric intake to a shortened eating duration, and has consistently demonstrated improvement in metabolic health. Additional interventions could harness circadian clocks, which help regulate daily rhythms of hormone release and maintain metabolic homeostasis. Circadian rhythms are influenced by timing of food intake and therefore meal timing may also impact metabolic health.

Objective: To examine whether timing of eating was associated with metabolic health independently of eating duration.

Methods: Data are from the National Health and Nutrition Examination Survey (NHANES), a nationally representative U.S. survey and physical exam. We analyzed two non-consecutive dietary recalls, fasting glucose and insulin from 10,575 adults (>18) over four cycles (2005–2012). We calculated eating interval duration as the time between first and last eating occasion (>10kcal) and formulated three groups: <10h, 10-13h, >13h. We then created 6 subgroups based on eating duration start time (before or after 0830 h) to analyze associations of eating interval timing. Linear regression analyses controlling for demographics were computed to determine whether eating interval duration and eating interval timing were associated with fasting glucose and estimated insulin resistance using HOMA-IR.

Results: Fasting glucose did not differ significantly among eating interval groups. Adjusted mean HOMA-IR increased with shorter eating interval duration (2.23, 2.20, 1.97 for <10h, 10-13h, >13h; p<0.05). When eating start time occurred before 0830 h compared to start time after 0830 h, mean adjusted HOMA-IR decreased across all eating interval subgroups (1.96 vs 2.28 for <10h, 2.13 vs 2.28 for 10-13h, 1.94 vs 2.13 for >13h; p <0.05). Adjusted mean fasting glucose had a similar pattern (96.3 mg/dL vs 98.7 mg/dL for <10h, 97.3 mg/dL vs 98.4 mg/dL for 10-13h, and 97.3 mg/dL vs 99.3 mg/dL for >13h; p < 0.05). In regression models where eating duration and timing were both entered as continuous variables, only timing was significantly associated with fasting glucose and HOMA-IR. Later time was associated with higher glucose and HOMA values (p<.001)

Conclusion: Shorter eating durations, i.e. time-restricted eating, was associated with worse metabolic outcomes, except when paired with an earlier start time. All subgroups with an early eating start time had better metabolic outcomes regardless of eating duration. These findings suggest that timing is more strongly associated with metabolic measures than duration and supports early eating strategies.