United States

Introduction: MEN2 is a rare Autosomal Dominant disorder resulting from mutations in the RET proto-oncogene. MEN2 is classified into two distinct syndromes: MEN2A and MEN2B. MEN2A is a syndrome that presents with Medullary Thyroid Carcinoma (MTC) in 90% of adult gene carriers, unilateral or bilateral pheochormocytoma in 50%, and multigland parathyroid tumors in 20-30% of affected individuals. Other rare variants of MEN2 include Familial Medullary Thyroid Carcinoma (FMTC), MEN2A with cutaneous lichen amyloidosis, and MEN2A or FMTC with Hirschprung&#39;s disease. We present a patient with incidentally noted elevated calcitonin levels, later diagnosed with MEN2A.Clinical Case: 37-year-old Caucasian male was referred to our clinic for elevated calcitonin levels noted on lab work done as part of evaluation and management for weight loss prior to initiating GLP-1 agonists. He was diagnosed with hypothyroidism and multinodular goiter and started on Synthroid. His only symptoms were weight gain, tiredness, soft stools and facial flushing He denied any family history of endocrine disorders. Physical exam was unremarkable. Pertinent labs included serum calcitonin 93 pg/mL (&lt;10 pg/mL), serum CEAg 5.2 ng/mL (0-3 ng/mL), and work up for pheochromocytoma and hyperparathyroidism was negative. USG thyroid showed a left lobe thyroid nodule measuring 7x5x7 mm with macrocalcifications, a right lobe thyroid nodule measuring 8x5x10mm, and an abnormal left lateral level III LN. He underwent left thyroid lobectomy with level VI neck dissection (total thyroidectomy aborted due to hypoxia), and subsequently completion thyroidectomy with right central neck dissection. Pathology showed metastatic MTC with pathologic staging pT1aN1a. Genetic testing showed RET c. 1826G&gt;A (p. C609Y) which is ATA – MOD risk. Patients&#39; father was also genetically screened and diagnosed with MEN2A and noted to have elevated calcitonin levels. He also subsequently underwent total thyroidectomy, which revealed medullary thyroid microcarcinoma.Conclusion: A number of studies support that measurement of serum calcitonin is the most sensitive screening test for detecting occult MTC in individuals with thyroid nodules. Yet, the use of serum calcitonin in the routine evaluation of thyroid nodules is controversial due to absence of uniform calcitonin thresholds, high false positive values and unavailability of pentagastrin stimulation testing. Moreover, there are no recommendations based on the current data to check calcitonin levels prior to initiating GLP-1 agonists but their use is not recommended in patients with personal or family history of MTC/MEN2. Based on the above case, measurement of calcitonin levels should be a part of the work up in patients who present with thyroid nodules and are receiving GLP-1 agonists. Attention should also be paid to the importance of genetic counseling in first-degree relatives of patients with MEN2A. This allows for timely diagnosis and reduces morbidity and mortality.

ENDO 2022

An Uncommon Path Leading to Diagnosis of Multiple Endocrine Neoplasia 2A

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Introduction: MEN2 is a rare Autosomal Dominant disorder resulting from mutations in the RET proto-oncogene. MEN2 is classified into two distinct syndromes: MEN2A and MEN2B. MEN2A is a syndrome that presents with Medullary Thyroid Carcinoma (MTC) in 90% of adult gene carriers, unilateral or bilateral pheochormocytoma in 50%, and multigland parathyroid tumors in 20-30% of affected individuals. Other rare variants of MEN2 include Familial Medullary Thyroid Carcinoma (FMTC), MEN2A with cutaneous lichen amyloidosis, and MEN2A or FMTC with Hirschprung's disease. We present a patient with incidentally noted elevated calcitonin levels, later diagnosed with MEN2A.Clinical Case: 37-year-old Caucasian male was referred to our clinic for elevated calcitonin levels noted on lab work done as part of evaluation and management for weight loss prior to initiating GLP-1 agonists. He was diagnosed with hypothyroidism and multinodular goiter and started on Synthroid. His only symptoms were weight gain, tiredness, soft stools and facial flushing He denied any family history of endocrine disorders. Physical exam was unremarkable. Pertinent labs included serum calcitonin 93 pg/mL (<10 pg/mL), serum CEAg 5.2 ng/mL (0-3 ng/mL), and work up for pheochromocytoma and hyperparathyroidism was negative. USG thyroid showed a left lobe thyroid nodule measuring 7x5x7 mm with macrocalcifications, a right lobe thyroid nodule measuring 8x5x10mm, and an abnormal left lateral level III LN. He underwent left thyroid lobectomy with level VI neck dissection (total thyroidectomy aborted due to hypoxia), and subsequently completion thyroidectomy with right central neck dissection. Pathology showed metastatic MTC with pathologic staging pT1aN1a. Genetic testing showed RET c. 1826G>A (p. C609Y) which is ATA – MOD risk. Patients' father was also genetically screened and diagnosed with MEN2A and noted to have elevated calcitonin levels. He also subsequently underwent total thyroidectomy, which revealed medullary thyroid microcarcinoma.Conclusion: A number of studies support that measurement of serum calcitonin is the most sensitive screening test for detecting occult MTC in individuals with thyroid nodules. Yet, the use of serum calcitonin in the routine evaluation of thyroid nodules is controversial due to absence of uniform calcitonin thresholds, high false positive values and unavailability of pentagastrin stimulation testing. Moreover, there are no recommendations based on the current data to check calcitonin levels prior to initiating GLP-1 agonists but their use is not recommended in patients with personal or family history of MTC/MEN2. Based on the above case, measurement of calcitonin levels should be a part of the work up in patients who present with thyroid nodules and are receiving GLP-1 agonists. Attention should also be paid to the importance of genetic counseling in first-degree relatives of patients with MEN2A. This allows for timely diagnosis and reduces morbidity and mortality.

technical paper

BackgroundAlpelisib is an oral α-specific phosphatidylinositol 3-kinase (PI3K) inhibitor use in combination with fulvestrant to treat postmenopausal women with HR+/HER2−, PIK3CA-mutated, advanced or metastatic breast cancer that has acquired resistance to endocrine-based therapy. (1)Alpelisib interferes with the PI3K/Akt signalling pathway resulting in impaired peripheral glucose uptake, increased liver glycogenolysis, loss of beta-cell mass and insulin secretion dysfunction(2). Hyperglycemia is a frequent adverse effect of alpelisib but diabetic ketoacidosis (DKA) is considered a rare occurrence. We describe a patient without a previous history of diabetes who developed DKA after 2 months on alpelisib.Clinical caseA 81 year-old woman with metastatic ER+ PR – Her2 - breast cancer, presented with a 1 week history of nausea, vomiting, and polyuria. Her hemoglobin A₁C was 5.5 % on two separate occasions last year. She had started alpelisib at 300 mg/day 7 weeks prior to presentation. She presented with a blood glucose (BG) of 659 mg/dL, anion gap of 21, serum bicarbonate 17 mmol/L, beta-hydroxybutyrate 3.82 mmol/L (normal < 0.27 mmol/L), serum osmolarity 319 mOsm/kg, serum creatinine 2.83 mg/dL (baseline 1.38 mg/dL), C-peptide 4.3 ng/mL (normal 1.1 – 4.4 ng/mL), negative GAD-65 antibodies and Islet Antigen 2 antibodies, septic workup were non-revealing, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with intravenous insulin and hydration. DKA resolved in 12 hours, however, she had persistent hyperglycemia. She was started with insulin regimen of 0.2 units/kg and discharged with Humalog 75/25 5 units twice daily.Conclusion:Patients with no pre-existing history of diabetes mellitus can also be at risk for DKA which may develop within weeks to months of initiation of alpelisib. Risk factors for development of DKA are yet to be identified, but would be useful to help tailor frequency of BG monitoring. This warrants further research. The hyperglycemic effects of alpelisib appear to be reversible upon drug discontinuation, however when DKA is the presenting syndrome, insulin therapy is indicated.Reference:
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20): 1929-1940. doi: 10.1056/NEJMoa1813904. PMID: 31091374.
Nguyen P, Musa A, Samantray J. Alpelisib-Induced Diabetic Ketoacidosis. Cureus. 2021 May 1;13(5): e14796. doi: 10.7759/cureus.14796. PMID: 34084688; PMCID: PMC8166359.

Alpelisib-induced Diabetic Ketoacidosis

Background: Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ~1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy³. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one.
Methods: We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC³: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range (<36 nmol/l) and A4 into the reference range. After 24 weeks, 31 patients from the prednis(ol)one prior therapy group participated in an ongoing MHRC single arm extension study with 28 patients completing 18 months follow up. Control of CAH was defined as a 0900h 17OHP <36 nmol/l.
Results: Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment.  At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively.  Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years).
Conclusions: Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients.
References: 1. Pickup ME. Clin Pharmacokinet 1979 4 111-128; 2. Toothaker RD. J Pharm Sci 1982 71 573-576; 3. Merke DP. JCEM 2021 106 e2063-e2077.

Comparison of prednisolone versus modified-release hydrocortisone (Efmody) in the treatment of Congenital Adrenal Hyperplasia (CAH)

Background: Traditionally, stimulated serum cortisol < 18 mcg/dL at 30 or 60 minutes has been used as the cutoff for diagnosis of adrenal insufficiency (AI) during high dose cosyntropin stimulation testing (CST). Recent studies suggest that a cutoff of 14-15 mcg/dL is more accurate when using more specific monoclonal immunoassays (IAs). In February 2017, our institution switched from a polyclonal IA to a monoclonal IA. Despite this change, providers were diagnosing AI based on the 18 mcg/dL cutoff. Long term glucocorticoid use has several unwanted pleiotropic effects such as impaired glucose tolerance or diabetes mellitus (DM), hypertension (HTN), and increased risk of infection. Our study aims to evaluate patients with peak stimulated cortisol levels between 14-18 mcg/dL diagnosed with AI and placed on steroids.
Methods: We retrospectively reviewed charts of patients with peak cortisol levels 14-18 mcg/dL at 30 or 60 minutes on high dose CST with 250 mcg cosyntropin between February 2017 and August 2021. Cortisol levels were assessed using the monoclonal IA Roche Elecsys Cortisol II. Data regarding type and etiology of AI as well as patient demographics, comorbidities, steroid regimen, and follow up cortisol testing was collected. Worsening HTN and DM were defined as increase in blood pressure and HgbA1c respectively and/or intensification of medications between baseline at time of CST and last follow up while on steroids.
Results: 41 patients met inclusion criteria. 29 (71%) patients were female and mean age at CST was 52 years (range 21-86). Most patients were diagnosed with secondary (71%) or partial secondary (19%) AI by provider. Most common etiologies were pituitary disease (45%), chronic steroid use (24%), and unilateral adrenalectomy (19%). Mean follow up was 23 months (range 0.5-57). 33 (80%) patients were started or continued on glucocorticoid replacement. Remaining patients who were never started on steroids had a peak cortisol ≥ 15.6 mcg/dL. 21/33 (64%) of patients started on steroids had repeat adrenal function testing a mean of 18 months (range 2-42) after the initial CST. Based on testing or clinical judgement, 19/33 (58%) were taken off steroids. In patients treated with steroids, 64% developed weight gain, 42% worsening HTN, and 6% worsening DM. Additionally, 48% developed an infection, 24% insomnia, and 15% psychiatric illness.
Conclusions: The majority of patients with peak stimulated cortisol between 14-18 mcg/dL on high dose CST had secondary AI. Over 50% of patients started on steroids were later able to stop. Steroid-related complications were observed, but this may not differ significantly from the general population. This study underscores the importance of interpreting CST results in the context of the cortisol assay used and evaluating patients with secondary AI for recovery of the hypothalamic-pituitary-adrenal axis.

Diagnosis of Adrenal Insufficiency Based on Peak Stimulated Cortisol Levels Between 14 and 18 mcg/dL on High Dose Cosyntropin Stimulation Testing

Background: Conventional management of adrenal insufficiency (AI) includes lifelong oral glucocorticoid replacement therapy. Currently, no glucocorticoid regimens adequately mimic the circadian rhythm of cortisol secretion. In some patients, this causes persistence of severe symptoms. Continuous subcutaneous hydrocortisone infusion (CSHI) is an alternative delivery method using an insulin pump. Previous studies have confirmed CSHI's potential to re-establish the diurnal cortisol profile and reduce total daily dose (TDD) of hydrocortisone. To date no reports are available regarding the long-term usage (>2 years) of CSHI in adults.
Methods: We report the use of CSHI in 27 patients seen at the Scottsdale Endocrinology Institute from 05/2012 to present. CSHI inclusion criteria were persistence of severe symptoms, high steroid dosage, or gastrointestinal intolerance, malabsorption or bleeding in willing and able patients. Individual basal rates were set using a novel method to re-establish patients' diurnal cortisol profiles. Patients were educated on pump basics including bolusing and temporary basal rates, allowing them to control their dosing during symptomatic and stressful periods and procedures, and using subcutaneous shots during pump failures. Quality of life (QOL) was assessed using the AddiQOL questionnaire periodically. Data was gathered from patient charts and surveys. We report patient preference of CSHI over oral therapy, and changes in QOL, TDD of hydrocortisone, and crises during pump therapy.
Results: In our patient sample, there were 2 males and 25 females, 9 had primary AI, 15 had secondary AI, and 3 had steroid-induced AI. Ages ranged from 26 to 78 years. 1 patient had 1 year of CSHI, 19 patients had 2-5 years of CSHI, and 7 patients had >5 years of CSHI. After at least 2 years of CSHI, 24/26 patients preferred CSHI over oral therapy, 25/26 patients continued to report improved symptoms and QOL, and average TDD reduction of hydrocortisone was 22 mg (2.5-55.8). 4 patients previously deemed disabled returned to a productive lifestyle. 2 patients underwent successful pregnancies without untoward events. Only 2 patients were hospitalized due to near adrenal crises. 4 chose to discontinue CSHI, 2 for a high out of pocket expense, and 2 for local skin reactions at infusion sites.
Conclusion: Our method of calculating basal rates and implementing CSHI was associated with improvement in symptoms and QOL and reduced TDD of hydrocortisone and hospitalizations over treatment duration. We expect this to reduce cumulative side effects of steroids and overall cost of treatment of these patients. Autonomy of dose regulation offered by pump therapy improves patient's ability to handle stressful situations and symptoms, including sleep quality and quantity. In summary, we found CSHI to be a safe and effective method to treat patients with AI experiencing problems with oral treatment over an extended period of time.

Management of Adrenal Insufficiency with Continuous Subcutaneous Hydrocortisone Infusion: Long-Term Experience in 27 Patients

Background: The Choosing Wisely campaign from the American Board of Internal Medicine (ABIM) Foundation has scrutinized the practice of routinely ordering tests that offer limited or no benefit to patients, and have the potential to cause harm. Although postoperative day 1 (POD1) hormonal testing is necessary for certain patients who undergo adrenalectomy (i.e. those with functional tumors), the clinical utility of routinely checking POD1 non-endocrine labs is unclear, particularly in patients with non-functional adenomas. We sought to investigate how often these non-endocrine labs were abnormal after adrenalectomy and whether they represent value-added care.
Methods: Patients who underwent open or laparoscopic adrenalectomy at our institution from 2011-2020 were identified, and those with non-endocrine serum labs (hemoglobin, potassium, creatinine, or glucose) obtained before 0800 on POD1 were analysed. The frequency of abnormal labs, and any associated intervention(s), was recorded. Exclusion criteria varied by lab type and included: preoperative hemoglobin <8 g/dL or intraoperative blood transfusion (hemoglobin analysis), presence of chronic kidney disease (potassium and creatinine analyses), diagnosis of primary aldosteronism (potassium analysis), and pheochromocytoma or diabetes mellitus (glucose analysis). Costs were calculated using the 2020 Medicare Clinical Laboratory Fee Schedule.
Results: Of 936 patients (56% female) who underwent adrenalectomy (92% laparoscopic), 91% (n=847) had ≥1 POD1 non-endocrine lab drawn. Only 0.4% (n=3) of 785 eligible patients had an abnormal POD1 hemoglobin (<8 g/dL), and 1 patient received a blood transfusion. Potassium abnormalities were present in 3.4% (n=21) of 624 eligible patients, including 9 with hypokalemia (<3.5 mmol/L) and 12 with mild hyperkalemia (5.5-5.9 mmol/L). Specific interventions for hypo/hyperkalemia were required in 5 patients (0.8% of all potassium values). AKI (creatinine increase of 0.3 g/dL or ≥1.5x baseline) was diagnosed in 4% of 759 eligible patients (n=28) and all were stage 1. Hyperglycemia (>180 mg/dL) was identified in 1% (n=6) of 577 eligible patients, and 1 patient received short-acting insulin. Of a total of 2,745 lab values, while only 2% were abnormal, the total aggregate cost of routine POD1 labs was ~$17,000 during the study period.
Conclusions: Routine POD1 hemoglobin and creatinine testing are rarely abnormal after adrenalectomy and infrequently impact clinical management. Although patients with functional disease may require monitoring of electrolytes and/or glucose on POD1, in the current era of value-based healthcare, routine ordering of these labs may be unnecessary in selected patients with non-functioning tumors.

Challenging the Status Quo: Are Routine Post-Operative Day 1 Non-Endocrine Labs Necessary After Adrenalectomy?

Background: Pheochromocytomas and paragangliomas (PPGLs) have the highest degree of heritability among endocrine tumors. Currently, ~40% of PPGL individuals have a genetic germline pathogenic variant and exist at least 12 different genetic syndromes related to these tumors. Pathogenic variants in the Succinate Dehydrogenase Complex Subunit B (SDHB) gene account for about 10% of PPGL cases. Moreover, SDHB pathogenic variants are the most well-established risk factor to predict metastatic disease (40%-50% of cases). Germline SDHB large deletions are very rare worldwide, but SDHB exon 1 deletion has been reported in patients with PPGLs from Portugal and Spain. Indeed, a putative founder effect for SDHB exon 1 deletion was suggested in PPGL patients from Iberian Peninsula. Aim: To investigate a putative founder effect for SDHB exon 1 deletion. Methods: Eighteen unrelated Brazilian patients with germline heterozygous SDHB pathogenic variants were included. Additionally, two unrelated individuals with SDHB exon 1 complete deletion from Argentina were studied. SDHB pathogenic variants were investigated by automated SAGER sequencing, multiplex ligation-dependent probe amplification (SALSA MLPA Probemix P226 SDH) and/or high-throughput sequencing. Five SDHB flanking microsatellite markers at chromosome 1p (D1S2697, GATA29A05, D1S2826, D1S2644, and D1S199) were used to investigate if patients carrying this deletion have a common origin. Haplotypes were reconstructed using the PHASE algorithm (v. 2.1). A control group comprising 26 unrelated Brazilian individuals was also studied. Results: Among 18 Brazilian patients with germline SDHB pathogenic variants, heterozygous SDHB exon 1 complete deletion was identified in 6 of them (33% of the cases). The remaining 12 patients presented intragenic SDHB pathogenic variants without hotspot location. All Brazilian index patients with SDHB exon 1 deletion presented with paraganglioma, located mostly in the abdomen (4 abdominal; one thoracic; two head and neck and one colonic). Median age was 31.5 years and metastatic disease occurred in 3 (50%) of them. Haplotype analysis showed that 4 apparently unrelated Brazilian patients (4 out of 6 cases, 67%) shared a common allele (SDHB-GATA29A05-D1S2826-D1S2644-D1S199 | SDHB-186-130-213-102), which was not seen in chromosomes without the SDHB exon 1 deletion (p= 0.01). The two cases from Argentina did not have this haplotype, suggesting that SDHB exon 1 deletion in Argentina have a different origin. Conclusion: SDHB exon 1 complete deletion was the most frequent SDHB defect in our cohort. Our findings indicate a founder effect for SDHB exon 1 complete deletion in Brazilian patients with paraganglioma.
Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6

Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma

Introduction: Frailty is characterized by multisystem function decline related to aging and can be measured using frailty Index (FI). FI is constructed based on the proportion of deficits present in an individual out of the total number of health variables considered. FI in various populations has been shown to predict adverse health outcomes. We aimed to determine the impact of hormone excess on frailty in a prospective cohort of patients with adrenal adenomas.
Methods: We conducted a multicenter prospective observational study of adult patients with adrenal adenomas and referent subjects without adrenal disorders (Jan 2019-Dec 2021). Adrenal adenomas comprised non-functioning adrenal adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS), defined as dexamethasone suppression test (DST)>1.8 mcg/dL, Cushing syndrome (CS), and primary aldosteronism (PA). FI was calculated as a sum of 47 variables (20 comorbidities, 13 symptoms, 14 activities of daily living) divided by 47.¹ Frailty was defined as FI>0.25. In a subset of patients (n=176), functional measurements (handgrip strength, timed up and go test, gait speed) were performed and compared to FI.
Results: Of 233 patients (72.1% women), 71 were diagnosed with NFA (median age 64.5 years), 108 with MACS (median age 60.7 years), 11 with CS (median age 58.0 years), 46 with PA (median age 52.4 years), and 33 were referent subjects (median age 51.3 years). When compared to referent subjects, age- and sex-adjusted frailty prevalence was highest in CS (OR 29, 95%CI 4.3-202), followed by MACS (OR 16, 95%CI 3.5-73.7), and PA (OR 11.7, 95%CI 2.4-56), but not in patients with NFA (OR 5.1, 95%CI 0.99-25.8). Compared to patients with NFA, age- and sex-adjusted frailty prevalence was higher in CS (OR 5.8, 95%CI 1.4-24.4) and in MACS (OR 3.2, 95%CI 1.5-6.7), but not in PA (OR 2.3, 95%CI 0.9-6.1) group. Subgroup-analysis based on DST demonstrated a similar increase in age- and sex-adjusted frailty prevalence in patients with DST>5 mcg/dL (OR 3.1, 95%CI 1.2-8.2) and DST 1.9-5 mcg/dL (OR 3.3, 95%CI 1.5-7.4) when compared to patients with DST<1.8 mcg/dL. Higher FI was associated with lower handgrip measurement (P<0.0001), longer time during timed up and go test (P <0.0001), and decreased gait speed (P<0.0001).
Conclusions: Patients with functional adrenal adenomas are more likely to be frail. In patients with MACS, the prevalence of frailty was not associated with the degree of DST abnormality. FI correlated with currently validated but more cumbersome functional measurements and is a valuable tool that could be easily used in clinical practice and help individualize management decisions in patients with adrenal adenomas.
¹ Singh S et al. Frailty in Patients With Mild Autonomous Cortisol Secretion is Higher Than in Patients with Nonfunctioning Adrenal Tumors. JCEM 2020

Increased Frailty in Patients With Functioning and Nonfunctioning Adrenal Adenomas

ARMC5 is a tumor suppressor gene responsible for 20 to 40% of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) with a function that remains unclear. Based on pathway analysis from RNAseq results obtained on zebrafish models of transient Armc5 up- and down-regulation, we identified transcriptional alterations of several members of SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1) signaling in our models and hypothesized that ARMC5 can regulate SIRT1 and its signaling in adrenocortical cells. Accordingly, the expression of the desacetylase SIRT1 is significantly increased in PBMAH tissues mutated for ARMC5 compared to tumors without mutations. However, this overexpression of SIRT1 is associated with an elevation of the profile of acetylated protein in the absence of ARMC5 suggesting that SIRT1 activity is actually decreased and that SIRT1 expression could increase to maintain its activity. Consistently, the measurement of SIRT activity on PBMAH tissues demonstrate a decrease of its activity when ARMC5 is mutated. Similar results are obtained in adrenal cells of 18-month-old Armc5+/- mice that are also hyper-corticosteronemic. Altogether, these data support that ARMC5 could regulate SIRT1 expression and/or activity. In vitro measurement of purified SIRT1 activity in the presence of ARMC5-enriched protein extracts demonstrated that the presence of ARMC5 protein does indeed alter SIRT1 activity. We hypothesize, therefore, that ARMC5 may be a new regulator of SIRT1 function but the underlying mechanism and the consequences of abnormal acetylated proteins on adrenocortical function require further investigation.

ARMC5 as a possible regulator of acetylation in the adrenal cortex in partnership with SIRT1

Introduction
In critically ill adults, high plasma free cortisol in face of suppressed plasma ACTH coincides with high plasma pro-opiomelanocortin (POMC), the ACTH precursor (1). Further augmenting the systemic glucocorticoid availability with hydrocortisone treatment further lowered plasma ACTH, while plasma POMC remained unaffected (2). The dynamics of POMC in relation to ACTH and free cortisol prior to intensive care unit (ICU) admission are unknown, as well as the impact hereon of glucocorticoid treatment. Also, elevated plasma POMC concentrations have not yet been confirmed in pediatric ICU (PICU) patients. In pediatric cardiac surgery-induced critical illness, we hypothesized that plasma POMC is elevated and that plasma ACTH transiently rises per-operatively and becomes suppressed once free cortisol has risen on PICU day 1 and 2. In addition, we hypothesized that in patients receiving glucocorticoids per-operatively, plasma ACTH is further suppressed while plasma POMC is unaffected.
Methods
From 53 children aged 0-36 months, who underwent cardiac surgery and were admitted to the PICU, blood samples were taken prior to surgery (pre-operatively, available samples N=51), during surgery (per-operatively, N=47), on the following morning (PICU day 1, N=40) and the day hereafter (PICU day 2, N=24). Blood samples were also collected from 24 age- and gender-matched healthy children. To investigate the impact of synthetic glucocorticoid treatment on the endogenous plasma hormone concentrations, patients were categorized into steroid-naive (total N=38) and steroid-treated patients (total N=15). Plasma hormone concentrations were quantified with highly-specific ELISA (POMC), RIA (ACTH, cortisol, CBG) or colorimetric assays (albumin). Cross reactivity with synthetic glucocorticoids within the used cortisol RIA is minimal (<0.27% for methylprednisolone, <0.1% for dexamethasone). Free cortisol was estimated with the adapted Coolens' formula.
Results
Plasma POMC was increased pre-operatively (p<0.0001) but no longer thereafter (p>0.05), irrespective of steroid treatment. Plasma ACTH in patients was never higher than in healthy children. While in steroid-naive patients, plasma ACTH became suppressed only by PICU day 1 (p<0.0001), steroid-treated patients had already suppressed plasma ACTH per-operatively (p≤0.0001). In steroid-naive patients, plasma free cortisol was increased from per-operatively onwards (p≤0.002), while in steroid-treated patients, plasma free cortisol (endogenous) concentrations always remained comparable to those of healthy children (p>0.05).
Conclusion
Pre-operatively high plasma POMC, not followed by increased ACTH, suggests a centrally-activated HPA-axis already prior to surgery and an immature pituitary processing of POMC into ACTH. Systemic glucocorticoid availability is elevated from surgery onwards, likely driven by ACTH-independent mechanisms. Further increasing systemic glucocorticoid availability exogenously with glucocorticoid administration accelerates the suppression of plasma ACTH. The long-term impact of early glucocorticoid treatment in critically ill children remains to be investigated.
References
(1) Téblick A. et al. Critical Care 2021.
(2) Téblick A. et al. Endocrinology 2022.

Pro-opiomelanocortin (POMC), ACTH and Cortisol Responses to Pediatric Cardiac Surgery

Purpose. To evaluate deep learning analysis of thyroid nodule ultrasound images as a rule-out test for thyroid malignancy.
Methods. Supervised deep learning (DL) classifier of thyroid nodules was trained on 32,545 thyroid US images from 621 nodules representing all major benign and malignant types of thyroid lesions and tested on an independent set of 145 nodules collected at a different healthcare system in the United States. The Big Transfer BiT-M ResNet-50x1 convolutional neural net architecture was modified to contain 3, 4, 6 and 3 PreActBottleneck units per block 1 through 4. Weights pretrained on the ImageNet-21k dataset were loaded and weights for blocks 3 and 4 were fine-tuned for the binary classification task of distinguishing benign and malignant thyroid nodules.
Results. The deep learning thyroid nodule classifier achieved an area under receiver operating characteristic curve (AUROC) of 0.889 on five-fold cross-validation. The AUROC improved when images were scaled by nodule size and six randomly selected cine clip frames were added to the training set per epoch. GradCAM class activation heatmaps revealed that microcalcifications and spongiform appearance were reliably recognized by the classifier as malignant and benign features, respectively. Spongiform nodules were found to be benign even when microcystic spaces constituted less than 50% of nodule volume.
To investigate the clinical relevance of the benign vs. malignant classifier, the binary classification threshold for the probability of malignancy generated by model was set at 7% to achieve sensitivity and negative predictive value (NPV) comparable to that of the fine needle aspiration biopsy (FNA). At this threshold, cross-validated deep-learning model achieved a sensitivity of 90%, specificity of 63%, positive predictive value (PPV) of 46% and negative predictive value of 94%. When tested on an independent image set that includes 18 classic papillary thyroid cancers (PTC), 5 follicular variant PTC, 4 medullary thyroid cancers, 3 follicular thyroid cancers (FTC), and 1 Hurthle cell thyroid cancer, the DL classifier achieved AUROC of 0.88, sensitivity of 97%, specificity of 61%, PPV of 40% and NPV of 99%. A single minimally-invasive FTC that had no suspicious features on thyroid ultrasound was incorrectly classified as benign.
Conclusions. This study demonstrates that the ultrasound-based deep-learning classifier of thyroid nodules achieves sensitivity and negative predictive value comparable to that of thyroid fine needle aspiration (FNA). Clinicians may use this tool to augment clinical judgment when determining whether to perform FNA procedures.

An Uncommon Path Leading to Diagnosis of Multiple Endocrine Neoplasia 2A

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