Adrenal Antibodies Research Articles

8705 Autoimmune Polyglandular Syndrome Type 2 Presenting As Recurrent Cardiac Tamponade

Abstract Disclosure: E.M. Niedzialkowska: None. D. Shelden: None. Introduction: Autoimmune polyglandular syndrome type 2 (APS2) is a rare endocrinopathy with co-occurrence of autoimmune adrenal insufficiency, autoimmune thyroiditis and/or type 1 diabetes. In rare cases, APS2 can predispose patients to recurrent pericardial effusion and tamponade. Case presentation: 32 y.o male with medical history of hypothyroidism on replacement therapy diagnosed 2 weeks prior to admission presented with progressive dyspnea and hypotension. The patient was found to have pericardial effusion with tamponade requiring pressor support. Initial lab tests showed TSH 148.7 uIU/ml (N 0.4-4.5), free t4 0.7 ng/dl(N 0.7-1.5 ), free t3 2 pg/ml (N 1.7-3.5), Hb a1c 4.7% (N <5.6%), thyroglobulin antibody 851 IU/ml (N <20), TPO antibody >1 000 IU/ml (N<=35), TSI 0.1 IU/l (<0.1), sodium 127 mmol/l (N 135-145), and a negative adrenal antibody panel. The patient was started on IV levothyroxine (400 mcg daily) and stress dose steroids in the setting of shock requiring 4 pressors. Shock resolved after pericardiocentesis and the patient was weaned off pressor support. Pericardial fluid showed neutrophil predominance and was negative for an infectious process, lab tests showed negative ANA, ANCA and GBM. The day following admission lab tests showed TSH of 23.86 uIU/ml, ft4 1.3 ng/dl, the patient was transitioned to oral levothyroxine 125 mcg and the steroid regimen was tapered and discontinued. Follow up tests showed normal TSH and resolution of pericardial effusion. Four weeks after initial admission the patient was readmitted due to hypotension. Laboratory tests showed random cortisol <1.0 ug/dl (N 2.9-19.4), ACTH 17 pg/ml (N 6-48), adrenal antibody titers 1:20 (N < 1:10), cosyntropin stimulation test was positive for adrenal insufficiency and the patient was started on steroid regimen with symptomatic improvement. He was diagnosed with APS type 2 based on his constellation of endocrinopathies. Repeat echocardiogram was negative for pericardial effusion. Two months later, the patient presented with chest pain. Imaging was positive for recurrent pericardial effusion requiring pressor support and pericardiocentesis. The patient was subsequently started on colchicine. Infectious and rheumatologic workup continued to be negative. The patient did not exhibit symptoms of connective tissue disease. Seven months after the initial presentation the patient was readmitted with COVID-19 infection complicated by hypotension and a small pericardial effusion. Symptoms improved after initiation of stress dose steroids. Conclusion: Cardiac tamponade is a rare presentation of APS2 with 9 cases reported in the literature up to date. Increased incidence of pericardial effusion is presumed to be a result of autoimmune inflammation leading to fluid accumulation. The patients are prone to tamponade due to intravascular volume depletion, decreased vascular tone and impaired stress response. Presentation: 6/3/2024

12616 Pembrolizumab-induced Autoimmune Adrenal Insufficiency: A Case Report And Literature Review

Abstract Disclosure: A. Calderon: None. E. Calderon-Martinez: None. J. Shakil, MD: None. A. Kansara: None. Immunechekpoint inhibitors (ICI)-related Primary Adrenal Insufficiency (PAI) is an uncommon entity. Compared to other endocrine-related adverse effects (irAES), antibody detection is less consistent. TPO and GAD65 antibodies are usually present in about 40-80% of the cases with hypothyroidism, hyperthyroidism, and diabetes. On the contrary, case reports and series for PAI seldom report the presence or absence of 21OH antibodies. We present a case and perform a literature review of PAI, in a patient who received pembrolizumab and developed PAI with 21 hydroxylase antibodies. A 62-year-old man with history HIV on ART (last CD4 count 590 cells/mm3) and locally advanced urothelial cancer on Pembrolizumab, presented with nausea, vomiting, abdominal pain, and decreased urine output. He was noted to be confused, and in hypoactive delirium. On admission, his chemistry panel he was noticed to have normal sodium and potassium levels. The CT scan of the abdomen revealed regional enteritis and was started on IV fluid therapy. His adrenal glands were described as normal on imaging. On the 16th day of hospitalization, the patient became unresponsive and hypotensive. He was transferred to the ICU. His sodium level was 132 mEq/L and potassium level was 6.1 mEq/L, bicarbonate level was 18 mEq/L, calcium of 10.3 mg/dl, and eosinophils of 15%. Random cortisol levels measured before administration of steroids were undetectable twice, 9 hours apart, with an ACTH level of 94. He underwent an ACTH stimulation test with cosyntropin 250 mcg IV with resulting undetectable cortisol levels after 30 and 60 minutes. CT and MRI of the brain showed no signs of hypophysitis. He was started on high-dose hydrocortisone with improvements in his mental status, hypotension, and gastrointestinal symptoms. He was discharged on hydrocortisone. His 21-Hydroxylase antibody was later found out to be positive. After combination immunotherapy regimens, CTLA-4 inhibitors are the most common to cause any irAE, however endocrine irAE particularly are mostly associated with PD-1 inhibitors. Among these, thyroid and pituitary disorders are the most common ones. Reports show that about 10% of patients receiving immunotherapy will develop endocrinopathy. ICI-induced PAI has been reported to occur in 7.6% of patients receiving combination therapy, and 2% of patients receiving Pembrolizumab. It has been reported that only 15% of patients will recover adrenal function. A meta-analysis that gathered 15 cases of ICI-induced PAI, found that only 2 cases had positive 21-hydroxylase antibodies. In our presented case, we have robust biochemical confirmation of PAI, with positive 21 hydroxylase antibody, after being on pembrolizumab for 9 months. Further information is needed to establish the pathophysiology, presentation, and prognosis of ICI-related PAI when anti adrenal antibodies are positive. Presentation: 6/1/2024

FRI241 Late Diagnosis Of Non-classical CAH In An Elderly Male Previously Diagnosed With Estrogen Producing Adrenal Tumor

Abstract Disclosure: R. Kaval: None. J. Subauste: None. In 2013 a 66-year-old Caucasian male presented to the VA outpatient endocrinology clinic to establish care; the patient carried a diagnosis of estrogen producing left adrenal tumor in 1989 at the age of 42 at an outside facility. On review of records the patient was initially worked up for hypogonadism and was noted to have an elevated estrogen level and a “left adrenal tumor”. He subsequently underwent an unilateral left adrenalectomy for treatment and pathology reported with benign tumor findings. Following surgery, the patient was started on steroid and mineralocorticoid replacement for primary adrenal insufficiency (PAI) and topical testosterone gel for hypogonadism. The question was raised as to why this patient had PAI as he had an intact right adrenal gland on CT scan. On laboratory work-up in 2006 the patient had baseline cortisol of 3.4 ug/dl, ACTH was elevated at 99 pg/ml [7.2- 63.3], and adrenal antibodies (21-OH antibody] were negative. Renin was 2.35 ng/ml/hr [0.167-5.380], Estradiol was 41.8 pg/ml [7.6 - 42.6], LH was low at 0.20 mIU/ml [1.2-8.6] and total testosterone was low at 2.2 ng/ml [1.8-7.8]. Repeat testing yielded ACTH that was elevated at 686.7 pg/ml [7.2- 63.3], electrolytes including sodium and potassium were normal. On physical examination the patient had hyperpigmented skin, normal height, weight and otherwise unremarkable. On CT scan of the abdomen the right adrenal gland was mildly diffusely enlarged. In 2019, 30 years after his initial diagnosis the team questioned whether the adrenal tumor was truly an estrogen producing tumor. As a result, 17-OH progesterone was obtained, and the unstimulated value resulted as 3522 ng/dl [27-199]. With the elevated 17 OH >1000 ng/dL this was diagnostic for Non-classical CAH. The unilateral adrenalectomy likely unmasked the underlying impairment of cortisol production leading to primary AI that is seen with Non-classical CAH patients. The patient was lost to follow up during the pandemic, hence we were not able to perform and further testing. Presentation: Friday, June 16, 2023

FRI556 Thyroid Autoimmunity Leading To Premature Ovarian Insufficiency (POI) In A Euthyroid Young Woman

Abstract Disclosure: P. rimal: None. M. Moeed: None. C. Musurakis: None. A. Ojha: None. W. Akhtar: None. C.P. Barsano: None. M.F. Siddiqui: None. Introduction: Premature Ovarian Insufficiency is rare in young women and affects only 0.1% before the age of 30. The causes of POI in most cases remain unidentified, with autoimmunity being responsible for 4-30% of the cases. We present the case of a young euthyroid woman who presented for the evaluation of primary amenorrhea and diagnosed with POI associated with thyroid autoimmunity. Clinical Case: A 28-year-old Afghani woman with no known co-morbidities was referred to endocrinology clinic for the work up of primary amenorrhea. She was a goitrous and had normal secondary sexual characteristics and a history of withdrawal bleeding with OCP. There was no known personal or family history of autoimmune disease. Work up revealed hypergonadotropic hypogonadism with high FSH, 55 mIU/ml[Ref range for postmenopausal woman 16.7-113], high LH, 20.28 mIU/ml [Ref range for postmenopausal woman 10.8-58.69] and low estradiol, <2 pg/ml. Anti-Mullerian hormone was low, <0.08ng/ml [RefRange 0.69-13.39] signifying inadequate ovarian reserves and pelvic ultrasound confirmed atrophic ovaries. Etiological work up revealed normal female karyotype, 46XX, and negative FMR gene mutation testing for Fragile X syndrome. Thyroid functions were normal TSH, 3.3 mIU/L (0.27-4.2) and Free T4, 1.29 ng/dl[Ref Range 0.70-2.7]. Autoimmune work up was negative for adrenal 21-OH antibody and anti-ovarian antibodies. However, patient had strongly positive thyroid peroxidase (TPO) antibodies, 613.77 mIU/L[Ref range 0.0-9.0] consistent with thyroid autoimmunity. DXA scan revealed osteopenia. Thus, the diagnosis of POI associated with thyroid autoimmunity was established. HRT with estradiol patch and progesterone was initiated. Calcium, Vitamin D supplements and fertility counseling were provided. Conclusion: Thyroid disease is the most common autoimmune disease associated with POI. Studies have shown higher risk of POI and infertility in patients with Hashimoto’s and Graves’ diseases with co-existing high titers of TPO or anti-thyroglobulin antibodies. Ovaries are subject to autoimmune attack that leads to diminished ovarian reserves. However, until now the association of isolated elevation of TPO antibodies with POI has not been established. A Study by Osuka et al. did not find any significant difference in AMH levels between TPO and non-TPO positive euthyroid women and concluded that unlike hypothyroid women, thyroid autoantibodies were not likely to influence ovarian reserves in euthyroid women. Our case is unique where POI is associated with isolated elevation of TPO antibodies in the absence of clinical thyroid disease. This signifies the possibility that ovarian failure may precede the onset of thyroid disease in patients with thyroid autoimmunity and should be suspected and treated at an early stage, before ovarian reserves are diminished. Presentation: Friday, June 16, 2023

O-303 Contribution of targeted sequencing for genetic diagnosis of premature ovarian insufficiency in clinical practice

Abstract Study question What is the diagnostic yield of custom designed gene panel for patients with premature ovarian insufficiency (POI)? Summary answer The diagnostic yield of our POI gene panel (POIGP) is 7.3% What is known already POI is a specific female syndrome with a high clinical and genetic heterogeneity. It is characterized by a premature exhaustion of the ovarian function and infertility and affects approximately 1% of women. POI can be related to genetic factors which include chromosomal abnormalities, FMR1 premutation and rare variants in numerous genes. The advent of high throughput sequencing methods has led to the identification of an increasing number of variants implicated in the development of POI over the last decades. However, POI etiologies still remain undetermined in the majority of cases. Study design, size, duration An observational analytic cohort study of 150 patients presenting idiopathic POI (normal karyotype, absence of FMR1 premutation, absence of adrenal and/or ovarian antibodies) recruited prospectively at three Belgian academic and university hospitals between 2016 and 2021. Participants/materials, setting, methods Patients were included if they experienced POI, as defined by ESHRE guidelines on POI (2016). POI genes included in the panel were selected from PubMed using different key words mainly premature ovarian insufficiency, gonadal dysgenesis, hypergonadotropic hypogonadism, ovarian failure and genetics. The panel included 156 genes, variants were filtered based on allele frequency (≤1%) in latest available population databases and classified according to ACMG/AMP (American College of Medical Genetics/Association for Molecular Pathology) guidelines 2015. Main results and the role of chance Our analysis revealed a potential causative variant for 11 patients in the following genes: MEIOB, BMP4, CFTR, FANCA, FSHR, FANCG, MLH1, MRPS22 and STARD9. This means that the diagnostic yield of our POI gene panel (POIGP) is 7.3%. Patients were mainly Caucasian (63%), North African (17%) and sub-Saharan African (13%). They presented primary amenorrhea in 14.7% of cases. Consanguinity and/or a family history of POI or early menopause in 28% of cases. Mean patient’s age (years) at POI diagnosis was 28.9± 8.5 (mean ± SD). The overall mean coverage was 229X, and more than 95% of the target exome was represented with more than 30-fold coverage. Limitations, reasons for caution The present study was limited to monogenic etiologies of POI, potential oligogenic causes have not been searched. Functional studies and/or family segregation were not performed for the identified variants. Wider implications of the findings Our findings show the importance of targeted next generation sequencing in clinical practice and highlight the limit of our current genetic knowledge in the field of POI. A regular update of genes included in POIGP will improve its diagnostic yield. Trial registration number P2016/196/CCB B406201628264

Adrenal insufficiency in thyroid cancer patients treated with tyrosine kinase inhibitors and detected by ACTH stimulation test

PurposeAdvanced thyroid cancer patients treated with tyrosine kinase inhibitors (TKI) can develop several adverse events (AEs), including adrenal insufficiency (AI).MethodsWe studied 55 patients treated with TKI for radioiodine-refractory or medullary thyroid cancer. The adrenal function was evaluated during follow-up by performing serum basal ACTH, and basal and ACTH-stimulated cortisol.ResultsTwenty-nine/55 (52.7%) patients developed subclinical AI during TKI treatment as demonstrated by a blunted cortisol response to ACTH stimulation. All cases showed normal values of serum sodium, potassium and blood pressure. All patients were immediately treated, and none showed an overt AI. Cases with AI were all negative for adrenal antibodies and did not show any adrenal gland alteration. Other causes of AI were excluded. The onset time of the AI, as measured in the subgroup with a first negative ACTH test, was < 12 months in 5/9 (55.6%), between 12 and 36 months in 2/9 (22.2%) and > 36 months in 2/9 (22.2%) cases. In our series, the only prognostic factor of AI was the elevated, although moderate, basal level of ACTH when the basal and stimulated cortisol were still normal. The glucocorticoid therapy improved fatigue in most patients.ConclusionsSubclinical AI can be developed in > 50% of advanced thyroid cancer patients treated with TKI. This AE can develop in a wide period ranging from < 12 to > 36 months. For this reason, AI must be looked for throughout the follow-up to be early recognized and treated. A periodic ACTH stimulation test, every 6–8 months, can be helpful.

ODP273 Schmidt Syndrome Causing Multiorgan Failure

Abstract Introduction To our knowledge there has not been a case report published on the acute presentation of Schmidt syndrome (Polyglandular Autoimmune Syndrome Type 2) in which all three manifestations of type 1 diabetes mellitus (T1DM), primary adrenal insufficiency, and hypothyroidism were found and diagnosed at the same time. Case Description A 32-year-old male with suspected alcohol abuse presented to the hospital with nausea, vomiting, and weakness of two weeks duration after sustaining a fall. He was admitted for Diabetic Ketoacidosis (DKA) and shock requiring three pressors with unclear etiology. Labs were significant for severe hyponatremia of 113 mmol/L (136-145), elevated anion gap of 22, glucose 206 mg/dL (70-100), bicarbonate 11mmol/L (21-31), beta hydroxybutyrate 5.90 mmol/L (0. 0-0.42), and pH 7.22 (7.35-7.45) with Hemoglobin A1c 14.5% (&amp;lt;5.7). An insulin drip was instituted for DKA and the hyponatremia persisted. Cortisol was found to be suppressed at 3. 0 ug/dL (3.1-22.4) with significantly elevated ACTH 220.4 pg/mL (7.2-63.3) suggesting a new diagnosis of primary adrenal insufficiency. IV hydrocortisone 100 mg q8H was started on day 2 of hospitalization. Thyroid labs showed elevated TSH 10.10 uIU/mL (0.36-3.74) confirming hypothyroidism, prompting initiation of IV levothyroxine. His hospital course was complicated by cardiac arrest and acute respiratory failure requiring intubation. Cardiac work up was negative except for severe non-ischemic cardiomyopathy with significantly reduced ejection fraction of 20-25%. Bronchoscopy was performed and showed no evidence of obstructing pulmonary etiologies. SARS Coronavirus PCR was negative. He also had shock liver along with Disseminated intravascular coagulation (DIC). His kidney function worsened requiring continuous kidney replacement therapy (CRRT). Urine microscopy showed granular casts consistent with acute tubular necrosis. TPO antibodies, adrenal antibodies, GAD antibodies, and Zinc Transporter 8 antibodies all came back positive along with an undetectable C- peptide confirming the diagnosis of Hashimotos hypothyroidism, primary adrenal insufficiency, and T1DM respectively. He was eventually discharged on basal bolus insulin regimen, levothyroxine 75 mcg po daily, fludrocortisone 0. 05 mg po daily, and prednisone 5 mg po daily. The patient had multifactorial shock from an acute presentation of DKA, primary adrenal insufficiency, and hypothyroidism all presenting simultaneously. Conclusion This case illustrates the severe impact of having three endocrine organs affected all at once. The prevalence of Schmidt syndrome is very low at 1: 20,000 in the general population and can be associated with other non-endocrine autoimmune disorders. Prevalence of autoimmune thyroid disease is 70%, T1DM 50%, and Addison's disease is almost 100%. Due to the low prevalence, one needs a high clinical suspicion with the correct lab findings to diagnose this disease. Incorrect diagnoses or a late diagnosis can lead to life threatening consequences to the patient. The mainstay of treatment is hormone replacement, with corticosteroids given before thyroid replacement. Presentation: No date and time listed

ODP580 A Case of New Onset Primary Adrenal Insufficiency in COVID Infection

Abstract Background Accumulating body of evidence shows that SARS-CoV-2 infection in COVID-19 is linked to a variety of autoimmune complications including autoimmune endocrinopathies. Here we report a case of newly diagnosed Addison's disease post-COVID-19 infection. Case Description A 23-year-old male with a history of three episodes of acute disseminated encephalomyelitis (ADEM) in childhood, was brought into the emergency department (ED) by EMS after being found down with a blood glucose of 28 at the field. Prior to presentation, he reported 3 days of sore throat, nausea, vomiting, fatigue, and chills. He takes no home medications, and is not vaccinated against COVID-19. In the ED, the physical exam is notable for temperature 39°C, pulse 145, BP 80/42, RR 39, and no mucocutaneous hyperpigmentation. Labs revealed a positive COVID test, serum sodium 125 mmol/L (135-145), potassium 3.1 mmol/L (3.5-4.1), and persistent hypoglycemia. TSH 1.89 μIU/mL (0.45-4.12). A morning baseline cortisol was 4 mcg/dl (ref: &amp;gt;18) with ACTH level of &amp;gt;1250 pg/ml (0-45). A high-dose 250 mcg ACTH stimulation test followed; with cortisol levels of 3, and 3 mcg/dl (ref: &amp;gt;18) at 30, and 60 minutes; respectively. Aldosterone &amp;lt;3. 0 ng/dl (4. 0-31. 0), and anti-21-hydroxylase antibody was positive (ref: negative). A CT scan of the abdomen with contrast demonstrated mildly atrophied bilateral adrenal glands. The hypotension and hyponatremia resolved after initiation of intravenous hydrocortisone, and he was discharged on hydrocortisone and fludrocortisone. Conclusion The patient's symptoms, elevated ACTH, low cortisol, and presence of 21-hydroxylase antibodies, are consistent with autoimmune Addison's disease. Since ADEM is an autoimmune condition, it is likely that the patient had underlying undiagnosed Addison's disease and COVID-19 triggered an adrenal crisis. There is also a possibility that SARS-CoV-2 infection may have induced a higher titer of adrenal antibody, leading to the exacerbation of Addison's disease. The case highlights the importance of considering adrenal insufficiency as a diagnostic differential in hemodynamically unstable COVID-19 patients, especially those with underlying autoimmune conditions. Presentation: No date and time listed

PMON317 Rapid Progression of Adrenal insufficiency in Child with Autoimmune Polyendocrine Syndrome Type 1

Abstract Background Autoimmune Polyendocrine Syndrome type 1 (APS-1) is an autosomal recessive rare disease resulting from mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. APS-1 was first described as a syndrome in 1946 as a triad of mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. With an AIRE gene mutation, the immune system will have a T-regulatory cell defect, which leads to a loss of immune tolerance. This will increase the risk of autoimmune disease in the body's organs such as the pancreas, thyroid, adrenal gland, liver, intestine, skin, and parathyroid gland. Clinical case A 6-year-old male was admitted to the pediatric floor for new-onset seizures and tetany. Initial laboratory assessment was concerning for severe hypocalcemia associated with low parathyroid hormone (PTH) and hyponatremia. Blood workup showed: low serum sodium 130 mmol/L (136-144), potassium 4.1 mmol/L(3.4-4.7), carbon dioxide 16 mmol/L; ionized calcium 0.67 mmol/L (1.19-1.41), phosphorus 7.4mg/dL (4.0-7.0), PTH 9.0pg/mL (12.0-88.0). Calcium replacement and calcitriol were initiated with a resolution of symptoms. Further investigations were done for the adrenal gland given his low sodium level. He underwent an ACTH stimulation test that he passed, with a cortisol baseline of 39mcg/dl with a peak of 48mcg/dl. ACTH level was high at 120pg/mL (5-27), and a repeat in 4 weeks was normal at 11pg/ml. His renin activity was elevated at 71ng/ml/hr (1.5-3.5). Renin activity was repeated and was elevated again at 34ng/ml/hr, prompting adrenal antibody testing, which revealed an elevated titer 1: 10 (&amp;lt;1: 10). Due to concern for APS-1, genetic testing was obtained and revealed a pathological variant of AIRE of c.892G&amp;gt;A and c.967_979del consistent with APS-1. He was started on 0.1mg Florinef and was later followed routinely at an outpatient endocrinology clinic. Fifteen months after diagnosis, he had a repeat ACTH stimulation test, and his baseline cortisol was 9.1mcg/dl with a peak at 60 minutes of 9.6mcg/dl (&amp;lt;18). ACTH level was elevated at 425pg/ml at this time. He was started on hydrocortisone replacement. Of note, investigation of siblings revealed a 10-month-old sister with abnormal AIRE mutation and a 17-month-old sister with unexplained death. Conclusion APS-1 can affect multiple organs, and cases can significantly vary in age and the number of affected organs at presentation. The patient presented with atypical presentation as he had hypocalcemia and hypoparathyroidism as an initial abnormality. Typically, adrenal insufficiency appears in the second decade of life but, the patient has it at the time of diagnosis, and it rapidly progresses. Family history plays an essential role in investigating autoimmune disease and warrants further assessment for autoimmune markers. While typically a disease that progresses insidiously into adulthood, cases like ours demonstrate rapid autoimmune disease progression. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP019 A Case Study of the Association of Autoimmune Polyglandular Syndrome and Pulmonary Artery Hypertension

Abstract We report a patient with combined pulmonary arterial hypertension (PAH) and autoimmune polyglandular syndrome (APS) type 2. A 41 y/o woman with hypothyroidism presented for right heart (RHC) in the work up of PAH. Pt had a medical history of PAH diagnosed by transthoracic echocardiogram (TTE) and hypothyroidism. She reported symptoms of fatigue, shortness of breath with increased pigmentation of her skin progressive for several years. Preadmission lab found hyponatremia of 126 and potassium of 6.6. She was admitted and treated with IV insulin with D50, kayexalate, IV fluids. A random 11 AM cortisol was 0.57 mcg/dl N: AM: 6. 0–30. 0 mcg/dl; PM: 3. 0–16. 0 mcg/dl. Acosyntropin test was ordered. Pt failed the stimulation test (baseline 0.39, 30 min 0.49, 60 min 0.50, with an ACTH at baseline of 1423 pg/ml N: 7.2-63.3). Pt was started on hydrocortisone 20 mg AM/10 mg PM with fludrocortisone 0.1mg. On follow up at 2 weeks, her energy, mood, appetite and breathing tolerance had improved. Follow up RHC in 4 weeks found normalization of right heart pressures. APS is a collection of autoimmune diseases. Type I APS, caused by a defect in the autoimmune regulator (AIRE) gene, is diagnosed with two of three conditions, chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal cortical insufficiency. Type II APS (formally "Schmidt's Syndrome"), associated with HLA haplotypes DR3 (DQB*0201) and DR4 (DQB1*0302), is diagnosed with chronic autoimmune adrenal insufficiency with either Type 1 DM or chronic autoimmune thyroid disease (commonly Hashimotos but can be Graves). It typically presents later in life compared to APS I, age 30-40s. The association between PAH is rare but has been noted in several case studies. It has been associated with APS I in Korniszewski et al. and Bhansali et al. For APS II, the first association was reported by Barrou et al. of a patient with hypothyroidism, hypogonadism, and adrenal insufficiency who later developed PAH. Two cases reported by García-Hernández et al found PAH with positive adrenal antibodies without adrenal insufficiency. In 2009 Walid R. et al. reported a case of severe adrenal insufficiency (hypotension, hypokalemia) with PAH. She improved with steroids, but her PAH was present on TTE four years after treatment started. Pt in that case declined RHC. The patient in this case study proceeded with a RHC which did show normalization of right heart pressures, the first reported case to document normalization of PAH with replacement steroid treatment. Presentation: No date and time listed

Endocrine Autoantibodies Determine Immune Checkpoint Inhibitor-induced Endocrinopathy: A Prospective Study.

Incidence and awareness of endocrine-related adverse events (ERAE) associated with use of immune checkpoint inhibitors (ICI) has grown with increased ICI use, yet mechanisms for ERAE prediction, surveillance, and development are not well established. We prospectively evaluated the impact of endocrine autoimmunity on ERAE development and overall survival (OS). Adults ≥ 18 years of age prescribed ICI treatment for advanced or metastatic solid tumors and no known active/past endocrine disorders were eligible for enrollment. Thyroid, adrenal, and pancreatic antibodies as well as hormone levels were assessed prior to ICI treatment and at 8 to 9 weeks and 36 weeks after treatment for ERAE in relation to presence and changes in endocrine-specific antibodies, hormone levels, and OS. Sixty patients were enrolled and ERAE were detected in 14 (23.3%), with a median onset of 52 days (IQR, 38.5-71.5) after first ICI dose. Hypothyroidism occurred in 12 (20%) patients, and 2 (3.33%) patients developed hypophysitis. Diabetes and primary adrenal insufficiency were not observed. Antibodies were detected in 14 patients (11 at baseline, 3 developed during follow-up) and their presence was significantly associated with ERAE (R2 59.3%, P < 0.001). Thyroid peroxidase antibody (20%) and thyroid-stimulating immunoglobulin (3.3%) were most common, and anti-GAD was present in 1 patient. The presence of ERAE was associated with a more favorable OS (P = 0.001). Endocrine-specific autoantibodies play an important role in ERAE pathogenesis and may serve as predictive markers for early identification and treatment of ICI-induced endocrinopathies.

Adrenal glands and diabetes

Adrenal glands and diabetes

An Case of Poems Syndrome With Primary Adrenal Insufficiency

POEMS syndrome is rare multi-system disorder characterised by a paraneoplastic plasma cell disorder. The acronym POEMS stands for Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes. The underlying mechanisms are poorly understood, but chronic overproduction of pro-inflammatory cytokines have an integral role in the disorder. Diagnosis of POEMS is difficult owing to the variety of clinical manifestations. Mandatory diagnostic criteria are (a) one major criterion of either polyneuropathy or monoclonal gammopathy, in association with (b) one minor criterion including, but not limited to, organomegaly, endocrinopathy or skin changes. Endocrinopathies have been identified in 67–84% of patients with POEMS [1]. While hypogonadism and hypothyroidism are relatively common, primary adrenal failure is rarely reported. We present a 54-year-old woman who was found to have a raised hemoglobin, hematocrit and thrombocytosis on routine blood testing. She was concomitantly investigated for a rapidly-ascending, bilateral peripheral motor and sensory neuropathy. Diagnosis of POEMS was made and she underwent chemotherapy with Lenalidomide and high dose dexamethasone in 2015. Since then, she has not received endogenous glucocorticoids. She had an unplanned admission in April 2020 with a likely viral illness and was found to be glucocorticoid deplete. A 250-mcg short synacthen test demonstrated an inadequate response in cortisol, from 4.31 µg/dl to 6.13 µg/dl, with a raised adrenocorticotrophic hormone (ACTH) level of 66 mU/L. Adrenal antibodies were not detected. CT scan of the abdomen reported no adrenal gland abnormalities. The patient denied symptoms of mineralocorticoid deficiency, with no postural blood pressure (BP) drop - sitting BP 123/69 mmHg and standing BP 131/74 mmHg. Serum electrolytes were normal (renin and aldosterone levels are pending) and androgen screen was within normal limits. Thyroid stimulating hormone (TSH) was 8.07 mIU/L, free thyroxine (fT4) levels 0.93 ng/dL, and thyroid receptor and thyroid peroxidase antibodies were both negative. The patient is now established on Hydrocortisone therapy: 10mg (morning), 5mg (lunchtime). In summary, we present a 54-year-old woman with POEMS syndrome with subacute primary adrenal failure, characterised by glucocorticoid deficiency and ACTH excess. Although rare, it is important for all clinicians to be aware of POEMS syndrome as a potential diagnosis if the diagnostic criteria described above are filled, and for Endocrinologists to be aware that POEMS endocrinopathies can occur in any gland, including the adrenal glands.1.Gandhi, G.Y., et al., Endocrinopathy in POEMS syndrome: the Mayo Clinic experience. Mayo Clin Proc, 2007. 82(7): p. 836–42.

Adrenal Insufficiency Masquerading as Primary Hypothyroidism Following Immune Checkpoint Inhibitors Treatment

Background: Immune checkpoint inhibitors (ICIs) are novel immunotherapy agents that have been used to treat multiple advanced cancer. Even though they confer potential clinical advantages by regulating immune reactions, they have been linked with serious immune-mediated adverse events. Here we present a case of a patient who was treated with ICIs, Nivolumab (programmed death-1 inhibitor) and Ipilimumab (cytotoxic T lymphocyte antigen-4 inhibitor), and subsequently developed two concurrent immune-related endocrine disorders. Clinical Case: An 83-year-old man with advanced renal cell carcinoma presented with generalized weakness. He had finished four cycles of immunotherapy with Nivolumab and Ipilimumab, and Ipilimumab was discontinued afterward. Two days after the fifth cycle of immunotherapy with Nivolumab, he developed worsening fatigue, nausea, and anorexia. He appeared mildly volume depleted with borderline hypotensive (104/63 mmHg). The rest of the physical exam was unremarkable. Initial tests showed elevated levels of TSH (13.15 uIU/mL, ref 0.45–5.33 uIU/L), reduced levels of free T4 (<0.25 ng/dL, ref 0.58–1.64 ng/dL), free T3 (1.72 pg/mL, ref 2.5–3.9 pg/mL), negative thyroglobulin antibody, and elevated levels of thyroid peroxidase antibody (429 IU/mL, ref <9 IU/mL), thus suggesting primary hypothyroidism. Serum levels of sodium and potassium were unremarkable (136 meQ/L, ref 136–145 mEq/L; 3.6 meQ/L, ref 3.5–5.1 meQ/L respectively). His baseline TSH was normal three months prior to arrival (1.31 uIU/mL) and suppressed one month prior to arrival (0.01 uIU/mL). Immune-related thyroiditis with immune checkpoint inhibitors was suspected. He was given levothyroxine and observed in the hospital. After two days of hospitalization, weakness had slightly improved. However, he still had persistent nausea. He also developed low blood pressure (90/47 mmHg) and mild hyponatremia (133 mEq/L) with a normal potassium level. Further investigation showed low cortisol (1.0 ug/dL, ref 5.0–21.0), low ACTH (13 pg/mL, ref 6–50 pg/mL), cortisol level at 30 and 60 minutes post-cosyntropin stimulation test of 10.8 ug/dL (ref 13.0–30.0 ug/dL) and 14.8 ug/dL (ref 14.0–36.0 ug/dL) respectively, and negative adrenal antibodies, suggesting of secondary adrenal insufficiency due to hypophysitis. The patient was started on hydrocortisone, and his symptoms improved afterward. Conclusion: This case report highlights the common pitfall of managing immune-related endocrine disorders of ICIs. Adrenal insufficiency may present with a broad range of nonspecific symptoms, which could be attributed to hypothyroidism, underlying illness, or medications. Although a rare adverse effect, it is prudent to recognize adrenal insufficiency superimposed on primary hypothyroidism. Introducing thyroxine before replacing glucocorticoids can lead to an adrenal crisis.

The study on the risk of other endocrine glands autoimmune diseases in patients with type 1 diabetes mellitus.

To study the changes of pancreas, thyroid, adrenal, parathyroid and gonadal organ-specific antibodies in patients with type 1 diabetic patients and to explore the risk of development to other endocrine gland autoimmune diseases.Fifty one patients with type 1 diabetes mellitus were selected. ELISA was used to detect islet, adrenal gland, Parathyroid, gonadal organ-specific antibody levels, the level of thyroid-related antibodies by lectrochemiluminescence.Compared with the healthy control group, the levels of the 17-α-OHAb, 21-OHAb, NALP5Ab, P450sccAb, and CaSRAb in the T1DM group were significantly higher. GADAb-positive patients were more likely to have TPOAb-positive patients than GADAb-negative patients, and the positive rate of 2 thyroid antibodies in GADAb-positive patients was significantly higher than that in GADAb-negative patients. The presence of these antibodies is related to the age of onset of type 1 diabetes or Patient age. In combination with 1 or 2 islet antibody-positive patients, the combined non-islet antibody positive rate was higher than that of islet antibody-negative patients.Patients with type 1 diabetes with other autoimmune diseases at risk significantly increased compared with normal, of which the most common thyroid autoimmune disease, thyroid antibodies and hormone levels should be routinely detected at the first visit and long-term follow-up.

MON-537 Primary Adrenal Insufficiency During Tyrosine Kinase Inhibitors Treatment in Advanced Thyroid Cancer Patients

Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI). Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts. Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation. Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (<12 months) or late (>36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.

SAT-LB43 Allgrove’s: A Syndrome for the “A”ges

Allgrove’s syndrome is an inherited condition caused by mutations in the AAAS gene (encoding the protein ALADIN) and is inherited in an autosomal recessive pattern (1). It classically is characterized by three specific features: achalasia, Addison’s disease, and alacrima (reduced or absent ability to secrete tears). This has led to the name “Triple A syndrome”, and some have suggested a 4th ‘A’ of autonomic disturbance (2). It is important to note that the phenotype of this condition is variable, and some patients may have all three (or four) of the manifestations at initial presentation, and that other patients may develop or have worsening of the ‘As’ over time. In this clinical vignette, we present a patient with Allgrove’s syndrome who developed clinical manifestations of the third ‘A’ of Addison’s disease later in life. A 46-year-old female patient presented to our tertiary referral center for follow-up of Allgrove’s disease after having been diagnosed with genetic testing as an adolescent. Prior to presentation, she underwent esophagectomy in 1995 and additionally had confirmed alacrima with ophthalmology. She was undergoing annual surveillance testing with 8 am cortisol and ACTH stimulation testing to monitor for the development of adrenal insufficiency. Prior to consultation, her baseline cortisol was 8.7 ug/dL. At presentation and the age of 46, her ACTH stimulation test (0.25 mg cosyntropin, 3 timepoints) was positive for adrenal insufficiency with a baseline cortisol of < 0.5 ug/dL (8 am), with 30-minute value of 4.4 ug/dL and 60-minute value of 6.3 ug/dL (peak). She was started on replacement dosing of hydrocortisone 20 mg at 8 am and 10 mg at 2 pm, in addition to calcium and vitamin D supplementation. Of note, her adrenal antibody (21-hydroxylase antibodies) were negative on two separate occasions. Allgrove’s syndrome is a rare condition described by the development of three, or at times four, characteristics with support of genetic testing. This case demonstrates that patients with Allgrove’s syndrome can present with two clinical manifestations of the condition (alicrima and achalasia) and develop the third (adrenal insufficiency) later in life. Therefore, regular screening for the missing clinical manifestation of this disease should be considered.

Significant barriers to diagnosis and management of adrenal insufficiency in Africa.

BackgroundThe burden and management of primary adrenal insufficiency (PAI) in Africa have not been well documented. We aimed to identify specific disease characteristics, patient demographics, and patterns of clinical management in established PAI in Africa.MethodsAn online survey of physicians’ experience relating to PAI.ResultsThere were 1334 responses received, 589 were complete, and 332 respondents reported managing patients with hypoadrenalism. The described responses were related to a calculated pool of 5787 patients with hypoadrenalism (2746 females, 3041 males), of whom 2302 had PAI. The likely causes of PAI in Sub-Saharan Africa (SSA) vs the Middle East and North Africa (MENA) regions included autoimmune disease (20% vs 60.3%; P < 0.001), tuberculosis (34% vs 4.1%; P < 0.001), AIDS (29.8% vs 1%; P < 0.001), malignancy, and genetic conditions. Sixteen percent of AD patients (376/2302) presented in an adrenal crisis. Medical emergency identification was not used by 1233 (83.6%) SSA vs 330 (40.4%) MENA patients (P < 0.001), respectively. Relative non-availability of diagnostic tests across both regions included adrenal antibodies 63% vs 69.6% (P = 0.328), s-cortisol 49.4 % vs 26.7% (P = 0.004), s-ACTH 55.7% vs 53.3% (P = 0.217), and adrenal CT scans 52.4% vs 31.8% (P = 0.017) in the SSA and MENA region, respectively. Across the entire cohort, the overall hydrocortisone use and extrapolated proportion of synacthen use were 59.4% and 50.7%, respectively.ConclusionsThrough the perception and practice of healthcare professionals, we identified significant challenges in the diagnosis and management of PAI which may herald high mortality. Differences between regions may reflect the allocation of healthcare resources.

SUN-412 A Unique Case of Isolated ACTH Deficiency Caused by Pembrolizumab

Background: The anti-programmed-death-receptor-1 (PD-1) antibody, pembrolizumab, is one of the key immunomodulators for different types of refractory cancers. It is known to cause a variety of endocrinopathies including hypothyroidism, hyperthyroidism, diabetes mellitus, hypophysitis and primary adrenal insufficiency. However, to our knowledge, there are no reports of isolated ACTH deficiency caused by pembrolizumab. Clinical Case: A 61 yo man with a history of Stage IVA (T3, N3, M1b) poorly differentiated pleomorphic NSCLC presented to hospital with 2 weeks of worsening weakness and lightheadedness. Biopsy results revealed >95% PD-L1 expression and he was started on pembrolizumab 200 mg (4.5 mg/kg) every 3 weeks, along with palliative radiation to the right upper chest. Approximately 1 week after the patient’s 6th dose of pembrolizumab, he became weak and lightheaded and was admitted for further management. BP was 95/58 mmHg and biochemical studies demonstrated hyponatremia with a Na 119 mEq/L and K 4.3 mEq/L. . Due to a high suspicion for adrenal insufficiency, an AM cortisol was checked and was undetectable (<1 mcg/dl). Radiologic images were reviewed and the adrenal glands normal in appearance, ruling out metastatic involvement. Subsequent studies demonstrated an undetectable ACTH but FSH, LH, PRL, TSH, free T4 and IGF-1 were all within normal limits. Aldosterone was also normal (13 ng/dL). A Cortrosyn stimulation test demonstrated a flat response (0 min: cortisol <1 microg/dL ; 60 min: cortisol 1.6 microg/dL), consistent with adrenal atrophy. Adrenal antibodies were absent. The patient was started on hydrocortisone, 10 mg in AM and 5 mg at PM. Sodium improved to 133 mEq/L on discharge and remained at 134 mEq/L on follow up with K of 4.0 mEq/L.. Conclusion: Although multiple endocrinopathies have been observed with pembrolizumab, isolated ACTH deficiency has not been previously reported. As immune checkpoint inhibitors are used widely for the treatment of multiple refractory cancers, one should have a heighted awareness for the development of autoimmune endocrine disorders that may include primary or secondary adrenal insufficiency.

The natural history of autoimmune Addison's disease from the detection of autoantibodies to development of the disease: a long-term follow-up study on 143 patients.

Adrenal cortex autoantibodies (ACAs) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison's disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0 to 90% in different studies. To assess the predictive value of different parameters in the progression toward AAD in patients with ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS). Twenty-nine patients with APS-1 and 114 patients with APS-2 or APS-4 were followed up for a median of 10 years (range 6 months to 33 years) and were assessed using ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis. The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases and adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow-up. A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.