Adrenal Insufficiency Research Articles

Metabolic emergencies in the NICU

Metabolic emergencies in neonates can present with nonspecific signs and symptoms. Sudden acute deterioration in a neonate should prompt consideration of metabolic disease. Common metabolic emergencies in the Neonatal Intensive Care Unit (NICU) include hypoglycemia, hyperammonemia, hyperbilirubinemia, metabolic acidosis, adrenal insufficiency, and electrolyte imbalances. These emergencies often require prompt recognition and intervention to prevent serious complications. Appropriate management depends on the diagnosis. However, initial resuscitation and stabilization can be started without a definitive diagnosis. Confirmatory testing and long-term management vary by condition and should be guided by symptoms and endocrinologist input.

Long-term outcome of unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a form of Cushing's syndrome (CS) characterized by heterogeneous cortisol secretion and clinical comorbidities. Previously, bilateral adrenalectomy was the standard treatment for PBMAH, but this approach carried a high risk of primary adrenocortical insufficiency. In recent decades, unilateral adrenalectomy (U-Adx) has emerged as an effective alternative. However, limited research exists on its postoperative efficacy and prognostic predictors. Therefore, the present study aimed to investigate the long-term effectiveness and prognostic predictors of U-Adx in treating PBMAH. A total of 61 patients with PBMAH diagnosis who underwent U-Adx at a single center between 2004 and 2022 were retrospectively evaluated. Patients were categorized into persistent hypercortisolism and remission groups based on postoperative biochemical outcomes at the last follow-up (>12 months after U-Adx). Clinical characteristics, comorbidities, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-h urinary-free cortisol (24-h UFC) levels were analyzed pre- and postoperatively. We further examined whether baseline plasma ACTH, serum cortisol, 24-h UFC levels, and the inhibition of cortisol and 24-h UFC after a low-dose dexamethasone suppression test (LDDST) could predict non-remission following U-Adx. Additionally, we explored the improvements in hypertension, abnormal glucose metabolism, osteoporosis, and other complications in patients with PBMAH post-U-Adx. After U-Adx, 22 of the 45 patients (48.89%) achieved initial remission within 6 months. At the last follow-up, 25 of the 45 patients underwent all required biochemical tests and cortisol assessment tests, among which eight of 25 (32.00%) were in remission and 17 of 25 (68.00%) were experiencing persistent hypercortisolism. Moreover, five of those 25 patients exhibited recurrence after initial remission. Baseline 24-h UFC level > 2 times the upper limit of normal (2ULN) and unsuppressed 24-h UFC after LDDST may predict persistent hypercortisolism postoperatively. Lastly, long-term postoperative follow-up revealed that hypertension decreased with hypercortisolism remission, whereas osteoporosis worsened with persistent hypercortisolism. The short-term remission rate of hypercortisolism was 48.89% in patients with PBMAH treated with U-Adx, while a long-term remission rate of 32.00% was achieved after a median follow-up of 38.58 months. Furthermore, this finding suggests that baseline 24-h UFC level > 2ULN and unsuppressed 24-h UFC after LDDST predict persistent hypercortisolism in the long-term post-U-Adx. Finally, U-Adx improved cortisol circadian rhythm alterations and ACTH suppression in the patients in the remission group, thereby substantially alleviating hypertension and delaying the development of osteoporosis linked to PBMAH.

Clinical characteristics and management of adipsic arginine vasopressin deficiency in children and adolescents with sellar germ cell tumors.

Adipsic arginine vasopressin deficiency(aAVP-D) is a rare, high-risk syndrome, particularly difficult to recognize and manage in children and adolescents. This investigation examined the clinical features and management of aAVP-D in children and adolescents with sellar germ cell tumors (GCTs). A retrospective survey was performed on 260 patients with sellar GCTs, categorized into aAVP-D and non-aAVP-D groups based on thirst presence. General characteristics, hypothalamic syndrome, pituitary function, metabolic indicators, and complications were compared. Biochemical indicator changes in the aAVP-D group were analyzed after systematic management, and receiver operating characteristic (ROC) curve analysis established the optimum serum sodium cut-off for predicting the aAVP-D. 25 patients (9.6%) developed aAVP-D. The aAVP-D group had larger tumors with hypothalamic involvement and more surgical resections. They also demonstrated more hypothalamic syndrome, central adrenal insufficiency, central hypogonadism, and insulin-like growth factor-1 levels below norms. Furthermore, aAVP-D patients exhibited significantly higher rates of hypernatremia (100% vs 20.9%, p < 0.001), hyperuricemia (60.0% vs 23.4%, p < 0.001), renal impairment (32.0% vs 1.7%, p < 0.001), and venous thrombosis (4.0% vs 0%, p = 0.002). Following systematic management, aAVP-D patients experienced significant reductions in serum sodium, uric acid, and creatinine levels, although these remained higher than in the non-aAVP-D group. ROC analysis indicated that a serum sodium level above 149.5mmol/L predicted aAVP-D. Conclusion Patients with aAVP-D had more tumor involvement in the hypothalamic region, surgical resections, hypothalamic syndrome, hypopituitarism, and complications. Serum sodium levels above 149.5mmol/L necessitated heightened vigilance for aAVP-D. Early identification and systematic management reduced complications, though clinical management remained challenging. What is Known •Adipsic arginine vasopressin deficiency (aAVP-D) is a rare and high-risk syndrome that is difficult to recognize and manage. •There are few reports on aAVP-D, most of which focus on adult patients. •The characteristics and management of aAVP-D in children and adolescents remain unclear. What is New •Children and adolescents with aAVP-D experienced higher rates of hypothalamic region tumor involvement, surgical resections, hypothalamic syndrome, hypopituitarism, and associated complications. •Serum sodium levels above 149.5mmol/L necessitated heightened vigilance for aAVP-D. •Early recognition and structured management of ADI lowered the risk of complications.

A Decade of Insights into Bilateral Adrenal Masses: Epidemiology, Clinical Profiles, and Therapeutic Approaches

Bilateral adrenal masses (BAMs) are rare, accounting for 10-15% of adrenal masses. Their diagnostic and therapeutic approaches differ from those of unilateral masses. This study aimed to analyze the epidemiological, clinical, paraclinical, and therapeutic profiles of BAMs. It is based on a retrospective analysis of 30 patient records from the Endocrinology, Diabetology, and Nutrition Department at CHU Hassan II in Fez, over a 12-year period. The average age of the patients was 53 years, with a male predominance (53.3%). BAMs were symptomatically revealed in 46.7% of cases, incidentally discovered in 23.3%, identified during tumor staging in 20%, and associated with a genetic syndrome in 10% of cases. Clinical examination revealed hypertension in 23.3% of patients, an abdominal mass in 10%, signs of adrenal insufficiency in 10%, hypercortisolism in 6.67%, and hyperandrogenism in 16% of cases. Biological assessment showed elevated urinary or plasma metanephrine derivatives in 9 patients, hypercortisolism in 3 patients, adrenal insufficiency in 3 patients, 11-β-hydroxylase enzyme block in 3 patients, and primary hyperaldosteronism in 1 patient. Adrenal computed tomography (CT) was performed in 29 patients. A staging workup, including PET scan, was requested in 20% of cases. MIBG scintigraphy was performed in 23.3% of patients. The investigations revealed 53% of BAMs were secreting and 47% non-secreting. There were 9 cases of pheochromocytomas, including 5 associated with a syndrome (3 MEN2a, 1 MEN2b, 1 VHL), 8 cases of non-secreting adenomas, 3 cases of congenital adrenal hyperplasia due to 11-β-hydroxylase enzyme block, 2 cases of adrenal metastases, 2 cases of adrenocortical carcinoma, 2 cases of adrenal cysts, 1 case of Conn’s adenoma, 1 case of cortisol-secreting adenoma, 1 case of primary adrenal lymphoma, and 1 case of adrenal hematoma. Treatment included the management of emergencies and preoperative preparation for patients eligible for surgery. Bilateral adrenalectomy was performed in 33.3% of patients, and unilateral adenectomy in 1 case of cortisol-secreting adenoma. Medical treatment was initiated in 16.6% of cases, and palliative treatment in 13.33% of cases. Surveillance alone was implemented in the remaining 33.3%. Prognosis depends on the type of adrenal mass, with outcomes marked by the death of one case of malignant adrenocortical carcinoma and one case of primary adrenal lymphoma. Our study, involving 30 cases of BAMs, highlights their clinical, biological, radiological, therapeutic, and prognostic characteristics. Data in the literature are limited compared to unilateral adrenal masses. Future larger studies are desirable for optimal management.

Adrenal insufficiency - causes and laboratory diagnosis.

Adrenal insufficiency (AI) manifests as a clinical syndrome arising from either the direct impairment of adrenal glands, leading to primary AI characterized by deficiencies in glucocorticoids and mineralocorticoids, or adrenal cortex atrophy due to diminished adrenocorticotropic hormone (ACTH) stimulation, a consequence of hypothalamic and/or pituitary damage, resulting in secondary AI. The diagnosis of AI is based on clinical assessment and biochemical tests, including basal hormone level measurements and stimulation tests. In evaluating the results of laboratory tests, it is necessary to consider factors that may influence both pre-analytical and analytical phases, as well as the chosen methodology. Correct diagnosis of adrenal insufficiency and timely initiation of suitable replacement therapy are paramount. These steps are crucial not only for managing the condition but also to avert potentially life-threatening adrenal crises.

Topical Steroids Are Effective and Safe in Patients With Eosinophilic Esophagitis Over a Median of 6.5 Years of Chronic Use.

To determine long-term efficacy and safety of tCS for treatment of EoE. Maintenance therapy with topical corticosteroids (tCS) is recommended for eosinophilic esophagitis (EoE), but data for long-term use are still needed. This retrospective cohort study assessed newly diagnosed patients with EoE who were treated with a tCS and had a follow-up endoscopy with biopsy after at least 5 years. Histologic symptomatic and endoscopic responses were extracted from medical records. Patients who did and did not have long-term tCS treatment were compared at baseline, and outcomes for patients were assessed at their last endoscopy while on tCS. Of 431 patients with EoE treated with tCS, 104 met inclusion criteria for long-term use. For patients with long-term tCS use, the median time (IQR) on tCS was 6.5 years (5.4 to 8.8y). At the last endoscopy, 54% had histologic response (<15eos/hpf), but those with excellent adherence had a histologic response of 64%. Endoscopic severity also decreased with improved adherence which was strongly associated with EREFS (1.7 vs. 2.8 vs. 4.0 for excellent, good, and poor adherence; P<0.001). Symptomatic response was 68% overall, but only 40% in those with poor adherence (P=0.07). Complications of taking tCS were uncommon (adrenal insufficiency: 1%; osteopenia: 1%; and esophageal candidiasis: 4% at final endoscopy). Long-term tCS (median 6.5y) were generally effective, especially with better adherence, and also safe, with only rare serious complications. These data can be used to help patients make clinical decisions about chronic tCS use in EoE.

6422 Identifying Predictive Symptoms Of Adrenal Insufficiency

Abstract Disclosure: A.J. Han: None. S.J. Achenbach: None. B.J. Atkinson: None. I. Bancos: None. Background: Diagnosis of adrenal insufficiency (AI) is often delayed due to its vague and non-specific symptomatology. As classic symptoms of AI such as fatigue and nausea are prevalent in the general population, identifying clinical features that are more specific to AI may help clinicians determine which patients require additional testing. Methods: A single-center retrospective study was performed of patients who underwent outpatient Cosyntropin stimulation testing (CST) between 2005-2018. Patients with oral glucocorticoid or estrogen use within 2 months of CST, and patients without available Current Visit Information (CVI) form at the time of CST were excluded. Presence of symptoms was obtained from CVI, and laboratory findings were electronically extracted. Adrenal insufficiency was defined as post-CST peak cortisol &amp;lt;18 mcg/dL. Morbidity was assessed using the Elixhauser index. Variables for multivariable analysis were defined a priori and included fatigue, dizziness, muscle pain, joint pain, weight loss &amp;gt;10 pounds, abdominal pain, nausea/vomiting, and hyponatremia. Results: Among 5347 patients who underwent CST, 376 (7.0%) of patients were found to have AI. There were no sex differences between patients with and without AI, however patients with AI were slightly older (median age 48.9 vs 47.1 years, p=0.026), and had a higher median BMI (26.5 vs 25.6 kg/m2, p=0.002). Prevalence of comorbidities was similar between the two groups, with a median Elixhauser index of 1 (IQR 1-3), however, patients with AI were more likely to report difficulties with activities of daily living (69% vs 57%, p&amp;lt;0.001). Hyponatremia was diagnosed in 4% of patients with AI and 3% of those without AI, p=0.208. Although patients in our cohort reported a high prevalence of fatigue (79%), dizziness (50%), joint pain (50%), muscle pain (48%), nausea (40%), abdominal pain (39%), and weight loss in the past 6 months (29%), there were no statistically significant differences in reported symptoms between patients with and without AI with the exception of joint pain (59% vs 49%, p&amp;lt;0.001) and muscle pain (54% vs 47%, p=0.009). Based on multivariable analysis, only joint pain (OR 1.51, 95% CI 1.14-1.99) and weight loss &amp;gt;10 pounds in the past 6 months (OR 1.31, 95% CI 1.02-1.68) were associated with higher odds of AI diagnosis. Interestingly, patients who reported fatigue had lower odds of AI diagnosis on CST (OR 0.66, 95% CI 0.49-0.88). Conclusions: Commonly associated symptoms of AI such as fatigue, dizziness, nausea, and abdominal pain were poor predictors of AI diagnosis based on CST. Consequently, the presence of these symptoms alone may not warrant additional testing. Notably, clinical features such as myalgia, arthralgia, and weight loss &amp;gt;10 pounds in the past 6 months were found to be more predictive of AI. Presentation: 6/1/2024

5112 Late-Onset And Reversible Adrenal Insufficiency In Survivors Of Coronavirus Disease 2019: Results From A 24-Month Longitudinal Study

Abstract Disclosure: S.K. Sahoo: None. J.C. Menon: None. S.B. Yadav: None. Purpose We studied the temporal course of hypothalamic-pituitary-adrenal (HPA) dysfunction in patients with corona-virus disease (COVID19). Methods Three-hundred and two patients (median age 54 years [interquartile range 42-64], 76% males, 97 with severe/critical illness) were recruited. HPA axis was evaluated by adrenocorticotrophic hormone (ACTH)-stimulation test (APST) at admission in 243, and 12-months after discharge in 90 patients. Those with adrenal insufficiency (AI) at 12-months were further assessed by APST 6-monthly for recovery of hypoadrenalism. Results The median 0-min cortisol, peak cortisol, and ACTH during COVID19 were 295 (IQR 136-461) nmol/L, 846 (719-1088) nmol/L, and 3.9 (0.8-6.9) pmol/L respectively. AI was present in 21 (8.6%) patients. Plasma ACTH was elevated in five patients with AI, while it was low or inappropriately-normal in rest. Additionally, CIRCI was present in 22% (19/87) patients who had severe illness. At 12-months, AI was seen in 13% (12/90) patients and was hypothalamic-pituitary in origin in all. Nine (75%) of these had late-onset AI, who had normal HPA axis during COVID19. AI diagnosed at admission persisted at 12-months in three patients and resolved in six; the remaining 12 patients were lost to follow-up. The presence of AI at 12-months was independent of severity, and steroid use during COVID19. All the patients showed recovery of HPA axis in ensuing 6-12 months. A lower morning cortisol during COVID19 predicted presence of AI at one year. Conclusion AI was common during acute COVID19 and at 12-months of follow-up. AI can be late-onset, developing after recovery from COVID19. The AI was predominantly hypothalamic-pituitary in origin and resolved in the ensuing 6-12 months. Presentation: 6/1/2024

8219 Biochemical Disease Severity Score For Hypercortisolism Can Predict Adrenal Insufficiency After Adrenalectomy For Mild Autonomous Cortisol Secretion

Abstract Disclosure: O. Hamidi: Advisory Board Member; Self; Corcept, Neurocrine Biosciences, Amryt Pharma, Recordati Rare Diseases, Lantheus, Xeris. B.H. Salama: None. P. Dogra: None. A.P. Dackiw: None. F. Nwariaku: None. A. Islam: None. A. Mehta: None. S.C. Oltmann: None. S. Mirfakhraee: None. T. McKenzie: None. T.R. Foster: None. M. Lyden: None. B.M. Dy: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) are at risk for adrenal insufficiency (AI) after unilateral adrenalectomy. We aimed to determine the prevalence, predictors, and duration of AI after unilateral adrenalectomy for MACS, and to compare baseline and peak cortisol post cosyntropin stimulation test (CST) in diagnosing AI. Methods: We conducted a dual-center retrospective cohort study of patients with MACS who underwent unilateral adrenalectomy and were evaluated with postoperative cosyntropin stimulation test (CST). AI was diagnosed when postoperative morning cortisol was &amp;lt;10μg/dL and/or CST peak cortisol was &amp;lt;18μg/dL. Baseline and CST peak cortisol levels were considered concordant when both met corresponding cut-offs. Biochemical (BSS) and clinical (CSS) severity scores for hypercortisolism were calculated. Results: In 100 adults with MACS (77% women, median age 56 years, interquartile range [IQR] 48-63), median adenoma size was 2.8 cm (IQR, 2.2-3.7), and 25 (25%) had bilateral nodules. Median BSS was 3 (IQR, 2-5) and median CSS was 4 (IQR, 2-8). After adrenalectomy, AI was diagnosed in 56 (56%) patients. AI was associated with higher BSS, larger tumor size, but not age, sex, BMI, tumor laterality. Baseline and CST peak cortisol levels were concordant in 76% of cases. In 14% of cases morning cortisol was &amp;lt;10μg/dL but CST peak cortisol was ≥18μg/dL, and in 10% of cases morning cortisol was ≥10μg/dL, but CST peak cortisol was &amp;lt;18μg/dL. On a multivariable analysis that included age, sex, BMI, BSS, laterality, and tumor size, only higher BSS (odd ratio [OR] = 1.6 per 1 point) was associated with postoperative baseline cortisol &amp;lt;10μg/dL (P&amp;lt;0.05 for all). Independent predictors of CST peak cortisol &amp;lt;18μg/dL were BSS (OR 1.5 per 1 point) and unilateral adenoma (OR 3.7). During a median postoperative follow up of 13 months, 33 (59%) patients recovered from AI. Median time to recovery was 6.0 months, with AI recovery in 28% of patients by 2 months, 42% by 3 months, 53% by 6 months, and 64% by 12 months. Conclusions: Prevalence of postoperative AI in MACS was 56%. Only 76% of patients had concordant baseline and CST peak cortisol, with peak CST cortisol being more commonly abnormal in patients treated for unilateral MACS. Patients with larger adenomas and higher BSS were at higher risk for AI. Patients with MACS should be counseled about the risk and duration of AI after adrenalectomy. 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

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be &amp;lt; 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

7432 Secondary Adrenal Insufficiency Caused By Concurrent Treatment With Budesonide And Itraconazole

Abstract Disclosure: F. Anjum: None. M.G. Jakoby: None. Introduction: Inhaled corticosteroids (ICS) are unlikely to affect corticotroph axis function even at high doses due to low systemic absorption. However, co-treatment with drugs that reduce hepatic clearance of ICS may predispose patients to secondary adrenal insufficiency (AI). We report a case of secondary AI that occurred during concurrent treatment with budesonide and itraconazole. Case presentation: A 42-year-old female with longstanding asthma managed with inhaled budesonide (160 μg twice daily) was started on itraconazole (200 mg twice daily) for management of pulmonary histoplasmosis. Over the next three months, she experienced severe fatigue, and laboratory evaluation was notable for an undetectable (&amp;lt; 0.4 μg/dL) 8 AM cortisol level. Serum sodium (140 mM, 136-145) and potassium (4.6 mM, 3.5-5.1) were unremarkable, and a diagnosis of drug induced secondary AI was made. Treatment with hydrocortisone (15 mg in the morning, 5 mg in the evening) was started, and the patient’s infectious disease specialist stopped itraconazole, substituting posaconazole (300 mg daily) for an additional six months. Her pulmonologist substituted fluticasone (250 μg twice daily) for budesonide. After an approximate two-month hydrocortisone taper, 8 AM ACTH level was easily detectable (37.2 pg/mL, 7.2-63.3), though 30 min stimulated cortisol level was subnormal (11.1 μg/dL, expected &amp;gt; 18). Hydrocortisone was successfully tapered off over an additional two-months (30 min stimulated cortisol 23.4 μg/dL). Discussion: The literature on ICS induced secondary AI is generally case reports and series, and the incidence is very low (1.1/10,000 patient-years at risk). Limited oral bioavailability, high deposition in lungs, extensive protein binding, and robust hepatic clearance are factors that minimize the effects of ICS on corticotroph axis function. However, concurrent treatment with potent CYP3A4 inhibitors like itraconazole can significantly reduce hepatic clearance of ICS and predispose to systemic effects, including Cushing syndrome when high dose ICS are prescribed or secondary AI at lower doses. In a series of 25 cystic fibrosis patients co-treated with itraconazole and budesonide, 11/25 (44%) developed secondary AI. Our patient likely developed secondary AI but not Cushing syndrome due to treatment with low dose budesonide. This case illustrates the importance that endocrinologists recognize CY3A4 inhibiting drugs as a risk factor for secondary AI in patient treated with ICS. Presentation: 6/3/2024

6572 Acute Adrenal Crisis Secondary To Undiagnosed Addison's Disease

Abstract Disclosure: J.M. Deirmenjian: None. H. Nickowitz: None. T. Kavafyan: None. Addison’s disease, also known as primary adrenal insufficiency, is when the adrenal gland has a defect in making cortisol. Signs and symptoms of Addison’s disease include nausea, vomiting, diarrhea, fatigue, dizziness, hyperpigmentation, and mood changes. Acute Adrenal Crisis can occur as a result of Addison’s disease when patients experience acute physiologic stress such as acute illness. Patient is a 35- year-old woman with a PMHx of iron deficiency anemia presenting with intractable nausea and vomiting for 10 days and a single witnessed syncopal episode two days prior to presentation. She was also had intermittent dizziness. Patient initially presented to urgent care where she was found to be hyponatremic and then was sent to the ED. She had no seizure like activity or rashes prior to admission. On initial physical exam, her skin was warm and dry with skin discoloration and hyperpigmentation. She was awake, alert, and oriented to person, place, time, and situation. Patient had no neurological deficits and no lateral or vertical nystagmus on initial assessment. On admission, patient was hyponatremic to 114 mEq/L, potassium was 5.0 mEq/L, and glucose level was 79 mg/dL. Despite receiving a 500 cc NS bolus, 1L NS bolus, 25 grams of albumin, and D5-0.45 NS at 50 cc/hr, the hyponatremia was difficult to correct. Her sodium initially corrected to 120 mEq/L but the sodium later decreased to 117 mEq/L. The morning after admission, patient became hypotensive and hypoglycemic. Random cortisol was measured and found to be 2.2 mcg/dL, raising concern for acute adrenal crisis as a result of undiagnosed Addison’s Disease. ACTH level was 17 pg/mL. Endocrinology was consulted and she was treated with IV 100 mg Hydrocortisone in addition to IV hydrocortisone 50 mg IV q6h. Patient was able to be transitioned to PO hydrocortisone 15 mg qAM and 5 mg qPM and was started on PO fludrocortisone 0.1 mg daily. On day of discharge, sodium improved to 127 mEq/L. CT Abdomen with contrast was completed to evaluate the adrenal glands and it showed a normal appearance of the adrenal glands. The etiology of the patient’s acute adrenal crisis was secondary to undiagnosed Addison’s Disease. It is interesting to note that patient was not hypoglycemic on admission but later became hypoglycemic during her hospital course. Adrenal crisis is a possible fatal complication of undiagnosed Addison’s disease. Therefore, a possible Addison’s Disease diagnosis is important to consider when patients are presenting with symptoms such as nausea, vomiting, dizziness, and electrolyte derangements including hyponatremia. If patient’s present with hyponatremia, ruling out possible adrenal insufficiency by checking a cortisol level may change the course of patient’s care. After discharge, she was able to establish care with Endocrinology and remain stable on treatment with PO hydrocortisone and PO fludrocortisone. Presentation: 6/3/2024

8239 Recurrent Superior Laryngeal Nerve Glucocorticoid Injections: A Likely Cause Of Secondary Adrenal Insufficiency In An Otherwise Healthy Man

Abstract Disclosure: A. Lorin: None. M.C. Pranger: None. J. Park: None. C.A. Clutter: None. Background: Secondary adrenal insufficiency is well described in the literature with various offending agents implicated. Superior laryngeal nerve (SLN) glucocorticoid injections, however, have rarely been recorded as causal agents of secondary adrenal insufficiency. We present a case of a generally healthy man with secondary adrenal insufficiency after chronic administration ofsuperior laryngeal nerve glucocorticoid injections without other identifiable etiologies. Clinical Case: A 68-year-old man with no significant medical history presented to endocrinology clinic due to persistent nausea and severe fatigue. His initial labs were notable for morning cortisol of 1.66 mcg/dL (5-25) and an undetectable ACTH (&amp;lt;3.2 pg/mL, 10-60) suggestive of adrenal insufficiency. FSH/LH, testosterone, FT4, and IGF-1 were otherwise normal. On initial review of his medication history, the only glucocorticoid exposure appeared to be intranasal beclomethasone, with remote courses of oral prednisone. Further history revealed that the patient was receiving superior laryngeal nerve glucocorticoid injections for chronic cough every three weeks for over a year. The injection consisted of 1:1 mixture of 1 mL of triamcinolone acetonide 200 mg/5 mL and local anesthetic, which is equivalent to triamcinolone 40 mg or hydrocortisone 200 mg. Given the volume and chronicity of the glucocorticoid injections, the patient developed secondary adrenal insufficiency as above. Since the diagnosis, the patient discontinued SLN glucocorticoid injections and was placed on physiologic hydrocortisone replacement, with gradual recovery of his HPA axis. Conclusions: Sequelae of percutaneous glucocorticoid injection into the superior laryngeal nerve for treatment of chronic cough are not well documented in terms of their effects on the HPA axis. While an effective and increasingly common treatment for chronic cough, SLN glucocorticoid injection has the potential to cause suppression of the HPA axis and cause secondary adrenal insufficiency. Excess glucocorticoid appeared to solely inhibit ACTH production, as the other anterior pituitary hormones were not affected. Understanding consequences of glucocorticoid use in any formulation is important when considering such therapies, as these may alter normal HPA function with recurrent dosing. Recovery from a disrupted HPA axis may be achieved with the use of physiologic doses of hydrocortisone replacement in the case of secondary adrenal insufficiency. Presentation: 6/3/2024

8295 Development of Type 1 Diabetes and Primary Adrenal Insufficiency Secondary to Immunotherapy Treatment for Chordoma in a Patient With Hypopituitarism

Abstract Disclosure: P. Kesavan Chary: None. J.M. Silverstein: None. Background: Cranio-cervical chordomas are rare locally aggressive, invasive, and slow-growing bone neoplasms. Treatment involves a combination of excision and radiation therapy, and sometimes immunotherapy for recurrent disease. Endocrine-related toxicities from immune checkpoint inhibitors are well recognized and include autoimmune thyroid disease, hypophysitis, and less commonly, type 1 diabetes mellitus (T1DM) and primary adrenal insufficiency (PAI). We present a case of a patient with hypopituitarism secondary to a recurrent and aggressive skull base chordoma with leptomeningeal spread who developed T1DM and PAI after treatment with nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody. Diagnosis of PAI was delayed because patient was on hydrocortisone replacement for secondary adrenal insufficiency. Case Report: A 38 year old male with history of primary hypothyroidism underwent endoscopic endonasal transsphenoidal resection and adjuvant proton beam radiation therapy for a sellar chordoma after presenting with diplopia. Testing was consistent with hypopituitarism and the patient was started on hydrocortisone, levothyroxine, and testosterone replacement. Due to recurrent disease and leptomeningeal spread, he subsequently underwent three additional surgeries and two courses of gamma knife radiosurgery. Five months after starting systemic therapy with nivolumab, the patient developed insulin dependent diabetes presumed to be T1DM secondary to immunotherapy. He was continued on nivolumab, and six months into treatment developed hyperkalemia and hyponatremia requiring inpatient admission. He was treated with diuretics and fluid restriction initially without improvement in his electrolyte abnormalities although he remained relatively asymptomatic. Laboratory evaluation showed a renin activity of 66 ng/mL/H and aldosterone &amp;lt; 4.0 ng/dL (&amp;lt;= 21) with sodium of 128 mmol/L (135-145) and potassium 5.8 mml/L (3.3-4.9). Due to suspicion for PAI secondary to checkpoint-inhibitor induced adrenalitis, 21-hydroxylase antibody was checked and was positive. It was felt that the patient had not had other signs or symptoms classic for PAI such as nausea and/or vomiting because he had already been on glucocorticoid replacement for his hypopituitarism. Ultimately, the patient was started on fludrocortisone, with resolution of his hyponatremia and hyperkalemia. Conclusion: Adrenal insufficiency from immunotherapy is most commonly caused by hypophysitis. T1DM and PAI due to adrenalitis are less common. In patients on steroid replacement for hypopituitarism, the development of electrolyte abnormalities with or without symptoms in a patient on immunotherapy should raise the suspicion for rarer endocrine side effects such as primary adrenal insufficiency. Presentation: 6/3/2024

7692 Morning Cortisol Levels In Patients With Established Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Primary adrenal insufficiency (PAI) is rare: prevalence ∼100-140/million and incidence 4:1 000 000/year in Western societies [1]. The diagnosis of PAI is suggested by an early-morning cortisol &amp;lt;140 nmol/L (5 µg/dL) [1]. The commonest cause in adults is autoimmunity (∼90% in Western countries) and it is generally considered progressive once the diagnosis is made, although it has been reported that residual cortisol secretion is present in ∼30% of patients 2. We have developed a modified-release formulation of hydrocortisone to replace the physiological cortisol circadian rhythm and are undertaking a Double-Blind, Double-Dummy, Two-Way Cross-Over, Randomised, Phase II Study of Modified-Release Hydrocortisones: Chronocort® Versus Plenadren® in PAI. During recruitment, we were surprised by the number of patients who were ineligible as they had detectable morning cortisol levels. Methods: Main inclusion criteria: Participants with known PAI on stable glucocorticoid replacement therapy and an early morning pre-dose cortisol &amp;lt;50 nmol/L (1.8 µg/dl). Baseline serum cortisol was taken at ∼0700h and measured in a central laboratory by ADVIA Centaur® immunoassay with the lower limit of detection &amp;lt;14nmol/l (&amp;lt;0.5 µg/dL). Results: 86 patients with PAI (autoimmune aetiology in 71), median age 52 years (range 20-73), 60 female, were screened in 8 centres in UK and Germany. 18 (21%) patients were excluded from the study based on morning cortisol &amp;gt;50 nmol/L (1.8 µg/dL), and of those 68 patients who qualified on the main inclusion criteria 51 (59% of screened) had a cortisol &amp;lt;14 nmol/L (&amp;lt;0.5 µg/dL). Of the 18 patients (autoimmune aetiology in 10) excluded based on their morning cortisol level, 9 (50%) were female and 11 (13% of screened), had morning cortisol ≥140 nmol/L (5.0 µ/dL). 12 patients with morning cortisol of &amp;gt;50nmol/L (1.8 µ/dL) were retested and only 2 then qualified; their initial morning cortisol levels were 70 and 51 nmol/L. In patients retested the median difference between retest and the initial sample was 13 nmol/L (range 1-421 nmol/L). Conclusions: In patients with an established diagnosis of PAI, the majority had undetectable morning cortisol, but cortisol was detectable in 41% of patients and above 140 nmol/L in 13% confirming previous publications 2. Retesting patients with a cortisol &amp;gt;50nmol/L showed very similar results suggesting that the detectable cortisol was not an artefact and likely due to background cortisol secretion. 1. Bornstein SR, et al. J Clin Endocrinol Metab 2016;101:364-89.2.Pearce SHS, et al. European Journal of Endocrinology (2021) 184, R61–R67 Presentation: 6/1/2024

7695 Impact Of Day Of Admission On Outcomes Of Adrenal Insufficiency- A National Inpatient Sample Study

Abstract Disclosure: S. Karki: None. B. Neupane: None. S. Neupane: None. A. Bhandari: None. U. Farooq: None. K. Rajamani: None. Introduction: Admission day (weekend vs. weekday) significantly influences hospital outcomes and mortality in various diseases, with evidence suggesting higher mortality rates associated with weekend admissions. However, the “weekend effect” on adrenal insufficiency remains underexplored in national inpatient samples. Objective of the study:To assess the impact of admission day on mortality rates, hospital stays, costs, and overall outcomes in adrenal insufficiency patients. Methods: A retrospective cohort study encompassing adult patients (age&amp;gt;18 years) was conducted using the National Inpatient Sample (NIS) data spanning from 2017 to 2020. The International Classification of Disease (ICD-10) was used to select codes for diseases and outcomes. STATA was employed for statistical analysis, using multivariate regression analysis to calculate adjusted odds ratios and account for potential confounding variables. Continuous variables were compared using the student t-test, while proportions were compared using the Fisher exact test. The primary outcome was mortality, with secondary outcomes encompassing length of stay (LOS), total hospitalization charges, acute coronary syndrome (ACS), septic shock, pulmonary edema, acute respiratory failure (ARF), mechanical ventilation, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and cerebrovascular accidents (CVA). Results: A total of 150,005 patients diagnosed with adrenal insufficiency were included in the analysis. Patients with adrenal insufficiency were categorized into two groups based on the day of admission: weekend and weekday. Weekend admissions constituted 23.5% of the total cases of adrenal insufficiency, with 35,330 patients. Significant differences in outcomes were observed in septic shock (aOR=1.16, 7.24 % vs. 6.30 %, p=0.007), ARF (aOR=1.23, 11.82% vs. 9.87%, p&amp;lt;0.001), mechanical ventilation (aOR=1.35, 6.29% vs. 4.76%, p&amp;lt;0.001), ARDS (aOR=1.83, 0.57% vs. 0.33%, p=0.003), and AKI (aOR=1.15, 24.74% vs. 22.58%, p&amp;lt;0.001) in weekend vs weekday admissions. However, no significant differences were observed in mortality rates, mean length of hospital stay, total hospital costs, ACS, pulmonary edema, and CVA. Conclusion: Weekend admissions for adrenal insufficiency showed poorer outcomes which prompts further investigation into underlying factors. Insights gained might be helpful for strategic planning at state and national levels, aiding in outcome improvement. Presentation: 6/1/2024

6611 ACTH deficiency due to TBX19 mutation mimics complete adrenal insufficiency in a newborn

Abstract Disclosure: T. Reinehr: None. P.M. Holterhus: None. S.A. Wudy: None. A. Richter-Unruh: None. C. Spratte: None. C. Roll: None. Isolated ACTH deficiency (IAD) is a rare cause of adrenocortical insufficiency. T-box transcription factor 19 (TBX19) mutations are responsible for more than 60% of neonatal cases of IAD. To the best of our knowledge, we present for the first time a newborn with ACTH deficiency due to a TBX19 mutation with almost steroid-free plasma and urine: At day 2 of life, the female newborn (birth weight 3190g, length 52 cm, 40+1 gestational age) was transferred to our neonatal intensive care unit for severe hypoglycemia (12 mg/dl), which responded to intravenous glucose infusion. Surprisingly, the sodium serum concentrations decreased from 140 mmol/l at day 2 of life to 126 mmol/l at day 7 of life. There were no clinical signs of adrenal insufficiency such as vomiting or hypotonia. Treatment with oral sodium-chloride 5.85% was started. Endocrine diagnostic work-up performed at day 8 of life demonstrated normal values of fT4, HGH and IGFBP-3 ruling out pituitary involvement of these axes, while ACTH serum concentrations were markedly decreased (1.5 pg/ml). Liquid- chromatography-mass spectrometry (LC-MS/MS) revealed nearly absent glucocorticoids (17-hydroxyprogesterone &amp;lt;0.12 nmol/l, 11-deoxycortisol &amp;lt;0.08 nmol/l, cortisol &amp;lt;4.2 nmol/l, and cortisone 1.3 nmol/l (norm value [nv]: 17-138 nmol/l)). Androgens were undetectable (testosterone &amp;lt;0.02 nmol/l, androstenedione &amp;lt;0.08 nmol/l). Mineralocorticoids were severely reduced (11-desoxycorticosterone 0.1 nmol/l (nv: 0.2-1.0 nmol/l), corticosterone 0.6 nmol/l (nv: 1-24 nmol/l), aldosterone 0.1 nmol/l (nv: 0.8-2.3 nmol/l)). In urine spot, gas chromatography-mass spectrometry (GC-MS) demonstrated subnormal excretion of C19 and C21 steroids including fetal zone steroids. Serum and urine measurements were interpreted by the labs as a typical finding similar to StAR defect. The genetic analyses revealed a normal female karyotype (46,XX) and ruled out CYP11A1 and StAR, mutations but demonstrated a homozygous missense mutation in TBX19 (c.172A&amp;gt;G, p.(Thr58Ala)). After 3 months of life under treatment with hydrocortisone (10mg/m² divided in 3 doses) and fludrocortisone (0.05 mg divided in 2 doses), cortisol was normal (320 nmol/l) and DHEAS was undetectable (&amp;lt;3 nmol/l). While androgens were in normal range (testosterone 2.6 nmol/l, androstenedione 0.28 nmol/l), 11-deoxycorticosterone was normal (0.74 nmol/l), corticosterone was undetectable (&amp;lt;0.5 nmol/l) and aldosterone was decreased (0.12 nmol/l nv: 0.8-1.2 nmol/l). At this time point, ACTH was &amp;lt;4 pg/ml, renin 1.6 mIU/l, LH 0.7 mIU/l and FSH 24.5 mIU/ml. This case demonstrated that isolated ACTH deficiency should be considered as a potential differential diagnosis in complete adrenal steroid insufficiency in newborns. Our data suggest that ACTH is not only necessary for cortisol biosynthesis but also for sufficient mineralocorticoid and androgen production by the adrenals in neonates. Presentation: 6/3/2024

7243 COVID-19 Associated Primary Autoimmune Adrenal Insufficiency: A New Clinical Entity

Abstract Disclosure: J. Naredo Rojas: None. B. Udegbe: None. I. Remba-Shapiro: None. S.L. Stockman: None. L.B. Nachtigall: None. Background: The adrenal glands express angiotensin converting enzyme and transmembrane serine protease 2 receptors for SARS-CoV-2 protein S, facilitating viral entry. Cortisol levels are decreased in COVID-19 infection in correlation with disease severity. A number of potential mechanisms could relate autoimmune adrenal insufficiency (AI) to COVID-19, but whether or not SARS-CoV-2 infection plays a direct role in the autoimmune pathogenesis of primary AI is unknown. Furthermore, while single cases have been reported, autoimmune-mediated primary adrenal insufficiency following COVID-19 illness has not been formally studied. Purpose: To determine the association and clinical presentation of primary autoimmune adrenal insufficiency in patients with COVID-19 disease. Methods: A retrospective chart review was performed on patients presenting to Massachusetts General Hospital (MGH) with primary AI in the setting of recent COVID-19 illness. Review of the literature was performed to identify additional cases. Clinical, biochemical and radiographic characteristics, and interval between the diagnosis of COVID-19 and primary AI diagnosis were evaluated. Criteria for inclusion were biochemical confirmation of AI, clinical signs and/or symptoms of adrenal insufficiency within 6 months of COVID-19 illness, and evidence of autoimmune etiology of AI. Results: Five novel cases of COVID-19 associated primary autoimmune-mediated adrenal insufficiency from our Center were identified. Review of the literature yielded five additional cases. This series combines our Center’s experience, and the cases reported to date, including a total of 10 patients, 6 men and 4 women. All men (6/6) and 2 women (2/4) were &amp;lt; 30 years old. Patients demonstrated clinical evidence of adrenal insufficiency in a median time frame of 14 days (IQR 8.5-23.3) after SARS-CoV-2 infection. Vomiting, hypotension, and hyponatremia were present in all (N=10). Other common symptoms were nausea (90%), fatigue (70%), hyperpigmentation (70%) and hyperkalemia (50%). Nine (90%) had a positive past medical and/or family history of autoimmune disease. Nine (90%) had positive 21-hydroxylase antibodies. The median serum morning cortisol level was 1.1μg/dL with an IQR of 0.7-3.0 μg/dL. The mean ACTH level was 1235.2 pg/mL with a SD of 580.1 pg/mL. The mean ACTH was 19.3 x ULN with a SD of 10.0. Adrenal imaging did not show hemorrhage or necrosis but showed atrophy in 50%. Conclusions: This series reveals that autoimmune-mediated primary adrenal insufficiency may be diagnosed in the aftermath of COVID-19 illness. Age under 30, family history and/or past medical history of autoimmune disease may be associated. Future prospective studies are needed to determine causality. Presentation: 6/1/2024

7761 Unmasking The Uncommon: A Case Of Primary Adrenal Insufficiency Presenting As Severe Hypercalcemia

Abstract Disclosure: A. Misbah: None. Z. Al-Hiti: None. A. Saleh: None. M. Joda: None. K. Rajamani: None. Adrenal insufficiency is a recognized but uncommon cause of hypercalcemia. The exact mechanism remains unknown; however, it is thought to be a combination of the hypovolemic state in adrenal insufficiency leading to decreased urinary clearance, as well as increased bone resorption. We present a case of primary adrenal insufficiency presenting with severe hypercalcemia. A 41 year old female with a past medical history of osteopenia, recently diagnosed postural orthostatic tachycardia syndrome (POTS), and hyponatremia attributed to SIADH presented with complaints of weakness and poor oral intake. She also reported a history of nausea, vomiting, weight loss, fatigue, and dizziness, for the last few months. She reported feeling well prior to a COVID-19 infection a few months back. At presentation, she was hypotensive with a blood pressure of 70/50 mmHg, while her other vital signs were stable. She appeared ill, and was noted to have dry oral mucous membranes. There was no increased pigmentation noted on exam. Initial laboratory evaluation revealed sodium of 130 (135-145 mmol/L), potassium of 5.3 (3.5-5.1 mmol/L), and creatinine of 1.7 (0.5-0.8 mg/dL). She had severe hypercalcemia with a calcium level of 15.5 (8.3-10.6 mg/dL) and had a blood glucose level of 53 (70-100 mg/dL). Venous blood gas indicated metabolic acidosis. Morning cortisol was low at 1 (3-23 ug/dL). Serum ACTH was elevated at 775 (0-46 pg/mL). Cosyntropin stimulation test confirmed primary adrenal insufficiency. She underwent work-up for hypercalcemia, which revealed a suppressed PTH, normal levels of PTHrP, vitamin D, and vitamin A. Serum and urine protein electrophoresis was normal. She was initially managed in the ICU and received aggressive fluid resuscitation. She was started on stress dose of hydrocortisone, which was then tapered to physiological doses of oral hydrocortisone and fludrocortisone. Subsequent improvements were observed in blood pressure, laboratory abnormalities, and normalized serum calcium levels. She was discharged home on hydrocortisone and fludrocortisone. On follow-up, she was doing well with the resolution of her symptoms. This case highlights the importance of recognizing adrenal insufficiency as one of the causes of hypercalcemia. Although hypercalcemia as a consequence of adrenal insufficiency is well-documented, the exact prevalence is not known but is estimated to be around 6%. After excluding more common diseases such as primary hyperparathyroidism and malignancy, the possibility of adrenal insufficiency should be considered as a cause of hypercalcemia. Treatment involves hormone replacement as well as hydration, bringing resolution to symptoms. Her presentation was unique, also due to the fact that her initial symptoms were diagnosed as POTS as well as SIADH. Given the onset of symptoms after a COVID-19 infection a few months ago, there could also be a potential link between the two. Presentation: 6/3/2024