When Your Pituitary Fails - A Rare Case of Pituitary Dysfunction Due to Nivolumab and Ipilimumab

Introduction: Immunomodulators like Nivolumab and Ipilimumab are important regimens in many malignancies. However, their use is linked with the rare side effect of pituitary dysfunction that if screened and treated can prevent misdiagnosis. Case Description: A 56-year-old male with a history of renal cell carcinoma status post bilateral partial nephrectomy with metastasis to the lung on Nivolumab/Ipilimumab presented with dizziness. He endorsed difficulty with balance, nausea, decreased appetite, feeling dehydrated and recent blood pressure readings in the 90s. Vitals on presentation were stable. An MRI, from 2 weeks ago, showed a slightly enlarged sella but no metastatic disease. The next day, he became hypotensive with minimal response to fluids and was started on Midodrine. However, considering his persistent hypotension, his cortisol level was checked and found to be profoundly low (<1). Literature review of his immunomodulator revealed the possibility of central adrenal insufficiency. In addition, he was noted to have a low TSH (0.02) with normal FT4 (1.08). Subsequently, his ACTH level was also found to be low (<1.5) which further elucidated a central cause for his adrenal insufficiency. Therefore, he was ultimately treated with PO hydrocortisone with plans to taper off in the next few weeks. Conclusion: This case demonstrates a rare yet significant side effect of Nivolumab/Ipilimumab therapy. Timely diagnosis and therapy can alleviate symptoms due to associated hormonal deficiencies. Moving forward it will be interesting to see if starting prophylactic steroids or routine screening will allow us to diagnose pituitary dysfunction due to Nivolumab/Ipilimumab earlier.

Exogenous Cushing’s Syndrome, Hypogonadism and Diabetes Secondary to Megestrol Acetate

Introduction: Megestrol acetate (MA) is a synthetic progestin that is often prescribed for anorexic patients with HIV due to its effects on weight gain and appetite stimulation. It can cause several endocrine/metabolic abnormalities. Chronic use of MA can cause exogenous Cushing’s Syndrome (ECS) and iatrogenic adrenal insufficiency (AI) due to its stronger affinity for the glucocorticoid receptor (GR). It can also cause gonadotropin suppression, diabetes and hyperprolactinemia. We present a case of a young woman with perinatal HIV/AIDS that developed ECS secondary to MA treatment in the setting of fatigue, rapid weight gain and irregular menses. Case: A 19 year old female with perinatal HIV/AIDS (CD4<200) was treated with MA (200mg/day for 5 months) for anorexia and weight loss. On exam she was pre-hypertensive (BP 138/62), obese (BMI 43.07, SDS +2.25; weight 114kg, SDS +2.34) with increased fat deposition over upper back and abdominal striae, excessive weight gain (21.5 kg in 5 months) suggestive of ECS. She had menarche at 13 years of age and had regular menses until starting MA, upon which she developed oligomenorrhea. A random serum cortisol level was <0.5ug/dl at 1pm with a low ACTH <1.5pg/ml and DHEAS of 13.4ug/dl. Her FSH was 3.4 mIU/L and LH 0.82 mIU/L, estradiol was <2pg/dl and total testosterone <2.5ng/dl consistent with secondary hypogonadism. Liver/kidney function, prolactin and lipid profile were normal. HbA1c increased from 5.3 to 6.4% in 8 months so she was started on metformin. ECS with AI, central hypogonadism and diabetes were all attributed to MA therapy. MA was discontinued gradually over two weeks. Stress dosing of glucocorticoids were advised as needed. Results: Gradual recovery of HPA axis was noted after discontinuation of MA. Two months after taper, serum ACTH level rose to 2.5pg/ml but AM cortisol level remained low at <0.5ug.dl. Her HPA axis showed partial recovery by 5 months with ACTH level of 53.2pg/ml and AM cortisol level of 5.5ug/dl. By 8 months after discontinuing MA therapy, AM cortisol was 9.3ug/dl, suggesting complete HPA axis recovery. Her HPG axis also normalized by 8 months with FSH 6.6 mIU/L and LH of 14.6 mIU/L, estradiol 32pg/dl with regular menses. Metformin was discontinued at 4 months due to hypoglycemia and HbA1C of 5.7%. Subsequently, euglycemia was achieved (HbA1C of 5.4%) within 9 months. BMI was stable (BMI 43.07, SDS +2.25; weight 114kg, SDS +2.34). Conclusion: Multiple endocrine abnormalities may occur due to MA therapy due to its affinity to bind with glucocorticoid and progesterone/androgen receptors. ECS and AI are known to occur with various forms of glucocorticoid use, but rarely can be seen with MA therapy. HPA axis, HPG axis and metabolic parameters should be evaluated and monitored carefully during MA therapy.

Variations in the Initial Presentation of a Rare Congenital Adrenal Hyperplasia: Steroidogenic Acute Regulatory Deficiency

Background: Steroidogenic Acute Regulatory (StAR) deficiency is a rare form of congenital adrenal hyperplasia characterized by dysregulated cholesterol transport mediated by StAR enzyme across mitochondrial membranes. Adrenal dysfunction is due to the two-hit hypothesis: 1) defective StAR protein and 2) cholesterol accumulation in the adrenals and gonads. With variable cellular damage, adrenal crisis can occur early or late. Clinical cases: We present two cases of StAR deficiency with contrasting presentations. Case 1: A 9-day old ex full term female from a nonconsanguineous union presented to a rural hospital with hypothermia, lethargy, and poor feeding. She had hypoglycemia 41 mg/dL (60–105), hyponatremia 120 mEq/L (135–145), hyperkalemia 7.7 mEq/L (3.5–5.5) and cortisol < 0.4 ug/dL (4.5–23). Baby was started on hydrocortisone (HCT) 100 mg/m2 and one-time fludrocortisone (FCT). She decompensated requiring chest compressions, intubation and pressors. She was transferred to our institution. Newborn screen was normal; she had typical female external genitalia. US demonstrated a uterus; ovaries and adrenals were not identified. Upon extubation and clinical improvement, her HCT was weaned to physiologic doses. She became hyponatremic requiring FCT and salt supplements. Post-HCT wean, ACTH level was 304 pg/mL (7–63) with aldosterone < 4.0 ng/dL (6.5–86). Karyotype was 46,XX. Genetic analysis revealed a novel heterozygous likely pathogenic variant in the STAR gene, (STAR c.65-12_68del variant) without defect in the other STAR gene. Case 2: A 9-month-old ex full-term female of Iraqi descent from a nonconsanguineous union presented with fatigue, poor oral intake and weight loss from 50%-ile to 3%-ile. She had hyponatremia 122 mEq/L, hyperkalemia 8.0 mEq/L, but was normoglycemic. She was normotensive; EKG was normal. Parents noted progressive hyperpigmentation including her gums, palmar and plantar creases. She had typical external female genitalia with a hypoplastic clitoris (2 mm x 2 mm). ACTH stimulation test showed low cortisol (0.5 ug/dL) at 60 minutes. She was treated with HCT 100 mg/m2 for 5 days, then tapered to maintenance dosing, with FCT and salt supplements. Her ACTH level returned > 5000 pg/ml. Aldosterone, 17-OH-Progesterone, 17-OH-Pregnenolone, 11-Deoxycortisol and androstenedione were undetectable. Pelvic US did not identify uterus or ovaries. Pelvic MRI identified bilateral inguinal testes with enlarged adrenal glands. Karyotype was 46, XY. We suspected StAR deficiency with sex-reversal. Genetic analysis revealed a known homozygous mutation in STAR (c.545G>A). Conclusion: StAR deficiency is clinically indistinguishable from P450scc deficiency and genetic testing is needed. Both entities can present with early or delayed adrenal crisis. While classic for StAR deficiency, adrenal enlargement is inconsistent. Karyotype is vital to identify sex reversal.

Bilateral adrenal haematoma complicated by adrenal insufficiency in a patient treated with bevacizumab

Bevacizumab (bev) significantly improves outcomes of patients with metastatic colorectal cancer (mCRC). However, the addition of bev to concurrent chemotherapy significantly increased the risk of haemorrhage. We describe the case of a patient with mCRC who presented with acute diffuse abdominal pain following four cycles of bev-containing systemic chemotherapy. A CT revealed the appearance of bilateral adrenal enlargement suggestive of acute adrenal haematoma. Blood test results showed a dramatic decrease in cortisol level and highly elevated Adrenocorticotropic Hormone (ACTH) level suggesting an adrenal insufficiency. After differential diagnosis, we hypothesised that bev may have contributed to the development of a bilateral adrenal haematoma complicated by adrenal insufficiency. Bev was immediately withdrawn and the patient was subsequently treated with hydrocortisone substitution with favourable outcome. This case highlights for the first time the possibility of adrenal bleeding with bev-containing chemotherapy.

Recurrence of a neuroendocrine tumor of adrenal origin: a case report with more than a decade follow-up

Background Neuroendocrine tumor (NET) with adrenocorticotropic hormone (ACTH) secretion are very rare. To our knowledge, no follow-up study is published for ACTH-secreting NET, regardless of the primary site, to show second occurrence of tumor after a long follow-up, following resection of primary tumor. Case presentation Here, we describe a 49-year-old-man with cushingoid feature, drowsiness and quadriparesis came to emergency department at December 2005. Laboratory tests revealed hyperglycemia, metabolic alkalosis, severe hypokalemia, and chemical evidence of an ACTH-dependent hypercortisolism as morning serum cortisol of 57 μg /dL without suppression after 8 mg dexamethasone suppression test, serum ACTH level of 256 pg/mL, and urine free cortisol of > 1000 μg /24 h. Imaging showed only bilateral adrenal hyperplasia, without evidence of pituitary adenoma or ectopic ACTH producing tumors. Importantly, other diagnostic tests for differentiating Cushing disease (CD) from ectopic ACTH producing tumor, such as inferior petrosal sinus sampling (IPSS), corticotropin releasing hormone (CRH) stimulation test, octreotide scan or fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan were not available in our country at that time. Therefore, bilateral adrenalectomy was performed that led to clinical and biochemical remission of hypercortisolism and decreased ACTH level to < 50 pg/mL, findings suggestive of a primary focus of NET in adrenal glands. After 11 years uncomplicated follow up, the ACTH level elevated up to 341 pg/mL and re-evaluation showed a 2 cm nodule in the middle lobe of the right lung. Surgical excision of the pulmonary nodule yielded a carcinoid tumor with positive immunostaining for ACTH; leading to decrease in serum ACTH level to 98 pg/mL. Subsequently after 7 months, serum ACHT levels rose again. More investigation showed multiple lung nodules with metastatic bone lesions accompanied by high serum chromogranin level (2062 ng/mL), and the patient managed as a metastatic NET, with bisphosphonate and somatostatin receptor analogues. Conclusion This case of surgically-treated NET showing a secondary focus of carcinoid tumor after one decade of disease-free follow-up emphasizes on the importance of long-term follow-up of ACTH-secreting adrenal NET.

Gamma Knife radiosurgery for the treatment of Nelson’s syndrome: a multicenter, international study

OBJECTIVENelson’s syndrome is a rare and challenging neuroendocrine disorder, and it is associated with elevated adrenocorticotrophic hormone (ACTH) level, skin hyperpigmentation, and pituitary adenoma growth. Management options including resection and medical therapy are traditional approaches. Ionizing radiation in the form of Gamma Knife radiosurgery (GKRS) is also being utilized to treat Nelson’s syndrome. In the current study the authors sought to better define the therapeutic role of stereotactic radiosurgery (SRS) in Nelson’s syndrome.METHODSStudy patients with Nelson’s syndrome were treated with single-fraction GKRS (median margin dose of 25 Gy) at 6 different centers as part of an International Radiosurgery Research Foundation (IRRF) investigation. Data including neurological function, endocrine response, and radiological tumor response were collected and sent to the study-coordinating center for review. Fifty-one patients with median endocrine and radiological follow-ups of 91 and 80.5 months from GKRS, respectively, were analyzed for endocrine remission, tumor control, and neurological outcome. Statistical methods were used to identify prognostic factors for these endpoints.RESULTSAt last follow-up, radiological tumor control was achieved in 92.15% of patients. Endocrine remission off medical management and reduction in pre-SRS ACTH level were achieved in 29.4% and 62.7% of patients, respectively. Improved remission rates were associated with a shorter time interval between resection and GKRS (p = 0.039). Hypopituitarism was seen in 21.6% and new visual deficits were demonstrated in 15.7% of patients.CONCLUSIONSGKRS affords a high rate of pituitary adenoma control and improvement in ACTH level for the majority of Nelson’s syndrome patients. Hypopituitarism is the most common adverse effect from GKRS in Nelson’s syndrome patients and warrants longitudinal follow-up for detection and endocrine replacement.

MON-188 The Diagnostic Value of DHEAS in Subtyping Patients with Cushing Syndrome

Objective: Serum dehydroepiandrosterone sulfate (DHEAS) can be used to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to evaluate the clinical value of DHEAS in differentiating adrenal Cushing syndrome (ACS) from Cushing’ disease (CD). Methods: We recruited 100 patients with Cushing syndrome, 36 with CD and 64 with ACS. 72 sex-, age- and BMI-matched nonfunctional adrenal adenomas (NFAAs) were served as controls. Clinical and laboratory data were collected. DHEAS levels were measured and DHEAS ratio was calculated by dividing the measured DHEAS by the lower limit of the respective reference range (age- and sex-matched). Results: 1) No significant differences in age, sex, or BMI were detected among the NFAAs, ACS and CD groups. Compared to NFAAs group, ACS patients had lower plasma ACTH levels [1.11(1.11,1.74) vs 5.0 ± 2.9 pmol/L, P&lt;0.01], lower DHEAS levels (24.00 ± 20.72 vs 189.05 ± 82.03 ug/dL, P &lt; 0.01) and lower DHEAS ratio [0.58(0.27,0.98) vs 5.34 ± 3.0]; Plasma ACTH (22.12 ± 14.22 pmol/L), DHEAS (309.4 ± 201.1 ug/dL) and DHEAS ratio (10.51 ± 7.65) in CD patients were significantly higher compared to those in NFAAs and ACS patients (all P&lt;0.01). 2) In ACS patients, there were 53 patients with suppressed ACTH level of &lt;2.0 pmol/L, 11 patients without plasma ACTH suppression (≥2.0pmol/L). Compared to NFAAs, lower DHEAS and DHEAS ratio were detected in these two groups, and no significant differences were found in the DHEAS [15(15, 23.5) vs 23.8 ± 14.4 ug/dL, P=0.86] and DHEAS ratio [0.58(0.27, 0.80) vs 1.0(0.25,2.09) ug/dL, P=0.40] between the two groups. 3) ROC analysis showed that the area under the curve (AUC) of plasma ACTH, serum DHEAS and DHEAS ratio in diagnosing 0.954, 0.997 and 0.990 respectively. The optimal cut-off values for DHEAS and its ratio were 79.1ug/dL, and 2.09, respectively. The diagnostic sensitivity and specificity of plasma ACTH (&lt;2.0pmol/L) were 84.1 and 100%, those of DHEAS were 97.5% and 100%, and those of DHEAS ratio were 95% and 100%, respectively. Conclusions: Patients with different subtype of Cushing syndrome showed distinctive DHEAS levels and DHEAS ratio. DHEAS and DHEAS ratio are useful in differential diagnosis of Cushing syndrome. Especially, when the plasma ACTH level is not conclusive. The measurement of DHEAS may offer a supplementary test to diagnosis ACS from CD. Keywords: Adrenal Cushing syndrome; Cushing disease; Adrenocorticotropic hormone; Dehydroepiandrosterone sulfate

SUN-170 Adrenal Insufficiency Due to Adrenal Hemorrhage

Introduction: Antiphospholipid Syndrome (APS) can involve multiple organ systems but endocrine manifestations are rare. In most cases adrenal insufficiency (AI) is the first endocrine manifestation of APS. The prompt diagnosis of adrenal insufficiency is critical. We present a case of AI associated with antiphospholipid syndrome who was managed successfully. Case presentation: A 50-year-old man was admitted with deep venous thrombosis of the distal left femoral vein extending to the popliteal vein and was started on xarelto, but he developed pleuritic chest pain and dyspnea in 48 hours. CT scan confirmed a pulmonary embolism and patient was treated with heparin drip. Two days following heparin drip patient developed acute bilateral flank pain and hypotension; and CT abdomen showed 2 masses replacing the adrenal glands that were concerning for hematomas. Laboratory results: serum potassium 4.9 mmol/L, serum cortisol 3.3 mcg/dL (reference 7.2–19.4), ACTH level 319 pg/mL (reference 7–53), aldosterone &lt;1.0 ng/dL (reference 0.0–3.0), and plasma renin activity 7.17 ng/ml/hr (reference, 0.15–3.95). Serum antiphospholipid antibody testing showed cardiolipin Ab Ig 140 GPL/mL (reference 0–14), cardiolipin Ab IgM 100 MPL/mL (reference 0–12) and cardiolipin Ab IgA &gt;150 APL/mL (reference 0–11). Further testing showed beta-2 glycoprotein 1 Ab IgG 103 GPI units (reference 1–20), IgM 94 GPI units (reference 0–32), and IgA 150 GPI units (reference 0–25). His hypotension dramatically improved upon administration of IV hydrocortisone and the abdominal pain resolved in 3 days. Upon discharge he was placed on hydrocortisone and continued warfarin therapy. At a 6-week follow-up visit, patient was asymptomatic. Additional lab tests revealed normal plasma renin activity and aldosterone levels. Two years later an ACTH stimulation test confirmed persistent AI. Basal plasma ACTH level was 230 pg/mL (ref 5–50). Additionally plasma renin activity and serum aldosterone levels indicated no mineralocorticoid deficiency. An adrenal CT scan revealed significant long-term interval decrease in size of bilateral adrenals with hypo-attenuating focus in the right adrenal gland, favored to represent post hemorrhage changes without convincing evidence of underlying neoplasm especially given decrease in size compared to 4-years prior. Presently, patient is doing well on hydrocortisone and warfarin treatment. Conclusion: In all cases of adrenal hemorrhage and infarction with unknown etiology, screening with lupus anticoagulant and anticardiolipin antibodies is imperative. Recognition of this high mortality condition will allow for appropriate screening and confirmatory tests leading to prompt diagnosis and timely management.

MON-483 Familial Dysalbuminemic Hyperthyroxinemia with False Hypercortisolemia

Background: Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disease characterized by hyperthyroxinemia without symptoms of thyrotoxicosis, due to a high affinity of mutant albumin for thyroxine. No report has described cortisol-albumin binding in FDH patient, and here we present a case of FDH presenting with false hypercortisolemia. Clinical Case: A 46-year man, previously diagnosed with FDH by genetic test (1), was pointed out hypercortisolemia with normal ACTH level (ACTH 64.7 pg/mL, Cortisol 34.7 μg/dL) during the investigation for Parkinson’s syndrome and referred to our department for further examination. Cortisol was 7.1 μg/dL at midnight, 14.9 μg/dL after low dose dexamethasone overnight test, and DDAVP test was positive. ACTH and cortisol responded to CRH load, although basal and peak cortisol levels were high (35.4 and 53.9 μg/dL, respectively). High dose dexamethasone overnight test showed suppressed ACTH and cortisol, and MRI showed no obvious pituitary adenoma. In spite of significant high cortisol level, no Cushing sign’s or metabolic abnormalities were observed and urinary free cortisol was within the normal range (30.7 μg/day), suggesting the presence of factors affecting the laboratory testing. We removed albumin from serum with immunoprecipitation using anti-albumin antibody and measured cortisol with LC-MS/MS. The decrease of cortisol was 4% in control serum but 38% in the patient serum after removing albumin, suggesting the binding rate of cortisol to mutant albumin in the patient was increased, leading to false hypercortisolemia. Conclusion: This is the first case demonstrating the false hypercortisolemia in a FDH patient. Clinicians should consider the possibility of the abnormal cortisol binding to albumin in differential diagnosis of hypercortisolemia with normal ACTH level. Reference: (1) Norio Wada, et al: A Novel Missense Mutation in Codon 218 of the Albumin Gene in a Distinct Phenotype of Familial Dysalbuminemic Hyperthyroxinemia in a Japanese Kindred. Journal of Clinical Endocrinology and Metabolism 1997;82;3246–3250

SUN-203 Hyponatremia and Hyperkalemia in a Child with Chylothorax: Is This Adrenal Insufficiency?

Hyponatremia and Hyperkalemia in a child with chylothorax: Is this adrenal insufficiency? Context: Chylothoraces are relatively rare within the pediatric population. Drainage of a chylothorax can lead to potentially serious complications including electrolyte imbalances and protein loss. The literature on hyponatremia and hyperkalemia developing after a chylothorax drainage is sparse. We report a case of electrolyte derangements after a chylothorax drainage in a pediatric patient. Repeated drainage of a large-volume chylothorax without adequate fluid replacement may lead to electrolyte imbalances that in our case mimicked adrenal insufficiency. Early identification and correct fluid replacement can avoid unnecessary complications of a chylothorax. Case Description: A 2-year-old female with history of congenital left pulmonary lymphangectasia and subsequent pleural effusion was admitted to a pediatric hospital for persistent tachycardia after an outpatient elective chest MRI. A chest tube was placed to drain the effusion with large volume output was noted over the first day (1200 cc/24 hours). Further chemical analysis determined the effusion to be consistent with a chylothorax. Blood work done after chest tube placement demonstrated severe hyponatremia and hyperkalemia. Additionally, the patient was noted to be irritable. Both lab and clinical findings raised concern for possible underlying adrenal insufficiency, and further work-up (i.e. cortisol level, ACTH level) was sent. The patient was started on stress-dose steroids. ACTH and cortisol levels resulted normal. Steroids were subsequently discontinued. The patient’s chest tube output was slowly replaced with normal saline with noted improvement in both lab and clinical findings. Conclusion: Although not well documented in pediatric literature, hyponatremia and hyperkalemia are complications of large-volume drainage of chylothoraces without proper fluid replacement. The subsequent lab findings could be consistent with adrenal insufficiency, however a full clinical picture along with a cortisol and an ACTH level can help differentiate etiologies.