INTRODUCTION: Liraglutide is a GLP -1 agonist, a class of type two diabetes mellitus injectable treatments, which has shown benefits of controlling blood glucose levels with a minimal risk of hypoglycemia. Liraglutide delays the movement of food from the stomach into the small intestine which causes early satiety and a decrease in appetite. CASE DESCRIPTION/METHODS: A 40-year-old female presented to the emergency department with a two-day history of acute onset of sharp epigastric pain radiating to the back associated with nausea. The lipase level was elevated at 1,595 U/L and triglycerides were normal. Upon further evaluation, right upper quadrant ultrasound revealed cholelithiasis. CT abdomen and pelvis revealed cholelithiasis without evidence of cholecystitis. Magnetic Resonance Cholangiopancreatography (MRCP) showed gallstones and mild gallbladder wall thickening. There were no signs of pancreatic ductal dilatation or mass lesions. The patient's medical history was significant for obesity, hypertension and asthma. Liraglutide injections were started four weeks prior to her presentation for weight loss. She denied any history of pancreatic disease, alcohol use, tobacco use or herbal supplementations. The patient medications were significant for lisinopril and pantoprazole. DISCUSSION: In 2014 liiraglutide has been approved by the Food and Drug Administration (FDA) for weight loss at a higher dose. In the phase III trials Liraglutide Effect and Action in Diabetes (LEAD), liraglutide was shown to have a substantial decrease not only in hemoglobin A1C over a placebo, but in weight reduction as well. Since its use for weight loss, there have been concerns for acute pancreatitis. Acute pancreatitis is an inflammatory disease of the pancreas. Etiologies most commonly include gallstones or alcohol use. In cases where there is no history of alcohol use or obstructive gallstone disease it is imperative to search for alternative causes. In the case we presented, the patient underwent MRCP which did not reveal signs of pancreatic ductal obstructions. A careful review of her medical history and medications did not provide any risk factors for developing pancreatitis except for liraglutide injections for weight loss. The possibility of autoimmune or viral acute pancreatitis was ruled out. Liraglutide has been reported to cause acute pancreatitis. It has been suggested that it is more common to develop acute pancreatitis while on liraglutide in patients who have a history of pancreatitis or gall bladder disease.

Background Prolactin (PRL) is responsible for the development of mammary glands and milk production. STAT1 and STAT3 are genes that express transcription factors that mediate PRL's intracellular signaling, but an association between their function and galactorrhea has not yet been identified. Here we describe three patients with somatic STAT mutations and galactorrhea. A 27-year-old woman with hyper-IgE syndrome (Job's Syndrome) due to a STAT3 deletion mutation (p.Val463del) associated with recurrent infections reported thin, white, bilateral discharge with breast manipulation beginning in adolescence. She did not have spontaneous leakage or pain. At presentation, PRL was slightly elevated to 27.9 (ref. 2.0-25.0 mcg/L) with otherwise normal levels of anterior pituitary hormones. She was not on any drugs known to cause hyperprolactinemia. MRI showed a 5×4 mm microadenoma without any mass effect. A 32-year-old woman also with Job's syndrome due to a heterozygous loss-of-function STAT3 mutation (p.R382Q) associated with recurrent infections and papillary thyroid cancer described unilateral, chronic, thin, white nipple discharge with light touch of her right breast for "as long as she could remember." She had a history of breast abscesses, but at presentation there was no evidence of abscess or infection. PRL was 15.1 mcg/L, and other anterior pituitary hormones were normal. MRI showed a structurally normal pituitary. A 22-year-old woman with a STAT1 activating mutation (p.E235A) associated with recurrent infections, autoimmune hypothyroidism, T1DM, and hypogonadotropic hypogonadism requiring pubertal induction at age 12y reported bilateral galactorrhea starting at age 18y. A white, milky discharge could be expressed with light manipulation, but no discharge was produced spontaneously. PRL was 16.2 mcg/L with serial dilution and has consistently been in the reference range. Anterior pituitary evaluation was normal except for elevated TSH of 12.5 (ref. 0.27-4.2) consistent with autoimmune hypothyroidism. MRI revealed a diffusely enlarged pituitary gland (12mm in the cranio-caudal dimension) without focal hypo-enhancement. Conclusions It is known that PRL signaling involves the JAK/STAT pathway, and an analysis of human milk cells showed upregulated STAT3 and downregulated STAT1 during lactation (PMID 26909879). These three cases provide clinical evidence for a mechanistic connection between STAT signaling and galactorrhea and suggest that STAT3 and STAT1 function in opposite directions to regulate lactation. In our cases, increased STAT1 or decreased STAT3 activity are associated with normal-PRL, inducible galactorrhea. Beyond understanding the specific intracellular signaling pathways leading to galactorrhea, these observations may be utilized for developing therapies for those with impaired lactation. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Introduction Ectopic ACTH syndrome (EAS)is responsible for 10% of Cushing’s syndrome. Multiple tumors, most commonly small cell carcinoma of lung are associated with EAS. Pancreatic neuroendocrine tumors (pNETs) are usually associated with secretion of pancreatic polypeptide, gastrinomas, insulinomas, glucagonomas and vasoactive intestinal peptide (VIPomas). EAS or “ACTHomas” are rarely associated with pNETs. Case 76y/o man with ah/o hairy cell leukemia, bladder cancer (both in remission), and stage M1 unresectable pNET tumor with liver metastases presented with generalized weakness. Discovery of his pNET was incidentally noted during routine surveillance with CT monitoring following successful bladder cancer treatment six years ago. Treatment of his pNET initially began with Everolimus and then switched to Lanreotide injections. No evidence of Cushing’s Syndrome at the time of diagnosis. The lesions remained stable in size and patient was doing well. Physical exam was notable for lethargy, frailty, and absence of Cushingoid features. Labs showed serum glucose 231mg/dl, sodium 141mEq/L, potassium 2.4mEq/L, AM cortisol 116 ug/dL (range 6.7-22.6ug/dl) and ACTH was 209.6pg/mL (range 7.2-63.3pg/mL). Renin-aldosterone levels were normal. Cortisol level did not suppress with low dose or high dose dexamethasone. His hospital course was significant for persistent hypokalemia despite aggressive supplementation, difficult to control blood glucose, and worsening kidney function. EAS with pNET is very refractory to management and may be rapidly progressive. They occasionally demonstrate classic manifestations of Cushingoid features. However, they often lack the traditional phenotypic features of Cushing syndrome. Treatment options for EAS in the setting of an unresectable tumor include medical management versus bilateral adrenalectomy. Metyrapone, a cortisol synthesis inhibitor, can be an effective therapy. Ketoconazole, an antifungal that inhibits cortisol production can be an alternative, but may need weeks to achieve control. Etomodate can rapidly reduce cortisol levels, but requires intensive care monitoring. Somatostatin analogs may be effective by reducing ectopic ACTH production and stabilize tumor growth. Medical versus surgical management of Cushing’s syndrome was discussed with the patient and family, but they opted for hospice care. Conclusion We present a case of pNET associated with late onset EAS without obvious signs of Cushing’s syndrome. To our knowledge this late presentation of ACTH secretion in the setting of a stable pNET has not been previously reported in the literature. EAS due to pNET is rare and metabolic abnormalities can occur rapidly without other Cushingoid manifestations which can pose significant management challenges. High index of suspicion is required for early diagnosis. Due to the aggressive nature, the 5 years survival rate is 16%.