Replacement Doses Of Hydrocortisone Research Articles

PSAT009 Cushing's Syndrome Developing 42 Years After Successful Treatment for Metastatic Adrenocortical Carcinoma

Abstract Introduction ACC is a rare malignancy with poor prognosis. ACC is associated with CS in about 10% of the cases. Herein we report a case of a patient with metastatic ACC who developed contralateral functional adrenal adenoma causing Cushing's syndrome 42 years later. Clinical Case A 72-year-old female presented for evaluation of right adrenal incidentaloma, measuring 4.4×3 cm, on CT abdomen and pelvis (CTAP), done as part of the evaluation for hip pain. In addition to the adrenal incidentaloma, a large left adnexal mass (8×7 cm) was also observed. Her past medical history was significant for left adrenal ACC diagnosed at the age of 30, The patient's initial presentation included virilization and menstrual abnormalities. Laboratory evaluation revealed hyperandrogenism and hypercortisolism. There was no evidence of metastatic disease, and the patient was managed surgically (total left adrenalectomy) with normalization of laboratory abnormalities and resolution of symptoms. Four years later, patient pulmonary metastasis were observed in a surveillance scan and the patient underwent wedge resection and chemotherapy. The patient did not have any evidence of recurrent disease thereafter. At the current presentation, there were no symptoms or signs of adrenal hormone excess. Hormonal workup revealed borderline elevation of plasma metanephrines, with normal 24 h urinary metanephrines and catecholamines. DHEA-S and testosterone levels, as well as other androgens, were normal. 1 mg dexamethasone suppression (DST) was abnormal, with cortisol of 5.5 mcg/dL 8 h after dexamethasone administration (normal <1.8 mcg/dL). High dose DST was repeatedly abnormal, with cortisol levels at 4.0 and 4.4 mcg/dL (normal <1.8 mcg/dL). AM cortisol was elevated, at 23.4 mcg/dL (normal 4-22 mcg/dL) with ACTH at 12 pg/mL (normal <45 pg/dL). 24 h urinary free cortisol (UFC) was repeatedly elevated at 123.2 and 83.8 mcg/d (normal <45.0 mcg/d). CA 125 was normal. As there are case reports of ectopic Cushing's syndrome related to ovarian malignancies, and the patient had a large adnexal mass, adrenal and ovarian vein sampling was performed. Cortisol levels were higher in the right adrenal vein compared to the periphery, and the gradient was normal for the left ovarian vein. The right ovary was not visualized, and it was not possible to catheterize the right ovarian vein. Whole body FDG scan revealed intermediate uptake by right adrenal mass and normal uptake by left adnexal mass. Based on these results, it was determined that the right adrenal was the source of excess cortisol, and the patient underwent laparoscopic right adrenalectomy. Pathology evaluation showed adrenal adenoma, without evidence of ACC. The patient was started on physiologic replacement doses of hydrocortisone and fludrocortisone. The patient has been doing very well clinically. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PMON49 Checkpoint Inhibitor Induced Hypophysitis with Growth Hormone Deficiency and Implications for the Treatment of ACTH Deficiency

Abstract Background/Purpose Hypophysitis is a known complication of immune checkpoint inhibitor (ICI) therapies used in the treatment of malignant cancers. In general, central adrenal insufficiency (AI) and hypothyroidism are the most recognized deficiencies following a diagnosis of ICI induced hypophysitis. As a result, other hypothalamic-pituitary axes (HPAs) are either incompletely evaluated or are disregarded from a therapeutic standpoint. Of particular importance is the growth hormone axis which is well established to affect tissue level metabolism of cortisol and cortisone through its effect on 11 beta hydroxysteroid dehydrogenase in target tissues. Our hypothesis is that growth hormone deficiency is also present in ICI induced hypophysitis. Methods We queried current and legacy electronic medical records of patients who received ICI for clinical notes mentioning adrenal insufficiency and concern for hypophysitis using the EMERSE tool. Patients with ICI exposure were included if they had 2 of the following 3 criteria; new onset central AI as defined by a low ACTH and cortisol, pituitary imaging suggestive of hypophysitis, or clinical presentation concerning hypophysitis. Patients were excludedfrom the analysis if there was a history of brain irradiation or in whom the diagnosis was not clear due to high dose steroid exposure prior to biochemical evaluation. Results Twenty-nine patients met inclusion criteria. Out of 29 patients, 16 underwent testing of the growth hormone axis with IGF-1 (11) and/or random growth hormone level (5). Seventeen patients (59%) had biochemical evidence of deficiency of 3 or more HPAs. Twenty-six patients (90%) had biochemical evidence of 2 or more PHAs. Two patients only underwent evaluation of 2 pituitary axes so it is unknown if they indeed suffered from panhypopituitarism. Most patients (28/29) were prescribed hydrocortisone for AI with an average dose of 20 mg per day. Conclusions Our findings are suggestive that growth hormone deficiency may be present in ICI induced hypophysitis. This finding holds implications for cortisol replacement therapy for coexisting AI. When one considers the average adrenal cortisol production is 5.7–7.4 mg/m2/day or 9.5–9.9 mg/day, 20 mg of daily cortisol replacementmay be too high in the face of concomitant growth hormone deficiency. Practice changes may include lower doses ofhydrocortisone replacement or adjustment to cortisone acetate which has been shown to have more favorable effectson tissue level metabolic effects. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Delay in Diagnosis of Autoimmune Polyendocrine Syndrome Type 2 as a Consequence of Misinterpretation of Gastrointestinal Symptoms

Background Type 2 autoimmune polyendocrine syndrome (APS-2) is characterized by the presence of at least two of three endocrinopathies: Addison's disease, autoimmune thyroiditis, and diabetes type 1. The prevalence of APS-2 is estimated to be 1 : 1000 to 1 : 20.000 in the general population. Diagnosis of APS-2 often is delayed due to its rarity and wide spectrum of clinical symptoms. Case Presentation. A 27-year-old presented with a 6-month history of abdominal pain, vomiting, diarrhea, weakness, fatigue, and 15 kg of weight loss. The patient was diagnosed with Crohn's disease in a local hospital and referred to our institution because of treatment failure. Colonoscopy performed in this hospital identified irregular mucosal erosions in terminal ileum, and the microscopy of biopsy specimens demonstrated nonspecific inflammation. On physical examination, the patient appeared cachectic. Blood pressure was 90/60 mmHg. Laboratory results were significant for severe hyponatremia and mild hyperkalemia. Morning cortisol was low, and adrenocorticotropic hormone (ACTH) concentration was high. An ACTH stimulation test did not present any increase in serum cortisol, which confirmed primary adrenal insufficiency. Antithyroid peroxidase antibody (anti-TPO) as well as both anti-21-hydroxylase antibodies and antiglutamic acid decarboxylase antibodies (GAD65) were positive. So, the diagnosis of APS-2 was made, and the replacement doses of hydrocortisone and fludrocortisone has brought a rapid improvement in all clinical symptoms; colonoscopy showed normal. Conclusion The case presented herein highlights rapidly progressive nature of untreated APS-2 and that the diagnosis of APS-2 may be challenging.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BackgroundPatients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.MethodsNarrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.SummaryTherapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.ConclusionsCRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

A Case of Relapse of Lymphocytic Hypophysitis Triggered by the Pregnancy of the Second Child

Lymphocytic hypophysitis is a rare immune-mediated inflammatory disorder that causes pituitary dysfunction. It has been reported that lymphocytic hypophysitis onset during pregnancy rarely relapses or exacerbates in subsequent pregnancies. We herein report a patient with relapse of lymphocytic hypophysitis triggered by the pregnancy of the second child. Case Presentation: At the age of 34, at 28 weeks of gestation of the first child, she became aware of left visual field disorder and was diagnosed as an upper left visual field defect. An MRI scan revealed an enlargement of the pituitary gland and the thickening of the stalk. She was referred to our hospital for diagnosis and treatment. Laboratory data showed central adrenocortical dysfunction and central hypothyroidism. Based on the course of the disease, MRI findings and laboratory data, we diagnosed her as lymphocytic hypophysitis occurred during pregnancy. With a replacement dose of hydrocortisone and levothyroxine, she gave birth by cesarean section at 38 weeks of gestation. We performed detailed assessment of anterior pituitary functions with hypothalamic hormone challenges after giving birth. It showed panhypopituitarism without diabetes insipidus. An MRI scan found the compression of the optic chiasm remained after childbirth, the patient underwent steroid pulse therapy. After that, visual field defect improved rapidly, and the patient continued to receive oral prednisolone with gradually reduced amount. An MRI scan performed over time and found the pituitary swelling gradually improved. The pituitary was completely intact 3 years after the onset of disease. At the age of 38, the patient became pregnant with her second child, showed no signs of hypopituitarism at the time of pregnancy. She still had been administrated with 3.5mg/day prednisolone. At the 21 weeks of pregnancy, she became aware of blurred vision and was diagnosed as a left paracenter scotoma. Laboratory data showed a decrease in blood glucose and neutrophil count, suggesting the occurrence of central adrenocortical insufficiency. Therefore, we suspected the relapse of hypophysitis due to second pregnancy. We started hydrocortisone supplementation in addition to prednisolone. No MRI scan was performed during pregnancy, since no progression of visual impairment was observed. She gave birth at 37 weeks of gestation, and postpartum MRI scan showed mild thickening of the stalk. Steroid pulse therapy was not performed because the visual field abnormality was spontaneously improved. Lymphocytic hypophysitis has a diverse course, and there is currently no confirmed risk factor for recurrence. In this case, hypophysitis recurred due to pregnancy despite the continuation of prednisolone administration, and the pathogenic mechanism may be different from the previously reported cases of recurrence of hypophysitis.

Tuberculosis in Intensive Care Unit.

About 3.4% of the hospitalized tubercular patients need admission to the intensive care unit (ICU). Patients requiring ICU admission had a poor prognosis and high mortality rate (60 vs 25%) as compared to other causes of severe pneumonia. The most common indication for tuberculosis-related ICU admission is acute respiratory failure due to pneumonia or acute respiratory distress syndrome (ARDS) (with or without miliary tuberculosis) followed by septic shock with multiple organ dysfunction, adrenal insufficiency, and neurological involvement, especially tubercular meningitis. Tuberculosis patients who require admission to ICU are mostly immunocompromised [human immunodeficiency virus (HIV) coinfection] and have underlying miliary tuberculosis or disseminated tuberculosis. Pulmonary tuberculosis presenting as ARDS is a rare phenomenon, but a most common cause of admission of tuberculosis patients to ICU. Tuberculous meningitis is the most severe form of tuberculosis with mortality more than 60% and residual neurological disability in 25% cases. Tuberculosis-related septic shock has been found in only 1% of all septic shock patients admitted to ICU. Patients with tuberculosis with refractory shock should be suspected for adrenal insufficiency. A trial of physiologic stress replacement dose of hydrocortisone (200–300 mg) should be given to all critically ill patients with vasopressor-dependent shock after correcting other causes. Diagnosis and treatment of tuberculosis in critically ill patients has various challenges, namely appropriate sample collection, issues with the route of administration, drug absorption, bioavailability, dose modification in hepatic and renal dysfunction, and interaction with other drugs.How to cite this article: Chaudhry D, Tyagi D. Tuberculosis in Intensive Care Unit. Indian J Crit Care Med 2021;25(Suppl 2):S150–S154.

The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy

BackgroundGlucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group.MethodsStudy design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens.Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS).ResultsDose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621–809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1–619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1–49] (r = − 0.42, p = 0.03), and PINP (r = − 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1–49] (r = − 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = − 0.39, p = 0.04), and OC [1–49] (r = − 0.35, p = 0.06).ConclusionSerum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover.Trial registrationIrish Medicines Board Clinical Trial Number – CT900/459/1 and EudraCT Number – 2007-005018-37. Registration date: 07-09-2007.

Health-related quality of life in patients with non-functioning pituitary adenoma: a special focus on hydrocortisone replacement dose.

Patients with non-functioning pituitary adenomas (NFPA) suffer from pronounced impairments in physical and mental measures that result in an impairment of health-related quality of life (HRQOL). The role of secondary adrenal insufficiency (SAI) and especially the one of the hydrocortisone (HC) replacement dose on the HRQOL seems to be conflicting. The primary aim of this study is to assess the HRQOL in patients with NFPA in terms of presence of SAI and in patients without SAI and the secondary to explore the impact of treatment parameters such as daily HC dose. In a cross-sectional study we evaluated parameters of HRQOL in 95 patients with NFPA of the Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry in Munich using standardized questionnaires like Short Form (SF-36), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and a self-constructed questionnaire about medical history. We could not find any significant difference between patients with and without SAI in the standardized questionnaires in terms of HRQOL. We could show that higher doses of HC were negatively correlated with HRQOL measured by SF-36 global health score regardless of using BDI or STAI in the block (β = - 0.397; p = 0.021, β = - 0.390; p = 0.016, respectively). NFPA patients with SAI do not have a worse HRQOL than patients with NFPA and intact corticotropic axis. We could show that higher doses of HC are associated with an impaired HRQOL measured by SF-36 global and physical health score, whereas mental health score is not significantly influenced by the HC dose.

SUN-927 Ectopic Cushing Syndrome Due to a Metastatic Neuroendocrine Tumor to the Breast

Introduction:We present a rare case of ectopic Cushing syndrome (CS) due to a neuroendocrine tumor (NET) metastatic to the breast.Case:A 38-year-old female was referred for ACTH-dependent CS. She had rapid development of cushingoid features and hypertension three months prior to presentation. A 24-hour urinary free cortisol (UFC) was elevated to 2548 μg (0-50 μg/24hr), and ACTH was 228 pg/mL (10-60 pg/mL). A pituitary MRI was normal, and inferior petrosal sinus sampling was not consistent with a central ACTH source. A DOTA-TATE scan showed mediastinal lymphadenopathy and a 0.8cm area of uptake in the right breast. The patient was placed on ketoconazole and UFC normalized. Following biopsy, she underwent breast lumpectomy at an outside hospital, and pathology showed triple negative invasive carcinoma of the breast. Chemotherapy was initiated.However, her CS rapidly worsened: repeat UFC was 4867 μg, and ACTH was 369 pg/mL. Re-review of her pathology slides at our facility showed that the tumor stained negative for breast markers and positive for markers of NET and ACTH. Ki67 staining was approximately 30%. Chemotherapy for breast cancer was immediately stopped. A follow-up PET-CT continued to show uptake in the mediastinal lymph nodes. FNA of these lymph nodes revealed metastatic NET. In order to maximize control of her CS prior to chemotherapy, she underwent bilateral adrenalectomy (BLA). Afterwards, the patient received 10 cycles of chemotherapy with modified FOLFOX-7 for her NET. Thus far, the tumor burden appears stable, and she has been recommended to hold off on radiation therapy. She is currently taking replacement doses of hydrocortisone and fludrocortisone.Conclusion:In this challenging case, determination of source of ACTH hypersecretion led to an initial diagnosis of breast cancer. Primary breast carcinoma with neuroendocrine differentiation has been reported to show significant overlap in pathology with NET metastatic to the breast1. However, worsening of the CS in this case led to consideration of an alternative diagnosis, resulting in diagnosis of an ACTH producing NET metastatic to the breast. Prior to chemotherapy, she underwent BLA, which may lower morbidity and mortality associated with ACTH-dependent CS2, particularly given plan for further chemotherapy.Reference:1. Mohanty SK, Kim SA, DeLair DF, et al. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. Mod Pathol. 2016;29(8):788-798. doi:10.1038/modpathol.2016.69.2.2. Morris LF, Harris RS, Milton DR, et al. Impact and timing of bilateral adrenalectomy for refractory adrenocorticotropic hormone-dependent Cushing’s syndrome. Surgery. 2013;154(6):1174-1183; discussion 1183-1184.

SUN-169 A Rare Case of Adrenocortical Carcinoma Presenting as Hyperaldosteronism Combined with Cushing’s Syndrome

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Most ACC cases are hormonally functional. Commonly produced hormones are cortisol, followed by adrenal androgens. Aldosterone secretion is quite rare (< 2%) (1). Co-secretion of multiple hormones is further rare. Case Presentation: A 59 year old female presented with progressive worsening hypertension. Initial biochemical evaluation confirmed primary hyperaldosteronism. Her potassium was low at 2.9 mEq/L (N: 3.5-5.3 meq/L). Aldosterone level was elevated at 23 ng/dL (N: < or = 28 ng/mL), renin value was 0.90 ng/mL/h (N: 0.25-5.82 ng/mL/h). Aldosterone Renin Ratio was 25. CT abdomen with and without contrast showed 2 lesions within the right adrenal gland. The larger nodule was 3.7 x 2.7 x 4.9 cm with an absolute washout of 61%. A smaller nodule was 2.3x1.8 cm with an absolute washout of approximately 64%. Left adrenal gland was unremarkable.Further biochemical workup showed plasma catecholamines and metanephrines were normal. A random cortisol value was 22.8 mcg/dL (N: 3.0-16.0 mcg/dL) with a low ACTH level of 3.3 pg/mL (N: 7.2 - 63.3 pg/mL). Given suspicion for adrenal Cushing’s syndrome, we further obtained a 24 hour free urinary cortisol which was elevated at 84.1 mcg/24 h (N: 4-50 mcg/24 h). 8 am Cortisol after an overnight 1 mg Dexamethasone failed to suppress at 17.5 mcg/dL (n<1.8 mcg/dL). DHEAS level was low at 14.1 ug/dL (N: 29.4-220.5 ug/dL). The patient eventually underwent a right adrenalectomy. Post-operatively, her cortisol was suppressed at 1.9 mcg/dL (8 am ref range: 4-22 mcg/dL), and Hydrocortisone replacement dose was initiated. Surgical pathology report was consistent with adrenocortical carcinoma. The patient continues to follow-up with the endocrinology and oncology department for treatment. Conclusion: This case is particularly interesting given the co-secretion of both aldosterone and cortisol by an adrenocortical carcinoma which has been reported in only a few cases in literature. The case highlights the importance of completing a comprehensive biochemical workup pre-operatively in patients with suspicious adrenal mass. There should especially be a low threshold for initiating workup for cortisol hypersecretion as early intervention can help avoid an adrenal crisis in the post-operative period for such patients. A low DHEAS level should raise suspicion for cortisol hypersecretion in a patient with adrenal lesions. As ACTH is the primary stimulant of DHEA, the suppression of ACTH secretion in the setting of adrenal Cushing’s syndrome can contribute to a low DHEAS level. Reference 1.Else, T et al. Adrenocortical Carcinoma. Endocr Rev. 2014; 35(2):282-326.

MON-902 Etomidate - an Under Utilized but Safe and Efficacious Drug to Treat Acute Severe Cushing’s Syndrome- Case Reports of Ectopic ACTH Syndrome from Neuroendocrine Malignancies

Background: Intravenous etomidate infusion, in non-hypnotic doses, rapidly lowers cortisol levels by blocking 11-beta hydroxylation of deoxycortisol to inhibit cortisol production. It is an underutilized drug due to concerns of excess sedation and ICU monitoring. Clinical Case 1: A 44 year-old female with HTN, diabetes, and recently diagnosed pancreatic neuroendocrine tumor with liver metastases presented with altered mentation. Labs showed severe hypokalemia, metabolic alkalosis, serum AM cortisol >60.2 ug/dL (n 6.7-22.6 ug/dL), ACTH of 698.1 pg/mL (n 7.2-63.3 pg/mL), 24-hour urine free cortisol (UFC) of 5791 ug/24hr (n 5-64 ug/24hr), midnight salivary cortisol of 8.04 ug/dL (n <0.01-0.09), and abnormal low dose (LDDST) and high dose (HDDST) dexamethasone suppression tests each with cortisol >60.2 ug/dL. She developed worsening psychosis, likely secondary to hypercortisolism. After ICU transfer, etomidate infusion was initiated at 2.5 mg/hr and titrated upward, leading to rapid drop in cortisol levels and concomitant improvement in mentation. No respiratory or airway difficulties developed. Ketoconazole and metyrapone were started and etomidate was weaned off. Steroids were added once cortisol levels fell below 10 ug/dL as part of “block and replace.” The patient eventually underwent bilateral adrenalectomy with improvement in hemodynamic and blood glucose parameters. She was discharged on physiologic replacement doses of hydrocortisone and fludrocortisone, with no reported issues two months later. Clinical Case 2: A 51 year-old man with one month of hematochezia presented with hypertension, severe hypokalemia, metabolic alkalosis, and QTc prolongation. Colonoscopy was unremarkable; however, labs revealed a cortisol of 43.1 ug/dL, ACTH of 83.6 pg/mL, and 24-hour UFC of 7,494 ug/L, with an abnormally elevated LDDST. Imaging showed a pancreatic mass and multiple hypodense liver lesions. The overall presentation was suggestive of ectopic ACTH syndrome due to metastatic neuroendocrine carcinoma, which was confirmed on biopsy. Chemotherapy, ketoconazole, and metyrapone inadequately lowered cortisol. Etomidate drip was initiated at 3 mg/hr in the ICU, with rapid reduction in cortisol levels to <20 ug/dL without respiratory compromise. Attempts to wean off etomidate were unsuccessful and the patient underwent bilateral adrenalectomy. The surgery was compromised due to extensive liver and pancreatic enlargement, and follow up imaging revealed incomplete resection. 8am cortisol level (off etomidate) was >60.0 ug/dL. Metyrapone and ketoconazole were resumed and hydrocortisone was later initiated for “block and replace”. The patient remains in critical condition. Conclusion: Etomidate-in non- hypnotic doses is useful for the rapid lowering of cortisol levels.

The incidence of adrenal crisis in the postoperative period of HPA axis insufficiency after surgical treatment for Cushing's syndrome.

Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing's syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown. Cohort study included consecutive patients with Cushing's syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000 to 2015. We summarized the incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence and assessed the effect of better education in time on incidence of adrenal crisis. We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval (CI): 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies. The incidence of adrenal crises after treatment for Cushing's syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing's syndrome, which is probably the period of severest HPA axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.

MON-348 Isolated ACTH Deficiency after Administrating Immune Checkpoint Inhibitors: Report of Three Cases and Review of Literature

[Introduction] Immune checkpoint inhibitors (ICIs) are widely used for the treatment of several malignancies. Despite their effectiveness, they may cause immune-related adverse effects on endocrine organs. Here we describe three cases of isolated ACTH deficiency (IAD) that has occurred after ICI therapy. [Case presentation] Case 1: An 80-year-old female patient with advanced melanoma received nivolumab (NIVO) (3 mg/kg intravenously (IV) every two weeks) for 16 weeks, followed by ipilimumab (3 mg/kg IV every three weeks). After the third injection of ipilimumab, she was alert but complained of general fatigue and anorexia. Her laboratory tests revealed hyponatremia (Na 126 mEq/l), hypoglycemia (Glu 65 mg/dl), low ACTH (ACTH <2.1 pg/ml), hypocortisolemia (cortisol (F) 3.6 µg/dl), and inflammation (white blood cell (WBC) 9,000/µl and C-reactive protein 12.87 mg/dl). Case 2: A 52-year-old diabetic male patient on sulfonylurea for the past two years was given 13 courses of NIVO (3 mg/kg IV every two weeks) for the treatment of recurrent lung cancer but could not proceed with the 14th treatment because of general malaise, appetite loss, and slight fever (37ºC). About three weeks after the 13th injection, he went into hypoglycemic coma (Glu 32 mg/dl) and received intravenous glucose. On admission, his Glasgow Coma Scale score was 14 (E4V4M6). Laboratory tests showed hyponatremia (Na 133 mEq/l), low ACTH (ACTH <2.1 pg/ml), and hypocortisolemia (F 0.2 µg/dl), but no leukocytosis (WBC 6,000/µl). Case 3: A 67-year-old male patient received NIVO (3 mg/kg IV every two weeks) as third-line therapy for advanced gastric cancer. After the seventh course of treatment, he complained of general fatigue, anorexia, joint pain, and palpitations. His blood laboratory test was unremarkable with normal serum sodium (Na 140 mEq/l). Six days later, he returned due to persistent symptoms. Laboratory investigation revealed hyponatremia (Na 135 mEq/l), normoglycemia (Glu 88 mg/dl), low ACTH (2.7 pg/ml), and hypocortisolemia (F 0.8 µg/dl), but no inflammation (WBC 3,200/µl). In all three cases, magnetic resonance imaging showed no abnormalities and endocrinological tests confirmed the clinical diagnosis of IAD. All of them were discharged on a physiological replacement dose of hydrocortisone. [Discussion] A recent report suggested that hyponatremia can be an early manifestation of ICI-induced IAD. Indeed, in Cases 1 and 2, adrenal insufficiency was suspected due to hyponatremia and hypoglycemia, although in Case 2, sulfonylurea presumably also contributed to the development of hypoglycemia. In Case 3, however, serum sodium and glucose levels were normal when he initially became symptomatic. This case illustrates the importance of suspecting IAD in ICI-treated patients who present with non-specific symptoms, such as malaise, even in the absence of hyponatremia or hypoglycemia.

Predicting Recovery Of The Hypothalamic-Pituitary-Adrenal Axis After Prolonged Glucocorticoid Use

Prolonged exposure to glucocorticoids lead to hypothalamic-pituitary-adrenal (HPA) axis suppression that recovers after cessation of treatment. We aimed to identify the predictive factors for HPA axis recovery after prolonged glucocorticoid use. Retrospective review of patients who had undergone first short Synacthen test (SST) to assess HPA axis recovery after prolonged use of glucocorticoids. A total of 61% (20/33) of patients had adequate SST response at a median time of 2 years after diagnosis of adrenal insufficiency. Those who had adequate response during SST had higher ambulatory early morning cortisol ( P<.01), shorter duration of exposure to glucocorticoids ( P = .01), and lower final cumulative hydrocortisone replacement dose ( P = .03). Age, gender, body mass index, indications for glucocorticoid use, and basal adrenocorticotropic hormone levels were not predictive of HPA axis recovery. On multivariate analysis, ambulatory early morning cortisol was the only independent predictor of adequate SST response (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; P = .02). Using receiver operating characteristic curve analysis, ambulatory early morning cortisol of 8.8 μg/dL predicted a positive SST response with a sensitivity of 70% and specificity of 93%. Early morning ambulatory cortisol could be used to decide on timely SST in order to prevent complications from unnecessary replacement with glucocorticoids. ACTH = adrenocorticotropic hormone; BMI = body mass index; CV = coefficient of variation; HPA = hypothalamic-pituitary-adrenal; SST = short Synacthen test.

The Yin and Yang Between Plasma Glucose Levels and Cortisol Replacement Therapy in Schmidt's Syndrome.

Objective: To illustrate how steroid replacement in adrenal insufficiency can influence the development of hypoglycemia in a patient with type 1 diabetes mellitus (T1D). Methods: We describe the case of a 36-year-old female patient with T1D and Addison’s disease (Schmidt’s syndrome) on multiple daily insulin injections who presented with recurrent hypoglycemia despite being on physiological replacement doses of hydrocortisone. Results: With the assistance of continuous glucose monitoring technology, a pattern of nocturnal hypoglycemia was clearly identified. The patient was taking her hydrocortisone 15 mg in the morning and 5 mg in the early afternoon. With the short half-life of oral hydrocortisone, the evening decline in plasma cortisol concentration led to an increased susceptibility to recurrent evening and nocturnal hypoglycemia. Hypoglycemic episodes were resolved when her morning hydrocortisone dose was changed and prednisolone was added to a later time in the evening. Conclusion: Patients with Schmidt’s syndrome can be susceptible to nocturnal hypoglycemia with inadequate steroid replacement. Identifying patients at risk for hypoglycemia in Schmidt’s syndrome provides an opportunity for precision management beyond the manipulation of antihyperglycemic agents.

A post menopausal female with empty sella syndrome

Empty sella syndrome is an incidental anatomical finding which can occasionally present as hypopituitarism. Here we report a post-menopausal female with emptysella syndrome and anterior pituitary hormone deficiency. She is a 69 year-old mother of four children presented with progressively worsening lethargy and constipation. Her last pregnancy at 24 years was complicated with post-partum haemorrhage. She had breastfed her last child for an year. She attained menopause at the age of 45. Investigations revealed normocytic anemia, and hyponatremia. Hormonal profile showed a normal TSH level(2.09mu/l)and low free T4 (&lt;0.07 ng/dl) suggestive of secondary hypothyroidism. She also had low level of 9am cortisol, and inappropriately low FSH and LH levels. Non-contrast computerized tomography of the brain revealed cerebrospinal fluid(CSF) within sella-turcica, suggestive of empty-sella syndrome. She was treated with replacement doses of hydrocortisone and thyroxine and with that her symptoms improved.

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- results from an RCT.

BackgroundBilirubin has anti‐oxidative and anti‐inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients.Materials and methodsA randomized double‐blind cross‐over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10‐week exposure to a higher hydrocortisone dose (0·4–0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2–0·3 mg/kg body weight)].ResultsPlasma total bilirubin was increased by 10% from 7 to 8 μM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001).ConclusionBilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro‐inflammatory state and enhanced liver fat accumulation.

Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial

Background: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. Methods: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. Results: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. Conclusions: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose.

Giant myelolipomas and inadvertent bilateral adrenalectomy in classic congenital adrenal hyperplasia.

SummaryMyelolipomas have been reported in patients with congenital adrenal hyperplasia (CAH). ACTH excess, as seen with non-adherence to glucocorticoid therapy, may be responsible for tumor development. We report a case of a 51-year-old man with classic salt-wasting CAH managed on prednisone 7.5 mg daily and fludrocortisone who presented with chronic back pain and was found to have giant bilateral retroperitoneal masses. On computed tomography (CT) imaging, the masses were heterogeneous, but contained predominantly low-density fat attenuation. The tumors were resected due to concern for malignancy and mass symptoms. Pathologic examination identified both retroperitoneal masses as myelolipomas. The left tumor was 34×20×13 cm and weighed 4.7 kg and the right tumor was 20 cm in the largest dimension. Adrenal tissue was present in the specimen. The patient reported long-term compliance with glucocorticoid treatment. However, no biochemical monitoring of ACTH levels had occurred. Therefore, it is unclear if ACTH excess contributed to the development of these large tumors in this patient. It was presumed that both adrenal glands were inadvertently removed during surgery and the patient was treated with physiologic replacement doses of hydrocortisone and fludrocortisone postoperatively. In this case, the bilateral adrenalectomy was inadvertent. However, adrenalectomy can be considered as a treatment option in patients with classical CAH under certain circumstances to avoid complications of glucocorticoid excess.Learning pointsMyelolipomas should be considered in the differential diagnosis of adrenal or retroperitoneal masses in patients with CAH.On CT imaging, myelolipomas are seen as heterogeneous masses with low-density mature fat interspersed with more dense myeloid tissue.Myelolipomas are usually unilateral and measure <4 cm; however, very large and bilateral tumors have been reported.Treatment of CAH typically involves using supraphysiologic doses of glucocorticoid to suppress adrenal hyperandrogenism. Bilateral adrenalectomy is an alternative treatment option in patients with CAH.There is an association between ACTH excess and increased incidence of adrenal myelolipoma but the direct causal link remains to be established.

Interpretation of dynamic test results in secondary hypocortisolism post pituitary surgery and hydrocortisone replacement doses

Interpretation of dynamic test results in secondary hypocortisolism post pituitary surgery and hydrocortisone replacement doses