Rates of adrenal insufficiency using a monoclonal vs. polyclonal cortisol assay

Objectives The diagnosis of adrenal insufficiency relies on clear cut-offs and accurate measurement of cortisol levels. Newer monoclonal antibody assays may increase the rate of diagnosis of adrenal insufficiency if traditional cortisol cut-off levels <18 mcg/dL (500 nmol/L) are applied. Determine if the rate of diagnosis of adrenal insufficiency using a 1 mcg Cosyntropin stimulation test varied with the change in cortisol assay from a polyclonal to a monoclonal antibody assay. Methods Cortisol levels obtained during the 1 mcg Cosyntropin stimulation test performed in the last semester of 2016 using a polyclonal antibody cortisol assay were compared to tests performed using a monoclonal antibody cortisol assay during the first semester of 2017. Cosyntropin tests included cortisol values obtained at baseline, 20 min and 30 min after IV administration of 1 mcg Cosyntropin. Peak cortisol cut-off value <18 mcg/dL was used to diagnose adrenal insufficiency. Results Stimulated cortisol values after 1 mcg Cosyntropin using the monoclonal assay in 2017 (n=38) were significantly lower (33%) compared to those obtained with the polyclonal assay in 2016 (n=27) (p-value <0.001). The number of passing tests with a peak cortisol value >18 mcg/dL fell from 74% in 2016 (20 out of 27 tests) to 29% in 2017 (11 out of 38 tests). Conclusions The change in cortisol assay substantially increased the number of patients diagnosed with adrenal insufficiency after 1 mcg Cosyntropin stimulation testing. Standardization of cortisol assays and diagnostic criteria is critical for the accurate diagnosis of adrenal insufficiency.

What Cut-off Value of 17-Hydroxyprogesterone Should Be an Indication to Perform a 250 µg Cosyntropin Stimulation Test When NCCAH Is Suspected? - a Retrospective Study

The Nonclassic Congenital Adrenal Hyperplasia (NCCAH) is a less severe form of CAH in which the activity of the 21-hydroxylase is estimated at about 20% to 50%. Cosyntropin stimulation test is the gold diagnostic standard used to test for this condition. The study was aimed at verifying the currently accepted threshold of 17-hydroxyprogesterone (17OHP) level (≥2.0 ng/mL) at which cosyntropin stimulation test should be performed. Material and methods. The study included 343 patients (328 females and 15 males) referred for a cosyntropin stimulation test due to suspected NCCAH. The median age at the time of evaluation was 27 years. Serum 17-OHP was measured with ELISA assay using Ledect96 Microplate Reader. The NCCAH diagnosis was made if cosyntropin-stimulated 17OHP level exceeded 10.0 ng/mL. The ROC curve was determined, and the cut-off point with the highest sensitivity and specificity was established. The study was approved by the Ethics Board of JUMC. Results:. Symptoms, which prompted testing for NCCAH, most often were: hirsutism in 187 patients, irregular menstrual cycles in 178 patients, and acne in 138 patients. A total of 79 patients (77 females and two males) were diagnosed with NCCAH based on cosyntropin stimulation test results. Seventy-one of them had baseline levels of 17OHP≥2.0 ng/mL. The mean age of patients with confirmed NCCAH was 28.86 years. The baseline 17OHP cut-off value that qualified patients best for testing was 2.79 ng/mL in our group, with sensitivity and specificity of 77.2% and 91.3%, respectively. The sensitivity and specificity for a guideline-recommended cut-off point (17OHP ≥2.0 ng/mL) was 86.1% and 76%, respectively. In five of six patients with secondary amenorrhea and a baseline level of 17OHP ≥2.0 ng/mL, NCCAH was confirmed in a cosyntropin stimulation test. Conclusions:. Our results suggest considering an upward shift in the 17OHP threshold at which patients suspected for NCCAH should be referred for further evaluation. This may reduce the number of unnecessary cosyntropin stimulation tests, mainly that patients with mild phenotype (or asymptomatic) frequently may not require any treatment. However, attention should be paid to patients with coexisting secondary amenorrhea and 17OHP levels ≥2.0 ng/mL, which may be a clinical predictor of NCCAH.

Concurrent Pseudohyperaldosteronism and Primary Glucocorticoid Deficiency From Posaconazole

Background: Posaconazole can cause pseudohyperaldosteronism via inhibition of 11-beta hydroxylase and 11-beta-hydroxysteroid dehydrogenase type 2 (1). The accumulation of 11-deoxycorticosterone and increased cortisol-to-cortisone ratio in the kidney causes apparent mineralocorticoid excess. The effect of posaconazole on the glucocorticoid axis is less established. Clinical Case: A 56-year-old Hispanic man with a history of chronic septic arthritis of the left ankle from Coccidioides presented with 3 months of malaise, nausea, weight loss of 30 pounds, and recurrent hypokalemia. He was recently switched from long-term fluconazole therapy to posaconazole around the time his symptoms began. His initial labs at our hospital were notable for low potassium (2.9 mmol/L, nl 3.5–5.5 mmol/L) and a random cortisol of 5.8 mcg/dL (nl ≥2.0 mcg/dL). A Cosyntropin stimulation test revealed elevated ACTH (168 pg/mL, nl 7.2–63.3 pg/mL) with minimal rise of cortisol from 4.6 to 7.2 mcg/dL at 1 hour after Cosyntropin administration (nl ≥18 mcg/dL at 1-hour post-Cosyntropin). His plasma renin activity was below detection (&lt;0.6 ng/ml/h, nl 0.6–3.0 ng/mL/h), consistent with renin suppression from apparent mineralocorticoid excess. Hydrocortisone for glucocorticoid deficiency was started. A posaconazole determination indicated elevation (5240 ng/mL, usual therapeutic range ≥1000 ng/mL). His posaconazole was stopped, and he was switched back to fluconazole. Three months later, his symptoms were improved with regain of lost weight. Repeat Cosyntropin stimulation test showed ongoing primary glucocorticoid deficiency (ACTH 123 pg/mL, cortisol 4.1 mcg/dL at 1-hour post-Cosyntropin) but normal levels of plasma renin activity (1.2 ng/mL/h), aldosterone (8.6 ng/dL, nl ≤21 ng/dL), and potassium. Quantiferon TB and 21-hydroxylase antibody tests were negative. Hydrocortisone has been continued with plans to repeat Cosyntropin testing in 3 months to reassess. Conclusion: Pseudohyperaldosteronism with glucocorticoid deficiency requiring hydrocortisone treatment has thus far not been reported with posaconazole. Our case shows that posaconazole may lead to true primary glucocorticoid deficiency that can persist after discontinuation of posaconazole and reversal of pseudohyperaldosteronism. Reference: (1) Sanchez-Niño MD, Ortiz A. Unravelling drug-induced hypertension: Molecular mechanisms of aldosterone-independent mineralocorticoid receptor activation by posaconazole. Clin Kidney J 2018;11(5):688–90.

CLINICAL PRESENTATION AND OUTCOMES OF OPIOID-INDUCED ADRENAL INSUFFICIENCY

Objective: Opioid-induced adrenal insufficiency (OIAI) may develop in patients treated with chronic opioids due to suppression of the hypothalamic-pituitary-adrenal axis. Our objective was to describe the clinical manifestations, biochemical presentation, and clinical course of OIAI. Methods: A retrospective study of adults diagnosed with OIAI between 2006 and 2018 at an academic center. Opioid daily dose was converted into morphine milligram equivalents (MMEs). Results: Forty patients (women, n = 29 [73%]) taking chronic opioids at a daily median MME dose of 105 (60 to 200) mg and median duration of 60 (3 to 360) months were diagnosed with OIAI. Patients reported fatigue (n = 29, 73%), musculoskeletal pain (n = 21, 53%), and weight loss (n = 17, 53%) for a median of 12 (range, 1 to 132) months prior to diagnosis, and only 7.5% (n = 3) of patients were identified with OIAI through case detection. Biochemical diagnosis of OIAI was based on ( 1) low morning cortisol, baseline adrenocorticotropic hormone and/or dehydroepiandrosterone sulfate in 59% (n = 26) of patients or ( 2) abnormal cosyntropin stimulation test in 41% (n = 14) of patients. With glucocorticoid replacement, 16/23 (70%) patients with available follow-up experienced improvement in symptoms. Opioids were tapered or discontinued in 15 patients, of whom 10 were followed for adrenal function and of which 7 (70%) recovered from OIAI. Conclusion: Minimum daily MME in patients diagnosed with OIAI was 60 mg. OIAI causes significant morbidity, and recognition requires a high level of clinical suspicion. Appropriate glucocorticoid treatment led to improvement of symptoms in 70%. Resolution of OIAI occurred following opioid cessation or reduction. Abbreviations: ACTH = adrenocorticotropic hormone; CST = cosyntropin stimulation test; DHEAS = dehydroepiandrosterone sulfate; HPA = hypothalamic-pituitary-adrenal; MME = morphine milligram equivalent; OIAI = opioid-induced adrenal insufficiency

SUN-307 Partial Secondary Adrenal Insufficiency and Growth Hormone Deficiency in Fibromyalgia

Introduction: Low or borderline cortisol concentrations and impaired response to dynamic testing have been reported in patients with fibromyalgia, potentially related to hypothalamus-pituitary dysfunction.1,2 Superimposed adrenal insufficiency (AI) may contribute to some fibromyalgia symptoms or delay improvement in patients enrolled in fibromyalgia treatment programs. We hypothesized that a subset of patients with fibromyalgia have: 1) partial secondary AI and concomitant growth hormone (GH) deficiency 2) a discordance in Cosyntropin stimulation test and 3) improvement in fibromyalgia symptoms with initiation of glucocorticoid and/or GH replacement. Design: This was a retrospective study of patients with fibromyalgia diagnosed with partial secondary AI based on abnormal insulin tolerance test (peak cortisol &lt; 18 mcg/dL) at our institution from June 2002 to August 2019. Patients were excluded if they had other reasons for adrenal insufficiency, including steroid exposure and opioid use. Results: We identified 22 patients (18 women, 82%) diagnosed with partial AI at a median age of 38 years (range 19-65). The fibromyalgia symptoms included fatigue (n=22, 100%), pain (n=22, 100%), sleep disturbance (n=15, 68%), and bowel changes (n=13, 59%). The median morning cortisol concentration was 8.6 mcg/dL (range 1.1-11); 9 patients (41%) had a morning cortisol concentration below the normal range (7 mcg/dL). The median ACTH level was 15.5 pg/mL (range 7.7-54). Nineteen patients had baseline IGF1 levels, with a median z-score of -0.94 (range -1.96 to 1.70). MRI pituitary imaging was performed in 20 patients and showed no significant pituitary pathology. All patients achieved hypoglycemia &lt;=40 mg/dL during the insulin tolerance test. Peak median cortisol level was 11 mcg/dL (range 5.4-17). Nineteen patients (86%) also had partial GH deficiency (defined as a peak GH &lt; 4 ng/mL) with a median GH level of 0.36 ng/mL (range 0.03-3.83). Cosyntropin stimulation test was performed in 13 patients (59%) with a 1 mcg dose in 2 patients and 250 mcg dose in 11 patients. The peak cortisol was &gt;=18 mcg/dL in 10 (77%) patients. All patients were started on physiologic glucocorticoid replacement, and 12 patients were started on GH replacement. Endocrinology follow-up information was available for 13 patients, and 8 (62%) reported symptom improvement after starting treatment. Conclusions: Patients with fibromyalgia can have co-existing partial secondary AI and GH deficiency as defined by insulin-induced hypoglycemia. Cosyntropin stimulation test can be used in patients with fibromyalgia, but a normal test does not rule out partial secondary AI. Replacing the underlying deficiency improved symptoms in some patients demonstrating certain fibromyalgia symptoms may overlap with AI and GH deficiency. 1Gur et al. Ann Rheum Dis. 2004. 63(11):1504-1506. 2Kirnap et al. Clin Endocrinol (Oxf). 2001. 55(4):455-459.

SUN-311 Adrenal Reserve Testing with the Glucagon Stimulation Test (GST) and Cosyntropin Stimulation Test (CST) in Deployed Veterans with Mild Traumatic Brain Injury

Introduction: Mild Traumatic Brain Injury (mTBI) is associated with anterior pituitary hormone dysfunction. The potential long-term effect of this injury on pituitary function in Veterans is not clear. We reviewed the utility of the fixed dose Glucagon Stimulation Test (GST) compared with the high dose Cosyntropin Stimulation test (CST) for hypothalamic-pituitary-adrenal (HPA) reserve over time in these patients with mTBI. Methods: We present an interim report of our 4-year longitudinal prospective pilot study of pituitary function in Veterans diagnosed with mTBI. Of the 34 mTBI Veterans enrolled, we have tested 28 of them (4 female, 24 male; age and BMI, 31.5±7.0 years and 30.4±6.2, mean±SD, respectively) for baseline pituitary hormone levels and cortisol response to the CST. In 22 subjects growth hormone and cortisol responses to GST were tested at baseline (Year 0). Follow-up testing was done for 18 mTBI subjects in Year 1, 13 subjects in Year 2, 10 subjects in Year 3 and 5 subjects in Year 4. The same baseline data were obtained for 14 age-, sex-, deployment- and BMI-matched control subjects without mTBI (2 female,12 male; age and BMI 34.4±6.8 years and 30.5±4.9, mean±SD, respectively). Cortisol cutoffs of &lt;18 mcg/dL with the CST and &lt;9.0 mcg/dL with the GST were used for the diagnosis of adrenal insufficiency. Results: Secondary adrenal insufficiency (AI), likely partial, was identified during this study on 6 occasions: 3/22 subjects at Year 0, 1/18 at Year 1, 0/13 at Year 2, 1/10 at Year 3 and 1/5 at Year 4. Two baseline subjects with AI reverted to normal in Years 1-3, one relapsed in Year 4 and a third had no further testing. Correlations of the cortisol levels from GST vs the 60-minute cortisol from CST were significant at Year 0 (n=22, r=0.553, p=0.008) and at Year 1 (n=18, r=0.802, p&lt;0.0001). Due to decreased numbers, there were no significant correlations at Years 2 through 4. Similar correlations were obtained using the 30-minute CST values. However, the CST cortisol value predicted the low GST value in only 2/6 subjects. The mean GST cortisol levels and 60-minute CST cortisol levels for subjects at each year were not significantly different over Years 0 through 4 based on ANOVA analyses (CST: F=1.519, p= 0.206; GST: F= 0.796, p=0.532). Conclusions: Secondary adrenal insufficiency, likely partial, related to mTBI was detected by GST on 6 occasions (twice in one patient) over 4 years of observation. GST can provide useful information about HPA axis reserve, and appears to be more reliable than CST. Identification of potential secondary adrenal insufficiency using the GST in Veterans with mTBI can provide a beneficial combined test for these patients when other testing is not feasible.

SUN-193 A Case of Cushing’s Syndrome Caused by Epidural Corticoidsteroid Injection

Introduction: Cushing’s syndrome (CS) is a collection of signs and symptoms caused by hypercortisolism that results from endogenous or exogenous glucocorticoid excess. It is associated with increased morbidity and mortality from musculoskeletal, metabolic, thrombotic, infectious and cardiovascular complications. The most common cause of CS today is the use of corticosteroid medications. It′s reported that more than 10 million American receive pharmacological doses of glucocorticoids each year. Case reports have shown that CS can be caused by non-systemic use of corticosteroids. Clinical case: A 53-year-old patient with past medical history of osteoarthritis who presented to outpatient endocrinology office for new onset facial swelling of 2 months. His PCP had attributed it to adverse effect of recent neck glucocorticoid injections and treated him with prednisone for 7 days without any relief. Subsequently, he was referred to Endocrinology due to concern about Cushing′s syndrome. The patient reported associated easy bruising and decreased libido. On further questioning, patient mentioned he had been receiving several epidural steroid injections in the neck, shoulders and back in the past. Per record review, from June to November 2018, he had received multiple triamcinolone and dexamethasone injections as follows: 10mg dexamethasone in each C4-5, C5-6 and C6-7 facet joints; 5mg triamcinolone injections in the right C4-5, C6-C7, left C4-5, C6 and C7, and 40mg of triamcinolone in C7-T1. The patient also reported he had multiple injections in 2019, but these records were not available. Physical exam showed hypertension, facial plethora, and scattered bilateral arm ecchymosis. Laboratory study showed hyperglycemia. Given suspicion for CS, further workup, including morning serum cortisol, ACTH, and 24-hour urine cortisol were ordered, which were 0.5 ug/dl (6.2-19.4 ug/dl), 4.3 pg/ml (7.2-63.3 pg/ml) and &lt;2 ug/24 hours (5-64 ug/24 hours) respectively, suggesting iatrogenic CS secondary to corticoid steroid injection. Also, given that the patient reported lightheadedness, and decreased libido, cosyntropin stimulation test and free testosterone, FSH and LH were ordered to rule out adrenal insufficiency and hypogonadism respectively. Hypogonadism was ruled out, however, cosyntropin stimulation test showed peak cortisol of 12 and 16 mcg/dL at 30 and 60 minutes (&gt;18 mcg/dL), suggesting adrenal insufficiency, due to suppression of endogenous cortisol production from exogenous glucocorticoid use. Patient was started on hydrocortisone and all glucocoirticoid injections were stopped. Conclusions: Many different non-systemic corticosteroid administrations can cause iatrogenic Cushing’s Syndrome, and therefore, physicians should be thoughtful when prescribing steroids regardless of administration form.