Gruber, Lucinda

Abstract Background Patients taking chronic opioids are at high risk of opioid induced adrenal insufficiency (OIAI). Previously, we showed that the prevalence of OIAI was 9% based on low morning cortisol, corticotropin (ACTH), and dehydroepiandrosterone sulfate (DHEAS). Data on the overnight metyrapone test to diagnose OIAI are sparse. We aimed to determine the prevalence of OIAI using overnight metyrapone test and identify changes in the steroid metabolome of patients treated with opioids. Methods Cross-sectional study of adult patients treated with opioid therapy of at least 20 morphine milligram equivalents (MME)/day for at least 3 months. Measurements included ACTH, cortisol, and DHEAS. Overnight metyrapone test was administered in all patients, and 24h urine steroid profiling was optional (25 steroids measured by liquid chromatography mass spectrometry1). All patients completed the quality-of-life survey (AddiQoL). Prevalence of OIAI was defined as sum of post-metyrapone 11-deoxycortisol and cortisol of <15 mcg/dL. Result: In 22 patients (median age 59 years [range, 38-74], 9, 41% women), median MME was 33 (20-161) mg, and median cumulative opioid exposure was 245 (10-2550) mg*years. Following the overnight metyrapone test, 7 (32%) patients were diagnosed with OIAI. Patients with OIAI had lower DHEAS concentrations (median of 21 mcg/dL[ 5-113] vs 54 [22-173], p =0. 03), but not cortisol (median 10[5.3-16] mcg/dL vs 13[5.3-22], p=0. 06) or ACTH (median 27[8.1-51] pg/mL vs 26[5.9-55], p=0.8). Patients with OIAI were treated with higher daily MME (100 mg[30-150] vs 30[20-161], p=0. 03) and had a higher cumulative exposure to opioids (median, 660 mg*years [250-2250] vs 150 [10-1288], p =0. 01). AddiQol scores were similar between groups (median of 68[56-84] vs 73[48-83], p= 0.97). Urine steroid profiling was performed in 18 patients. Patients with OIAI demonstrated 4 times lower total urine glucocorticoids (16334 mcg/24h vs 4377 mcg/24h, p=0. 003), all <10% of the reference range, and 3 times lower total urinary androgens (median of 805 mcg/24h vs 2320 mcg/24h, p=0.14). Conclusion Prevalence of OIAI using overnight metyrapone test is high at 32%. Patients diagnosed with OIAI were treated with higher doses of MME/day and had a higher cumulative exposure to opioids when compared to those without OIAI. Applying 24h urine steroid profiling we showed that total glucocorticoids are 4 times lower in those with OIAI (and all <10% of reference ranges) as opposed to those without OIAI. We showed that baseline measurements of ACTH, DHEAS, and cortisol may incorrectly exclude OIAI, and a dynamic test, such as overnight metyrapone test is needed when suspicion for OIAI is high. | 1. Hines JM, Bancos I, Bancos C, et al. High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders. Clin Chem. 2017;63(12): 1824-1835. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Abstract Background: Evaluation for adrenal insufficiency (AI) includes dynamic testing that is cumbersome, expensive, and may not always be accessible. Our objective was to evaluate the diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) in diagnosing AI. Methods: This is a single-center retrospective study of patients evaluated for AI between July 10th, 2012 to January 7th, 2020 who underwent Cosyntropin stimulation testing (CST) or Insulin tolerance test (ITT), and had baseline measurement of DHEAS. Diagnosis of adrenal insufficiency was based on peak cortisol of <18 ug/dL during either CST or ITT. Results: We identified 491 patients (379 [77.2%] women, median age 42 years [range 18–84]) who met inclusion criteria. Primary adrenal insufficiency (PAI) was diagnosed in 16 (3%) patients, secondary adrenal insufficiency (SAI) was diagnosed in 211 (43%) patients, and AI was excluded in 264 (54%) patients. CST was performed in 478 (97%) patients, ITT was done in 45 (9%) patients, with 32 patients having both CST and ITT performed. Using a peak cortisol of <18 mcg/dl during CST to diagnose AI, ROC analysis of DHEAS demonstrated an area under the curve of 0.79, p<0.0001. A DHEAS cutoff of 100 mcg/dL excluded AI with a sensitivity of 93%, specificity of 41%, and a false negative rate of 3%. A DHEAS cut-off of 25 mcg/dl diagnosed AI with a false positive rate of 9% (Sensitivity 57% and specificity 85%). Notably, of 32 patients who had both CST and ITT performed, the diagnosis of AI was concordant in only 5 patients, while additional 27 patients had discordant results (26 were diagnosed with SAI based on ITT, but with a normal CST, and 1 patient was diagnosed with AI on CST but not on ITT). When excluding the 27 patients with discordant results, the overall performance of DHEAS in diagnosis of AI based on CST has not changed. Conclusion: DHEAS is a valuable baseline diagnostic test for AI. DHEAS >100 mcg/dl predicts a normal response during CST with a false negative rate of 3%, while DHEAS <25 mcg/dl is reflective of underlying adrenal insufficiency and predicts an abnormal CST with a false positive rate of 9%. In these situations, CST can be avoided.

Abstract Variants in the 4 genes encoding subunits A-D of succinate dehydrogenase (SDH) are associated with paraganglioma and pheochromocytoma. Intuitively, loss-of-function variants affecting any of the subunits should equally diminish SDH function leading to succinate accumulation and tumorigenesis after loss of heterozygosity. However, variants in SDHB are associated with a higher prevalence of metastatic disease and a more aggressive clinical course. Evaluation of the SDH protein structure shows the fraction of amino acids in contact with other subunits or essential prosthetic groups to be: 13% (SDHA), 40% (SDHB), 28% (SDHC), and 28% (SDHD). We therefore hypothesized that SDHB missense variants are more penetrant because a larger fraction alter sensitive interfaces with other SDH subunits or essential molecular features (e.g. the three SDHB iron-sulfur clusters). We also wondered if truncating variants are more common for SDHB than other subunits. To test these hypotheses, we combined three databases (Genome Aggregation Database, ClinVar-NCBI-NIH, and Leiden Open Variant Database) and our institution’s data to create a pool of all known SDH variants. We categorized variants as truncating or missense and evaluated missense variants in the context of the SDH protein structure, scoring each variant in relation to important structures/interfaces and the severity of the amino acid change. This provided an ad hoc impact score for each variant, where a higher score predicts a more deleterious effect. We compared these scores to those obtained using the “Sorting Intolerant from Tolerant” (SIFT) tool that predicts impacts of amino acid changes based on evolutionary sequence conservation. SIFT scores of 0 to 0.05 predict deleterious effects. Both mean impact and SIFT scores could be weighted for the prevalence of each variant in the population. Our database included 2333 total SDH variants: SDHA (838, 36%), SDHB (703, 30%), SDHC (381, 16%), and SDHD (412, 18%). The fractions of truncating variants were 38%, 50%, 51%, and 53% for A-D subunits, respectively. When weighted for prevalence, these fractions were 0.39%, 6.8%, 8.2%, and 0.2%. The number of truncating variants per coding region length and the distribution of locations were similar between subunits. Ad hoc impact scores for A-D subunits were 3.08, 14.9, 9.93, and 11.0, respectively and, when weighted for prevalence, were 0.28, 3.25, 6.32, and 1.15. Mean SIFT scores for subunits A-D were: 0.185, 0.162, 0.238, and 0.410 respectively, and, when weighted for prevalence, were 0.58, 0.70, 0.22, and 0.018. Our results do not support the hypothesis SDHB variants predict a worse clinical outcome because average SDHB variants are, by chance, more biochemically severe. This suggests that SDHB loss may uniquely impact SDH biochemical function.

Abstract Context Treatment of pheochromocytoma and paraganglioma (PPGL) requires preintervention titration of alpha- and beta-adrenergic blockade, but patients may still be at risk for complications from catecholamine excess. Metyrosine decreases catecholamine production, making it an attractive therapeutic adjunct for select patients. Evidence Acquisition A systematic literature review was performed (Ovid Medline and Scopus databases) on December 17, 2019, including studies with humans and original data. Studies with 10 or more patients on metyrosine for PPGL were included. Studies were screened for overlapping populations, and the most comprehensive study was included. The references of included studies were reviewed for additional data. Patient data from our institution between 2000 and 2015 were also reviewed. Evidence Synthesis Metyrosine is well tolerated when used for a short course and can improve intraoperative outcomes in PPGL. Metyrosine should be considered when a difficult PPGL resection is expected (eg, pericardiac paraganglioma, abdominal paraganglioma with great vessel involvement), a large release of catecholamines is anticipated (eg, ablative therapy, chemotherapy), or when standard alpha- and beta-adrenergic blockade are not tolerated or cannot adequately control hypertension. Side effects are generally mild and self-limited, with sedation in a majority of patients. Extrapyramidal side effects are rare but can limit use of metyrosine. Because of its expense and limited availability, metyrosine use should be carefully planned and timed in relation to surgery. Conclusions Metyrosine is a safe addition to traditional alpha- and beta-adrenergic blockade and should be considered in those patients with PPGL at high risk for acute release of catecholamines.

AbstractObjectiveComprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma.DesignA retrospective study at a tertiary care centre.PatientsAll patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015.MeasurementsTumour size, genetic testing, plasma/urine metanephrines and catecholamines.ResultsA total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4‐70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1‐38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical‐sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow‐up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy.ConclusionsBilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.

Abstract 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 < 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 <=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 < 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 >=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.

Abstract Context Cross-sectional imaging with CT or MRI is regarded as a first-choice modality for tumor localization in patients with pheochromocytoma and paraganglioma (PPGL). 123I-labeled metaiodobenzylguanidine (123I-MIBG) is widely used for functional imaging but the added diagnostic value is controversial. Objective To establish the virtual impact of adding 123I-MIBG scintigraphy to CT or MRI on diagnosis and treatment of PPGL. Design International multicenter retrospective study. Intervention None. Patients Two hundred thirty-six unilateral adrenal, 18 bilateral adrenal, 48 unifocal extra-adrenal, 12 multifocal, and 26 metastatic PPGL. Main Outcome Measures Patients underwent both anatomical imaging (CT and/or MRI) and 123I-MIBG scintigraphy. Local imaging reports were analyzed centrally by two independent observers who were blinded to the diagnosis. Imaging-based diagnoses determined by CT/MRI only, 123I-MIBG only, and CT/MRI combined with 123I-MIBG scintigraphy were compared with the correct diagnoses. Results The rates of correct imaging-based diagnoses determined by CT/MRI only versus CT/MRI plus 123I-MIBG scintigraphy were similar: 89.4 versus 88.8%, respectively (P = 0.50). Adding 123I-MIBG scintigraphy to CT/MRI resulted in a correct change in the imaging-based diagnosis and ensuing virtual treatment in four cases (1.2%: two metastatic instead of nonmetastatic, one multifocal instead of single, one unilateral instead of bilateral adrenal) at the cost of an incorrect change in seven cases (2.1%: four metastatic instead of nonmetastatic, two multifocal instead of unifocal and one bilateral instead of unilateral adrenal). Conclusions For the initial localization of PPGL, the addition of 123I-MIBG scintigraphy to CT/MRI rarely improves the diagnostic accuracy at the cost of incorrect interpretation in others, even when 123I-MIBG scintigraphy is restricted to patients who are at risk for metastatic disease. In this setting, the impact of 123I-MIBG scintigraphy on clinical decision-making appears very limited.