Latent Adrenal Insufficiency: From Concept to Diagnosis.

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses.

Incidentally discovered adrenal masses are common and mostly benign and non-functioning adenomas. However, evolving evidence suggests that a notable proportion of these adrenal adenomas may demonstrate mild autonomous cortisol secretion (MACS), which has been associated with an increased risk for hypertension, hyperglycemia, obesity, dyslipidemia, vertebral fractures, adverse cardiovascular events, and mortality. Therefore, it is advised that all patients with an incidentally discovered adrenal mass be tested for MACS. When there is convincing evidence for MACS, surgical adrenalectomy has been associated with an improvement in certain metabolic parameters and a reduction in vertebral fractures; however, conclusive evidence demonstrating decreased cardiovascular outcomes or mortality are not yet available. Future studies with adequate randomization and follow-up to assess adverse clinical endpoints are needed to determine the optimal management and follow-up of patients with MACS.

Computed tomography combined with confirmatory tests for the diagnosis of aldosterone-producing adenoma.

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and a simpler non-invasive method for identification of aldosterone-producing adenoma (APA) is required to improve the standard of medical treatment for PA patients. We retrospectively analyzed the clinical data of hypertensive patients with an aldosterone/renin ratio (ARR) ≥30 (ng/dL)/(ng/mL/h), and surgical and/or adrenal venous sampling (AVS) results served as the gold standard for APA diagnosis. The study aimed to determine whether positive CCT and SIT results plus a unilateral adrenal nodule found by CT allow unambiguous identification of an APA with high diagnostic specificity. Clinical data from 71 APA and 47 non-APA patients were collected, and logistic regression analysis was performed to construct models. Receiver operating characteristic (ROC) curves were used to analyze the efficacy of diagnostic tests. The areas under the ROC curves (AUCs) were similar between the post-SIT plasma aldosterone concentration (PAC) and post-CCT PAC (p > 0.05). The optimal post-SIT and post-CCT PAC cutoff values were 17.2 and 21.2 ng/dL, respectively. Positive CT findings combined with a post-SIT PAC >17.2 ng/dL or post-CCT PAC >21.2 ng/dL provided specificities of 97.8% and 95.7% for predicting APA, respectively. Logistic diagnostic models 1 (M1, CT finding + post-SIT PAC) and 2 (M2, CT finding + post-CCT PAC) were built, which showed equivalent diagnostic value (AUC = 0.959 and 0.932, respectively) (p > 0.05). The models combining CT findings with post-SIT PACs or post-CCT PACs represent an easier method to distinguish APA patients from other hypertensive patients with positive upright ARR results, especially in primary care where AVS may be unavailable.

Early assessment of postoperative adrenal function is necessary after adrenalectomy for mild autonomous cortisol secretion.

BACKGROUND: The diagnostic threshold for mild autonomous cortisol secretion using low dose, overnight, dexamethasone suppression testing is recognized widely as a serum cortisol ≥1.8 mcg/dL. The degree to which these patients require postoperative glucocorticoid replacement is unknown. METHODS: We reviewed adult patients with corticotropin (ACTH)-independent hypercortisolism who underwent unilateral laparoscopic adrenalectomy for benign disease with a dexamethasone suppression testing ≥1.8 mcg/dL at our institution from 1996 to 2018. Patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL were compared with those with a dexamethasone suppression testing >5 mcg/dL. RESULTS: We compared 68 patients with a preoperative dexamethasone suppression testing of 1.8 to 5 mcg/dL to 53 patients with a preoperative dexamethasone suppression testing >5 mcg/dL. Preoperative serum ACTH (mean 10.0 vs 9.2 pg/mL), adenoma size (mean 3.4 vs 3.5 cm), and side of adrenalectomy (37 and 47% right) were similar between groups (P > .05 each). Patients with a dexamethasone suppression testing 1.8 to 5 mcg/dL were older (mean values 58 ± 11 vs 52 ± 16 years ; P = .01), less likely to be female (63 vs 81%; P = .03), had greater body mass indexes (33.1 ± 8.4 vs 29.1 ± 5.6; P = .01), and had lesser 24 hour preoperative urine cortisol excretions (32.6 ± 26.7 vs 76.1 ± 129.4 mcg; P = .03). Postoperative serum cortisol levels were compared in 22 patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL to 14 patients with a dexamethasone suppression testing >5 mcg/dL. Those with dexamethasone suppression testing 1.8 to 5 mcg/dL had greater postoperative serum cortisol levels (8.0 ± 5.7 vs 5.0 ± 2.6 mcg/dL; P = .03), were less likely to be discharged on glucocorticoid replacement (59% vs 89%; P = .003), and had a decreased duration of treatment (4.4 ± 3.8 vs 10.7 ± 18.0 months; P = .04). CONCLUSION: Assessment of early postoperative adrenal function with mild autonomous cortisol secretion is necessary to minimize unnecessary glucocorticoid replacement.

Adrenal haemorrhage as a complication of COVID-19 infection.

We report an unusual complication of COVID-19 infection in a 53-year-old Caucasian man. He presented with shortness of breath, fever and pleuritic chest pain. A CT pulmonary angiogram (CTPA) demonstrated acute bilateral pulmonary embolism and bilateral multifocal parenchymal ground glass change consistent with COVID-19 (SARS-CoV-2) infection. Right adrenal haemorrhage was suspected on the CTPA which was confirmed on triple-phase abdominal CT imaging. A short Synacthen test revealed normal adrenal function. He was treated initially with an intravenous heparin infusion, which was changed to apixaban with a planned outpatient review in 3 months' time. He made an uncomplicated recovery and was discharged. Follow-up imaging nearly 5 months later showed near complete resolution of the right adrenal haemorrhage with no CT evidence of an underlying adrenal lesion.

Evaluation of Adrenal Vein Sampling Use and Outcomes in Patients With Primary Aldosteronism.

BACKGROUND: Primary aldosteronism (PA) occurs in 10%-20% of patients with resistant hypertension. Guidelines recommend adrenal vein sampling (AVS) to identify patients for surgical management. We evaluate the use of AVS in managing PA to better understand the selection and outcomes of medical versus surgical treatment. METHODS: A retrospective review was performed, and patients were divided into those who did (AVS) and did not have AVS (non-AVS). Demographics, aldosterone and renin levels, blood pressure, comorbidities, and antihypertensive medications were recorded. Reasons to defer AVS and medical versus surgical decision-making were examined and groups were compared. RESULTS: We included 113 patients; 39.8% (45/113) had AVS, whereas 60.2% (68/113) did not. Groups were similar in age, body mass index, and initial systolic blood pressure (SBP). In patients who underwent AVS, 31 of 45 (68.9%) had unilateral secretion and were referred for surgery, whereas 13 of 45 (28.9%) had bilateral secretion. Of the 31 referred for surgery, 26 underwent laparoscopic adrenalectomy, all cured; four refused surgery; and one counseled toward medical management by their physician. In 68 non-AVS patients, 6 (8.8%) underwent adrenalectomy without sampling and 2 with no clinical improvement. The remaining deferrals were because of normal or bilateral adrenal nodules on imaging (8/68, 11.8%); medical management due to poor surgical candidacy (12/68, 17.6%); patient refusal of intervention (13/68, 19.1%); or reasons not stated (28/68, 41.1%). At the follow-up, patients who underwent AVS had lower median SBP (135.4 mmHg versus 144.7 mmHg, P = 0.0241) and shorter follow-up (17.7 mo versus 54.0 mo, P < 0.0001). Surgically managed patients had biochemical resolution of PA with normalization of potassium levels (3.6 to 4.7mEq/L, P < 0.00001). CONCLUSIONS: AVS correctly selects patients for surgical management avoiding unnecessary surgery. However, despite guidelines, AVS is not always pursued as part of PA treatment, potentially excluding surgical candidates.

Low-grade Cortisol Cosecretion Has Limited Impact on ACTH-stimulated AVS Parameters in Primary Aldosteronism.

CONTEXT: In primary aldosteronism, cosecretion of cortisol may alter cortisol-derived adrenal venous sampling indices. OBJECTIVE: To identify whether cortisol cosecretion in primary aldosteronism alters adrenal venous sampling parameters and interpretation. DESIGN: Retrospective case-control study. SETTING: A tertiary referral center. PATIENTS: 144 adult patients with primary aldosteronism who had undergone both adrenocorticotropic hormone-stimulated adrenal venous sampling and dexamethasone suppression testing between 2004 and 2018. MAIN OUTCOME MEASURES: Adrenal venous sampling indices including adrenal vein aldosterone/cortisol ratios and the selectivity, lateralization, and contralateral suppression indices. RESULTS: 21 (14.6%) patients had evidence of cortisol cosecretion (defined as a failure to suppress cortisol to ≤50 nmol/L post dexamethasone). Patients with evidence of cortisol cosecretion had a higher inferior vena cava cortisol concentration (P = .01) than those without. No difference was observed between the groups in terms of selectivity index, lateralization index, lateralization of aldosterone excess, or adrenal vein cannulation rate. CONCLUSIONS: Cortisol cosecretion alters some parameters in adrenocorticotrophic hormone-stimulated adrenal venous sampling but does not result in alterations in patient management.

The Concordance Between Imaging and Adrenal Vein Sampling Varies With Aldosterone-Driver Somatic Mutation.

BACKGROUND: Correct subtyping of primary aldosteronism (PA) is critical for guiding clinical management. Adrenal imaging is less accurate than adrenal vein sampling (AVS); nonetheless, AVS is invasive, technically challenging, and scarcely available. OBJECTIVE: To identify predictors of concordance between cross-sectional imaging and lateralized AVS in patients with PA that could help circumvent AVS in a subset of patients. METHODS: We retrospectively studied all patients with PA who underwent AVS in a tertiary referral center from 2009 to 2019. AVS was performed before and after cosyntropin stimulation. Patients with lateralized AVS in at least one condition were included. Aldosterone synthase-guided next-generation sequencing was performed on available adrenal tissue. Logistic regression was implemented to identify predictors of imaging-AVS lateralization concordance. RESULTS: A total of 234 patients (62% men), age 20 to 79 years, 73% white, 23% black, and 2% Asian were included. AVS lateralization was found: 1) both pre- and post-cosyntropin (Uni/Uni) in 138 patients; 2) only at baseline (Uni/Bi) in 39 patients; 3) only after cosyntropin stimulation (Bi/Uni) in 29 patients. Catheterization partially failed in 28 patients. AVS-imaging agreement was higher in patients with KCNJ5 versus other aldosterone-driver somatic mutations (90.3% versus 64.6%; P < 0.001); in Asian and white versus black Americans (75%, 70%, and 36%, respectively); in younger patients; and those with left adrenal nodules and contralateral suppression. Conversely, AVS-imaging agreement was lowest in Uni/Bi patients (38% vs. 69% in Uni/Uni, and 62% in Bi/Uni; P = 0.007). CONCLUSIONS: While AVS-imaging agreement is higher in young white and Asian patients, who have KCNJ5-mutated aldosterone producing adenomas, no predictor confers absolute imaging accuracy.

Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a noninvasive Short Synacthen Test.

CONTEXT: The Short Synacthen Test (SST) is the gold standard for diagnosing adrenal insufficiency. It requires invasive administration of Synacthen, venous sampling, and is resource-intensive. OBJECTIVE: To develop a nasally administered SST, with salivary glucocorticoids measurement, to assess the adrenal response. DESIGN: We conducted 5 studies: 4 open-label, sequence-randomized, crossover, pharmacodynamic studies testing 6 doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our pediatric study. SETTING: Adult and children's clinical research facilities. PARTICIPANTS: A total of 36 healthy adult males and 24 healthy children. INTERVENTION: We administered all 6 nasal formulations using an European regulator endorsed atomization device. The IV comparators were 250 µg or 1 µg SST. MAIN OUTCOME MEASURES: We analyzed paired blood and saliva samples for plasma cortisol and salivary cortisol and cortisone. RESULTS: The addition of chitosan to tetracosactide and dose escalation increased peak cortisol response (P = 0.01 and 0.001, respectively). The bioavailability of Nasacthin003 was 14.3%. There was no significant difference in plasma cortisol at 60 minutes between 500 µg Nasacthin003 and 250 µg IV Synacthen (P = 0.17). The repeatability coefficient at 60 minutes was 105 nmol/L for IV Synacthen and salivary cortisol and cortisone was 10.3 and 21.1 nmol/L, respectively. The glucocorticoid response in children was indistinguishable from that of adults. CONCLUSIONS: Nasal administration of Nasacthin003 generates equivalent plasma cortisol values to the 250-µg IV SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a noninvasive test for adrenal insufficiency.

Comparison of the shortened and standard saline infusion tests for primary aldosteronism diagnostics.

The saline infusion test (SIT) is widely used to confirm PA, but some patients may not tolerate the standard loading volume of 2 L saline over 4 h. The shortened SIT, loading only 1 L saline over 2 h, is suggested to be useful and would be more acceptable if the diagnostic utility of the shortened SIT is comparable to that of the standard SIT. We compared the diagnostic values of the plasma aldosterone concentration after 2 h of 1 L saline loading (2 h PAC) and that after 4 h of 2 L saline loading (4 h PAC) for the prediction of unilateral aldosterone hypersecretion and postoperative outcome. This retrospective, single-center study involved 555 PA-suspected patients who underwent SIT, 153 patients with adrenal vein sampling (AVS) results, and 37 patients with a 1-year postoperative evaluation. To detect the Japanese cutoff of 4 h PAC > 60 pg/mL, a 2-h PAC Youden Index at 66 pg/mL showed 91% sensitivity and 75% specificity. For unilateral aldosterone hypersecretion, the sensitivity and specificity of 2 h PAC were not inferior to those of 4 h PAC by Markov chain Monte Carlo (MCMC) methods. The sensitivity and specificity of 2 h PAC for postoperative reduction of anti-hypertensive drugs were also not inferior to those of 4 h PAC. Although using the 2 h PAC > 66 pg/mL cutoff may increase false positives for PA diagnosis, the shortened SIT, possibly using a cutoff value higher than 66 pg/mL, may be as useful as the standard SIT for selecting PA patients for AVS and to predict postoperative outcomes with reduced burden on patients.

Possible adrenal insufficiency among fatigue patients in a psychosomatic medical clinic.

Fatigue is a common symptom in patients visiting the clinic of psychosomatic medicine. A 250-µg synthetic ACTH (1-24) test (rapid ACTH test) and Beck depression inventory (BDI) were performed for 62 patients presenting with fatigue who visited the Department of Psychosomatic Medicine at Fukuoka Tokushukai Hospital. Patients were divided into 3 groups according to the serum cortisol response to the rapid ACTH test; those with a peak serum cortisol level of <15 µg/dL were defined as the adrenal insufficiency (AI) probable group, ≥15 µg/dL and <18 µg/dL as the AI suspected group, and ≥18 µg/dL as the non-AI group. Patients prescribed anti-depressants, had a BDI ≥16, and/or met the full criteria for major depression were diagnosed with depression. Five (8.0%) and 7 patients (11.3%) were assigned to the AI probable and AI suspected groups, respectively. All others were assigned to the non-AI group. Depression was observed in 37 patients (59.6%; 4 in the AI probable group [80.0%], 4 in the AI suspected group [57.1%], and 29 in the non-AI group [58.0%]). Users of exogenous steroids, such as inhaled steroids for bronchial asthma, were seen in the AI probable group (2; 40.0%), the AI suspected group (3; 42.8%), and the non-AI group (7; 14.0%) (χ2 = 4.761, p = 0.0925). In conclusion, probable or suspected AI was observed in about one-fifth of patients presenting with fatigue at the psychosomatic medical clinic. A CRH test and insulin tolerance test (ITT) may help the he mechanism underlying these possible AIs.

Outcomes of the short Synacthen test: what is the role of the 60 min sample in clinical practice?

In recent years, the short Synacthen test (SS) has become the most widely used test to assess adrenal reserve. Despite its frequent use, there are still several areas related to the short Synacthen test (SST), which have no consensus including the optimum sampling times, that is, whether a 60 min post-Synacthen administration cortisol is necessary or not. METHODOLOGY: We performed a retrospective data analysis of 492 SSTs performed on adult patients in a tertiary referral teaching hospital in Ireland. The SSTs were performed in the inpatient and outpatient setting and included patients across all medical disciplines and not exclusively to the endocrinology department. RESULTS: 313 patients had 0, 30 and 60 min samples available for analysis. A total of 270/313 (82%) were deemed to pass the test, that is, cortisol ≥500 nmol/L at both 30 and 60 min. Of the 313 patients, 19 (6%) patients had an indeterminate response, cortisol <500 nmol/L at 30 min, but rising to ≥500 nmol/L on the 60 min sample. Of these 19 patients, only 9/19 patients had a serum cortisol level at 30 min <450 nmol/L, requiring clinical treatment with glucocorticoid replacement. All 24/313 (8%) patients who had insufficient responses at 60 min were also insufficient at 30 min sampling. No individuals passed (≥500 nmol/L) at 30 min and then failed (<500 nmol/L) at 60 min. CONCLUSION: Using the 30 min cortisol sample post-Synacthen administration alone identifies clinically relevant adrenal insufficiency in the majority of cases. A small subset of patients have a suboptimal response at 30 min but have a 60 min cortisol concentration above the threshold for a pass. Data regarding the long-term outcomes and management of such patients are lacking and require further study.

Intramuscular Short-term ACTH Test for the Determination of Adrenal Function in Children: Safe, Effective and Reliable

Objective: Standard short adrenocorticotropic hormone (ACTH) stimulation test (SST) has traditionally been used for assessing adrenal gland fuction by intravenous (iv) application. However the iv form is not readily available in all countries, including Turkey. The aim of this study was to evaluate the effectiveness of the intramuscular (im) SST. Methods: Patients underwent im SST with suspected adrenal insufficiency (AI) and hyperandrogenism. The SSTs were done with 250 mcg ACTH (Synacthen Depot ampul, concentration 1 mg/mL). The cases were divided into two groups: suspected AI (group 1 n=87); and hyperandrogenism group (group 2 n=124). Definite AI was defined as peak cortisol <18 µg/dL, suspected AI as a peak cortisol of 18-21 µg/dL and normal result was defined as a peak cortisol ≥22 µg/dL. Results: The mean age of the patients was 11.7±5.2 years. In 164 patients (78%) all of the peak cortisol tests were normal (≥22 mcg/dL). The rates were 64% and 88% in group 1 and 2, respectively. Only 8.5% (n=18) of all cases had an inadequate peak cortisol response of <18 mcg/dL. On follow up, 15 patients whose peak cortisol was <18 mcg/dL needed cortisol therapy. Of all cases 3.3% (n=8) had 17-OHP ≥10 ng/dL. Clinical findings suggestive of non-classical congenital adrenal hyperplasia and/or mutation were found in six of these cases (75%). No local and systemic side effects or allergic reactions were observed in any patient. Conclusion: IM ACTH SST is a safe, effective and reliable test in children with suspected AI. There were no local or systemic side effects, supporting the reliability of the im ACTH test.

A combination of captopril challenge test after saline infusion test improves diagnostic accuracy for primary aldosteronism.

CONTEXT: The saline infusion test (SIT) is a common confirmatory test for primary aldosteronism (PA). According to the guideline, a postinfusion plasma aldosterone concentration (PAC) of 5-10 ng/dL is considered indeterminate, and recommendations for diagnostic strategies are currently limited in this situation. OBJECTIVE: To explore whether an addition of the captopril challenge test (CCT) could improve the diagnostic accuracy in patients with indeterminate SIT. METHODS: A total of 280 hypertensive patients with high risk of PA completed this study. Subjects were defined as SIT indeterminate based on their PAC post-SIT. These patients then underwent the CCT where PACs post-CCT >11 ng/dL were considered positive. Using fludrocortisone suppression test (FST) as the reference standard, diagnostic parameters including area under the receiver-operator characteristic curves (AUC), sensitivity and specificity were calculated. RESULTS: There were 65 subjects (23.2%) diagnosed as PA indeterminate after SIT. With the addition of CCT, true-positive numbers increased from 134 to 147, and false-negative numbers decreased from 27 to 14. Compared to SIT alone, a combination of SIT and CCT showed a higher AUC (0.91 [0.87,0.94] vs 0.87 [0.83,0.91], P = .041) and an increased sensitivity for the diagnosis of PA (0.91 [0.86,0.95] vs 0.83 [0.76,0.89], P = .028), while the specificity remained similar. In the subgroup with indeterminate SIT results, using PAC post-CCT resulted in a 36% higher AUC than using PAC post-SIT alone for the diagnosis of PA. CONCLUSION: For patients under investigation for possible PA who have indeterminate SIT results, an addition of CCT improves the diagnostic accuracy.

Three Discrete Patterns of Primary Aldosteronism Lateralization in Response to Cosyntropin During Adrenal Vein Sampling.

CONTEXT: Cosyntropin [ACTH (1-24)] stimulation during adrenal vein (AV) sampling (AVS) enhances the confidence in the success of AV cannulation and circumvents intraprocedure hormonal fluctuations. Cosyntropin's effect on primary aldosteronism (PA) lateralization, however, is controversial. OBJECTIVES: To define the major patterns of time-dependent lateralization, and their determinants, after cosyntropin stimulation during AVS. METHODS: We retrospectively studied patients with PA who underwent AVS before, 10, and 20 minutes after cosyntropin stimulation between 2009 and 2018. Unilateral (U) or bilateral (B) PA was determined on the basis of a lateralization index (LI) value ≥4 or <4, respectively. Available adrenal tissue underwent aldosterone synthase-guided next-generation sequencing. RESULTS: PA lateralization was concordant between basal and cosyntropin-stimulated AVS in 169 of 222 patients (76%; U/U, n = 110; B/B, n = 59) and discordant in 53 patients (24%; U/B, n = 32; B/U, n = 21). Peripheral and dominant AV aldosterone concentrations and LI were highest in U/U patients and progressively lower across intermediate and B/B groups. LI response to cosyntropin increased in 27% of patients, decreased in 33%, and remained stable in 40%. Baseline aldosterone concentrations predicted the LI pattern across time (P < 0.001). Mutation status was defined in 61 patients. Most patients with KCNJ5 mutations had descending LI, whereas those with ATP1A1 and ATP2B3 mutations had ascending LI after cosyntropin stimulation. CONCLUSION: Patients with severe PA lateralized robustly regardless of cosyntropin use. Cosyntropin stimulation reveals intermediate PA subtypes; its impact on LI varies with baseline aldosterone concentrations and aldosterone-driver mutations.

Plasma Aldosterone After Seated Saline Infusion Test Outperforms Captopril Test at Predicting Clinical Outcomes After Adrenalectomy for Primary Aldosteronism.

OBJECTIVE: The saline infusion test (SIT) and the captopril test (CT) are widely used as confirmatory tests for primary aldosteronism (PA). We hypothesized that post-SIT and post-CT plasma aldosterone concentrations (PAC) indicate the severity of aldosterone-producing adenoma (APA) and might predict clinical outcome. METHODS: We recruited 216 patients with APA in the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry who received both seated SIT and CT as confirmatory tests. The data of 143 patients who underwent adrenalectomy with complete follow-up after diagnosis were included in the final analysis. We determined the proportion of patients achieving clinical success in accordance with the Primary Aldosteronism Surgical Outcome consensus. Logistic regression analysis was conducted to identify preoperative factors associated with cure of hypertension. RESULTS: Complete clinical success was achieved in 48 (33.6%) patients and partial clinical success in 59 (41.2%) patients; absent clinical success was seen in 36 (25.2%) of 143 patients. Post-SIT PAC but not post-CT PAC was independently associated with clinical outcome. Higher levels of post-SIT PAC had a higher likelihood of clinical benefit (complete plus partial clinical success; odds ratio = 1.04 per ng/dl increase, 95% confidence interval = 1.01, 1.06; P = 0.004). Patients with post-SIT PAC > 25 ng/dl were more likely to have a favorable clinical outcome after adrenalectomy. This cutoff value translated into a positive predictive value of 86.0%. CONCLUSIONS: We suggest that post-SIT PAC is a better predictor than post-CT PAC for clinical success in PA post adrenalectomy.

Long-acting intramuscular ACTH stimulation test for the diagnosis of secondary adrenal insufficiency in children.

Background The diagnosis of adrenal insufficiency (AI) is based on the basal and stimulated levels of serum cortisol in response to the short Synacthen test (SST). In patients with secondary AI (SAI) due to hypothalamic-pituitary-adrenal (HPA) axis defects, the SST has been validated against the insulin tolerance test (ITT), which is the gold standard. However, injection Synacthen is not easily available in some countries, and endocrinologists often use Acton-Prolongatum (intramuscular [IM] long-acting adrenocorticotropic hormone [ACTH]) in place of Synacthen. There are no studies validating the use of IM-ACTH in children with suspected AI. We evaluated the diagnostic value of the IM-ACTH test against the ITT for the diagnosis of SAI in children. Methods All children with suspected growth hormone deficiency (GHD) undergoing a routine ITT were evaluated using the IM-ACTH test within 1 week. Results Forty-eight patients (36 boys/12 girls, age range: 5-14 years) were evaluated using both the ITT and the IM-ACTH test. Twenty-eight patients had a normal cortisol response (≥18 µg/dL, 500 nmol/L) in the ITT and 20 had low values. In patients with a normal cortisol response on the ITT, the peak value obtained after the IM-ACTH test was higher than that on the ITT (28.7 µg/dL [± 8.8] vs. 23.8 µg/dL [± 4.54], respectively; p=0.0012). Compared to the ITT, the sensitivity and specificity of the IM-ACTH test for the diagnosis of SAI at cortisol cut-offs <18 µg/dL (500 nmol/L) and <22 µg/dL (600 nmol/L) were 57.1% and 92.8%, and 100% and 73.5%, respectively. Conclusions A peak cortisol value <18 µg/dL on the IM-ACTH test is highly suggestive of SAI, whereas a value >22 µg/dL rules out SAI.

Role of sampling times and serum cortisol cut-off concentrations on the routine assessment of adrenal function using the standard cosyntropin test in an academic hospital from Spain: a retrospective chart review.

OBJECTIVES: Aiming to validate the use of a single poststimulus sampling protocol for cosyntropin test short standard high-dose test (SST) in our institution, our primary objectives were (1) to determine the concordance between 30 and 60 min serum cortisol (SC) measurements during SST; and (2) to evaluate the diagnostic agreement between both sampling times when using classic or assay-specific and sex-specific SC cut-off values. The secondary objectives included (1) estimating the specificity and positive predictive value of 30 and 60 min sampling times while considering the suspected origin of adrenal insufficiency (AI); and (2) obtaining assay-specific cut-off values for SC after SST in a group of subjects with normal hypothalamic-pituitary-adrenal (HPA) axis. DESIGN AND SETTING: This is a retrospective chart review study conducted at a Spanish academic hospital from 2011 to 2015. PARTICIPANTS AND INTERVENTIONS: Two groups were evaluated: (1) a main study group including 370 patients in whom SC was measured at 30 and 60 min during SST; and (2) a confirmative group that included 150 women presenting with a normal HPA axis in whom SST was conducted to rule out late-onset congenital adrenal hyperplasia. Diagnostic agreement between both sampling times was assessed by considering both classic (500 nmol/L) and assay-specific SC cut-off concentrations. RESULTS: Diagnostic agreement between both sampling times was greater when applying sex-specific and assay-specific cut-off values instead of the classic cut-off values. For suspected primary AI, 30 min SC determination was enough to establish a diagnosis in over 95% of cases, without missing any necessary treatment. When central AI is suspected, 60 min SC measurement was more specific, establishing a diagnosis in over 97% of cases. CONCLUSIONS: Sex-specific and assay-specific SC cut-off values improve the diagnostic accuracy of SST. For primary disease, a subnormal SC response at 30 min is a reliable marker of adrenal dysfunction. On the contrary, when central AI is suspected, 60 min SC measurement improves the diagnostic accuracy of the test.

Evaluation of the Saline Infusion Test and the Captopril Challenge Test in Chinese Patients With Primary Aldosteronism.

Context: The aim of this study was to determine whether the diagnosis cutoff values associated with the saline infusion test (SIT) and captopril challenge test (CCT) in the Endocrine Society guidelines are applicable to Chinese subjects. Objective and Design: We performed a head-to-head comparison of the SIT and CCT among Chinese subjects with primary aldosteronism (PA) and essential hypertension (EH). Participants and Setting: One hundred sixty-four hypertensive patients were enrolled. Intervention: All participants underwent both the SIT and CCT. Main Outcome Measures: The plasma aldosterone concentration (PAC) and plasma renin activity were measured before and after the SIT and CCT. The degree of PAC decline after CCT was calculated. Results: This study included 115 PA and 49 EH subjects. The prevalence of hypokalemia was 74.8% in the PA group. Supine PACs in the EH and PA groups were 15.1 ± 4.7 mmol/L and 30.4 ± 12.1 mmol/L. Post-SIT PACs were 8.8 ± 1.7 ng/dL and 22.7 ± 10.2 ng/dL in the EH and PA groups. The degree of PAC decline after CCT was 17.7% and 14.2% in the EH and PA groups; post-CCT PACs were 11.7 ± 3.3 ng/dL and 25.9 ± 10.6 ng/dL. PAC values of 11.2 ng/dL and 16.7 ng/dL after the SIT and CCT represented the optimal cutoff values for PA diagnosis. The post-SIT and post-CCT area under the receiver operating characteristic curve values were 0.972 [95% confidence interval (CI) = 0.934 to 0.991] and 0.933 (95% CI = 0.883 to 0.966). Conclusions: Post-SIT and post-CCT PACs, but not the degree of PAC suppression, were both reliable for PA diagnosis. However, the optimal cutoffs were slightly higher in Chinese subjects than those recommended by the Endocrine Society.