Diagnosis Of ACTH-dependent Cushing's Syndrome Research Articles

Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery.

Alternative Approach to BIPSS in the Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

Alternative Approach to BIPSS in the Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

PS-R03-10: CASE REPORT: CUSHING SYNDROME IN A YOUNG MALE

A 27-year-old male without any significant past medical history was advised to visit a hospital for elevated blood pressure, elevated liver enzymes, and dyslipidemia in a workplace health checkup. His body weight had increased by more than 10 kg in the last two years. He presented to our department and underwent laboratory work-up. He had bilateral lower limb pitting edema, hypokalemia, and elevation of low-density lipoprotein. No sign of dysthyroidism, renin-angiotensin-aldosterone system disorder, or increased catecholamine secretion was found. Diet and exercise therapy and calcium channel blocker did not improve his hypertension, and he suffered from lumber vertebral fracture, refractory hypokalemia, and lower leg cellulitis. He was admitted to our department for detailed examination of worsening lower limb edema. On admission, he had striae on his abdomen and legs as well as edema of both lower extremities. The endocrinological data showed high levels of adrenocorticotropic hormone (ACTH) and cortisol. Overnight 1 mg dexamethasone suppression test resulted in a non-suppression response, and his circadian rhythm of cortisol was absent. Urine cortisol level was high. These findings confirmed the diagnosis of ACTH-dependent Cushing syndrome. A contrasted magnetic resonance imaging (MRI) scan demonstrated enlargement of the pituitary gland more than 1 cm in length. Taking into account drug-resistant hypokalemia and vulnerability to infection, he was administered with metyrapone 500 mg per day until he underwent transsphenoidal hypophysectomy. The pathological findings were consistent with that of a pituitary adenoma. Postoperative MRI scan showed remnant lesions which stretch to the bilateral cavernous sinuses and the right middle cranial fossa. Although a decrease in urine cortisol was observed, the absence of a circadian rhythm of cortisol, hypertension, and hypokalemia persisted. He is now treated with somatostatin analog and craniotomy followed by gamma knife surgery is planned. Cushing syndrome should be suspected in cases of early-onset hypertension with symptoms including weight gain, hypokalemia, and bone fracture.

Dynamic Testing for Differential Diagnosis of ACTH-Dependent Cushing Syndrome: A Systematic Review and Meta-analysis.

Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.

PSAT043 Liraglutide Ameliorates Symptoms of Cushing Syndrome in a Pediatric Patient

Abstract Background Cushing Syndrome (CS) is a rare disease characterized by hypercortisolism. Pituitary adenomas resulting in ACTH-dependent disease may be difficult to visualize radiologically, resulting in a prolonged diagnostic course and delay in definitive treatment. Adjuvant medical treatment with pharmacologic agents, including steroidogenesis inhibitors and adrenolytics, can be utilized for symptom management. However, hypercortisolemia may be refractory to medical therapy making it necessary to consider symptomatic treatments. We present a case of a pediatric patient with Cushing syndrome in whom treatment with liraglutide, a GLP-1 agonist approved for the treatment of hyperglycemia and obesity, resulted in improvement of symptoms of hypercortisolemia. Case A 13 year old Caucasian female presented with a 2 year history of linear growth arrest, accelerated weight gain and delayed puberty. Her physical examination was remarkable for overt signs of hypercortisolemia. Initial laboratory evaluation showed normal thyroid function, hyperglycemia with HbA1c 7.2% (normal &amp;lt; 5.7%), dyslipidemia and elevated midnight salivary cortisol 0.898 (normal &amp;lt; 0.112 mcg/mL). Hypercortisolemia was confirmed when morning serum cortisol was 25.6 mcg/dL after 1 mg overnight dexamethasone suppression test (DST). This along with an elevated morning ACTH level, 72.8 (7.2- 63.3 pg/mL), confirmed a diagnosis of ACTH-dependent Cushing syndrome. Magnetic Resonance Imaging of the pituitary gland with contrast showed a 4 mm non- enhancing lesion consistent with a Rathke's cleft cyst which was unlikely to be the source of excess ACTH. Results from high dose (8 mg overnight) DST, Corticotropin Releasing Hormone (CRH) stimulation test, and Inferior Petrosal Sinus Sampling for ACTH post CRH stimulation were partially inconsistent with pituitary disease. Further workup for ectopic source(s) of ACTH showed normal imaging of the neck, chest, abdomen and pelvis. A DOTATATE PET scan failed to identify an ACTH source. Adrenolytic adjuvant treatment with mitotane was started but was discontinued due to intolerable gastrointestinal effects. Treatment was changed to ketoconazole, however, hypercortisolemia remained refractory to treatment as evidenced by continued elevation of 24- hour urine free cortisol levels. Metformin was initiated for hyperglycemia treatment but was not tolerated due to persistent nausea and vomiting. The patient was switched to liraglutide and within 3 months she had 10% weight loss, normalization of fasting blood glucose levels and reduction of HbA1c to 5.7%. Additionally, the patient's energy level and baseline hidradenitis suppurativa improved. Conclusion In some pediatric patients with CS, definitive treatment of hypercortisolemia may be delayed or not feasible due to a lack of biochemical or radiological evidence showing the specific etiology for CS. Medical treatment with pharmacologic agents can be utilized for symptom management, however, hypercortisolemia may persist and even be recalcitrant to therapy. In this setting, clinicians should consider using liraglutide to ameliorate some of the cardinal symptoms of CS in pediatric patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Pitfalls in Performing and Interpreting Inferior Petrosal Sinus Sampling: Personal Experience and Literature Review.

Inferior petrosal sinus sampling (IPSS) helps differentiate the source of ACTH-dependent hypercortisolism in patients with inconclusive biochemical testing and imaging, and is considered the gold standard for distinguishing Cushing disease (CD) from ectopic ACTH syndrome. We present a comprehensive approach to interpreting IPSS results by examining several real cases. We performed a comprehensive review of the IPSS literature using PubMed since IPSS was first described in 1977. IPSS cannot be used to confirm the diagnosis of ACTH-dependent Cushing syndrome (CS). It is essential to establish ACTH-dependent hypercortisolism before the procedure. IPSS must be performed by an experienced interventional or neuroradiologist because successful sinus cannulation relies on operator experience. In patients with suspected cyclical CS, it is important to demonstrate the presence of hypercortisolism before IPSS. Concurrent measurement of IPS prolactin levels is useful to confirm adequate IPS venous efflux. This is essential in patients who lack an IPS-to-peripheral (IPS:P) ACTH gradient, suggesting an ectopic source. The prolactin-adjusted IPS:P ACTH ratio can improve differentiation between CD and ectopic ACTH syndrome when there is a lack of proper IPS venous efflux. In patients who have unilateral successful IPS cannulation, a contralateral source cannot be excluded. The value of the intersinus ACTH ratio to predict tumor lateralization may be improved using a prolactin-adjusted ACTH ratio, but this requires further evaluation. A stepwise approach in performing and interpreting IPSS will provide clinicians with the best information from this important but delicate procedure.

Is it Time for a New Approach to the Differential Diagnosis of ACTH-Dependent Cushing Syndrome?

Is it Time for a New Approach to the Differential Diagnosis of ACTH-Dependent Cushing Syndrome?

In vivo response to growth hormone-releasing peptide-6 in adrenocorticotropin-dependent Cushing’s syndrome by lung carcinoid tumor is associated with growth hormone secretagogue receptor type 1a mRNA expression

GH secretagogues (GHS) have been used for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) since 1997 due to their ability to increase ACTH and cortisol levels in Cushing's disease. The aim of this study was to correlate ACTH response to GH-releasing peptide-6 (GHRP-6) in vivo with GH secretagogue receptor type 1a (GHSR-1a) mRNA expression in a patient with lung carcinoid tumor. The patient was a 26-yr-old male with diagnosis of ACTH-dependent CS. He presented negative responses to human CRH and desmopressin tests; yet, a significant increase in ACTH after the GHRP-6 test was observed. Sellar magnetic resonance imaging (MRI) showed slight posterior hypointensity, but bilateral petrosal sinus sampling did not show central gradient. Computed tomography (CT) and MRI of thorax/abdomen/cervical were negative and 111In-pentetreotide scintigraphy depicted abnormal uptake on the right lung. The patient was submitted to right thoracotomy for exeresis of lung nodule and hilar lymph node which were characterized as atypical lung carcinoid tumor and he presented clinical and laboratorial remission after surgery. GHSR-1a mRNA expression was studied with real-time quantitative PCR and tumor data were compared with fragments of normal lung and pituitary. There was a higher GHSR-1a expression in the lung carcinoid tumor as compared with normal tissues. The ACTH response to GHRP-6 in a patient with ectopic ACTH production by a lung carcinoid tumor was associated with GHSR-1a expression in the tumor tissue, suggesting an association between GHSR-1a mRNA overexpression and the in vivo response to GHS.

ACTH Measured by Immunoradiometric Assay (IRMA) Offers Similar Diagnostic Accuracy Compared with Radioimmunoassay (RIA) During the Differential Diagnosis of Cushing's Syndrome

Measurement of plasma ACTH levels by RIA was originally used to identify adrenal causes (AA) of Cushing's syndrome (CS) and for the differential diagnosis of ACTH-dependent CS with ovine corticotropin-releasing hormone (CRH) stimulation testing and inferior petrosal sinus sampling (IPSS). It is unclear whether diagnostic criteria developed with RIA also work for IRMA. Methods: ACTH was measured by RIA and IRMA (Covance Laboratories, Vienna VA) in paired samples i.) basally (63 Cushing's disease (CD), 5 AA, 2 ectopic CS (EAS) and 37 non-CS patients) ii.) in 44 CD patients following CRH (1 μ g/kg i.v.) iii) in 6 EAS and 17 CD patients during IPSS. Results were analyzed using Spearman's rank correlations, the Wilcoxon signed-rank test, linear regression and McNemar's test. Results: i)Basal RIA and IRMA results were highly correlated (r = 0.9, p 2.0 before or ≥3.0 after CRH, IRMA had the same sensitivity (100%) but higher specificity (100% vs 83%, p = 1.0) vs. RIA. Conclusion: ACTH measured by IRMA correlates closely to RIA values and offers similar diagnostic accuracy during the CRH and IPSS testing. However in ACTH samples < 15 pg/ml IRMA probably offers better diagnostic accuracy.