Diagnosis Of Cushing's Syndrome Research Articles

Relevance of inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome: a case report.

Non-specific signs and symptoms of Cushing's syndrome (CS) can pose a diagnostic challenge. We report the case of a man referred to the service of endocrinology for suspected CS. Hypercortisolism was confirmed on CS screening tests, whereas diagnostic tests confirmed the presence of adrenocorticotropin (ACTH) -dependent CS. The corticotropin-releasing hormone stimulation (CRH) test was performed to determine whether CS hadan endogenous or ectopic origin. Since the CRH and the magnetic resonance imaging (MRI) test were negative, IPSS was performed and suggested that CS was originated in the pituitary glands. Transsphenoidal pituitary resection was carried out. Histopathological analysis confirmed the cortitotrope origin of the tumor. The etiological study and differential diagnosis of CS are complex processes that involve a variety of biochemical and imaging tests. It is important that a sequence of biochemical screening and diagnostic tests is performed, along with studies for establishing the location of the lesion, to determine whether CS has an adrenal, pituitary or ectopic origin. Despite its good diagnostic performance, the results of biochemical tests may not be conclusive, especially in ACTH-dependent CS. In the case reported, the inconclusive results obtained in the CRH test rendered an invasive procedure (IPSS) necessary, which ultimately confirmed diagnosis.

ODP621 Hypertension with Hypokalemia in Pregnancy? Think "Cushing's Syndrome"

Abstract Introduction Pregnancy is uncommon in women with Cushing's syndrome (CS) as hypercortisolism and hyperandrogenism suppress gonadotropins leading to anovulatory cycles. Such pregnancies carry a higher rate of fetal morbidity and mortality. Therefore, it is of paramount importance to diagnose and treat CS in pregnancy. The diagnosis of CS in pregnancy is challenging due to the physiologic changes of the hypothalamic-pituitary-adrenal axis during pregnancy. We describe a case of CS in pregnancy that was a successfully treated with surgery. Case description An asymptomatic 39-year-old pregnant female patient with gestational hypertension was admitted to the hospital after she was found to have uncontrolled hypertension (while on 3 anti-hypertensive medications) and severe hypokalemia with potassium level of 2.8 mEq/L. She was 14 weeks pregnant at the time. She has a family history of primary aldosteronism in her father successfully treated with adrenalectomy at the age of 60. Her work up included blood work (done at 13: 42) which showed sodium level of 146 mEq/L, plasma aldosterone concentration of <1 ng/dL, plasma renin activity of 1.0 ng/mL/hr, total testosterone of 46 ng/dL, DHEA-S of 31 mcg/dL, plasma metanephrines <50 pg/mL, 24-hour urine metanephrines 70 ug, 24-hour urine normetanephrines 164 ug/24 hrs, ACTH 5 pg/mL, and cortisol 28.2 mcg/dl. MRI abdomen without contrast showed a 3.5×3.0×4.2 cm left adrenal nodule consistent with adenoma. Patient was diagnosed with non-ACTH dependent subclinical CS based on her elevated cortisol and low ACTH levels. She underwent left laparoscopic adrenalectomy and was discharged on oral hydrocortisone. Pathology showed adrenal cortical adenoma. Her blood pressure normalized shortly after surgery and her anti-hypertensive medications were stopped. Discussion Pregnancy is associated with multiple changes in the hypothalamic-pituitary-adrenal axis making diagnosis of CS in pregnancy challenging. Those changes include increased Cortisol binding globulin production leading to increased serum cortisol level and lack of suppression with Dexamethasone beside placental production of CRH and ACTH, all leading to increased salivary and urinary free cortisol levels, as well. This case of hypertension and hypokalemia in pregnancy presented a diagnostic dilemma. Furthermore, the clinical presentation was confounded by a family history of primary aldosteronism. However, the low serum ACTH level highly suggested the diagnosis of CS. Unfortunately, there are no pregnancy-specific guidelines for the diagnosis of CS. The dexamethasone suppression test is not recommended as it often yields false-positive results. The use of urinary free cortisol and late-night salivary cortisol is recommended, and the diagnosis is established when results are three to four times the upper limit of normal. ACTH levels <10 pg/ml are suggestive of adrenal CS. MRI without contrast can be used for imaging. To date, there have been over 260 reported cases of CS in pregnancy with more than half of them being. Presentation: No date and time listed

LBMON176 Management, Safety, And Efficacy Of Osilodrostat Treatment In US Patients With Non-pituitary Cushing's Syndrome: Results From The ILLUSTRATE Study

Abstract Background Osilodrostat, a potent cortisol synthesis inhibitor, demonstrated safety and efficacy in the treatment of Cushing's disease (CD). No information is available describing use of osilodrostat in non-pituitary Cushing's syndrome (CS) in US patients. Data from a real-world study in US patients with non-pituitary CS is presented. Methods The ILLUSTRATE study is a real-world characterization of osilodrostat usage in patients with endogenous CS treated May 1, 2020 - October 29, 2021. Forty-two adult patients with a confirmed diagnosis of endogenous CS and a prescription for osilodrostat were included in this real-world study. We report patient characteristics, osilodrostat dose, efficacy, and safety in the subset of patients with non-pituitary CS (n=8,19%). Results The 8 non-pituitary CS patients enrolled comprised 5 with adrenal CS and 3 with ectopic CS. Baseline urinary free cortisol (UFC) was 2.57–75.2×ULN in patients with ectopic CS, and 0.42–27.76×ULN in the 4 adrenal patients with baseline UFC available. In the adrenal CS patients, starting dose ranged from 1–4 mg daily. In adrenal patients with more than one documented clinical encounter (n=4): 2 remained on starting doses of 1 mg BID and 2 mg BID, 1 increased from 1 mg QD to 2 mg BID on day (D) 50, and 1 increased from 2 mg BID to 4 mg BID on D5 and required down-titration on D18 with treatment interruption on D27. The 3 patients with ectopic CS were all initiated at 2 mg BID: 1 patient's dose was unchanged throughout the observation period, and the other 2 patients were up-titrated, both on D91 to 4 mg BID or 5 mg QD. The two ectopic CS patients with available UFC data experienced substantial UFC | reductions (from 57.1×ULN to 2.9×ULN at D91 and 75.2×ULN to 0. 076×ULN at D134). The one adrenal CS patient with available UFC data and prior medical therapy for CS maintained UFC ≤ ULN during osilodrostat treatment. Osilodrostat was generally well tolerated and one ectopic CS patient had treatment interrupted on D214 for adrenal insufficiency (AI). Two of five adrenal CS patients (40%) had symptoms suggestive of glucocorticoid withdrawal (e. g., fatigue, nausea, and headache) and one had an interruption in therapy. Neither had documented AI. Conclusion In this real-world cohort of patients treated with osilodrostat for non-pituitary CS, large UFC reductions were seen in two patients with ectopic CS. All 8 were initiated on ≤2 mg BID, with 3 (38%) remaining on their original dose. In the majority of those up-titrated, there was an extended titration interval. The observed safety profile in this subset (albeit small) of non-pituitary CS patients was consistent with the known osilodrostat safety profile. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON123 Diagnostically Challenging Case of Cushing's Syndrome from a Pancreatic Neuroendocrine Tumor Treated with Radiofrequency Ablation

Abstract Background The delayed diagnosis of Cushing's syndrome (CS) results in advanced disease, treatment delays and poor outcomes. We present a patient with ectopic ACTH-syndrome (EAS) from a pancreatic neuroendocrine tumor (NET) whose care posed significant diagnostic and therapeutic challenges. Clinical Case 59F with classic Cushing's stigmata (including striae, plethora, supraclavicular and dorsocervical fat pads, muscle wasting), and two-year history of rapid weight gain, hypertension, T2DM, hyperlipidemia, severe osteoporosis complicated by multiple vertebral compression fractures, presented for workup and management of ACTH dependent CS. CS was confirmed (Baseline: ACTH 96 [7.2-63.3 pg/ml], serum cortisol 19.6 [4.8 - 19.5 mcg/dL]; LDSST: cortisol 18.5 [<1.8 mcg/dL], dexamethasone 547 [>200 ng/dL]; 24-hour Urine Free Cortisol: 191.60 [<45 mcg/d], 24-hour Cr 484 mg/day; LNSC: 436, 464 [29-101 ng/dL]; 8 mg ODST cortisol 7.2 mcg/dL). Pituitary MRI showed possible 0.5 cm left anterior pituitary lesion. Inferior petrosal sinus sampling (IPSS) to differentiate between Cushing's disease and EAS was initially planned, however, her course was complicated by an NSTEMI and acute/subacute lacunar infarcts in the left parietal and frontal lobes, and IPSS was deemed contraindicated. Additional workup was pursued including POMC 154 [<40 fmol/ml], Chromogranin A 538 [0-103 ng/ml] (on pantoprazole), pancreatic polypeptide 798 [0 - 435 pg/mL], 24-hour 5HIAA/Creatinine 3 [0 - 15 mg/24hr]. Chest/Abdominal/Pelvis CT showed a 1.5 cm incidental lipid rich adrenal adenoma; workup was negative for pheochromocytoma/ Conn's tumor/ adrenocortical carcinoma. Given elevated POMC and clinical suspicion for EAS, the patient underwent 68Ga-DOTATATE PET-CT scan which revealed an avid 7 mm lesion (SUVmax 14.5) in the pancreatic tail suspicious for a pancreatic NET- the presumed ectopic source of ACTH. Given the patient's poor functional status she was not a candidate for tumoral resection via distal pancreatectomy. Ketoconazole was initiated for treatment of hypercortisolism with good biochemical control, but the patient developed liver toxicity. The decision was made to pursue endoscopic ultrasound guided biopsy and radiofrequency ablation of the lesion. Pathology confirmed ACTH immunoreactive low-grade pancreatic NET. Post-procedure, morning ACTH was 8 pg/ml and cortisol was 9.1 mcg/dL, and the patient required steroids for relative adrenal insufficiency. Further follow up with repeat POMC, cortisol, ACTH levels, 24-hour UFC is required to monitor response. Conclusion IPSS is the gold standard test for differentiating Cushing's disease from EAS but is only available in select centers and for suitable candidates. This case supports the potential utility of POMC peptide measurements in the differential diagnosis of CS and the use of advanced nuclear imaging modalities for tumor localization. For patients with functional pNET who are poor surgical candidates or intolerant of pharmacotherapy, novel endoscopic ablation may offer a lower risk therapeutic option and its use should be further investigated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Ectopic-Adrenocorticotropic Hormone secretion in adolescents and young adult patients with neuroendocrine neoplasm: a challenge for clinical and social management

Well and poorly differentiated neuroendocrine neoplasms (NENs) may be associated with an ectopic production of Adrenocorticotropic Hormone (ACTH) [1] that leads to a paraneoplastic Cushing Syndrome (CS). This heterogeneous clinical pattern is the result of a hypercortisolism [2] due to an uncontrolled and continuous hyperstimulation of the adrenal cortex, which escapes the negative feedback of the Hypothalamus-Hypophysis axis [3]. Among NENs, ectopic-ACTH secretion (EAS) has been historically associated with small-cell lung cancers (SCLCs), but the improvement of the knowledge and diagnostic techniques led to a broadening of the causes also to NENs with different morphologies and from other sites [4]. According to the previous published data, EAS by gastro-entero-pancreatic (GEP) NENs occurs in almost 13% of cases. Irrespective of the NENs site of origin and the biology (which means morphology and proliferation index), the CS may represent a life-threatening condition for the patients due the consequences of the mineralocorticoid effect of persistent high levels of cortisol. These patients may experience a plethora of different symptoms which includes diffuse oedema, overweight/obesity of the trunk and striae rubrae, but also severe hypokalemia and hypertension, that represent medical emergencies and tumor fatal consequences even without a progression disease [1]. EAS may initially occur with non-specific clinical manifestations, as psychiatric complaints, recurrent orthopedic issues, sexual and reproductive disfunctions [3] that are not easily related to a tumoral cause and lead the patient presents to many specialists before being referred to an endocrinology / oncology Center. For all these reasons, CS diagnosis is often delayed. In a very small pool of cases [5], EAS may occur in the peculiar category of the adolescents and young adults (AYA) patients, worldwide defined as the cancerpopulation between 15 and 39 years of age [6]. Generally, the cancer diagnosis in AYA population is delayed, on one hand due to the sense of invulnerability and the minimizing of the symptoms of AYA patients and, on the other, the trend of the providers to a low suspicion of cancer in AYA population. Therefore, the features of the AYA category together with the equivocal clinical patterns of CS may lead to a delay of the diagnosis and management of EAS by extra-pituitary NENs [3, 7]. Here we reported the case of a NEN AYA patient with CS by EAS and a review of the literature on this topic in this peculiar population.

White blood cell count: a valuable tool for suspecting Cushing's syndrome.

Simple screening tests to determine whether Cushing's syndrome (CS) should be ruled out are lacking. Tools that enable early diagnosis could reduce morbidity and associated sequelae. The potential of glucocorticoid-induced changes in the white blood cell (WBC) count for raising suspicion of CS is assessed. This was a retrospective case‒control study. The WBC counts of 73 cases with CS and 146 matched controls were compared. The number of leukocytes (Leu), the number and percentage of neutrophils (N, Np), the number and percentage of lymphocytes (L, Lp), neutrophil-to-lymphocyte differences in the number and percentage (N-L, Np-Lp), neutrophil-to-lymphocyte ratio in the number and percentage (NLR, NLRp), and leukocyte-to-lymphocyte differences (Leu-L) were evaluated. The area under the ROC curve (AUC) was calculated for each of these parameters. Reference values were estimated that could help disclose occult CS. All ten parameters showed significant differences between cases and controls. The AUC was greater than 0.7 for all ten parameters, and was the best for the NLRp and Lp (AUC: 0.89). An Lp of 23.9% showed a diagnostic accuracy of 84.9% for the diagnosis of CS. The concordance of an Lp below 24% and more than 8000 leucocytes had a PPV of 78.2% for CS, while the pairing of an Lp over 24% and a Leu below 8000 cells had an NPV of 97.3% for CS. WBC count assessment can be an effective tool to raise suspicion of CS, prompting diagnostic testing. This simple and universally available test may allow earlier diagnosis of CS before highly evolved phenotypes develop.

Diagnostic workup of Cushing's syndrome.

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late- night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH-dependent and non-ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non-ACTH dependent forms. Differentiation between the ACTH-dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS.

Overnight 1mg dexamethasone suppression test and 24h urine free cortisol-accuracy and pitfalls when screening for Cushing's syndrome.

Diagnosis of Cushing's syndrome (CS) is often delayed due to variable clinical features and its rarity. Simple and accurate screening tests are required to enhance screening for hypercortisolism. Both overnight 1mg dexamethasone suppression test (DST) and urinary free cortisol (UFC) demonstrate high sensitivity and specificity for the diagnosis of CS. However, each test has its own distinctive features, making it preferable in specific clinical conditions. This review will discuss the pitfalls for each of those tests.

Endogenous Cushing's syndrome during pregnancy.

Endogenous Cushing's syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism.

ADENOCARCINOMA OF THE ADRENAL GLAND IN A FEMALE DOG

The aim of this article is to describe a case of adrenocortical neoplasm with manifestation of hyperadrenocorticism. Adrenocortical tumors originate from different types of cells and present varied clinical manifestations, which can be functional or non-functional. Adenocarcinomas are autonomous and functional in most cases, leading to excessive secretion of glucocorticoids, regardless of pituitary control. They corroborate the occurrence of hyperadrenocorticism (HAC) due to interference in the synthesis of cortisol. Clinical signs can be observed, as polyuria, compensatory polydipsia, polyphagia, blood pressure alterations, cardiac, renal and endocrine dysfunctions, among others. Diagnosis can be made in various ways, such as urinary cortisol measurements, adrenocorticotropic hormone stimulation, low-dose dexamethasone suppression tests, and imaging tests and histopathology. This article reports the case of a 13-year-old mixed-breed female dog with signs of polyuria and polydpsia. After discarding the initial diagnoses (diabetes mellitus and/or renal alterations), HAC was suspected, with further tests being performed. The test results showed an increase in the adrenal region, and adrenalectomy and hormone replacement with trilostane were recommended. The diagnosis of HAC was confirmed by histopathology as HAC secondary to adrenal gland adenocarcinoma. The patient also developed diabetes mellitus during postoperative treatment with prednisone, which made it necessary to discontinue the medication.

Midnight ACTH vs morning ACTH levels in Cushing's syndrome diagnosis

Midnight ACTH vs morning ACTH levels in Cushing's syndrome diagnosis

Abstract #1183815: Diagnosis of Cushing’s Disease Post Bariatric Surgery

Obesity is a major risk factor for the development of metabolic comorbidities and is the leading cause of preventable death. Despite recent advances in pharmacotherapy, bariatric surgery (BS) remains the most effective treatment for obesity, leading to weight loss and improvement of metabolic comorbidities. The preoperative evaluation for BS does not recommend for the routine screening of secondary causes for weight gain such as hypercortisolism, unless clinically indicated. The diagnosis of Cushing syndrome can be challenging and many BS patients do not see an endocrinologist preoperatively.

Abstract #1160337: Mifepristone Use in Hypercortisolism from an Unknown Source: A Case Study

The diagnosis of Cushing syndrome (CS) can be challenging because clinical features overlap with numerous common disorders, the sensitivity and specificity of diagnostic tests are imperfect, and discordant biochemical findings are often obtained. Diagnosis and management are further complicated if a source of hypercortisolism is not readily apparent. We describe the medical management of a patient with suspected CS, whose initial evaluation did not reveal a source.

Usefulness of 68 Ga-Pentixafor PET/CT on Diagnosis and Management of Cushing Syndrome.

This pilot study investigated the performance of C-X-C motif chemokine receptor 4 (CXCR4) molecular imaging ( 68 Ga-pentixafor PET/CT) in Cushing syndrome (CS) and the correlation between CXCR4 signaling interactions and glucose metabolism in adrenocorticotropin-cortisol pathway. We retrospectively evaluated 31 patients (16 patients with CS and 15 patients with nonfunctioning pituitary or adrenal adenomas). All patients underwent 68 Ga-pentixafor PET/CT, and 11 with pituitary adenoma also underwent 18 F-FDG PET/CT. The diagnosis accuracy of 68 Ga-pentixafor PET/CT was calculated. The correlation between radiouptake along the pituitary-adrenal axis and hormone levels was calculated. Patients with Cushing disease characterized a focal uptake in adrenocorticotropic hormone-producing pituitary adenoma (ACTH-PA). In ACTH-independent CS, there was increased uptake of 68 Ga-pentixafor in adrenal lesions but not in the pituitary fossa. The nonfunctioning pituitary or adrenal adenomas showed negative 68 Ga-pentixafor signal. The one patient with metastatic ectopic ACTH syndrome had multiple 68 Ga-pentixafor-avid lesions. Using the threshold of SUV max >8.5 in the adrenal lesions, the sensitivity and specificity of 68 Ga-pentixafor PET/CT to diagnose cortisol-producing adenoma were 100% and 84.9%. A cutoff SUV max value of 3.0 on 68 Ga-pentixafor PET/CT had 100% sensitivity and specificity for differentiating ACTH-PA. The corresponding hormone level was significantly correlated with uptake of 68 Ga-pentixafor in pituitary adenoma and adrenal tissue but not with glucose metabolism. We have characterized the performance of 68 Ga-pentixafor in different subtypes of CS. 68 Ga-pentixafor PET/CT is promising in the differential diagnosis of both ACTH-independent and ACTH-dependent CS. Activated CXCR4 molecular signaling along the pituitary-adrenal axis was found in patients with Cushing disease.

The Importance of DHEA-S Levels in Cushing's Syndrome; Is There a Cut-off Value in the Differential Diagnosis?

The purpose of this study was to determine possible cut-off levels of basal DHEA-S percentile rank in the differential diagnosis of patients with Cushing's syndrome (CS) with ACTH levels in the gray zone and normal DHEA-S levels. In this retrospective study including 623 pathologically confirmed CS, the DHEA-S percentile rank was calculated in 389 patients with DHEA-S levels within reference interval. The patients were classified as group 1 (n=265 Cushing's disease; CD), group 2 (n=104 adrenal CS) and group 3 (n=20 ectopic ACTH syndrome).ROC-curve analyses were used to calculate the optimal cut-off level of DHEA-S percentile rank in the reference interval in the differential diagnosis of CS, and the effectiveness of this cut-off level in the identification of the accurate etiology of CS was assessed in patients who were in gray zone according to their ACTH levels. The DHEA-S percentile rank in the reference interval were significantly lower in group 2 compared to the other two groups (p<0.001), while group 1 and group 3 had similar levels. The optimal cut-off level of DHEA-S percentile rank in the reference interval providing differential diagnosis between group 1 and group 2 was calculated as 19.5th percentile (80.8% sensitivity, 81.5% specificity) and the level demonstrated the accurate etiology in 100% of CD and 76% of adrenal CS patients who were in the gray zone. This study showed that the cut-off value of DHEA-S level less than 20% of the reference interval could be used for differential diagnosis of CD and adrenal CS with high sensitivity and specificity, and it should be taken into the initial evaluation.

Achados ultrassonográficos em cães diagnosticados com hiperadrenocorticismo – estudo retrospectivo (2013 a 2020)

Hyperadrenocorticism is a relatively common endocrinopathy in middle-aged and older dogs, which has become increasingly frequent in the clinical routine. The diagnosis is made by information obtained by history, physical exam findings and results of screening and specific endocrine tests. In addition to laboratory tests, imaging diagnosis, such as ultrasound, can aid on evaluation of possible changes in these cases; also, they may reveal the possible involvement of other organs and systems. The aim of this study was to present the main ultrasonographic changes observed in 18 dogs with hyperadrenocorticism, diagnosed from 2013 to 2020 by the low-dose dexamethasone suppression test, among which hepatomegaly, splenomegaly, gallbladder sludge, renal changes, cystitis and changes in adrenal size, such as bilateral and/or unilateral adrenomegaly, can be cited. Ultrasound examination, therefore, is an examination that can help the clinician in confirming the diagnosis of hyperadrenocorticism, in addition to allowing differentiation between pituitary-dependent hyperadrenocorticism (PDH) and adrenal tumors, and the evaluation of possible secondary changes to the disease.

Diurnal Salivary Cortisol Profiles in Patients with Cushing's Syndrome.

Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing's syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping. Among 428 patients including those with confirmed Cushing's syndrome (N=111, of those 75 with Cushing's disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day. At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing's disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low. The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS.

Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome.

Endogenous Cushing's syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed "Cushing's disease") and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

Second-Line Tests in the Diagnosis of Adrenocorticotropic Hormone-Dependent Hypercortisolism.

Cushing’s syndrome (CS) is a rare disease caused by chronic and excessive cortisol secretion. When adrenocorticotropin hormone (ACTH) is measurable, autonomous adrenal cortisol secretion could be reasonably ruled out in a differential diagnosis of CS. ACTH-dependent CS accounts for 80%–85% of cases and involves cortisol production stimulated by uncontrolled pituitary or ectopic ACTH secretion. Pituitary adenoma is not detected in up to one-third of cases with pituitary ACTH secretion, whereas cases of CS due to ectopic ACTH secretion may be associated with either malignant neoplasia (such as small cell lung carcinoma) or less aggressive neuroendocrine tumors, exhibiting only the typical symptoms and signs of CS. Since the differential diagnosis of ACTH-dependent CS may be a challenge, many strategies have been proposed. Since none of the available tests show 100% diagnostic accuracy, a step-by-step approach combining several diagnostic tools and a multidisciplinary evaluation in a referral center is suggested. In this review, we present a clinical case to demonstrate the diagnostic work-up of ACTH-dependent CS. We describe the most commonly used dynamic tests, as well as the applications of conventional or nuclear imaging and invasive procedures.

An Optimized Pathway for the Differential Diagnosis of ACTH-Dependent Cushing's Syndrome Based on Low-Dose Dexamethasone Suppression Test.

ContextTraditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing’s syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing’s disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial.ObjectivesTo develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST.Design and SettingSingle-center retrospective study (2011–2019).PatientsTwo hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST.ResultsFor the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of <26%, the sensitivity and specificity of LDDST were 39.4% and 100%. We designed a new pathway in which BIPSS was only reserved for those patients with unsuppressed LDDST and adenoma <6mm, yielding an overall sensitivity of 97.7% and specificity of 86.7%.ConclusionLDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately.