The conundrum of differentiating Cushing's syndrome from non-neoplastic hypercortisolism: a systematic review and meta-analysis.

CONTEXT: Once hypercortisolemia is confirmed, differential diagnosis between Cushing's syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing's syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed. OBJECTIVE: Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH. METHODS: Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist. DATA SYNTHESIS: A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87-94%; I2 0%) and 82% (73-88%; I2 50%), desmopressin test 86% (81-90%; I2 28%) and 90% (84-94%; I2 15%), MSC 91% (85-94%; I2 66%) and 81% (70-89%; I2 71%), and LNSC 80% (67-89%; I2 57%) and 90% (84-93%; I2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate. CONCLUSION: Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians' confidence when deciding which test to perform.

COEXISTENCE OF PHEOCHROMOCYTOMA AND HYPERCORTISOLEMIA. DIAGNOSTIC DIFFICULTIES.

OBJECTIVE: Aim: Our study aimed to present diagnostic problems in the case of hypercortisolism, pheochromocytoma, hypertension, type 2 diabetes, and chronic kidney disease. PATIENTS AND METHODS: Materials and Methods: Description of a patient with resistant hypertension admitted to the Department of Endocrinology for hormonal diagnostics. The results of hormonal tests and imaging tests before the procedure were analyzed, and the patient's condition was checked after the procedure. The analysis was extended with a literature review, considering the diagnostic problems in the described case. Electronic databases were the primary way to search, mainly MEDLINE and PubMed. We described a case of a 61-year-old woman diagnosed with right adrenal pheochromocytoma, hypercortisolemia, chronic kidney disease, drug-resistant hypertension, type 2 diabetes, and hypercholesterolemia. During hospitalization in the Department of Endocrinology, i.a., imaging tests and tests to assess adrenal function were performed. During the diagnostic process, a decision was made to perform surgical treatment of the pheochromocytoma, resulting in clinical improvement of the patient's condition. CONCLUSION: Conclusions: The described case presents diagnostic problems endocrinologists face in the coexistence of several diseases. Often, the diagnosis to make a final diagnosis is complicated, hindered by the patient's multi-morbidity, as well as by the medications taken. There are few studies analyzing the coexistence of the diseases as described by us and their impact on the results of diagnostic tests that would facilitate the diagnosis.

[Pitfalls in the diagnosis of hypercortisolemia]. / Pulapki diagnostyczne w hiperkortyzolemii.

Cushing's syndrome (CS) is relatively rare disorder affecting 2-5 per million per year, although the issue of establishing the diagnosis of CS and differential diagnosis of the disease are a significant clinical problem. CS is usually the result of excessive exogenous glucocorticoids usage (iatrogenic CS), endogenous CS can be divided into ACTH-dependent and ACTH-independent. Regardless of its etiology, the most important steps in establishing the diagnosis of CS are taking careful history and examination. The symptoms with high discriminatory value are myopathy, reddish purple striae, easy bruising and plethora. Knowledge of the pathomechanisms leading to the development of CS symptoms, facilitates establishing the diagnosis and understanding the importance of early diagnosis. Although the sensitivity and specificity of laboratory test have increased and imaging techniques developed, establishing the diagnosis of CS is still a challenging problem in clinical practice. When choosing appropriate diagnostic test we should remember of both advantages and limitations of each of them. The increasing popularity of late night/midnight salivary cortisol measurement as a first line diagnostic test is observed, also urinary free cortisol measurement, 1mg dexamethasone overnight suppression test and midnight serum cortisol measurement are used in the initial testing for hypercortisolemia. Subclinical CS as well as cyclical or episodic CS may be challenging especially. Another diagnostic problem is differentiation between functional hypercortisolism (pseudo-Cushing's syndrome) and pathological hypercortisolism with organic changes (CS). Right and early diagnosis is of vital importance in patients with CS because of large extent of complications resulting from untreated hypercortisolemia. In the course of CS many different organs and systems can be affected, leading to increase in total morbidity and mortality.

Accuracy of the 10 µg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis.

We evaluated the accuracy of the 10 µg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85634, identifier CRD42018085634; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68317, identifier CRD42017068317.

Pseudo-Cushing Syndrome With an Atypically High Cortisol Burden and Clinical Improvement With Adrenal Enzyme Inhibitor.

Distinguishing between Cushing syndrome (CS) and pseudo Cushing syndrome (PCS), also known as physiological hypercortisolism, can be difficult. PCS is caused by nonneoplastic overactivity of the hypothalamic-pituitary-adrenal axis and may be secondary to a range of conditions, including obesity, physical stress, malnutrition, and chronic alcoholism, and typically results in a lesser degree of hypercortisolism and fewer clinical features than CS. Management of PCS includes treatment of the underlying cause and reassessment of hypercortisolemia following improvement in the underlying etiology, as this may result in normalization of cortisol levels. The role of adrenal enzyme inhibitors in lowering cortisol levels in those with PCS is poorly understood. We report a case of a man presenting with weight loss who was found to have severe hypercortisolemia and elevated adrenocorticotropin (ACTH) complicated by infection, neuropsychiatric disturbance, and hypokalemia. Despite high cortisol levels, he was phenotypically not cushingoid, and the circadian rhythm of cortisol was preserved. Extensive investigations did not demonstrate a cause of symptoms or source of ACTH. Medical management with ketoconazole improved neuropsychiatric symptoms, and weight gain with nasogastric feeds resulted in the normalization of cortisol levels and resolution of symptoms following ketoconazole cessation.

Emerging diagnostic methods and imaging modalities in cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Impaired dexamethasone resorption in two patients with pseudo-Cushing after bariatric surgery: Implications for immunosuppressive treatment.

Two cases of middle-aged female patients treated by gastric bypass surgery for weight loss presented to our clinic for a follow-up examination 3-6 months after the surgical procedure (a mini gastric bypass and a modified single anastomosis sleeve-ileostomy). In both patients increased ACTH levels and either high serum cortisol or an increased urinary cortisol excretion was apparent and triggered further endocrine testing. Serum cortisol could not be suppressed adequately by 2 and 4 mg dexamethasone in the standardized oral overnight suppression test while midnight salivary cortisol dropped well below the desired cut-off. This led to the hypothesis of an impaired dexamethasone resorption and could be further substantiated by suppression of serum cortisol below the cut-off by an intravenous dexamethasone application. The data presented point to an impairment of enteral synthetic corticosteroid resorption in patients after gastric bypass surgery and could be of importance for individuals in need for immunosuppressive treatment. In view of the growing number of bariatric procedures, pharmacokinetics of corticosteroids and other drugs should be tested in clinical trials.

Approach to patients with pseudo-Cushing's states.

The distinction between pseudo-Cushing's states (PCS) and Cushing's syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient's clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient's hormone status will ultimately orient the diagnosis and treatment options over time.

Glycogen storage disease presenting as Cushing syndrome.

Impaired growth is common in patients with glycogen storage disease (GSD), who also may have "cherubic" facies similar to the "moon" facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic-pituitary-adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2, leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was "appropriate" and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin-releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo-CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed "stress-induced Cushing (SIC) syndrome" to distinguish it from the other causes of CS and pseudo-CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

Hypokalemia associated with pseudo-Cushing's syndrome and magnesium deficiency induced by chronic alcohol abuse.

Hypokalemia and hypomagnesemia are frequently observed in patients with chronic alcoholism. However, the involvement of deranged cortisol regulation in patients with those conditions has not been reported. A 63-year-old Japanese male with chronic alcoholism was referred to the Department of Diabetes, Endocrinology and Metabolism for examination and treatment of hypokalemic periodic paralysis. Laboratory findings showed hypokalemia (2.3 mmol/l), as well as a high level of urinary excretion of potassium and hypomagnesemia (1.2 mg/dl), whereas urinary excretion of magnesium was undetectable. Potassium infusion treatment recovered that level in serum to 4.1 mmol/l, though it decreased to 2.2 mmol/l following discontinuation. A dexamethasone suppression test and urinary cortisol level showed corticotropin-dependent hypercortisolemia. However, gadolinium-enhanced MRI revealed no evidence of pituitary adenoma. The patient recovered from hypokalemia following an administration of magnesium in addition to potassium, which was accompanied by potassium over-excretion improvement. After being discharged, serum potassium level was maintained within a normal range with only magnesium infusion treatment. Furthermore, alcohol intake was reduced from 160 to 20 g/day and an endocrinological re-examination after that restriction showed normal cortisol regulation. The patient was diagnosed with pseudo-Cushing's syndrome induced by alcohol abuse. Serum potassium level was maintained within a normal range even after discontinuation of magnesium supplementation. Our findings in this case indicate that pseudo-Cushing's syndrome in conjunction with hypomagnesemia may be involved in development of hypokalemia in patients with chronic alcoholism.

The difficulties of pseudo-Cushing's syndrome (or "non-neoplastic hypercortisolism").

Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH-secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end-stage kidney disease. Glucocorticoid resistance is one differential diagnosis, as are some cases of primary adrenal disease with incompletely suppressed ACTH. Differentiating between NNH and mild-to-moderate Cushing's disease can be a real challenge. Clinical analysis, based on thorough history taking and screening for catabolic signs is essential; useful explorations include midnight serum or salivary cortisol and Dex/CRH and ddAVP stimulation response. Pituitary MRI suffers from limitations regarding both sensitivity and specificity, while bilateral inferior petrosal sinus sampling cannot distinguish between pituitary ACTH secretion by a tumor or by normal cells stimulated by endogenous CRH. Definitive diagnosis of functional etiology requires demonstrating that treatment of the underlying condition restores normal secretion of ACTH and cortisol, but this is not always possible. Lingering diagnostic uncertainty has to be accepted in certain patients, who will have to be followed up for some time before diagnosis can be considered more or less definitive.

Performance of the 4-mg intravenous dexamethasone suppression test in differentiating Cushing disease from pseudo-Cushing syndrome.

CONTEXT: Discriminating Cushing disease (CD) from pseudo-Cushing syndrome (PCS) is a challenging task that may be overcome with the 4-mg intravenous (IV) dexamethasone suppression test (DST). OBJECTIVE: Assess the performance of the 4-mg IV DST in the differential diagnosis between CD and PCS in well-characterized patients. DESIGN: Retrospective comparative study of subjects seen in a tertiary care unit (November 2008 to July 2011). METHODS: Thirty-six patients with PCS and 32 patients with CD underwent 4-mg IV dexamethasone infusions from 11 am to 3 pm. Areas Under ROC Curves (AUCs) were estimated and compared for ACTH and cortisol measured at 4 pm the same day (day 1) and 8 am the next day (day 2). The ROC curve of the marker with the highest AUC was used to determine the threshold with the highest specificity for 100% sensitivity. RESULTS: The AUC of ACTH at 8 am on day 2 was estimated at 98.4% (95% CI: [92.1-100]), which is significantly greater than that of ACTH at 4 pm on day 1 (P=0.04) and that of cortisol at 8 am on day 2 (P=0.05). For ACTH at 8 am on day 2, the threshold with the highest specificity for 100% sensitivity was estimated at 14.8 ng/L. At this threshold, the sensitivity was estimated at 100% [89-100] and the specificity at 83.3% [67-94]. CONCLUSION: The 4-mg IV DST is an easy and accurate tool in distinguishing CD from PCS. It deserves thus a better place in establishing the diagnosis of CD.

Reassessing the reliability of the salivary cortisol assay for the diagnosis of Cushing syndrome.

OBJECTIVE: The cortisol concentration in saliva is 10-fold lower than total serum cortisol and accurately reflects the serum concentration, both levels being lowest around midnight. The salivary cortisol assay measures free cortisol and is unaffected by confounding factors. This study analysed published data on the sensitivity and specificity of salivary cortisol levels in the diagnosis of Cushing syndrome. METHODS: Data from studies on the use of different salivary cortisol assay techniques in the diagnosis of Cushing syndrome, published between 1998 and 2012 and retrieved using Ovid MEDLINE®, were analysed for variance and correlation. RESULTS: For the 11 studies analysed, mean sensitivity and specificity of the salivary cortisol assay were both >90%. Repeated measurements were easily made with this assay, enabling improved diagnostic accuracy in comparison with total serum cortisol measurements. CONCLUSIONS: This analysis confirms the reliability of the saliva cortisol assay as pragmatic tool for the accurate diagnosis of Cushing syndrome. With many countries reporting a rising prevalence of metabolic syndrome, diabetes and obesity--in which there is often a high circulating cortisol level--salivary cortisol measurement will help distinguish these states from Cushing syndrome.

Estados de pseudo-Cushing: [revisão] / Pseudo-Cushing states: [review]

Síndromes de pseudo-Cushing são um grupo heterogêneo de doenças, incluindo alcoolismo, anorexia nervosa, obesidade visceral e depressão, que compartilham muitas das características clínicas e bioquímicas da síndrome de Cushing. Os mecanismos responsáveis para a gênese da síndrome de pseudo-Cushing são fracamente compreendidos. Tem sido sugerido que o hipercortisolismo da síndrome de pseudo-Cushing pode ser resultante do aumento da secreção do hormônio liberador de corticotrofina (CRH) hipotalâmico no contexto de um eixo hipotálamo-hipofisário-adrenal que, de outra maneira, está normalmente constituído. A sobreposição substancial entre as características clínicas e laboratoriais entre muitos pacientes com síndrome de Cushing e aqueles com síndrome de pseudo-Cushing pode tornar o diagnóstico diferencial difícil. Distinguir entre síndrome de pseudo-Cushing e síndrome de Cushing verdadeira é crítico para se prevenir o tratamento desnecessário e potencialmente prejudicial de tais pacientes. Esta breve revisão sumariza os principais eventos patofisiológicos das síndromes de pseudo-Cushing e fornece uma estratégia útil para o seu diagnóstico diferencial.

Pseudo-Cushing syndromes are a heterogeneous group of disorders, including alcoholism, anorexia nervosa, visceral obesity, and depression, which share many of the clinical and biochemical features of Cushing's syndrome. The mechanisms responsible for the genesis of pseudo-Cushing's syndrome are poorly understood. It has been suggested that hypercortisolism of pseudo-Cushing syndrome may be the result of increased hypothalamic corticotrophin-releasing hormone (CRH) secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical and biochemical features among several patients with Cushing syndrome and those with pseudo-Cushing syndromes can make the differential diagnosis difficult. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. This brief review summarizes the main pathophysiological events of pseudo-Cushing syndromes and provides a useful strategy for differential diagnosis.