Ty B. Carroll

Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis.

OBJECTIVE To report a meta-analysis of late-night salivary cortisol testing for the diagnosis of Cushing syndrome. METHODS MEDLINE and EMBASE computer databases were searched to identify relevant articles published between January 1950 and December 2007. The search strategy used the following medical subject headings and keywords: cortisol, Cushing or Cushings, saliva, salivary, late-night, nocturnal, and nighttime. The results were limited to studies in humans older than 18 years. Titles and abstracts of all articles, as well as full text of relevant articles, were reviewed. Sensitivity, specificity, likelihood ratio positive, likelihood ratio negative, and diagnostic odds ratio were extracted by 2 authors. Discrepancies were resolved by mediation and discussion with a third author. RESULTS Seven articles contained sufficient information to be included in the analysis. A total of 947 patients (339 with Cushing syndrome) were identified. Pooled data from the 7 studies revealed a sensitivity of 92% (95% confidence interval [CI], 88%-94%), specificity of 96% (95% CI, 94%-97%), and diagnostic odds ratio of 311 (95% CI, 92-1059). Likelihood ratio positive was 21 (95% CI, 10-43), with a likelihood ratio negative of 0.08 (95% CI, 0.02-0.32). Inconsistencies for each of these results measured by the I2 statistic ranged from moderate to high. CONCLUSION This analysis demonstrates that late night salivary cortisol has excellent diagnostic characteristics and as such, is a robust, convenient test for screening and diagnosis of Cushing syndrome.

Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome

Making a definite diagnosis of Cushings syndrome is a challenging problem. Unsuspected Cushings syndrome occurs in 2–3% of patients with poorly controlled diabetes, 0.5–1% with hypertension, 6–9% with incidental adrenal masses, and 11% with unexplained osteoporosis and vertebral fractures. The increasing recognition of this syndrome highlights the need for a simple, sensitive, and specific diagnostic test. Patients with Cushings syndrome consistently do not reach a normal nadir of cortisol secretion at night. The measurement of late-night salivary cortisol levels might, therefore, provide a new diagnostic approach for this disorder. Salivary cortisol concentrations reflect those of active free cortisol in plasma and saliva samples can easily be obtained in a nonstressful environment (e.g. at home). Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for Cushings syndrome, with a sensitivity of 92–100% and a specificity of 93–100%. Several factors can, however, make interpretation of results difficult; these factors include disturbed sleep–wake cycles, contamination of samples (particularly by topical corticosteroids), and illnesses known to cause physiologic activation of the pituitary–adrenal axis. In this Review, we discuss the methods and value of measuring salivary cortisol for the diagnosis of Cushings syndrome, and put forward some recommendations to maximize accuracy of results.

Cushing's syndrome: from physiological principles to diagnosis and clinical care

The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin‐releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic–pituitary–adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism – Cushings syndrome. Endogenous Cushings syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH‐secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushings disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol‐secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushings syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms.

POSTSURGICAL RECURRENT CUSHING DISEASE: CLINICAL BENEFIT OF EARLY INTERVENTION IN PATIENTS WITH NORMAL URINARY FREE CORTISOL

OBJECTIVE To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC). METHODS The design was a single-center, retrospective chart review. Patients treated by the authors from 2008-2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST). RESULTS We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements. CONCLUSION LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker. ABBREVIATIONS ACTH = adrenocorticotropic hormone CD = Cushing disease CS = Cushing syndrome CV = coefficient of variation DST = dexamethasone suppression test IPSS = inferior petrosal sinus sampling LNSC = late-night salivary cortisol QoL = quality of life TSS = transsphenoidal adenoma resection UFC = urinary free cortisol.

Cushing's syndrome of nonpituitary causes

Purpose of reviewCushings syndrome is being recognized with greater frequency and in patients with milder disease. Many of these individuals have nonpituitary causes of their hypercortisolism. This review discusses the classification, presentation, diagnosis, and therapy of patients with Cushings syndrome from nonpituitary causes. Recent findingsMany previously unrecognized or poorly understood causes of Cushings syndrome have been elucidated. It is now appreciated that essentially any form of exogenous glucocorticoid is capable of causing Cushings syndrome. Additionally, new findings have led to a more complete understanding of bilateral nodular adrenal disease. SummaryThe diagnosis of patients with less profound cortisol excess has increased the prevalence of Cushings syndrome and made nonpituitary causes more common. As a result, clinicians must be cognizant of such patients and pursue the diagnosis when appropriate.

Differential Diagnosis of Cushing’s Syndrome

Determining the cause of spontaneous Cushing’s syndrome is essential so that appropriate therapy can be recommended. Most patients (80%) have an ACTH-secreting neoplasm (pituitary or ectopic), while the rest have an adrenal-dependent (ACTH-independent) etiology. After hypercortisolism has been convincingly established, plasma adrenocorticotropic hormone (ACTH) levels are obtained to subdivide Cushing’s syndrome into ACTH-dependent (>20 pg/ml) or ACTH-independent (<5 pg/ml) categories. Corticotropin-releasing hormone (CRH) stimulation testing can help to define these categories when ACTH levels are equivocal (5–20 pg/ml). Since clinical features are unreliable in distinguishing between subtypes of ACTH-dependent and ACTH-independent Cushing’s syndrome, additional biochemical, radiologic, and angiographic tests are needed. Diagnostic accuracy of high-dose dexamethasone suppression testing and CRH stimulation testing are poor when trying to refine the diagnosis of ACTH-dependent Cushing’s syndrome. Bilateral inferior petrosal sinus ACTH sampling with CRH stimulation has become the gold standard in this setting and should be used when magnetic resonance images of the pituitary do not reveal an unequivocal pituitary abnormality in a patient with clinical and biochemical findings consistent with ACTH-dependent Cushing’s syndrome. In patients with ACTH-independent Cushing’s syndrome, computed tomography of the adrenal glands is performed and will demonstrate either a single nodule (benign or malignant) or bilateral nodular hyperplasia caused by several unique pathophysiological mechanisms.

Swallow Syncope in Association with Schatzki Ring and Hypertensive Esophageal Peristalsis: Report of Three Cases and Review of the Literature

Syncope caused by swallowing-induced cardiac arrhythmia is an uncommon condition. The recognition of this syndrome is paramount but often difficult. We report three cases of deglutition syncope evaluated at our institution over a three-year period. Two patients had distal esophageal (Schatzki) ring and two had hypertensive peristaltic waves (commonly referred to as “nutcracker esophagus”), neither of which had been described before in association with deglutition syncope. Two patients underwent placement of a demand cardiac pacemaker with subsequent resolution of their syncopal symptoms, while the third patient refused any further intervention. Swallow syncope usually follows a benign course from a cardiac standpoint. Placement of a demand cardiac pacemaker can prevent recurrence of presyncopal and syncopal attacks and their untoward consequences.

Chemotherapy-Induced Regression of an Adrenocorticotropin-Secreting Pituitary Carcinoma Accompanied by Secondary Adrenal Insufficiency

Purpose. Adrenocorticotropin- (ACTH-) secreting pituitary carcinomas are rare and require multimodality treatment. The aim of this study was to report the response to various therapies and discuss the potential development of secondary adrenal insufficiency with cytotoxic chemotherapy. Methods. This report describes a man with a large silent corticotroph adenoma progressing to endogenous hypercortisolism and metastatic ACTH-secreting pituitary carcinoma over a period of 14 years. Results. Seven years after initial presentation, progressive tumor enlargement associated with the development of hypercortisolism mandated multiple pituitary tumor debulking procedures and radiotherapy. Testing of the Ki-67 proliferation index was markedly high and he developed a hepatic metastasis. Combination therapy with cisplatin and etoposide resulted in a substantial reduction in tumor size, near-complete regression of his liver metastasis, and dramatic decrease in ACTH secretion. This unexpectedly resulted in symptomatic secondary adrenal insufficiency. Conclusions. This is the first reported case of secondary adrenal insufficiency after use of cytotoxic chemotherapy for metastatic ACTH-secreting pituitary carcinoma. High proliferative indices may be predictive of dramatic responses to chemotherapy. Given the potential for such responses, the development of secondary adrenal insufficiency may occur and patients should be monitored accordingly.

Cosyntropin stimulation testing on postoperative day 1 allows for selective glucocorticoid replacement therapy after adrenalectomy for hypercortisolism: Results of a novel, multidisciplinary institutional protocol

BACKGROUND Secondary adrenal insufficiency (AI) can occur after unilateral adrenalectomy for adrenal-dependent hypercortisolism. Postoperative glucocorticoid replacement (GR), although given routinely, may not be necessary. We sought to identify factors that, in combination with postoperative day 1 cosyntropin stimulation testing (POD1-CST), would predict the need for GR. METHODS We reviewed 31 consecutive patients who underwent unilateral adrenalectomy for hypercortisolism (study patients) or hyperaldosteronism (control patients). A standard POD1-CST protocol was used. Hydrocortisone was started for clinical evidence of AI, basal plasma cortisol ≤ 5 (μg/dL), or a stimulated plasma cortisol <18. RESULTS A normal POD1-CST was found in all nine control patients and 11 of 22 patients (50%) with Cushings syndrome; the other 11 study patients (50%) received GR based on the POD1-CST. These patients were younger (51 vs 62 years; P = .017), had a higher body mass index (BMI; 31 vs 29 kg/m(2)), and smaller adrenal neoplasms (16.9 vs 33.0 g; P = .009) than non-GR study patients. CONCLUSION After unilateral adrenalectomy for hypercortisolism, only 50% of patients received GR. No preoperative biochemical characteristics were associated with postoperative AI, although patients who received GR were younger, and tended to have a higher BMI and smaller adrenal nodules. Use of this novel protocol for postoperative dynamic adrenal function testing prevented unnecessary GR in 50% of patients and allowed for individualized patient care.

The use of mifepristone in the treatment of Cushing's syndrome.

Patients with endogenous hypercortisolism, Cushings syndrome, have significant morbidity and increased mortality when inadequately treated. When surgical therapy has been unsuccessful other treatment modalities are necessary. Previously available therapies have limited effectiveness or significant toxicity. Mifepristone, a glucocorticoid receptor antagonist, provides a novel approach to the treatment of hypercortisolism. It is rapidly absorbed, highly protein bound and has a long plasma half-life. Since it also serves as a progesterone receptor antagonist, mifepristone has been used in several other medical conditions. A recently published prospective trial of mifepristone therapy for Cushings syndrome resulted in its recent approval by the U.S. Food and Drug Administration for use in Cushings syndrome.