Bowel perforation associated with Cushing's disease: a case report with literature review.

Although rare, endogenous hypercortisolemia, including Cushing's disease (CD), is known to cause bowel perforation and to mask typical symptoms of bowel perforation, leading to delayed diagnosis. Additionally, elderly patients with CD are considered to be at a higher risk for bowel perforation because intestinal tissue fragility tends to increase in the elderly. Herein, we describe a rare case in which a young adult patient with CD was diagnosed with bowel perforation associated with CD following severe abdominal pain. A 24-year-old Japanese man was admitted to the hospital for the evaluation of ACTH-dependent Cushing's syndrome. He suddenly complained of severe abdominal pain on the 8th day of hospitalization. Computed tomography revealed free air around the sigmoid colon. The patient was diagnosed with bowel perforation, underwent emergency surgery, and was saved. He was subsequently diagnosed with CD, and the pituitary adenoma was resected transsphenoidally. To date, eight cases of bowel perforation due to CD had been reported, with a median age of 61 years at the time of bowel perforation. Hypokalemia was detected in half of the patients, and all had a history of diverticular disease. Nevertheless, not many patients complained of peritoneal irritation. In conclusion, this is the youngest reported case with bowel perforation due to CD and the first report of bowel perforation in a patient without a history of diverticular disease. Bowel perforation may occur in patients with CD, irrespective of age and the presence of hypokalemia, diverticular disease, or peritoneal irritation.

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.

Novel insights in endocrine and metabolic pathways in sepsis and gaps for future research.

Sepsis is defined as any life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains an important cause of critical illness and has considerable short- and long-term morbidity and mortality. In the last decades, preclinical and clinical research has revealed a biphasic pattern in the (neuro-)endocrine responses to sepsis as to other forms of critical illness, contributing to development of severe metabolic alterations. Immediately after the critical illness-inducing insult, fasting- and stress-induced neuroendocrine and cellular responses evoke a catabolic state in order to provide energy substrates for vital tissues, and to concomitantly activate cellular repair pathways while energy-consuming anabolism is postponed. Large randomized controlled trials have shown that providing early full feeding in this acute phase induced harm and reversed some of the neuro-endocrine alterations, which suggested that the acute fasting- and stress-induced responses to critical illness are likely interlinked and benefical. However, it remains unclear whether, in the context of accepting virtual fasting in the acute phase of illness, metabolic alterations such as hyperglycemia are harmful or beneficial. When patients enter a prolonged phase of critical illness, a central suppression of most neuroendocrine axes follows. Prolonged fasting and central neuroendocrine suppression may no longer be beneficial. Although pilot studies have suggested benefit of fasting-mimicking diets and interventions that reactivate the central neuroendocrine suppression selectively in the prolonged phase of illness, further study is needed to investigate patient-oriented outcomes in larger randomized trials.

Cardiovascular health and mortality in Cushing's disease.

Exposure to cortisol excess in Cushing's disease (CD) results in increased cardiovascular morbidity and reduces survival, with cardiovascular disease being a leading cause of death. At diagnosis, a significant number of patients have adverse cardiovascular profiles (e.g., obesity, diabetes or impaired glucose tolerance, dyslipidemia, hypertension, cardiac abnormalities and vascular disease). Remission of hypercortisolemia reduces but does not completely eliminate the cardiovascular complications; hazard ratios for myocardial infarction and stroke are high during long-term monitoring, highlighting the long-lasting effects of hypercortisolism and the importance of the timely diagnosis and successful management of this condition. Data on mortality of patients in remission are not consistent but in a multicenter study, an increased all-cause and circulatory mortality in patients with CD in remission for at least 10 years has been demonstrated. Cardiovascular morbidity requires particular focus and effective management during the care of patients with CD, from their presentation until long-term follow up.

Cushing's disease: role of bilateral adrenalectomy.

INTRODUCTION: Laparoscopic bilateral adrenalectomy (BAD) is one of the treatments of Cushing's Disease (CD), but its indications and outcome is debated. METHODS: The literature on BAD was reviewed as part of a work performed for the Cushing's disease guideline. RESULTS: The surgical morbidity of BAD is reported between 10 and 18% and no mortality has been reported in the largest series. Because of the endocrine sacrifice it will be mostly performed after a multidisciplinary team discussion in selected cases of refractory CD (mostly after failure of pituitary surgery and/or medical treatment). It is also frequently discussed in female patients desiring pregnancy. Corticotroph tumor progression occurs in 40% of the patients but is in most patients manageable when detected early by a careful long term monitoring with pituitary MRI and ACTH assays after BAD. CONCLUSION: BAD is a safe and effective treatment of CD used in specific situations and requiring long term monitoring.

EFFECTIVENESS OF UNILATERAL ADRENALECTOMY IN BILATERAL ADRENAL INCIDENTALOMA PATIENTS WITH SUBCLINICAL HYPERCORTISOLEMIA.

Objective: Unilateral adrenalectomy (UA) is an alternative for treatment in bilateral adrenal incidentaloma (AI) to avoid possible long-term risks of bilateral adrenalectomy. In this study, we aimed to evaluate the effectiveness of UA in bilateral AI patients with subclinical hypercortisolemia (SH). Method: A total of 35 patients were included in this study. The patients were divided into two groups; those who underwent UA (n=27) and patients without adrenalectomy (PWA) (n=8). Hormone tests related to cortisol mechanism were reviewed to analyze results at the time of diagnosis compared to the latest available results to figure out any changes in cortisol mechanism and determine whether SH has recovered or not. Results: Median age of PWA group were higher compared to UA group (p=0.03). Median duration of follow-up in groups were similar (p=0.3). In the PWA group, none of the patients recovered from hypercortisolemia during their follow-up. In UA group 92.6% of the patients went into remission, whereas during follow-up 3.3% had recurred and another 3.3% were found to have post-adrenalectomy persistent SH. Patients in UA group had lower final cortisol level following dexamethasone suppression (p=0.003) and higher final adrenocorticotrophic hormone (ACTH) levels (p=0.001) than patients in PWA group. In UA group, final basal cortisol level (p=0.009) and final cortisol level after 1 mg dexamethasone suppression test (DST) (p=0.004) were lower than corresponding levels at the time of diagnosis. Discussion: Our study demonstrates unilateral adrenalectomy targeting the side with the larger lesion is an effective approach to reduce excess cortisol levels in bilateral AI patients with SH.

Clinical utility of plasma progesterone and blood and plasma glucose concentrations in predicting parturition in Holstein cows.

An accurate, practical, and low-cost method for predicting parturition is urgently needed in the dairy industry. The objective of this study was to evaluate changes in plasma progesterone concentration ([prog]) and glucose concentration in whole blood ([gluc]b) and plasma ([gluc]p) as predictors of parturition within 6, 12, and 24 h in primiparous and multiparous Holstein cows. Blood samples were obtained daily at approximately 0900 h from 34 primiparous and 72 multiparous Holstein cows in late gestation and the time of calving recorded to the nearest hour. Plasma [prog] was measured using an ELISA, and [gluc]b and [gluc]p using a low-cost point-of-care glucose meter. The optimal cut-point for predicting parturition was determined using binomial logistic regression with general estimating equations, because the data set consisted of repeated measures for each cow. Diagnostic test performance was evaluated by comparing the area under the receiver operating characteristic curve (AUC) and calculating the sensitivity, specificity, and κ at the optimal cut-point for predicting parturition. Plasma [prog] was the most accurate predictor of parturition within 24 h (AUC = 0.96) and 12 h (AUC = 0.93), whereas [gluc]b was the most accurate predictor of parturition within 6 h (primiparous, AUC = 0.96; multiparous, AUC = 0.86). We conclude that a decrease in plasma [prog] is currently the most accurate test for predicting calving within 24 h. Measurement of [gluc]b is a promising new test for the cow-side prediction of parturition in dairy cows due to its accuracy, practicality, and low cost.

ACTH-dependent Hypercortisolemia in a Patient with a Pituitary Microadenoma and an Atypical Carcinoid Tumour of the Thymus.

Cushing's syndrome (CS) is a set of clinical symptoms which occur as a result of hypercortisolemia. Endogenous ACTH-dependent CS related to an ectopic ACTH-secreting tumour constitutes 12%-17% of CS cases and is one of the most common causes of paraneoplastic syndromes. This study presents a case of a 31 year-old man with diabetes, hypertension, rosacea, purple stretch marks and hypokalemia. Findings of diagnostic procedures include high concentrations of cortisol and ACTH, pituitary microadenoma and a tumour in the anterior mediastinum. Dynamic hormone tests determined the source of excess hormone secretion and ectopic ACTH-dependent CS was diagnosed. Due to increasing symptoms of superior vena cava syndrome, an emergency resection of almost the whole tumour was performed, with only a small part of the upper pole left because of the proximity of large vessels and a risk of damaging them. On the basis of histopathological tests, an atypical carcinoid tumour of the thymus was identified. Immediately after the surgical procedure, there was a significant reduction of clinical and laboratory traits of hypercortisolemia, yet, during the 46 weeks of postoperative observation, despite chemotherapy, the progression of residual masses of the tumour occurred with metastases and increased hormone indices. The presented case shows and discusses the differentiation of ACTH-dependent hypercortisolemia and its causes, difficulties in surgical therapy and chemotherapy, as well as prognosis for atypical carcinoid of the thymus, which is a rare disease.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

Pregnancy-associated Cushing's disease? An exploratory retrospective study.

PURPOSE: In most clinical series of Cushing's disease (CD), over 80% of patients are women, many of whom are of reproductive age. The year following pregnancy may be a common time to develop CD. We sought to establish the incidence of CD onset associated with pregnancy. METHODS: A retrospective review was conducted for patients with biochemically-proven CD. Demographics, clinical history, biochemistry, imaging, pathology, and outcomes were reviewed. Pregnancy-associated CD was defined as symptom onset within 1 year of childbirth. RESULTS: Over 10 years, 77 patients including 64 women (84%), with CD underwent endonasal surgery. Of the 64 women, 64% were of reproductive age (15-45 years) at the time of diagnosis, and 11 (27%) met criteria for pregnancy-associated CD. Of these 11 women, median number of pregnancies prior to onset of CD was 2 (range 1-4) compared to zero (range 0-7) for 30 other women with CD onset during reproductive age (p = 0.0024). With an average follow-up of 47 ± 34 months, sustained surgical remission rates for woman with pregnancy-associated CD, other women of reproductive age, and women not of reproductive age were 91%, 80% and 83%, respectively. The average lag-time from symptom onset to diagnosis for women with pregnancy-associated CD was 4 ± 2 years. CONCLUSIONS: In this exploratory study, over one quarter of women of reproductive age with CD appeared to have symptomatic disease onset within 1 year of childbirth. This relatively high rate of pregnancy-associated CD suggests a possible causal relationship related to the stress of pregnancy and pituitary corticotroph hyperactivity in the peripartum period. This possible association suggests a heightened degree of clinical suspicion and biochemical testing for CD may be warranted after childbirth. Further study of this possible link between pregnancy and CD is warranted.

11ß-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11ß-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11ß-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11ß-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11ß-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11ß-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

UNCOMPLICATED PREGNANCY IN A PATIENT WITH CUSHING'S DISEASE.

The coexistence of Cushing's syndrome (CS) and pregnancy is uncommon due to the suppression of gonadotropin secretion in CS. Adrenocorticotropic hormone (ACTH) dependent CS in pregnancy is less frequent than adrenal causes. The diagnosis of CS during pregnancy is difficult since physiological changes in the hypothalamo-pituitary-adrenal axis may cause dynamic tests to be misinterpreted. Radiological imaging is limited. We report the case of a 27-year old woman with Cushing's disease (CD) diagnosed in the 5th-week of pregnancy. The mild symptoms of hypercortisolism did not lead to serious complications for the mother or the fetus, so insulin was the only treatment used. The pregnancy was completed without any complications, and at 38 weeks of gestation a healthy female infant was delivered vaginally. Complications, such as hypocortisolemia and hypoglycemia, were not observed in the infant. Postpartum tests were consistent with CD. Contrast-enhanced pituitary magnetic resonance imaging revealed a microadenoma which was removed with transsphenoidal surgery. Histopathology revealed a pituitary adenoma with positive immunohistochemical staining for ACTH. Biochemical remission required prednisolone treatment, but the insulin requirement decreased significantly over time. As a conclusion, CD with mild features can be well tolerated during pregnancy, but the mother and the fetus must be monitored closely.

Adrenal (131)I-6ß-iodomethylnorcholesterol scintigraphy in choosing the side for adrenalectomy in bilateral adrenal tumors with subclinical hypercortisolemia.

PURPOSE: Adrenal scintigraphy with 131I-6ß-iodomethylnorcholesterol is considered by several authors the gold standard for assessing tumors with subclinical hypercortisolemia. However, most of the described series consist mainly of cases with unilateral lesions. The aim of our study was to assess whether scintigraphy is useful in choosing the adrenalectomy side in the case of bilateral adrenal tumors with subclinical hypercortisolemia. METHODS: The study focused on 15 consecutive patients with benign bilateral adrenal tumors and subclinical hypercortisolemia. The scintigraphy with 131I-6ß-iodomethylnorcholesterol was performed. Fourteen patients underwent unilateral adrenalectomy; the gland with predominant uptake on scintigraphy was removed. Cortisol and ACTH concentrations were measured one and six months after surgery. Post-dexamethasone cortisolemia was assessed six months after surgery. To date, the patients have been under postoperative observation for 1-4 years. RESULTS: Four patients showed unilateral uptake of radiotracer, and nine patients showed predominant accumulation of radiotracer in one of the adrenal glands. The smaller tumor was predominant in 2 cases. Percentage of activity on the predominant side correlates positively with the difference between tumors' diameters. Unilateral uptake of radiotracer predicts long-lasting postoperative insufficiency of the second adrenal gland. Excision of predominating tumor led to cessation of hypercortisolemia in all patients. CONCLUSIONS: The corticoadrenal scintigraphy is useful in choosing the side for operation in the case of bilateral adrenal tumors with subclinical hypercortisolemia.

Venous Thromboembolism and Prevention Strategies in Patients with Cushing's Disease: A Systematic Review.

BACKGROUND: There is a well-documented association between Cushing's syndrome (CS) and hypercoagulability. However, there is limited data on the risk of venous thromboembolic events (VTEs) after surgery for Cushing's disease (CD). There is no consensus on optimal postoperative anticoagulation strategies in this group. This review gathers information on the rates of VTE after surgery for CD, as well as reported prophylaxis strategies in this population. METHODS: A literature search was performed using Cochrane Library, EMBASE, and Ovid MEDLINE databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A narrative review of papers discussing mechanisms of hypercoagulability in CS was conducted. RESULTS: Twenty-five relevant papers were identified out of 944 papers yielded. Pooled postoperative VTE incidence in patients undergoing transsphenoidal surgery for CD was 2% (58 out of 2997). The pooled rate of VTE-associated mortality based on the 23 studies that reported this information was 0.2% (6 out of 2077). There were no cases of postoperative VTE in the 191 patients undergoing adrenalectomy for benign adrenocorticotropic hormone-independent CS. Ten studies reported information on perioperative thromboprophylaxis strategies in transsphenoidal surgery for CD and adrenalectomy for adrenocorticotropic hormone-independent CS. CONCLUSIONS: Postoperative VTE in CD is a source of morbidity, with a rate of 2% and mortality rate of 0.2%, highlighting that surgical resection of the corticotroph adenoma does not necessarily result in immediate resolution of hypercoagulability. Increased production of coagulation factors, impaired fibrinolysis, inflammation, and CS-associated metabolic risk factors all factor into the pathogenesis of CS-associated hypercoagulability. Further study is needed on an optimal pharmacologic prophylaxis strategy.

Effect of mitotane in patients with ectopic adrenocorticotropic hormone syndrome caused by advanced pancreatic neuroendocrine tumors: a case series and review of the literature.

Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition caused by pancreatic neuroendocrine tumors (p-NETs). The severe hypercortisolemia that characterizes EAS is associated with a poor prognosis and survival. Mitotane is the only adrenolytic drug approved by the Food and Drug Administration and is often used to treat adrenocortical carcinoma. Combination therapy with mitotane and other adrenal steroidogenesis inhibitors is common for patients with Cushing's syndrome (CS). Here, we describe three patients who developed EAS secondary to the liver metastasis of p-NETs. All three rapidly developed hypercortisolemia but no typical features of CS. They underwent anti-tumor and mitotane therapy, which rapidly reduced their blood cortisol concentrations and ameliorated their symptoms. Their hypercortisolemia was controlled long term using a low dose of mitotane. The principal adverse effects were a slight loss of appetite and occasional dizziness, and there were no severe adverse effects. Importantly, even when the tumor progressed, the patients' circulating cortisol concentrations remained within the normal range. In summary, the present case series suggests that mitotane could be used to treat hypercortisolemia in patients with EAS caused by advanced p-NETs, in the absence of significant adverse effects.

Vitamin C supplementation alleviates hypercortisolemia caused by chronic stress.

The aim of this study was to determine whether ascorbic acid (AA) supplementation can lower plasma levels of Cortisol and dehydroepiandrosterone-sulphate (DHEA-S) in patients diagnosed with functional hypercortisolemia due to unspecified chronic stress. Study includes data from 69 female with elevations in the cortisol and DHEA-S levels. Duration of follow-up was 2 months. Patients were divided into 3 groups. Group I included patients 23 with elevated cortisol, Group II-patients 24 with elevated levels of both hormones, Group III- patients 22 with normal cortisol and increased DHEA-S. Each group was randomly divided into two subgroups. The first subgroup was prescribed 1000 mg daily oral dose of AA. The diet of the second subgroup were left unaltered. All patients have their hormones levels re-examined 2 months later. After 2 months of AA supplementation the mean levels of elevated plasma cortisol and DHEA-S decreased. In Group I the level of cortisol fell from 780 ± 57-446 ± 26 nmol/L, p = 0.000065 in Group II from 657 ± 47-515 ± 29 nmol/L, p = 0.005. The elevated levels of DHEA-S have also declined in patients from AA-treated subgroups (from 13.9 ± 1.6-9.9 ± 1.2, p = 0.0007 in Group II, and from 12.8 ± 1.0-7.8 ± 1.4, p = 0.003 in Group III). In untreated subgroups changes in hormone levels were insignificant. The study shows that female patients with functional hypercortisolemia or elevated levels of DHEA-S can be treated with AA to bring level of these hormones closer to a normal range.

Gene Mutations in Cushing's Syndrome.

Background: Prolonged exposure to glucocorticoids can result in the development of Cushing's syndrome. Excess serum cortisol can occur due to several factors including exogenous steroids, pituitary and adrenal adenoma, and ectopic ACTH secretion. Summary: The last 2 decades have seen significant progress in identifying new genetic and molecular mechanisms underlying hypercortisolemia. This has implicated mutations seen in a multitude of aberrant pathways that underpin the pathophysiology of Cushing's syndrome. Key Messages: There is much overlap between the different, with mutations affecting well-understood molecular pathways such as the cAMP/PKA/MAPK and Wnt signalling systems. Further work should delineate the exact involvement of specific mutations in Cushing's syndrome and the effect of epigenetic/microenvironmental interactions. This could have implications for screening, as the identification of specific mutations may lead to earlier identification and subsequently improved prognosis.

Alcohol-induced Cushing syndrome: report of eight cases and review of the literature.

Introduction: Alcohol-induced hypercortisolism (AIH) is underrecognized and may masquerade as neoplastic hypercortisolism [Cushing syndrome (CS)] obscuring its diagnosis. Objective and methods: In order to characterize AIH, we performed a chart review of eight patients (4 males and 4 females; 2014-2022) referred for evaluation and treatment of neoplastic hypercortisolism - six for inferior petrosal sinus sampling, one due to persistent CS after unilateral adrenalectomy, and one for pituitary surgery for Cushing disease (CD). Five underwent dDAVP stimulation testing. Results: All eight patients had clinical features of hypercortisolism and plasma ACTH levels within or above the reference interval confirming hypothalamic-pituitary mediation. All had abnormal low-dose dexamethasone suppression test and increased late-night salivary cortisol. Only one had increased urine cortisol excretion. In contrast to CD, the 5 patients tested had blunted or absent ACTH and cortisol responses to desmopressin. Two had adrenal nodules and one had abnormal pituitary imaging. Most patients underreported their alcohol consumption and one denied alcohol use. Elevated blood phosphatidyl ethanol (PEth) was required in one patient to confirm excessive alcohol use. All patients had elevations of liver function tests (LFTs) with AST>ALT. Conclusion: AIH is an under-appreciated, reversible cause of non-neoplastic hypercortisolism that is indistinguishable from neoplastic CS. Incidental pituitary and adrenal imaging abnormalities as well as under-reporting of alcohol consumption further confound the diagnosis. Measurement of PEth helps to confirm an alcohol use disorder. Elevations of LFTs (AST>ALT) and subnormal ACTH and cortisol responses to dDAVP help to distinguish AIH from neoplastic hypercortisolism.

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.