pseudo-Cushing's Syndrome Research Articles

Endocrine dysregulation in COVID-19: molecular mechanisms and insights.

This review describes the impact of COVID-19 on the endocrine system, focusing on cortisol signaling and growth factor-induced endocrine resistance. As expected, SARS-CoV-2 infection induces systemic inflammation, resulting in stimulation of the adrenal glands leading to elevated cortisol levels with normal adrenocorticotropic hormone (ACTH) levels. The cytokine storm could also stimulate cortisol production. However, in some instances, cortisol levels rise independently of ACTH due to a phenomenon known as "pseudo-Cushing's syndrome," where adrenal glands become less responsive to ACTH. Plasma proteomic analyses showed that this pattern was variably observed among COVID-19 patients, potentially involving calcium dysregulation and GNAS-regulated activities, ultimately impacting the regulation of microvascular permeability. COVID-19 also exhibited a syndrome resembling endocrine resistance, governed by receptor tyrosine kinase signaling pathways. Mild cases displayed elevated activity of EGFR and MMP9, along with increased expression of survival factors like Bax and Bcl2. In contrast, more severe cases involved IGFR-I and enhanced NOTCH signaling, with altered expression of Bcl2, AKT1, and MAPK8. In summary, these findings describe the complex interplay between COVID-19 and endocrine pathology, particularly endocrine resistance. These insights suggest potential endocrine targets for therapeutic interventions to improve short- and long-term outcomes for COVID-19 patients.

The Differential Diagnosis between Cushing's Disease and Pseudocushing Syndrome in a Pre-agonic Patient.

The pseudo-Cushing's encompass several disorders that can occur in high-stress situations and that show biochemical features like those of Cushing's syndrome. We present a case with difficult differential diagnosis for overlapping laboratory findings. A 74-year-old man was admitted to our hospital for worsening dyspnoea for a month, 15 kilograms of weight loss in the previous months, asthenia, hypotonia, and muscle hypotrophy. Moreover, due to the onset of acute hypoxic-hypercapnic respiratory failure, the patient was treated with non-invasive ventilation and then admitted to the intensive care unit, for pneumonia and respiratory failure due to Meticillin-sensitive Staphylococcus aureus and Klebsiella Aerogenes. Antibiotic therapy was started. During the treatment in the ICU, the patient underwent endotracheal intubation for the worsening of respiratory function, and inotropic drug therapy was introduced for the development of septic shock. Hormones were tested, showing an ACTH-dependent hypercortisolism. The results of Nugent, Liddle, and the dexamethasone- suppressed CRH stimulation tests suggested a not-neoplastic ACTH-dependent hypercortisolism. The pituitary contrasted magnetic resonance image showed gland hypertrophy, and the abdominal computed tomography ruled out adrenal lesions. Unfortunately, the patient developed a multi-organ failure and died. The autopsy finding confirmed the absence of pituitary and other neuroendocrine tumors and showed bilateral adrenal hypotrophy. Our clinical case described a patient with pseudo-Cushing's syndrome during sepsis and pre-agonist phase, with a difficult differential diagnosis, in which the combination of the low-dose dexamethasone suppression test and the CRH test allowed a conclusive and correct diagnostic orientation.

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

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. 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. 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. 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 characteristicsareas 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. 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, theresultspresented here should increase clinicians' confidence when deciding which test to perform.

기능의학 의사가 고려해야 할 고코르티솔증의 임상적 평가 및 치료

Hypercortisolism is a phenomenon identified in traditional medicine for Cushing's syndrome, an endocrine disease, but is commonly discovered during clinical evaluation in functional medicine. Endogenous Cushing's syndrome itself is an uncommon disease, but if not properly evaluated, it can cause various complications in patients, so early detection and treatment are important. Additionally, pseudo-Cushing's syndrome, which may appear to be Cushing's syndrome, is often closely related to mental illness and stress reactions. As a functional medicine physician, it is important to understand cortisol metabolism and testing methods to evaluate hypercortisolism, and it is necessary to consider various patient’s conditions and solutions when hypercortisolism is confirmed.

Pseudo cushing syndrome with gastrointestinal sarcoidosis: case report

Pseudo cushing syndrome with gastrointestinal sarcoidosis: case report

The differential diagnosis between cushing's disease and pseudocushing syndrome in a pre-agonic patient

The differential diagnosis between cushing's disease and pseudocushing syndrome in a pre-agonic patient

Obesity-Related pseudo-cushing syndrome and pituitary incidentaloma: a case study

Obesity-Related pseudo-cushing syndrome and pituitary incidentaloma: a case study

Pheochromocytoma-induced pseudo-Cushing syndrome

Pheochromocytoma-induced pseudo-Cushing syndrome

Alcohol use disorders and liver fibrosis: an update.

Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.

Trends in Alcohol-Related Deaths by Sex in the US, 1999-2020

Alcohol consumption rates have been increasing among women in the US, which may affect mortality rates and sex gaps. Therefore, conducting a comprehensive assessment of sex differences in alcohol-related deaths is essential to inform targeted interventions and policies aimed at reducing the burden of alcohol-related harm among the population. To examine sex differences in the burden and trends of alcohol-related mortality in the US from 1999 to 2020. This cross-sectional time series study used Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data on alcohol-related deaths from 1999 to 2020. Alcohol-related deaths were identified from the underlying cause of death files using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes, including alcohol-related poisoning, liver disease, gastritis, cardiomyopathy, myopathy, polyneuropathy, and pseudo-Cushing syndrome, among others. Age-adjusted mortality rates (AAMRs) were analyzed by sex and substratified by race and ethnicity, age, and census region. Rate ratios and 95% CIs calculated by Taylor series were used to assess sex differences in mortality burden. Joinpoint regression was used to assess temporal trends. A total of 605 948 alcohol-attributed deaths were identified in the US from 1999 through 2020 (AAMR, 8.3 per 100 000 persons; 95% CI, 8.3-8.3 per 100 000 persons). The mortality burden was higher among male individuals than female individuals, with male individuals being 2.88 (95% CI, 2.86-2.89) times more likely to die compared with female individuals. However, temporal trends showed an increase in alcohol-related deaths for both male and female individuals in recent years, with higher rates of increase among female individuals relative to male individuals. The AAMR increased by 12.5% (95% CI, 6.4%-19.1%) per year among male individuals from 2018 to 2020 but increased by 14.7% (95% CI, 9.1%-20.5%) per year among female individuals during the same period. Trend differences were observed across subtypes of age, race and ethnicity, cause, and region. This study of alcohol-related mortality in the US suggests there has been a significantly higher rate of increase in deaths among female individuals in recent years. These findings underscore the need for further research to understand the specific factors associated with this trend. The development of targeted interventions and evidence-based treatments for alcohol use among female individuals becomes imperative in effectively addressing the increasing rates of alcohol-related deaths.

Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome.

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism.

The diagnostic accuracy of dex-CRH test in differentiating between Cushing's disease and pseudo-Cushing syndrome. A single-center experience

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Interest of serum and salivary cortisol diurnal cycle in the positive diagnostic of Cushing syndrome and in the differential diagnosis of pseudo-Cushing syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Approach to the Patient: Diagnosis of Cushing Syndrome.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

Stress as cause of signs and symptoms of pseudo‐Cushing’s syndrome in buffy‐tufted marmosets (Callithrix aurita)

Hyperadrenocorticism is a medical condition caused by the increase in cortisol production by the cortex of the adrenal gland. Although infrequently described in most animal species, its naturally occurring form, called Cushing's syndrome, is the most prevalent endocrinopathy in dogs. Cushing's syndrome is also present in humans and might be confused with the pseudo-Cushing's syndrome (PCS), rarely described in animals. PCS shares many of the clinical and biochemical features of Cushing's syndrome. However, the hypercortisolemia seen is usually idiopathic and, in some circumstances, associated with psychological disruptions. This report describes PCS-like disorder in two marmosets Callithrix aurita that were exposed to environmental changes, suggesting stress as the main cause of the process and reviewing the mechanisms involved in the pathogeny of the two syndromes.

Human Corticotropin-Releasing Hormone Tests: 10 Years of Real-Life Experience in Pituitary and Adrenal Disease.

The human corticotropin-releasing hormone (CRH) test (hCRHtest) is used to differentiate Cushing disease (CD) from ectopic adrenocorticotropin (ACTH) secretion (EAS), to assess autonomous cortisol secretion by the adrenal glands, and to characterize pseudo-Cushing syndrome (CS) or adrenal insufficiency (AI). The main outcome measure of this study was to assess the diagnostic accuracy of the hCRHtest. We measured ACTH and cortisol levels; collected the peak values (peakACTH and peakcortisol), and calculated the percentage increases (∆%ACTH and ∆%cortisol) after an intravenous bolus of 100 μg hCRH. This cross-sectional study of hCRH tests from 2010 to 2019 took place in a referral university hospital center. We enrolled 200 patients: 86 CD, 15 EAS, 18 adrenal CS, 25 mild adrenal autonomous cortisol secretion, 31 pseudo-CS, and 25 suspected AI. The hCRHtest was performed mainly for the differential diagnosis of ACTH-dependent CS or adrenal lesions (P = .048). PeakACTH and peakcortisol were higher in CD, and ∆%ACTH and ∆%cortisol were able to differentiate CD from EAS with a sensitivity and specificity greater than 80%. In patients with low (< 10 pg/mL) or indeterminate (10-20 pg/mL) basalACTH levels, an absent or reduced peakACTH response was able to differentiate adrenal from ACTH-dependent forms. PeakACTH and peakcortisol after hCRHtest were lower in pseudo-CS than in CD, but ∆%ACTH and ∆%cortisol were similar. The role of hCRHtest in patients with AI was limited. The hCRHtest test is the mainstay of the differential diagnosis of ACTH-dependent CS. It is also useful for pointing to a diagnosis of CD in the event of bilateral adrenal masses, and in patients with low basalACTH.

SUN-205 Pseudo-Cushing Syndrome Secondary to Malnutrition and Gluco-Toxicity Mimicking Type 1 Diabetes Mellitus

Background: Pseudo-Cushing Syndrome (PCS) is an under-recognized clinical entity that is a reversible consequence of alterations in cortisol production. We present a case of a patient with presumed type 1 Diabetes Mellitus (DM) who was found to have PCS secondary to malnutrition. Once the nutritional status normalized, the patient’s glycemic control remarkably improved and became well-controlled on metformin alone. Clinical case: A 54-year-old female with poorly controlled insulin-dependent DM for 10 years was referred for concern for adrenal insufficiency after an ACTH came back elevated in the setting of intractable nausea, vomiting and considerable weight loss over 1 year. Prior HbA1c was 16.2% (RR 4.4–6.7). On exam her vitals were normal, body mass index (BMI) was 15 kg/m2. Workup confirmed an elevated ACTH of 100 pg/ml (RR 6–50 pg/ml), however, random PM cortisol was unexpectedly elevated at 26.58 ug/dL (RR 4.46 – 22.7). 8 AM labs for ACTH and cortisol were similarly elevated at 91 pg/ml and 28.33 ug/dl, respectively. She had no evidence of classic Cushingoid features. Subsequent low dose dexamethasone suppression test and 24-hour urine free cortisol were negative. Over 18 months, with optimization of her insulin therapy, BMI improved to 19 kg/m2, ACTH and cortisol started to downtrend spontaneously. After 30 months, her BMI improved to 20 kg/m2. Repeat blood work showed A1C 6.5%, ACTH and cortisol completely normalized to 42 pg/dl and 8 ug/dL, respectively. After being adherent to insulin for a few years, her gluco-toxicity state resolved. A month prior to following up, she self-discontinued insulin due to hypoglycemia but continued on metformin. Currently she continues to remain off insulin. Discussion: PCS is a challenging diagnosis to recognize and differentiate from Cushing Disease (CD) especially due to overlap in biochemical profile. It is important to be aware of this clinical condition to avoid misdiagnosis, delay in treatment or over-treatment. Common etiologies causing PCS include depression, chronic alcoholism, obesity, physical stress, malnutrition, eating disorders, uncontrolled DM, obstructive sleep apnea. PCS occurs due to chronic activation of the hypothalamic-pituitary-adrenal axis, it is usually mild and resolves with treatment of underlying etiology. In our case, first-line screening tests could differentiate between PCS and CD hence she did not require late-night salivary cortisol testing or corticotropic-releasing hormone testing. Conclusion: In our patient, PCS occurred secondary to malnutrition and severe gluco-toxicity which mimicked insulin-dependent type 1 DM. Interestingly, once her nutritional status and insulin compliance improved, cortisol levels normalized, gluco-toxicity state resolved and she no longer required exogenous insulin therapy.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

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.