Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity.

PURPOSE: The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how. METHODS: A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS. RESULTS: The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1 mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1 mg DST and late-night salivary cortisol are the most accurate screening tests for CS. CONCLUSIONS: Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1 mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1 mg DST could be equally used for the screening of hypercortisolism.

NTpro-BNP levels in patients with primary hyperaldosteronism and autonomous cortisol co-secretion.

CONTEXT: Patients with primary aldosteronism (PA) have higher cardiac comorbidities including more pronounced left ventricular hypertrophy than patients with essential hypertension. OBJECTIVE: Autonomous cortisol co-secretion (ACS) is a common subtype in PA associated with a worse metabolic profile. HYPOTHESIS: ACS may affect myocardial parameters and result in a worse cardiac outcome compared to patients with PA and without ACS. METHODS: 367 patients with PA undergoing 1mg dexamethasone suppression test (DST) and echocardiography at baseline from two centers of the German Conn´s Registry were included. Follow-up for up to 3.8yrs was available in 192 patients. RESULTS: Patients with PA and ACS had higher NTpro-BNP levels at baseline compared to patients with PA without ACS (114vs75.6pg/ml,p=0.02), but showed no difference in echocardiography values. NTpro-BNP levels showed a significant positive correlation (r=0.141,p=0.011) with cortisol levels after DST at baseline. In response to therapy of PA, NTpro-BNP levels decreased, but remained significantly higher in patients with ACS compared to patients without ACS. At follow-up, left ventricle end diastolic dimension (LVEDD) decreased significantly only in patients without ACS. Left atrial diameter (LAD) decreased significantly in patients without ACS and in female patients with ACS but not in male patients. Left ventricular mass index (LVMI) significantly improved in female patients without ACS but remained unchanged in female patients with ACS as well as in male patients at follow-up. CONCLUSION: In patients with PA, concomitant ACS is associated with a worse cardiac profile and only partial recovery even years after initiation of targeted PA therapy.

Pre-Surgery Cortisol Levels as Biomarker of Evolution after Bariatric Surgery: Weight Loss and Weight Regain.

Background: Bariatric surgery (BS) is effective for achieving significant weight loss. However, weight regain (WR) is an emerging problem. Objective: To assess the prognostic value of morning serum cortisol, a 1 mg dexamethasone suppression test (DST), 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) in a cohort of patients with severe obesity (pwSO) undergoing BS in terms of weight loss and WR. Methods: Patients scheduled for BS underwent the following procedures at baseline, 12 months and 24 months after BS: medical history, anthropometric data, blood analysis and cortisol tests. We evaluated total weight loss (TWL) ≥ 30% at 1 year and WR after 2 years as an increase of ≥10% of the maximum weight lost. Results: In total, 142 subjects were included; 101 (71.1%) were females and the mean age was 45.9 ± 9.2 years. Up to 76.8% of subjects achieved ≥30% TWL, without statistically significant differences in DST results or morning serum cortisol, UFC or LNSC levels. However, a higher pre-surgery morning serum cortisol level was a significant predictor of a WR ≥ 10% (cortisol 17.8 [IQR 13.1-18.5] vs. 12.0 [IQR 8.8-15.8] µg/dL; p < 0.01); OR of 1.216 (95% CI 1.069-1.384); AUC [0.761, CI: (0.616-0.906); p < 0.01]. A cut-off value of cortisol > 13.0 µg/dL was predictive of a WR ≥ 10% (sensitivity 0.71; specificity 0.63). Conclusions: No cortisol test was useful in predicting weight loss; however, the pre-surgery morning serum cortisol level was able to predict a WR ≥ 10% in a cohort of pwSO 2 years after BS. A cut-off value of cortisol > 13 µg/dL might be an easy tool to identify patients at higher risk of WR, enabling healthcare providers to implement tailored, long-term strategies to minimize this outcome.

The dexamethasone suppression test as a biomarker for suicidal behavior: A systematic review and meta-analysis.

BACKGROUND: The dexamethasone suppression test (DST), which measures HPA-axis functioning, is a potential biomarker for suicidal behavior. The current study aimed (a) to synthesize available knowledge on the association between DST non-suppression and suicidal behavior, and (b) to study potential moderators. METHODS: A total of 4236 studies were screened, 43 were included. Suicide attempts and suicide completion were studied separately. The meta-analysis included 37 effect sizes for suicide attempts (n = 3733) and 11 effect sizes for suicide completion (n = 1626). RESULTS: DST non-suppression was associated with completed suicide (odds ratio (OR) = 2.10, (95 % CI [1.37, 3.23]). For suicide attempts, we found no evidence that DST status was associated in the overall meta-analysis including all patient samples. However, moderator analysis indicated that the DST status was associated with suicide attempts in patient samples that included psychopathology other than just mood disorders, such as psychotic, substance use and personality disorders (OR = 2.34, 95 % CI [1.39-3.93], k = 11). LIMITATIONS: The potential influence of publication bias and exclusion of some relevant published studies (since effect sizes could not be calculated, authors could not supply data or authors could not be reached) are limitations. Furthermore, missing moderator data decreased our ability to explain heterogeneity between studies. CONCLUSIONS: The results of this meta-analysis support the hypothesis that DST non-suppression is predictive of suicidal behavior. More research is needed to investigate optimal cut-off values, confounding factors and the potential usefulness of the DST in clinical practice in terms of personalized medicine.

Unusual Presentation of Case of a Lung Carcinoid Tumor With Ectopic Adrenocorticotropic Secretion (EAS) Associated With Acute Weight Gain and Peripheral Edema.

Ectopic adrenocorticotropic secretion (EAS) is classically related to small-cell lung cancer but is caused by a wide variety of tumors. In approximately one-fifth of cases, the cause remains unidentified. Excess adrenocorticotropic hormone (ACTH) leads to Cushing's syndrome, and the presentation can be due to biochemical derangements such as hypokalemia and hyperglycemia. Alternatively, it may manifest with secondary symptoms such as weight gain, hypertension, skin thinning, abdominal striae, and/or psychotic manifestations. The diagnosis is established through dynamic testing after confirming excess cortisol and ACTH levels. Imaging is then used to identify the hormonally active lesion. Controlling hypercortisolism with steroidogenesis inhibitors is the initial step before proceeding to definitive treatment. Ideally, tumor resection, if possible, but bilateral adrenalectomies are considered in cases not amenable to curative surgery.

Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion.

OBJECTIVE: To investigate the clinical, laboratory findings and signal intensity index (SII) on magnetic resonance imaging (MRI) of patients with bilateral and unilateral macronodular mild autonomous cortisol secretion (MACS). PATIENTS AND MEASUREMENTS: Clinical and laboratory findings of 81 patients with MACS were examined from retrospective records. SII of adenomas and internodular areas were evaluated by MRI. The unilateral group included patients with an adrenal macronodule (≥1 cm) in a single adrenal gland, while the bilateral group included patients with at least one macronodule in both adrenal glands. RESULTS: In total, 46 patients were in the unilateral (57%), while 35 (43%) patients were in the bilateral groups. The dehydroepiandrosterone sulphate (DHEA-S) level was lower in the unilateral than in the bilateral group (p < .001). The presence of type 2 diabetes mellitus (T2DM), glycosylated haemoglobin (HbA1c) and low-density lipoprotein (LDL) concentrations were higher in the bilateral group (p < .05). However, no significant difference was detected in terms of adrenocorticotropic hormone (ACTH) and overnight 1 mg dexamethasone suppression test (DST) between the two groups (p > .05). There was no difference in SII between adenomas within the same patient, as well as between the unilateral and bilateral groups (p > .05). Logistic regression analysis based on the differentiation between unilateral and bilateral macronodular MACS demonstrated that DHEA-S, HbA1c and LDL concentrations were associated factors. CONCLUSION: DHEA-S levels may not be as suppressed in patients with bilateral macronodular MACS as compared to those with unilateral adenoma. T2DM and hypercholesterolaemia have a higher frequency in bilateral patients. However, ACTH, overnight 1 mg DST and SII may not provide additional information for differentiation of bilaterality and unilaterality.

Unveiling the Uncommon: Cushing's Syndrome (CS) Masquerading as Severe Hypokalemia.

Cushing's syndrome (CS) arises from an excess of endogenous or exogenous cortisol, with Cushing's disease specifically implicating a pituitary adenoma and exaggerated adrenocorticotropic hormone (ACTH) production. Typically, Cushing's disease presents with characteristic symptoms such as weight gain, central obesity, moon face, and buffalo hump. This case report presents an unusual manifestation of CS in a 48-year-old male with a history of hypertension, where severe hypokalemia was the primary presentation. Initial complaints included bilateral leg swelling, muscle weakness, occasional shortness of breath, and a general feeling of not feeling well. Subsequent investigations revealed hypokalemia, metabolic alkalosis, and an abnormal response to dexamethasone suppression, raising concerns about hypercortisolism. Further tests, including 24-hour urinary free cortisol and ACTH testing, confirmed significant elevations. Brain magnetic resonance imaging (MRI) identified a pituitary macroadenoma, necessitating neurosurgical intervention. This case underscores the rarity of CS presenting with severe hypokalemia, highlighting the diagnostic challenges and the crucial role of a collaborative approach in managing such intricate cases.

Relationship Between Dexamethasone Suppression Test Cortisol Level >0.9 µg/dL and Depression and Quality of Life in Adrenal Incidentalomas: A Single Center Observational Case-Control Study.

OBJECTIVE: There has been increasing evidence that patients with adrenal incidentalomas (AIs) who have 1-mg dexamethasone suppression test (DST) cortisol levels >0.9 µg/dL may be exposed to the adverse consequences of hypercortisolaemia. We aim to evaluate whether there is a difference in Beck Depression Inventory-II (BDI-II) and quality of life (QoL) score in patients with AI based on the threshold of a DST cortisol level >0.9 µg/dL. METHODS: This case-control study included 42 nonfunctional adrenal incidentaloma (NFAI), 53 mild autonomic cortisol secretion (MACS) and 42 healthy controls (HCs). In addition, patients were categorized as ≤0.9 and >0.9 µg/dL according to their DST cortisol results. RESULTS: There was no difference in the QoL and BDI-II scores of MACS compared to NFAI. The BDI-II score was higher and QoL was lower in MACS and NFAI compared to HCs. The difference in QoL and BDI-II scores between MACS and NFAI remained insignificant when the DST cortisol levels threshold was graded upward (5.0 µg/dL). The prevalence of depression was higher in the AI >0.9 µg/dL group than the AI ≤0.9 µg/dL group (respectively, 16.7% and 55.8%, P = .003), BDI-II scores were higher in the AI >0.9 µg/dL group than in the AI ≤0.9 µg/dL group and HCs. The DST was an independent factor affecting the frequency of depression (odds ratio: 1.39, P = .037). CONCLUSION: MACS and patients with NFAI had similar QoL and depression scores according to the 1.8 µg/dL and above, whereas, had lower QoL and higher depression scores according to the 0.9 µg/dL.

Hair cortisol and changes in cortisol dynamics in chronic kidney disease.

Objective: We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status. Design and methods: A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied. Results: A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m2) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m2). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI. Conclusion: Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study.

Encephalopathy After a High-Dose Dexamethasone Suppression Test in a Woman With X-Linked Ornithine Transcarbamylase Deficiency.

Background/Objective: The high-dose dexamethasone suppression test is a common and usually benign endocrine procedure. We report a patient with ornithine transcarbamylase deficiency (OTCD) who developed hyperammonemic encephalopathy after a high-dose dexamethasone suppression test. Case Report: A 46-year-old woman with a 1.3-cm right adrenal incidentaloma causing mild autonomous cortisol secretion underwent a high-dose dexamethasone suppression test for confirming adrenocorticotropic hormone independency. On the next day, she presented to the emergency room with confusion and somnolence. Her Glasgow Coma Scale score was 10 on arrival. The initial laboratory results showed ammonia, alanine transaminase, creatinine, and blood urea nitrogen levels of 289.51 (18.73-54.5) µg/dL, 21 (≤33) IU/L, 0.6 (0.6-1.1) mg/dL, and 13 (7-20) mg/dL, respectively. Electroencephalography showed triphasic morphology with no pathologies on brain imaging. Her husband told us that her brother and son had died in the neonatal period. On further review of medical records, we found that she was diagnosed as an OTCD carrier. We administered L-arginine, L-carnitine, rifaximin, and continuous renal replacement therapy. After 3 days, the serum ammonia level was 78.34 µg/dL with an increased Glasgow Coma Scale score of 15, and electroencephalography abnormalities disappeared. Discussion: Liver diseases and urea cycle disorders are the leading causes of hyperammonemia. This causes encephalopathy and death if the ammonia levels are too high. X-linked OTCD urea cycle disorder affects men more severely as they have only the carrier X chromosome. Glucocorticoids can exacerbate this disorder because they increase protein substrates converted to ammonia. Conclusion: This case reminds that it may be particularly important to have a complete medical history when administering glucocorticoids.

Assessment of plasma dexamethasone levels after 1-mg dexamethasone suppression test in adults with obesity.

BACKGROUND: The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing's syndrome. It has been proposed that people with obesity may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg dexamethasone suppression test in healthy obese participants and in optimal-weight participants. METHODS: A total of 30 optimal-weight participants (BMI ≤ 25 kg/m2 ) and 62 obese participants (BMI > 25 kg/m2 ) were enroled in the study. Obese participants were further divided into class 1 (25-29.9 kg/m2 ) and class 2 (>30 kg/m2 ). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). RESULTS: No significant difference in plasma dexamethasone levels were found between obese and optimal-weight participants (3.31 ± 1.35 vs. 2.82 ± 1.11 nmol/L, mean ± SD; p = .09 respectively). There were also no correlations found between sex, BMI, body surface area and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level >3.3 nmol/L in comparison between obesity class 1, obesity class 2, and optimal-weight groups. CONCLUSION: Our results suggest that obesity does not affect plasma dexamethasone levels. However, dexamethasone measurement may still be helpful in patients who are being investigated for Cushing's syndrome and suspected to have a false-positive DST.

Diagnostic performance of an automated immunoassay for salivary cortisol.

Automated immunoanalysis (AI) is an interesting alternative for measuring salivary cortisol, as the gold standard HPLC-MS/MS method is not yet readily available. The aim of this study was to evaluate the diagnostic performance of salivary cortisol immunoassay on the iSYS immunoanalyzer in adrenal dynamic tests. Cortisol was measured on iSYS and on HPLC-MS/MS in saliva samples collected after 1mg-dexamethasone suppression test (DST) in 115 patients suspected of Cushing syndrome, and during Synacthen® stimulation test (SST) in 108 patients suspected of adrenal insufficiency. Concentrations on AI correlated well with HPLC-MS/MS (Spearman r=0.9496; P<0.0001), but with a significant positive bias. ROC analysis of salivary cortisol identified optimal cut-off values on AI and HPLC-MS/MS of respectively 3.5 and 0.77nmol/L for DST and 32.6 and 13.8nmol/L at T60 after SST. Automated immunoassays for salivary cortisol are suitable in daily practice but require determination of specific cut-off and reference values.

The role of confirmatory tests in the diagnosis of primary aldosteronism.

Confirmatory tests for diagnosis of primary aldosteronism (PA) play an important role in sparing patients with a false-positive aldosterone-to-renin ratio (ARR) screening test from undergoing invasive subtyping procedures. We recommend that patients with a positive ARR test should undergo at least one confirmatory test to confirm or exclude the diagnosis of PA before directly proceeding to subtype studies, except for patients with significant PA phenotypes, including spontaneous hypokalemia, plasma aldosterone concentration >20 ng/dL plus plasma renin activity below a detectable level. Although a gold standard confirmatory test has not been identified, we recommend that saline infusion test and captopril challenge test, which were widely used in Taiwan. Patients with PA have been reported to have a higher prevalence of concurrent autonomous cortisol secretion (ACS). ACS is a biochemical condition of mild cortisol overproduction from adrenal lesions, but without the typical clinical features of overt Cushing's syndrome. Concurrent ACS may result in incorrect interpretation of adrenal venous sampling (AVS) and may lead to adrenal insufficiency after adrenalectomy. We recommend screening for ACS in patients with PA scheduled for AVS examinations as well as for adrenalectomy. We recommend the 1-mg overnight dexamethasone suppression test as screening method to detect ACS.

Relationship Between Overnight Dexamethasone Suppression Test and Aging.

Background This study aims to investigate the relationship between suppressed cortisol levels measured after the 1-mg dexamethasone suppression test (DST) and age based on the hypothesis that aging can alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Methodology Data obtained by the retrospective evaluation of suppressed 1-mg overnight DST results of adults aged ≥18 years with adrenal incidentaloma or suspected endogenous hypercortisolemia between December 2021 and March 2023 were subjected to age-dependent correlation analysis. Individuals aged between 18 and 90 years (n = 1111) were classified into the following four groups: <30 years, 30-49 years, 50-69 years, and >70 years. DST results were compared according to age groups. Results Median post-DST cortisol was 18.49 nmol/L, with a level of 17.9 nmol/L in females and 20.7 nmol/L in males. The overall rate of DST suppression was 62.7%, with a rate of 63.8% in females and 59.7% in males. On pairwise comparisons of all age groups, there was a difference in post-DST cortisol levels (p = 0.000). Our statistical analysis revealed a strong positive correlation between age and cortisol levels after DST. Conclusions The negative feedback mechanism for cortisol may be altered in older patients. Therefore, the 1-mg DST may yield a higher rate of false positives in the elderly.

Dexamethasone Suppression Testing in a Contemporary Cohort with Adrenal Incidentalomas in Two U.S. Integrated Healthcare Systems.

Autonomous cortisol secretion (ACS) from an adrenal adenoma can increase the risk for comorbidities and mortality. The dexamethasone suppression test (DST) is the standard method to diagnose ACS. A multi-site, retrospective cohort of adults with diagnosed adrenal tumors was used to understand patient characteristics associated with DST completion and ACS. Time to DST completion was defined using the lab value and result date; follow-up time was from the adrenal adenoma diagnosis to the time of completion or censoring. ACS was defined by a DST > 1.8 µg/dL (50 nmol/L). The Cox proportional hazards regression model assessed associations between DST completion and patient characteristics. In patients completing a DST, a logistic regression model evaluated relationships between elevated ACS and covariates. We included 24,259 adults, with a mean age of 63.1 years, 48.1% obese, and 28.7% with a Charlson comorbidity index ≥ 4. Approximately 7% (n = 1768) completed a DST with a completion rate of 2.36 (95% CI 2.35, 2.37) per 100 person-years. Fully adjusted models reported that male sex and an increased Charlson comorbidity index were associated with a lower likelihood of DST completion. Current or former smoking status and an increased Charlson comorbidity index had higher odds of a DST > 1.8 µg/dL. In conclusion, clinical policies are needed to improve DST completion and the management of adrenal adenomas.

Pseudo Primary Aldosteronism as Initial Presentation of Ectopic ACTH Syndrome in Metastatic Small Cell Lung Cancer.

Ectopic adrenocorticotropic hormone (ACTH)-secreting syndrome (EAS) is a rare but often aggressive paraneoplastic syndrome. Patients with EAS typically present with high ACTH levels and rapid clinical progression in the setting of acute cortisol elevation, which can delay diagnosis due to a lack of typical Cushingoid features. High levels of ACTH have also been shown to stimulate the adrenal zona glomerulosa to oversecrete aldosterone. We present the case of a 58-year-old male individual presenting with new-onset hypertension and severe metabolic alkalosis with spontaneous hypokalemia, in the setting of elevated aldosterone and low renin levels, suggestive of primary aldosteronism. Subsequent biochemical testing, imaging, and pathology, however, revealed suppression of aldosterone with evidence of hypercortisolism in the setting of metastatic small cell lung cancer. This was, therefore, suggestive of pseudo primary aldosteronism in the setting of a paraneoplastic ectopic ACTH-producing syndrome. This case highlights that hypercortisolism, in the setting of EAS, can initially present with a clinical picture suggestive of hyperaldosteronism. The use of a dexamethasone suppression test can allow the clinician to differentiate between idiopathic bilateral adrenal hyperplasia and ectopic ACTH syndrome.

Inflammation-based scores in benign adrenocortical tumours are linked to the degree of cortisol excess: a retrospective single-centre study.

OBJECTIVE: Benign adrenocortical tumours are diagnosed in ∼5% of adults and are associated with cortisol excess in 30%-50% of cases. Adrenal Cushing's syndrome (CS) is rare and leads to multiple haematological alterations. However, little is known about the effects of the much more frequent mild autonomous cortisol secretion (MACS) on immune function. The aim of this study was to evaluate the haematological alterations in benign adrenocortical tumours with different degrees of cortisol excess. DESIGN AND METHODS: We investigated 375 patients: 215 with non-functioning adrenal tumours (NFAT), 138 with MACS, and 22 with CS. We evaluated the relationship between the degree of cortisol excess and full blood count as well as multiple inflammation-based scores, including the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), and the systemic immune-inflammation index (SII). RESULTS: We observed a gradual and significant increase of leucocytes, neutrophils, and monocytes across the spectrum of cortisol excess, from NFAT over MACS to CS. Neutrophil-to-lymphocyte ratio and SII were significantly higher in both MACS and CS when compared to NFAT (P < .001 and P = .002 for NLR and P = .006 and P = .021 for SII, respectively). Conversely, LMR was lower in MACS and CS than in NFAT (P = .01 and <.001, respectively) but also significantly lower in CS compared to MACS (P = .007). CONCLUSIONS: Neutrophil-to-lymphocyte ratio, SII, and LMR correlated with the degree of cortisol excess in benign adrenocortical tumours and were altered in patients with CS and MACS. These findings suggest that, similar to clinically overt CS, MACS also affects the immune function, potentially contributing to the MACS-associated comorbidities.

Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors.

BACKGROUND: 18Fluorine-Fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of 18F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve 18F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing's disease (CD). METHODS: We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET. RESULTS: Twenty-two patients were included (age at diagnosis: 37 [13-56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006*), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010*; gray matter, 6.25 vs. 7.95, P = 0.010*). CONCLUSION: DEX suppression did not improve 18F-FDG PET/CT localization in patients with CD.

Overnight 1-mg Dexamethasone Suppression Test for Screening Cushing Syndrome and Mild Autonomous Cortisol Secretion (MACS): What Happens when Serum Dexamethasone Is Below Cutoff? How Frequent Is it?

OBJECTIVE: To determine the frequency of "invalid" 1-mg overnight dexamethasone (Dex) suppression tests (DSTs) (1-mg DST) on a large series of patients investigated for hypercortisolism and examine the interference of substances and clinical conditions that may explain low serum Dex levels. METHODS: A retrospective analysis of 1300 Dex-controlled 1-mg DST applied to patients screened for Cushing syndrome or mild autonomous cortisol secretion in a single center for which there were identified invalid tests and distinctive characteristics that may have interfered with the outcome. RESULTS: Among all tests, 146 (11.2%) were considered invalid (serum Dex levels <140 ng/dL, 36 [24.7%] of which were undetectable [<19.5 ng/dL]). In the Dex-undetectable group, 17% failed to take Dex correctly, 25% were on glucocorticoids (GCs), and 20% were on anticonvulsants and moderate CYP3A4 inducers. In the remaining 110 tests (serum Dex 20-140 ng/dL), 6.5% did not take Dex or were using GC, 22% were on anticonvulsants or CYP3A4 inducers, and another 13% had previous gastrointestinal tract abnormalities impairing drug absorption. CONCLUSION: Inappropriately low serum Dex levels during the 1-mg DST may lead to false-positive results. This is associated with recurrent use of CYP3A4-inducing drugs and/or gastrointestinal abnormalities. When serum Dex is undetectable, the key reason is failure to take the medication or the use of GC (when cortisol is suppressed). Simultaneous measurement of serum cortisol and Dex allows for DST validation, improving its accuracy and avoiding unnecessary repetitions. Adherence to verbal/written recommendations and actual use of medication are critical for interpreting the test.