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info:eu-repo/grantAgreement/ISCIII/Programa Estatal Para Afrontar las Prioridades de Nuestro Entorno./PMP22%2F00021/ES/ACROMICS: medicina de precisión de futuro en el diagnóstico y tratamiento de la Acromegalia

Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.

To evaluate the diagnostic accuracy of the different tests commonly used in the evaluation of adrenal incidentalomas (AIs) for the identification of autonomous cortisol secretion (ACS) and comorbidities potentially related to ACS. In a retrospective study of patients with AIs ≥ 1 cm, we evaluated the diagnostic reliability and validity of the dexamethasone suppression test (DST), urinary free cortisol (UFC), ACTH, late-night salivary cortisol (LNSC), and dehydroepiandrosterone-sulphate (DHEAS) for the diagnosis of comorbidities potentially related to ACS. Diagnostic indexes were also calculated for UFC, ACTH, LNSC, and DHEAS considering DST as the gold standard test for the diagnosis of ACS, using three different post-DST cortisol thresholds (138 nmol/L, 50 nmol/L and 83 nmol/L). We included 197 patients with AIs in whom the results of the five tests abovementioned were available. At diagnosis, 85.9% of patients with one or more AIs had any comorbidity potentially related to ACS, whereas 9.6% had ACS as defined by post-DST cortisol > 138 nmol/L. The reliability of UFC, ACTH, LNSC, and DHEAS for the diagnosis of ACS was low (kappa index < 0.30). Of them, LNSC reached the highest diagnosis accuracy for ACS identification (AUC = 0.696 [95% CI 0.626–0.759]). The diagnostic performances of these tests for comorbidities potentially related to ACS was poor; of them, the DST was the most accurate (AUC = 0.661 [95% CI 0.546–0.778]) and had the strongest association with these comorbidities (OR 2.6, P  = 0.045). Patients presenting with increased values of both DST and LNSC had the strongest association with hypertension (OR 7.1, P  = 0.002) and with cardiovascular events (OR 3.6, P  = 0.041). In conclusion, LNSC was the test showing the highest diagnosis accuracy for the identification of ACS when a positive DST was used as the gold standard for its diagnosis. The DST test showed the strongest association with comorbidities potentially related to ACS. The definition of ACS based on the combination of elevated DST and LNSC levels improved the identification of patients with increased cardiometabolic risk.

PurposeTo review the literature assessing the diagnostic performance of urinary steroid profiling (USP) by high-performance liquid chromatography (LC–MS) or gas chromatography (GC) coupled to mass spectrometry (MS) in the evaluation of adrenal lesions, both in terms of functionality and malignancy.ResultsThe evaluation of adrenal incidentalomas (AI) aims to rule out malignancy and hormone excess. Current diagnostic protocols have several limitations and include time consuming and relatively complicated multi-step processes in most cases. On the contrary, USP by LC–MS/MS or LC-GC/MS offer an easy, comprehensive and non-invasive assessment of adrenal steroid secretion. USP complements current workups used in the evaluation of AIs by improving our ability to identify malignancy and/or autonomous hormone secretion.ConclusionsUrine steroid profiling by LC–MS/MS and GC–MS allows a thorough, non-invasive, assessment of adrenal steroidogenesis as a whole which complement the current evaluation of AIs, and holds a promising role in the diagnosis of autonomous cortisol secretion, primary aldosteronism, and adrenal malignancy.

BackgroundTwo types of ectopic Cushing syndrome (ECS) are described: ECS associated with aggressive neoplasms, and ECS with indolent and occult tumors, however, there is a lack of studies that thoroughly review their characteristics.MethodsA systematic review was carried out on PUBMED of all the papers about the ECS, in order to better define the types of this subcategory of Cushing’s syndrome, highlighting the differential aspects between these subgroups.ResultsIt was found that in 50% of cases the prototypic “aggressive” ECS is caused by small cell lung carcinomas (SCLC). In these cases, the clinical presentation may be atypical, predominating the signs and symptoms derived from the protein catabolism. Cortisol and ACTH levels are extremely high, the clinical presentation is abrupt (< 3–6 months) and the tumor is usually advanced, being impossible a curative treatment. On the other hand, “indolent” ECS is mainly represented by carcinoid tumors (CT). In these cases the clinical presentation overlaps enormously with that of Cushing’s disease (CD). Cortisol and ACTH levels are slightly elevated, the clinical presentation is progressive (> 6 months) and the prognosis is usually good, and a curative treatment is possible in about 75% of the cases.ConclusionAlthough there is no absolute differentiation between the two extremes of ECS, a classification could be established in two groups, guided by its clinical and biochemical characteristics, and mainly by the type and stage of the ACTH-secreting tumor. However, a small percentage of tumors do not fit in this simple grouping, and may present both phenotypes or an intermediate one.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension and is associated with a higher cardiometabolic risk than essential hypertension. The aim of this consensus is to provide practical clinical recommendations for its surgical and medical treatment, pathology study and biochemical and clinical follow-up, as well as for the approach in special situations like advanced age, pregnancy and chronic kidney disease, from a multidisciplinary perspective, in a nominal group consensus approach of experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology and Spanish Association of Surgeons (AEC). Keypoints The treatment of choice for PA is medical therapy with mineralocorticoid receptor blockade for bilateral cases and unilateral adrenalectomy for unilateral PA. The goals of PA treatment are to normalize blood pressure (BP) and excessive aldosterone production, with the final aim of improving associated comorbidities and reducing mortality. Spironolactone is usually the mineralocorticoid receptor antagonist (MRA) of choice for medical treatment of PA. However, eplerenone has a similar efficacy to that of spironolactone when used in doses 2–3 times higher than the latter and administered 2–3 times a day. Eplerenone has the advantage of not inducing the anti-androgenic side effects commonly seen with spironolactone. Adrenalectomy is the gold standard procedure used to remove the aldosterone-hypersecreting adrenal tissue. The Primary Aldosteronism Outcome (PASO) group criteria are recommended for defining the control objectives of biochemical and clinical response to treatment.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 ± 33.2 versus 20.6 ± 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 ± 43.1 versus 4.7 ± 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the “out of phase” MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytoma.

PurposeTo investigate the status of preoperative anterior pituitary function in patients undergoing pituitary adenoma (PA) resection and to identify factors associated with preoperative anterior pituitary dysfunction (APD).MethodsPatients with functioning and nonfunctioning PAs who underwent pituitary adenoma resection for first time, from January 2009 to December 2019 were analyzed.ResultsTotal sample included 232 patients; 123 (53.2%) females, mean age at diagnosis was 53.3 years. Sixty-three percent presented as nonfunctioning PAs and 37.1% as functioning PAs. Eighty-eight percent were macroadenomas and 34.9% had cavernous sinus invasion. APD was demonstrated in 36.2% (n = 84) of the patients. The FSH/LH deficit was the most frequent anterior pituitary deficit (31.9%); followed by ACTH (18.1%); TSH (16.4%) and GH (13.8%). We identified as independent risk factors of APD, male sex (OR = 6.1, 95% CI = 3.3–11.0); age (OR = 1.03 for each year, 95% CI = 1.01–1.04), diabetes mellitus (OR = 3.5, 95% CI = 1.63–7.69), pituitary apoplexy presentation (OR = 4.3, 95% CI = 1.3–14.5) and tumor size (OR = 1.06 for each mm, 95% CI = 1.04–1.09). Nonfunctioning PAs (NFPA) had higher risk of APD than functioning PAs (FPA) (OR = 2.8 (95% CI = 1.5–5.0), but these differences disappeared after adjusted by tumor size (OR adjusted by tumor size = 1.7, 95% CI = 0.9–3.3). The tumor size with the highest diagnostic accuracy to predict hypopituitarism was 22 mm (sensitivity of 61.9% and specificity of 70.1%).ConclusionMore than one third of PAs candidates for surgery had APD. The male sex, diabetes, an older age, pituitary apoplexy, and larger PAs were risk factors of APD. Hence, in these patients, the hormonal study should be prioritized and the need for dynamic tests must be carefully assessed.

Recurrent pituitary apoplexy: a rare event with favorable outcomes Pituitary apoplexy is a sudden bleeding or infarction within a pituitary tumor that can cause headache, visual loss, and hormonal imbalance. Most patients experience this event only once in their lifetime, but in rare cases, it may happen again, this condition is called recurrent pituitary apoplexy. In this study, we analyzed nearly 300 patients from the Spanish Pituitary Apoplexy Registry, one of the largest series worldwide. Only 3% of patients had a second episode, and these recurrences were generally not more severe than the first. Recurrence was slightly more common in patients with larger or invasive tumors and in those previously treated with dopamine agonists, such as cabergoline. Overall, the study shows that recurrent pituitary apoplexy is very uncommon and that patients can be reassured about their favorable long-term prognosis. Continued follow-up is recommended, especially for those with residual or invasive tumors, but no specific additional monitoring is usually required.