Evaluation of plasma cortisol during fasting test in patients with endogenous hyperinsulinemic hypoglycemia. Fifteen years experience.

BACKGROUND: Endogenous hyperinsulinemic hypoglycemia (EHH) is a rare clinical condition. The aim of this study was to evaluate baseline plasma cortisol concentration and its concentration during hypoglycemic crisis in fasting tests (FT) performed in our center. Secondarily, the aim was to establish the relationship between baseline cortisol and the time of evolution of EHH. MATERIAL AND METHODS: A retrospective, observational, descriptive study was carried out which included patients with hypoglycemic disorder with positive FT. RESULTS: Of a total of 21 patients, 16 presented insulinoma, 1 nesidioblastosis, 2 malignant insulinoma and 2 EHH without pathological diagnosis. The time from the onset of symptoms to diagnosis was 2 years (Q1=1.5-Q2=5.5). The comparison between median baseline cortisol (BC)=11.8 mcg/dl (nmol/L 340.68) (Q1=9-Q3=14.1) and median cortisol during hypoglycemic episode (HC)=11.6 mcg/dl (nmol/L: 303.44) (Q1=7.8-Q3=16.1) showed no differences (Z=-0.08; P>.05). When correlating BC with HC, no significant relationship was observed (r=0.16; P>.05). When correlating the glycemic value in the crisis and the HC, a slight negative trend was found (r=-0.53; P=.01). In addition, we found that recurrent hypoglycemic disorder is associated with lower baseline cortisol values ​​the longer the time of its evolution. CONCLUSION: We confirmed that cortisol values ​​remain low during hypoglycemic episodes, reinforcing the hypothesis of lack of response of this counterregulatory hormone in cases of recurrent hypoglycemia.

Hereditary Renal Cell Carcinoma: Is Age an Independent Criterion for Genetic Testing? A Large Cohort from a Latin America Referral Center.

Although age younger than 46 years has been an independent criterion for genetic testing in hereditary renal cell carcinoma (hRCC), there is a lack of evidence in the literature. This study aims to analyze whether a 46-year-old cut-off should be considered an independent genetic testing criterion and to elucidate risk factors predicting a positive genetic test. Observational study from January 2010 to December 2021. All patients under 46 years with a non-metastatic kidney mass and surgical indication were included. We assume patients who relapse in the first 5 years of follow-up could have a positive genetic test. As risk factors for relapse, ergo positive genetic test, we consider those patients who presented multifocal, bilateral, or previous renal tumor. Of 2,232 nephrectomies for kidney cancer, 301 patients met the inclusion criteria. The median follow-up was 60 months (IQR 29-101). The estimated five-year RFS was 94.4% (95% CI 91.3-97.5). Tumor size, previous renal tumor, multifocality, bilaterality, and pT3 or pT4 stage were independent recurrence risk factors. Genetic testing was performed on 24 patients. 10 patients had pathogenic variants in the test, 8 of which recurred during their life. 46-year-old cut-off has shown low performance in genetic testing. Therefore, we recommend that it be considered only if other hRCC risk criteria exist. Multifocality, bilaterality, and previous renal tumor could predict a positive genetic test.

Metastatic pheochromocytoma and paraganglioma: a retrospective multicentre analysis on prognostic and predictive factors to chemotherapy.

Background: Prognostic and predictive markers in metastatic pheochromocytoma and paraganglioma (mPPGL) are unknown. We aimed to evaluate epidemiology of mPPGL, and prognostic factors of overall survival (OS) and predictive markers of treatment duration with first-line chemotherapy (TD1L). Patients and methods: Retrospective multicentre study of adult patients with mPPGL treated in Latin American centres between 1982 and 2021. Results: Fifty-eight patients were included: 53.4% were female, median age at diagnosis of mPPGL was 36 years and 12.1% had a family history of PPGL. The primary site was adrenal, non-adrenal infradiaphragmatic and supradiaphragmatic in 37.9%, 34.5% and 27.6%, respectively. 65.5% had a functioning tumour and 62.1% had metachronous metastases. Positive uptakes were found in 32 (55.2%) 68Gallium positron emission tomography (PET/CT), 27 (46.6%) 2-deoxy-2-[fluorine-18]fluoro-D-glucose PET/CT and 37 (63.8%) of 131Iodine-metaiodobenzylguanidine (MIBG) tests. Twenty-three (40%) patients received first-line chemotherapy, with cyclophosphamide, vincristine and dacarbazine used in 12 (52%) of patients. At a median follow-up of 62.8 months, median TD1L was 12.8 months. Either functional exams, tumour functionality, pathological characteristics or primary tumour location were significantly associated with response or survival. Yet, negative MIBG, Ki67 ≥ 10%, infradiaphragmatic location and functional tumours were associated with numerically inferior OS. Conclusions: In patients with mPPGL, prognostic and predictive factors to chemotherapy are still unknown, but negative MIBG uptake, Ki67 ≥ 10%, infradiaphragmatic location and functional tumours were numerically linked to worse OS. Our results should be further validated in larger and independent cohorts.

[Adrenal crisis associated with modafinil use]. / Crisis adrenal asociada al uso de modafinilo.

Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treatment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembolism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose replacement in subjects receiving metabolism-inducing drugs.

La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser desencadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Crisis adrenal asociada al uso de modafinilo / Adrenal crisis associated with modafinil use

Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.

[Current role of bilateral adrenalectomy in Ectopic Cushing syndrome.] / Rol actual de la adrenalectomía bilateral en el manejo del síndrome de Cushing Ectópico.

OBJECTIVES: The aim of this paper is to describe the clinical features and the perioperative results of the bilateral laparoscopic adrenalectomy (BLA) of salvaje in 5 patients treated for an Ectopic Cushing Syndrome (CS) who were refractory to medical treatment. MATERIALS AND METHODS: We performed a retrospective analysis of the clinical records of our institution. Five BLAs were performed in patients with Ectopic CS refractory to medical treatment during the period from January 2009 and June 2017. All patients were evaluated by a multidisciplinary team that jointly decided the most appropriate time for surgery. The following protocol data were analyzed: age, sex, location of the secreting tumor, duration of hypercortisolism, reason for hospitalization, initial therapeutic management), biochemical data (pre-op serum cortisol, plasma ACTH and free urinary cortisol), surgical data (surgical approach, surgical time, type of surgery, need for conversion toopen surgery), perioperative data (post op surgical stay, post op complications according to the Clavien-Dindo scale 14, mortality, clinical cure rate and biochemical cure rate, follow up time). RESULTS: Five patients underwent BLA. The approach for the BLA was minimally invasive, either trans peritoneal (n=3) or posterior retroperitoneoscopic (n=2). Mean hospitalization time was 23.4 days (r=4-81). None of the patients died because of surgical complications, and all of them achieved biochemical and clinical remission of their hypercortisolism after surgery. CONCLUSIONS: BLA is an effective salvage alter native to control the symptoms associated with overproduction of corticosteroids in patients with ectopic CS refractory to medical treatment.

OBJETIVO: Describir las características clínicas y los resultados perioperatorios de la adrenalectomía bilateral laparoscópica (ABL) en 5 pacientes tratados con diagnóstico de Síndrome de Cushing Ectópico (SCE).MATERIALES Y MÉTODOS: Se realizó un estudio retrospectivo y descriptivo de todos los pacientes con SCE sometidos a una ABL, entre enero de 2009 y junio de 2017. Todos los pacientes fueron evaluados por un equipo multidisciplinario que decidió conjuntamente el momento más adecuado para la cirugía. Fueron analizados los siguientes datos protocolares: edad, sexo, origen del tumor secretor, duración del hipercortisolismo, motivo de internación, manejo terapéutico inicial, datos bioquímicos (cortisol sérico preoperatorio, ACTH plasmática y cortisol libre urinario), datos quirúrgicos (vía de abordaje, tiempo quirúrgico, tipo de cirugía, necesidad de conversión a cirugía abierta), datos perioperatorios (tiempo de internación postoperatoria, complicaciones según la escala de Clavien-Dindo, mortalidad, tasa de curación clínica y tasa de curación bioquímica, tiempo de seguimiento). RESULTADOS: Cinco pacientes fueron sometidos a ABL. El abordaje fue mínimamente invasivo, ya sea transperitoneal (n=3) o retroperitoneoscópico posterior (n=2). El tiempo de internación fue de 23,4 días (r=4-81). Ningún paciente falleció por complicaciones quirúrgicas, y todos lograron la curación bioquímica y clínica de su hipercortisolismo después de la cirugía. CONCLUSIONES: ABL es un procedimiento de rescate eficaz para controlar los síntomas asociados al hipercortisolismo en pacientes con SCE refractario al tratamiento médico.

Fluconazole treatment in severe ectopic Cushing syndrome

Summary: Severe Cushing syndrome (SCS) is considered an emergency that requires immediate treatment to lower serum cortisol levels. Fluconazole may be considered an alternative treatment in Cushing syndrome when ketoconazole is not tolerated or unavailable. We report a 39-year-old woman with a history of partial pancreaticoduodenectomy due to a periampullary neuroendocrine tumor with locoregional extension. Three years after surgery, she developed liver metastases and was started on 120 mg of lanreotide/month, despite which, liver metastases progressed in the following 6 months. The patient showed extreme fatigue, muscle weakness, delirium, moon face, hirsutism and severe proximal weakness. Laboratory tests showed anemia, hyperglycemia and severe hypokalemia. 24-h urinary free cortisol: 2152 nmol/day (reference range (RR): <276), morning serum cortisol 4883.4 nmol/L (RR: 138­690), ACTH 127.3 pmol/L (RR: 2.2­10). She was diagnosed with ectopic ACTH syndrome (EAS). On admission, she presented with acute upper gastrointestinal tract bleeding and hemodynamic instability. Intravenous fluconazole 400 mg/day was started. After 48 h, her mental state improved and morning cortisol decreased by 25%. The dose was titrated to 600 mg/day which resulted in a 55% decrease in cortisol levels in 1 week, but then had to be decreased to 400 mg/day because transaminase levels increased over 3 times the upper normal level. After 18 days of treatment, hemodynamic stability, lower cortisol levels and better overall clinical status enabled successful bilateral adrenalectomy. This case report shows that intravenous fluconazole effectively decreased cortisol levels in SCS due to EAS. Learning Points: Severe Cushing syndrome can be effectively treated with fluconazole to achieve a significant improvement of hypercortisolism prior to bilateral adrenalectomy. Intravenous fluconazole is an alternative treatment when ketoconazole is not tolerated and etomidate is not available. Fluconazole is well tolerated with mild side effects. Hepatotoxicity is usually mild and resolves after drug discontinuation.

Bilateral pheochromocytoma after kidney transplantation in neurofibromatosis type 1.

We present the case of a 25-year-old male with a history of neurofibromatosis type 1 and bilateral pheochromocytoma 4 years after kidney transplantation that was successfully treated with simultaneous bilateral posterior retroperitoneoscopic adrenalectomy. Learning points: Hypertensive patients with NF1 should always be screened for pheochromocytoma. Pheochromocytoma is rarely associated with transplantation, but it must be ruled out in patients with genetic susceptibility. Posterior retroperitoneoscopic adrenalectomy (PRA) allows more direct access to the adrenal glands, especially in patients with previous abdominal surgeries.

Adrenalectomía laparoscópica: ¿abordaje retroperitoneal posterior o transperitoneal lateral? / Laparoscopic Adrenalectomy: posterior retroperitoneoscopic or lateral transperitoneal approach?

Objetivo: comparar los resultados obtenidos en adrenalectomía retroperitoneoscópica posterior (ARP) con los obtenidos por vía transperitoneal lateral (ATL) a corto y mediano plazo. Material y métodos: estudio de cohortes prospectivo. Se incluyeron 22 pacientes a quienes se les realizaron 24 adrenalectomías (12 ARP y 12 ATL) entre los meses de enero de 2015 y mayo de 2016. En el grupo ARP se realizó a 1 paciente adrenalectomía bilateral simultánea y a 1 paciente, bilateral sincrónica. Fueron comparados datos basales, clínicos, quirúrgicos y evolutivos. Resultados: la mediana de tiempo de seguimiento fue de 6,5 meses (r 1-16). Los grupos ARP y ATL fueron comparables en edad, sexo, BMI y presencia de cirugías previas. Los adenomas fueron las lesiones predominantes (41,7% en cada grupo). El promedio de tiempo operatorio en ART y ATL fue 104,3 ± 21,2 y 146 ± 32,9 minutos, respectivamente (p 0,05). No hallamos diferencias en tiempo de internación, sangrado y complicaciones. Todos los pacientes lograron curación clínica. Conclusiones: la técnica ARP es una vía segura, con resultados comparables a ATL y menor tiempo operatorio. También permite intervenir de manera simultánea y sincrónica ambas glándulas adrenales sin necesidad de reposicionar al paciente.

Objetive: to compare the results of posterior retroperitoneoscopic (PRA) or lateral transperitoneal approach (LTA) in laparoscopic adrenalectomy in the short and medium term. Material y methods: prospective cohort study. We included 22 patients who underwent 24 adrenalectomies (12 PRA and 12 LTA) between January 2015 and May 2016. In the PRA group, two simultaneous bilateral laparoscopic adrenalectomies were performed (1 synchronous bilateral adrenalectomy). Baseline, clinical and surgical outcome were compared. Results: the median follow-up time was 6.5 months (range: 1-16). The PRA and LTA groups were comparable in age, gender, BMI and presence of previous surgeries. Adenomas were the predominant lesions (41.7% in each group). The average operating time in PRA and LTA was 104.3 ± 21.2 and 146 ± 32.9 minutes, respectively (p=0.05). We found no differences in length of hospital stay, bleeding and complications. All patients achieved clinical cure. Conclusions: the PRA technique is a safe approach, with results comparable to LTA and shorter operating time. It also allows to intervene simultaneously and synchronously both adrenal glands without the need of repositioning the patient.

Carney complex review: Genetic features. / Revisión del complejo de Carney: Aspectos genéticos.

Carney complex is a multiple neoplasia syndrome having endocrine and non-endocrine manifestations. Diagnostic criteria include myxoma, lentigines, and primary pigmented nodular adrenocortical disease, amongst other signs/symptoms. In most cases it is an autosomal dominant disease, and diagnosis therefore requires study and follow-up of the family members. Inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 other disease-related genes, including PRKACA and PRKACB activating mutations, have also been related with Carney complex. This review will address the genetic aspects related to Carney complex.

Aberrant expression of glucagon receptors in adrenal glands of a patient with Cushing's syndrome and ACTH-independent macronodular adrenal hyperplasia.

Adrenocorticotropin (ACTH) independent bilateral macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing's syndrome, characterized by bilateral adrenal lesions and excess cortisol production despite ACTH suppression. Cortisol synthesis is produced in response to abnormal activation of G-protein-coupled receptors, such as gastric inhibitory peptide, vasopressin, beta adrenergic agonists, LH/hCG and serotonin receptors. The aim of this study was to analyze the expression of glucagon receptors in adrenal glands from an AIMAH patient. A patient with ACTH-independent Cushing's syndrome and bilateral macronodular adrenal hyperplasia was screened for altered activation of adrenal receptors by physiological (mixed meal) and pharmacological (gonadotrophin releasing hormone, ACTH and glucagon) tests. The results showed abnormally high levels of serum cortisol after stimulation with glucagon. Hypercortisolism was successfully managed with ketoconazole treatment. Interestingly, a 4-month treatment with a somatostatin analogue (octreotide) was also able to reduce cortisol secretion. Finally, Cushing's syndrome was cured after bilateral adrenalectomy. Abnormal mRNA expression for glucagon receptor in the patient's adrenal glands was observed by Real-Time PCR procedure. These results strongly suggest that the mechanism of AIMAH causing Cushing's syndrome in this case involves the illicit activation of adrenal glucagon receptors. This is the first case reported of AIMAH associated with ectopic glucagon receptors.

Retrospective multicentric study of pituitary incidentalomas.

Previously unsuspected pituitary tumors (incidentalomas) were analyzed in autopsies (4.8-27%) and magnetic resonance imaging (MRI) (10-37%), most of them being micro-pituitary incidentalomas (PI). However, patients with PIs sometimes had macroadenomas which may relate to previously unsuspected neurological and/or endocrine abnormalities. This study aims to establish the incidence of macro- vs. micro-PIs, the need for medical and/or surgical treatment and the neurological and endocrine dysfunction in a retrospective evaluation of patients with PIs studied over six years (1994-2000). Thirty-eight of 46 patients with PIs (22 males), aged 16-77, were followed for a mean of 3.2 years. Initial hormonal testing, ophthalmologic evaluation and MRI were repeated during follow-up. Twenty-nine (63%) of 46 patients had macro-PIs and 17 (17%) micro-PIs. Twenty-three males (75%) had macro-PIs, 10 (34.5%) with visual field defects. Consultations leading to PI diagnosis were chronic headache (28%), cranial trauma (15.3%), sinusitis (13%) and stroke (13%). Partial deficiencies of the anterior pituitary function were confirmed in 19 PIs (41.3%), with secondary hypogonadism prevailing (30%). Seven PIs (15%) were prolactinomas treated with dopamine agonists. Seventeen PIs (37%) underwent surgery. Immunohistochemical analysis showed gonadotrophinomas (30%), plurihormonal non-secreting adenomas (40%), and pituitary adenomas not reacting to any of the anterior pituitary hormone antibodies (30%). One operated macro-PI was a craniopharyngioma. Our data show a high percentage of PIs are macro-incidentalomas against expectations from necropsy and imaging studies. Most macro-PIs are found in males and are clinically non-functioning adenomas, 37% requiring surgery and hormonal substitution.