Carles Villabona

Profile, mean residence time of ACTH and cortisol responses after low and standard ACTH tests in healthy volunteers

Objective  No consensus exists until now about the suitable dose of tetracosactin in the ACTH stimulation test for detecting adrenal insufficiency. Our aim was to characterize both the ACTH(1–24) and the cortisol profiles after standard high‐dose test (250 µg) (HDT) and low‐dose test (1 µg) (LDT) in healthy subjects in order to provide a deeper knowledge about the relationship between stimulus and response.

Prolactinomas in men: a multicentre and retrospective analysis of treatment outcome

To assess treatment outcome in male patients with micro‐ and macroprolactinomas.

Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study

Pegvisomant is an effective treatment for acromegaly.

Guía clínica del diagnóstico y tratamiento de la apoplejía hipofisaria

La apoplejia hipofisaria (AH) es un fenomeno isquemico o hemorragico que aparece generalmente en un adenoma hipofisario. La AH se produce como consecuencia de un infarto con aparicion posterior de hemorragia y edema del tumor. La forma aguda se considera una urgencia neuroendocrinologica, ocurre de forma brusca y se caracteriza por un cuadro de cefalea brusca, junto con nauseas, vomitos, alteraciones del campo visual y afeccion de pares craneales. La forma subclinica es mas frecuente y es silente. El diagnostico de la AH se basa en un cuadro clinico tipico en el contexto de un tumor hipofisario. La AH puede provocar cualquier deficiencia hormonal hipofisaria transitoria o permanente. El deficit brusco de corticotropina y de cortisol es el mas importante, por el riesgo vital que conlleva. En el momento de la sospecha diagnostica se debe llevar a cabo una evaluacion endocrinologica con determinacion de las hormonas basales hipofisarias y las correspondientes perifericas. Posteriormente, se realizara una valoracion endocrinologica en la fase de estabilizacion encaminada a evaluar el funcionamiento remanente de la hipersecrecion hormonal, en el caso de tumores funcionantes previos, y al diagnostico de un posible hipopituitarismo permanente como secuela de la AH. Para la confirmacion de la sospecha diagnostica clinica se debe realizar una prueba de neuroimagen, una tomografia computarizada o una resonancia magnetica hipofisarias. No existe un consenso sobre el tratamiento optimo de la AH. Clasicamente, dado que el determinante de la lesion por AH es el aumento de la presion intraparaselar, la cirugia descompresiva se consideraba el tratamiento de eleccion. Sin embargo, en los ultimos anos se ha utilizado el tratamiento medico conservador con esteroides, especialmente si no existen deficit visuales.

Development of a new tool for assessing Health-Related Quality of Life in patients with primary hyperparathyroidism

BackgroundSeveral studies in recent years have evaluated Health Related Quality of Life (HRQoL) of patients with primary hyperparathyroidism (PHPT). No disease specific questionnaires are available to assess the impact of the disease. The aim of this research is to describe the development of a new disease specific Quality of Life (QoL) questionnaire for use specifically with PHPT patients.MethodsA conceptual model was developed describing the impact of the disease and its symptoms on QoL domains. A literature review was conducted to identify the most relevant domains. A focus group with experts was used to validate the domains; 24 patients were also interviewed to complement the information from the patient’s perspective. A content analysis of the interviews was performed to identify items related with the impact of the disease, leading to PHPQoL-V.1 which was presented to a sample of 67 patients. Reliability was assessed by Cronbach’s coefficient alpha and item-total score correlations. Validity was assessed by a factor analysis performed to determine the number of domains. Rasch analysis was carried out in order to refine the questionnaire items.Results259 items were extracted from the interviews that were subsequently reduced to 34 items. Cronbach’s coefficient alpha was 0.92. The factor analysis extracted two domains (physical and emotional). After Rasch analysis the questionnaire PHPQoL-V.2 kept 16 items (9 physical and 7 emotional). The questionnaire was developed in a Spanish population and the final version was translated to English through translation and back-translation.ConclusionThe first disease specific HRQoL questionnaire for PHPT patients (PHPQoL-16) has been developed. Validation studies designed to assess measurement properties of this tool are currently underway.

Guía clínica de manejo de la diabetes insípida y del síndrome de secreción inapropiada de hormona antidiurética en el postoperatorio de la cirugía hipofisaria

Changes in water metabolism and regulation of vasopressin (AVP) or antidiuretic hormone (ADH) are common complications of pituitary surgery. The scarcity of studies comparing different treatment and monitoring strategies for these disorders and the lack of prior clinical guidelines makes it difficult to provide recommendations following a methodology based on grades of evidence. This study reviews the pathophysiology of diabetes insipidus and inappropriate ADH secretion after pituitary surgery, and is intended to serve as a guide for their diagnosis, differential diagnosis, treatment, and monitoring.

Antagonistas del receptor de vasopresina: los vaptanes

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca(++) being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.We herein report a 30 years old male patient with AIDS and Cryptosporidium diarrhea diagnosed by intestinal biopsy. After some days of unsuccessful conventional anti-diarrheal treatment, an analog of somatostatin (octreotide acetate) Sandostatin was started. The stool volume and the bowel movements decreased dramatically and in spite of some collateral effects the patient could be clinically improved and discharged from the hospital.Resumen Los antagonistas no peptidicos de la vasopresina (AVP), llamados vaptanes, se desarrollaron en la decada de los noventa con el fin de antagonizar tanto su efecto presor como antidiuretico. Se distinguen 3 subtipos de receptores de la AVP: V1a, V1b y V2. Los primeros se hallan ampliamente distribuidos en el organismo, y las localizaciones en vasos y miocardio son las mas destacadas. Los receptores V1b esencialmente estan en la hipofisis anterior y median la liberacion de corticotropina (ACTH). Por su parte, los receptores V2 se encuentran principalmente en las celulas del tubulo colector renal. Tanto los receptores V1a como V1b actuan a traves del calcio (Ca ++ ) intracelular. El receptor V2 actua a traves de la generacion de adenosin monofosfato-3’,5’ ciclico (AMPc), que en ultimo termino genera la movilizacion de la aquaporina 2 (AQP2), que produce un aumento de la permeabilidad y permite la entrada de agua al interior de la celula. Los vaptanes actuan de forma competitiva a nivel de receptor de la AVP. Los mas importantes son mozavaptan, lixivaptan, satavaptan y tolvaptan, que son antagonistas selectivos V2 y se administran por via oral. Conivaptan es un antagonista tanto de V1 como de V2 y su empleo es por via intravenosa. Las caracteristicas generales mas importantes de todos ellos son su efecto sobre la eliminacion unicamente de agua libre sin afectar la excrecion de electrolitos. Hay diferentes estudios de todos ellos, tanto en estado de hiponatremia hipervolemica, como la insuficiencia cardiaca o cirrosis hepatica, como en la normovolemica, como el sindrome de secrecion inadecuada de hormona antidiuretica (SIADH). Los estudios actuales muestran que los vaptanes son efectivos y bien tolerados, aunque las limitaciones se derivan de un conocimiento insuficiente de estos farmacos. No hay estudios de los vaptanes en cuadros de hiponatremia grave y no se han descrito cuadros de desmielinizacion osmotica por correccion excesiva de la hiponatremia.

Prevalence, Clinical Features, and Natural History of Incidental Clinically Non-Functioning Pituitary Adenomas

The objective of the study was to assess the prevalence and clinical features of incidentally discovered clinically non-functioning pituitary adenoma (CNFPA) and to analyze its natural history. A multicenter retrospective study in patients diagnosed with incidental CNFPA periodically followed-up in 3 specialized neuroendocrinology units from 1992 to 2015 was performed. Out of a total of 189 CNFPA patients, 57 cases (30.1%; 29 women; age at diagnosis 55.8±16.7 years) were incidental. Most patients (n=55, 96.5%) were diagnosed by magnetic resonance imaging (MRI). A sum of 71.9% (n=41) were macroadenomas; 2 of them (3.5%) were giant adenomas (≥4 cm). Patients with macroadenomas were older than those with microadenomas (59.5±16.7 vs. 46.4±18.1 years, p=0.007). Macroadenomas were more common in men (85.7% vs. 58.6%, p=0.023). Twenty-eight patients (49.1%) showed suprasellar extension; of these, 19 were accompanied by chiasmatic compression. Hypopituitarism was present in 14 (24.6%) patients; which was partial in 13 patients (22.8%) and complete in one patient (1.8%). The gonadal axis was the most frequently affected (n=13, 22.8%). Twenty four patients (42.1%) underwent surgery. Of the non-operated patients, 26 patients could be evaluated morphologically after a median follow-up of 15.5 months (interquartile range, 5.7-32.7 months). No significant changes were found in the maximum tumor diameter at the end of follow-up (1.2±0.6 vs 1.2±0.7 cm). The majority of CNFPAs evaluated (n=23, 88.5%) did not show any changes in size. In 2 cases (7.7%) tumor size decreased, and in one patient (3.8%) increased. In our series of CNFPA patients, approximately one-third were incidental. These tumors were diagnosed by MRI preferably from the 5th decade of life without sex predilection. Most of them were macroadenomas, more commonly diagnosed in men and at an older age, compared to microadenomas. The suprasellar extension with chiasmatic compression and hypopituitarism were frequent at diagnosis. Most of the non-operated incidental CNFPAs remain with stable tumor size over time, growth being an unusual event.

Non-functioning pituitary adenoma underwent surgery: A multicenter retrospective study over the last four decades (1977–2015)

OBJECTIVE To assess clinical features, diagnostic procedures, therapies and outcomes in patients with clinically non-functioning pituitary adenomas (NFPAs) surgically treated over the last four decades. DESIGN AND METHODS A multicenter retrospective study in NFPA patients periodically followed up in specialized neuroendocrinology units who underwent surgery in the period 1977-2015 was performed. RESULTS A total of 131 patients were studied [66 women (50.4%); mean age 52.6±14.8years (range, 15-82)]. Median diameter of the adenoma was 2.6cm (interquartile range, 2.0-3.1). The most frequently type of surgery used was endoscopic endonasal surgery (58.5%) followed by microscopic transsphenoidal surgery (37.4%). Radiation therapy was used in 19 patients (14.5%). Ki-67 labeling index performed in 54 patients was ≤2% in 70% samples. After a median follow-up time of 57months (25 to 128months), tumor diameter significantly decreased to 0.9cm (0-1.8cm), p<0.001. Multivariant analysis showed that endoscopic endonasal surgery (HR 2.74, 1.06-6.87, p=0.036) and radiotherapy (HR 0.04, 0.02-0.65, p=0.024) behaved as positive and negative predictors, respectively, of tumor absence in the follow-up. Endoscopic endonasal surgery (HR 6.71, 1.45-31.05, p=0.015) was the only positive predictor for complete cure in the follow-up. CONCLUSION NFPAs surgically treated in Spain are usually macroadenomas diagnosed around the sixth decade of life with no sex predilection. Type of surgery is associated with clinical outcome. Endoscopic endonasal surgery behaves as a positive predictor for the absence of tumor imaging and complete cure in the follow up.

Biología molecular, epidemiología y clasificación de los tumores neuroendocrinos gastroenteropancreáticos (TEGEP)

Los tumores neuroendocrinos gastroenteropancreaticos (TEGEP) constituyen un grupo de tumores poco frecuentes con rasgos biologicos comunes. El estudio de la biologia molecular de estos tumores ha revelado que las alteraciones mas frecuentes se encuentran en genes relacionados con la regulacion de la transcripcion genica, los genes reguladores del ciclo celular y los genes de mantenimiento de la estabilidad del genoma celular. En el caso de los tumores neuroendocrinos hereditarios, el gen alterado con mas frecuencia es el gen supresor tumoral de la neoplasia endocrina multiple tipo 1 (MEN1), que codifica para la proteina menina, cuya funcion se desconoce. El analisis especifico de los genes y sus alteraciones implicados en la iniciacion y el desarrollo de los TEGEP puede ser de utilidad clinica, tanto para un diagnostico mas preciso, como en el desarrollo de marcadores predictivos de la evolucion clinica o de la respuesta al tratamiento, y tambien en el diseno de farmacos especificos. La incidencia de los TEGEP es inferior a 2,2/100.00 habitantes/ano, y globalmente son mas frecuentes en mujeres y en poblacion de raza negra. La localizacion mas frecuente es la digestiva, seguida del area pulmonar. Aunque la mayoria son esporadicos, se pueden asociar a algunos sindromes hereditarios. En esta circunstancia, presentan una evolucion mas lenta, lo que se traduce en una supervivencia superior a la de los esporadicos. La clasificacion general de los TEGEP incluye 3 categorias: tumores endocrinos bien diferenciados, que en el caso de los pancreaticos se dividen en los que presentan un comportamiento benigno y aquellos cuyo comportamiento es incierto, carcinomas endocrinos bien diferenciados y carcinomas endocrinos mal diferenciados.