Aspects récents dans le diagnostic du phéochromocytome

Phaeochromocytomas are catecholamine-secreting tumours that arise from chromaffin cells of the adrenal medulla and extra-adrenal sites. Extra-adrenal phaeochromocytomas are called paragangliomas. A diagnosis of phaeochromocytoma is suspected by typical paroxysmal symptoms, unusual or refractory hypertension, discovery of an adrenal incidentaloma or a family history of phaeochromocytoma or paraganglioma, possibly associated with other genetic syndromes (multiple endocrine neoplasia type 2 A or B, neurofibromatosis type 1 and von Hippel-Lindau disease). It can be confirmed by measurements of urinary and plasma fractionated metanephrine and catecholamines. Experts currently recommend a determination of free or fractionated plasma metanephrine as the first test. Increased serum chromogranin-A levels, combined with high catecholamine or metanephrine in a patient with normal renal function is also a tool, virtually diagnostic of phaeochromocytoma. Recent studies have suggested that 25 % of patients with phaeochromocytoma had germline mutations of certain genes (NFI, VHL, SDHD, SDHB and RET). Thus, genetic testing should be carried out according to an algorithm of risk factors and specific characteristics. Once a biochemical diagnosis of phaeochromocytoma is made, a CT Scan or MRI of the abdomen and pelvis should be performed first. If these investigations remain negative, the chest and neck should be explored. After anatomical imaging, functional imaging by 123I-MIBG should be considered. If the MIBG scan is negative, other imaging modalities have recently proven to be useful (PET, Octreoscan)

Expression accrue de l'endothéline-1 et de son récepteur mitogène ET(A) dans le cancer papillaire de la thyroïde chez l'homme.

Since its discovery in 1988, endothelin has initiated intense research activities, showing that it was not only a vasoconstrictor and mitogenic peptide produced by the vascular endothelium but also a ubiquitous molecule with various functions. A production of ET-1 has been evidenced in the thyroid and ET-1 receptors have been detected on thyroid cells. Produced by the vessels and the thyrocytes, ET-1 could exert paracrine and/or autocrine effects on vascular tone in the thyroid and on some functions of thyrocytes. Because of proliferative effects, its role in thyroid diseases could involve goitrogenesis and carcinogenesis. Using thyroid samples obtained at the time of surgery, we demonstrated increased expressions of ET-1 and its mitogenic receptor ET(A) in papillary carcinoma of the thyroid. Immunohistochemical studies and real-time quantitative polymerase chain reaction (RTQ-PCR) were used for this purpose. As demonstrated in other cancers, activation of endothelin axis, particularly through ET(A) receptor could contribute to cell proliferation, cell survival, angiogenesis and the development of bone metastases. ET-1 is also a proinflammatory mediator and we demonstrated an overexpression of ET-1 and of its receptor ET(A) in Hashimoto's thyroiditis. This suggests a role of ET-1 as a cytokine. In nodular goitre, ET-1 is also overexpressed but to a lesser extent than in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Finally, antagonists of ET-1 receptors are currently under development and could be used in man. They could open new therapeutic perspectives in the treatment of metastatic thyroid carcinoma

Therapeutic role of bosentan in hypertension: lessons from the model of perinephritic hypertension.

Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET(A) receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET(B) receptor releasing nitric oxide (NO). In certain instances, ET(B) smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET(A) and ET(B)) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated

Atrial natriuretic factor and endothelin : study of regulatory mechanisms and pathophysiological roles

Cette thèse est consacrée à deux peptides de découverte récente appartenant tout deux au système cardiovasculaire, l’hormone natriurétique cardiaque (ou ANF pour « atrial natriuretic factor ») et l’endothéline. L’ANF est produit par les cellules est sécrétée par les cellules endothéliales des vaisseaux. A. Etudes sur l’ANF nos premiers travaux ont démontré que l’ANF est actuellement un facteur indispensable à considérer pour étudier la régulation de l’équilibre hydro-sodé. En effet, à concentrations physiologiques, il induit une perte rénale d’eau et de sodium ainsi qu’une inhibition de l’activité de la rénine. Dans la vie quotidienne, il existe une régulation très fine de l’ANF, qui est à la fois sujet à une modulation posturale et à un rythme biologique. De plus, l’AFN augmente durant l’effort et pourrait intervenir dans certaines modifications hémodynamiques liées à l’effort. Enfin, nous avons démontré que le principal stimulus de la production d el’ANF chez l’homme est la distension des oreillettes et qu’il existe une relation étroite entre les taux circulants d’ANF et les pressions de remplissage du cœur. Plusieurs travaux avaient suggéré un rôle du système nerveux autonome sur la libération de l’ANF. Dans le but de cerner les rôles respectifs du système nerveux autonome et de la distension des oreillettes dans la stimulation de l’ANF induite par l’effort, nous avons analysé la réponse de l’ANF à l’effort dans la neuropathie autonome diabétique ainsi qu’en présence d’une inhibition bêta-adrénergique. Ces deux études ont permis de conclure à un rôle mineur de l’activation adrénergique dans la libération de l’ANF et à l’effort et à un rôle prépondérant de la distension auriculaire. Il nous a également paru important d’évaluer de manière directe le rôle des pressions de remplissage du cœur à l’effort. Cette étude a été réalisé chez des patients présentant une insuffisance cardiaque congestive. Nous avons ainsi démontré que les taux d’ANF (déjà augmentés en état basal dans l’insuffisance cardiaque) augmentent à l’effort en relation directe avec l’augmentation des pressions de remplissage du cœur. Nous avons également étudié l’ANF dans diverses situations pathophysiologiques : le jeûne, le syndrome de sécrétion inappropriée de l’hormone antidiurétique, le phéochromocytome, le syndrome de Cushing et les tachycardies supraventriculaires. B. Etudes sur l’endothéline-1 Pour étudier les effets cardiovasculaires et endocrines de l’endothéline à concentrations pathophysiologiques et pharmacologique, nous avons choisi le modèle du chien conscient, car il permet une évaluation hémodynamique très complète chez un animal dont les divers mécanismes de régulation neuro-humoraux et réflexes sont opérationnels. En reproduisant des taux circulants d’endothéline semblables à ceux observés dans l’infarctus du myocarde, nous avons démontré que l’endothéline, au lieu d’induire la vasoconstriction attendue, produit une vasodilatation et les phénomènes réflexes associés (tachycardie, stimulation sympathique). Par contre, à concentrations pharmacologiques, nous reproduisons les effets vasoconstricteurs connus. L’étude de la fonction cardiaque révèle qu’à doses pathophysiologiques, l’endothéline induit une augmentation de contractilité cardiaque. Par contre, des taux pharmacologiques d’endothéline dépriment la fonction myocarde. Ces fonctions importantes de l’endothéline n’avaient pas encore été décrites auparavant. D’autres effets pharmacologiques de l’endothéline ont aussi été constatés : une stimulation de l’ANF, une altération de la fonction rénale et un effet hypoglycémiant. Dans une deuxième étape, nous avons recherché si l’endothéline, à taux pathophysiologiques, peut moduler la libération de l’ANF induite pas l’hypervolémie. Cette étude a également été réalisée chez le chien conscient. Comme chez l’homme, nous avons trouvé chez le chien une stimulation de l’ANF par l’hypervolémie et une corrélation avec les pressions auriculaires. Un effet stimulant direct de l’endothéline sur l’ANF indépendant de l’effet de la pression a été mis en évidence, ce qui apporte par rapport à l’étude antérieure une information importante et complémentaire. Par contre, les antagonistes du calcium ne modifient pas la stimulation de l’ANF par l’hypervolémie. En conclusion, nous avons étudié deux peptides aux effets antagonistes sur le système cardiovasculaire et rénal. L’un et l’autre sont actuellement des facteurs indispensables à considérer parmi les mécanismes régulant le volume circulant et l’équilibre hydro-sodéOur studies have contributed to a better knowledge of regulatory mechanisms and of the pathophysiology of two recently discovered peptides, ANF and endothelin. A. ANF studies Our first works have demonstrated that studying ANF is currently a prerequisite when regulation of body fluid volume or of sodium balance is considered. Indeed, at physiological plasma concentrations, ANF provokes a renal loss of water and sodium as well as an inhibition or renin activity. In the normal daily life, ANF is finely regulated and subject to postural and diurnal variations. Moreover, ANF is stimulated by exercise and could play a role in the hemodynamic changes associated with exercise. We also demonstrated that the main stimulus of ANF release in man is atrial distension and that close relationships are found between circulating ANF concentrations and cardiac filling pressures. These studies, thus, suggest the existence of a feed back system where distension of atria leads to a release of ANF which, in turn, by its biological effects on vessels and kidney, initiates a decrease in cardiac filling pressures. Several works have suggested a role of the autonomic nervous system in the release of ANT. To evaluate the respective roles of the autonomic nervous system and of atrial distension in the release of ANF, we have analysed the ANF response to exercise in diabetic autonomic neuropathy and after beta-adrenergic blockage. Both of these studies allowed to conclude that beta-adrenergic activation does not play a role in the release of ANF during exercise but that atrial distension is the main determinant. We also examined directly the role of filling pressures during exercise by invasive measurements. This was achieved in patients with congestive heart failure, in whom a functional assessment during exercise was required. These studies also demonstrated that ANF levels (already increased in basal state in congestive heart failure) were regulated during exercise directly by left filing pressures. in a series of other studies, we evaluated the potential role of ANF in various physiopathological situations. Thus, a study was conducted to evaluate whether changes in ANF concentrations could account for the unexplained fasting natriuresis. A potential role of ANF in this natriuresis was excluded. We also measured ANF in several pathological conditions. Plasma ANF concentrations were found to increase in supraventircular tachycardia and to return to normal levels after a successful cardioversion, suggesting a role of ANF in the well-known polyuria associated with these tachyarrhythmias. Studies of endocrine disorders, such as hypersorticism and SIADH, also suggested that some hormones like cortisol and AVP, could stimulate directly the release of ANF. In pheochromocytoma, catecholamines also stimulate AFN release but their direct or indirect ‘hemodynamic) effects are difficult to differentiate. The role of ANF in these pathological states is to counteract the effects of abnormal hormonal secretions. B. ET-1 studies We have studied the cardiovascular and endocrine effects of endothelin at pathophysiological and pharmacological plasma concentrations in conscious dogs. This animal model allowed to provide extensive hemodynamic measurements in conditions where reflexes were intact and in response to a substance, potentially dangerous on man. We created circulating endothelin levels similar to those observed in myocardial infraction (2-3 fold increase above baseline) and demonstrated that these endothelin levels induce vasodilatations and the reflex responses associated with this condition (tachycardia, sympathetic stimulation). In contrast, at pharmacological concentration (170-fold above baseline), endothelin exhibited its typical vasoconstrictor activity. Hemodynamic data also suggested an increase followed by a decrease in contractility. These important endothelin were also observed: a stimulation of ANF, an impairment of renal function and a hypoglycaemic effect. To explain the stimulation of ANF release, a direct effect of endothelin was difficult to establish because ANF and left atrial pressure increased concomitantly. As calcium could be involved as mechanism in ANF release as well as in endothelin effect, we investigated in a second step whether pathophysiological doses of endothelin could influence the release of ANF, stimulated by volume expansion. This study was also performed in conscious dogs. Like in man, we found in dogs that hypervolemia stimulated ANF release, which also correlated with changes of atrial pressure. Moreover, endothelin had per se, independently of the hemodynamic changes, a potentiating effect on the stretch-mediated release of ANF. In contrast, a calcium channel antagonist did not impair the release of ANF. Altogether, an intracellular release of calcium could be suspected to intervene in the ANF release mediated by stretch. In conclusion, we studied two newly discovered peptides that exert opposite effects on renal and cardiovascular systems. Measurement of these peptides are currently a prerequisite in studies related to cardiovascular, endocrine and renal physiology. Moreover, important pathophysiological and clinical relevances are also emergingThèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 199