High blood pressure is a major cardiovascular risk factor affecting nearly a third of the population. It is idiopathic (essential hypertension) in most cases, but can be secondary in 5–15% of cases. Primary hyperaldosteronism is the most frequent cause of secondary hypertension, with a prevalence estimated at 5–13% of all hypertensive patients 1. It stems from hypersecretion of aldosterone not adequately regulated by the renin–angiotensin system, and occurs in two main forms: unilateral, Conn’s adenoma, sometimes called unilateral hyperplasia, and bilateral hyperplasia. Patients with primary hyperaldosteronism are at a higher risk of cardiovascular complications compared with patients with essential hypertension of comparable age, sex, and blood pressure.
Pheochromocytoma is a rare (0.05–0.2%) 2,3, but particularly dangerous cause of hypertension, secreting catecholamines. This secretion commonly produces symptoms, but is sometimes completely asymptomatic.
The association of primary hyperaldosteronism and pheochromocytoma is very rare, but poses diagnostic and therapeutic problems exemplified in the case presented here.
A 50-year-old man, with a BMI 26 kg/m2, was referred for resistant and severe hypertension that he had had for about 10 years; he presented with a history of sleep apnea syndrome over the past 3 years and type 2 diabetes treated by metformin and an inhibitor of DPP4 (HbA1c 6.5%). He had no family history of hypertension. Despite treatment with five antihypertensive classes (angiotensin-converting enzyme inhibitor, thiazide, calcium inhibitors, α1 blockers, and central), ambulatory blood pressure monitor showed a nondipper profile: daytime blood pressure 162/120 mmHg, with heart rate 60 beats/min and nocturnal blood pressure 171/122 mmHg, with heart rate 51 beats/min. He was asymptomatic.
Laboratory tests indicated low serum potassium 3 mmol/l before supplementation and only 3.72 mmol/l with potassium supplementation (3 g/day), normal renal function (serum creatinine 61 μmol/l, clearance 129 ml/min/1,73 m2), and no significant proteinuria.
Echocardiography showed good systolic function with left ventricular hypertrophy.
An adrenal scan indicated a nodule of the right gland of 35×30 mm with 12 HU density before contrast administration. In view of an allergy to iodine, tomography was not injected. Doppler echocardiography of the renal arteries was normal. In view of the strong suspicion of primary hyperaldosteronism, medications acting on the renin–angiotensin–aldosterone system were withdrawn for 2 weeks to enable hormonal investigations.
The main results were as follows:
- Thyroid hormones and plasma cortisol circadian rhythm were normal.
- Plasma aldosterone of 670 pmol/l with low plasma renin activity (0.25 ng/ml/h) and aldosterone/plasma renin activity ratio 2680 pointing to a diagnosis of primary hyperaldosteronism; a salt-loading suppression test was not performed.
- An increase in urinary noradrenaline of 2327 nmol/24 h (normal<780 nmol/24 h) and its urinary methoxylated derivative of 6770 nmol/24 h (normal<4030 nmol/24 h) pointed to pheochromocytoma, but metaiodobenzylguanidine iodine 123 (123I-MIBG) scintigraphy was negative.
The initial diagnosis from the combined data was that of primary hyperaldosteronism probably because of a Conn’s adenoma.
A right adrenalectomy was proposed to the patient in view of the highly resistant hypertension and was carried out on January 2012 by laparoscopy covered by an α blocker 4,5.
The tissue removed was a pheochromocytoma: proliferation of the adrenal medulla with chromaffin cells in small nests within a dense fibrovascular network. The tissue of the adrenal cortex was pushed to the periphery. On immunohistochemical analysis, the tumoral cells expressed chromogranin A, but were negative for cytokeratin AE1–AE3 and melan A; Mib1 were 1%.
The postoperative course was marked by persistence of high blood pressure over the 24 h recordings, with average values of 154/111 mmHg. Oral antidiabetic agents were stopped, fasting blood glucose remained normal, and HbA1c was 5.3%.
After laboratory tests, levels of urinary catecholamines and metanephrines were normalized, but serum potassium remained low, leading to repetition of the hormonal investigations. This indicated again a picture of primary hyperaldosteronism (plasma aldosterone 428 pmol/l, plasma renin activity 0.02 ng/ml/h, aldosterone/plasma renin activity=21 400).
The diagnosis was thus bilateral aldosterone-secreting hyperplasia.
Treatment with spironolactone, followed by amiloride because of poor clinical tolerance, was thus introduced, allowing a good control of blood pressure (systolic blood pressure<130 mmHg over a series of home measurements).
Our patient thus presented a very rare association of a pheochromocytoma with a bilateral hyperplasia of the adrenals.
This association raises two types of problems: the difficulty of diagnosis and the possible reasons for the association: chance or otherwise.
In our patient, the very resistant nature of the hypertension, the low potassium, and the adrenal tumor were suggestive of Conn’s adenoma. As assays of plasma renin activity and aldosterone were consistent with this diagnosis, no further explorations were carried out. Selective assay of cortisol and aldosterone in the adrenal veins would probably have detected bilateral secretion of aldosterone and helped correct the diagnosis 6. The results of assay of metanephrines and the diabetes were more suggestive of pheochromocytoma. However, the rarity of the condition and the negative 123I-MIBG scintigraphy, along with the clear-cut primary hyperaldosteronism, the aspect of the scanned image (homogeneous tumor), and the very weak probability of a double anomaly of adrenal secretion led us to a diagnosis of Conn’s adenoma. At this stage, two solutions were possible: surgery or treatment by spironolactone. The surgical solution was preferred by the patient and enabled correction of the diagnosis. Fortunately, even if the diagnosis of pheochromocytoma and adrenal hyperplasia had been made initially, the outcome would have been the same.
The second problem is the association between these two adrenal pathologies in the same patient. In the literature, we only found a few cases associating hypersecretion of the adrenal cortex and medullar.
Five cases of involvement of both the adrenal cortex and the medulla have been reported; 4/5 were hypertensive (Table 1) 7–9.
The scarcity of the cases published favors a fortuitous association. However, other possibilities could be envisaged.
The adrenal is the zone of convergence of two endocrine systems: the hypothalamo–hypophyseal–adrenal axis and the sympathetic nervous system. Catecholamines and steroids are important regulators of the response to stress, immune function, blood pressure, and homeostasis.
The medullary zone of the adrenal, stemming from the neuroectoderm, is made up of neuroendocrine cells, the chromaffin cells immunohistochemically labeled by synaptophysin, and chromogranin A.
The cortical zone of the adrenal, stemming from the mesoderm, consists of three zones: the glomerulous zone secreting mineralocorticoids, the fasciculated zone secreting glucocorticoids, and the reticular zone secreting of androgens. It is labeled immunohistochemically by 17α-hydroxylase.
The initial impression is of two independent adrenal populations, whereas in fact, there are numerous interactions between them; an animal study highlights this phenomenon 10:
- In the adrenal gland of the rat and pig, one finds chromaffin cells and β adrenergic receptors in the three zones of the cortex. There is probably a paracrine role for the chromaffin cells on neuroregulation of the adrenal cortex and a susceptibility to stimulation of the sympathetic nerve for steroidogenesis.
- In the bovine adrenal gland, there is a common observation of cortical cells in the medullary zone in the form of ilots concentrated around the blood vessels, surrounded by chromaffin cells. However, chromaffin cells are seldom found in the cortical zone.
In these three species, there is a closer relation between the cortical and medullary cells, supported by gap junctions and the filopods of the chromaffin cells, which play an important role in the regulation of the endocrinal function of the adrenal gland.
The colocalization of the cells, secreting catecholamines and steroids, coordinates adaptation to stress and the environment by a paracrine mechanism.
The medulla seems to exert a regulating influence on steroidogenesis in the cortical zone by secretion of neuromediators (acetylcholine, serotonin, and natriuretic antipeptide).
The cortical cells may induce the production of catecholamines by the medulla by influencing the enzymatic activity of phenylethanolamine NR methyltransferase 10,11.
Another possibility could be stimulation by adrenaline of the release of ACTH and renin, inducing cortical hyperplasia and stimulating the secretion of aldosterone, which could become self-perpetuating.
Finally, there may be a genetic predisposition to the endocrine dysplasias involving a double hormonal secretion by the adrenal gland.
The association of pheochromocytoma and primary hyperaldosteronism can present in the same patient and needs to be diagnosed from the clinical and biochemical findings. This coincidence is probably fortuitous, but an adrenal corticomedullary interaction cannot be ruled out.
Conflicts of interest
There are no conflicts of interest.
1. Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies – a review of the current literature. Horm Metab Res 2012; 44:157–162.
2. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet 2005; 366:665–675.
3. Plouin PF, Gimenez-Roqueplo AP. Pheochromocytomas and secreting paragangliomas. Orphanet J Rare Dis 2006; 1:49.
4. Tauzin-Fin P, Sesay M, Gosse P, Ballanger P. Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. Br J Anaesth 2004; 92:512–517.
5. Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma
or secreting paraganglioma. J Clin Endocrinol Metab 2005; 90:2110–2116.
6. Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al.Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:3266–3281.
7. Gordon RD, Bachmann AW, Klemm SA, Tunny TJ, Stowasser M, Storie WJ, Rutherford JC. An association of primary aldosteronism and adrenaline-secreting phaeochromocytoma. Clin Exp Pharmacol Physiol 1994; 21:219–222.
8. Valdés G, Roessler E, Salazar I, Rosenberg H, Fardella C, Martínez P, et al.. Association of adrenal medullar and cortical nodular hyperplasia: a report of two cases with clinical and morpho-functional considerations. Endocrine 2006; 30:389–396.
9. Bernini M, Bacca A, Casto G, Carli V, Cupisti A, Carrara D, et al.. A case of pheochromocytoma
presenting as secondary hyperaldosteronism, hyperparathyroidism, diabetes and proteinuric renal disease. Nephrol Dial Transplant 2011; 26:1104–1107.
10. Bornstein SR, Ehrhart-Bornstein M, Usadel H, Böckmann M, Scherbaum WA. Morphological evidence for a close interaction of chromaffin cells with cortical cells within the adrenal gland. Cell Tissue Res 1991; 265:1–9.
11. Schinner S, Bornstein SR. Cortical-chromaffin cell interactions in the adrenal gland. Endocr Pathol 2005; 16:91–98.