Please also see the clinical vignette presented before Grand Rounds on the 21st of May.
The Medical Grand Rounds presentation on May 21, 2009 titled “Primary Aldosteronism, Beyond Conn’s Syndrome” was delivered by Dr. William F. Young M.D., Professor of Medicine at the Mayo Clinic College of Medicine. Dr. Young’s talk began with the index case of hyperaldosteronism that was described by Dr. Jerome Conn in the 1950’s, through the advances in the diagnosis of hyperaldosteronism, and on to present day treatment of the disease. The major objectives of his talk were: 1) How common is primary aldosteronism? 2) What is the best way to distinguish between an Aldosterone Producing Adenoma (APA) and Bilateral Idiopathic Adrenal Hyperplasia (IHA)? 3)What is the treatment of primary aldosteronism?
Dr. Young’s talk began with the background and history behind the discovery of primary aldosteronism, otherwise known as Conn’s Syndrome. Dr. Jerome Conn, for which the syndrome is named, was an endocrinologist whose major work during World War II in the 1940s was focused on the regulation of salt loss in the sweat of subjects exposed to elevated heat and humidity, as was of military concern in the South Pacific at the time. Through his investigations, Dr. Conn established that acclimation to such heat and humidity involved the retention of salt via the production of endogenous corticoids acting on the concentration of sodium and chloride in sweat. In 1955, Dr. Conn described a case of a 34 year old female patient who had been complaining of seven years of episodic muscle weakness, muscle spasms and cramping of her hands. Dr. Young described the data that Dr. Conn had collected on this patient, noting that the patient was markedly hypokalemic, mildly hypernatremic, hypertensive and alkalotic. Due in part to his previous work on the regulation of salt loss in heat exposed patients, Dr. Conn hypothesized that endogenous corticoids might have also played a role in this patients pathophysiology, and so was able to demonstrate that the patient had elevated mineralocorticoid levels compared to normotensive controls. This marked the first description of primary aldosteronism, which Dr. Young defines as “the adrenal hypersecretion of aldosterone independent of renin production.”
To address the first objective in his talk, “How common is primary aldosteronism?” Dr. Young described epidemiological studies of primary aldosteronism. A series of patients was described from 1955-1985, in which 248 patients with hypertension and hypokalemia were screened in order to investigate for Conn’s adenoma, of which about 68% were found to have the disease . Dr. Conn had predicted that primary aldosteronism patients may develop hypertension prior to developing hypokalemia. Dr. Young supported this prediction with the description of a subsequent case series during the modern era of CT scanning and the use of plasma aldosterone concentration to plasma renin activity (PAC/PRA). In this series, only 37% of patients had hypokalemia. While only 28% on patients studied were diagnosed with Conn’s adenoma, an overall greater number patients were diagnosed in a shorter time period. In conclusion of this section of the talk, Dr. Young cited that about 5-10% of hypertensive patients have primary aldosteronism.
Dr. Young went on to suggest that primary aldosteronism should be tested for in the following groups of patients. 1) Hypertensive patients with hypokalemia, 2) Patients with resistant hypertension, ie on 3 anti-hypertensive medications with poor control, 3) Patients with adrenal incidentalomas and hypertension, 4) Patient with the onset of hypertension under the age of 20, 5)Patients with severe hypertension, 6)Any patient in which one is considering a secondary cause of hypertension. Screening with a morning matched plasma aldosterone concentration level and plasma renin activity is the initial step in testing for primary aldosteronism. When the PAC is greater than 15 ng/mL, the PRC is less than 1 ng/mL/h, and the ratio of the two (PAC/PRC) is greater than 20, the sensitivity and specificity is approximately 75%. This test is valid as long as a patient is not taking aldosterone antagonists, such as spironolactone or epleranone, or renin inhibitors, such as aliskerin.
This lead onto the second objective of the talk, “What is the best way to distinguish between an Aldosterone Producing Adenoma (APA) and Bilateral Idiopathic Adrenal Hyperplasia (IHA)?” Dr. Young displayed an overview of the different subtypes of hyperalosteronism, such as Familial Hyperaldosteronism I and II. However, he stated that because the other forms of hyperaldosteronism are so rare in comparison, the clinically important subtypes are from an aldosterone producing adenoma and from bilateral idiopathic adrenal hyperplasia. One cannot assume when one discovers both hyperaldosteronism and an adrenal adenoma that the adenoma is the source of aldosterone through hypersecretion. Quite often in fact, a patient may have a non-secretory adenoma along with bilateral idiopathic adrenal hyperplasia not apparent on imaging. If one makes the assumption that the adenoma is the source of aldosterone, and one pursues an adrenalectomy of the tumor, the patient still will not have been correctly treated and the patient would have been put at risk for an unnecessary surgery.
The solution to distinguishing between APA and IHA is through selective adrenal vein sampling. Adrenal vein sampling involves the placement of catheters into both the adrenal veins and the distal vena cava. During administration of cosyntropin, blood is sampled from both adrenal veins, and the demonstration of an elevated ratio between the bilateral aldosterone to cortisol ratios greater than 4 secures the anatomical side from which aldosterone is being secreted. The procedure itself is known to have a relatively low success rate due to the difficult nature of correctly placing the catheters in anatomically difficult to reach areas, namely the right adrenal vein. Dr. Young went on to describe a study in which he had participated where he had investigated the key factors in determining successful catheterization of both adrenal veins (What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism? (Young WF, Stanson AW. Clin Endocrinol (Oxf). 2009 Jan;70(1):14-7). The most important factors found were the experience, dedication and presence of repetition of the radiologist performing the procedure, suggesting that referral centers should focus the expertise to one or two individuals to perform adrenal vein sampling. Using these strategies, Dr. Young cited a success rate as high a 96% at his home institution, the Mayo Clinic in Rochester, Minnesota. In addition, this study recommends that each center should have a written protocol in order to prevent mislabeling of samples and appropriate processing of the sampled blood.
Next, Dr. Young briefly touched upon his final objective in the talk “What is the treatment of primary aldosteronism?” The mainstays of therapy for APA include surgical adrenalectomy, and alternatively the use of aldosterone antagonists, such as spironolactone. The decision to opt for medical therapy involves an assessment of a patient’s individual risk for surgery, such as their medical comorbidities, as well as patient preference. On the other hand, the mainstays of treatment of IHA are mainly medical, again with the use of aldosterone antagonists.
Thus concluded Dr. Young’s Grand Rounds talk on hyperaldosteronism, shedding light on the history behind its discovery in the works of Dr. Conn, and educating the audience on the clinical importance of this disease as well as the potential steps in which we as clinicians might significantly impact the health of our patients with hypertension.
Dr. Chu is a second year internal medicine resident at NYU Medical Center.