Diagnosis of primary hyperaldosteronism. Apropos of 3 cases

Primary hyperaldosteronism (HA1) represent a rare etiology of arterial hypertension (less than 1%). It concerns, most of the time, aldosterone-producing adenomas or bilateral adrenal hyperplasias although intermediate forms have been reported. The diagnosis of HA1 is based on simple examinations, especially systematic measurement of kaliemia in every hypertensive patient with a normal sodium diet before treatment. The elevation of aldosterone blood levels associated with a low plasma renin activity confirms the autonomous nature of the hormonal secretion which is dissociated from the renin-angiotensin system. Study of the ratio aldosterone blood level/ARP and the captopril test are particularly useful in borderline cases. Once the diagnosis of HA1 is made, a topographic analysis may be undertaken; tomodensitometry and adrenal scintigraphy are currently the examinations of choice in the diagnosis of adrenal tumors. Due to biological, morphological and topographic factors, aldosterone-producing adenomas may be identified with a great deal of certainty: surgical excision ensures a cure in a large majority of cases. The treatment of bilateral hyperplasias remains medical.     

]Diagnosis and therapy of primary hyperaldosteronism in general practice

Taking into consideration an own observation of Conn's syndrome the diagnostics and therapy of the primary hyperaldosteronism is described. The recognition of Conn's syndrome is important for that account as it coincides with an operatively curable hypertension. Therefore, a diagnostic step programme is proposed. Thus, the first tentative diagnosis shall be made already by a general practitioner. Other specialised and highly specialised investigations have the task to ascertain the diagnosis and to find the right way in therapy.     

Primary hyperaldosteronism.

Primary hyperaldosteronism (PHA) is regarded as a rare disease with prevalence rates of 0.5 to 2% within the hypertensive population. Recent studies using more detailed screening procedures in small hypertensive cohorts have suggested that PHA may be more common than previously thought (3-18%). Since a validated and cost-effective routine screening protocol for this entity is not established, many clinicians are reluctant to consider PHA as an underlying cause for a patient's high blood pressure. The insufficient perception of PHA may have fatal consequences since most patients are curable by an operation and missing the diagnosis often leads to significant and irreversible end-organ damage. This review focuses on the diagnosis of PHA and gives a rational and cost-effective flow chart for routine screening and differential diagnosis of PHA in hypertensive patients.     

Localization of primary hyperaldosteronism

After diagnosis of primary aldosteronism on the basis of biochemical evidence, the detection of the tumour is of crucial importance in the management of the disease. We reviewed the efficacy of CT-Scan, Iodo-Cholesterol Scintigraphy, digitalized phlebography, adrenal vein sampling for steroid measurements (AVS), and Nuclear Magnetic Resonance (NMR) in 160 hypertensive patients with primary aldosteronism. Diagnosis of Conn's adenoma (n = 96) or Adrenal Hyperplasia (n = 40) was confirmed by surgery or at least two concordant tumour localization tests. Scintigraphy gave a correct diagnosis in 53% of the 51 exams, CT-Scan in 82% of the 85 exams, and phlebography in 79% of 61 exams. Plasma Aldosterone/Cortisol ratio was 5 times higher on the side of adenoma in 55% of the 47 cases but this ratio was also present in 23% of 22 patients with adrenal hyperplasia. Each procedure exhibited few false positive and false negative cases. NMR performed in 15 patients with Conn's adenoma identified all the cases. But tumours displayed a signal close to the liver signal and identical to the normal adrenal. These results and the risk of invasive procedure (failure of catheterization of the right adrenal vein (n = 6) and adrenal haematoma (n = 2) lead us to propose a schema of exploration of patients with primary aldosteronism. The CT-Scan could be performed at the first step once the biological diagnosis confirmed. Phlebography and AVS will be performed only if tumour was less than 1 cm at the CT-Scan despite important biological abnormalities. This schema requires to be validated by a prospective evaluation.     

Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism

Theoretically, the relationship between plasma aldosterone (PA) and PRA in normal subjects under random conditions should differ from that in patients with primary hyperaldosteronism or primary adrenal failure, but should be similar to that in patients with secondary hyperaldosteronism or hyporeninemic hypoaldosteronism. PA, expressed as a function of PRA, the PA/PRA ratio, provides an index of adrenal sensitivity in normal subjects under routine conditions. The random PA/PRA ratios in patients with primary adrenal disorders did not overlap with those in normal subjects, patients with secondary adrenal disorders, hypertensive subjects, or other patients. A single elevated PA/PRA ratio, i.e. more than 920, associated with elevated PA in 4 patients or normal PA in 6 patients indicated primary hyperaldosteronism in 10 patients. However, 5 of 17 patients with chronic renal failure had elevated PA/PRA ratios, but did not have primary hyperaldosteronism. All 14 patients with secondary hyperaldosteronism had elevated PA associated with normal PA/PRA ratios. A single PA/PRA ratio of less than 28 associated with low PA in 18 patients and a normal PA in 1 patient indicated primary adrenal insufficiency, while a low PA associated with a normal PA/PRA ratio indicated hyporeninemic hypoaldosteronism in 7 patients. Fifty-nine patients with nonadrenal disorders other than renal failure had normal PA and PA/PRA ratios. Therefore, with the exception of patients with advanced renal failure, only a single blood sample is required to establish all diagnoses of disorders of the renin-angiotensin-aldosterone axis under random conditions.     

Plasma immunoreactive proopiolipomelanocortin-derived peptides in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism

Immunoreactive plasma levels of the proopiolipomelanocortin-derived peptides, ACTH, beta-endorphin-lipotropin, and gamma 3MSH, were measured in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, infusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism.     

Resistant hypertension and hyperaldosteronism

Resistant hypertension is defined as blood pressure that remains uncontrolled in spite of ≥ 3 antihypertensive medications at effective doses, ideally including a diuretic. Although exact prevalence is unknown, clinical trials suggest that 20% to 30% of study participants are resistant. Hyperaldosteronism, obesity, refractory volume expansion, and obstructive sleep apnea are common findings in resistant hypertension patients. Multiple studies indicate that primary aldosteronism (PA) is common (∼ 20%) in patients with resistant hypertension. Screening for PA is recommended for most patients with resistant hypertension, ideally by measurement of 24-hour urinary aldosterone excretion, or by the plasma aldosterone/plasma renin activity ratio. Successful treatment of resistant hypertension is predicated on improvement of lifestyle factors; accurate diagnosis and treatment of secondary causes of hypertension; and use of effective multidrug regimens. A long-acting diuretic, specifically chlorthalidone, is recommended as part of the treatment regimen. Recent studies demonstrate that mineralocorticoid receptor antagonists provide substantial antihypertensive benefit when added to multidrug regimens, even in patients without demonstrable aldosterone excess.     

Aldosterone in primary hyperaldosteronism

The conditions which must be respected to ensure the validity of the biochemical diagnostic criteria of primary hyperaldosteronism, conditions of blood sampling, timing posture and age of the patient, sodium intake and intercurrent drug therapy. As none of the tests is 100 p. 100 specific in distinguishing adrenal adenoma from hyperplasia, an association of several investigations has to be used. In cases of adenoma, the authors recommend the investigations which demonstrate the autonomy of secretion and the prevalence of circadian rhythm over the influence of change in posture. The measurement of aldosterone levels may be completed by that of its precursor, 18-hydroxy-corticosterone (18 OH CS).     

Medical management of primary hyperaldosteronism

Most forms of primary aldosteronism are surgically correctable. However, when surgery is not appropriate, medical management is just as effective in correcting the pathophysiologic abnormalities due to aldosterone excess. A prerequisite for the rational medical management of primary aldosteronism is an understanding of the mechanisms that sustain hypertension. Primary aldosteronism can be associated with severe and resistant hypertension, and persistent hypervolemia is the primary reason for resistance to therapy. Patients with overriding comorbidities or strong preferences have been medically treated over the intermediate term of 5 to 7 years without evidence of escape or evidence of malignant transformation of adrenal adenomas.     

Renal impact of primary hyperaldosteronism

The impact of hyperaldosteronism on target organs, and particularly kidney function, is greater than that of essential hypertension. Hyperaldosteronism provokes a glomerular hyperfiltration and hypertension that may cause renal alterations. Those may explain why elevated blood pressure may persist, even after radical treatment of the cause of hyperaldosteronism.