New aspects on primary aldosteronism

The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.     

Regulation of aldosterone secretion in primary aldosteronism.

Plasma aldosterone, plasma renin activity and plasma cortisol were determined in patients with primary aldosteronism in response to posture and at short-time intervals overnight while the patient were supine. In the 5 patients with an aldosterone-producing adenoma postural changes in plasma aldosterone were paralleled by those in cortisol while plasma renin activity was generally undetectable indicating an ACTH-dependent secretion of aldosterone. This concept was supported by the observation that in 3 of these patients who were tested overnight 1. episodic secretion of plasma aldosterone was paralleled by those of cortisol and 2. episodic secretion of plasma aldosterone could be blunted by dexamethasone. In the patient with idiopathic adrenal hyperplasia concomittant changes in plasma aldosterone and plasma renin activity occurred. The assumption that in this patient the fluctuations in plasma aldosterone were mediated through changes in renal renin secretion was supported by the finding that episodic secretion of plasma aldosterone persisted under suppression of ACTH-secretion by dexamethasone. Our results indicate, that the described procedures may all serve as diagnostic criteria to differentiate between aldosterone-producing adenoma and idiopathic adrenal hyperplasia.     

Leptin levels are suppressed in primary aldosteronism.

Primary aldosteronism is associated with hypertension secondary to salt and water retention, hypokalemia and impaired insulin secretion with glucose intolerance in some patients. The secretion of leptin, a hormone produced by adipocytes, may be altered by reduced insulin secretion in primary aldosteronism. We measured plasma leptin approximately 3 months before and 3 months after curing of primary aldosteronism in 18 patients (12 male, 6 female, body mass index 29.1+/-4.4, mean +/- SD). Patients were treated by unilateral laparoscopic adrenalectomy to remove an aldosterone-producing adenoma. There was a 46% postoperative increase in plasma leptin concentrations from 6.65+/-0.81 to 9.68+/-1.50 ng/ml (P=0.004), despite a non-significant fall in body mass index. Plasma leptin was noted to increase after adrenalectomy in 16 of the 18 patients. The patients also had improved blood pressure and a significant increase in plasma potassium post-operatively. It is proposed that increased insulin secretory capacity associated with correction of negative potassium balance may account for the increase in plasma leptin after curing primary aldosteronism. Further studies are indicated to identify the mechanism of plasma leptin suppression in primary aldosteronism.     

Localization of aldosterone-producing adenoma: venous sampling in primary aldosteronism

Adrenal venous sampling of blood was performed for nine patients with aldosterone-producing adenoma (APA). Measurement of adrenal venous aldosterone is useful for localization of APA but difficult, because catheterization of the right adrenal vein is not easy, and the blood is diluted by nonadrenal flow. To solve these problems, levels of aldosterone (A; ng/dl) and cortisol (C; micrograms/dl) were measured in samples from the left adrenal vein (LAV) and the inferior vena cava (IVC), and the LAV A/C and (LAV A/C)/(IVC A/C) ratios were calculated. These ratios were also obtained for 16 patients with essential hypertension. The adenoma could be localized in three of the nine cases by the measurement of aldosterone alone, but the use of a LAV A/C ratio greater than 5 x 10(-3) and a (LAV A/C)/(IVA A/C) ratio less than 1.0 as criteria separated the patients into those with a left APA, right APA, or essential hypertension. Consequently, adrenal venous sampling and the calculation of these ratios enables preoperative localization of APA with more accuracy, especially when the tumor is small or the result of CT and adrenal scintigraphy is not consistent.     

Fecal and salivary electrolytes in the diagnosis of primary aldosteronism

Fecal and salivary sodium and potassium concentrations were measured in 22 hypertensive patients with hypokalemia who were undergoing investigation for primary aldosteronism due to an adrenocortical adenoma (Conn''s syndrome). Of eight patients with a high aldosterone secretion rate, five had clearly low fecal Na/K ratios, (including all four patients with Conn''s syndrome), in three the ratios were equivocal. Of 14 patients with hypertension and a normal aldosterone secretion rate, none had a sufficiently low fecal Na/K ratio strongly to suggest hyperaldosteronism, although two were borderline. Salivary electrolyte concentrations were not as consistent an indicator of mineralocorticoid hormone excess. Estimation of fecal sodium and potassium concentrations may be useful in the diagnosis of mineralocorticoid hormone excess and in assessing the results of therapy.     

An easy diagnostic approach to primary aldosteronism.

The infusion of 40 mEq potassium (aspartate) in 250 ml isotonic 1-fructose at a rate of 20 mEq/h into 5 patients (34-56 years old) with aldosteronoma and 2 patients with bilateral primary aldosteronism consistently raised their mean arterial pressure by 15-20 mmHg. Their pressure values returned to the baseline levels 4-5 h after the infusion. In contrast, in controls (10 patients with idiopathic arterial hypertension, matched for age, sex, and magnitude of the untreated hypertension, and 7 patients with inactive adrenal nodules as incidental findings on upper abdomen ultrasound or computerized tomography) the same procedure caused negligible arterial pressure changes. The cause of the rise in blood pressure observed uniquely in patients with primary aldosteronism after infusion of potassium (aspartate) cannot be accounted for by an increase in plasma aldosterone, blood volume, or plasma angiotensin II. The cause of this response thus remains obscure; nonetheless, this simple procedure may prove useful in differentiating primary aldosteronism from idiopathic hypertension, in excluding the adrenal disorder, and in revealing even its mildest forms.     

Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism

Circulating factor with ouabain-like immunoreactivity was studied in patients with primary aldosteronism. Anti-ouabain antibody was prepared from specific pathogen-free rabbits. In the plasma of patients with primary aldosteronism, the level of a factor with ouabain-like immunoreactivity was 2.59 +/- 1.39 pmol ouabain equivalent/ml plasma. This value was significantly (p less than 0.05) higher than that of age-matched normotensive subjects, 1.06 +/- 0.86 pmol ouabain equivalent/ml plasma. The plasma level of ouabain-like immunoreactivity correlated significantly (p less than 0.05) with blood pressure. These results indicate that the factor with ouabain-like immunoreactivity may play a pathophysiological role in the maintenance of the high blood pressure observed in patients with primary aldosteronism.     

Night-day differences in the ultradian rhythmicity of plasma renin activity

During night-sleep, plasma renin activity displays periodic oscillations which are closely related to the alternation of REM-NREM sleep. To see whether this nocturnal rhythm persisted during the day-time, plasma renin activity was measured every 10 min for 24 hours in 4 human volunteers and in 4 others over a 10-h day-time period. To avoid the influence of repeated food intake which stimulates renin release, the subjects were on continuous enteral nutrition. Spectral analyses of the data revealed clear differences between the nocturnal and the diurnal PRA patterns. In subjects on enteral nutrition, sustained 100-min oscillations with strong spectral densities persisted during the night. They were closely related to REM-NREM cycles. During the day-time, however, the fluctuations were damped and less regular, and power spectra were split into 2 or 3 peaks without any predominant period. These results demonstrate that regular 100-min PRA oscillations could only be detected during night-sleep. The clear night-day differences suggest that the underlying oscillatory mechanisms may be weaker during day-time or may be counteracted by other physiological processes.     

Hypokalemic myopathy associated with primary aldosteronism and glycyrrhizine-induced pseudoaldosteronism

Enzymatic and histological features of muscular disorders associated with primary aldosteronism and glycyrrhizine-induced pseudoaldosteronism were studied. Among 10 patients with primary aldosteronism and 3 patients with pseudoaldosteronism, 5 patients were admitted to our hospital because of muscular weakness. The serum potassium (K) level was 1.86 +/- 0.21 mEq/l in a myopathy group on admission, a value significantly less than that of the 2.74 +/- 0.10 mEq/l in a non-myopathy group (p less than 0.01). Serum creatine phosphokinase (CPK), glutamate-oxyloacetate transaminase (GOT), and lactate dehydrogenase (LDH) were increased in the myopathy group compared to the non-myopathy group; serum CPK was 1412.6 +/- 902.6 vs. 22.8 +/- 5.0 mU/ml, serum GOT was 186.4 +/- 75.3 vs. 24.2 +/- 5.4 mU/ml (p less than 0.05), and serum LDH was 1133.4 +/- 377.3 vs. 387.6 +/- 42.5 mU/ml (p less than 0.05) in the groups with and without myopathy. Analysis of CPK isozymes revealed that the MM type exceeded 95%. The elevated serum CPK, GOT and LDH rapidly decreased to the normal range and muscular strength completely improved within 6 to 13 days after hospitalization, when the serum K level remained below than normal. Light microscopic finding of damaged muscle showed the diffuse necrosis and vacuolization of muscle fibers. Electron microscopic study clearly demonstrated complete dissolution of myofilaments with disappearance of sarcoplasmic reticulum and T-tubules in the necrotic muscle fibers. These results indicate that muscular lesions may occur in primary aldosteronism and pseudoaldosteronism when the serum K level is decreased to below 2.0 mEq/l. This myopathy is not periodic paralysis but hypokalemic myopathy. The mechanism by which K deficiency causes muscular damage remains unknown.     

Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism

Background

A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown.

Methods

We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats.

Results

Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF.

Conclusion

These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.     

Alpha-h-ANP injection in normals, low renin hypertension and primary aldosteronism

Atrial natriuretic peptide, a hormone secreted by the heart, is involved in salt and fluid homeostasis and also exerts an inhibitory effect on aldosterone production in vitro. In order to elucidate if this effect is also present in man, 6 normal volunteers, 5 low renin hypertensive patients (LRH) and 7 patients with primary aldosteronism (PA) have received 100 micrograms of alpha-h-Anp as bolus i.v. (The decrease in blood pressure was mild and transient in all groups, whereas a marked diuretic effect was observed in all hypertensives even in PA where high levels of endogenous ANP have been found. In normals we observed a significant decrease of plasma aldosterone values while in PA and LRH this effect was not evident. This phenomenon associated with a greater natriuretic effect in LRH and PA, as compared with normals, demonstrates the lack of the correlation between ANP-induced diuresis and aldosterone inhibiting properties.     

Radioimmunoassay of urinary 21-deoxytetrahydroaldosterone in primary aldosteronism and 21-hydroxylase deficiency

A radioimmunoassay of 21-deoxytetrahydroaldosterone was developed. Normal daily excretion of the unconjugated metabolite was 1.2 +/- 1.3 micrograms and of the glucuronized metabolite, 11.9 +/- 7 micrograms. The tetrahydroaldosterone/21-deoxytetrahydroaldosterone ratio varied more in patients with primary aldosteronism than in control subjects. Thus, measurements of the urinary excretion of the tetrahydroaldosterone or 21-deoxytetrahydroaldosterone alone did not provide an accurate expression for aldosterone production. Their sum correlated well with the clinical condition, i.e. clear-cut elevation in patients with primary aldosteronism. The diminished tetrahydroaldosterone/21-deoxytetrahydroaldosterone ratio found in patients with 21-hydroxylase deficiency may be attributed to increased bacterial conversion of tetrahydroaldosterone to 21-deoxytetrahydroaldosterone but could also stem from a deficiency implicating zona glomerulosa (aldosterone biosynthesis) regardless of the stage and clinical presentation of the disease.     

Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review

Aldosterone hypersecretion in primary aldosteronism is unilateral (aldosterone producing adenoma and primary unilateral hyperplasia) or bilateral (idiopathic adrenal hyperplasia). Laparoscopic adrenalectomy is nowadays the preferred approach to treat patients with unilateral primary aldosteronism. We review the outcomes of this intervention in recently published series. Laparoscopic adrenalectomy has a morbidity of 5-14%, mortality below 1%, and a mean hospital stay around 3 days. It generally results in the normalization of aldosterone secretion and in a large decrease of blood pressure and antihypertensive medication, but normotension without treatment is only achieved in 42% of all cases. Normotension following adrenalectomy is more likely in young and lean women with recent low grade hypertension than in obese men with long-standing high grade hypertension or a family history of hypertension. However, individual prediction of the blood pressure outcome is not accurate and predictors of hypertension cure should not be used to select patients for surgery. Age, associated health conditions and preferences of the patient are more relevant to this end.     

Twenty-Four hour blood pressure profile in subjects with different subtypes of primary aldosteronism

The aim of our study was to evaluate the potential differences in blood pressure (BP) profile in subjects with different forms of primary aldosteronism (PA). Simultaneously, we studied the effects of PA treatment on BP curve. We therefore monitored 24-hour ambulatory blood pressure values in 22 subjects with aldosterone-producing adenoma (APA), 22 subjects with idiopathic hyperaldosteronism (IHA) and 33 subjects with essential hypertension (EH) as controls. We found a significantly attenuated nighttime systolic BP decline in the APA group (P=0.02). Patients with IHA had lower nighttime systolic BP values (P=0.01) and also a diastolic BP decline (P=0.02) during the night in comparison with EH. We did not detect any significant differences in BP profile characteristics between APA and IHA. Specific treatment of primary aldosteronism (adrenalectomy, treatment with spironolactone) led to the normalization of the BP curve with a marked BP decline. Our study thus demonstrates a blunted diurnal BP variability in patients with primary aldosteronism the specific treatment of which normalized previously attenuated nocturnal BP fall.