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.     

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.     

Effects of corticotropin-releasing factor (CRF) on aldosterone and 18-hydroxycorticosterone in essential hypertension and primary aldosteronism

The effects of ovine corticotropin releasing factor (o-CRF) on plasma aldosterone, 18-OH-corticosterone (18-OHB), plasma adrenocorticotropin (ACTH) and cortisol were determined in eight patients with primary aldosteronism, six with aldosterone-producing adenoma (APA) and two with idiopathic hyperaldosteronism (IHA). The results were compared with those in six normal subjects and eleven patients with essential hypertension (EHT, 5 with low renin and 6 with normal renin). In patients with APA, the peak plasma aldosterone and 18-OHB responses to 100 micrograms iv of o-CRF (226% and 113% increase from baseline, respectively) were greater than those in EHT and normal subjects. The net integrated aldosterone and 18-OHB responses (840 +/- 156, and 419 +/- 121 ng/dl.hr, respectively) were also significantly greater (p less than 0.01) in APA than those in normals and EHT. In two patients with IHA, both the peak and net integrated aldosterone response were smaller than those in APA, in spite of nearly identical plasma ACTH and cortisol responses. These results suggest that augmented responses of mineralocorticoids to o-CRF may be characteristic of aldosteronism due to APA, mediated by CRF-induced ACTH, and possibly other proopiomelanocortin (POMC)-derived peptides.     

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.     

Studies on lipoprotein and adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density lipoprotein-cholesterol for steroid production in functioning human adrenocortical adenoma cells in culture

We examined the utilization of human low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol for steroid production in primary monolayer culture cells from adenomas of primary aldosteronism and Cushing's syndrome and an adrenal of nodular hyperplasia of Cushing's syndrome. We compared the data obtained with findings in the case of cultured normal human adrenocortical cells. In the presence of 10(-7) M adrenocorticotropin (ACTH), the addition of either LDL or HDL to the culture medium at a cholesterol concentration of 100 micrograms/ml led to a significant increase in the daily secretion rates of cortisol, dehydroepiandrosterone sulfate (DHEA-S) and aldosterone in the adenoma and nodular hyperplasia cells, as in the normal cells. Although LDL greatly increased the secretion of steroid hormones, no significant difference in steroid secretion following the treatments with LDL and HDL were observed in these cultured cells. The contribution of endogenous cholesterol to steroid production was also high, thereby indicating that the neoplastic transformation did not have untoward effects. Cells from adenomas of primary aldosteronism secreted not only aldosterone, but also cortisol and DHEA-S. The daily secretion rates of these steroids were markedly increased when ACTH was added to the medium. With prolonged exposure to ACTH, however, the rate of aldosterone secretion showed a gradual decrease with the incubation time. This decrease might be due to the impaired conversion of corticosterone to 18-hydroxycorticosterone. In case of adenomas in patients with Cushing's syndrome, the secretion of steroid hormones varied in quantity and quality, depending on the type of plasma cortisol response to the rapid ACTH test in vivo, thereby suggesting that the adrenocortical adenoma of Cushing's syndrome might be divided into two subtypes. These results indicate that human functioning adrenocortical adenoma cells utilize plasma lipoproteins as a source of cholesterol for steroidogenesis during the prolonged stimulation of steroid secretion.     

Primary aldosteronism caused by unilateral adrenal hyperplasia

In the hypertensive population, primary aldosteronism has been reported to have a prevalence of 0.1% to 2%, with the main causes being aldosterone-producing adenomas and bilateral hyperplasia. However, there is a third rare entity, called unilateral adrenal hyperplasia, that contributes to primary aldosteronism. Unilateral hyperplasia and primary aldosteronism are the subjects of this case review.     

Predictive factors of left ventricular mass changes after treatment of primary aldosteronism

A variety of abnormalities that occur in patients with primary aldosteronism indicate the capability of elevated aldosterone to induce cardiac damage over that induced by hypertension itself. This study investigates factors that can predict structural and functional changes of the heart after treatment of primary aldosteronism in a post-hoc analysis of 54 patients who were enrolled in a long-term follow-up study that was conducted after either adrenalectomy or treatment with spironolactone. Cardiac ultrasound assessment was performed before treatment and after with an average follow-up of 6.4 years. During follow-up, blood pressure decreased significantly and comparably in both treatment groups. In both treatment groups, left ventricular mass decreased significantly with a trend to improved diastolic filling profile and no changes in ventricular geometry. At univariate analysis, changes in left ventricular mass induced by treatment of primary aldosteronism were directly related with changes in systolic blood pressure and pretreatment plasma aldosterone levels measured both at baseline and after an intravenous saline load. This relationship was maintained when patients treated with adrenalectomy and spironolactone were analyzed separately. Multivariate regression analysis showed that changes in systolic blood pressure and pretreatment aldosterone levels were independent predictors of left ventricular mass changes after treatment. This study strongly supports a role of aldosterone in promoting left ventricular hypertrophy that is independent of the hypertension-related hemodynamic load and suggests a practical way to predict left ventricular mass changes following surgical and medical treatment of primary aldosteronism.     

Two-site automated chemiluminescent assay for measurement of immunoreactive renin

Measurement of renin is important for the clinical assessment of hypertensive patients and for the screening for primary aldosteronism. The aim of this study was to evaluate the performances of an automated immunoassay for measurement of immunoreactive renin. Functional sensitivity, in vitro stability, and reference values were determined. Method comparison with the plasma renin activity assay was also performed. Our results demonstrate that the Liaison(?) direct renin assay may assist the clinician in the assessment of hypertensive patients and in the screening for primary aldosteronism.     

Plasma vasopressin variation and renin activity in normal active humans.

Plasma concentrations of vasopressin and plasma renin activity were measured every 30 min for 24 h in 5 normal active humans, in 1 normal woman confined to bed (except for brief periods up to the bathroom), in 2 active patients with primary aldosteronism and in 1 patient with low-renin hypertension. Plasma vasopressin varied markedly over the day and night in a pattern suggesting episodic secretion of the hormone in the normal subjects. Assumption of upright posture was accompanied by a rise in plasma levels from undetectable to 20--50 pg/ml. Episodic secretion, however, also occurred during bed rest and sleep. In contrast, patients with primary aldosteronism and low-renin hypertension had plasma vasopressin levels considerably lower than the normals, and their profiles of plasma concentration lacked the peaks seen in normals. In the normals, although vasopressin and renin secretion often coincided, only 2 of 6 studies showed a significant correlation between the plasma levels of the two hormones. This study, therefore, shows that vasopressin is secreted periodically in normal humans, that upright posture is an important modulator of secretory activity and that the renin-angiotensin system may or may not influence the pattern of secretion. In addition, it underlines the necessity of recumbency in establishing the existence of a circadian rhythm of plasma vasopressin levels.     

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.     

Relationships among urinary kallikrein, mineralocorticoids and human hypertensive disease.

Urinary kallikrein excretion is reduced in patients with hypertension of unknown etiology. In addition, the excretion of this renal, kinin-forming enzyme was found to be elevated in hypertensive patients with primary aldosteronism. Aldosterone regulates kallikrein excretion, as normal subjects show increased kallikrein excretion in response to a low sodium intake, high potassium intake, or the synthetic mineralocorticoid, fludrocortisone, whereas kallikrein excretion falls during treatment with spironolactone. The relationship between kallikrein excretion and aldosterone activity may directly reflect the intrarenal activity of the kallikrein-kinin system, as determined by studies of kallikrein levels from isolated renal cells or of plasma kinin levels in man in response to postural changes or saline loads. Some patients with essential hypertension do not show a normal increase in kallikrein excretion in response to low dietary sodium intake despite an apparently normal aldosterone response, suggesting that there may be a defect in the renal kallikrein-kinin system in these patients. Whether these findings are of pathogenetic significance in human hypertensive disease remains to be determined.     

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.     

Two-site automated chemiluminescent assay for measurement of immunoreactive renin

Measurement of renin is important for the clinical assessment of hypertensive patients and for the screening for primary aldosteronism. The aim of this study was to evaluate the performances of an automated immunoassay for measurement of immunoreactive renin. Functional sensitivity, in vitro stability, and reference values were determined. Method comparison with the plasma renin activity assay was also performed. Our results demonstrate that the Liaison^® direct renin assay may assist the clinician in the assessment of hypertensive patients and in the screening for primary aldosteronism.     

Shock Caused by Continuous Infusion of Metaraminol Bitartrate (Aramine)

Increasing doses of metaraminol bitartrate (Aramine) in a continuous intravenous infusion were used to support the blood pressure in four patients. Under such treatment a state of shock developed, characterized by intense peripheral vasoconstriction, hypotension and anuria. In spite of an adequate fluid intake all patients showed severe hemoconcentration, and a critically low plasma volume could be demonstrated in two. While metaraminol (Aramine) was ineffective, noradrenaline still caused a moderate blood pressure response. Treatment with plasma expanders (Intradex) and small doses of noradrenaline (Levophed) resulted in transient improvement in one patient and complete recovery from shock in three. The peripheral vasoconstriction persisted up to 12 hours and renal function improved on the second day after the withdrawal of metaraminol. The etiology of this shock syndrome is believed to be similar to that of experimental shock produced with adrenaline and noradrenaline.     

New mechanisms to control aldosterone synthesis.

Arterial hypertension is a frequent and leading cardiovascular risk factor, and primary aldosteronism is a well-recognized cause of secondary hypertension. Aldosterone is the basic regulator of extracellular fluid volume and electrolyte balance. Alterations in plasma aldosterone levels significantly contribute to the development and the severity of hypertension. Adrenal steroidogenesis is controlled by two major feedback loops: the hypothalamic-pituitary-adrenal axis, which regulates cortisol synthesis, and the renin-angiotensin-aldosterone system, which directs aldosterone production. In addition to angiotensin, potassium, and corticotropin-which belong to the classic stimulators of aldosterone-neuropeptides, catecholamines, and prostaglandins are also known to stimulate aldosterone synthesis. Recently, several new mechanisms have been characterized that control the release of aldosterone by adrenocortical cells, among them endothelial cell-derived factors and adipokines. Further identification and characterization of these factors may help in the development of novel therapies for the treatment of arterial hypertension, various metabolic diseases, and other disorders.     

Prolonged pseudoaldosteronism induced by glycyrrhizin.

We describe the natural recovery from the aggravated hypertension, hypokalemia and suppression of the renin-aldosterone axis after the glycyrrhizin discontinuation in two mild hypertensive women aged 71 and 68 years, who had been administered 273 to 546 mg glycyrrhizin daily for 1.5 and 6 months, respectively, for the treatment of liver disease. About one month after the glycyrrhizin discontinuation, acceleration of hypertension, hypokalemia and suppression of the renin-aldosterone system still continued in both patients. At this stage, sodium restriction resulted in the normalization of blood pressure with weight loss and the subsequent sodium repletion produced a rapid increase in blood pressure to hypertensive levels observed before sodium restriction, with weight gain. Plasma renin activity and plasma aldosterone were low and did not respond to sodium restriction. Inappropriately excessive amounts of potassium were also excreted in the presence of hypokalemia. About one and a half months later, the improvements of aggravated hypertension, hypokalemia and suppressed renin-aldosterone system gradually occurred in both patients. Sodium restriction performed about three months later in case 2 no longer produced the changes in blood pressure and body weight. Plasma renin activity and plasma aldosterone responded subnormally to sodium restriction. These results demonstrate that both patients had a prolongation of the syndrome resembling primary aldosteronism except the low plasma aldosterone level about one month after the glycyrrhizin discontinuation. The possible mechanisms by which this prolongation was caused are discussed.     

Dystocia due to urinary bladder carcinoma in two water buffaloes (bubalus bubalis) - Clinical case report

Two buffaloes with full-term pregnancy suffered from dystocia because the cervix did not dilate in spite of strong labour pains and other parturition signs shown by each animal. The urinary bladder, cervix, vagina and surrounding area were very firm. Dead, emphysemated fetuses were removed by caesarean in each case and anuria was also noticed. One buffalo died and the other was euthanised after surgery because it did not improve. The post-mortem examinations revealed transitional cell carcinoma of urinary bladder infiltrating the cervix, vagina and surrounding area in each case.     

Lymphangitic sporotrichosis: An uncommon bilateral localization

Sporotrichosis is a mycotic disease caused by cutaneous inoculation of the dimorphic fungus Sporothrix schenckii. The primary lesion can spread and often develop a unilateral lymphocutaneous lesions or, rarely, disseminated disease. We report a lymphangitic sporotrichosis case with ulcerated erythematous nodules distributed bilaterally on the posterior and medial aspect of the both legs, probably due to multiple inoculations. The treatment with oral potassium iodide was satisfactory. This revised version was published online in June 2006 with corrections to the Cover Date.     

In vivo and in vitro studies on steroid metabolism in a case of primary aldosteronism with multiple lesions of adenoma and nodular hyperplasia

In order to systematically analyze the regulation and metabolism of steroid hormones in a case of primary aldosteronism with multiple lesions, including adenoma and nodular hyperplasia of the left adrenal gland, the amounts of 9 steroids (progesterone (P), 11-deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone (18-OH-B), aldosterone (Aldo), 17 alpha-hydroxyprogesterone (17-OH-P), 11-deoxycortisol (S), cortisol (F) and dehydroepiandrosterone sulfate (DHEAS)) contained in the plasma and in the adrenal tissues were measured. The patient (a 39-year-old female) was admitted to our hospital because of hypokalemia and hypertension. A diagnosis of primary aldosteronism was made on the basis of a complete evaluation, and an adenoma (1.8 x 1.2 cm), a nodular hyperplasia (0.5 x 0.5 cm), a microadenoma and a cortical nodule were found on the left adrenal gland. In vivo studies revealed that the plasma level of Aldo was high, but those of the other steroid hormones were within the normal range. After ACTH infusion, the plasma levels of the 9 steroid hormones increased by 2 to 17 times the base levels. In particular, the responses of DOC and B were markedly high. In vitro studies on P, DOC, B, Aldo and F content in the adenoma (A), the nodular hyperplasia (A'), the adjacent adrenal tissue (C) and the right normal adrenal tissue (D) revealed that, except for F, they were highest in A, followed by A', D and C in that order. In incubation studies with ACTH using A and C, it was found that the levels of 8 steroid hormones with the exception of DHEAS were high in A than in C. In particular, the response of B in A was markedly increased. These findings suggest that aldosteronoma produces 8 steroid hormones under conditions of excess ACTH, while at physiological levels of ACTH, it produces only Aldo in excess.