Chiara Bertello

Long-Term Cardio- and Cerebrovascular Events in Patients With Primary Aldosteronism

BACKGROUND Aldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH. OBJECTIVES The objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH). METHODS We retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone-producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH. RESULTS A significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone-producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients. CONCLUSIONS This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.

Roles of clinical criteria, computed tomography scan, and adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes.

CONTEXT In patients with primary aldosteronism (PA), it is fundamental to distinguish between subtypes that benefit from different therapies. Computed tomography (CT) scans lack sensitivity and specificity and must be followed by adrenal venous sampling (AVS). Because AVS is not widely available, a list of clinical criteria that indicate the presence of an aldosterone-producing adenoma (APA) has been suggested. OBJECTIVE AND DESIGN The objective of the study was to test the sensitivity and specificity of the last generation CT scans, test prospectively the usefulness of clinical criteria in the diagnosis of APA, and develop a flow chart to be used when AVS is not easily available. SETTING Hypertensive patients referred to our hypertension unit were included in our study. PATIENTS Seventy-one patients with confirmed PA participated in our study. INTERVENTION All patients had a CT scan and underwent AVS. MAIN OUTCOME MEASURE Final diagnosis of APA was the main measure. RESULTS A total of 44 and 56% of patients were diagnosed as having an APA and a bilateral adrenal hyperplasia (BAH), respectively. Twenty percent of patients with PA displayed hypokalemia. CT scans displayed a sensitivity of 0.87 and a specificity of 0.71. The posture test displayed a lower sensitivity and specificity (0.64 and 0.70, respectively). The distribution grades of hypertension were not significantly different between APA and BAH. Biochemical criteria of high probability of APA displayed a sensitivity of 0.32 and a specificity of 0.95. CONCLUSIONS This study underlines the central role of AVS in the subtype diagnosis of PA. The use of the clinical criteria to distinguish between APA and BAH did not display a satisfactory diagnostic power.

Impact of Different Diagnostic Criteria During Adrenal Vein Sampling on Reproducibility of Subtype Diagnosis in Patients With Primary Aldosteronism

In patients with primary aldosteronism, adrenal vein sampling (AVS) is considered the only reliable technique to distinguish between unilateral and bilateral autonomous production of aldosterone, but agreement is lacking on the best criteria indicating successful cannulation and lateralization. The objective of this study was to assess the impact of differing criteria for the successful cannulation and lateralization on the reproducibility of subtype diagnosis. Sixty-two patients with confirmed primary aldosteronism underwent AVS on 2 separate occasions, because the first was unsatisfactory. We compared the different diagnoses of primary aldosteronism subtype reached using AVS data assessed by permissive (type 1), intermediate (type 2), and strict (type 3) criteria. Although 91.1% of all of the (both first and second) AVSs were “successful” by type 1 criteria (50.8% by type 2 and 33.9% by type 3), in only 35.3% of patients was the diagnosis concordant between the first and second AVS. Type 1 criteria also led to a higher rate of diagnosis of unilateral primary aldosteronism (67.3% of successful procedures) than type 2 (36.5%) or type 3 (26.2%). There was considerable disparity in the diagnosis reached using the 3 different criteria, with concordance in only 32.2%. Using either type 1 or 2 criteria, the minimal adrenal/peripheral vein cortisol ratio necessary to obtain the same diagnosis in the first and second AVS procedures was ≥2.75. In conclusion, permissive criteria for successful cannulation and lateralization on AVS achieve poor diagnostic reproducibility and should be avoided.

Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families.

Background Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. Objective To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). Methods Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. Results All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (&thetas; = 0) for markers D7S462 and D7S517. Conclusion Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.

Prevalence and Characteristics of Familial Hyperaldosteronism: The PATOGEN Study (Primary Aldosteronism in TOrino-GENetic forms)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and patients display an increased prevalence of cardiovascular events compared with essential hypertensives. To date, 3 familial forms of PA have been described and termed familial hyperaldosteronism types I, II, and III (FH-I to -III). The aim of this study was to investigate the prevalence and clinical characteristics of the 3 forms of FH in a large population of PA patients. Three-hundred consecutive PA patients diagnosed in our unit were tested by long-PCR of the CYP11B1/CYP11B2 hybrid gene that causes FH-I, and all of the available relatives of PA patients were screened to confirm or exclude PA and, thus, FH-II. Urinary 18-hydroxycortisol and 18-oxocortisol were measured in all of the familial PA patients. Two patients were diagnosed with FH-I (prevalence: 0.66%), as well as 21 of their relatives, and clinical phenotypes of the 2 affected families varied markedly. After exclusion of families who refused testing and those who were not informative, 199 families were investigated, of which 12 were diagnosed with FH-II (6%) and an additional 15 individuals had confirmed PA; clinical and biochemical phenotypes of FH-II families were not significantly different from sporadic PA patients. None of the families displayed a phenotype compatible with FH-III diagnosis. Our study demonstrates that familial forms of hyperaldosteronism are more frequent than previously expected and reinforces the recommendation of the Endocrine Society Guidelines to screen all first-degree hypertensive relatives of PA patients.

Psychological assessment of primary aldosteronism: a controlled study.

OBJECTIVE Our objective was to investigate psychological correlates in a population with primary aldosteronism (PA) using methods found to be sensitive and reliable in psychosomatic research. METHODS Twenty-three PA patients (12 male, 11 female; mean age 50 ± 9 yr) were compared with 23 patients with essential hypertension (EH) (15 male, eight female; mean age 47 ± 8 yr) and 23 matched normotensive subjects. A modified version of the Structural Clinical Interview for DSM-IV, a shortened version of the structured interview for the Diagnostic Criteria for Psychosomatic Research, and two self-rating questionnaires, the Psychosocial Index and the Symptom Questionnaire, were administered. RESULTS Twelve of 23 patients with PA (52.2%) suffered from an anxiety disorder compared with four of 23 with EH (17.4%) and one control (4.3%) (P < 0.001). Generalized anxiety disorder was more frequent in PA than in EH patients and controls (P < 0.05). As assessed by Diagnostic Criteria for Psychosomatic Research, irritable mood was more frequent in PA and EH compared with controls (P < 0.05) but did not differentiate PA from EH. According to Psychosocial Index results, patients with PA had higher levels of stress (P < 0.01) and psychological distress (P < 0.01) and lower level of well-being (P < 0.05) than controls. Compared with EH patients, PA patients had higher scores in stress subscale (P < 0.05). The Symptom Questionnaire showed higher levels of anxiety (P < 0.01), depression (P < 0.01) and somatization (P < 0.01) and lower physical well-being (P < 0.05) in PA than controls. CONCLUSION A role of mineralocorticoid regulatory mechanisms in clinical situations concerned with anxiety and stress is suggested.

Hypertension and Cognitive Function

Arterial hypertension, cerebrovascular disease, and dementia are related pathologies. This paper has reviewed comparatively the incidence of arterial hypertension and adult-onset dementia disorders. Hypertension is associated with cerebrovascular disease, which is in turn associated with dementia. It is the most important modifiable risk factor for stroke, which is a recognized cause of vascular dementia. In terms of pathophysiology of hypertensive brain damage, several hypotheses were developed, such as that vascular alterations induced by hypertension can induce lacunar or cortical infarcts and leucoaraiosis, that hypertension is responsible for cerebrovascular disease and acts into the contest of a pre-existing subclinic Alzheimers disease (AD), that hypertension determines neurobiologic alterations (such as β-amyloid accumulation) resulting in neuropathologic damage, and that aging and cerebrovascular risk factors act together to cause cerebral capillary degeneration, mitochondrial disruption, reduced glucose oxidation, and reduced ATP synthesis. The consequence of these alterations are neuronal death and dementia. Macroscopic results of these mechanisms are the so-called white matter lesions (WML), the significance of which is analyzed. Increasing clinical evidence suggests a close relationship between the reduction of elevated blood pressure and countering of both vascular dementia and AD. Antihypertensive treatment probably influences cognitive performances and prevents cognitive function alterations and the development of dementia. It is therefore important to evaluate as soon as possible cognitive functions of hypertensive patients.

Captopril Test Can Give Misleading Results in Patients With Suspect Primary Aldosteronism

To the Editor: Primary aldosteronism (PA) has emerged as the most common form of secondary hypertension.1 The widespread use of the plasma aldosterone/plasma renin activity ratio as a screening test for both hypokalemic and normokaliemic hypertensive subjects has allowed the demonstration of a high prevalence of this disease, with PA accounting for up to 5% to 10% of all hypertensive patients.1,2 The diagnosis of PA is of particular importance for the clinician, because it has been demonstrated recently that patients with PA are more prone to cardiovascular and cerebrovascular complications, and to target organ damage compared with essential hypertensive subjects with similar risk profiles.3 A positive plasma aldosterone concentration/plasma renin activity ratio should always be followed by a suppression test to definitively confirm the diagnosis. The confirmatory diagnosis is usually made with a saline load test (SLT; oral or intravenous) or with the fludrocortisone suppression test (FST).1 Confirmation of the diagnosis of PA should subsequently undergo a …

Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study.

Background Primary aldosteronism is the most frequent cause of secondary hypertension and is responsible for an increased risk of cardiometabolic complications. A concomitant subtle cortisol hyperproduction could enhance cardiovascular risk. We prospectively estimated the occurrence of subclinical hypercortisolism in primary aldosteronism patients. Methods In a large population of hypertensive patients without clinical signs of hypercortisolism, 76 consecutive patients with primary aldosteronism were investigated. Differential diagnosis between unilateral and bilateral aldosterone hypersecretion was made by computed tomography/MRI and/or adrenal venous sampling (AVS). Subclinical hypercortisolism was defined as failure to suppress plasma cortisol to less than 50 nmol/l after 1 mg-overnight dexamethasone, used as screening test, and at least one of two other abnormal hormonal parameters, that is, adrenocorticotrophin (ACTH) less than 2 pmol/l and urinary cortisol more than 694 nmol/24 h. Results Three out of 76 patients had postdexamethasone plasma cortisol more than 50 nmol/l. Only one also showed low-normal ACTH and mildly elevated urinary cortisol. The patient had a right 4 cm adrenal mass. Laparoscopic adrenalectomy was followed by short-term steroid replacement to prevent adrenal insufficiency. In-situ hybridization showed CYP11B1 expression exclusively in tumoral tissue, whereas CYP11B2 was expressed only in a peritumoral region composed of zona glomerulosa-like cells, suggesting the co-existence of a cortisol-producing adenoma and an aldosterone-producing hyperplasia in the same adrenal. The restoration of hormone abnormalities to normal levels was confirmed at 12 months of follow-up. Conclusion Concurrent aldosterone and subclinical cortisol hypersecretion seems to be a rare event in primary aldosteronism patients; however, its detection by appropriate testing is important to avoid AVS misinterpretation.

Nonalcoholic fatty liver disease in primary aldosteronism: a pilot study.

BACKGROUND An impairment of glucose metabolism, contributing to the increased cardiovascular risk, has been shown in primary aldosteronism (PA). Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and may play a role in its pathophysiology. The aim of this study was to investigate the association between NAFLD and PA, and to identify determinants of NAFLD in this condition. METHODS A total of 40 patients with PA, 40 sex-, age-, and body mass index matched patients with low-renin essential hypertension (LREH) and 40 normotensive subjects were studied. According to ultrasound detection of fatty liver, each group was subdivided in two subsets: with NAFLD and without NAFLD. Patients with diabetes, obesity, and hyperlipidemia were excluded. RESULTS Prevalence of NAFLD in PA was similar to that observed in LREH patients, and higher (P < 0.01) than in normotensive controls. Serum potassium was lower in PA than in LREH patients with NAFLD (P < 0.001), while it was similar in PA and LREH patients without NAFLD. At univariate analysis, plasma aldosterone, homeostasis model assessment (HOMA) index and hypokalemia were determinants of NAFLD in PA (P < 0.05), while HOMA index was associated with NAFLD in LREH (P < 0.05). At multivariable analysis, only hypokalemia remained associated with NAFLD in PA (P = 0.02). CONCLUSIONS The results of this pilot study suggest that, in the absence of major risk factors for liver disease, NAFLD is a frequent finding in PA. Patients with PA and hypokalemia are more insulin resistant and have higher prevalence of NAFLD than those with normokalemia, indicating greater risk for metabolic and liver disease in this subgroup.