Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing's syndrome

We examined circadian blood pressure (BP) variation (expressed as a relative night-time BP decline) in subjects with primary aldosteronism (78 patients), pheochromocytoma (n=45) and Cushing's syndrome (n=18). Subjects with aldosterone-producing adenoma (n=21) and pheochromocytoma (n=27) were also investigated after the tumour removal. In all, 65 patients with essential hypertension served as a control group. The night-time BP decline was significantly attenuated in all three forms of endocrine hypertension compared to the control group (primary aldosteronism P<0.0001, pheochromocytoma P<0.0001 for systolic and diastolic BP and Cushing's syndrome P<0.0001/<0.001 vs essential hypertension). In the case of pheochromocytoma, the absence of the night-time BP decrease was more prominent compared to the primary aldosteronism group (P=0.003/0.001) and for the diastolic BP also in comparison with the Cushing's syndrome group (P=0.03). Tumour removal led in both groups to the restoration of the previously altered circadian rhythm (aldosterone-producing adenoma: P=0.0005/0.0009; pheochromocytoma: P=0.001/0.0007). Our study demonstrates a blunted circadian BP variation in all forms of adrenal hypertension in comparison with essential hypertension. This reduction of the night-time BP decrease was more prominent in pheochromocytoma than in primary aldosteronism or Cushing's syndrome.     

Abolished nocturnal blood pressure fall in a boy with glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is a rarely recognised cause of arterial hypertension. We report the features of a 13-year-old boy with hypertension (casual blood pressure (BP) 140-180/95-110 mm Hg) discovered during a routine paediatric check. Ambulatory BP monitoring (ABPM) revealed significant hypertension with an abolished nocturnal BP fall (mean daytime BP 155/108 mm Hg, mean night-time BP 156/104 mm Hg, nocturnal BP fall 0/4%) which was indicative of secondary hypertension. Despite triple antihypertensive drug therapy the hypertensive control was unsatisfactory. Laboratory tests revealed hypokalaemia (3.0 mmol/l), suppressed plasma renin activity (0.012 nmol/l/h) and high plasma aldosterone (1.190 nmol/l). The diagnosis of primary hyperaldosteronism was established and GRA was further confirmed by the presence of the chimaeric GRA-gene and dexamethasone therapy was initiated. During the next 2 months of dexamethasone therapy all three antihypertensive drugs were discontinued and BP remained under control with restoration to a normal nocturnal BP fall (mean daytime BP 129/77 mm Hg, mean night-time BP 113/64, nocturnal BP fall 12/17%). A change of therapy from dexamethasone to spironolactone was necessary due to the side effects of corticosteroids after 3 months. Spironolactone alone (0.8-2 mg/kg/day) was able to control the BP sufficiently. In conclusion, to our knowledge, this is the first reported case of abolished nocturnal BP fall in a patient with genetically proven GRA. This study indicates that GRA can cause severe hypertension even in children, associated with an abolished nocturnal BP fall. GRA thus should be excluded in all hypertensive patients with circadian BP rhythm disturbances.     

Ambulatory Blood Pressure Monitoring–Derived Short‐Term Blood Pressure Variability in Primary Aldosteronism

The aim of this study was to investigate the short‐term blood pressure (BP) variability (BPV) derived from ambulatory blood pressure monitoring (ABPM) in patients with primary aldosteronism (PA), either idiopathic hyperaldosteronism (IHA) or aldosterone‐producing adenoma (APA), in comparison with patients with essential hypertension (EH) and normotensive (NT) controls. Thirty patients with PA (16 with IHA and 14 with APA), 30 patients with EH, and 30 NT controls, matched for sex, age, body mass index, and antihypertensive therapy, were studied. The standard deviation (SD) of 24‐hour, daytime, and nighttime BP; 24‐hour weighted SD of BP; and 24‐hour BP average real variability were not different between patients with PA and those with EH (P=not significant). All BPV indices were higher in patients with PA, either IHA or APA subtypes, and patients with EH, compared with NT controls (P<.001 to P<.05). ABPM‐derived short‐term BPV is increased in patients with PA, and it may represent an additional cardiovascular risk factor in this disease. The role of aldosterone excess in BPV has to be clarified.     

Circadian blood pressure profile in patients with Cushing's syndrome before and after treatment

The aim of the study was to evaluate the circadian blood pressure (BP) profiles in patients with two forms of Cushing's syndrome, and to compare them to those in patients with essential hypertension. The study included 100 patients with Cushing's syndrome (80 with pituitary adenomas and 20 with adrenal adenomas) and 40 with essential hypertension. Twenty-four-h ambulatory BP monitoring was performed before and after therapy. All 3 groups had similar office-, 24-h-, awake-, and sleep BP mean values. The awake-sleep differences between the patients with two forms of Cushing's syndrome were similar. The night-time BP decline in the patients with Cushing's disease, as well as in those with adrenal adenomas, was significantly lower than that in the patients with essential hypertension. In the patients with both forms of Cushing's syndrome, there was a highly significant decline in the office and ambulatory BP levels after the treatment, and the awake-sleep systolic BP difference became significantly higher. The night-time diastolic BP decline was significantly higher after treatment in patients with adrenal adenomas and not-significantly higher in patients with Cushing's disease. In the patients with Cushing's disease, the duration of hypertension was greater, and lower percentage of normalized BP after treatment was observed in comparison with the patients with adrenal adenomas. The significant negative correlation between duration of the disease and extent of the night-time BP decline suggests that the 'non-dipping' profile is related not only to hypercortisolism itself but also to the severity of hypertension and duration of the disease.     

In Primary Aldosteronism the Circadian Blood Pressure Rhythm is Similar to That in Primary Hypertension

To investigate whether the 24-hour blood pressure (BP) profile of primary aldosteronism differs from that of primary hypertension, ambulatory BP monitoring was performed in 11 patients with primary aldosteronism (9 with an adrenal adenoma and 2 with idiopathic hyperaldosteronism) and in 11 primary hypertensives, matched for sex (5M,6F), age (mean: 52 vs 49 yrs) and casual BP. We found no difference in 24-hour BP, nocturnal BP fall, BP variability (standard deviation and peaks of pressure) response to postural changes (lying-standing BP) between the two groups (all p values n.s.). Within the patients with primary aldosteronism no correlation was observed between BP, plasma renin activity, blood and urine aldosterone levels, blood and urine K⁺, and size of the tumour. Thus, at variance with previous reports, these results show that diurnal rhythm of BP and BP variability are similar in primary aldosteronism and primary hypertensives with similar demographic features and casual BP levels. They also show that an orthostatic fall of BP is not a common feature in this disease.     

Adrenal mineralocorticoids causing hypertension

The three major adrenal mineralocorticoid hormones are aldosterone, deoxycorticosterone (DOC) and corticosterone (B). To date, there are four recognized types of primary aldosteronism: (1) aldosterone-producing adenoma (APA), (2) idiopathic hyperaldosteronism (IHA), (3) indeterminate hyperaldosteronism (IndHA) and (4) glucocorticoid-remediable hyperaldosteronism (GRHA). Preoperative distinction between APA and IHA is best achieved by plotting the basal recumbent plasma renin concentration against the level of aldosterone production after administration of deoxycorticosterone acetate (DOCA). Preoperative predictability has been accurate in thirteen cases. Adrenalectomy effects cure or a marked improvement of hypertension in patients with APA, whereas the results are poor in patients with IHA although the number of patients still remains small. Patients with IndHA have all the features of hyperaldosteronism except aldosterone excretion is readily suppressed by the administration of DOCA, and the administration of spironolactone, 200 to 400 mg/day, corrects the hypertension. GRHA is readily correctable by replacement doses of dexamethasone.     

老老年原发性高血压患者脑白质病变与夜间血压下降率的相关性

目的探讨在老老年（≥80岁）原发性高血压患者中,动态血压状况与脑白质病变（WML）的相关性。方法我们回顾性地选取了高血压患者共130例,均行头颅磁共振检查和动态血压监测,并同时收集患者的临床和实验室数据,并应用年龄相关的脑白质视觉评定法评分将患者分为三组：轻度WML,中度WML,重度WML。结果在三组患者之间,夜间平均收缩压、夜间平均舒张压及夜间血压下降率的差异有统计学意义;并且与轻度WML组相比,中度WML和重度WML组患者非杓型血压的发生率显著升高。进一步的多因素logistic回归分析示,夜间舒张压升高和夜间血压下降率减小是WML的独立的危险因素。结论在老老年原发性高血压患者中,夜间血压异常升高以及昼夜节律的异常在WML的进展中起重要作用。     

Genetic alterations in patients with primary aldosteronism.

The syndrome of primary aldosteronism is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. The most common clinical subtypes of primary aldosteronism are aldosterone-producing adrenocortical adenoma (APA) and bilateral adrenal cortical hyperplasia (idiopathic hyperaldosteronism, or IHA). It has been reported that renin suppression and aldosterone levels are lower and hypokalemia milder in patients with IHA than in patients with APA. In the present study, we investigated the genetic analysis of aldosterone synthase gene, CYP11B2 in patients with primary aldosteronism and review the recent studies. The chimeric CYP11B1/CYP11B2 gene, which is a candidate gene for glucocorticoid-remediable hyperaldosteronism, was not found in either the DNA from aldosteronoma or in the genomic DNA from patients with APA or IHA. Mutations in the CYP21 or CYP11B1 gene were not present in patients with APA. No mutations in the coding region of the CYP11B2 gene were found in patients with IHA or APA. The level of CYP11B2 messenger RNA (mRNA) was much higher in the aldosteronoma portion than in nonadenomatous portion. The overexpression of CYP11B2 mRNA seen in the mononuclear leukocytes of patients with IHA suggests that unidentified aldosterone-stimulating factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA. The variants of the CYP11B2 gene may also contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.     

Aldosterone excess and resistance to 24-h blood pressure control

BACKGROUND: Aldosterone excess has been reported to be a common cause of resistant hypertension. To what degree this represents true treatment resistance is unknown. OBJECTIVE: The present study aimed to compare the 24-h ambulatory blood pressure monitoring (ABPM) levels in resistant hypertensive patients with or without hyperaldosteronism. METHODS: Two hundred and fifty-one patients with resistant hypertension were prospectively evaluated with an early-morning plasma renin activity (PRA), 24-h urinary aldosterone and sodium, and 24-h ABPM. Daytime, night-time, and 24-h blood pressure (BP) and nocturnal BP decline were determined. Hyperaldosteronism (H-Aldo) was defined as suppressed PRA (<1.0 ng/ml per h or <1.0 mug/l per h) and elevated 24-h urinary aldosterone excretion (>/= 12 mug/24-h or >/= 33.2 nmol/day) during ingestion of the patient's routine diet. RESULTS: In all patients, the mean office BP was 160.0 +/- 25.2/89.4 +/- 15.3 mmHg on an average of 4.2 medications. There was no difference in mean office BP between H-Aldo and normal aldosterone status (N-Aldo) patients. Daytime, night-time, and 24-h systolic and diastolic BP were significantly higher in H-Aldo compared to N-Aldo males. Daytime, night-time, and 24-h systolic BP were significantly higher in H-Aldo compared to N-Aldo females. Multivariate analysis indicated a significant interaction between age and aldosterone status such that the effects of aldosterone on ambulatory BP levels were more pronounced with increasing age. CONCLUSIONS: In spite of similar office BP, ABPM levels were higher in resistant hypertensive patients with H-Aldo. These results suggest that high aldosterone levels impart increased cardiovascular risk not reflected by office BP measurements.     

Unique cases of unilateral hyperaldosteronemia due to multiple adrenocortical micronodules, which can only be detected by selective adrenal venous sampling

Primary aldosteronism is classified as aldosterone-producing adenoma (APA), idiopathic hyperaldosteronism (IHA), unilateral adrenal hyperplasia (UAH), primary adrenal hyperplasia (PAH), adrenal cancer, and glucocorticoid-remediable aldosteronism. We describe here 4 cases of primary aldosteronism due to unilateral hyperaldosteronemia, demonstrating unique histopathologic findings, such as unilateral multiple adrenocortical micronodules in the affected adrenals. Thirty-three patients with primary aldosteronism were consecutively admitted; 27 of them were treated by unilateral adrenalectomy. Four of them also had unilateral adrenal hypersecretion of aldosterone by selective adrenal venous sampling and adrenocortical multiple micronodules without an adenoma. These patients had hyporeninemic hyperaldosteronism with normokalemic hypertension. In these patients, furosemide plus upright test failed to increase plasma renin activity (PRA); the ratio of plasma aldosterone concentration (PAC) to PRA at 90 minutes after captopril administration was similar to that in patients with IHA and APA. Aldosterone concentrations were increased in each unilateral adrenal vein, and poorly encapsulated multiple adrenocortical micronodules from 2 to 3 mm in diameter were microscopically detected in the resected adrenal glands. Immunohistochemical analysis of steroidogenic enzymes, including cholesterol side chain cleavage, 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase, 17alpha-hydroxylase, and 11beta-hydroxylase, indicated that the cortical cells within these micronodules were active in aldosterone production, while the non-nodular zona glomerulosa cells were inactive. We conclude that the clinical and pathologic characteristics of our 4 cases with unilateral multiple adrenocortical micronodules (UMN) are distinct from those of APA, IHA, UAH, and PAH. Furthermore, unilateral hyperaldosteronemia induced by UMN may be frequently misdiagnosed, because standard imaging tests, which cannot always detect tiny abnormalities of adrenals, showed "normal adrenal glands" in these patients. Thus, primary aldosteronism due to UMN should be carefully examined for differential diagnosis of each form of hyperaldosteronemia.     

Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study

OBJECTIVE: Primary aldosteronism (PA) is characterized by the onset of both cardiac and gluco-metabolic alterations. The aim of this study was to evaluate the impact of aldosterone excess on the development of such complications, and the effects of surgical and pharmacological treatment on their long-term outcome. METHODS: We prospectively re-examined 61 patients: 25 with aldosterone-producing adenoma (APA), after surgery, and 36 patients with idiopathic hyperaldosteronism (IHA) on pharmacological treatment. The lipid, fasting and dynamic glucose profiles and the echocardiographic parameters were evaluated at diagnosis and at follow-up. RESULTS: After adrenalectomy all patients had normalization of aldosterone levels and were cured of hypokalaemia, and a resolution of hypertension was achieved in 12 of 25 patients. APA patients showed a significant reduction of both plasma glucose (P=0.017) and insulin levels (P=0.001) after 75 g oral glucose tolerance test. Stabilization of glucose metabolism complications was observed in IHA patients. Multiple regression analysis at diagnosis showed a positive correlation between homeostasis model assessment (HOMA) insulin resistance index and HOMA beta cell and serum aldosterone levels in both APA and IHA. Echocardiographic parameters were improved in both APA and IHA at follow-up and the difference was statistically significant for left ventricular mass index (P=0.017) and interventricular septum thickness (P=0.007) in APA patients. CONCLUSIONS: The removal of aldosterone excess in APA patients induces the regression of both cardiac and gluco-metabolic complications, indicating aldosterone as a main determinant of such alterations. In IHA patients the medical treatment seems to avoid the possible progression of the these alterations that appear to be stable.     

18-羟皮质醇测定在原发性醛固酮增多症鉴别诊断中的意义

目的　探讨１８羟皮质醇在原发性醛固酮增多症（ 原醛） 鉴别诊断中的应用价值。方法　应用竞争性亲和素生物素酶联免疫吸附测定法检测３６ 例原醛（ 包括２６ 例腺瘤和１０ 例特发性增生） ,２２ 例除原醛外的其它肾上腺疾病,６ 例继发性醛固酮增多症,２５ 例原发性高血压和２１ 名正常人的血、尿１８羟皮质醇水平并进行比较,同时比较部分原醛腺瘤患者手术前后１８羟皮质醇的变化。结果　原醛腺瘤病人１８羟皮质醇水平明显高于包括原醛增生在内的其它组病人（ Ｐ＜ ０ ．０５） ,其它各组之间１８羟皮质醇水平无明显差异（ Ｐ＞ ０ ．０５） ,原醛腺瘤术后１８羟皮质醇水平明显低于术前（ Ｐ＜ ０ ．０５） 。结论　１８羟皮质醇在原醛的鉴别诊断上是一个敏感性高、特异性强的指标。     

Hormones Other Than Aldosterone May Contribute to Hypertension in 3 Different Subtypes of Primary Aldosteronism

Blood pressure (BP) level is similar in patients with 3 subtypes of primary aldosteronism (PA), even though aldosterone levels may vary. Glucocorticoids and adrenomedullary hormones may be influenced and may contribute to hypertension in PA. The authors' objective was to investigate the influence of PA on adrenal gland secretion and the roles of these hormones in hypertension. Patients diagnosed with PA (229 cases) were enrolled and classified into 3 subgroups: aldosterone‐producing adenoma (APA), unilateral nodular adrenal hyperplasia (UNAH), and idiopathic hyperaldosteronism (IHA). Patients with essential hypertension served as the control group (100 cases). Concentration of the above hormones was measured and compared between groups. Level of plasma adrenocorticotrophic hormone (ACTH) in patients with APA was significantly lower than that in patients with IHA (P<.001) and UNAH (P<0.5). The 24‐hour urinary free cortisol and adrenomedullary hormone levels were highest in patients with IHA, lower in patients with APA, and lowest in patients with UNAH. Systolic BP level was positively correlated with 8 am plasma cortisol level (r=0.142, P=.039) and plasma ACTH level (r=0.383, P=.016). Cortisol and adrenomedullary hormones were different between PA subtypes and they might involve regulation of BP in those patients.     

Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas

Primary aldosteronism (PA) and, in particular, its two commonest subtypes (i.e. idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA)) have been recognized as the most common cause of secondary hypertension. While 'conservative' medical treatment with aldosterone receptor antagonists is the therapeutic approach of choice in controlling blood pressure in patients with PA due to IHA, the more invasive (laparoscopic) adrenalectomy seems to be the most suitable therapy for patients with APA. In this review, we focus on the medical approach for the management of APA in cases where surgical excision of the adrenal is not possible.     

Detecting and treating primary aldosteronism: primary aldosteronism.

Primary aldosteronism (PA) is the most common cause of mineralocorticoid hypertension. Different studies, using the plasma aldosterone concentration to plasma renin activity ratio (PAC/PRA) for the screening of patients with hypertension, have shown a marked increase in the detection rate of PA. Idiopathic bilateral adrenal hyperplasia (IHA) and aldosterone-producing adrenal adenoma (APA), are the leading causes of primary aldosteronism. Glucocorticoid-remediable aldosteronism (GRA), also called familial hyperaldosteronism type I, familial hyperaldosteronism type II and carcinomas are rare causes of PA. Patients with hypertension and hypokalemia, those with a family history of hypertension and stroke at an early age, or patients with medication-resistant hypertension should be screened for PA using the PAC/PRA ratio. If a high ratio is found, a sodium loading test or a captopril test is warranted to confirm the diagnosis. Adrenal gland imaging is important in subtype differentiation (APA vs IHA). Adrenal venous sampling should be used when other tests prove inconclusive. Genetic testing has facilitated detection of GRA. Surgery is considered the treatment of choice for patients with APA, while bilateral hyperplasia subtypes are treated medically. Normalization of aldosterone levels or aldosterone receptor blockade are necessary to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage.     

原发性醛固酮增多症的分型诊断

目的 探讨用于原发性醛固酮增多症(原醛症)分型诊断检查方法的价值.方法 收集本院近7年来57例临床确诊的原醛症患者[醛固酮瘤22例,特发性醛固酮增多症(特醛症)26例,原发性肾上腺增生9例],检测患者的血电解质、血浆肾素活性及血、尿醛固酮,将结果与19例原发性高血压患者对照.再通过肾上腺CT、体位激发试验及肾上腺静脉采血检查对原醛症患者分型并随访.结果 (1)醛固酮瘤患者血压及血、尿醛固酮较特醛症患者高,血钾及血浆肾素活性则低,而原发性肾上腺增生患者临床及生化改变介于两者之间.肾上腺CT检查在原醛症分型诊断中的符合率为醛固酮瘤86.4%,特醛症73.1%,原发性肾上腺增生22.2%;肾上腺静脉采血检查以两侧醛固酮之比作为判定标准时符合率为86.4%、80.8%和77.8%,以醛固酮与皮质醇之比为判定标准则符合率分别为95.5%、92.3%及100.0%.(2)醛固酮瘤及原发性肾上腺增生患者术后随访血醛固酮均下降,血压恢复正常者分别为22.7%及44.9%,血钾恢复正常者为83.3%及100.0%,而特醛症患者随访中各项测值无明显变化,另有33.3%诊断时血钾正常的患者随访中出现低血钾.结论 原醛症的分型诊断需依靠多种检查手段综合分析,单纯依赖影像学检查或体位激发试验并不可靠,肾上腺静脉采血检查可作为影像学检查的补充,用两侧醛固酮与皮质醇的比值分析较单纯比较两侧醛固酮之比更为可靠;醛固酮瘤及原发性肾上腺增生患者术后临床及生化测值均得以明显改善,而特醛症患者随访中无明显变化.     

原发性醛固酮增多症

原发性醛固酮增多症(原醛症)是继发性高血压的常见病因之一,部分患者亦可伴有低血钾,醛固酮瘤及特发性醛固酮增多症是其主要的病理亚型。原醛症的诊断包括筛查、确诊及分型诊断3个步骤,传统影像学结合体位刺激的方法进行分型诊断,假阳性及假阴性率均较高,肾上腺静脉插管采血可作为影像学检查的补充。醛固酮瘤及原发性肾上腺增生患者应予手术治疗,特发性醛固酮增多症患者多采用药物治疗,螺内酯是其首选药物。     

Acute and Chronic Effect of Nifedipine in Primary Aldosteronism

Since calcium entry blocker drugs can interfere with aldosterone secretion in vitro, a similar effect in vivo, in man, has been suggested and partially confirmed. The data available in primary aldosteronism are more controversial. Therefore, we have studied the acute and chronic effect of nifedipine in 7 patients with idiopathic hyperaldosteronism (IHA) and 8 with aldosterone producing adenoma (APA). On 2 different days, 10 mg of nifedipine or placebo were given sublingually to the patients and blood pressure and heart rate were recorded every 5 min. for 60 min. Plasma aldosterone, cortisol, PRA and serum K were measured at 0, 30 and 60 min. 5 patients with IHA and 6 with APA received nifedipine 20 mg per os bid for 3 months; the same parameters were evaluated on days 0, 30, 60 and 90; urinary aldosterone was measured on days 0, 30, 60 and 90. BP decreased in both groups both after acute and chronic administration of nifedipine. Plasma aldosterone showed a similar trend either after acute nifedipine or placebo; however, during chronic treatment it was slightly decreased in IHA patients. Cortisol, PRA, urinary aldosterone and K⁺ remained unchanged. In conclusion, nifedipine is an effective antihypertensive agent also in primary aldosteronism; its aldosterone inhibiting properties are minimal and seem to be present only during long-term therapy in IHA.     

Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin responsive adenoma

Among 154 cases of primary aldosteronism seen in the General Clinical Research Center at San Francisco General Hospital, twelve patients did not fulfill established characteristics of an aldosterone producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). Eight patients had nodular adrenocortical hyperplasia; plasma and urinary aldosterone were elevated and responses to stimulatory and suppressive maneuvers demonstrated the same autonomy seen in patients with APA. This subset is designated primary adrenal hyperplasia. Four additional patients also had elevated aldosterone levels that were responsive to these maneuvers, similar to IHA, but had unilateral tumors. This group has been designated as aldosterone-producing renin-responsive adenoma. Eleven patients had unilateral adrenalectomy and one preferred prolonged spironolactone therapy, resulting in a sustained cure or amelioration of hypertension, hypokalemia and normalization of aldosterone production.