Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood.

OBJECTIVES: To review the childhood course of glucocorticoid-remediable aldosteronism (GRA) in order to provide management guidelines for hypertension in children. METHODS: Records for 20 children with GRA (aged 1 month to 18 years; 16 with hypertension) were retrospectively reviewed. RESULTS: Of the 16 children with GRA who developed hypertension, 50% had moderate-severe hypertension (blood pressure [BP] >99th centile for age and sex); 32% had mild hypertension (BP >95th and <99th centile), and 18% had borderline normal BP (BP >90th and <95th centile). Eight of 16 children with hypertension who received directed monotherapy (glucocorticoid suppression or aldosterone receptor/sodium epithelial channel antagonists) maintained BP below the 90th centile. Three additional subjects receiving a combination of directed therapies or a combination of directed therapies and nifedipine were unable to achieve BP control. At GRA diagnosis, 5 of 8 children were normokalemic, and plasma renin activity was suppressed in 5 of 5 subjects. CONCLUSIONS: Clinicians should have a high index of suspicion for GRA, especially in children with severe hypertension and a positive family history of early-onset hypertension and/or premature hemorrhagic stroke. Directed monotherapy is often successful in controlling BP in GRA.

Glucocorticoid-remediable aldosteronism and pregnancy.

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism that presents with hypokalemia and hypertension from childhood onward. GRA is characterized by the ectopic production of aldosterone in the cortisol-producing zona fasciculata under the regulation of adrenocorticotrophic hormone. Despite the early age of onset, no previous reports of pregnancy and GRA exist. Therefore, we set out to describe the maternal and fetal outcomes of pregnancy in women with GRA. Data regarding the blood pressure and pregnancy outcomes were collected in a retrospective chart review of prenatal and hospital records of 35 pregnancies in 16 women with genetically proven GRA. A total of 6% of pregnancies in women with GRA (GRA+) were complicated by preeclampsia. The published rates of preeclampsia in general obstetric populations vary from 2.5% to 10%. Despite the lack of an apparent increase in the rate of preeclampsia, GRA+ women with chronic hypertension had a high rate (39%) of pregnancy-aggravated hypertension. Starting with a higher baseline blood pressure, maternal blood pressure plotted over the time course of pregnancy followed a quadratic curve similar to that previously described in normal pregnancy. Mean gestational age at delivery was 39.1 weeks. Mean birth weight, excluding the 3 sets of twins, was 3219 g. However, infants of GRA+ mothers with pregnancy-aggravated hypertension tended to have lower birth weights than those that did not (3019 g versus 3385 g, respectively; P=0.08). The primary cesarean section rate was 32%, which is approximately double that seen in other general or hypertensive obstetric populations. In summary, GRA+ women did not seem to have an increased risk of preeclampsia. However, GRA+ women with chronic hypertension seem to be at an increased risk for an exacerbation of their hypertension during pregnancy.

Clinical relevance of inhaled corticosteroids and HPA axis suppression.

Although hypothalamic-pituitary-adrenal (HPA) axis suppression has traditionally been viewed as an adverse event after long-term administration of corticosteroids, this effect can also be used to compare the potency of different inhaled corticosteroids. However, various factors such as the dose, frequency of administration, treatment duration, study population (patients with asthma versus normal volunteers), and prior systemic steroid therapy influence adrenal suppression with inhaled corticosteroids. The different adrenal function tests available and the results produced with these tests also must be considered along with the clinical relevance of such results. Whereas low doses of inhaled corticosteroids are likely to cause minimal or no HPA axis suppression, long-term high-dose inhaled corticosteroid use may result in significant suppression by effectively replacing endogenous steroid production. The risk of acute adrenal insufficiency in patients taking low/medium-dose inhaled corticosteroids is minimal, but patients receiving long-term high-dose treatment may require supplementary systemic steroids during stress challenges, especially if they have previously received long-term systemic steroid treatment.

Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism.

There are anecdotal reports of early cerebrovascular complications occurring in patients with glucocorticoid-remediable aldosteronism (GRA). The issue has never been systematically evaluated. In this study, we retrospectively reviewed the International Registry for GRA to see if there was an association between cerebrovascular complications and GRA. We searched the records of 376 patients from 27 genetically proven GRA pedigrees for premature death or cerebrovascular complications. Each case was subsequently verified through the referring physician, or autopsy reports. The number of complications occurring in patients with proven GRA were compared to GRA negative subjects from the same pedigrees. There were 18 cerebrovascular events in 15 patients with proven GRA (n=167) and none in the GRA negative group (n=194; P<.001). There were an additional 15 events in 15 subjects that were suspected of having GRA based on clinical history. Seventy percent of events were hemorrhagic strokes; the overall case fatality rate was 61%. The mean (+/- SD) age at the time of the initial event was 31.7+/-11.3 years. In total, 48% of all GRA pedigrees and 18% of all GRA patients had cerebrovascular complications, which is similar to the frequency of aneurysm in adult polycystic kidney disease. GRA is associated with high morbidity and mortality from early onset of hemorrhagic stroke and ruptured intracranial aneurysms. Screening for intracranial aneurysm with magnetic resonance angiography is advised for patients with genetically proven GRA.

Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is a rare form of inherited hypertension caused by a characteristic gene duplication. With the advent of definitive genetic testing for GRA, the performance of the traditional screening test for GRA, the dexamethasone suppression test (DST), can be evaluated. We compared the DST to direct genetic testing in 24 patients referred for genetic screening for GRA (12 GRA positive and 12 GRA negative) based on clinical and biochemical findings, DST, and family history. Plasma aldosterone was measured before and after oral dexamethasone administration to determine the extent to which aldosterone was suppressed by glucocorticoids in each patient group. The results of the DST in these subjects were also compared to those in 19 historical patients with primary aldosteronism [4 bilateral hyperplasia and 15 aldosterone-producing adenoma (APA)] reported previously. The DST differentiated GRA-positive from GRA-negative patients with 92% sensitivity and 100% specificity. Cutoffs based on the post-DST plasma aldosterone level (< 4 ng/dL) or percent suppression compared to baseline (> 80%) were equally effective in correctly diagnosing GRA (only one GRA-positive patient would have been incorrectly diagnosed). However, DST in 15 APA patients revealed that 33% had greater than 80% suppression of aldosterone, and 1 had aldosterone levels below 4 ng/dL. We conclued that a post-DST aldosterone level below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity. Suppression compared to baseline can be misleading, as evidenced by the results in APA patients and referred subjects who genetically screened negative.

Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum.

PURPOSE: Although Angiotensin II (Ang II) is a major modulator of regional blood flow in the extracavernosal segments of the vascular bed, its role in erectile function is unknown. The corpus cavernosum penis is a modified vascular tissue that contains endothelial and smooth muscle cells. In other segments of the vascular bed, these cell types produce Ang II. Therefore, we explored the presence and function of an Ang II producing paracrine system in the corpus cavernosum. METHODS: The angiotensin content of the human corpus cavernosum was measured by radioimmunoassay. The distribution pattern of Ang II containing cells within the corpus cavernosum was assessed by an immunohistochemical technique, and the rate of its secretion was determined by superfusion. The effects of Ang II and its antagonist, losartan, on intracavernosal pressure were determined under in vivo conditions, in anesthetized dogs. RESULTS: Human corpus cavernosum contained 1178 +/- 223 (SEM) fmol Ang II, 528 +/- 171 fmol Ang I, 475 +/- 67 fmol des-asp-Ang I, and 1897 +/- 371 fmol des-asp-Ang II/gm. tissue (n = 4). Ang II was found mainly in endothelial cells lining blood vessels and smooth muscle bundles within the corpus cavernosum. Superfused cavernosal tissue secreted immuno-reactive Ang II (Ang II(ir)) at a rate of 57 +/- 36.5 fmol Ang II(ir)/gm. tissue/minute (n = 10). The amount of Ang II released per gram of tissue in an hour was 3-fold greater than the Ang II content/gm. tissue, suggesting a local production of Ang II. Papaverine and prostaglandin E1 suppressed Ang II secretion significantly (p <0.001, p = 0.013). The responsiveness to inhibition was a function of the initial rate of Ang II secretion. Tissue samples with a high rate of secretion were less responsive to the inhibitors than tissue that secreted small amounts of Ang II (n = 6). In anesthetized dogs, intra-cavernosal injection of Ang II terminated spontaneous erections, while losartan increased the intracavernosal pressure in a dose dependent manner up to the mean arterial pressure (n = 4). CONCLUSIONS: The corpus cavernosum produces and secretes physiologically relevant amounts of Ang II. The rate of Ang II secretion can be modulated by pharmacologic agents that regulate cytosolic calcium levels and are used clinically to treat erectile dysfunction. Intracavernosal injection of Ang II causes contraction of cavernosal smooth muscle and terminates spontaneous erection in anesthetized dog, while administration of an Ang II receptor antagonist results in smooth muscle relaxation and thus erection.

Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism.

Unlike other forms of primary aldosteronism, recent prospective studies have paradoxically revealed that glucocorticoid-remediable aldosteronism (GRA) is usually characterized by normal potassium (K+) levels. To evaluate this paradox we studied 10 GRA subjects and 14 healthy controls in two protocols: 1) the renal K+ excretory response to acute oral administration of 50 mmol K+ chloride and to fludrocortisone, 0.2 mg p.o. q12 h x 4 doses; and 2) the aldosterone response to administration of 50 mmol K+ chloride. The K+ excretion rate (KER) in GRA subjects (n = 6) at baseline (45.6 +/- 8.3 microEq/min), after K+ (134 +/- 34.2 microEq/min), and after fludrocortisone (100 +/- 35.0 microEq/min) was not significantly different than that seen in the control (n = 8) subjects (54.9 +/- 19.0, 154 +/- 35.5, 112 +/- 45.8 microEq/min, respectively). Thus the renal kaliuretic response to K+ ingestion and exogenous mineralocorticoid is normal in GRA. Serum aldosterone increased from 5.0 +/- 3.8 at baseline to a maximum of 13.1 +/- 6.6 ng/dL 60 min after K+ ingestion in control subjects (n = 7), but failed to increase in GRA subjects (n = 14), going from 8.7 +/- 3.8 (baseline) to 8.8 +/- 5.4 ng/dL at 60 min (P = 0.004 vs. control). The blunted aldosterone response to K+ in GRA in association with the sharp diurnal decline in aldosterone in this ACTH-regulated syndrome probably results in a milder degree of hyperaldosteronism compared with other forms of primary aldosteronism, thereby producing volume expansion with minimal renal K+ wasting.

The biology and clinical relevance of somatostatin receptor scintigraphy in adrenal tumor management.

Somatostatin receptors are present in the normal adrenal cortex and medulla. These receptors are also expressed by tumors that cause Cushing's syndrome and by pheochromocytomas. Somatostatin analogues such as octreotide have been developed to target somatostatin receptors for diagnostic and therapeutic purposes. This article reviews the current knowledge of the biology of somatostatin receptors in the normal adrenal gland and in adrenal tumors and defines the current role of the somatostatin receptor in the diagnosis, staging and management of Cushing's syndrome and pheochromocytomas.

Assessment of systemic corticosteroid activity.

The potency of the inhaled corticosteroid, dose, duration of treatment, and the study subject receiving treatment all play a role in the effects observed on the HPA axis. At low/medium doses of inhaled corticosteroids, where there is minimal/modest HPA axis suppression, there should be no risk of adrenal crisis even under stressful conditions (6). Thus, the risk of acute adrenal insufficiency, culminating in adrenal crisis, in patients taking inhaled steroids is extremely unlikely.

Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity.

OBJECTIVE: Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 --> threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II. METHODS: Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. RESULTS: After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response. CONCLUSIONS: Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.

Glucocorticoid-remediable aldosteronism.

Although GRA is said to be one of the least common of the mineralocorticoid-excess states, it is probably underdiagnosed. Moreover, recent advances in our understanding of its pathogenesis has greatly broadened the understanding of this disorder. The development of direct genetic testing for GRA has simplified the diagnostic approach to GRA and will likely increase the detection of many previously undiagnosed cases. Since appropriate treatment can often result in normalization of this refractory form of hypertension, a high index of suspicion should be maintained for this diagnosis when a patient is diagnosed with mineralocorticoid-induced hypertension. It is only through early detection and institution of directed treatment that the morbidity and mortality associated with GRA can be reduced.

Primary aldosteronism.

The mineralocorticoid-excess state caused by primary aldosteronism usually causes hypokalemia and moderate to sever hypotension. A directed approach to the patient with suspected primary aldosteronism is essential. Appropriate use of biochemical and diagnostic imaging studies can identify the etiology of the primary aldosteronism in an efficient and noninvasive way in most cases. Precision in defining the etiology of the mineralocorticoid-excess state logically leads to therapeutic strategies that usually cure or improve the hypertensive state.

Glucocorticoid-remediable aldosteronism.

GRA is an inherited disorder of aldosterone biosynthesis. To date, all cases have been the result of chimeric gene duplications in which the regulatory region of the 11-beta hydroxylase gene is fused to more distal coding sequences of the aldosterone synthase gene. This results in ectopic expression of aldosterone synthase in fasciculata cells. Genetic testing has been remarkably precise in identifying these individuals with 100% concordance of the presence of the chimeric gene with increases in 18-oxygenated cortisol products. Several implications follow from these findings. First, GRA may be more common in the hypertensive population than had been previously estimated, and second, genetic testing of subsets of the essential hypertensive population (e.g., those who have low plasma renin activity) may allow the identification of GRA patients who could then be treated specifically. We recommend that hypertensive patients with signs of aldosteronism and no radiologic evidence of an aldosteronoma, especially young hypertensive subjects with low renin activity, be genetically screened for GRA. To track the success of this approach and to identify responses to various therapeutic programs, a central international registry for GRA has been established. This registry not only provides access to screening for GRA, but also informational resources for patients and physicians.

Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis.

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary cause of human hypertension in which aldosterone secretion is regulated by adrenocorticotropin (ACTH). A genetic mutation which causes GRA has recently been identified in our laboratory, a hybrid or chimeric gene fusing nucleotide sequences of the 11 beta-hydroxylase and aldosterone synthase genes. The finding that these chimeric gene duplications are sensitive and specific markers for GRA allows for a simple, direct genetic test for this disorder. In preliminary studies, we found a wide range of blood pressure levels (including normotension) in affected GRA subjects. Studies to data indicate that this is not related to environmental factors such as sodium intake. Another possibility is that chimeric gene expression is variable, with low blood pressure subjects having reduced gene expression. However, the data have not demonstrated differences in steroid levels in subjects with severe versus mild hypertension. In fact, it is likely that the wide range in blood pressure levels in affected subjects involves interaction of other systems which control blood pressure. Preliminary data in two kindreds suggest that blood pressure levels are reciprocally related to levels of urinary kallikrein excretion, supporting the notion that GRA is a hypertension-predisposing syndrome, with the resultant blood pressure the interaction of the gene mutation with other blood pressure regulatory systems. Although GRA is a mineralocorticoid excess state, as evidenced by profoundly suppressed levels of plasma renin activity, we have observed (contrary to the reported literature) that normokalemia is a typical finding. In one large normokalemic pedigree, preliminary findings indicate that these subjects have a normal capacity to excrete potassium.(ABSTRACT TRUNCATED AT 250 WORDS)