Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome.

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.

Clinical, biochemical, and miRNA profile of subjects with positive screening of primary aldosteronism and nonclassic apparent mineralocorticoid excess.

Primary aldosteronism (PA) and nonclassic apparent mineralocorticoid excess (NCAME) have been recognized as endocrine-related conditions having a broad clinical-biochemical spectrum, spanning from normotension to severe arterial hypertension (AHT). However, the coexistence of both phenotypes have not been reported to date. AIM: To identify and characterize clinical and biochemical parameters of subjects with both PA and NCAME conditions (NCAME&PA) and study the miRNA cargo in their urinary extracellular vesicles as potential biomarkers for this novel condition. METHODS: We performed a cross-sectional study of 206 Chilean adult subjects from a primary care cohort. We measured blood pressure (BP), cortisol (F), cortisone (E), aldosterone, plasma renin activity (PRA), microalbuminuria (MAC), plasma NGAL, MMP9, fractional-potassium-excretion (FEK). Subjects were classified as NCAME&PA, PA, NCAME, essential hypertensives (EH), or healthy controls (CTL). EV-miRNAs were quantified by Taqman-qPCR. RESULTS: We found that 30.6% subjects had an abnormal endocrine phenotype: NCAME&PA (6.8%), PA (11.2%) or NCAME (12.6%), and the prevalence of AHT was 92.9%, 82.6%, and 65%, respectively. NCAME&PA subjects had both lower cortisone (p < 0.05) and lower PRA (p < 0.0001), higher FEK (p = 0.02) and higher MAC (p = 0.01) than EH or CTL. NCAME&PA subjects had also higher NGAL levels than CTL and PA (p < 0.05). Exosome miR-192, miR-133a and miR-21 expression decreased with phenotype severity and correlated with BP and PRA (p < 0.05). CONCLUSION: We identified adult subjects with a combined condition of NCAME and PA associated with higher BP, increased renal and endothelial damage markers than control and EH. Additionally, we observed a differential expression of a specific miRNAs, suggesting a potential role of these miRNAs associated to this novel combined phenotype.

Primary Aldosteronism, Aldosterone, and Extracellular Vesicles.

Primary aldosteronism (PA) is an endocrine related condition leading to arterial hypertension due to inappropriately high and unregulated aldosterone concentration. Recently, a broad spectrum of PA has been recognized, which brings new challenges associated with early identification of this condition that affect renal epithelial and extrarenal tissues. Reports have shown the potential role of extracellular vesicles (EVs) and EV cargo as novel and complementary biomarkers in diagnosis and prognosis of PA. In vivo and in vitro studies have identified specific EV surface antigens, EV-proteins, and EV microRNAs that can be useful to develop novel diagnostic algorithms to detect, confirm, or follow up the PA. Moreover, the study of EVs in the field of PA provides further insight in the pathophysiological mechanism of the PA disease.

Proteomic Profile of Urinary Extracellular Vesicles Identifies AGP1 as a Potential Biomarker of Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) represents 6% to 10% of all essential hypertension patients and is diagnosed using the aldosterone-to-renin ratio (ARR) and confirmatory studies. The complexity of PA diagnosis encourages the identification of novel PA biomarkers. Urinary extracellular vesicles (uEVs) are a potential source of biomarkers, considering that their cargo reflects the content of the parent cell. OBJECTIVE: We aimed to evaluate the proteome of uEVs from PA patients and identify potential biomarker candidates for PA. METHODS: Second morning spot urine was collected from healthy controls (n = 8) and PA patients (n = 7). The uEVs were isolated by ultracentrifugation and characterized. Proteomic analysis on uEVs was performed using LC-MS Orbitrap. RESULTS: Isolated uEVs carried extracellular vesicle markers, showed a round shape and sizes between 50 and 150 nm. The concentration of uEVs showed a direct correlation with urinary creatinine (r = 0.6357; P = 0.0128). The uEV size mean (167 ±â€…6 vs 183 ±â€…4nm) and mode (137 ±â€…7 vs 171 ±â€…11nm) was significantly smaller in PA patients than in control subjects, but similar in concentration. Proteomic analysis of uEVs from PA patients identified an upregulation of alpha-1-acid glycoprotein 1 (AGP1) in PA uEVs, which was confirmed using immunoblot. A receiver operating characteristic curve analysis showed an area under the curve of 0.92 (0.82 to 1; P = 0.0055). CONCLUSION: Proteomic and further immunoblot analyses of uEVs highlights AGP1 as potential biomarker for PA.

Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism.

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. OBJECTIVE: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. METHODS: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. RESULTS: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). CONCLUSION: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.

Different effects of progesterone and estradiol on chimeric and wild type aldosterone synthase in vitro.

BACKGROUND: Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. METHODS: We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. RESULTS: In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann-Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. CONCLUSIONS: Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.

A new presentation of the chimeric CYP11B1/CYP11B2 gene with low prevalence of primary aldosteronism and atypical gene segregation pattern.

Familial hyperaldosteronism type I is caused by an unequal crossover of 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, giving rise to a chimeric CYP11B1/CYP11B2 gene (CG). We describe a family carrying a CG with high levels of free 18-hydroxycortisol but low prevalence of primary aldosteronism (PA) and an atypical CG inheritance pattern in a family of 4 generations with 16 adults and 13 children, we measured the arterial blood pressure, serum aldosterone, and plasma renin activity and then calculated the serum aldosterone:plasma renin activity ratio and urinary free 18-hydroxycortisol. We identified the CG by long-extension PCR and predicted its inheritance pattern. The CG was found in 24 of 29 subjects (10 children and 14 adults). In CG+ patients, hypertension and high 18-hydroxycortisol were prevalent (83% and 100%, respectively). High serum aldosterone:plasma renin activity ratio was more frequent in pediatric than adult patients (80% versus 36%; P<0.001). An inverse association between serum aldosterone:plasma renin activity ratio and age was observed (r=-0.48; P=0.018). Sequence analysis identified the CYP11B1/CYP11B2 crossover in a 50-bp region spanning intron 3 of CYP11B1 and exon 4 of CYP11B2. The CG segregation differs from an autosomal disease, showing 100% of CG penetrance in generations II and III. Statistical analysis suggests that inheritance pattern was not attributed to random segregation (P<0.001). In conclusion, we describe a family with an atypical CYP11B1/CYP11B2 gene inheritance pattern and variable phenotypic expression, where the majority of pediatric patients have primary aldosteronism. Most adults have normal aldosterone and renin levels, which could mask them as essential hypertensives.

Frequency of familial hyperaldosteronism type 1 in a hypertensive pediatric population: clinical and biochemical presentation.

Familial hyperaldosteronism type 1 is an autosomal dominant disorder attributed to a chimeric CYP11B1/CYP11B2 gene (CG). Its prevalence and manifestation in the pediatric population has not been established. We aimed to investigate the prevalence of familial hyperaldosteronism type 1 in Chilean hypertensive children and to describe their clinical and biochemical characteristics. We studied 130 untreated hypertensive children (4 to 16 years old). Blood samples for measuring plasma potassium, serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. The detection of CG was performed using long-extension PCR. We found 4 (3.08%) of 130 children with CG who belonged to 4 unrelated families. The 4 patients with CG had very high aldosterone/renin ratio (49 to 242). In addition, we found 4 children and 5 adults who were affected among 21 first-degree relatives. Of the 8 affected children, 6 presented severe hypertension, 1 presented prehypertension, and 1 presented normotension. High serum aldosterone levels (>17.7 ng/dL) were detected in 6 of 8 subjects (range: 18.6 to 48.4 ng/dL) and suppressed plasma renin activity (≤0.5 ng/mL per hour) and high aldosterone/renin ratio (>10) in 8 of 8 children (range: 49 to 242). Hypokalemia was observed in only 1 of 8 children. We demonstrated that the prevalence of familial hyperaldosteronism type 1 in a pediatric hypertensive pediatric population was surprisingly high. We found a high variability in the clinical and biochemical characteristics of the affected patients, which suggests that familial hyperaldosteronism type 1 is a heterogeneous disease with a wide spectrum of presentations even within the same family group.

A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I.

UNLABELLED: Familial hyperaldosteronism type I (FH-I) is an autosomal dominant disorder caused by an unequal cross-over of the gene encoding steroid 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), giving rise to a chimeric CYP11B1/CYP11B2 gene that displays aldosterone synthase activity regulated by ACTH instead of angiotensin II. AIM: To report an unprecedented case of a de novo unequal crossover mutation between CYP11B1 and CYP11B2 genes causing FH-I. PATIENTS AND METHODS: The index case is a 45-yr-old Chilean male diagnosed with primary aldosteronism (PA). All family members were also studied: his biological parents, 1 brother, 6 sisters, 2 daughters, and 1 son. Plasma renin activity, serum aldosterone, and its ratio were measured in all patients. Genetic analyses were performed using long-extension PCR (XL-PCR), DNA sequencing and Southern blot methods. RESULTS: PA was diagnosed for the index case, 1 of his daughters, his son but not for his parents or siblings. XLPCR and Southern blotting demonstrated the presence of the chimeric CYP11B1/CYP11B2 gene solely in PA-affected subjects, suggesting a case of a de novo mutation. Sequence analysis showed the unequal cross-over CYP11B1/CYP11B2 at intron 2 (c.2600-273 CYP11B2). We also identified a polymorphism at the same intron (c.2600-145C>A CYP11B2) in the genome of the index case's father. CONCLUSION: We describe an unprecedented case of unequal cross-over mutation for the chimeric CYP11B1/CYP11B2 gene causing FH-I, which may be linked to a polymorphism in the index case's father germ line.

Genetics of hypertensive syndrome.

The knowledge of the genetic bases of hypertension has improved over the last decade; this area of research has high priority due to the high incidence of hypertension and its impact on public health. Monogenetic mineralocorticoid hypertension syndromes are associated with suppressed plasma renin activity due to excessive activation of the mineralocorticoid pathway. We review the pathophysiology, phenotype, and method of diagnosis for familial hyperaldosteronism type I and type II, hypertensive forms of congenital adrenal hyperplasia, 11beta-hydroxysteroid dehydrogenase type 2 deficiency, Liddle's syndrome, an activating mutation of the MR, and glucocorticoid resistance. We also review some genes that could contribute to essential hypertension.

[Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation]. / Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo.

BACKGROUND: Type I familial hyperaldosteronism is caused by the presence of a chimaeric gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase activity regulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. AIM: To evaluate subclinical endothelial inflammation markers, like Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. PATIENTS AND METHODS: We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by long-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13-year-old boy with hypertension stage 2 (in agree to The Joint National Committee VII, JNC-VII), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. RESULTS: All affected subjects had approximately a 50% increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. CONCLUSIONS: We report a family carrying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

Marcadores de inflamación endotelial subclínica en una familia con hiperaldosteronismo familiar tipo I por mutación de novo / Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation

Background: Type I familial hyperaldosteronism is caused by the presence of a chimaetic gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase activityregulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. Aim: To evaluate subclinical endothelial inflammation markers, Me Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. Patients and methods: We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by ¡ong-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13year-old boy with hypertension stage 2 (in agree to The JointNational Committee VII, JNC-vIl), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. Results: All affected subjects had approximately a 50 percent increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. Conclusions: We report a family canying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

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 (theta = 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.

Variabilidad fenotípica y estrés oxidativo endotelial en una familia con hiperaldosteronismo familiar tipo I / Phenotypical variability and endothelial oxidative stress in a family with type I familial hyperaldosteronism

Type I familial hyperaldosteronism (HAF-I) is caused by the presence of a chimeric gene CYP11B1/CYP11B2 which encodes an enzyme with aldosterone synthetase activity regulated by ACTH. HAF-I patients present with severe hypertension at young ages and a greater risk of stroke. AIM: To characterize clinical and biochemical presentation of family members with HAF-I. To evaluate endothelial oxidative stress markers before and after glucocorticoid treatment. PATIENTS AND METHODS: We evaluated three family members with HAF-I confirmed with a genetic test (XL-PCR) for chimeric gene CYP11B1/CYP11B2. The index case was a 13 years old boy with stage 2 hypertension (Joint National Committee VIIth report), plasma aldosterone/ plasma renin activity (AP/ARP) ratio of161 and normal plasma potassium. His father had primary hyperaldosteronism diagnosed at 25 years of age with hypertension and hypokalemia. His sister was 15 years old, with a normal blood pressure and an AP/ARP ratio of 37.6. RESULTS: All subjects had plasma xanthine-oxidase levels in the upperlimit of normal. Malondialdehyde was above normal in the index case and his father. These markers returned to normal with glucocorticoid treatment. CONCLUSIONS: We report a HAF-I carrying family with a wide phenotypical variability between affected members. Elevation of endothelial oxidativestress markers and its normalization after glucocorticoid treatment, may indicate that aldosterone produces endothelial damage and increases cardiovascular risk.

A genética das síndromes hipertensivas endócrinas / Genetic aspects of endocrine hypertensive disorders

A hipertensão arterial sistêmica está associada a altos índices de morbi-mortalidade e constitui um dos grandes problemas de saúde pública no mundo, dada sua alta prevalência e baixa porcentagem de controle com os tratamentos adotados. Este último problema é justificado, pelo menos em parte, porque ainda utilizamos medidas empíricas para o tratamento, ao invés de uma abordagem específica para cada caso. Os determinantes primários da hipertensão permanecem desconhecidos na maioria dos pacientes, ao qual damos o nome genérico de hipertensão essencial ou primária. Estas limitações estão alicerçadas pelo conceito de que a hipertensão é uma doença complexa, poligênica em sua maioria e com direta interação com fatores ambientais, tais como dieta, ingestão de sal e obesidade, entre outras. A utilização de técnicas de biologia molecular tem trazido uma enorme contribuição para a compreensão de fenômenos biológicos complexos. Sabe-se que em uma minoria dos casos a hipertensão arterial ocorre pela presença de mutações específicas, ditas formas mendelianas, que resultam em ganho de função de transportadores do néfron distal, bem como de vários componentes do sistema renina-angiotensina-aldosterona com conseqüente retenção excessiva de sal. De interesse particular na endocrinologia, estas síndromes podem ser divididas em aumento na produção ou na atividade dos mineralocorticóides e estarão expostas nesta revisão.

Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is a monogenic form of human hypertension that predisposes to cerebral hemorrhage. As a result of a chimeric gene duplication, aldosterone is ectopically synthesized in the cortisol-secreting zona fasciculata of the adrenal gland under the control of adrenocorticotropin (ACTH). Hypertension frequently has its onset during childhood and is usually refractory to standard anti-hypertensives such as ACE inhibitors and beta-blockers. Hypokalemia can develop in those treated with a potassium-wasting diuretic, but random potassium levels are usually normal. Diagnosis has been facilitated by the availability of a genetic test. Suppression of ACTH release with exogenous dexamethasone is a useful diagnostic and therapeutic strategy. Treatment with the mineralocorticoid receptor antagonists spironolactone and epleronone is also efficacious. The diagnosis of GRA facilitates directed therapies and screening of at-risk individuals and kindreds.