Advances in Medical Treatment of Primary Aldosteronism / 中国医学科学杂志(英文版)

Primary aldosteronism (PA) is the most common form of secondary hypertension, with its main manifestations including hypertension and hypokalemia. Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation, stroke, and myocardial infarction. The past decade has witnessed the rapid advances in the genetics of PA, which has shed new light on PA treatment. While surgery is the first choice for unilateral diseases, bilateral lesions can be treated with mineralocorticoid receptor antagonists (MRAs). The next-generation non-steroidal MRAs are under investigations. New medications including calcium channel blockers, macrophage antibiotics, and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Hiperaldosteronismo primario en una población de pacientes hipertensos / Primary hyperaldosteronism in a population of hypertensive patients

El diagnóstico de hiperaldosteronismo primario (HPAP) aumentó en los últimos años y algunos autores lo consideran la principal causa de hipertensión arterial secundaria. Estudiamos la prevalencia de HPAP en el total de pacientes hipertensos atendidos en la Unidad de Hipertensión Arterial, en el período comprendido entre julio 1999 a julio 2017. Se incluyeron 2500 pacientes y en 79 se diagnosticó HPAP (3.2%). El HPAP fue más frecuente en mujeres (55.7%), observándose un incremento en la edad geriátrica con relación a estudios previos (27.8%). El diagnóstico se sospechó ante la presencia de kaliuria inapropiada y alcalosis metabólica, acompañada de un cociente aldosterona/actividad de renina plasmática superior a 30 (ng/dl)/(ng/ ml/h). Tras su confirmación se realizaron estudios de imagen para determinar la etiología. Se detectaron así 29 casos (36.8%) de adenomas productores de aldosterona y 5 de hiperplasia bilateral suprarrenal con nódulos. La tomografía computarizada identificó el 100% de los adenomas y de las hiperplasias con nódulos corticales bilaterales. El tratamiento con suprarrenalectomía y/o antialdosterónicos resultó eficaz en el control de la presión arterial en el 69.9% de los casos. Se comentan aspectos particulares de esta serie, como la remisión de la insuficiencia renal, la elevada presencia de litiasis urinaria hipercalciúrica y la detección de un carcinoma de mama tras dosis prolongadas de espironolactona.

The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio > 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/o r antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone.

Diagnosis and management of primary aldosteronism

ABSTRACT Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.

Screening for primary aldosteronism in an argentinian population: a multicenter prospective study

Objectives Primary aldosteronism (PA) is characterized by the autonomous overproduction of aldosterone. Its prevalence has increased since the use of the aldosterone (ALD)/plasma renin activity (PRA) ratio (ARR). The objective of this study is to determine ARR and ARC (ALD/plasma renin concentration ratio) cut-off values (COV) and their diagnostic concordance (DC%) in the screening for PA in an Argentinian population.Design multicenter prospective study.Subjects and methods We studied 353 subjects (104 controls and 249 hypertensive patients). Serum aldosterone, PRA and ARR were determined. In 220 randomly selected subjects, 160 hypertensive patients and 60 controls, plasma renin concentration (PRC) was simultaneously measured and ARC was determined.Results According to the 95th percentile of controls, we determined a COV of 36 for ARR and 2.39 for ARC, with ALD ≥ 15 ng/dL. In 31/249 hypertensive patients, ARR was ≥ 36. PA diagnosis was established in 8/31 patients (23/31 patients did not complete confirmatory tests). DC% between ARR and ARC was calculated. A significant correlation between ARR and ARC (r = 0.742; p < 0.0001) was found only with PRA > 0.3 ng/mL/h and PRC > 5 pg/mL. DC% for ARR and ARC above or below 36 and 2.39 was 79.1%, respectively.Conclusion This first Argentinian multicenter study determined a COV of 36 for ARR and 2.39 for ARC. Applying an ARR ≥ 36 in the hypertensive group, we confirmed PA in a higher percentage of patients than the previously reported one in our population. As for ARC, further studies are needed for its clinical application, since DC% is acceptable only for medium range renin values.

Hipertensión arterial secundaria en el adulto: evaluación diagnóstica y manejo / Secondary arterial hypertension in adults: diagnostic assesment and management

La Hipertensión arterial (HTA) es un grave problema de salud pública mundial. En efecto, sus complicaciones causan anualmente 9,4 millones de muertes. La HTA también es un problema de salud de alto impacto en Chile. De hecho, la Encuesta Nacional de Salud (ENS) 2009-2010 del Ministerio de Salud, reportó una prevalencia del 26,9%. La HTA se define como una Presión arterial sistólica (PAS) 140mmHg y/o una Presión arterial diastólica (PAD) 90mmHg. Tradicionalmente, se ha clasificado la HTA en primaria o esencial, que agrupa a más del 90% de los hipertensos adultos; y en secundaria, que reúne a menos del 10% de los hipertensos. En la evaluación inicial de un paciente con HTA, se debe: Confirmar el diagnóstico; 2) Detectar causas de HTA secundaria, y 3) Evaluar riesgo cardiovascular (CV), daño orgánico y comorbilidades. Para ello, se necesita determinar la Presión Arterial (PA) y la historia clínica, que incluya antecedentes familiares, examen físico, pruebas de laboratorio y pruebas diagnósticas adicionales. En un pequeño porcentaje de adultos con HTA, se puede identificar una causa específica y potencialmente reversible; no obstante, debido a su elevada prevalencia, las formas secundarias pueden afectar a millones de pacientes en todo el mundo. Se puede sospechar una forma secundaria de HTA por un alza marcada de la PA, la aparición o empeoramiento repentinos de una HTA, una mala respuesta de la PA al tratamiento farmacológico y por un daño orgánico desproporcionado para la duración de la HTA. Si la evaluación inicial hace pensar que el paciente tiene una HTA secundaria, entonces se debe tener en consideración las causas más relevantes, que se describen en este artículo.

Arterial hypertension is a serious public health problem worldwide. Indeed, its complications cause 9.4 million deaths annually. Hypertension is also a health problem with high impact in Chile. In fact, the National Health Survey 2009-2010, conducted by the Ministry of Health, showed a prevalence of 26.9%. Arterial hypertension is defined as systolic blood pressure (SBP) 140mmHg and/or diastolic blood pressure (DBP) 90mmHg. Traditionally, hypertension has been classified into primary or essential, which represents over 90% of adults with hypertension; and secondary, which includes less than 10% of hypertensive patients. The initial evaluation of a patient with hypertension should: 1) Confirm the diagnosis of hypertension; 2) Detect causes of secondary hypertension; and 3) Assess cardiovascular risk, organ damage (OD) and concomitant clinical conditions. This calls for blood pressure (BP) measurement, medical history including family history, physical examination, laboratory investigations and further diagnostic tests. A specific, potentially reversible cause of BP elevation can be identified in a relatively small proportion of adult patients with hypertension. However, because of the overall high prevalence of hypertension, secondary forms can affect millions of patients worldwide. A secondary form of hypertension can be indicated by a severe elevation in BP, sudden onset or worsening of hypertension, poor BP response to drug therapy and OD disproportionate to the duration of hypertension. If the initial assessment suggests that the patient has a secondary hypertension, then you should take into consideration the relevant causes, which are described in this article.

Hipertensión de causa adrenal y embarazo / Hypertension of adrenal origin and pregnancy

La hipertensión arterial de causa adrenal asociada al embarazo es infrecuente. Su presencia genera una elevada morbilidad y mortalidad materna y fetal. Los cambios de la fisiología endocrina que acontecen en esta etapa, modifican el cuadro clínico y bioquímico de las enfermedades adrenales causantes de hipertensión. El objetivo de esta revisión es brindar información actualizada sobre el hipercortisolismo endógeno, el aldosteronismo primario y el feocromocitoma en la gestación -a los profesionales de la salud vinculados con la atención a embarazadas- que les permita diagnosticar y tratarlas temprana y adecuadamente mediante la aplicación del método clínico. Se revisa la literatura y se exponen los avances médicos en el tema(AU)

Blood hypertension of adrenal origin associated to pregnancy is unfrequent and generates high maternal and fetal morbidity and mortality. Changes in the endocrine physiology during this phase modify the clinical and biochemical picture of hypertension-causing adrenal diseases. The objective of this review was to provide health professionals in charge of pregnancy care with updated information on endogenous hypercortisolism, primary aldosteronism and pheochromocytoma in pregnancy. This will allow them to diagnose and treat this disorder early and adequately by means of the clinical method. Relevant literature was reviewed and the latest medical advances in this field were presented(AU)

Hipertensión arterial secundaria en el hiperaldosteronismo primario / Secondary blood hypertension in primary hyperaldosteronism

El hiperaldosteronismo primario es una de las formas de hipertensión arterial secundaria de etiología endocrina potencialmente curable. Fue descrita por primera vez por Jerome Conn en 1955. Se caracteriza por la producción inapropiadamente elevada de aldosterona con relativa autonomía del sistema renina-angiotensina. Su diagnóstico se sospecha en pacientes con hipertensión arterial con o sin hipokaliemia y se confirma con la elevación del índice aldosterona/ actividad de renina plasmática. El tratamiento de elección es el quirúrgico, pero el empleo de agentes antagonistas de mineralocorticoides puede ser otra alternativa terapéutica, previa a la cirugía, o cuando esta no sea posible(AU)

Primary hyperaldosteronism is one of the potentially curable secondary blood hypertension forms of endocrine etiology. This disease was firstly described by Jerome Conn in 1955 and characterized by high production of aldosterone with relative autonomy of the renin-angiotensin system. This disease may be suspected in patients with blood hypertension with or without hypokalemia and confirmed with the increase of aldosteron/plasma rennin activity index. The treatment of choice is surgery, but the use of antagonist agents of mineralocorticoids can be another therapeutic alternative before the surgery or when this procedure is not possible(AU)

A Rare Case of Primary Hyperparathyroidism Associated with Primary Aldosteronism, Hurthle Cell Thyroid Cancer and Meningioma

Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of endocrine and non-endocrine tumors. There are also a considerable number of atypical MEN1 syndrome. In this case, a 68-yr-old woman was referred to the Department of Endocrinology for hypercalcemia. Five years ago, she had diagnosed as primary hyperaldosteronism and now newly diagnosed as parathyroid hyperplasia with laboratory and pathologic findings. Hurthle-cell thyroid cancer was also resected during the parathyroid exploration and small meningioma was found on brain MRI. Her general condition has markedly improved and her adrenal mass and meningioma are being closely observed now. We could find the loss of heterozygosity of the MEN1 locus in parathyroid glands, suggesting a MEN1-related tumor, but not a germline mutation. Considering a variety of phenotypic expression and a limitation of current molecular analysis, periodic follow up will be needed in patients with a MEN1-like phenotype.

Predictors of Resolution of Hypertension after Adrenalectomy in Patients with Aldosterone-producing Adenoma

Primary aldosteronism (PA) is a frequent cause of secondary hypertension and is amenable to surgical intervention when it is caused by aldosterone-producing adenoma (APA). Many patients, however, continue to require antihypertensive medications to control their blood pressure after adrenalectomy. The aim of this study was to determine the preoperative factors that predict clinical outcomes after adrenalectomy in patients with APA. We studied 27 patients (mean age 45+/-4 yr) who had APA and underwent unilateral adrenalectomy between December 1995 and September 2008 at our institution. Clinical and biochemical data were evaluated at baseline and after a mean follow-up of 51.8+/-47.0 months (range, 6-159). At the end of the follow-up, 16 patients (59.3%) were considered to experience "complete resolution" without postoperative medications, whereas 7 patients (25.9%) "improved" with medications and 4 patients (14.8%) were "uncontrolled." Three factors (< or =2 antihypertensive medications [P=0.007], duration of hypertension <6 yr [P=0.002], and serum aldosterone <350 pg/mL [P<0.001]) were the predictive for complete resolution in univariate analysis. Multivariate regression analysis showed that serum aldosterone level (<350 pg/mL) was the single most important factor that predicted complete resolution after surgery (P<0.001). The best preoperative clinical factor that predicted resolution of postoperative hypertension after adrenalectomy is serum aldosterone level (<350 pg/mL).

Symptomatic Hypocalcemia in Primary Hyperaldosteronism: A Case Report

The metabolic alterations caused by hyperaldosteronism are being increasingly recognized and have generated considerable interest among the medical fraternity. Hyperaldosteronism is suspected to have a pivotal role in the patho-physiology of congestive cardiac failure where it has been studied extensively. But its effects on calcium metabolism, parathyroid metabolism and renal handling of calcium are less well described. Recent experimental models have shed light into the roles played by previously unknown mechanisms in causing these metabolic alterations. We hereby report a case of primary hyperaldosteronism due to adrenal adenoma (Conn's syndrome) who presented with a myriad of clinical features including symptomatic hypocalcemia, significant weight loss along with uncontrolled hypertension for a prolonged period before eventually detected to have primary hyperaldosteronism. Surgical removal of the causative tumor resulted in prompt disappearance of all the symptoms and signs and regain of lost weight.

Hipertensión arterial infantil de origen monogénico / Hypertension Infant monogenic origin

La hipertensión arterial (HTA) es una patología frecuente en el adulto, en cambio, en pediatría es una patología subdiagnosticada y con una prevalencia del 1 al 2 por ciento. La hipertensión arterial de origen monogénico, representa a menos del 1 por ciento del total, sin embargo es importante su diagnóstico debido a que puede tener riesgo de recurrencia en la familia y ser transmitida a la descendencia. En esta revisión se describen los elementos de sospecha de HTA de origen monogénico, las causas principales, etiopatogenia molecular, clínica, técnicas diagnósticas, modos de herencia y tratamientos. Además se comenta el estado del arte sobre los genes candidatos en la HTA esencial. Conclusión: la HTA de origen monogénico es una señal de alerta de una condición subyacente, la historia personal, los antecedentes familiares y los exámenes de laboratorio, condicionarán el diagnósitco y el asesoramiento genérico para el paciente, como también una búsqueda dirigida en sus familiares.

Hiperaldosteronismo primario / Primary aldosteronism

Primary aldosteronism (PA) is a known cause of hypertension. In the kidney, aldosterone promotes sodium and water reabsorption, increasing the intravascular volume and blood pressure (BP). In the cardiovascular system, aldosterone modifies endothelial and smooth muscle cell response, increasing cardiovascular risk in a blood pressure-independent way. Recently a high prevalence of PA (near to 10 percent) in hypertensive population, has been detected measuring plasma aldosterone/renin activity ratio (ARR) as screening test. This ratio increases along with the severity of the hypertensive disease. The diagnostic work up of PA should confirm the autonomy of aldosterone secretion from the renin-angiotensin system and should differentiate the clinical subtypes of the disease. These are idiopathic aldosteronism (IA) and aldosterone-producing adenoma (APA). Other causes are familial hyperaldosteronism (FH) type I (glucocorticoid-remediable aldosteronism), FH-II (non glucocorticoid-remediable aldosteronism), primary adrenal hyperplasia and adrenal carcinoma. This article reviews the prevalence, diagnosis and treatment of PA and also the clinical, biochemical and genetic characteristics ofits different subtypes.

Diagnosis and management of metabolic alkalosis.

Elevated pH and elevated plasma bicarbonate level above normal characterise metabolic alkalosis. When bicarbonate is elevated pCO2 must also be elevated to maintain pH to its normal range. Therefore with metabolic alkalosis, the compensation is to decrease alveolar ventilation, and increase pCO2. The causes of metabolic alkalosis are gastro-intestinal hydrogen and chloride loss and due to renal cause. For metabolic alkalosis to continue both generation and maintenance of high levels of bicarbonate are necessary. The diagnosis of metabolic alkalosis is established by noting pH, serum bicarbonate (elevated) and pCO2 (compensatory) elevation. To establish the causes it is necessary to determine intravascular volume, supine and standing blood pressure and renin angiotension alolosterone axis. In chloride responsive alkalosis in which the conditions are extracellular volume depletion, hypokalaemia and hypochloraemia correction of intravascular volume with sodium chloride is needed. In severe metabolic alkalosis of any cause dilute hydrochloric acid (0.1 N HCl) may be infused intravenously but haemolysis may be a complication. In emergency situation with severe hypokalaemia dialysis with higher K+, Cl- and low HCO3- bath will be appropriate.

Aetiological, clinical and metabolic profile of hypokalaemic periodic paralysis in adults: a single-centre experience.

BACKGROUND: Hypokalaemic periodic paralysis constitutes a heterogeneous group of disorders that present with acute muscular weakness. In this analysis, we discuss the aetiological factors that appear to be more common in the Indian population. METHODS: From 1995 to 2001, 31 patients presented with periodic paralysis (mean age 34.5 years, range 11-68 years). Of the 31 patients, 19 were men. The clinical and laboratory data of these patients were analysed. Patients were investigated for possible secondary causes of hypokalaemla. RESULTS: There were 13 patients (42%) with renal tubular acidosis, 13 with primary hyperaldosteronism (42%), 2 each with thyrotoxic periodic paralysis and sporadic periodic paralysis, and I with Gitelman syndrome. Of the 13 patients with renal tubular acidosis, 10 had proximal and 3 distal renal tubular acidosis. Three of these patients with renal tubular acidosis had Sjogren syndrome. The patients diagnosed to have renal tubular acidosis had significantly lower serum bicarbonate (18.7 [14.6] v. 29.6 [5.0] mEq/L; p < 0.05) and higher levels of chloride (107.5 [6.0] v. 99.5 [3.4] mEq/L; p < 0.05) compared with those who had primary hyperaldosteronism, although the potassium values were similar (2.4 [0.65] v. 2.26 [0.48] mEq/L; p = 0.43). All patients with primary hyperaldosteronism had hypertension at presentation and were proven to have adrenal adenomas. CONCLUSION: A significant number of patients in this study had secondary and potentially reversible causes of hypokalaemic periodic paralysis. The common causes were renal tubular acidosis and primary hyperaldosteronism. A detailed work-up for secondary causes should be undertaken in Indian patients with hypokalaemic periodic paralysis.

Mielolipoma adrenal e hiperaldosteronismo primário / Adrenal myelolipoma and primary hyperaldosteronism

Objetivo: Mielolipomas são tumores raros e benignos do córtex adrenal de etiologia desconhecida. São compostos de células gordurosas maduras e tecido hematopoiético em vários graus de diferenciação. A maioria desses tumores são nódulos pequenos e assintomáticos. Assim, o diagnóstico desses tumores no passado era geralmente realizado por ocasião da realização de autópsia. Entretanto, devido aos atuais métodos de imagem, tem-se aumentado a descoberta ocasional desses tumores em pacientes portadores de outras patologias. Os mielolipomas são quase sempre não-funcionantes, mas há relatos desses tumores associados a distúrbios endócrinos.Relato de caso: Paciente JHN, 60 anos, masculino,portador de diabetes mellitus controlado com insulina,hipertensão arterial e hipercolesterolemia, evoluindocom insuficiência renal crônica abordada por tratamentodialítico, seguida por transplante renal. O paciente apresentou quadro de hipopotassemia sintomática na vigência de função renal limítrofe, tendo sido aventada a hipótese diagnóstica de hiperaldosteronismo primário. Essa hipótese foi confirmada pelas dosagens de renina e aldosterona plasmáticas, além do achado de massa adrenal esquerda através de tomografia computadorizada e de ressonância nuclear magnética. Foi realizada adrenalectomia esquerda videolaparoscópica, sendo que o paciente evoluiu com nomalização da hipopotassemia e da hiperglicemia, incluindo a suspensão da insulinoterapia. O estudo anatomopatológico foi compatível com o diagnóstico de mielolipoma, sem achados sugestivos de aldosteronoma. Conclusão: É bastante evidente neste relato de caso a relação do mielolipoma adrenal com o hiperaldosteronismo primário, reforçando a hipótese de queeste tipo de tumor possa associar-se às endocrinopatiase a outras condições clínicas potencialmente reversíveisou controláveis pela ressecção do mielolipoma, como foi o caso desse relato

Manejo diagnóstico e terapêutico do hiperaldosteronismo primário / Diagnostic and therapeutic management of primary hyperaldosteronism

O hiperaldosteronismo primário é causa rara de hipertensão arterial persistente, de difícil controle, com hipo ou normocalemia, hiperaldosteronemia e hiporeninemia. A suspeita diagnóstica é baseada na relação aldosterona/renina plasmáticas elevada. O hiperaldosteronismo primário pode raramente associar-se a outros distúrbios metabólicos. Neste trabalho, é relatado o caso de paciente de 56 anos com sinais e sintomas compatíveis com hipotireoidismo, comprovado por alterações laboratoriais e associado à hipertensão arterial persistente e de difícil controle após 10 meses de evolução. A propedêutica revelou hiperaldosteronismo primário causado por microhiperplasia adrenal em paciente com tireoidite de Hashimoto. O tratamento clínico efetivo constituiu-se de orientação dietética, atividade física moderada e terapia farmacológica. Ressalta-se, neste trabalho, a conduta diagnóstica e terapêutica do hiperaldosteronismo primário, de forma racional e com baixos custos.

A 56 years old female with signs and symptoms of hypothyroidism, confirmed by laboratory analysis, is presented. During 10 months, the patient had severe systemic hypertensive disease with the presence of primary hyperaldosteronism caused by bilateral adrenal microhyperplasia and Hashimoto's thyroiditis. The treatment was based on dict orientation, physical education and pharmacological therapy, with an improved evolution. This study emphasizes the therapeutic and diagnostic management of primary hyperaldosteronism. A rational and inexpensive treatment of secondary hypertension is proposed.