Classic and current concepts in adrenal steroidogenesis: a reappraisal

ABSTRACT Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.

Aumento de la lipocalina orosomucoide-1 (ORM1) en sujetos con hiperaldosteronismo primario / Increase of lipocalin ORM1 in primary aldosteronism

El hiperaldosteronismo primario (HAP) es la causa más común de hipertensión arterial secundaria. A pesar de la prevalencia del HAP (6-10%) y sus consecuencias, los mecanismos que median los efectos deletéreos renales y extrarenales originados por la aldosterona más allá de la hipertensión arterial (ej. inflamación renal, alteraciones cardiacas y disfunción vascular), siguen siendo poco conocidos. Estudios previos sugieren que el exceso de aldosterona aumentaría proteínas sensibles a la activación del receptor de mineralocorticoides (MR), como las lipocalinas LCN2 (NGAL) y ORM1. OBJETIVO: Determinar la concentración de las lipocalinas ORM1, NGAL y NGAL-MMP9 en sujetos HAP. SUJETOS Y MÉTODOS: Estudio de cohorte transversal en sujetos adultos (similares en sexo, edad e IMC) separados en controles normotensos (CTL), hipertensos esenciales (HE) y con screening positivo de HAP (aldosterona ≥9 ng/dL y ARP < 1 ng/mL*h acorde a las guías internacionales de HAP). Se determinó la presión arterial sistólica (PAS) y diastólica (PAD), aldosterona plasmática, actividad renina plasmática (ARP) y la relación aldosterona / actividad de renina plasmática (ARR). Se determinó la concentración de NGAL, NGAL-MMP9 y ORM1 en suero por ELISA. RESULTADOS: Detectamos mayores niveles de ORM1 en sujetos HAP. No se detectaron diferencias en NGAL ni NGAL-MMP9 entre los grupos. Detectamos una asociación positiva de ORM1 con ARP (rho= -0,407, p=0,012) y con ARR (rho= 0,380 p= 0,021). CONCLUSIÓN: La mayor concentración de ORM1 en sujetos HAP y las asociaciones de ORM1 con aldosterona, ARP y ARR, proponen a esta proteína como un potencial biomarcador de HAP y de utilidad en el desarrollo de algoritmos diagnósticos de HAP.

Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension. Despite the prevalence of PA (6-10%) and its consequences, the mechanisms that mediate the deleterious renal and extrarenal effects caused by aldosterone beyond arterial hypertension (eg renal inflammation, cardiac alterations and vascular dysfunction), remain barely known. Previous studies suggest that excess aldosterone would increase proteins sensitive to activation of the mineralocorticoid receptor (MR), such as lipocalins LCN2 (NGAL) and ORM1. AIM: To determine the concentration of the lipocalins ORM1, NGAL and NGAL-MMP9 in PA subjects. SUBJECTS AND METHODS: Cross-sectional study in adult subjects (similar in sex, age and BMI) grouped as normotensive controls (CTL), essential hypertensive (HE) and subjects with positive PA screening (aldosterone ≥ 9 ng/dL and PRA <1 ng/mL*h, according to international PA guidelines). Systolic (SBP) and diastolic (DBP) blood pressure, plasma aldosterone, plasma renin activity (PRA), and plasma aldosterone renin ratio (ARR) were determined. The concentration of NGAL, NGAL-MMP9 and ORM1 in serum was determined by ELISA. RESULTS: We detected higher levels Recibido: 03-09-2021 of ORM1 in PA subjects. No differences in NGAL or NGAL-MMP9 were detected between the groups. We detected a positive association of ORM1 with ARP (rho = -0.407, p < 0.05) and with ARR (rho = 0.380 p <0.05). CONCLUSION: The high levels of ORM1 in PA subjects and the associations of ORM1 with aldosterone, ARP and ARR, suggest ORM1 is a potential biomarker of PA, and useful in the development of a diagnostic algorithm for PA.

Hipertensão resistente em paciente com diagnótico de hiperaldosteronismo primário: resposta ao eplerenone / Resistant hypertension in a patient with primary hypereraldosteronism diagnosis: response to eplerenone

A maioria dos pacientes com hipertensão arterial (HA) não tem etiologia clara e é classificada como hipertensão primária. No entanto, 5% a 10% desses pacientes podem ter hipertensão secundária, o que indica presença de uma causa subjacente e potencialmente reversível. Em adultos com 65 anos ou mais, estenose da artéria renal aterosclerótica, insuficiência renal e hipotireoidismo são causas comuns. A hipertensão secundária deve ser considerada na presença de sintomas e sinais sugestivos, como hipertensão grave ou resistente, idade de início inferior a 30 anos (especialmente antes da puberdade), hipertensão maligna ou acelerada e aumento agudo da pressão arterial a partir de leituras previamente estáveis. Outras causas subjacentes da hipertensão secundária incluem hiperaldosteronismo, apneia obstrutiva do sono, feocromocitoma, síndrome de Cushing, doença da tireoide, coarctação da aorta e uso de certos medicamentos. A hipertensão arterial resistente (HAR) é definida quando a pressão arterial (PA) permanece acima das metas recomendadas com o uso de três anti-hipertensivos de diferentes classes, incluindo um bloqueador do sistema renina- -angiotensina (inibidor da enzima conversora da angiotensina [IECA] ou bloqueador do receptor de angiotensina [BRA]), um bloqueador dos canais de cálcio (BCC) de ação prolongada e um diurético tiazídico (DT) de longa ação em doses máximas preconizadas e toleradas, administradas com frequência, dosagem apropriada e comprovada adesão. Hipertensão arterial acompanhada de supressão da atividade da renina plasmática (ARP) e aumento da excreção de aldosterona caracteriza a síndrome de aldosteronismo primário. Esse quadro foi descrito, pela primeira vez em 1955 por Conn, em um paciente hipertenso grave hipocalêmico e com secreção elevada de aldosterona, que submetido à adrenalectomia direita resultou em cura da HA

Patients with arterial hypertension have no clear etiology and are classified as primary hypertension. However, 5% to 10% of these with hypertension may have the secondary form of disease, which indicates the presence of an underlying and potentially reversible cause. In adults aged 65 and over, the common causes of secondary hypertension are atherosclerotic renal artery stenosis, renal failure and hypothyroidism. Secondary hypertension should be considered in the presence of suggestive symptoms and signs, such as severe or resistant hypertension, age at onset less than 30 years (especially before puberty), malignant or accelerated hypertension and acute increase in blood pressure from previously stable readings. Other underlying causes of secondary hypertension include hyperaldosteronism, obstructive sleep apnea, pheochromocytoma, Cushing's syndrome, thyroid disease, coarctation of the aorta and use of others medications. Resistant arterial hypertension is defined when blood pressure remains above the recommended targets with the use of three antihypertensives of different classes, including a blocker of the renin-angiotensin system (inhibitor of the angiotensin-converting enzyme or angiotensin receptor blocker ), a calcium channel blocker and a thiazide diuretic in maximum recommended and tolerated doses, administered frequently, appropriate dosage and proven adherence. Arterial hypertension accompanied by suppression of plasma renin activity and increased aldosterone excretion characterizes the primary aldosteronism syndrome. This condition was described in 1955 by Conn, in a severe hypohypokalemic hypertensive patient with high aldosterone secretion, who underwent right adrenalectomy resulted in a cure for the hypertension

Hipertensión Arterial Secundaria ¿por dónde empezar? / Secondary Arterial Hypertension, where to start?

30 to 40% of the adult population worldwide has been diagnosed with hypertension, among these patients 5 to 10% of them could have a possibly curable condition. In order to recognize this special population, the clinician must perform a complete work up and be aware of the main underlying causes of secondary hypertension. Often this could be a goal difficult to accomplish. The purpose of this article is to discuss the most frequent causes of secondary hypertension and offer a diagnostic approach for these patients. Clinicians should never forget that drug-related hypertension is a common cause that is discovered only with the help of a good medical history.

Polimiopatia hipocalêmica e hipertensão secundária a hiperaldosteronismo primário felino / Hypokalemic polymyopathy and secondary hypertension to feline primary hyperaldosteronism

O hiperaldosteronismo se define pela hipersecreção de aldosterona pelas suprarrenais, resultando em excesso de sódio e redução de potássio sanguíneo. Esta hipersecreção deve-se à síntese autônoma de aldosterona por células adrenais hiperplásicas ou neoplásicas, que agem independentemente da estimulação pelo sistema renina-angiotensina. A doença acomete felinos de adultos maduros a idosos. O excesso de aldosterona culmina em hipertensão sistêmica e/ou hipocalemia, que levam à fraqueza muscular e alterações oculares. O diagnóstico é baseado em exames laboratoriais e de imagem, e o tratamento pode ser clínico ou cirúrgico. O prognóstico é considerado favorável quando as medicações são capazes de melhorar as manifestações clínicas ou quando é possível realizar o procedimento cirúrgico. O presente trabalho visa relatar o caso de um felino macho de 13 anos, castrado, sem raça definida, com hipocalemia persistente secundária a um presuntivo tumor adrenal.

Hyperaldosteronism is defined by the hypersecretion of aldosterone by the adrenal glands resulting in excess sodium and reduced blood potassium. This hypersecretion is due to the autonomous synthesis of aldosterone by hyperplastic or neoplastic adrenal cells, which act independently of stimulation by the renin-angiotensin system. The disease affects felines in the age group from mature adults to the elderly. The excess of aldosterone culminates in systemic hypertension and/or hypokalemia, which leads to muscle weakness and ocular changes. The diagnosis is based on laboratory and imaging tests and treatment can be clinical or surgical. The prognosis is considered favorable when the medications are able to improve the clinical manifestations or when it is possible to perform the surgical procedure. The present paper aims to report the case of a 13-year-old male cat, castrated, crossbred, with persistent hypokalemia secondary to a presumptive adrenal tumor.

Polimiopatia hipocalêmica e hipertensão secundária a hiperaldosteronismo primário felino / Hypokalemic polymyopathy and secondary hypertension to feline primary hyperaldosteronism

O hiperaldosteronismo se define pela hipersecreção de aldosterona pelas suprarrenais, resultando em excesso de sódio e redução de potássio sanguíneo. Esta hipersecreção deve-se à síntese autônoma de aldosterona por células adrenais hiperplásicas ou neoplásicas, que agem independentemente da estimulação pelo sistema renina-angiotensina. A doença acomete felinos de adultos maduros a idosos. O excesso de aldosterona culmina em hipertensão sistêmica e/ou hipocalemia, que levam à fraqueza muscular e alterações oculares. O diagnóstico é baseado em exames laboratoriais e de imagem, e o tratamento pode ser clínico ou cirúrgico. O prognóstico é considerado favorável quando as medicações são capazes de melhorar as manifestações clínicas ou quando é possível realizar o procedimento cirúrgico. O presente trabalho visa relatar o caso de um felino macho de 13 anos, castrado, sem raça definida, com hipocalemia persistente secundária a um presuntivo tumor adrenal.

Hyperaldosteronism is defined by the hypersecretion of aldosterone by the adrenal glands resulting in excess sodium and reduced blood potassium. This hypersecretion is due to the autonomous synthesis of aldosterone by hyperplastic or neoplastic adrenal cells, which act independently of stimulation by the renin-angiotensin system. The disease affects felines in the age group from mature adults to the elderly. The excess of aldosterone culminates in systemic hypertension and/or hypokalemia, which leads to muscle weakness and ocular changes. The diagnosis is based on laboratory and imaging tests and treatment can be clinical or surgical. The prognosis is considered favorable when the medications are able to improve the clinical manifestations or when it is possible to perform the surgical procedure. The present paper aims to report the case of a 13-year-old male cat, castrated, crossbred, with persistent hypokalemia secondary to a presumptive adrenal tumor.

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.

Rabdomiólisis por hipopotasemia severa en paciente con síndrome de Conn / Rhabdomyolysis and profound hypokalemia in a patient with Conn´s syndrome

El Síndrome de Conn o hiperaldosteronismo primario se caracteriza por hipertensión, hipopotasemia con alcalosis metabólica y una masa adrenal. La rabdomiólisis puede ser secundaria a traumatismos, excesiva actividad muscular, enfermedades musculares hereditarias y otras causas médicas, como la hipopotasemia. Presentamos el caso de un hombre de 46 años con rabdomiólisis secundaria e hipopotasemia severa como expresión de hiperaldosteronismo primario por un adenoma suprarrenal(AU)

Conn's syndrome or primary hyperaldosteronism is characterized by hypertension, hypokalemia with metabolic alkalosis and the presence of an adrenal mass. Rhabdomyolysis can be secon- dary to trauma, excessive muscle activity, hereditary muscle diseases and other medical causas, such as hypokalemia. We present the case of a 46-year-old man with secondary rhabdomyolisis and hypokalemia as an-expresión of primary hyperaldosteronism due to an adrenal adenoma(AU)

Resistant Hypertension: A Clinical Case / Hipertensión resistente: un caso clínico / Hipertensão resistente: um caso clínico

Abstract Introduction: Secondary hypertension corresponds to 15 % of the causes of arterial hypertension, and among them, primary hyperaldosteronism presents a variable incidence of about 3 % in hypertensive patients. It has a slightly higher prevalence in women, between 30 and 60 years, and is usually unilateral. Case presentation: The authors describe the clinical case of a patient, followed by a severe hypertension medicated with four antihypertensive drugs for tension stabilization, maintaining systolic arterial tensions superior to 170 mmHg. In the aetiological study of hypertension, analytical alterations suggested hyperaldosteronism and a nodular lesion was detected in the left adrenal gland. The patient was submitted to surgery and excision of the lesion was done with histological confirmation of the diagnosis of corticomedullary adenoma of the adrenal gland. The patient presented improvement of the tension profile, with need to suspend two of the four antihypertensive drugs and to reduce the dose of the remaining ones. Conclusion: A tumor of the adrenal cortex producing aldosterone is the main cause of primary hyperaldosteronism and should always be excluded when the presence of difficult to control, severe hypertension is detected, since the standard treatment is surgical, leading to a stabilization of the tension pattern after a few months.

Resumen Introducción: la hipertensión secundaria corresponde al 15 % de las causas de hipertensión arterial, y entre ellas, el hiperaldosteronismo primario presenta una incidencia variable de sobre 3 % en pacientes hipertensos. Tiene una prevalencia ligeramente mayor en mujeres, entre 30 y 60 años, y generalmente es unilateral. Presentación del caso: los autores describen el caso clínico de un paciente, seguido por una hipertensión resistente medicada con cuatro fármacos antihipertensivos para la estabilización de la tensión, con mantenimiento de las tensiones arteriales sistólicas superiores a 170 mmHg. Las alteraciones analíticas en el estudio etiológico de la hipertensión sugirieron hiperaldosteronismo y una lesión nodular en la glándula suprarrenal izquierda. El paciente fue sometido a cirugía y se realizó la escisión de la lesión con confirmación histológica del diagnóstico de adenoma corticomedular de la glándula suprarrenal. El paciente presentó una mejora en el perfil de tensión, con la necesidad de suspender dos de los cuatro fármacos antihipertensivos y reducir la dosis de los restantes. Discusión: un tumor de la corteza suprarrenal que produce la aldosterona es la principal causa de hiperaldosteronismo primario y siempre debe excluirse cuando se presenta hipertensión grave, difícil de controlar, ya que el tratamiento estándar es quirúrgico y conduce a una estabilización del patrón de tensión después de unos meses.

Resumo Introdução: a hipertensão secundária corresponde ao 15 % das causas de hipertensão arterial, e entre elas, o hiperaldosteronismo primário apresenta uma incidência variável de sobre 3 % em pacientes hipertensos. Tem uma prevalência ligeiramente maior em mulheres, entre 30-60 anos, e geralmente é unilateral. Apresentação do caso: os autores descrevem o caso clínico de um paciente, seguido por uma hipertensão resistente medicada com quatro fármacos anti-hipertensivos para a estabilização da tensão, com manutenção das tensões arteriais sistólicas a 170 mmHg. As alterações analíticas no estudo etiológico da hipertensão sugeriram hiperaldosteronismo e uma lesão nodular na glândula suprarrenal esquerda. O paciente foi submetido a cirurgia e se realizou a incisão da lesão com confirmação histológica do diagnóstico de adenoma córtico-medular da glândula suprarrenal. O paciente apresentou uma melhora no perfil de tensão, com a necessidade de suspender dois dos quatro fármacos anti-hipertensivos e reduzir a dose dos restantes. Discussão: um tumor do córtex suprarrenal que produz a aldosterona é a principal causa de hiperaldosteronismo primário e sempre deve excluir-se quando se apresenta hipertensão grave, difícil de controlar, pois o tratamento standard é cirúrgico e conduz a uma estabilização do patrão de tensão depois de uns meses.

Abordaje diagnóstico de la hipertensión arterial secundaria / Diagnostic Approach Of Secondary Hypertension

Introducción: La hipertensión arterial es una de las enfermedades más prevalentes en atención primaria y el principal factor de riesgo para enfermedad cardivoascular. La hipertensión arterial secundaria es frecuente entre los pacientes con diagnóstico de hipertensión arterial, con una prevalencia del 10 % que puede incrementar hasta 20 % o 40 % en pacientes con hipertensión refractaria al tratamiento. Su identificación temprana se asocia con mejores desenlaces. Objetivo: Evaluar en la literatura las principales causas de hipertensión arterial secundaria e identificar el abordaje diagnóstico inicial de las patologías asociadas. Métodos: Selección y lectura de artículos de bases de datos Pubmed y Google Scholar y de revisiones de UpToDate que trataran el tema de hipertensión arterial secundaria. Conclusiones: Es importante reconocer aquellos pacientes que puedan estar cursando con hipertensión arterial de causa secundaria, ya que esto modifica el enfoque terapéutico, facilita el tratamiento y mejora los desenlaces; incluso puede llegar a la cura y resolución.

Hypertension is one of the most common diseases encountered in primary care settings and a major risk. factor for cardiovascular disease. Secondary hypertension is common in patients with hypertension diagnosis; its prevalence is about 10% and can be as high as 40% in patients whom are resistant to treatment. Its early recognition and treatment allows for better outcomes. Objective: To evalúate and identify the main causes for secondary' hypertension and to identify the diagnosis and evaluation of related conditions. Nfethods: Selection and review of articles from Pubmed and Google scholar and Iiterature reviews from Uptodate. Conclusions: It is important to identify secondary hypertension since this will modify treatment, outcomes and in some scenarios might be curable.

Adrenalectomía unilateral para hiperaldosteronismo primario por hiperplasia adrenal unilateral / Unilateral adrenalectomy for primary hyperaldosteronism due to unilateral adrenal hyperplasia

Resumen El hiperaldosteronismo primario es una causa en ascenso de hipertensión arterial, patología que cada día toma mayor importancia por los desenlaces asociados como infarto agudo de miocardio y enfermedad cerebrovascular, entre otras. Se describen diferentes subtipos de hiperaldosteronismo, la hiperplasia unilateral es uno de estos subtipos, siendo una entidad rara. Aquí presentamos un caso de una paciente femenina de 32 años de edad con antecedente de hipertensión arterial, en quien se documentó hipopotasemia, se realizó la relación entre aldosterona plasmática y renina, que estuvo elevada, con aldosterona de 43.9 pg/mL después de test de carga de solución salina, confirmando un hiperaldosteronismo primario, decidiendo adrenalectomía unilateral basada en el muestreo venoso de aldosterona. La patología mostró normalidad sugiriendo hiperplasia. En su seguimiento posoperatorio se logró mejor control de presión arterial y normalización del nivel de aldosterona, se demuestra así que cuando una lateralización de aldosterona es notada por muestreo venoso, la adrenalectomía provee una opción de mejoría. (Acta Med Colomb 2017; 42: 195-197).

Abstract Primary hyperaldosteronism is an increasing cause of arterial hypertension, pathology that is increasingly important due to the associated outcomes such as acute myocardial infarction and cerebrovascular disease, among others. Different subtypes of hyperaldosteronism are described, being one of these unilateral hyperplasia, which is a rare entity. The case of a 32-year-old female patient with a history of arterial hypertension, in whom hypokalemia was documented, is presented. The relationship between plasma aldosterone and renin, which was elevated, was performed with aldosterone of 43.9 pg / mL after a saline load test, confirming a primary hyperaldosteronism. Unilateral adrenalectomy based on venous sampling of aldosterone was decided. The pathology showed normality suggesting hyperplasia. In postoperative follow-up, better control of blood pressure and normalization of the aldosterone level was achieved, thus demonstrating that when aldosterone lateralization is noticed by venous sampling, adrenalectomy provides an option for improvement. (Acta Med Colomb 2017; 42:195-197).

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.

Hiperaldosteronismo primario y otras formas de hipertensión arterial endocrina / Primary hyperaldosteronism and other forms of endocrine arterial hypertension

La hipertensión arterial (HTA) dependiente de mineralocorticoides representa actualmente una de las formas secundarias de hipertensión de mayor prevalencia. Entre las causas más prevalentes está el hiperaldosteronismo primario (HAP) cuya prevalencia es cercana al 10 por ciento de la población de hipertensos. El HAP se detecta principalmente por una elevación de la razón aldosterona a actividad renina plasmática (ARR), ya que la hipokalemia es infrecuente de encontrar. La fisiopatología del HAP se presenta como un desequilibrio en el control electrolítico a nivel renal, por mayor actividad del receptor mineralocorticoides (MR), lo cual aumenta el volumen intravascular y la presión arterial. Recientemente se ha demostrado también que el exceso de aldosterona afecta también el endotelio vascular, el tejido cardiaco entre otros. Este exceso puede ser por una alteración a nivel de la glándula suprarrenal (generalmente hiperplasia o adenoma) o formas genéticas (familiares). Por otra parte, alteraciones parciales o totales de la enzima 11ß-Hidroxiesteroide deshidrogenasa tipo 2 (11ß-HSD2) resulta en una metabolización total o parcial de cortisol, imitando los efectos de aldosterona sobre MR. La actividad de esta enzima se evalúa midiendo la razón cortisol a cortisona en suero por HPLC-MS/MS. La prevalencia de alteraciones parciales de la actividad de la enzima 11ß-HSD2 en estudios de cohorte alcanza en alrededor del 15 por ciento en población hipertensa. El diagnóstico del HAP o deficiencias de 11BHSD2, permitiría un tratamiento específico del cuadro hipertensivo mediantes el uso de bloqueadores del receptor mineralocorticoideo y/o uso de corticoides de acción prolongada sin actividad mineralocorticoidea como dexametasona o betametasona.(AU)

Mineralocorticoid arterial Hypertension represents currently one of the secondary forms of hypertension most prevalent. Among the most prevalent causes is the primary aldosteronism (PA) whose prevalence is close to 10 percect of the hypertensive population. PA is detected by elevated aldosterone to plasma renin activity ratio (ARR) and the hypokalemia is rare to find. The pathophysiology of PA is presented as a renal electrolyte imbalance, increasing mineralocorticoid receptor (MR) activity, intravascular volume and blood pressure. Recently it has also shown that excessive aldosterone also affects vascular endothelium, heart tissue among others. This excess can be associated to an adrenal gland (usually hyperplasia or adenoma) or genetic (familiar) alteration. Similarly, partial or total impairment in 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) enzyme affects the cortisol metabolism, mimicking the effects of aldosterone on MR. The activity of this enzyme is evaluated by measuring the serum cortisol to cortisone ratio by HPLC-MS/MS. The prevalence of partial alterations of the activity of 11ß-HSD2 enzyme in cohort studies reached at around 15 percent in hypertensive population. The diagnosis of PA or an impairment in 11ß-HSD2 activity allows specific treatments of hypertensive patients using mineralocorticoid receptor blockers and/or use of long-acting corticosteroids without mineralocorticoid activity as dexamethasone or betamethasone.(AU)

Hiperaldosteronismo primário, como descrito por Conn. Relato decaso / Hyperaldosteronism, as described by Conn. Case report

O hiperaldosteronismo primário é causa de hipertensão arterialsecundária, com possibilidade de cura após cirurgia em 30a 75% dos casos. O objetivo deste estudo foi relatar um casode hipertensão arterial secundária a adenoma adrenal produtorde aldosterona. Paciente feminino, 35 anos, natural de Beruri(AM), procedente de Manaus, foi admitida com pressão arterialde 220x125mmHg associada a fraqueza muscular de membrosinferiores e câimbras. Na história patológica pregressa, havia orelato de hipertensão arterial diagnosticada há 2 anos, em tratamentocom três classes de anti-hipertensivos. Durante internaçãoem hospital geral, o quadro relatado associado à hipocalemiae alcalose metabólica sugeriram diagnóstico de hipertensão arterialsecundária a hiperaldosteronismo primário. Níveis elevadosde aldosterona plasmática, com renina suprimida e relação aldosterona-renina elevada, confirmaram o diagnóstico de hiperaldosteronismoprimário. A tomografia computadorizada deabdome evidenciou lesão tumoral com 2,3x2,0cm em glândulasuprarrenal esquerda sugestiva de adenoma adrenal. Pacientefoi submetida a adrenalectomia à esquerda com histopatologiacompatível com adenoma adrenal. Seis meses após a cirurgia,paciente evoluiu com normalização da calemia, porém mantevehipertensão arterial com necessidade de terapia anti-hipertensiva,sem novos picos hipertensivos. Se hiperaldosteronismo primáriodiagnosticado precocemente, há possibilidade de cura dahipertensão arterial secundária após adrenalectomia, reduzindo o efeito deletério da mesma sobre os sistemas cardiovascular, cerebrovasculare renal.(AU)

The primary hyperaldosteronism is a cause of secondaryhypertension, with the possibility of healing after surgery in 30to 75% of cases. The objective of this study was to report a caseof secondary hypertension to aldosterone-producing adrenaladenoma. A female patient, 35 years, from Beruri (AM), Brazil,who came to Manaus, was admitted into the emergency room withblood pressure of 220x125mmHg, associated with lower limbmuscle weakness and cramps. In the past medical history, there wasa report of hypertension diagnosed 2 years before, and she was undertreatment with three classes of antihypertensive drugs. Duringhospitalization in a general hospital, the case reported associatedto hypokalemia and metabolic alkalosis suggested a diagnosis ofhypertension secondary to primary hyperaldosteronism. Elevatedlevels of plasmatic aldosterone, suppressed renin and highaldosterone-renin relation suggested primary hyperaldosteronism.The abdominal computerized tomography scan revealed a tumor of2.3x2.0cm in the left adrenal gland, suggesting adrenal adenoma.Patient underwent left adrenalectomy and histopathology wascompatible to adrenal adenoma. After 6 months of surgery, thepatient experienced normalization of kalemia but kept arterialhypertension, requiring anti-hypertensive therapy, but had no othershypertensive peaks. Early diagnosis of primary hyperaldosteronismallowed the cure of hypertension after adrenalectomy, reducingdeleterious effects of high blood pressure levels on the cardiovascular,cerebrovascular and renal systems.(AU)

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.

Incidentaloma adrenal Estado del arte / Adrenal incidentaloma State of the art

Propósito: el uso creciente de las imágenes diagnósticas ha permitido descubrir lesiones adrenales en pacientes sin sospecha previa de una enfermedad originada en las mismas, hallazgo conocido como incidentaloma suprarrenal. Nuestro propósito es presentar una revisión del tema para la actualización del personal médico que se encuentre ante un paciente con esta entidad. Fuente de los datos: se realizó una búsqueda con el término MESH "adrenal incidentaloma" en español, portugués e inglés en la base de datos Medline desde el año 2000. Se obtuvieron 352 referencias. Se realizó una búsqueda regional de la literatura con el término "incidentaloma" en las bases de datos Scielo, Lilacs y Bireme. Se excluyeron las referencias a incidentalomas hipofisiarios, hepáticos y tiroideos. En Lilacs se encontraron 42 referencias y se excluyó un artículo por tratarse de incidentalomas hepáticos. En Scielo se encontraron 37 referencias y se excluyeron cinco por tratarse de incidentalomas tiroideos, hipofisiarios y una referencia a carcinoma renal. La mayoría de referencias en nuestra región son de reportes de casos y revisiones con pocos estudios originales. Selección de los estudios: se excluyeron aquellos estudios que se referían a incidentalomas en otros órganos. Resultados de la síntesis de datos: los incidentalomas adrenales pueden ser lesiones benignas como los mielolipomas, infecciones por hongos y micobacterias o lesiones infrecuentes como los schwanomas. También se pueden encontrar adenomas, los cuales pueden ser productores de hormonas o no productores. También se pueden encontrar lesiones malignas, como carcinomas adrenales y metástasis. Ante la presencia de un incidentaloma suprarrenal con tamaño mayor de 4 cm, irregularidad en los bordes, alta atenuación de la lesión (en unidades Hounsfield) y un bajo porcentaje de lavado en el estudio contrastado se debe sospechar carcinoma adrenal, en cuyo caso el manejo es quirúrgico, una vez se haya descartado feocromocitoma. Ahora bien, si la lesión no sugiere malignidad, el clínico debe preguntarse si el incidentaloma es productor o no de hormonas. En este sentido se debe evaluar la posibilidad de síndrome de Cushing (mediante una prueba de supresión con dosis bajas de dexametasona), feocromocitoma (con medición de metanefrinas en orina o en plasma) y si es hipertenso descartar hiperaldosteronismo primario midiendo la relación aldosterona/renina. Acorde a estos resultados se definirá la conducta quirúrgica o el seguimiento clínico e imagenológico. Conclusiones: el incidentaloma adrenal se ha convertido en una enfermedad frecuente en la práctica clínica cotidiana del internista. Aunque la mayoría de estas lesiones no son malignas y corresponden a adenomas no productores, siempre debe considerarse basado en las características clínicas y paraclínicas la posibilidad de una enfermedad endocrina. Se requieren estudios para conocer la epidemiología y la etiología de esta enfermedad en nuestro medio. (Acta Med Colomb 2015; 40: 318-325).

Purpose: increased use of diagnostic imaging has led to the discovery of adrenal masses in patients without prior suspicion of a disease originated in adrenals, known as adrenal incidentaloma finding. Our purpose is to present a review of the topic to update the medical staff faced with a patient with this condition. Data Source: a search with the MeSH term "adrenal incidentaloma" was conducted in Spanish, Portuguese and English in the Medline database since 2000. 352 references were obtained. Regional literature search with the term "incidentaloma" on Scielo, Lilacs and Bireme databases was performed. References to pituitary, liver and thyroid incidentalomas were excluded. 42 references were found in Lilacs and 1 article was excluded because they were liver incidentalomas. 37 references were found in Scielo and 5 were excluded, being treated thyroid, pituitary incidentalomas and a reference to renal carcinoma. Most references in our region are case reports and reviews with few original studies. Study Selection: studies that referred to incidentalomas in other organs were excluded. Results of data synthesis: adrenal incidentalomas can be benign like myelolipomas, fungal and mycobacterial infections or infrequent lesions as schwannomas. Adenomas which can be hormone producing and non-producing hormones can also be found. Also malignant lesions such as adrenal carcinomas and metastases can be found. In the presence of an adrenal incidentaloma larger than 4 cm, irregular edges, high attenuation of the lesion (in Hounsfield units) and a low percentage of washing in the contrast study, adrenal carcinoma should be suspected, in which case management is surgical once pheochromocytoma has been excluded. However, if the injury does not suggest malignancy, the clinician should wonder whether incidentaloma is or is not hormone- producing. In this regard we must assess the possibility of Cushing's syndrome (via a suppression test with low doses of dexamethasone), pheochromocytoma (with measurement of metanephrines in urine or plasma) and if the patient is hypertensive, discard primary aldosteronism by measuring the aldosterone / renin ratio. According to these results the surgical treatment or clinical and imaging follow-up will be defined. Conclusions: The adrenal incidentaloma has become a common disease in daily clinical practice of the internist. Although most of these lesions are not malignant and correspond to non-producing adenomas, the possibility of an endocrine disease should always be considered based on clinical and paraclinical features. Studies to acknowledge the epidemiology and etiology of this disease in our environment are required. (Acta Med Colomb 2015; 40: 318-325).

Influence of preoperative propranolol on cardiac index during the anhepatic phase of liver transplantation / Influência do propranolol pré-operatório no índice cardíaco durante a fase anepática do transplante hepático / Influencia del propranolol preoperatorio en el índice cardíaco durante la fase anhepática del trasplante hepático

INTRODUCTION: Liver transplantation is the best therapeutic option for end-stage liver disease. Non-selective beta-blocker medications such as propranolol act directly on the cardiovascular system and are often used in the prevention of gastrointestinal bleeding resulting from HP. The effects of propranolol on cardiovascular system of cirrhotic patients during liver transplantation are not known. OBJECTIVE: Evaluate the influence of propranolol used preoperatively on cardiac index during the anhepatic phase of liver transplantation. METHOD: 101 adult patients (73 male [72.2%]) who underwent cadaveric donor orthotopic liver transplantation by piggyback technique with preservation of the retrohepatic inferior vena cava performed at Hospital das Clinicas, Federal University of Minas Gerais were evaluated. There was no difference in severity between groups by the MELD system, p = 0.70. The preoperative use of propranolol and the cardiac index outcome were compared during the anhepatic phase of liver transplantation in 5 groups (I: increased cardiac index, II: cardiac index reduction lower than 16%, III: cardiac index reduction equal to or greater than 16% and less than 31%, IV: cardiac index reduction equal to or greater than 31% and less than 46%, V: cardiac index reduction equal to or greater than 46%). RESULTS: Patients in group I (46.4%) who received propranolol preoperatively were statistically similar to groups II (60%), III (72.7%), IV (50%) and V (30.8%), p = 0.57. CONCLUSION: The use of propranolol before transplantation as prophylaxis for gastrointestinal bleeding may be considered safe, as it was not associated with worsening of cardiac index in anhepatic phase of liver transplantation. .

INTRODUÇÃO: O transplante hepático (TH) é a melhor opção terapêutica para doença hepática em estágio terminal (DHET). As medicações betabloqueadoras não seletivas, como o propranolol, atuam diretamente no sistema cardiovascular (SCV) e são frequentemente usadas na prevenção de hemorragia digestiva decorrente da HP. Os efeitos do propranolol no SCV de cirróticos durante o TH não são conhecidos. OBJETIVO: Avaliar a influência do uso pré-operatório do propranolol no índice cardíaco (IC) durante a fase anepática do TH. MÉTODO: Avaliaram-se 101 pacientes adultos (73 homens, 72,2%) submetidos a transplante ortotópico de fígado doador cadáver, pela técnica de piggyback com preservação da veia cava inferior retro-hepática, feito no Hospital das Clínicas da Universidade Federal de Minas Gerais. Não houve diferença de gravidade pelo sistema MELD entre os grupos, p = 0,70. Foram comparados o uso pré-operatório de propranolol com o desfecho do IC durante a fase anepática do TH em cinco grupos (I: aumento do IC; II: redução do IC inferior a 16%; III: redução do IC igual a ou maior do que 16% e menor do que 31%; IV: redução do IC igual a ou maior do que 31% e menor do que 46%;V: redução do IC igual a ou maior do que 46%). RESULTADOS: Pacientes que fizeram uso pré-operatório de propranolol no grupo I (46,4%) foram estatisticamente semelhantes aos dos grupos II (60%), III (72,7%), IV (50%) e V (30,8%), p = 0,57. CONCLUSÃO: O propranolol no pré-transplante, como profilaxia para hemorragia digestiva, pode ser considerado seguro, pois não se associou à pioria do IC na fase anepática do TH. .

INTRODUCCIÓN: El trasplante hepático (TH) es la mejor opción terapéutica para la enfermedad hepática en estado terminal. Los betabloqueantes no selectivos, como el propranolol, actúan directamente en el sistema cardiovascular y a menudo son usadas en la prevención de la hemorragia digestiva proveniente de la hipertensión portal. Los efectos del propranolol en el sistema cardiovascular de cirróticos durante el TH no se conocen. OBJETIVO: Evaluar la influencia del uso preoperatorio del propranolol en el índice cardíaco (IC) durante la fase anhepática del TH. MÉTODO: Se estudiaron 101 pacientes adultos (73 hombres [72,2%]) sometidos a trasplante ortotópico de hígado de donante cadáver, por la técnica de piggyback con preservación de la vena cava inferior retrohepática, en el Hospital das Clínicas de la Universidad Federal de Minas Gerais. No hubo diferencia respecto a la gravedad por el sistema Meld entre los grupos (p = 0,70). Se comparó el uso preoperatorio del propranolol con el resultado del IC durante la fase anhepática del TH en 5 grupos (i: aumento del IC; ii: reducción del IC < 16%; iii: reducción del IC ≥ 16% y < 31%; iv: reducción del IC ≥ 31% y < 46%;v: reducción del IC ≥ 46%). RESULTADOS: El número de pacientes que usaron el propranolol en el preoperatorio en el grupo i (46,4%) fue estadísticamente similar a los grupos ii (60%), iii (72,7%), iv (50%) y v (30,8%), p = 0,57. CONCLUSIÓN: El propranolol en el pretrasplante, como profilaxis para la hemorragia digestiva, puede ser considerado seguro porque no se asoció con el empeoramiento del IC en la fase anhepática del TH. .

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)