RESUMO
An 11-year old girl was seen in 1981 with hypokalemia, low renin, low aldosterone, and severe hypertension. A medical adrenalectomy with dexamethasone and aminoglutethimide, and the blockade of mineralocorticoid receptors with spironolactone improved her condition, but the blockade of glucocorticoid receptors with RU-486 worsened it. An aldosterone infusion induced no changes. A sister was born in 1982 with similar findings. Both patients had an impaired ability to convert cortisol to cortisone after an oral load of 200 mg cortisol. In urine, an elevated ratio for metabolites of cortisol to metabolites of cortisone was found. These data suggested a defect in the activity of renal 11 beta-hydroxysteroid dehydrogenase. Both parents were asymptomatic, phenotypically normal and non-consanguineous. Their urinary metabolites of cortisol and cortisone were normal before and after stimulation with ACTH. However, the mother reached a peak plasma cortisone concentration 3 SD below the mean reached by normal subjects after an oral 200-mg cortisol load, a fact that suggests that this test could be used to detect heterozygotes. The genetic studies revealed a homozygous mutation on exon 3 of the HSD11K gene, which by substituting TGC for CGC changes Arg 213 for Cys and induces a loss of 84% of the enzymatic activity in transfected cells. Both unrelated parents had the same heterozygous mutation. Both patients have been treated with dexamethasone but have also required spironolactone. The older sister has also required high doses of nifedipine to lower her blood pressure. After 19 years of follow-up, the older sister has become normotensive and normokalemic under therapy, and reached a final height of 140 cm at age 17. The younger sister has increased her mean blood pressure at a rate of 1 mm Hg per year, in spite of treatment. Her final height is 143.5 cm.
Assuntos
Cortisona/metabolismo , Hidrocortisona/metabolismo , Hidroxiesteroide Desidrogenases/deficiência , Hipertensão/genética , Hipopotassemia/genética , Mineralocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Adolescente , Aminoglutetimida/uso terapêutico , Pressão Sanguínea , Estatura , Criança , Pré-Escolar , Dexametasona/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipopotassemia/tratamento farmacológico , Hipopotassemia/metabolismo , Lactente , Recém-Nascido , Masculino , Mineralocorticoides/genética , Mutação/genética , SíndromeRESUMO
There is a group of genetic alterations that are phenotypically related to mineralocorticoid hypertension. They include, among others, some forms of primary hyperaldosteronism and of hyporeninemic aldosteronism that can be specifically treated, thus becoming secondary forms of hypertension. These could account for 10 to 15% of cases of essential hypertension, but more studies are required to accept these figures. The screening for these forms of hypertension should be done measuring aldosterone levels and plasma renin activity. An aldosterone/plasma renin activity ratio over 25 should lead to the suspicion of the disease. However, the cost effectiveness of the widespread measurement of these parameters would be very low. Therefore it is mandatory to determine the epidemiological features of these diseases to perform a selective screening among subjects with essential hypertension.
Assuntos
Hiperaldosteronismo/complicações , Hipertensão/etiologia , Mineralocorticoides , Sistema Renina-Angiotensina/genética , Aldosterona/sangue , Humanos , Hiperaldosteronismo/genética , Mineralocorticoides/genética , Renina/sangueRESUMO
Recently, some genetic forms of hypertension have been well characterized. These forms can be globally called mineralocorticoid hypertension and are due to different alterations of the renin-angiotensin-aldosterone system (SRAA). Among these, classic primary hyperaldosteronism and its glucocorticoid remediable variety, in which hypertension is secondary to aldosterone production, must be considered. There are also conditions in which mineralocorticoid activity does not depend on aldosterone production. These conditions generate a hyporeninemic hyperaldosteronism, observed in Liddle syndrome, apparent mineralocorticoid hypertension, 11- and 17-hydroxylase deficiency, among others. The detection of these forms of hypertension is only feasible if the renin-angiotensin-aldosterone system is assessed, measuring renin and aldosterone levels. This article reviews these forms of hypertension, their clinical workup and their relevance in the usual hypertensive patients.
Assuntos
Hiperaldosteronismo/complicações , Hipertensão/etiologia , Mineralocorticoides , Aldosterona/sangue , Eletrólitos/sangue , Humanos , Hipoaldosteronismo/fisiopatologia , Mineralocorticoides/genética , Mineralocorticoides/fisiologia , Renina/sangue , Sistema Renina-Angiotensina/fisiologiaRESUMO
A hipertensão arterial é uma doença poligênica com grande heterogeneidade e que sofre influências importantes de fatores ambientais para a manifestação do fenótipo. Recentemente, com o advento das técnicas de biologia molecular e abordagens de genética molecular. Tornou-se possível iniciar a investigação sistemática dos determinantes primários da hipertensão arterial essencial. Existem exemplos de sucesso na identificação dos defeitos primários responsáveis pela gênese de três formas raras de hipertensão arterial mendelianas ou dependentes de defeito único para a manifestação do fenótipo. Nesses três casos, o aumento da pressão arterial é secundário ao aumento de reabsorção de sal e água pelo rim. A utilização dessas técnicas está permitindo também que progressos importantes sejam feitos na compreensão dos mecanismos moleculares que participam dos sistemas de controle da pressão arterial. Acredita-se que, por meio da abordagem multidisciplinar utilizando-se modelos experimentais e populações humanas, seja possível, num futuro próximo, a identificação dos determinantes primários da hipertensão arterial essencial. Isso propiciará a identificação precoce de indivíduos afetados e a oportunidade de intervenção pré-clínica, ou o desenvolvimento de terapêutica eficaz na causa primária com redução das altas taxas de morbidade e mortalidade associadas à doença.
Assuntos
Humanos , Hipertensão/genética , Mapeamento Cromossômico , Hiperaldosteronismo/genética , Mineralocorticoides/genética , Mineralocorticoides/metabolismo , Sistema Renina-Angiotensina/fisiologia , SíndromeRESUMO
Mineralocorticoids are adrenal steroid hormones that regulate the retention of sodium by the kidney and, hence, are crucial in the regulation of sodium balance, intravascular volume, and blood pressure. The molecular biology of mineralocorticoid biosynthesis and action has only recently been elucidated. The genes encoding the various enzymes that convert cholesterol to mineralocorticoids have now been cloned. This has revealed the molecular basis of several inherited forms of mineralocorticoid excess, which cause hypertension, and several forms of mineralocorticoid deficiency, which cause salt loss. The cloning of the mineralocorticoid receptor revealed a paradox. Both the mineralocorticoid and the glucocorticoid receptor are activated equally by cortisol, even though cortisol has very modest mineralocorticoid activity. This is explained by the cloning of two genes for the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). Type-II 11 beta HSD, found primarily in the kidney, irreversibly converts cortisol to cortisone, which does not activate the mineralocorticoid receptor. Type-II 11 beta HSD thus defends the mineralocorticoid receptor from being activated by the very high concentrations of cortisol in the blood. Recent studies in genetically hypertensive rats suggest that other enzymes or factors that regulate salt balance may remain undiscovered. Thus the study of mineralocorticoid biosynthesis and action remains one of the most promising approaches to understanding hypertension.