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Endocrine Abstracts (2013) 32 S22.1 | DOI: 10.1530/endoabs.32.S22.1

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University Clinic Munich, Munich, Germany.


Excessive autonomous aldosterone secretion by the adrenal gland, so called primary aldosteronism (PA), causes drug-resistant and often life threatening arterial hypertension accompanied by severe hypokalemia. Long-term consequences include increased risk for stroke, myocardial infarction and atrial fibrillation. PA is present in up to ~10% in referred patients and 7% in primary care, but as high as 20% in patients with resistant hypertension. The early detection of PA has clear impact on clinical outcome and survival, given the major cardiovascular adverse effects of aldosterone excess, which are independent of blood pressure, and predict outcome following surgical.

With an increasing pace genetic mechanisms have been identified that contribute to autonomous aldosterone secretion. These include both familial forms as well as acquired somatic cases which partly overlap. Familial hyperaldosteronism type I (FH-1), also called glucocorticoid suppressible aldosteronism, is characterized by early and severe hypertension with biochemical abnormalities of PA and production of hybrid steroids. Fusion of the promoter region of CYP11B1 to the coding region of CYP11B2 produces a chimeric gene, with activity of aldosterone synthase, but regulatory specificity of that of 11β hydroxylase, which results in the synthesis of aldosterone under control of ACTH. FH-2 has an autosomal dominant mode of inheritance with a variable phenotype including APA and BAH even within the same family. Clinical and biological features of FH-2 are indistinguishable from that of sporadic PA. While in one large family a locus associated with the disease has been mapped to chromosome 7p22 no underlying genetic mutation has been resolved. Recently, exome sequencing in sporadic APAs has revealed somatic mutations in the KCNJ5 gene which is present in up to 30% of cases. Furthermore, some rare familial cases with germ-line mutations of KCNJ5 have been described and attributed to FH-3. This condition is responsible for increased calcium influx into the glomerulosa cell leading to constitutive secretion of aldosterone and possibly cell proliferation.

Recently, a number of approaches including genome wide association studies, exome sequencing and mutagenesis screens have been applied to patient cohorts and in vivo models of PA. Thereby, it is likely that in the near future further pathophysiological mechanisms that result in autonomous aldosterone secretion will be unraveled. Combination of genetic marker with clinical annotations from prospective studies will be required to allow for disease stratification and individualized treatment decisions for affected patients.

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