Primary Aldosteronism

SE-3-1

The Genetic Study in Primary Aldosteronism

TaKasHI Yoneda

Division of Endocrinology and Metabolism, Kanazawa University Hospital, Japan

KCNJ5 gene mutations are reported to be frequently identified in aldosterone producing adenomas (APA). We performed genetic study in 27 APAs (9 micro- and 15 macro- APAs) and identified somatic KCNJ5 mutations in 20 of 27 APAs (83.3%). The prevalence of KCNJ5 mutation in micro- and macro-APAs was 78% (7/9) and 87% (13/15), respectively and there was no significant difference in the prevalence (P=0.09).

We examined clinical characteristics difference between patients with micro- and macro-APAs. Serum potassium level in the patients with macro APAs (3.2±0.8mEq/L, n=13) was lower than that of micro-APA (4.0±0.6 mEq/L, n=7) (p<0.05). There were no significant differences in age (54±13 vs 49±14 years old.), blood pressure (156±16/91±14 vs 156±36/96±20 mmHg), plasma aldosterone concentration (164±73 vs 259±141 pg/mL) and plasma renin activity (0.3±0.2 vs 0.3±0.2 ng/mL/h) between micro- and macro-APAs with KCNJ5 gene mutations. Tumor size did not seem to be related to clinical characteristics other than serum potassium level.

We also identified some interesting cases with APA harboring somatic KCNJ5 mutations such as two cases with recurrence of primary aldosteronism in remaining adrenal gland long after adrenalectomy, a case of multiple aldosterone producing microadenomas with different mutations of KCNJ5 gene, and two cases with unilateral APA demonstrating diagnostic discrepancy in AVS between with and without ACTH stimulation.

SE-3-2

Pathophysiology of Primary Aldosteronism

Kwan-dun wu

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; TAPAI Study Group

Using aldosterone-renin ratio as screening test has increased the incidence of primary aldosteronism (PA) since the last three decades. Genetic mutations were identified in several subtypes of PA, e.g., hybrid gene in glucoticoid remendiable hyperaldosteronism, KCNJ5 somatic mutations in APA etc. Also linkage study suggested several candiadate genes. However, the pathogenesis of PA or its tumorgenesis is still unclear. We have demonstrated that dopamingergic regulation plays an important role in aldostereone production and cell proliferation of adrenocortical cells. Recently, we also revealed a dysregulation of microRNAs in PA patients. The finding may provide a therapeutic potential.

Several mechanisms, in addition to high blood pressure, are proposed to explain the high incidence of cardiovascular diseases in patients with primary aldosteronism (PA).In vitro and in vivo studies demonstrate that aldosterone can induce insulin resistance, and PA is associated with metabolic syndrome. Aldosterone may increase intercellular adhesion molecule-1 expression of endothelial cell and promotes leukocyte adhesion through activating minorocorticoid receptor. Aldosterone has rapid non-genomic effects in the human vasculature. We have demonstrated that PA patients had lower numbers of circulating EPCs and endothelial colony forming unit than EH. Adrenalectomy or treatment with spironolactone can increase the number of EPCs in PA patients. This indicates impairment of the repair of endothelial damage may be a crucial factor of the development of CVD in PA.

SE-3-3

Diagnosis and Management Strategies for Primary Aldosteronism

rICHard auCHus

Department of Internal Medicine,University of Michigan Medical School, USA

Primary aldosteronism (PA) is the most common secondary cause of hypertension, accounting for 5-8% of all hypertensive adults. It is estimated that <1% of all patients with PA are ever screened for the disease. Obstacles to screening for PA include poor awareness of the disease, misunderstanding of diagnostic pitfalls, fear of embarking on the workup, and limited access to expertise in adrenal vein sampling (AVS). AVS remains the gold standard for distinguishing unilateral disease, largely caused by aldosterone-producing adenomas (APA) from bilateral disease, which is almost always due to idiopathic hyperaldosteronism (IHA).

I will review the important principles and practical approaches to screening, confirming and subtyping PA. I will also review important advances for improving the success of AVS. Finally, recent advances in genetics of PA have provided insight to the pathogenesis of APA, and these advances might guide additional therapeutic strategies.