It has been just over 65 years since Jerome W. Conn published the clinical description of primary aldosteronism (PA) about a case with a unilateral aldosterone-producing adenoma (APA). PA has since been characterized by renin-independent adrenal aldosterone production causing hypertension and often hypokalemia. Chronic aldosterone excess leads to target organ damage exceeding that of essential hypertension, including left ventricular hypertrophy, stroke, and kidney impairment. Although PA was initially considered a rare endocrine disorder, it is currently recognized as the most common form of endocrine hypertension. Its estimated prevalence is 5-10% of hypertensive patients and 20% of patients with resistant hypertension. Recent studies suggest that PA has a wide spectrum of disease severity ranging from mild to overt, and that the early stages of disease can be seen in normotensive subjects who present with renin-independent aldosterone production. Because excess aldosterone causes peripheral organ damage, early detection of PA and appropriate treatment are highly recommended. However, PA appears to still be largely underdiagnosed.
Recent advances in genetic analysis methodologies and development of adrenal disease biomarkers have provided the tools to describe the molecular and histologic pathogenesis of this disease. The application of immunohistochemistry-guided capture of disease-causing lesions and the ability to sequence formalin-fixed paraffin-embedded (FFPE) archival adrenal material has resulted in the identification of somatic mutations in adrenals from both lateralized (in most cases unilateral disease) and bilateral PA cases. The vast majority of aldosterone-producing lesions in resected adrenals harbor aldosterone-driver somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CTNNB1, SLC301A1, CADM1 or CLCN2. Disease-causing mutations converge on intracellular calcium ion homeostasis whereby they cause inappropriate aldosterone production. Accumulating evidence suggests that patient age, race, and sex impact the somatic mutation spectrum causing PA. For example, somatic mutations in the KCNJ5 gene (encoding an inwardly rectifying K+ channel) are common in APAs from Asian populations as well as women regardless of race, while mutations in the L-type calcium channel CACNA1D are more common men of African descent. In my seminar, I will review recent findings regarding somatic mutations causing PA, discuss newly discovered somatic mutations, and provide an update on the implications of these findings on personalized disease diagnosis.
Acknowledgments: The work presented would not have been possible without collaboration and support from the University of Michigan Adrenal Research Team, collaborators within the American, Australian, Asian Adrenal Alliance (A5) and financial support from the NIH and American Heart Association.