醛固酮是类固醇激素分泌从the adrenal gland in response to sodium deficiency, blood volume loss or potassium loading. It acts on the kidney and the colon to retain sodium and excrete potassium, in a feedback loop the return to status quo. If aldosterone is secreted – and sodium retained – outside this normal feedback loop the result is primary aldosteronism (PA). Primary is medical for ‘we’re not sure what causes this’.

Familial genetic disorders are due to defective genes in sperm or egg, transmitted to offspring and thus found in all cells. Somatic mutations, on the other hand, result from accidental damage to a cell in a particular organ. In both cases, the mutation gives some advantage to that cell, so it multiplies faster than normal, and in the adrenal makes aldosterone not ‘turned off’ by the normal feedback mechanisms. The result is hypertension and a greater risk of heart attack/stroke/ atrial fibrillation than age-, sex-, and blood pressure matched essential hypertensives. Essential is an alternative medical word for ‘we don’t really know what causes this’.

Primary aldosteronism can be the result of one-sided overproduction from an adenoma (a benign tumor) or bilateral adrenal hyperplasia. Five years ago 8 of 22 aldosterone producing adenomas were shown to have a mutation in the gene coding for KCNJ5, a component of a potassium ‘channel’ in the cell membrane, leading to aldosterone overproduction. This was followed by a much larger study, on over 300 patients, confirming and extending the first; subsequently a number of other mutations – in enzymes (sodium ATPases, calcium ATPases), calcium channels, and a key intracellular protein – have been discovered and described. Over 60% of all APA examined to date show one of the mutations, and are negative for the mutation in other tissues.

Familial hyperaldosteronism (FH) is a fascinating mixed bunch. FH-1 was first described over 50 years ago, and 25 years ago the molecular mechanisms clarified. The enzyme CYPIIB1 is responsible for making cortisol while CYBIIB2 makes aldosterone. The genes encoding CYPIIB1/B2 lie next to one another, and when sperm and egg combine they may not line up right, which produces a composite gene – front end CYPIIB1, back end CYPIIB2, which makes aldosterone out of control by the normal homeostatic loop. The ‘chimeric’ gene from the ancestral misalignment is transmitted, and gives young people severe (but fortunately, very rare, and easily treated) hyperaldosteronism.

FH-II is defined as two first degree relatives – parent/child, siblings – having PA. The best study puts the prevalence at 6% of hypertensives, a conservative figure. Family sizes are smaller, intergenerational time longer, people are more mobile – all making finding two family members with primary aldosteronism less likely. Secondly, and lamentably, fewer than 1% of hypertensives are ever screened for PA…

FH-III is rare, and caused by inherited mutations in KCNJ5. These vary in severity – from requiring bilateral adrenalectomy at a young age, to adequately treated by an antagonist of aldosterone at mineralocorticoid receptors.

Why is this important? Hypertension is the most important cause of cardiac damage in developed countries, and PA may in fact account for closer to 50% than 10% of hypertension. If this is the case, FHII may be either very much more common (or a non-starter). We are used to just looking at disease, and doing clinical trials to see what helps: getting down to pathways and mechanisms provides new insights and the promise of rational, evidence based treatment for high blood pressure and cardiovascular disease.

John Funder
Hudson Institute of Medical Research and Monash University, Clayton, Victoria, Australia

Publication

Genetic disorders in primary aldosteronism-familial and somatic.
Funder JW.
J Steroid Biochem Mol Biol. 2016 Mar 21

Read offline:

Related Articles:

	Preventing over-treatment in euthyroid patients with thyroid…Up to 12% of the U.S. population will be diagnosed with a thyroid condition. Because thyroid hormones affect every cell in the body, hypo- (low) and hyper-(high) thyroidism can be…
	Is milk and meat from the offspring of a bull genome edited…Horns on cattle are an animal welfare and human safety concern, but most high producing dairy breeds grow horns. Introducing the polled (hornless) trait into the dairy population by crossbreeding…
	Defects in mismatch repair increase cancer risk and…Microsatellites are formed by 1-6 nucleotide base pairs that are repeated in direct order 5-50 times. Repetitive DNA including microsatellites are mainly present in non-coding DNA regions that occupy more…
	Macrophage-myofibroblast transition: a novel target for…Kidney is one of the major organs in our body for detoxification. Its failure is an important cause of patient mortality that serves as a primary disease and a lethal…
	The complex regulation and functional significance of size…Across animals, variation in body size is often influenced by environmental conditions and is considered to have adaptive value. In bees, in which many species show various degrees of sociality,…
	Feedback between organisms and the environment shape…How does the environment shape biodiversity? This is a central question for both the scientific understanding of ecosystems and for practical initiatives in sustainability. Previous work has shown that a…