Keeping up with the genes in primary aldosteronism
William Drake and Morris Brown | Features
Primary aldosteronism (PA or Conn’s syndrome) was previously considered a ‘niche’ area of endocrinology, limited to patients with hypertension and hypokalaemia. Clinical and molecular discoveries have propelled it into the limelight, as one of the most exciting, fast-moving areas of endocrine practice.
PREVALENCE AND PENALTY
Prospective studies indicate that 8–13% of unselected hypertensive patients have PA, of whom only a minority have hypokalaemia.1 Meta-analysis shows that the cardiometabolic penalty of PA (stroke, atrial fibrillation, ischaemic heart disease) exceeds that of essential hypertension by at least 2:1.2 These data should trigger a ‘call to arms’ for development of screening strategies to detect PA, to reverse (medically or surgically) the excess morbidity. The reality is sobering; fewer than 1% of cases of PA are detected and treated.
DETECTION AND DIAGNOSIS
No ‘real-world’ case-finding protocols (other than measuring renin and aldosterone in all hypertensive patients) are available. Endocrine Society guidelines acknowledge their inappropriateness for primary care. A recent large trial, PATHWAY-2, indicated major benefits from the addition of spironolactone in patients with resistant hypertension. This study supports the high prevalence of PA, and may add weight to calls for spironolactone to be considered earlier than step 4 in the treatment of hypertension.
LOCALISATION AND LATERALISATION
Even at current diagnosis rates for PA, invasive investigation by adrenal vein sampling (AVS) is a major ‘bottleneck’. Only a handful of centres are able to reliably cannulate both veins – and both the end (to find unilateral PA) and the means (measurement of aldosterone/cortisol ratio) may be outdated. Fewer than half the patients with unilateral PA are cured by adrenalectomy. When 1% of the population has PA, precision medicine is required to ensure that expensive procedures lead to years of drug-free cure in a high proportion of those selected.3
Positron emission tomography–computed tomography (PET-CT) scanning has the potential to expand capacity for investigation. The most advanced PET tracer is metomidate, a methyl analogue of the anaesthetic agent etomidate. A large, prospective study, MATCH, comparing 11C-metomidate PET-CT with AVS, will report in 2020. Alternative 18F tracers are in development, making PET available nationally.
GROWTHS AND GENETICS
Knowledge of the aetiopathogenesis of PA has blossomed during the past decade and is an important ‘driver’ of renewed interest and advances in practice. Most aldosterone-producing adenomas (APAs) harbour a somatic mutation of an ion channel or transporter. First recognised were mutations in the KCNJ5 gene, a potassium channel that helps maintain cell membrane hyperpolarisation. Loss of selectivity for potassium results in sodium influx and cell membrane depolarisation, inward movement of calcium and activation of aldosterone synthesis and secretion. KCNJ5 mutations are by far the commonest in classical Conn’s adenomas of younger women.4 But their discovery revealed the paradox that these adenomas resemble cortisol-producing, rather than aldosterone-producing, cells of normal adrenal, and indeed secrete more cortisol than aldosterone. Even if their cortisol secretion is clinically insignificant, it can confound the aldosterone/cortisol ratio at AVS.
The paradox was resolved by the discovery of commoner but smaller APAs with somatic mutations in sodium or calcium ATPases (ATP1A1, ATP2B3) or calcium channels (CACNA1D and CACNA1H). These APAs resemble physiological aldosterone-producing cells, and typically elude diagnosis – at least until the onset of resistant hypertension. Their hallmark mutations, and development of PET ligands and specific antisera for aldosterone synthase, permitted recognition of an inverse correlation between enzyme density and size of APA.5 No nodule on CT/magnetic resonance imaging is too small to be an APA. Indeed, the most common sites of autonomous aldosterone production are microscopic aldosterone-producing cell clusters, 60% of which have similar mutations of CACNA1D to those found in APAs.6 More than 40 activating mutations are now described, all in/near the Ca2+ pores. Investigational inhibitors of Cav1.3, encoded by CACNA1D, completely suppress aldosterone secretion by adrenocortical cells, and could become the precision medicine for PA.
None of the ion channel mutations is implicated in tumour formation, nor predicts higher cure rates. However, co-existence of cortisol and aldosterone synthesis leads to secretion of unusual hybrid steroids, whose measurement as a biomarker for solitary APAs with KCNJ5 mutation may become a valuable diagnostic and prognostic tool.7 Alternatively, somatic mutations are now being found in non-ion channel genes previously associated with tumour formation, and these may identify a subset of patients with sustained clinical cure after removal of the APA. For example, CTNNB1 mutations are found in ~5% of APAs, which allow activated β-catenin to enter the nucleus and re-direct cell differentiation towards its adrenogonadal origin.8 The consequent high expression of luteinising hormone/human chorionic gonadotrophin receptors leads to explosive onset of PA in early pregnancy or menopause. Removal of the APA achieves sustained clinical cure, attributed to the briefness of vascular exposure to high aldosterone levels.
RESECTION AND REDUCTION
Laparoscopic adrenalectomy is the mainstay of non-medical treatment for PA, but several factors contribute towards caution in recommending surgery: limited NHS capacity, uncertain clinical outcome, and the 1960s timewarp of resecting a whole organ as treatment for a 1-cm, benign lesion. Radiofrequency ablation (RFA) of APAs is a developing alternative. A UK safety and feasibility study of endoscopic, transgastric RFA of left-sided APAs (FABULAS) is currently recruiting.
CONCEPTS AND CONCLUSIONS
The PA landscape has transformed since Jerome Conn’s original description in 1954,9 and long held assumptions may shortly appear naïve or oversimplistic. Is the distinction between unilateral and bilateral PA truly binary? Do we ‘cure’ patients by surgery or merely ‘debulk’ their disease? For anyone with a developing clinical and/or academic interest in PA – your timing is impeccable.
William Drake, Professor of Clinical Endocrinology, Barts and the London School of Medicine
Morris Brown, Professor of Endocrine Hypertension, Barts and the London School of Medicine
- Funder JW et al. 2016 Journal of Clinical Endocrinology and Metabolism 101 1889–1916.
- Hundemer GL et al. 2018 Lancet Diabetes & Endocrinology 6 51–59
- Williams B & Brown MJ 2018 Lancet Diabetes & Endocrinology 6 600–601.
- Choi M et al. 2011 Science 331 768–772.
- Azizan EA et al. 2013 Nature Genetics 45 1055–1060.
- Omata K et al. 2018 Hypertension 72 874–880.
- Tezuka Y et al. 2019 Hypertension HYPERTENSIONAHA11812064.
- Teo AE et al. 2015 New England Journal of Medicine 373 1429–1436.
- Conn JW 1956 American Practitioner and Digest of Treatment 7 749.