Postgrad Med J 2001;77:639–644 639 Hyperaldosteronism: recent concepts, diagnosis, Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from and management R Foo, K M O’Shaughnessy, M J Brown As a cause for hypertension, aldosterone excess modulate sgk gene transcription and further- is now thought to be more prevalent than previ- more, a simple hormone response element has ously quoted in textbooks. Classical features of been found in the rat sgk gene 5'-flanking hypokalaemia and metabolic alkalosis can be region.2 Sgk mRNA is rapidly stimulated by absent even in the presence of marked hyper- mineralocorticoids but receptor ligand activa- tension. This implies the need for a high index of tion results in both an early phase increase in suspicion and possibly argues the case for ENaC activity and a late phase upregulation of routine screening, especially in patients with ENaC number. Apart from action on ENaC in “diYcult to treat” hypertension. Given multisys- apical cells, aldosterone appears to also increase tem target organ damage and increased cardio- activity of the Na+/K+-ATPase pump in the vascular risk associated with chronic uncon- basolateral membrane of distal tubular cells.3 trolled hypertension, a readily treatable cause Furthermore, rapid 2–10 min eVects of aldoster- such as hyperaldosteronism is an important one have been described that are not inhibited diagnosis to make. In addition, hyperaldos- by mineralocorticoid receptor antagonist, teronism related hypertension is now known to spironolactone.4 Unknown mechanisms mediat- cover other recently identified monogenic disor- ing aldosterone receptor binding, including the ders such as glucocorticoid remediable aldos- possibility of unknown membrane receptors not teronism. These rarer monogenic hypertensive involving protein synthesis, thus remain to be disorders provide clues to cracking the mystery defined. Nevertheless aldosterone is responsible behind polygenic “essential” hypertension. physiologically for electrolyte balance in the kid- Apart from patients with hyperaldosteronism, a ney, salivary glands, sweat glands, and gastro- subset of the well recognised “low renin intestinal tract and in the kidney it has the hypertension” patient group also appears to important function of mediating sodium reten- produce a dramatic and remarkable response tion and increasing potassium excretion. when treated with spironolactone. We suggest In the renin-angiotensin-aldosterone axis, that spironolactone sensitive hypertension may decreased renal perfusion pressure stimulates represent a wider spectrum of disorders where the â-adrenoreceptor dependent release of renin blood pressure is readily controlled by the addi- that is synthesised by juxtaglomerular cells. In tion of aldosterone receptor antagonist. extracellular volume overexpansion, “excessive stretch” signals in the juxtaglomerular cells Aldosterone physiology Glucocorticoids and mineralocorticoids are syn- result in decreased renin secretion. The sub- http://pmj.bmj.com/ thesised from cholesterol mainly in the adrenal strate for renin is angiotensinogen, which is a cortex. The two forms of cytochrome P-450 glycoprotein of variable structure and molecular enzymes, CYP11B1 (aldosynthase) and weight synthesised in the liver. Ten N-terminal CYP11B2 (11â-hydroxylase), that catalyse the amino acid residues of angiotensinogen contain final step of these synthetic pathways are the amino acid sequence of angiotensin I and encoded by two closely related genes on angiotensin converting enzyme is responsible for chromosome 8. CYP11B1 synthesises corticos- the removal of two amino acids from angiotensin on October 3, 2021 by guest. Protected copyright. terone from deoxycorticosterone in the zona I to produce the key aldosterone stimulating fasiculata reticularis and is mainly regulated by factor, angiotensin II. Angiotensin II is itself a adrenocorticotrophic hormone (ACTH). potent vasoconstrictor. CYP11B2 catalyses the synthesis of aldosterone from deoxycorticosterone in the zona glomeru- Clinical features and making the diagnosis losa and its activity is principally regulated by Conn’s original description was that of a patient angiotensin II and potassium; and it is weakly with hypertension, hypokalaemia, and neuro- regulated by sodium and ACTH. As mito- muscular symptoms associated with an chondrial enzymes, CYP11B1 and 11B2 are aldosterone-producing adrenal adenoma.5 It is Clinical Pharmacology highly sensitive to tissue oxygen concentration. now recognised that the same clinical and Unit, University of Aldosterone is the major and most potent biochemical picture can be produced by other Cambridge, Box 110, Addenbrooke’s mineralocortcoid in man. It interacts with conditions in which there is aldosterone excess Hospital, Cambridge specific intracellular receptors to form dimers without adenoma. Primary aldosteronism either CB2 2QQ, UK which in turn bind to response elements in the through adrenal adenoma or adrenal hyperplasia RFoo promoter regions of target genes to initiate hor- is characterised by low or undetectable plasma K M O’Shaughnessy mone mediated transcription. Precise aldoster- renin activity suppressed via negative feedback M J Brown one induced proteins have not been identified by autonomous aldosterone secretion. While in Correspondence to: but recent evidence suggests that a member of some instances, the plasma aldosterone level is Dr Foo the serine-threonine kinase pathway, serum glu- high as would be expected; it can also be within [email protected] cocorticoid regulated kinase (sgk) regulates the normal range. Instead the aldosterone:renin Submitted 27 February 2001 activity of the epithelial sodium channel ratio (ARR) appears to be a more reliable means Accepted 23 April 2001 (ENaC).1 Mineralocorticoids appear to directly (93% sensitivity6) of identifying patients with www.postgradmedj.com 640 Foo, O’Shaughnessy, Brown primary hyperaldosteronism and whose hyper- and aldosterone synthesis is angiotensin II Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from tension is treatable by the aldosterone receptor insensitive but ACTH sensitive. In contrast, antagonist, spironolactone. familial hyperaldosteronism II is yet another The first study using the ARR was published condition that has been described where in 1981 where out of 348 hypertensive patients patients have cortical hyperplasia,12 and in who were screened, nine were found to have many kindreds there is an associated progres- adrenal adenoma using a much higher cut oV sion to adenoma (tumour) formation where ARR of 2081 units together with subsequent aldosterone synthesis is not glucocorticoid nuclear scintigram and computed tomogram.7 remediable and remains angiotensin II sensi- In this study, only three of the nine had tive. Familial hyperaldosteronism II has re- potassium less than 3.5 mmol/l. Plasma aldos- cently been mapped to chromosome 7p22. terone levels were equally non-discriminatory. On the background of this, diVerence in All nine had suppressed plasma renin activity aldosterone levels with change of posture but so did 39% of all the other 348 patients therefore requires careful interpretation in without adenomata. If present day ARR cut oV relation to family history and adrenal imaging of 750 units were used, more patients may have results. When entire adrenal glands were been diagnosed as having primary aldos- removed in cases of a solitary benign adenoma, teronism. In the late 1990s Gordon showed that the “non-tumorous” section of zona glomeru- by screening all hypertensive patients reviewed losa often appeared histologically hyperplastic, in a tertiary centre for ARR >750 units, the consisting of multiple small cortical nodules. prevalence of primary aldosteronism was closer This may well represent a spectrum of overlap to 15% than the 1% that has previously been as seen in familial multiple neoplasia syn- quoted in textbooks.8 Percentages of prevalence dromes where both neoplasia and hyperplasia based on the finding of a raised ARR have are variously and sometimes simultaneously ranged from 2.7% to 32%.9 expressed. The genetic abnormality is unlikely In a primary care setting, a group in Dundee to be limited to cells within the adenoma. has recently shown that the prevalence of When determining the ARR, concomitant primary aldosteronism diagnosed through a antihypertensive therapy can alter renin and high ARR was 25%.10 aldosterone levels. Calcium channel antagonists In an Australian tertiary practice, Hamlet et al suppress aldosterone synthesis. Angiotensin reportedly found the recognition of hyperaldos- converting enzyme inhibitors suppress aldoster- teronism as defined by a high ARR abruptly one levels as would the newer angiotensin II increased from two to five cases per year before receptor antagonists. Thiazide diuretics lead to routine use of the ARR, to over 50 per year after increase in renin levels more marked than that of its use.11 In their screening programme, Hamlet aldosterone. All antihypertensives in these et al also found that the majority of patients classes, however, improve the discriminatory (70%) with primary aldosteronism were power of the ARR. A false negative is unlikely in normokalaemic. Patients can rarely present with view of the autonomous nature of aldosterone severe resistant hypokalaemia with symptoms of excess. However â-blockers suppress renin syn- muscle weakness and parasthesia. We have thesis and may lead to a