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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 , 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 can be region.2 Sgk mRNA is rapidly stimulated by absent even in the presence of marked hyper- 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 receptor antagonist, teronism related hypertension is now known to .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 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 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 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. either CB2 2QQ, UK which in turn bind to response elements in the through adrenal adenoma or adrenal 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

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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- and parasthesia. We have thesis and may lead to a false positive and we observed that hypokalaemia is more likely to generally require patients to stop â-blocker http://pmj.bmj.com/ occur after starting thiazide diuretic as an therapy one week before testing for plasma renin antihypertensive. But hypokalaemia is clearly activity and aldosterone in our protocols. Others not necessary for the diagnosis of hyperaldos- believe valid data can be obtained even in the teronism. In fact, patients with primary aldos- presence of various drugs.13 teronism are more likely to be normokalaemic. We have previously used a protocol of daily In our practice we have noted that patients with salt loading with 10 g sodium two weeks before

primary aldosteronism almost always have testing for plasma renin activity and aldosterone. on October 3, 2021 by guest. Protected copyright. serum sodium above 140 mmol/l. The rationale behind this is to suppress plasma Under normal circumstances, aldosterone aldosterone, which will be seen in normal levels, initially measured decubitus in the early subjects but not in patients with primary aldos- morning hours, increase and double after four teronism. In our experience this protocol has not hours of erect posture. This was previously used proved to increase the diagnostic power of the to diVerentiate between adrenal adenoma ARR significantly to justify the complex and (tumour) and idiopathic zona glomerulosa uncomfortable testing method. Measurement of hyperplasia because in hyperplasia marked 24 hour urinary sodium excretion may be an enhancement of adrenal responsiveness to easier alternative to give an idea of sodium angiotensin II resulted in higher aldosterone intake. Others have also employed suppression levels in the erect posture. In patients with tests using the synthetic mineralocorticoid, adenoma on the other hand, it was observed that fludrocortisone. Although useful for clinical the tumour responded more to ACTH instead study purposes we have generally found sup- of angiotensin II. In these patients therefore, pression tests in hyperaldosteronism lacking in aldosterone levels were unchanged with erect diagnostic value. posture and they followed a circadian rhythm similar to that for . Management However the monogenic disorder of gluco- ALDOSTERONE EXCESS—ADRENAL ADENOMA OR corticoid remediable aldosteronism or familial HYPERPLASIA hyperaldosteronism I was discovered where Once the diagnosis of aldosterone excess is there is adrenocortical hyperplasia with no made with a high ARR, the next investigational apparent progression to adenoma formation steps are radiological.

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The tool of choice for imaging adrenal glands alternative (amiloride acts directly on ENaC to Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from requires superior resolution and we have gener- reduce sodium retention). Patients with angio- ally preferred using magnetic resonance imaging tensin II sensitive adenoma or hyperplasia may unless there are technical contraindications. The need further control with diagnosis of adrenal adenomata is likely if angiotensin converting enzyme inhibitors or discrete nodule or nodules are detected. Unilat- angiotensin II receptor antagonists. eral suggests that surgical resolution of hypertension is possible. Further to magnetic ALDOSTERONE EXCESS—OTHER CAUSES resonance imaging, diVerential adrenal vein Glucocorticoid remediable aldosteronism (fa- sampling is the logical next step to confirm or milial hyperaldosteronism I) is the first mono- refute unilateral disease and help predict the genic disorder related to hypertension that has success of unilateral adrenalectomy. Adrenal been identified.14 In this autosomal dominant vein catheterisation is technically diYcult to disorder there is a single crossover mutation perform but is a useful tool in the hands a skilled where aldosterone synthesis becomes under the operator. Part of the diYculty lies with catheter- control of ACTH. The aldosynthase ising the right adrenal vein which unlike the left (CYP11B2) and 11â-hydroxylase (CYP11B1) drains, in the normal human anatomy, into the genes which both lie on chromosome 8q21-q22 right renal vein instead of directly into the infe- undergo mutation possibly during meiosis to rior vena cava. Apart from the left and right form a hybrid gene that is ACTH sensitive (like adrenal veins, blood is taken from the suprarenal CYP11B1) but has the coding sequence of inferior vena cava. Aldosterone and cortisol CYP11B2 (aldosynthase). In this condition, concentrations are determined from the col- there is adrenocortical hyperplasia which may be lected blood samples. The reason for determin- nodular, and histological features suggest over- ing cortisol concentration is twofold. The aldo- activity of the zona fasciculata. There is no sterone:cortisol ratio helps to provide a report of progression to tumour formation. normalised ratio for bilateral comparison. If a Patients with this condition tend to be young unilateral were responsible for hypertensives who are otherwise asymptomatic, excess aldosterone production, one would ex- and diagnosis can be made by dexamethasone pect the ratio to be at least thrice that of the suppression of plasma aldosterone or by simple contralateral side. On the contralateral side, Southern blotting now with the discovery of the aldosterone secretion is expected to be sup- genetic defect. Treatment in this condition is pressed. The ratio on the suppressed contra- glucocorticoid therapy with low dose dexam- lateral side should approximate that seen in the ethasone to suppress ACTH production, which suprarenal inferior vena cava. The caveat to in turn suppresses aldosterone synthesis. looking at the aldosterone:cortisol ratio is one needs to be certain that cortisol concentrations APPARENT ALDOSTERONE EXCESS are comparable bilaterally because occasionally Some patients have hypertension with features the right adrenal vein may receive tributaries of hyperaldosteronism (hypokalaemia, de- from the hepatic circulation and give rise to creased renin activity) but actually have low or much higher cortisol levels on that side. The undetectable aldosterone. Such conditions second purpose of determining cortisol concen- include rare congenital conditions such as http://pmj.bmj.com/ tration is to confirm that the catheters are within apparent mineralocorticoid excess, Liddle’s the adrenal veins at the time of blood sampling. syndrome, and recently identified activating Cortisol concentrations in the adrenal veins “gain of function” mutations in the mineralo- should approach twice of that found in the corticoid receptor.15 intoxication suprarenal inferior vena caval sample. produces a similar syndrome to apparent min- Nuclear scintigraphy with 131I-labelled eralocorticoid excess. 75

iodomethyl-19-norcholesterol or Se-6- In the congenital condition of apparent min- on October 3, 2021 by guest. Protected copyright. selenomethylcholesterol is another possible eralocorticoid excess there is a genetic absence method for distinguishing unilateral disease of the cell specific enzyme, 11â hydroxysteroid from bilateral hyperplasia but generally scinti- dehydrogenase isoform 2 (11âHSD2). grams are diYcult to interpret in patients 11âHSD2 converts cortisol to inactive corti- taking various antihypertensive medications. sone in distal tubular cells. Under normal Spironolactone must be stopped for at least six circumstances cortisol exists in 100-fold higher weeks before scanning. circulating concentrations than aldosterone In patients who have homogenous or nodu- and has a high aYnity for the mineralocorticoid lar hyperplasia or normal looking adrenal receptor. In distal tubular cells therefore, glands radiologically, surgery is inappropriate 11âHSD2 is responsible for converting and and sometimes not curative. Antihypertensive inactivating glucocorticoids so that the miner- treatment with the inclusion of spironolactone alocorticoid receptors in these cells are only is usually adequate for blood pressure control. activated by mineralocorticoids and protected Often, response to the addition of spironolac- from the local eVects of glucocorticoids. In tone is dramatic and many patients can be apparent mineralocorticoid excess where there maintained adequately on spironolactone is 11âHSD2 deficiency, cortisol is unconverted monotherapy. After an initial high dose therapy and free to bind with high aYnity to mineralo- it may be possible to reduce to a maintenance corticoid receptor thereby activating it. Plasma dose of 25 to 50 mg/day. The side eVects of renin activity and plasma aldosterone are both impotence, gynaecomastia, and menorrhagia markedly suppressed with a raised ratio of uri- are sometimes intolerable and unacceptable; nary cortisol to cortisone metabolites. Children such patients may be given amiloride as an with congenital apparent mineralocorticoid

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excess invariably have severe hypertension, and and lisinopril 20 mg twice a day. Interestingly, a Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from high mobidity and mortality. Spironolactone year before he had had the dramatic experience may control but blood of an out-of-hospital cardiac arrest and further pressure control usually requires further agents subsequent episodes of ventricular tachycardia, such as angiotensin converting enzyme inhibi- all of which eventually led onto electrophysi- tors and thiazide diuretics. Low dose dexam- ological studies and the implantation of an auto- ethasone (dexamethasone does not bind min- mated cardiac defribillator. Routine tests re- eralocorticoid receptor) may be of major vealed a persistently low potassium of 3.2 benefit by suppressing endogenous cortisol mmol/l; and aldosterone and renin profiling led production and removing the mineralocorti- to the finding of a high ARR (4250 units). Com- coid receptor agonist. The gene for 11âHSD2 puted tomography revealeda1cmnodule in the is found on chromosome 16q22 and so far 11 left adrenal gland and he is presently waiting to mutations have been identified. Analysis of undergo diVerential adrenal vein sampling. Fig- kindreds with this enzyme defect has shown an ure 1A shows his dramatic blood pressure autosomal recessive inheritance. response upon the addition of spironolactone. The acquired form of apparent mineralocor- ticoid excess is seen with excess ingestion of CASE 2 liquorice or related drugs such as carbenox- A 68 year old woman had high blood pressure olone. Liquorice contains an active component for 40 years and despite being on atenolol 100 glycyrrhetinic acid and carbenoxolone is a mg, enalapril 20 mg, bendrofluazide 2.5 mg, hemisuccinate derivative of this. Glycyrrhetinic indoramin 12.5 mg, lacidipine 60 mg, hydrala- acid binds to and potently inhibits 11âHSD, zine 50 mg twice a day and clonidine 75 µg preventing the renal conversion of cortisol to twice a day, her blood pressure was 230/110 cortisone. The clinical picture mimics a milder mm Hg. Her electrolytes showed borderline form of congenital apparent mineralocorticoid hypokalaemia (3.5 mmol/l); plasma aldoster- excess. Plasma renin activity and plasma aldos- one was within normal limits (290 pmol/l) but terone are suppressed but the ratio of urinary plasma renin activity was markedly suppressed cortisol to cortisone metabolites is less mark- (<0.2 pmol/ml/hour). The ARR was high at edly raised. 1450 units. Magnetic resonance imaging Liddle’s syndrome is the condition where “gain-of-function” mutations are found in the A 190 subunits of the epithelial sodium channel such 180/105 176/100 that there is sodium retention and potassium 170 loss, mimicking hyperaldosteronism. In these 150 144/80 patients, however, aldosterone and renin levels, 130 as in apparent mineralocorticoid excess, are extremely suppressed. Treatment, however, is 110 similar to Conn’s syndrome and involves 90 spironolactone but often also requires amilo- 70

Blood pressure (mm Hg) Atenolol Bisoprolol Bisoprolol ride or triamterene. Lisinopril Irbesartan Doxazosin Doxazosin Doxazosin Spironolactone http://pmj.bmj.com/ Spironolone sensitive hypertension: does this represent a spectrum of ? Spironolactone can be used to control hyper- B tension in patients with adrenal adenomata and 240 230/110 hyperplasia. Other indications are rarer genetic conditions aforementioned. In identifying hy- 200 192/91 pertensive patients who may be treatable with 165/93 on October 3, 2021 by guest. Protected copyright. spironolactone, a high ARR is the useful descri- 160 minant irregardless of imaging findings. How- 126/88 ever, we are accumulating evidence (M J Brown 120 et al 2001, unpublished data) that show patients 80

with low suppressed plasma renin activity, Blood pressure (mm Hg) Atenolol Atenolol Atenolol Spironolactone normal aldosterone level, and normal or accept- Enalapril Enalapril Co-amilozide Bendrofluazide Bendrofluazide able ARR appear to have hypertension equally Indoramin Indoramin responsive to spironolactone. The following Lacidipine Amlodipine Clonidine Hydralazine three cases of longstanding hypertension Hydralazine illustrate the suggestion that spironolactone sen- C 220 208/116 sitivity may represent a spectrum not previously 200/100 thoroughly appreciated. 190

160 Case reports 144/90 CASE 1 130 128/80 A man, aged 64, had a 10 year history of hyper- tension that was “diYcult to treat” in spite of 100 attempts with angiotensin converting enzyme 70

Blood pressure (mm Hg) Losartan Losartan Spironolactone inhibitors, calcium channels blockers, Bisoprolol Bisoprolol â-blockers and diuretics, singly and in combina- Spironolactone tion. He was seen in our clinic with a blood Figure 1 Blood pressure response on taking spironolactone pressure of 170/100 mm Hg, on atenolol 100 mg in (A) case 1, (B) case 2, and (C) case 3.

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showed normal looking adrenal glands. Figure observation has practical value in understand- Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from 1B shows her dramatic blood pressure re- ing the physiology underlying NASSH. In one sponse upon the addition of spironolactone. study, a subset of patients with a normal/high level of renin activity demonstrated a similarly flat adrenal response to angiotensin II infusion CASE 3 when stressed by salt restriction.16 This subset A man, aged 57, had a six year history of of normal/high renin hypertensives appears to uncontrolled hypertension and blood pressure be a distinct group of essential hypertensives remained high at 220/116 mm Hg in spite of known as non-modulators. Although adrenal bisoprolol 5 mg and losartan 100 mg. Plasma responsiveness to angiotensin II is lacking in electrolytes were normal, plasma aldosterone LREH patients, angiotenin II infusion pro- was normal (190 pmol/l) but plasma renin duces a pressor response that is significantly activity was low (0.4 pmol/ml/hour). The ARR greater compared with that seen in non- was acceptable at 600 units and computed modulating essential hypertension, modula- tomography showed normal looking adrenal tors, and normotensive controls. It has been glands. Figure 1C shows his blood pressure shown repeatedly in hypertension marked by response upon the addition of spironolactone. sodium retention that there is a heightened Case 1 represents the classical spironolac- sensitivity of the vasculature to angiotensin II tone response of patients with hyperaldos- attributed to upregulation of vascular angio- teronism and adrenal adenomata. Persistent tensin II receptors. The overlap between hypokalaemia may well be the explanation in LREH and NASSH is further suggested by the part for his ventricular tachyarrhythmias. additive blood pressure response in NASSH Surgery is an option if proof of unilateral patients to the combination therapy of disease and contralateral suppression is found. spironolactone and an angiotensin II receptor Case 2 illustrates the practical usefulness of a antagonist such as irbesartan. The pathophysi- high ARR in that hypertension may be ological mechanisms underlying NASSH re- treatable with spironolactone despite normal main to be determined. Meanwhile using looking adrenal glands on radiological imaging. spironolactone to treat NASSH patients, who Lim et al have previously described a similar usually have a longstanding history of resistant cohort of patients with spironolactone sensitive hypertension, produces dramatic and remark- hypertension.10 In these patients, adrenal mi- ably impressive results. cronodules cannot be excluded but diVerential adrenal venous sampling as a prelude to surgi- Conclusion cal therapy is diYcult to justify given the Recent evidence suggests that the prevalence of normal scan findings. Alternatively, the long- primary hyperaldosteronism is higher than standing history of hypertension, as seen with originally thought. Even in the absence of this patient, implies mechanisms of inappropri- hypokalaemia and especially in patients with ate aldosterone secretion devoid of adenomata diYcult to control hypertension, ARR may be or hyperplasia formation. useful. DiYcult to control hypertensives are Case 3 represents a group of patients with ones who do not respond in spite of three or spironolactone sensitive hypertension not pre- more antihypertensive drugs.9 In patients who http://pmj.bmj.com/ viously described. These are patients who, as have a high ARR, treatment with spironolac- case 2, have normal aldosterone level, low sup- tone has been shown to readily produce pressed renin activity, normal adrenal glands successful blood pressure control. Surgical on imaging but, unlike case 2, have a “normal” therapy for Conn’s adenoma may be consid- ARR. We are accumulating data on more than ered after appropriate radiological imaging and 20 of such patients in our tertiary practice and adrenal venous sampling.

primary care screening (M J Brown et al 2001, While low renin essential hypertensives with on October 3, 2021 by guest. Protected copyright. unpublished data), all of whom have had the a normal ARR are classically treatable with thi- dramatic response to spironolactone as seen in azide diuretics, there appears to be a subset of fig 1C. We now call this group normoaldoster- patients who are treatable instead with one spironolactone sensitive hypertension spironolactone but not thiazides. We have (NASSH). The low suppressed renin activity called this subset “normoaldosterone spironol- appear to represent a further overlap with the actone sensitive hypertension” or NASSH. We well recognised subset of essential hyper- propose that spironolactone sensitive hyper- tension known as “low renin essential hyper- tension may represent a wider spectrum of tension” (LREH). Classically, patients with conditions potentially treatable by the simple LREH are salt sensitive and are more likely to addition of a single tablet. This may raise the respond to diuretics than to agents that block justification for a trial of spironolactone in the renin system. In NASSH, however, we have patients with resistant hypertension, especially found that thiazide diuretics are ineVective and in situations where there is inadequate access often unmask hypokalaemia. Recent evidence to plasma aldosterone or renin measurement. has refuted previous belief that patients with Other patients with the clinical and biochemi- LREH maintain normal basal plasma aldoster- cal picture of hyperaldosteronism may alterna- one levels in the face of suppressed renin tively have rarely causes of hypertension system via excessive responsiveness to angio- including glucocorticoid remediable aldos- tensin II.16 Instead when stimulated with a low teronism, Liddle’s syndrome, and acquired sodium diet, LREH patients demonstrated apparent mineralocorticoid excess. only a small rise in aldosterone and blunted A summary of conditions described is shown responsiveness to angiotensin II infusion. This in table 1.

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Table 1 Summary of conditions described in the text Postgrad Med J: first published as 10.1136/pmj.77.912.639 on 1 October 2001. Downloaded from Learning points Key pathological features x Hyperaldosteronism, as a cause of hyper- Conn’s adenoma + High aldosterone:renin ratio (ARR) tension and as defined by high + Adenoma on adrenal imaging aldosterone-renin ratio (ARR), has a + Adrenal vein sampling and subsequent surgery may be higher prevalence (∼10%) than previously considered if there is unilateral disease and contralateral suppression of aldosterone secretion appreciated. + However hypertension usually responds well to x Ethnic subgroups have classically been spironolactone shown to have predominantly low renin Adrenal hyperplasia + Usually bilateral disease activity if hypertensive. The high preva- + High ARR lence of hyperaldosternonism however + Bulky adrenal glands on imaging appears to be found even in the primary + Hypertension control usually achieved with spironolactone care setting in Scotland and in mixed Glucocorticoid remediable + First monogenic disorder in hypertension to be described population studies in Australia. aldosteronism or familial + Adrenocortical hyperplasia without progression to x Measuring plasma aldosterone concen- hyperaldosteronism I adenoma formation + Aldosterone synthesis is adrenocorticotrophic hormone tration and plasma renin activity is useful, (ACTH) sensitive and hypertensive patients with high ARR + Young hypertensives, otherwise asymptomatic are likely to respond to spironoloactone. + Diagnosis made by dexamethasone suppression of plasma aldosterone or simple Southern blotting x If surgery is to be considered, the investi- + Blood pressure control achieved by low dose gation of choice in patients with Conn’s dexamethasone therapy to suppress ACTH syndrome who have scan evidence of Familial hyperaldosteronism II + Adrenocortical hyperplasia with associated adenoma adrenal adenoma, is diVerential adrenal formation vein sampling. + Aldosterone synthesis is not ACTH sensitive but x Even in the absence of adrenal gland angiotensin II sensitive abnormality on scan, patients with high Apparent mineralocorticoid excess + Features of hyperaldosteronism (hypokalaemia and ARR are responsive to spironolactone. decreased renin activity) x We have identified patients (M J Brown et + But low/undetectable aldosterone + Genetic absence (likely autosomal recessive) of al, unpublished results) with low plasma 11â-hydroxysteroid dehydrogenase 2, which is responsible renin activity and normal ARR but show for cortisol inactivation in distal tubular cells dramatic response to spironolactone and + Un-inactivated glucocorticoids therefore act on mineralocorticoid receptors with high aYnity to produce chosen to name this normoaldosterone deleterious eVects spironolactone sensitive hypertension + Congenital apparent mineralocorticoid excess has high (NASSH.) morbidity and mortality + Management usually requires spironolactone and other x We suggest that there is a spectrum of antihypertensive agents, together with low dose spironolactone sensitive hypertensive pa- dexamethasone for suppressing endogenous cortisol tients, overlapping further with patients synthesis conventionally called low renin hyperten- Acquired apparent + Ingestion of liquorice or related drugs such as sives who have traditionally shown best mineralocorticoid excess carbenoxolone, which binds to and inhibits response to thiazide diuretics. 11â-hydroxysteroid dehydrogenase 2 x As with other causes of hyperaldos-

Liddle’s syndrome + “Gain-of-function” mutations found in the subunits of the teronism where genetic mutations have http://pmj.bmj.com/ epithelial sodium channel, resulting in sodium retention been identified, genetic variation in these and potassium loss + Renin and aldosterone levels, as in apparent spironolactone sensitive patients remains mineralocorticoid excess, are markedly suppressed to be elucidated. + Blood pressure control requires spironolactone, and often amiloride

Normoaldosterone spironolactone + As defined by Brown et al (see text), likely to be a subgroup sensitive hypertension of low renin hypertension plasma renin activity. Results in hypertensive patients. Arch

Suppressed renin activity on October 3, 2021 by guest. Protected copyright. (NASSH) + Intern Med 1981;141:1589–93. + Normal plasma aldosterone and normal ARR 8 Gordon R. Mineralocorticoid hypertension. Lancet 1994; + Normal adrenal glands on imaging 344:240–3. + Marked blood pressure response to spironolactone, usually 9 Kaplan NM. Cautions over the current epidemic of primary on the background of longstanding, diYcult to treat aldosteronism. Lancet 2001;357:953–4. hypertension 10 Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive eYcacy of spironolactone: a prospective cohort follow-up study. Br J 1 Webster MK, Goya L, Ge Y, et al. Characterization of sgk, a Clin Pharmacol 1999;48:756–60. novel member of the serine/threonine protein kinase family 11 Hamlet SM, Tunny TJ, Woodland E, et al. Is aldosterone/ which is transcriptionally induced by glucocorticoids and renin ratio useful to screen a hypertensive population for serum. Mol Cell Biol 1993;13:2031–40. primary aldosteronism? Clin Exp Pharmacol Physiol 1985;12: 2 Chen SY, Bhargava A, Mastroberardino L, et al. Epithelial 249–52. sodium channel regulated by aldosterone-induced protein 12 Gordon RD, Stowasser M, Tunny TJ, et al. Clinical and patho- sgk. Proc Natl Acad Sci U S A 1999;96:2514–19. logical diversity of primary aldosteronism including a new 3 Verrey F, Kraehenbuhl JP, Rossier BC. Aldosterone induces familial variety. Clin Exp Pharmacol Physiol 1991;18:283–6. a rapid increase in the rate of Na/K-ATPase gene transcrip- 13 Gallay BJ, Ahmad S, Xu L, Screening for primary aldos- tion in cultured kidney cells. Mol Endocrinol 1989;3:1369– et al. 76. teronism without discontinuing hypertensive medications: the 4 Wehling M, Spes CH, Win N, et al. Rapid cardiovascular plasma aldosterone-renin ratio. Am J Kidney Dis (in press). action of aldosterone in man. J Clin Endocrinol Metab 1998; 14 Lifton RP, Dluhy RG, Powers M, et al. A chimeric 83:3517–22. 11â-hydroxlase/aldosterone synthase and human hyper- 5 Conn JW. Primary aldosteronism: a new clinical syndrome. tension. Nature 1992;355:262–5. J Lab Clin Med 1955;45:6–17. 15 Geller DS, Farhi A, Pinkerton N, et al. Activating mineralo- 6 Lim PO, Rodgers P, Cardale K, et al. Potentially high preva- corticoid receptor mutation in hypertension exacerbated by lence of primary aldosteronism in a primary-care popula- pregnancy. Science 2000;289:119–23. tion. Lancet 1999;353:40. 16 Fisher ND, Hurwitz S, Ferri C, et al. Altered adrenal sensi- 7 Hiramatsu K, Yamada T, Yukimura Y, et al. A screening test tivity to angiotensin II in low-renin essential hypertension. to identify aldosterone-producing adenoma by measuring Hypertension 1999;34:388–94.

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