Approach
Treatment decisions should not only take into account the results of adrenal venous sampling (AVS) and other diagnostic procedures, but should also be tailored to the particular characteristics and wishes of the individual patient.[6][7][10][28] Surgical treatment may therefore be inappropriate for some patients who lateralise on AVS, for example due to comorbidities, and, conversely, may be a reasonable option in rare patients with bilateral disease who do not, for example, tolerate medical treatment.
Careful discussion with the patient (and family, if appropriate) is a critical component of treatment. All management options and their possible outcomes should be fully explored and explained before a treatment is chosen.
Surgical treatment of PA
Approximately 30% of patients with primary aldosteronism (PA) who undergo AVS demonstrate clear lateralisation, with definite aldosterone production by one adrenal and contralateral suppression of the other.[6][7] These patients are candidates for unilateral adrenalectomy, which results in cure of hypertension in 50% to 60% and significant improvement in the remainder.[115][116][117] Less than 20% of patients require equivalent or increased medicine doses after surgery.[103] In order to obtain optimal results from surgery, an essential prerequisite is to have performed suppression testing and successful AVS, that is, all appropriate criteria have been met. Importantly, cure or improvement is universally seen regardless of whether patients are hypokalaemic or normokalaemic preoperatively.[106] Laparoscopic surgery enables a faster recovery and fewer complications than the open approach.[118] These may include haemorrhage, wound infection, wound hernia, and DVT/pulmonary embolism, but incidence rates are low.[118]
Surgery almost invariably results in correction of hypokalaemia if present preoperatively, and patients consistently report a marked improvement in quality of life.[115][116][117]
Almost always, the entire adrenal is removed even when an apparent adenoma is seen on CT scanning or on visualisation of the gland. This is because AVS as currently performed indicates only which adrenal is at fault, and cannot establish whether the visualised nodule is actually an aldosterone-producing adenoma. For example, it could be a non-secreting nodule that happens to be situated in the same gland as a smaller, non-visualised, hyper-functioning one. A possible exception can be made in the patient who presents with a recurrence of PA associated with a definite nodule on CT in the remaining adrenal some years after unilateral adrenalectomy for aldosterone-producing adenoma. In this situation, an option is to remove the nodule and preserve the residual adrenal tissue, provided it appears morphologically normal and the blood supply can be preserved.[119] This may avoid the need for replacement steroid therapy, but the patient should be warned that steroid cover may be required for any future operation or emergency, especially if the remnant is small. This approach also carries the risk of permitting a further recurrence of PA.
Immediately before surgery, potassium supplementation should be withdrawn, aldosterone antagonists discontinued, and other antihypertensive therapy reduced, if appropriate.
Particularly in patients with lateralising PA whose hypertension has been severe and/or long-standing and has caused significant hypertensive heart disease, preoperative treatment with an aldosterone antagonist over a period of several months will usually improve cardiovascular function and general condition by optimising hypertension control, repleting body potassium stores and antagonising other adverse effects of aldosterone excess, which will reduce operative risk.[6][7] Furthermore, the perioperative period and the postoperative recovery are smoother, with postoperative hypoaldosteronism (with hyperkalaemia) due to continuing renin suppression being avoided. It could be argued that this approach would benefit all patients coming to unilateral adrenalectomy for PA.
In the uncommon circumstance that a patient with unilateral PA is suspected of having concomitant autonomous adrenal overproduction of cortisol, the need for steroid cover peri-operatively and for a variable period following surgery should be anticipated.
In patients with bilateral forms of PA, rarely it may be appropriate to consider and carefully discuss with the patient the option of unilateral adrenalectomy. For example, both spironolactone and, less commonly, amiloride have sometimes been tolerated poorly even at low doses, or the dose of spironolactone required to control hypertension has produced adverse effects such as painful gynaecomastia in males, and mastalgia and menstrual disturbance in females. The appropriate action in this situation is to remove the gland that has the higher aldosterone/cortisol ratio on AVS, or if both are equally affected, the larger gland, which greatly reduces the dosage of aldosterone-blocking drug required for control.
If bilateral adrenal hyperplasia is disclosed by AVS but one adrenal contains a mass 2.5 cm or larger (some centres use higher cutoffs of 3.0 cm or even 4.0 cm), the surgical option should also be considered and discussed because of the risk of developing a malignancy.[6]
For rare patients with marked, bilateral adrenal hyperplasia and severe, bilateral PA (including those with severe forms of FH-III), bilateral adrenalectomy (often in 2 stages, to gauge the effect of unilateral adrenalectomy first) may be required to control hypertension and biochemical manifestations of PA.[16][47]
Successful removal of an aldosterone-producing adenoma during pregnancy has been rarely reported.[120] Although case reports suggest the optimal time for surgery is during the middle trimester, it is clearly preferable when possible to postpone surgery in patients found to have an aldosterone-producing adenoma during pregnancy until after delivery. This, however, raises the question of possible adverse effects of aldosterone-blocking drugs on the fetus. Fortunately, most or all of the adverse effects of aldosterone excess on the mother can disappear during pregnancy, only to reappear postnatally.[77] This is thought to be due to very high placentally derived progesterone levels blocking aldosterone action.
Postoperative treatment
Perioperative and postoperative fluids should be given as normal saline 1 litre every 12 hours or 8 hours. All potassium replacement is withheld during the operation and in the first 24 hours postoperatively. Potassium-sparing diuretics (such as spironolactone, eplerenone, and amiloride) should be withheld peri-operatively. Other antihypertensives can generally be withheld while the situation is assessed and only reintroduced if required. Sometimes, especially in young females, no further antihypertensives are required after surgery, but more usually a gradual withdrawal of antihypertensive medications is possible over the ensuing 3 to 12 months.[6]
Due to chronic suppression of renin-aldosterone and hence of aldosterone production by the contralateral adrenal, there is a significant risk of hyperkalaemia once the overproducing adrenal has been removed. Hypokalaemia observed in the immediate postoperative period is mainly due to the cessation of potassium supplements and/or aldosterone antagonists immediately preoperatively, plus the perioperative and postoperative administration of normal saline or other potassium-free fluids intravenously. However, this is often transient and is improved or corrected once the patient starts eating. Plasma potassium levels should therefore be monitored at least twice daily for the first 2 days following unilateral adrenalectomy for aldosterone-producing adenoma, and at least daily thereafter for another 3 days. Patients who have been treated for several months preoperatively with aldosterone antagonist agents such as spironolactone or amiloride usually demonstrate a smoother perioperative course, with BP levels that are easier to control and a lower likelihood of developing either hypokalaemia or hyperkalaemia once medicines are withdrawn postoperatively.
In at least one centre, patients undergo fludrocortisone suppression testing (FST) 1 to 3 months postoperatively to assess if any persisting autonomous aldosterone production by the remaining adrenal is present. In one centre, all patients lateralising preoperatively on AVS showed either biochemical cure of PA (70%) or significant improvement (30%) on postoperative FST.[106][116] Patients with residual hypertension and remaining unsuppressible aldosterone production demonstrate excellent responses to small doses of amiloride or spironolactone.
Twenty percent of patients diagnosed with unilateral PA preoperatively show evidence of ongoing PA after surgery. If residual hypertension is due to aldosterone excess, it may respond well to aldosterone antagonist medication, but, because aldosterone levels have been reduced by surgery, caution is required. As BP may continue to fall for months after surgery, especially in males, commencement of this or non-specific medication is often deferred for several weeks after surgery.
Medical treatment of PA
In patients with PA who do not lateralise aldosterone production to one side, or who lateralise but prefer medical to surgical treatment or are unfit for surgery, treatment with drugs that block aldosterone action is indicated.[28] Spironolactone has a steroidal structure and competitively inhibits aldosterone at its receptor. Amiloride acts directly on the epithelial sodium channel where aldosterone exerts its effects.
Treatment with aldosterone antagonists usually brings about a relatively slow-onset marked improvement in hypertension control and corrects hypokalaemia easily and swiftly in all but the severest cases of PA.[27][106][121][122] Potassium supplements should therefore be ceased or serially reduced based on plasma potassium measurements when these drugs are commenced. There is also evidence that spironolactone is able to ameliorate non-BP-dependent adverse cardiovascular and renal effects of aldosterone excess.[58][61][123][124][125] Whether similar benefits are associated with amiloride treatment remains uncertain.
The BP responses to medical treatment, however, are generally not as complete as those in lateralising patients who undergo unilateral adrenalectomy, and improvements in quality of life are significant, but less striking.[106]
In most patients, only modest doses of spironolactone or amiloride are required for optimal therapeutic effect.[6][7] Occasionally, with florid cases, spironolactone at higher doses may be necessary, but dose-dependent adverse effects are then much more likely. Even at lower doses, adverse pro-oestrogen effects by blocking androgen receptors (e.g., gynaecomastia and reduced libido, menstrual irregularities, and aggravation of breast fibrocystic change) occur in approximately 10% of patients taking spironolactone.[106][122] Side-effects from amiloride are rare. Eplerenone, a more selective aldosterone antagonist, appears to be relatively free of these adverse effects and has been shown to be effective as an antihypertensive agent in essential hypertension and to reduce morbidity and mortality in patients with heart failure post-MI.[126][127] While one study has shown eplerenone to be at least as effective in controlling hypertension as spironolactone in patients with PA, another has reported a lesser degree of efficacy.[128][129] At present, recognised indications for use in different countries vary and in some countries it is not approved for government-subsidised use in PA. Its use is then relatively expensive, and in Australia many patients decline to use it on a long-term basis. This will presumably change when its patent expires. It has been suggested that eplerenone be given to all hypertensive patients as an alternative to screening for PA.[130][131] However, this opinion is not based on experience treating PA patients, and should not be seriously considered.
Eplerenone can be used in patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. As there can be causes other than aldosterone excess contributing to failure of complete response of blood pressure to aldosterone blockade, an indicator of adequacy of blockade is required. Provided that there are no medicines in use that influence the aldosterone-renin ratio, and that the assays are sound, the normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
Since over-treatment with these anti-aldosterone agents can cause volume contraction with pre-renal failure, elevated creatinine levels, and life-threatening hyperkalaemia, their use should always be accompanied by regular close monitoring of potassium levels. Aldosterone antagonists must be used with great caution in patients with any reduction in renal glomerular function, because of the increased potential for hyperkalaemia. In such patients, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalaemia, but potassium and creatinine levels should still be carefully monitored.
Amiloride, spironolactone, and eplerenone have a slow onset of antihypertensive action. Patience is therefore essential. Reduction in blood pressure after their commencement or increase in dose may not be apparent for 2 weeks. It takes much longer, even months, before their full effect is seen. If necessary, other antihypertensive agents with more rapid onset of action could be employed during this period, and then later reduced or withdrawn.
Treatment for familial hyperaldosteronism type I
In familial hyperaldosteronism type I (FH-I), hypertension is readily controlled by giving glucocorticoids in low doses.[132][133] The hybrid gene that causes excessive aldosterone production is regulated tightly by adrenocorticotrophic hormone (ACTH). By suppressing ACTH and hybrid gene expression, glucocorticoids rapidly and effectively ameliorate hypertension.[13][22][44][45][132]
Complete suppression of ACTH-regulated aldosterone production is not usually necessary and raises the risk of Cushingoid adverse effects.[133] A reasonable approach is to use the lowest dose of glucocorticoid treatment required to maintain normotension (as assessed by clinic, home, and ambulatory BP monitoring) and by periodic (e.g., yearly) echocardiographic assessments of left ventricular mass index and diastolic function. Patients on long-term glucocorticoids should be monitored for the development of glucocorticoid-induced osteoporosis by dual energy-ray absorptiometry (DXA) performed every 1 to 2 years (and in children for slowing of height advancement). Because of the known adverse effects of aldosterone which are independent of BP, it remains uncertain whether avoidance of left ventricular hypertrophy, impaired diastolic function, and proteinuria during treatment with glucocorticoids is sufficient to guarantee optimal treatment of FH-I in comparison with aldosterone blockade.
Spironolactone, eplerenone, and amiloride are alternative treatments to glucocorticoids. Amiloride may be the preferred option when treating affected children, because it avoids the potential impairment of growth associated with the use of glucocorticoids, and the potential adverse effects resulting from blockade of sex steroid receptors by spironolactone. A similar argument could be raised for using eplerenone in children with FH-I, but data on its safety and efficacy in this situation are lacking.
For pregnant patients, low-dose glucocorticoids have been used successfully to control hypertension. Prednisolone and hydrocortisone are thought to be preferable to dexamethasone, as the latter is incompletely metabolised by placental 11beta-hydroxysteroid dehydrogenase and is readily transferred to the fetus. Alternatives to glucocorticoids are any of the recognised pregnancy-safe antihypertensives.
Family screening by genetic testing should always be undertaken to identify affected relatives as early as possible in their lives in order to avoid unnecessary morbidity.[13][20]
Treatment for other types of familial hyperaldosteronism
To date, no targeted treatment is available for patients with FH-II, FH-III, or FH-IV; however, some therapeutic possibilities are emerging.[134]Treatment for FH-II and FH-IV follows similar guidelines to that for apparently sporadic bilateral PA.[37][135]
In families with FH-III, some KCNJ5 mutations cause severe, bilateral PA requiring, bilateral adrenalectomy may be required to control hypertension and other manifestations.[14][37][135] For patients with mutations causing milder disease, treatment with medicines which antagonise aldosterone action (spironolactone, eplerenone, or amiloride) following similar guidelines to that for apparently sporadic bilateral PA, may be sufficient.
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