Approach

The diagnosis of primary aldosteronism (PA) should be considered in all patients with hypertension, regardless of severity and plasma potassium level. When present, symptoms suggestive of hypokalaemia (such as muscle weakness, paraesthesias, muscle cramps, nocturia, polyuria, and palpitations) are highly suggestive of PA. However, these symptoms are usually absent, as most patients are normokalaemic.​[31] Other symptoms or signs that may be present are usually non-specific and non-contributory to diagnosis. These may include lethargy, difficulty concentrating, and mood disturbances such as irritability, anxiety, and depression.

A critical component of the diagnostic work-up is careful discussion with the patient. Each phase of the diagnostic process should be explained in detail to the patient before a decision is made whether to proceed with it.

Screening

Because only a minority (approximately 20%) of patients with PA are hypokalaemic, measurement of plasma potassium lacks sensitivity as a screening test. However, when hypokalaemia is present (especially when not provoked by the use of diuretics), it serves as a valuable clue towards the presence of this condition.

The aldosterone/renin ratio is the most reliable available screening test, being more specific than renin measurement (levels of which are almost always suppressed) and more sensitive than plasma potassium or aldosterone measurement.[10][28][41]​​[70]​ The ratio becomes elevated before aldosterone or plasma potassium leave their normal ranges.​[6][71][72] However, false positives and negatives are possible.[10][28]​​[73]

  • Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy (in which high levels of progesterone antagonise aldosterone action at the mineralocorticoid receptor), and treatment with diuretics (including spironolactone), dihydropyridine calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists can all lead to false-negative ratios by stimulation of renin secretion.​[6][71][72]​​[74][75][76]​​[77][78]

  • Because potassium is a powerful chronic regulator of aldosterone secretion, hypokalaemia may also be associated with false-negative ratios.​[73]

  • Beta-blockers, alpha-methyldopa, clonidine, and non-steroidal anti-inflammatory drugs (NSAIDs) can suppress renin levels and produce false-positives.​[6][10][41]​​​[71][74][79]​​​

  • False-positives can occur in premenopausal women during the luteal phase of the menstrual cycle, and also in women receiving oestrogen-containing contraceptive agents or hormone replacement therapy, but only when renin is measured as direct active renin concentration and not as plasma renin activity.[80][81][82]

  • False-positives may also be seen in patients with impaired renal function (renin production is reduced, whereas any associated hyperkalaemia tends to elevate aldosterone), in advancing age (during which production of renin falls more quickly than that of aldosterone), and in familial hyperkalaemic hypertension, also known as pseudohypoaldosteronism type II or Gordon syndrome.[10][72][83]​​

  • Treatment with antidepressants of the selective serotonin reuptake inhibitor (SSRI) class lowers the aldosterone/renin ratio, but whether they can cause false-negatives in patients with PA remains uncertain.[84]

Diuretics should be discontinued for at least 6 weeks and other interfering medicines for at least 2 (and preferably 4) weeks before measuring the ratio, substituting other medicines that have a lesser effect on results, such as verapamil slow-release (plus or minus hydralazine), prazosin, and moxonidine, in order to maintain hypertension control.[71][72][85] In cases where a potentially interfering medicine cannot be withdrawn, useful information can still be obtained by taking into account its known effects when interpreting the ratio result. For example, an elevated ratio in patients receiving a diuretic, ACE inhibitor, angiotensin receptor blocker, or dihydropyridine calcium blocker would make PA very likely, whereas a normal ratio in the presence of beta-blocker treatment would make the diagnosis very unlikely.

Hypokalaemia should be corrected and the patient should be encouraged to follow a liberal salt diet before ratio measurement. Because of the effects of posture and time of day, sensitivity of the ratio is maximised by collecting blood mid-morning from seated patients who have been upright (sitting, standing, or walking) for 2 to 4 hours.[71][72]

The ratio should be regarded as a screening test only, and should be measured more than once (serially if conditions of sampling, including medicines, are being altered) before deciding whether to go on to a suppression test to definitively confirm or exclude the diagnosis.

Confirmation of diagnosis

Because the aldosterone/renin ratio is not without occasional false-positive results, even under the conditions described above, confirmatory testing is required before the diagnosis of PA can be definitively confirmed or excluded.[10][41]​​

While fludrocortisone suppression testing, in which the aldosterone response during 4 days' administration of oral fludrocortisone and oral salt loading is determined, is widely regarded as the most reliable means of confirming or excluding PA,​​​ measurement of plasma aldosterone at the conclusion of an intravenous infusion of 0.9% saline (usually 2 L over 2-4 hours),​​​ or 24-hour urinary aldosterone excretion rates following 3 days of oral salt loading are also employed in some centres.[6][28][72][86][87][88][89]​ A study involving 100 patients (77 with PA) found saline suppression testing demonstrated better sensitivity for PA when performed in the upright (seated) position compared with the traditional recumbent position.[89]

Subtype differentiation

If the confirmatory test is positive, further investigations are directed towards determining the subtype of PA (unilateral aldosteronism, mainly caused by aldosterone-producing adenoma; or bilateral adrenal hyperplasia), as the treatment of first choice for each subtype differs.[28] Familial hyperaldosteronism type I (FH-I) is rare, but important to diagnose as hypertension is readily controlled by treatment with glucocorticoids.[11]

  • If FH-I is suspected (for example, on the basis of early onset of PA or a family history of early onset hypertension, PA, or stroke), genetic testing of peripheral blood for the hybrid gene should be performed before going on to other tests aimed at subtype differentiation, as a positive genetic test will make them superfluous. Because presence of the hybrid gene is diagnostic for FH-I, testing for it has virtually supplanted the tedious and less reliable biochemical methods of diagnosing this subtype (e.g., demonstration of marked, persistent suppression of plasma aldosterone during several days of dexamethasone administration).[90][91][92]​ The great majority of patients with PA, however, will test negative for the hybrid gene, leaving the more difficult task of separating the unilateral tumourous forms from varieties of bilateral adrenal hyperplasia (BAH). In patients with early onset PA who test negative for the hybrid gene, consideration should be given for genetic testing for mutations in CLCN2, KCNJ5, and CACNA1H for diagnosis of FH-II, FH-III, and FH-IV respectively.[41]

  • Adrenal CT scanning is recommended in all patients to confirm subtype and exclude adrenocortical carcinoma.[10][28][41]​ It is usually able to detect aldosterone-producing carcinomas because of their relatively large size (usually >3 cm) but frequently misses aldosterone-producing adenomas (which have an average size of approximately 1 cm).[9]​ CT may be misleading, as it cannot distinguish aldosterone-producing adenomas from non-functioning nodules.[6][27][71][93][94]​ Similar limitations apply to adrenal MRI.[95]

  • Responsiveness of plasma aldosterone (defined as a rise of at least 50% over basal) during 2 or 3 hours of upright posture following overnight recumbency or during angiotensin II infusion was once considered specific for BAH among patients with PA.[96][97] However, similar findings are also observed in the angiotensin II-responsive variety of aldosterone-producing adenoma, which accounts for over 50% of aldosterone-producing adenomas in some series.[4][98][99] Examination of the aldosterone response to posture in patients with PA is nevertheless worthwhile, as its absence narrows the diagnosis to angiotensin II-unresponsive aldosterone-producing adenoma or FH-I in most cases. Hybrid steroid levels (18-hydroxy- and 18-oxo-cortisol) are elevated in FH-I and angiotensin II-unresponsive aldosterone-producing adenoma, and are useful evidence suggesting one or the other of these two conditions. However, they are not widely available, and because they are normal in both BAH and angiotensin II-responsive aldosterone-producing adenoma, they do not distinguish unilateral from bilateral PA.[91][98][99]

For the above reasons, adrenal venous sampling (AVS) is the only dependable way to differentiate bilateral from unilateral PA.[28][71][94][100][101]​​ Some centres therefore recommend this procedure in all patients with PA (other than those with FH-I).​​​[102]​ Some guidelines suggest that AVS may be bypassed in patients aged <35 years with unilateral adenoma before proceeding to unilateral adrenalectomy.​[10][28][41]​​​[103][Figure caption and citation for the preceding image starts]: CT showing lesion in right adrenal gland in patient with right aldosterone-producing adenomaFrom the personal collection of Dr Michael Stowasser; used with permission [Citation ends].com.bmj.content.model.Caption@32456bb8[Figure caption and citation for the preceding image starts]: Computed tomography (CT) showing lesion in right adrenal gland in patient with bilateral adrenal hyperplasiaFrom the personal collection of Dr Michael Stowasser; used with permission [Citation ends].com.bmj.content.model.Caption@610544b1

  • Nuclear imaging using positron emission tomography-computed tomography (PET-CT) with labelled metomidate as a ligand of CYP11B1 and CYP11B2 has been proposed to be a viable alternative to AVS, or as an adjunct to AVS in difficult cases.[104][105] In this protocol dexamethasone pre-treatment is used to suppress adrenocorticotropic hormone and CYP11B1 expression. The short half-life and lack of specificity for CYP11B2 of the currently used isotope limits the widespread application and reliability of this technique, however, work is ongoing to find alternatives.

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