Investigation of disorders of aldosterone production. Both initial diagnosis and differentiation between the conditions listed below require concomitant plasma renin activity (PRA) measurements.
These disorders are:
1 Primary hyperaldosteronism. Conn’s syndrome and related conditions.
2 Secondary hyperaldosteronism. The only form of secondary hyperaldosteronism in which the assay of aldosterone is of value is Bartter’s syndrome. [Aldosterone assays are not helpful in patients with secondary hyperaldosteronism associated with nephrotic syndrome, cirrhosis etc. or with renal hypertension, although the measurement of PRA may assist management. (See Renin Activity )].
3 Primary hypoaldosteronism. Isolated deficiency of aldosterone synthesis.
4 Secondary hypoaldosteronism. Hyporeninaemic hypoaldosteronism.
5 Pseudohypoaldosteronism. Aldosterone insensitivity syndrome.
1 Primary hyperaldosteronism.
These conditions, where patients present with hypertension and sustained hypokalaemia, may be subdivided into:
- that due to a unilateral adenoma of the zona glomerulosa: Conn’s syndrome.
- that due to bilateral nodular hyperplasia of the adrenal zona glomerulosa: idiopathic hyperaldosteronism
- Glucocorticoid-suppressible hyperaldosteronism.
2 Bartter’s syndrome.
This results from a resistance of the vasculature to the pressor action of angiotensin II. This resistance is associated with a compensatory increase in PRA and with juxtaglomerular cell hyperplasia. The consequent increase in aldosterone levels exacerbates potassium loss and patients present with sustained hypokalaemia but without hypertension.
3 Primary hypoaldosteronism.
Isolated primary hypoaldosteronism results from specific interference with aldosterone production, either through enzyme deficiency or atrophy/ destruction of the zona glomerulosa. (Aldosterone assays are not appropriate for the initial investigation of steroid 21-hydroxylase deficiency or Addison’s disease).
4 Secondary hypoaldosteronism.
Hyporeninaemic hypoaldosteronism results from kidney damage and may be associated with diabetes mellitus or interstitial nephritis.
This condition results from end-organ insensitivity to aldosterone and may be suspected in salt-losing infants who fail to thrive but in whom 21-hydroxylase deficiency has been excluded.
All drugs should be discontinued for 2 weeks before samples are collected. If a patient is on treatment with aldosterone antagonists (e.g. spironolactone) or oestrogens, the therapy must be discontinued for at least 6 weeks before the aldosterone-renin system is assessed. If the patient’s hypertension is such that all drug therapy cannot be withdrawn safely, the b-blocker, prazosin, has little effect on the aldosterone-renin system. b-blockers and diuretics have predictable effects but calcium channel blockers and ACE inhibitors must be avoided. Interpretation is particularly difficult when the patient is on a mixed-drug regime. The patient must be receiving an adequate intake of sodium (100-150 mmol/day) and potassium (50-100 mmol/day).
1,2 Primary and secondary hyperaldosteronism.
Administer potassium salt to restore plasma potassium concentration to within the reference range or, if this is not attainable, to the maximum concentration possible. Discontinue this supplementation 24h before blood samples are taken.
- *Screening procedure – In some instances a diagnosis may be possible from investigation at an out-patient clinic without the need for overnight hospital admission. However, the results of this screening procedure may be equivocal and the patient will then require further investigation as an in-patient.Patient completes a 24h urine collection early on the morning of attendance and brings this to the hospital for the measurement of electrolytes and aldosterone. After the patient has rested quietly for at least 10 min, take blood for measurement of aldosterone (5 mL) and PRA (5 mL, see Renin Activity) and electrolytes.*In-patient procedure – (N.B. A 24h urine specimen for the measurement of aldosterone and electrolytes is required but may be collected as an out-patient). Patients must observe strict overnight recumbency. After waking, the patient must remain lying down and must not alter posture in any way until after the initial blood sample has been taken.
Collect blood samples as follows:
- *08.00h: after overnight recumbency and before breakfast take blood for measurement of aldosterone (5 mL) and PRA (5 mL, see Renin Activity).*08.30h: after the patient has been out of bed for 30 min and before breakfast take blood (5 mL) for PRA measurement.*12.00h: after the patient has been out of bed since the 08.00h sample and before lunch take blood (5 mL) for plasma aldosterone and cortisol measurement.
3,4 Primary and secondary hypoaldosteronism.
A short Synacthen test is helpful in making a diagnosis of hypoaldosteronism. The patient must be supine for 60 min before and throughout the test. Take the baseline blood for the measurement of aldosterone and cortisol (5 mL) and PRA (5 mL, see Renin Activity page 91). Give Synacthen (250 microgram i.m.) and take a further sample (5 mL) 30 min later for the measurement of aldosterone and cortisol.
A single sample of blood (1 mL) for the measurement of aldosterone and PRA, (5 mL, see Renin Activity) drawn under random conditions but before initiating any treatment, is adequate for the diagnosis of this condition.
Urine: Collect a 24h specimen and measure the total volume. Send a small portion to the local laboratory for urinary electrolyte determination. Add 1% w/v boric acid solution (10 mL) to the remainder of the collection. Mix well and send 25 mL to the SAS laboratory. Record on the SAS request form the total urine volume collected and the urinary electrolyte results.
Samples for the assay of aldosterone only may be made on plasma or serum
[If renin activity measurement is required, the sample must be plasma which has been separated rapidly. The plasma must be stored and transported frozen (see Renin Activity).]
Send one portion to the local laboratory for measurement of plasma electrolytes. Send another portion (1 mL) to the SAS laboratory. Store remaining sample frozen until results of assay are available.
Samples requiring the assay of aldosterone and PRA should be sent in two portions where possible to facilitate rapid turnround time.
Record on the SAS request form the plasma and the urine electrolyte values, blood pressure and drug history if medication has not been discontinued.
Please contact the appropriate SAS laboratory.
Adults (age 20 to 40 years)
(Sodium intake 100 – 150 mmol/day, potassium intake 50 – 100 mmol/day):
Urine: 10 – 50 nmol/24h.
The upper limit of the reference range for urinary aldosterone excretion established for young adults is decreased by about 50% for subjects more than 60 years of age.
08.00h after overnight recumbency: 100 – 450 pmol/L.
In adults, baseline plasma/serum aldosterone concentrations and the increment in response to changing from a supine to an upright position decline with advancing age. According to some authorities, the mean values for both these indices, after 60 years of age, are about half those of young adults.
Reference ranges for plasma/serum aldosterone are poorly defined in infants, but in the first few weeks of life values of up to 5000 pmol/L have been reported. These high concentrations decline rapidly in the first year and then more slowly attaining, by 6 years, values similar to those of adults.
These reference ranges should be considered with those quoted for PRA – see Renin Activity).
Interpretation of Results
Electrolyte levels in plasma and urine and PRA values must be taken into account in the interpretation of aldosterone results (see Renin Activity).
A level of urinary aldosterone above the reference range is indicative of hyperaldosteronism but a normal value does not exclude it.
1 Primary hyperaldosteronism.
Diagnosis of primary hyperaldosteronism rests on the finding of suppressed PRA with inappropriately elevated aldosterone levels in a patient who is hypertensive and hypokalaemic and in whom urine potassium levels show kaliuria inappropriate for the corresponding plasma potassium levels.
Screening procedure – If the ratio of aldosterone (in pmol/L) to PRA (in pmol/mL/h) is 2000 or more, the patient almost certainly has primary hyperaldosteronism.
In-patient procedure – Primary hyperaldosteronism is indicated by an elevated aldosterone value at 08.00h together with a suppressed PRA which shows little or no increase after 30 min of mobility. To aid the distinction between hyperaldosteronism due to adrenal adenoma and that due to bilateral adrenal hyperplasia, it is helpful to consider the plasma aldosterone concentrations at 08.00h and 12.00h. If cortisol values at 08.00h and 12.00h show a decrease due to normal diurnal rhythm, an elevated aldosterone level at 08.00h decreasing by 50% or more at 12.00h is suggestive of, but not exclusive to, an adenoma.
If primary hyperaldosteronism is indicated, ultrasound or CAT scanning should be advised to try to locate an adenoma. If biochemical or imaging procedures are equivocal, there are further investigations that have been used for this purpose including adrenal vein catheterisation, scintigraphy, salt-loading and other dynamic tests, but the patient should be referred to an endocrinologist with experience in these procedures.
N.B. When adrenal vein catheterisation is undertaken, it is preferable to give Synacthen (250 mg i.m.) 30 min before the procedure. This ensures that both adrenal glands are actively secreting cortisol which can be used to assess retrospectively whether the catheters were placed correctly. Samples should be taken from the low I.V.C., the high I.V.C., the left and right adrenal veins and a peripheral vein. The measurement of cortisol will be carried out by the SAS laboratory to facilitate interpretation of the results obtained. There will be no charge for this additional assay.
2 Bartter’s syndrome.
Both the plasma concentration of aldosterone and the PRA at 08.00h after overnight recumbency are raised. In such patients who are normotensive, Bartter’s syndrome should be suspected provided diuretic/laxative abuse and psychogenic vomiting have been excluded.
3 Primary hypoaldosteronism.
Failure of aldosterone concentrations to increase by at least 150 pmol/L from baseline 30 min after administration of Synacthen (250 microgram i.m.) is indicative of inadequate zona glomerulosa function. A diagnosis of isolated primary hypoaldosteronism rests upon raised PRA, low plasma aldosterone concentration, inadequate response of aldosterone to ACTH associated with a normal cortisol response.
4 Secondary hypoaldosteronism.
In this condition, both plasma aldosterone concentration and PRA are subnormal.
This disorder, usually found in children, is associated with a high plasma aldosterone concentration and high PRA in the face of salt loss. The patient responds to high sodium intake and the condition eventually resolves.
Centres offering this assay
Leeds General Infirmary Steroid Centre
London Imperial Charing Cross Renin and Aldosterone Service
London UCL Hospital Adrenal Steroid Genetics Service.