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REF: UpToDate 2006 |
- is a syndrome of hypertension and
hypokalemia secondary to elevated plasma aldosterone
that occurs in 0.05 -2 % of hypertensive
of Primary Hyperaldosteronism:
Hypokalemia & hypertension
Increased bicarbonate (alkalosis), hypochloremia.
- Be aware that in hypokalemia, >30 mmol/d of urinary potassium
(off diuretics and potassium supplement x 4 days) is indicative of
potassium wastage, usually driven by mineralocorticoid excess.
- Ensure that urine sodium is >100 mmol/d, because potassium wastage
is ameliorated by intense dietary sodium restriction and a urine creatinine
of >800 mg/d to ensure a complete collection.
Decreased 8 A.M. plasma renin (< 1-2 ng/ml/hr) after 1-2 hours
of upright posture.
Elevated 8 A.M. plasma aldosterone concentration (> 14-15
Elevated 24 hours urine aldosterone level > 14
mcg after 3 days of high salt diet aldosterone suppression
Orally administered high sodium chloride diet (to achieve a
5000 mg sodium diet) x 3 days and measurement of urine aldosterone
excretion and measurement of PAC.
- In circumstances of high sodium dietary intolerance, patients can
be given oral sodium chloride tablets (eg, two 1 g sodium chloride tablets
taken three times daily with food will provide approximately 90 meq of sodium).
The risk of increasing dietary sodium in patients with
severe hypertension must be assessed in each
case. In addition, since sodium loading typically increases kaliuresis
and hypokalemia, serum potassium should be measured
daily and vigorous replacement of potassium chloride should be prescribed
- On the third day of the high sodium diet, serum electrolytes are
measured and a 24-hour urine specimen is collected for measurement of
aldosterone, sodium, and creatinine. The 24-hour urine sodium excretion should
exceed 200 meq to document adequate sodium loading. Urine aldosterone excretion
>14 µg/24 hours (39 nmol/day) in this setting is consistent with
IV administration of two liters of isotonic saline over four hours
(while the patient is recumbent). The PAC will fall below 6 ng/dL (166 pmol/L)
in normal subjects, whereas values above 10 ng/dL (277 pmol/L) are consistent
with primary hyperaldosteronism.
A single plasma aldosterone concentration/plasma
renin activity (PAC/PRA) ratio > 20-25 as screening
Abnormal adrenal CT or MRI scan to localize the adrenal
- If unilateral adenoma >1.0 cm is located, surgery can be recommended.
Bilateral adrenal vein sampling for both aldosterone and cortisol.
- To establish the need for surgery, recommend adrenal venous sampling in
patients with ambiguous adrenal CT or MRI scans to establish the source of
- Consider an increase in aldosterone-to-cortisol ratio (on the affected
side compared to the presumed normal side) of at least two-fold to define
A. Primary Aldosteronism
Unilateral benign adrenal adenoma
(in about 70 percent of such patients)
Bilateral adrenal hyperplasia of the
zoma glomerulosa idiopathic (in 20 to 30 percent)
Idiopathic hyperplasia; and
The rare glucocorticoid-remediable aldosteronism, which responds to
the administration of exogenous glucocorticoid.
Dexamethasone-suppressible hyperaldosteronism is a rare familial cause
of hyperaldosteronism and is transmitted as an autosomal dominant trait.
The aldosterone secretion becomes entrained to ACTH secretion and
is blind to renin-angiotensin levels. Because ACTH secretion
is not modulated by aldosterone, aldosterone secretion becomes independent
of salt balance, blood potassium levels, and vascular volume. Treatment
for this disorder starts with the use of a potassium-sparing diuretic such
as amiloride or triamterene. This regimen has the advantage of not suppressing
the HPA axis. If it is unsuccessful, ACTH secretion can be suppressed with
dexamethasone, usually 0.5 mg in a single daily dose.
Adrenocortical carcinoma, rarely.
B. Secondary aldosteronism
- should be considered when both the PRA and PAC
(plasma renin activity and aldosterone) are increased
and the PAC/PRA ratio is <10 (as in renovascular disease); it
may or may not be associated with hypertension. Patients with hypertension
usually have underlying renal pathology, including renal artery stenosis,
renin-secreting tumors, and chronic renal failure.Treatment should be directed
at the underlying cause.
a. Unilateral renal hypertension
b. Malignant hypertension
c. Oral contraceptive related hypertension; Glucocorticoid-remediable
d. Renin secreting renal tumor (primary reninism)
e. Licorice ingestion induced hypertension and hypokalemia .
- An alternate source of mineralocorticoid receptor stimulation
(eg, hypercortisolism, licorice ingestion)
should be considered when both the PRA and PAC are
a. Nephrotic syndrome
c. Congestive heart failure
d. Bartter's synd juxtaglomerular cell hyperplasia
e. Decreased effective plasma volume (diuretics, blood loss, salt depletion)
Differential Diagnosis of Hypertension with
Renovascular disease (in which hypersecretion of renin leads sequentially
to increased angiotensin II and then aldosterone secretion)
Diuretic therapy, which may be surreptitious.
Less common causes include Cushing's syndrome, licorice ingestion, certain
forms of congenital adrenal hyperplasia, and rare renin-secreting tumors.
Causes of Increased Plasma Aldosterone and PRA (renin) levels:
Renal tubular acidosis
Familial chloride diarrhea
Liver failure with ascites
Findings in Primary Hyperaldosteronism
Plasma aldosterone (PAC) to renin ratio (PAC/PRA)
>20-25 ,more than 30-50 in most patients with primary
- is performed by measuring a morning (preferably 8 AM), ambulatory, paired,
random PAC and PRA. Most antihypertensive medications (except
aldosterone receptor antagonists, ACE inhibitors or ARB) can be
continued and posture stimulation is not required.
It is impossible to interpret data obtained from patients treated
with aldosterone receptor antagonists. Thus, spironolactone and eplerenone
should not be initiated until the evaluation is completed and the final decisions
about treatment are made. If primary aldosteronism is suspected in a patient
already receiving spironolactone, therapy should be discontinued for at least
Other potassium-sparing diuretics, such as amiloride and triamterene,
usually do not interfere with testing unless the patient is on high
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) may "falsely elevate" the PRA in patients with primary
aldosteronism. Thus, in a patient treated with an ACE inhibitor or ARB, a
detectable PRA level or a low PAC/PRA ratio does not exclude the diagnosis
of primary aldosteronism. On the other hand, a strong predictor for primary
aldosteronism is an undetectable PRA in a patient taking an ACE inhibitor
24-hour urine collection of potassium and
Increased Aldosterone excretion can also be
measured, with high values (>14 µg/day [39 nmol/day]) on a high sodium
diet (urine sodium excretion >200 meq/day) being consistent with primary
aldosteronism if the PRA is low.
Increased urinary potassium excretion
(defined as more than 30 meq/day in a patient with hypokalemi).
At present, we do not order a 24 hour urine collection unless the PRA is
not suppressed, the PAC is not elevated, or there is a clinical suspicion
of surreptitious vomiting or laxative abuse.
The patient must not have a low-sodium intake or hypovolemia (as evidenced
by less than 50 meq of sodium being excreted per day), since the associated
decrease in sodium and water delivery to the distal potassium secretory site
can diminish potassium excretion even in patients with hyperaldosteronism.
On the other hand, the degree of potassium wasting and therefore the diagnostic
accuracy can be increased by a high-sodium diet, because the combination
of increased distal flow and hypersecretion of aldosterone will maximize
A high-sodium diet can also be given as a provocative test in patients
with an initial serum potassium concentration in the normal or low-normal
range. Sodium-induced hypokalemia is strongly suggestive of nonsuppressible
hyperaldosteronism. Normal subjects do not waste potassium during sodium
loading, because the increase in distal flow is offset by reduced secretion
Nonaldosterone mineralocorticoid excess The combination of
a suppressed PRA and a low plasma or urinary aldosterone value indicates
the presence of some nonaldosterone mineralocorticoid. This can occur in
Some types of congenital adrenal hyperplasia or familial cortisol resistance,
which has a similar presentation.
Chronic licorice ingestion, the rare genetic syndrome of apparent
mineralocorticoid excess, and severe cases of Cushing's syndrome, in which
cortisol acts as the primary mineralocorticoid. In the last setting, there
may also be hypersecretion of other mineralocorticoids such as
deoxycorticosterone and corticosterone.
A deoxycorticosterone-producing tumor, which can usually be detected by CT
or magnetic resonance imaging (MRI).
Liddle's syndrome, a rare autosomal dominant condition in which there is
a primary increase in sodium reabsorption in the collecting tubules and,
in most cases, potassium secretion. This disorder is due to a genetic abnormality
that increases the collecting tubule sodium channel, which is the effect
produced by mineralocorticoids.
The treatment for unilateral adenomas is adrenalectomy. Idiopathic aldosteronism,
bilateral hyperplasia, and bilateral adenomas are generally treated medically.
The aldosterone antagonist spironolactone is generally used for women,
whereas amiloride is used for men because spironolactone causes
gynecomastia in some patients.
GOALS OF THERAPY for primary
Normalization of blood pressure and hypokalemia,
Normalization of plasma aldosterone concentrations or blockade of aldosterone
activity with a mineralocorticoid receptor antagonist
Treatment of UNILATERAL ADRENAL ADENOMA
A unilateral adrenal adenoma is responsible for the hypersecretion of aldosterone
in 30 to 60 percent of cases.
Surgery (Unilateral adrenalectomy or adrenal
enucleation) is the preferred therapy in this setting; alternatives
include medical therapy with a potassium-sparing diuretic and, rarely, ablative
Laparoscopic adrenalectomy is the surgical
procedure of choice.
1. Surgery Rx for unilateral adrenal
Unilateral adrenalectomy or adrenal enucleation induces
a marked reduction in aldosterone secretion, a fall in blood pressure, and
correction of the hypokalemia in almost all patients. However, a lesser degree
of hypertension persists in as many as 40 to 65 percent of cases. Resolution
of hypertension after adrenalectomy is independently associated with a lack
of family history of hypertension and preoperative use of two or fewer
2. Medical therapy
for unilateral adrenal adenoma
A mineralocorticoid receptor antagonist
is an effective alternative in patients who refuse or are not
candidates for surgery.
Spironolactone 12.5 to 50 mg twice daily with food (The maximum
of 200 mg twice daily.)
- often not well tolerated, since it also blocks the androgen and
progesterone receptors. These effects can result in impotence, decreased
libido, gynecomastia (the incidence of gynecomastia was dose-dependent: 6.9
percent at doses below 50 mg/day and 52 percent at doses above 150 mg/day)
, menstrual irregularities, and minor gastrointestinal tract
Eplerenone 25 mg twice daily (The maximum dose approved for
hypertension is 100 mg daily.)
- Eplerenone has equal to 25 to 50 percent less mg per mg potency
- a highly selective mineralocorticoid receptor antagonist that is
associated with a low incidence of endocrine side effects.
- It has been approved for the treatment of uncomplicated essential hypertension
[21,22] and for heart failure after myocardial infarction.
If the hypertension persists, we titrate back to the dose that normalized
the plasma potassium and add another antihypertensive drug (eg, 12.5 to 25
mg of hydrochlorothiazide daily).
Dietary sodium restriction (<100
meq/day), maintenance of ideal body weight, avoidance of alcohol,
and regular aerobic exercise contribute significantly to the success of
Potassium-sparing diuretics that block
the aldosterone-sensitive sodium channel in the collecting tubules
(amiloride, triamterene) can block the renal
effects of aldosterone, lowering the blood pressure and raising the plasma
potassium concentration. However, these drugs are not recommended for
first-line therapy because of persistence of hyperaldosteronism with
its possible deleterious effect on the heart.
Amiloride is the drug of choice for men and women intolerant
of spironolactone and eplerenone.
- Amiloride dosing may be started at 5 mg twice daily and increased
up to 15 mg twice daily if needed to correct the hypokalemia.
- Amiloride is not an effective antihypertensive agent and, if hypertension
persists, a second-step drug should be added. Low doses of a thiazide diuretic
(eg, 12.5 to 25 mg of hydrochlorothiazide daily) are preferred because
hypervolemia is a major reason for resistance to amiloride.
3. Ablative procedures Although
published data are limited, some centers have advocated
percutaneous ablative therapy, including
percutaneous acetic acid injection and radiofrequency ablation, for unilateral
Percutaneous ablative therapy requires overnight hospitalization.
It is also associated with a variety of adverse effects, including abdominal
pain, hematuria, pancreatitis, pneumothorax, bleeding, adrenal abscess formation,
tumor tracking, and incomplete ablation. In the era of laparoscopic adrenalectomy
and selective aldosterone receptor antagonists, it is difficult to justify
the uncertainties of adrenal percutaneous ablative therapy.
There are two forms of primary aldosteronism due to adrenal hyperplasia:
idiopathic hyperplasia; and
the rare glucocorticoid-remediable aldosteronism, which responds to the
administration of exogenous glucocorticoid.
has generally been disappointing in idiopathic hyperplasia,
as only a minority of patients have a clinically significant hypotensive
response. This observation has led to the hypothesis that idiopathic adrenal
hyperplasia may be a variant of essential hypertension in which enhanced
sensitivity of the zona glomerulosa to angiotensin II is responsible for
the aldosteronism and hypokalemia, which are typically milder than in patients
with an adrenal adenoma.
Thus, optimal treatment of idiopathic adrenal hyperplasia consists of
mineralocorticoid receptor blockade with spironolactone or eplerenone as
described above for medical therapy of a unilateral adrenal adenoma.
The goals of therapy are normalization of the plasma potassium in hypokalemic
patients, normalization of the blood pressure, reversal of the effects of
hyperaldosteronism on the heart, which cannot be determined clinically.
After initial higher doses, low doses (such as 12.5 to 25 mg twice daily
of spironolactone) are often effective in maintaining control of hypertension
and potassium levels . A thiazide diuretic or an angiotensin converting
enzyme (ACE) inhibitor can be added if the hypertension persists. The efficacy
of an ACE inhibitor in the low plasma renin state may in part reflect the
role of even low concentrations of angiotensin II as an aldosterone secretagogue
in adrenal hyperplasia.