Diagnostic Considerations
Delayed diagnosis of hypertension can lead to prolonged exposure to hypertension and secondary damage, as well as permanent remodeling of the blood vessels, thereby raising potential medicolegal problems. Differentiation of primary hyperaldosteronism from more common secondary causes is another area where medicolegal problems may arise, whether from failure to discontinue medications, failure to appreciate factors that may confound testing results or failure to control blood pressure when the relevant medications are stopped.
An important condition to be considered in the differential diagnosis of primary hyperaldosteronism is congenital adrenal hyperplasia. Other problems to be considered include the following:
-
Secondary hyperaldosteronism
-
Chronic stress-induced hyperaldosteronism [19]
-
Apparent mineralocorticoid excess (types I and II)
-
Liddle syndrome
-
Gain of function mutation of mineralocorticoid receptor
-
Primary glucocorticoid resistance (Chrousos syndrome)
-
Exogenous mineralocorticoid excess
-
Drug-induced apparent mineralocorticoid excess
Congenital adrenal hyperplasia
11β-Hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (accounting for about 5% of all cases), with a frequency of 1 in 100,000 live births. Because the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to aldosterone are both reduced, hypersecretion of adrenocorticotropic hormone (ACTH) leads to excessive production of adrenal androgens as well as steroid hormone precursors. 11-Deoxycorticosterone has mineralocorticoid activity and can produce hypertension and sometimes hypokalemia.
The extent of virilization varies widely, ranging from newborn female infants with ambiguous genitalia to early male virilization to hirsutism and infertility in adult women.
The diagnosis should be considered in patients with features of hyperandrogenism and hypertension of the mineralocorticoid-excess type. The age at presentation correlates with the severity of the defect.
Treatment in younger children is with hydrocortisone or cortisone acetate. Those who have finished growing may be treated with dexamethasone. This treatment must be administered carefully; it may precipitate a salt-losing state, because this synthetic steroid has no mineralocorticoid activity and suppresses levels of 11-deoxycorticosterone by inhibiting ACTH release. Patients with 11β-hydroxylase deficiencies who are treated with glucocorticoids may require mineralocorticoid therapy during acute intercurrent illness.
Various mutations of the P-450c11 gene have been described. The diagnosis can be made on the basis of elevated levels of 11-deoxycorticosterone after ACTH stimulation, though basal levels are often diagnostic in affected neonates and infants. Treatment involves glucocorticoid replacement at physiologic doses.
Lyase and 17α-hydroxylase deficiencies are very rare. P-450c17 mutations produce a block in production of a single enzyme with both 17α-hydroxylase and 17,20-lyase activities.
Blockade of sex steroid production can lead to failure of female pubertal development and variable degrees of incomplete virilization with ambiguous genitalia in males. Deficient cortisol production results in ACTH hypersecretion with increased production of aldosterone precursors, including 11-deoxycorticosterone. Plasma renin activity and aldosterone are low.
Treatment involves glucocorticoid treatment similar to that employed for 11β-hydroxylase deficiencies. Males respond to testosterone in the neonatal period with phallic growth that may improve the outcome of corrective surgery. Both sexes also need pubertal induction.
Secondary hyperaldosteronism
Secondary hyperaldosteronism may be due to a physiologic attempt of the organism to maintain an adequate blood volume. The patient may be normotensive and edematous or may be hypertensive with no edema. Secondary hyperaldosteronism may be secondary to renal ischemia. Secondary hyperaldosteronism can be distinguished clinically and biochemically from primary hyperaldosteronism.
Syndrome of apparent mineralocorticoid excess
The syndrome of apparent mineralocorticoid excess is a rare cause of juvenile hypertension that was first described in 1979; since then, an additional 25-30 cases have been reported. Patients present with severe hypokalemia and metabolic alkalosis and suppressed plasma renin activity (PRA) and aldosterone levels. Two types of apparent mineralocorticoid excess have been described.
Type I apparent mineralocorticoid excess is characterized by impaired 11β-hydroxysteroid dehydrogenase (11β-HSD) activity with impaired conversion of cortisol to cortisone and impaired 5β-reductase activity. These patients have markedly elevated urinary ratios of cortisol, tetrahydrocortisol (THF), and allo-THF to cortisone, tetrahydrocortisone (THE), and allo-THE. Many of these patients have molecular defects of 11β-HSD type 2 (11β-HSD2).
Type II apparent mineralocorticoid excess is characterized by a decreased rate of cortisol clearance and turnover but a normal urinary THF-to-THE ratio.
Treatment of apparent mineralocorticoid excess is often difficult. A low-sodium diet in conjunction with spironolactone 1-4 mg/kg/day is often effective but may not yield long-lasting results. Patients with type II apparent mineralocorticoid excess respond to suppression of cortisol production with dexamethasone, a steroid with little mineralocorticoid activity. The problem is that dexamethasone has its significant growth-suppressing properties and therefore is not suitable for growing children.
Liddle syndrome
Liddle syndrome is an autosomal dominant disorder that can partially mimic hyperaldosteronism. Patients present at a young age with hypertension and hypokalemia. Both PRA and aldosterone levels are suppressed. It is caused by mutations of the carboxy terminus of the beta-subunits or gamma-subunits of the renal epithelial sodium channel (ENaC), which result in a constitutively open channel. Treatment with the potassium-sparing diuretic triamterene or amiloride is often effective.
Gain of function mutation of mineralocorticoid receptor (MR)
An even less common autosomal-dominant cause of mineralocorticoid hypertension is associated with an activating mutation, resulting in the substitution of leucine for serine at codon 810 (S810L) in the human mineralocorticoid receptor. In this case, MRAs, such as progesterone, develop agonist properties, whereas cortisone, rather than being inactive at the mineralocorticoid receptor, is actually an agonist. This gain of function mutation of the mineralocorticoid receptor results in early-onset hypertension in men and gestational hypertension in women. Both spironolactone and eplerenone are not only unable to block the constitutive activity of the mutant MRS810L, but paradoxically activate this mutant receptor, exacerbating hypertension. The patients, on the other hand, respond to amiloride acting downstream at the epithelial sodium channel. [21]
Primary glucocorticoid resistance (Chrousos syndrome)
Primary familial or sporadic glucocorticoid resistance, or Chrousos syndrome, is a rare disorder that has been identified in several patients or members of kindreds. When familial, it is transmitted in both an autosomal recessive and an autosomal dominant fashion. Point mutations and microdeletions of the glucocorticoid receptor have been described.
Affected patients have an absence of cushingoid features, increased cortisol and ACTH levels (compensating for reduced glucocorticoid receptor function), and resistance to dexamethasone suppression of cortisol levels. The clinical manifestations are highly variable, though increased production of adrenal steroidogenic precursors, including deoxycorticosterone and adrenal androgens (eg, δ-4-androstenedione and dehydroepiandrostenedione), can produce hypertension in both sexes and hyperandrogenism in children and women.
Treatment consists of high-dose synthetic glucocorticoids with minimal mineralocorticoid activity (eg, dexamethasone 1-3 mg/day) to suppress plasma levels of ACTH and, ultimately, the secretion of adrenal steroids with androgenic and mineralocorticoid activity.
Drug-induced apparent mineralocorticoid excess
Some drugs can cause a clinical and biochemical picture consistent with hyperaldosteronism. Biochemically, the features of the disorder include suppression of both aldosterone and renin.
One drug that can cause this disorder is carbenoxolone, a synthetic derivative of glycyrrhizinic acid that is used to treat peptic and oral ulcers and gastroesophageal reflux. Carbenoxolone causes fluid and sodium retention and may cause hypokalemia, headaches, and myopathy. Excessive ingestion of licorice also produces a picture similar to apparent mineralocorticoid excess; the glycyrrhetinic acid in licorice blocks the enzyme 11β-HSD2 at the distal tubule, thereby giving circulating glucocorticoid access to the mineralocorticoid receptor.
Differential Diagnoses
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Steroid biosynthetic pathway.
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Physiologic regulation of the renin-angiotensin-aldosterone axis.
Tables
False Negative Results |
|||
Factor |
Aldosterone |
Renin |
ARR |
Medications |
|
|
|
K-sparing diuretics |
↑ |
↑↑ |
↓ |
K-wasting diuretics (Non-K-sparing diuretics, such as thiazides, induce renal potassium losses and reduce plasma potassium concentrations, leading to decreased aldosterone secretion.) |
→↑ |
↑↑ |
↓ |
ACE inhibitors |
↓ |
↑↑ |
↓ |
Angiotensin receptor blockers |
↓ |
↑↑ |
↓ |
DHPs (It is a shared opinion that dihydropyridinic calcium channel blockers do not significantly affect aldosterone secretion, mainly causing an increase in PRA, which rarely gives false negatives.) |
→↓ |
↑ |
↓ |
Other conditions |
|||
Hypokalemia |
↓ |
→↑ |
↓ |
Sodium-restricted diet |
↑ |
↑↑ |
↓ |
Pregnancy |
↑ |
↑↑ |
↓ |
Renovascular hypertension |
↑ |
↑↑ |
↓ |
Malignant hypertension |
↑ |
↑↑ |
↓ |
False Positive Results |
|||
Beta-adrenergic blockers |
↓ |
↓↓ |
↑ |
Central alpha-2 agonists (eg, clonidine, alpha-methyldopa) |
↓ |
↓↓ |
↑ |
NSAIDS |
↑ |
↓↓ |
↑ |
Other conditions |
|||
Potassium loading |
↑ |
→↓ |
↑ |
Sodium-loaded diet |
↓ |
↓↓ |
↑ |
Advancing age |
↓ |
↓↓ |
↑ |
Renal dysfunction |
→↑ |
↓ |
↑ |
PHA-2 |
→ |
↓ |
↑ |
Luteal phase of menstrual cycle |
↑ |
PRA: Unchanged |
↑ |
Antihypertensive Medications With Minimal Effect on the ARR |
|||
Prazosin, doxazosin, terazosin |
|
←→ |
|
Verapamil, hydralazine |
|
←→ |
|
Other medications |
|||
Renin inhibitors (Renin inhibitors raise the ARR if renin is measured as PRA [false positive] and lower it if measured as DAR concentration [false negative.]) |
↓ |
↑↓ |
↑↓ |
SSRIs |
↑ |
↑ |
↓ |
OCPs (OCPs have little effect on ARR when renin is measured as PRA. Use of immunometric measurements of DAR rather than PRA may give false positive results. Subdermal etonogestrel has no effect on ARR.) |
↑ |
↓DAR |
↑ |
Liddle syndrome |
↓ |
↓ |
Normal |
ARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1 receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2; PRA, plasma renin activity; DAR, direct active renin; OCPs, oral contraceptive agents; SSRIs, selective serotonin reuptake inhibitors |
|||
Drug |
Class |
Pediatric Dose |
Spironolactone |
Aldosterone antagonist |
0-10 kg: 6.25 mg/dose PO q12h 11-20 kg: 12.5 mg/dose PO q12h 21-40 kg: 25 mg/dose PO q12h >40 kg: 25 mg PO q8h |
Potassium canrenoate |
Aldosterone antagonist |
3-8 mg/kg IV qd; not to exceed 400 mg |
Amiloride |
Potassium-sparing diuretic |
0.2 mg/kg q12h |
Triamterene |
Potassium-sparing diuretic |
2 mg/kg/dose q8-24h |
Nifedipine |
Dihydropyridine calcium channel antagonist |
0.25-0.5 mg/kg PO q6-8h |
Amlodipine |
Calcium channel antagonist |
0.05-0.2 mg/ day PO |
Doxazosin |
Alpha1 -specific adrenergic antagonist |
0.02-0.1 mg/day; not to exceed 4 mg |
Prazosin |
Alpha1 -specific adrenergic antagonist |
0.005 mg/kg test dose, then 0.025-0.1 mg/kg/dose q6h; not to exceed 0.5 mg/dose |
