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Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)

Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)
Literature review current through: Sep 2023.
This topic last updated: May 10, 2022.

INTRODUCTION — The syndrome of apparent mineralocorticoid excess (AME), a genetic disorder, and chronic ingestion of licorice (the root of glycyrrhiza glabra), licorice-like compounds (such as carbenoxolone), or triazole antifungals (posaconazole and itraconazole) can result in findings similar to those in primary aldosteronism: hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity. However, plasma aldosterone levels are low in these disorders, rather than elevated, as in primary aldosteronism. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)

The pathogenesis of these disorders has been elucidated. Summarized briefly, renal mineralocorticoid receptors bind aldosterone and cortisol with similar affinity. Although the plasma concentration of cortisol is approximately 100-fold higher than aldosterone, activation of mineralocorticoid receptors by cortisol is normally limited due to its conversion to inactive cortisone at the sites of aldosterone action by the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) [1]. This conversion is impaired in AME because of a pathogenic variant in the 11-beta-HSD2 gene and by licorice ingestion or treatment with triazole antifungals because these agents inhibit the enzyme [2]. (See 'Pathogenesis' below.)

By somewhat different mechanisms, hypersecretion of cortisol can also induce an excess mineralocorticoid state in patients with ectopic ACTH syndrome [3]. (See 'Ectopic ACTH syndrome' below.)

Other hypermineralocorticoid states are presented separately. (See "Diagnosis of primary aldosteronism".)

SYNDROME OF APPARENT MINERALOCORTICOID EXCESS

Clinical manifestations — The syndrome of apparent mineralocorticoid excess (AME) is a rare form of severe juvenile hypertension that is usually transmitted as an autosomal recessive trait [4-6]. AME is characterized by low birth weight, failure to thrive, onset of severe hypertension in early childhood with extensive target organ damage, hypercalciuria and nephrocalcinosis from an unknown mechanism, and kidney failure [7]. These manifestations are accompanied by all of the findings of primary aldosteronism (hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity) except for the low plasma aldosterone concentration. Affected patients may also have polyuria due to nephrogenic diabetes insipidus that is presumably induced by the chronic hypokalemia [4,8]. (See "Pathophysiology and clinical features of primary aldosteronism" and "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Clinical manifestations and causes", section on 'Hypokalemia'.)

A late-onset syndrome has been reported in adults with compound heterozygous pathogenic variants who have a milder phenotype [9]. The heterozygous mothers of two probands had a phenotype indistinguishable from primary hypertension (formerly called "essential" hypertension). Another patient with a different pathogenic variant also had less severe disease with low-renin hypertension in the absence of hypokalemia [10].

Pathogenesis — The syndrome of AME is due to deficiency in the 11-beta-hydroxysteroid dehydrogenase enzyme type 2 isoform (11-beta-HSD2), which is the kidney isoform of 11-beta-HSD [11].

11-beta-HSD2 normally converts cortisol to cortisone, a steroid that does not bind to the mineralocorticoid receptor [11]. This effect is physiologically important, because cortisol binds as avidly as aldosterone to the mineralocorticoid receptor, and the plasma cortisol concentration is approximately 100-fold higher than the plasma aldosterone concentration.

Thus, cortisol would be the primary mineralocorticoid if it were not converted by 11-beta-HSD2 to cortisone at the aldosterone-sensitive sites. The persistence of cortisol resulting from deficiency in 11-beta-HSD2 leads to an often marked elevation in net mineralocorticoid activity.

Genetics — The defect in the syndrome of AME is due to pathogenic variants in the 11-beta-HSD2 gene, located on chromosome 16, which encodes the kidney isoform of 11-beta-HSD [12]. A number of different pathogenic variants have been found, and a defect has been noted in all patients tested [6,7,9,13,14].

Some of these pathogenic variants result only in partial inhibition of the 11-beta-HSD2 gene. There is a rough correlation between the severity of the enzymatic defect induced by these pathogenic variants and the clinical findings, including the ratio of cortisol to cortisone metabolites and the clinical course [4,6,10].

Diagnosis — The predominant clinical features of the syndrome of AME are hypertension and, in infants, low birth weight, failure to thrive, and muscle weakness due to hypokalemia. Patients with full expression of the syndrome may also have hypercalciuria, nephrocalcinosis, and kidney function impairment.

The biochemical abnormalities suggesting the diagnosis include:

Hypokalemia

Metabolic alkalosis

Low plasma renin activity

Low plasma aldosterone levels

The urinary free cortisol to urinary free cortisone ratio as measured on a 24-hour urine collection is a sensitive diagnostic test [15,16]. If 11-beta-HSD is functioning normally, urinary free cortisone levels exceed urinary cortisol levels, and the ratio of cortisol to cortisone is approximately 0.3 to 0.5 [17].

In most patients with a defective enzyme, the urinary free cortisone levels are very low or undetectable, so the ratio of cortisol to cortisone is very high [7]. In classically affected patients with the syndrome of AME, the ratio was 5 in children and 18 in adults [15,17].

Genetic testing to confirm the diagnosis of the syndrome of AME is commercially available. A list of clinically approved molecular genetic diagnostic laboratories is available at www.ncbi.nlm.nih.gov/gtr/.

Differential diagnosis — The presenting symptoms and signs of AME are similar to those of primary aldosteronism, but the plasma aldosterone concentration is low. (See "Pathophysiology and clinical features of primary aldosteronism".)

Licorice ingestion, treatment with triazole antifungals (posaconazole and itraconazole), and ectopic ACTH syndrome, which are described below, can present with biochemical findings that are similar to those of the syndrome of AME. However, measurement of urinary free cortisol and cortisone levels permits differentiation of these disorders [17]:

With licorice ingestion, urinary free cortisone is only modestly decreased, and the ratio of cortisol to cortisone is therefore only modestly elevated (eg, >1; normal 0.3 to 0.5).

Treatment with the triazole antifungals posaconazole and itraconazole can mimic AME [18,19]. Both of these triazole antifungals potently inhibit CYP11B1 and 11-beta-HSD2 [18]. The development of clinical features in patients treated with posaconazole is dose dependent, occurring primarily in those with drug levels >3 mcg/mL. Substitution with fluconazole, isavuconazole, or voriconazole leads to resolution of symptoms and signs [18,19].

Ectopic ACTH production may result in a similarly elevated urinary free cortisol to cortisone ratio, but urinary cortisol and cortisone levels are markedly increased in contrast to the very low levels of urinary free cortisone excretion in the syndrome of AME. (See "Establishing the cause of Cushing syndrome".)

AME must also be distinguished from other rare causes of mineralocorticoid excess in which aldosterone levels are reduced, including Liddle's syndrome (due to a gain-of-function mutation in the collecting tubule sodium channel), deoxycorticosterone-secreting tumors, deficiency in the 5-reductase enzyme (leading to defective conversion and thus persistently high levels of cortisol), and two forms of congenital adrenal hyperplasia [20]. Urinary cortisol metabolites are normal in the first two disorders. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency' and "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies' and "Diagnosis of primary aldosteronism", section on 'Other causes of hypertension and hypokalemia'.)

Therapy — Therapy of the syndrome of AME has been directed at reducing endogenous cortisol production or blocking the mineralocorticoid receptor [21].

Dexamethasone has been given in doses of 1.5 to 2 mg/day to suppress ACTH and reduce endogenous cortisol production without appreciably activating the mineralocorticoid receptor. However, dexamethasone does not correct the hypokalemia and hypertension in all patients, and long-term therapy has adverse effects [1]. Thus, we use dexamethasone only if mineralocorticoid blockade is not effective or not tolerated.

We prefer therapy based upon blockade of mineralocorticoid effects, which can be achieved by decreasing sodium channel activity with amiloride or triamterene or by direct mineralocorticoid receptor blockade with spironolactone or eplerenone [21,22]. (See "Mechanism of action of diuretics".)

Direct comparison of these agents is unavailable, but it has been suggested that high doses of spironolactone (with a higher likelihood of side effects) are required to block the mineralocorticoid effects of cortisol [1]. It seems reasonable to initiate therapy with drugs with fewer side effects, particularly in men (eg, amiloride or eplerenone). The end point of therapy has not been clearly defined, but normalization of the plasma potassium concentration seems reasonable. A similar goal is recommended in patients with primary aldosteronism who are treated medically. (See "Treatment of primary aldosteronism".)

Potassium supplements may be required initially to treat hypokalemia but should not be needed after the attainment of mineralocorticoid antagonism. (See "Clinical manifestations and treatment of hypokalemia in adults".)

A thiazide is indicated if hypercalciuria or nephrocalcinosis is present [1,4]. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium'.)

Cure has been reported in two patients after transplantation of a kidney with normal 11-beta-HSD2 activity [23,24].

LICORICE INGESTION — Chronic ingestion of licorice or licorice-like compounds (such as carbenoxolone) induces a syndrome with findings similar to those with the syndrome of apparent mineralocorticoid excess (AME): hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity and low plasma aldosterone levels [25].

Relatively small amounts of confectionery licorice, as little as 50 g daily for two weeks, produce a rise in blood pressure in normal people [26]. Licorice contains a steroid, glycyrrhetinic acid, that inhibits (both competitively and by reducing gene expression) 11-beta-HSD2, the same enzyme that is deficient in AME [27]. As in AME, normal levels of cortisol can markedly increase net mineralocorticoid activity in patients chronically ingesting licorice [27]. (See 'Pathogenesis' above.)

The diagnosis is typically based upon the biochemical abnormalities and an elicited history of licorice ingestion [28]. The source of the ingested licorice may not be obvious; it is present, for example, in some forms of flavored chewing gum, chewing tobacco, and tea [29,30]. As noted above, urinary free cortisone and cortisol levels may help make the diagnosis, but such testing is not necessary if a history of licorice ingestion has been obtained. (See 'Differential diagnosis' above.)

Cessation of licorice ingestion (or other source of glycyrrhetinic acid) is usually the only treatment necessary. Potassium supplements or a potassium-sparing diuretic may be initially required to treat hypokalemia but should not be needed once the effect of licorice has worn off (typically less than one week).

TREATMENT WITH TRIAZOLE ANTIFUNGALS — Treatment with the triazole antifungals posaconazole and itraconazole mimics AME [18,19]. Both of these triazole antifungals potently inhibit CYP11B1 and 11-beta-HSD2 [18].

A systematic review of 18 studies documented 39 cases in which findings suggestive of AME developed following treatment with posaconazole or itraconazole [19]. The median duration of treatment before diagnosis was 11.5 weeks and was dose dependent, occurring primarily in those with drug levels >3 mcg/mL. Substitution with fluconazole, isavuconazole, or voriconazole led to resolution of symptoms and signs [18,19].

ECTOPIC ACTH SYNDROME — Cortisol can contribute to the excess mineralocorticoid effect in Cushing's syndrome due to ectopic ACTH release (most commonly arising from small cell carcinoma of the lung) [31]. This can occur by the following mechanisms:

Cortisol secretion may be so high that it exceeds the metabolic capacity of 11-beta-HSD2 [3].

Very high circulating levels of ACTH may inhibit 11-beta-HSD2 [32].

Hypersecretion of nonaldosterone mineralocorticoids such as deoxycorticosterone [33].

The diagnosis of the ectopic ACTH syndrome is suggested by hypokalemia, the demonstration of markedly increased 24-hour urinary free cortisol excretion, and elevated serum ACTH. A Cushingoid appearance may be present but these features can be minimal in patients with malignancies. (See "Establishing the cause of Cushing syndrome" and "Overview of the treatment of Cushing syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS — Congenital (syndrome of apparent mineralocorticoid excess [AME]) and acquired (chronic licorice ingestion or treatment with triazole antifungals) deficiencies of the 11-beta-hydroxysteroid dehydrogenase enzyme type 2 isoform (11-beta-HSD2) lead to failure of conversion of cortisol to cortisone at aldosterone binding sites, such as the kidney cortical collecting tubules. Cortisol binds avidly to the mineralocorticoid receptor in the kidneys, and without the normal conversion to cortisone, usual levels of cortisol production induce a mineralocorticoid excess state. (See 'Pathogenesis' above.)

Excess mineralocorticoid activity leads directly to sodium retention, hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity, and, in contrast to primary aldosteronism, low plasma aldosterone. In addition, the syndrome of AME, a rare autosomal recessive disorder, is characterized by low birth weight, failure to thrive, muscle weakness, and severe hypertension in early childhood, often with hypercalciuria, nephrocalcinosis, polyuria due to hypokalemia-induced nephrogenic diabetes insipidus, and kidney failure. (See 'Syndrome of apparent mineralocorticoid excess' above.)

Cortisol can also contribute to the mineralocorticoid excess in Cushing's syndrome due to ectopic ACTH release via a variety of mechanisms. (See 'Ectopic ACTH syndrome' above.)

Diagnosis — The diagnosis of these disorders is largely based upon the history, clinical features, and the associated biochemical abnormalities, including the low plasma renin activity and aldosterone level. If a history of chronic licorice ingestion or treatment with triazole antifungals is not elicited, we suggest obtaining a 24-hour urine collection to measure the urinary free cortisol and free cortisone, and determining the ratio (see 'Differential diagnosis' above). The diagnosis of ectopic ACTH is characterized by markedly increased 24-hour urinary free cortisol excretion and elevated serum ACTH.

Treatment — With licorice ingestion, therapy simply involves stopping the ingestion of licorice (or other source of glycyrrhetinic acid). With triazole antifungal treatment, substitution with fluconazole, isavuconazole, or voriconazole leads to resolution of symptoms and signs. The treatment of Cushing's syndrome is discussed separately. (See "Overview of the treatment of Cushing syndrome".)

The optimal therapy of the syndrome of AME is unknown. We suggest the following approach (see 'Therapy' above):

Potassium repletion, if required for hypokalemia. This can be discontinued once therapy with mineralocorticoid antagonism is instituted. (See "Clinical manifestations and treatment of hypokalemia in adults".)

We suggest antagonism of mineralocorticoid effects with amiloride or eplerenone (Grade 2B).

For patients who have hypercalciuria or nephrocalcinosis, we suggest therapy with a thiazide diuretic (Grade 2B).

We suggest dexamethasone to suppress ACTH and reduce endogenous cortisol production only if mineralocorticoid antagonism is not effective or not tolerated (Grade 2B).

The end point of therapy has not been clearly defined, but normalization of the plasma potassium concentration seems reasonable. A similar goal is recommended in patients with primary aldosteronism who are treated medically. (See "Treatment of primary aldosteronism".)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Norman M Kaplan, MD, who contributed to an earlier version of this topic review.

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