Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

Ferrari, Paolo; Bianchetti, Mario G.; Sansonnens, Aurelie; Frey, Felix J.

doi:10.1097/01.asn.0000028640.78526.0f

Cited by 28 publications

(19 citation statements)

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“…A decrease in serum calcium concentration and increased urinary calcium excretion have been reported in primary aldosteronism and in glucocorticoid-treated patients [4,5]. Significant changes in renal calcium handling in healthy volunteers have also been demonstrated following inhibition of 11b-HSD type 2 by GA [6].We describe an interesting case of pseudoaldosteronism, accompanied with hypocalcemia and an exaggerated ACTH response. The hypocalcemia and the exaggerated ACTH response to CRH both improved in parallel with normalization of hypokalemia and the renin-aldosterone system.…”

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confidence: 71%

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confidence: 95%

“…Significant changes in renal calcium handling in healthy volunteers have also been demonstrated following inhibition of 11b-HSD type 2 by GA [6].…”

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A Case of Pseudoaldosteronism, Accompanied with Hypocalcemia and Exaggerated ACTH Response

et al. 2004

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Abstract. Glycyrrhizic acid (GA) inhibits the activity of 11b-hydroxysteroid dehydrogenase type 2 in the kidney, with the resulting increase in intrarenal cortisol concentration leading to hypertension and suppression of the renin-aldosterone system. In this paper we describe an interesting case of pseudoaldosteronism, associated with hypocalcemia and an exaggerated ACTH response. A 72-year-old woman was referred to our department for further evaluation of hypokalemia and hypocalcemia. The patient had been taking GA (150 mg/day) for the previous year for treatment of liver damage. Plasma renin activity and aldosterone concentration were both within lower normal limits. Urinary excretion of potassium and calcium was within the upper limit of the normal range and increased with administration of supplements. Plasma ACTH levels increased markedly in response to an intravenous injection of CRH. Cessation of GA and the potassium and calcium supplements on admission, led to a gradual normalization of serum potassium and calcium levels and blood pressure. The hypocalcaemia in our patient was related to decreased tubular reabsorption of calcium as a consequence of renal corticoid excess. It is possible that an increase in the number of CRH receptors in the pituitary following GA treatment caused the exaggerated ACTH response in association with pseudoaldosteronism. The existence of hypocalcemia and an exaggerated ACTH response should be observed carefully when managing pseudoaldosteronism. GLYCYRRHIZIC acid (GA) inhibits the activity of 11b-hydroxysteroid dehydrogenase (11b-HSD) type 2, an enzyme that inactivates cortisol and allows selective access to the aldosterone receptor [1,2]. The increased intrarenal concentration of cortisol resulting from inhibition of this enzyme causes stimulation of the mineralocorticoid receptor, leading to hypertension, hypokalemia, and suppression of the reninaldosterone system. As a consequence of these changes administration of GA causes pseudoaldosteronism [3]. A decrease in serum calcium concentration and increased urinary calcium excretion have been reported in primary aldosteronism and in glucocorticoid-treated patients [4,5]. Significant changes in renal calcium handling in healthy volunteers have also been demonstrated following inhibition of 11b-HSD type 2 by GA [6].We describe an interesting case of pseudoaldosteronism, accompanied with hypocalcemia and an exaggerated ACTH response. The hypocalcemia and the exaggerated ACTH response to CRH both improved in parallel with normalization of hypokalemia and the renin-aldosterone system. These findings indicate that the hypocalcemia was related to decreased tubular reabsorption of calcium under conditions of renal corticoid excess [6]. We also speculate on the mechanism responsible for the exaggerated ACTH response in this case of pseudoaldosteronism.

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A Case of Pseudoaldosteronism, Accompanied with Hypocalcemia and Exaggerated ACTH Response

et al. 2004

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“…The distinguishing factor between Bartter and Gitelman is the urinary calcium excretion, which is high in the former and low in the latter (34). Inhibition of 11␤HSD2 by licorice has been shown to increase urinary calcium excretion (35). Nephrocalcinosis usually reflects a serious metabolic defect.…”

Section: Genotype-phenotype Correlations In Amementioning

confidence: 99%

Apparent Mineralocorticoid Excess

Morineau

Sulmont²,

Salomon³

et al. 2006

Journal of the American Society of Nephrology

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In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF ؉ 5␣THF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11␤HSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11␤HSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11␤HSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects. (1) described a case of a 3-yr-old girl who had short stature, polydipsia, and polyuria without obvious external abnormalities, including her genitalia, and who had features of mineralocorticoid hypertension with hypokalemia and metabolic alkalosis. She had suppressed plasma renin and aldosterone, and gas-chromatographic analysis of her urinary steroid profile excluded hypertensive forms of congenital adrenal hyperplasia but showed an abnormal steroid profile (1). At that time, the authors failed to realize the true nature of the condition that this girl had, a syndrome that later was characterized biochemically and recognized by New et al. (2) and Ulick et al. (3). An inherited deficiency in the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) has been shown to cause a disorder in the peripheral metabolism of cortisol that presents with hypokalemic hypertension and suppressed circulating renin and aldosterone (1-3). The typical clinical signs and symptoms of the originally described apparent mineralocorticoid excess (AME) also included low birth weight and failure to thrive. This form of mineralocorticoid hypertension was inherited as an autosomal recessive trait. The pathogenesis of AME was found to b...

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“…At high doses, furosemide inhibits 11␤-HSD2 64 , which has been shown to be associated with an enhanced calciuria. 65 Thus, although not commonly used in clinical practice, a calcium-sparing potent thiazide such as metolazone might be a more logical candidate in patients with a preserved glomerular filtration rate, especially when the activation of the aldosteronesensitive NaCl cotransporter in cirrhosis is confirmed in future studies.…”

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confidence: 99%

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

Frey

2006

Hepatology

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Exaggerated renal sodium retention with concomitant potassium loss is a hallmark of cirrhosis and contributes to the accumulation of fluid as ascites, pleural effusion, or edema. This apparent mineralocorticoid effect is only partially explained by increased aldosterone concentrations. I present evidence supporting the hypothesis that cortisol confers mineralocorticoid action in cirrhosis. The underlying molecular pathology for this mineralocorticoid receptor (MR) activation by cortisol is a reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians. (HEPATOLOGY 2006;44:795-801.) R enal sodium retention and potassium loss are observed in many patients suffering from cirrhosis. Traditionally, this abnormality is attributed to secondary hyperaldosteronism as a consequence of renal hypoperfusion related to intra-abdominal fluid sequestration. 1 This concept has been questioned for 2 reasons. First, patients with cirrhosis accumulating ascites can show renal sodium retention in the presence of normal plasma aldosterone concentration and increased circulating concentrations of natriuretic peptides 2-8 and second, renal sodium retention precedes intra-abdominal fluid sequestration in some situations, and therefore a secondary hyperaldosteronism does not explain the abnormal renal handling of sodium and potassium. 2-4 Many of these patients have a normal renal plasma flow and glomerular filtration rate. Therefore, sodium retention cannot be explained on the basis of an impaired renal perfusion or a decreased filtered sodium load 7 and an unknown mechanism might induce sodium retention. 9 Because this type of renal sodium avidity is linked with enhanced renal potassium loss and blocked by aldosterone antagonists, one is tempted to speculate that the underlying mechanism is an activation of mineralocorticoid receptor (MR). Several independent groups of investigators demonstrated that for a given renal sodium excretion the values for aldosterone were too low in patients with cirrhosis and therefore hypothesized that these findings are explained by an increased renal tubular sensitivity to aldosterone. [10][11][12] Here, the evidence is given for another hypothetical mechanism, which might mimic the presumed increased renal tubular sensitivity to aldosterone, i.e., the presence of a MRactivating ligand other than aldosterone. This ligand is most likely cortisol. MR activation by cortisol is not explained by an enhanced adrenal production rate and/or increased serum concentrations of cortisol in these patients, but by a reduced activity of the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2), which allows promiscuous activation of MR by the glucocorticoid cortisol. Activation of MR by CortisolInitially identified in the classic mineralocorticoid-responsive tissues including the aldosterone-sensitive part of the distal nephron, colon, or salivary glands, MR acts as a ligand-inducible transcription factor. 13,14 The cor...

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Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

Cited by 28 publications

References 48 publications

A Case of Pseudoaldosteronism, Accompanied with Hypocalcemia and Exaggerated ACTH Response

A Case of Pseudoaldosteronism, Accompanied with Hypocalcemia and Exaggerated ACTH Response

Apparent Mineralocorticoid Excess

Impaired 11β-hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact?

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