Apparent mineralocorticoid excess in Israel: a case series and literature review.

BACKGROUND AND OBJECTIVE: Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. DESIGN: Retrospective cohort study. METHODS: Clinical, laboratory, and molecular data from patients' records were collected. RESULTS: Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. CONCLUSIONS: In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.

[Adverse effects of licorice consumed as food: An update]. / Toxicités de l'exposition alimentaire à la réglisse : mise au point.

The word "licorice" refers to the plant, its root, and its aromatic extract. From a commercial point of view, Glycyrrhiza glabra is the most important species with a wide range of uses (herbal medicine, tobacco industry, cosmetics, food and pharmaceutical). Glycyrrhizin is one of the main constituents of licorice. Glycyrrhizin is hydrolyzed in the intestinal lumen by bacterial ß-glucuronidases to 3ß-monoglucuronyl-18ß-glycyrrhetinic acid (3MGA) and 18ß-glycyrrhetinic acid (GA), which are metabolized in the liver. Plasma clearance is slow due to enterohepatic cycling. 3MGA and GA can bind to mineralocorticoid receptors with very low affinity, and 3MGA induces apparent mineralocorticoid excess syndrome through dose-dependent inhibition of 11ß-hydroxysteroid dehydrogenase type 2 in renal tissue. The cases of apparent mineralocorticoid excess syndrome reported in the literature are numerous and sometimes severe, even fatal, most often in cases of chronic high dose consumption. Glycyrrhizin poisonings are characterized by hypertension, fluid retention, and hypokalemia with metabolic alkalosis and increased kaliuresis. Toxicity depends on the dose, the type of product consumed, the mode of consumption (acute or chronic) and a very large inter-individual variability. The diagnosis of glycyrrhizin-induced apparent mineralocorticoid excess syndrome is based on the history, clinical examination, and biochemical analysis. Management is primarily based on symptomatic care and stopping licorice consumption.

A life-threatening case of pseudo-aldosteronism secondary to excessive liquorice ingestion.

BACKGROUND: Liquorice is found in many food products, soft drinks, and herbal medicines. Liquorice ingestion is an uncommon cause of apparent mineralocorticoid excess or pseudo-aldosteronism. The mechanism involves the inhibition of 11-beta-hydroxysteroid dehydrogenase type-2 by the active ingredient called glycyrrhizin. This leads to the uninhibited activation of mineralocorticoid receptors by cortisol. Confectionary products that contain liquorice are readily available in many countries around the world. CASE PRESENTATION: We report a case of severe refractory hypokalaemia with hypertensive crisis and acute pulmonary oedema due to excessive liquorice consumption. A 79-year-old female presented to the emergency department following a road traffic accident. She described feeling weak and dizzy while driving before the collision. She attended her general practitioner (GP) several weeks earlier for fatigue and was being managed for hypokalaemia on oral potassium supplements. Investigations revealed hypertension (BP 180/69 mmHg), severe hypokalaemia (K 2.2 mmol/l), normal renal function, normal serum magnesium with metabolic alkalosis. Spot urinary potassium was 22 mmol/l. The patient denied taking medications including over-the-counter or herbal medication that can cause hypokalaemia. Hypokalaemia persisted despite aggressive intravenous (i.v.) and oral potassium replacement. She later developed a hypertensive crisis (BP 239/114 mmHg) with pulmonary oedema. She required admission to the intensive care unit and was managed with intravenous furosemide infusion and isosorbide dinitrate infusion. On further discussion, our patient admitted to struggling with nicotine cravings since quitting smoking two months earlier. She began eating an excessive amount of liquorice sweets to manage her cravings. Suppression of plasma renin and aldosterone supported the diagnosis of apparent mineralocorticoid excess secondary to excessive liquorice consumption. Her symptoms and hypokalaemia resolved after stopping liquorice intake. CONCLUSIONS: This case highlights the life-threatening and refractory nature of hypokalaemia secondary to excessive liquorice consumption. This case also emphasizes the importance of comprehensive history taking including dietary habits. Increased awareness among the public is required regarding the potential health hazards of excessive liquorice consumption.

Amiloride Is Effective in the Management of Abiraterone-Induced Mineralocorticoid Excess Syndrome without Interfering with Its Antineoplastic Activity.

BACKGROUND: The administration of abiraterone acetate (abiraterone) leads to an adrenocorticotropic hormone (ACTH)-driven increase in mineralocorticoid hormones, requiring glucocorticoid supplementation that may stimulate the growth of prostate cancer (PCa). Amiloride is a drug that selectively reduces the aldosterone-sensitive Na+/K+ exchange and could be effective in the management of mineralocorticoid excess syndrome (MCES). METHODS: The efficacy of amiloride + hydrochlorothiazide (HCT) in the clinical management of abiraterone-induced MCES was assessed in 5 consecutive patients with castration-resistant PCa (CRPC). Then, using the in vitro experimental model of PCa cell lines, the possible effects of drugs usually used in the clinical management of CRPC patients on PCa cell viability were investigated. RESULTS: Amiloride/HCT led to a complete disappearance of all clinical and biochemical signs of abiraterone-induced MCES in the 5 treated patients. The in vitro study showed that abiraterone treatment significantly decreased cell viability of both androgen receptor (AR)-expressing VCaP (vertebral-cancer of the prostate) and LNCaP (lymph node carcinoma of the prostate) cells, with no effect on AR-negative PC-3 cells. Prednisolone, spironolactone, and eplerenone increased LNCaP cell viability, while amiloride reduced it. The non-steroid aldosterone antagonist PF-03882845 did not modify PCa cell viability. CONCLUSIONS: The combination of amiloride/HCT was effective in the management of abiraterone-induced MCES. Amiloride did not negatively interfere with the abiraterone inhibition of PCa cell viability in vitro.

Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department.

A 65-year-old woman with a background of myalgic encephalitis, who was taking alternative medicines and dietary supplements, presented with hypokalaemia and hypertension. After a thorough history it became apparent that this was most likely secondary to regular consumption of liquorice tea. The patient was advised to discontinue drinking this tea and was discharged. Follow-up showed normalising blood pressure and hypokalaemia, with a normal aldosterone:renin ratio.

Remission of hypertension and electrolyte abnormalities following renal transplantation in a patient with apparent mineralocorticoid excess well documented throughout childhood.

Apparent mineralocorticoid excess syndrome (AME) is an autosomal recessive genetic disorder caused by a deficiency in the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD). We report a 36-year-old male who was hypertensive from birth and was diagnosed with AME at 8 years of age. There was continuous documentation of his hypertension and hypokalemic alkalosis throughout childhood, during which spironolactone and supplemental potassium were administered. At 33 years of age, the patient received a renal transplant, and following this the AME appears to have been cured clinically with remission of his low renin hypertension and hypokalemic alkalosis despite termination of treatment with spironolactone and potassium supplements.

Strategies for managing ACTH dependent mineralocorticoid excess induced by abiraterone.

BACKGROUND: Abiraterone strongly inhibits androgen synthesis but may lead to an increase in mineralocorticoid hormones that may impair its long term tolerability in patients with prostate cancer. How to implement available therapies in the management and prevention of these potential side effects is a matter of current clinical research. METHODS: The acute and long term consequences of mineralocorticoid excess and the effects of available treatments have been reviewed. Prospective studies in which abiraterone was employed were identified to assess the frequency and severity of the mineralocorticoid excess syndrome and the efficacy of ameliorating therapeutic approaches. RESULTS: Glucocorticoids to inhibit the ACTH increase that drives mineralocorticoid synthesis and mineralocorticoid receptor (MR) antagonists can be used in the management of the abiraterone-induced mineralocorticoid excess syndrome. Phase I and II trials of abiraterone without additional therapies revealed that mineralocorticoid excess symptoms occur in the majority of patients. Eplerenone, a specific MR antagonist, seems to be effective but it does not control the mineralocorticoid excess. Glucorticoid supplementation to control ACTH drive is therefore needed. In several randomized trials the addition of prednisone (10mg daily) to abiraterone was not able to prevent mineralocorticoid excess syndrome in many cases and thus cannot be considered the gold standard. CONCLUSION: At present, the best conceivable treatment for managing the abiraterone-induced mineralocorticoid excess consists of the administration of glucocorticoid replacement at the lowest effective dose ± MR antagonists and salt deprivation. The drug doses should be modulated by monitoring blood pressure, fluid retention and potassium levels during therapy.

Apparent mineralocorticoid excess syndrome: report of one family with three affected children.

The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disorder characterized by hypertension, hypokalemia, low renin, and hypoaldosteronism. It is caused by deficiency of 11ß-hydroxysteroid dehydrogenase, which results in a defect of the peripheral metabolism of cortisol to cortisone. As a consequence, the serum cortisol half-life (T½) is prolonged, ACTH is suppressed, and serum cortisol concentration is normal. The hormonal diagnosis of the disorder is made by the increased ratio of urine-free cortisol to cortisone. In patients with AME, this ratio is 5-18, while in normal individuals it is <0.5. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME. We report three siblings - two female and one male - with the syndrome of apparent mineralocorticoid excess who presented with hypertension, hypokalemia, low renin, and low aldosterone levels. The finding of abnormally high ratios of 24-h urine-free cortisol to cortisone in our three patients (case 1, 8.4; case 2, 25; and case 3, 7.5) confirmed the diagnosis of apparent mineralocorticoid excess syndrome in these children. They were treated with oral potassium supplements. The addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity in all three. In this study, the genetic testing of those three siblings with the typical clinical features of AME has detected missense mutation c.662C>T (p.Arg208Cys) in exon 3 of the HSD11B2 gene in the homozygous state.

Apparent mineralocorticoid excess: time of manifestation and complications despite treatment.

Here we describe the case of a patient followed from birth because of a positive family history for apparent mineralocorticoid excess (AME) in an older brother. The patient, a girl, had normal serum electrolyte and blood pressure measurements in the first months after birth. Not until the age of 11 months did she develop anorexia and failure to thrive in combination with hypertension, hypokalemia, and metabolic alkalosis, which are consistent with the diagnosis of AME. This diagnosis was confirmed by mutation analysis of the HSD11B2 gene (C1228T). Treatment with amiloride and furosemide electrolyte disturbances normalized her blood pressure. At the age of 19 years she unexpectedly suffered a stroke. Additional investigations revealed no accepted risk factor for stroke. We discuss the possible underlying mechanisms for the delayed manifestation of hypertension and electrolyte disturbances in AME, propose an additional explanation for the stroke in this patient, and advise treatment with a mineralocorticoid receptor antagonist to reduce stroke risk in patients with AME.

[From gene to disease; 'apparent mineralocorticoid excess' syndrome, a syndrome with an apparent excess of mineral corticoids]. / Van gen naar ziekte; 'apparent mineralocorticoid excess'-syndroom, een syndroom met ogenschijnlijke overmaat aan mineralocorticoïden.

Apparent mineralocorticoid excess (AME) is an autosomal recessive disease caused by deficiency of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). 11beta-HSD2 converts cortisol into inactive cortisone and prevents the stimulation of the mineralocorticoid receptor by cortisol. In patients with AME, an enhanced stimulation of mineralocorticoid receptors by cortisol in the distal nephron causes an elevated sodium reabsorption and increased potassium excretion. Sodium retention leads to severe low renin hypertension. The diagnosis of AME is based on the detection of an increased concentration of cortisol metabolites and a low or undetectable concentration of cortisone metabolites in urine. Molecular analysis of the HSD11B2 gene confirms the diagnosis. AME is successfully treated by potassium-sparing diuretics, sometimes in combination with loop diuretics (furosemide). Mild forms of AME might occur more frequently than is currently known and should be suspected in patients with hypertension, hypokalemia and decreased plasma renin concentration. Since liquorice can induce the clinical symptoms of AME due to reversible inhibition of the 11beta-HSD2 enzyme by glycyrrhetinic acid, the active ingredient of liquorice, patients suspected of having AME should not consume liquorice.