Therapeutic management of congenital forms of endocrine hypertension.

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism (FH), congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.

In vitro methods to assess 11ß-hydroxysteroid dehydrogenase type 2 activity.

11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) converts active 11ß-hydroxyglucocorticoids to their inactive 11-keto forms, fine-tuning the activation of mineralocorticoid and glucocorticoid receptors. 11ß-HSD2 is expressed in mineralocorticoid target tissues such as renal distal tubules and cortical collecting ducts, and distal colon, but also in placenta where it acts as a barrier to reduce the amount of maternal glucocorticoids that reach the fetus. Disruption of 11ß-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypernatremia, hypokalemia and hypertension. Secondary hypertension due to 11ß-HSD2 inhibition has been observed upon consumption of excessive amounts of licorice and in patients treated with the azole fungicides posaconazole and itraconazole. Furthermore, inhibition of 11ß-HSD2 during pregnancy with elevated exposure of the fetus to cortisol can cause neurological complications with a lower intelligence quotient, higher odds of attention deficit and hyperactivity disorder as well as metabolic reprogramming with an increased risk of cardio-metabolic disease in adulthood. This chapter describes in vitro methods for the determination of 11ß-HSD2 activity that can be applied to identify inhibitors that may cause secondary hypertension and characterize the enzyme's activity in disease models. The included decision tree and the list of methods with their advantages and disadvantages aim to enable the reader to select and apply an in vitro method suitable for the scientific question and the equipment available in the respective laboratory.

[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.

Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11ß-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

Clinical, biochemical, and miRNA profile of subjects with positive screening of primary aldosteronism and nonclassic apparent mineralocorticoid excess.

Primary aldosteronism (PA) and nonclassic apparent mineralocorticoid excess (NCAME) have been recognized as endocrine-related conditions having a broad clinical-biochemical spectrum, spanning from normotension to severe arterial hypertension (AHT). However, the coexistence of both phenotypes have not been reported to date. AIM: To identify and characterize clinical and biochemical parameters of subjects with both PA and NCAME conditions (NCAME&PA) and study the miRNA cargo in their urinary extracellular vesicles as potential biomarkers for this novel condition. METHODS: We performed a cross-sectional study of 206 Chilean adult subjects from a primary care cohort. We measured blood pressure (BP), cortisol (F), cortisone (E), aldosterone, plasma renin activity (PRA), microalbuminuria (MAC), plasma NGAL, MMP9, fractional-potassium-excretion (FEK). Subjects were classified as NCAME&PA, PA, NCAME, essential hypertensives (EH), or healthy controls (CTL). EV-miRNAs were quantified by Taqman-qPCR. RESULTS: We found that 30.6% subjects had an abnormal endocrine phenotype: NCAME&PA (6.8%), PA (11.2%) or NCAME (12.6%), and the prevalence of AHT was 92.9%, 82.6%, and 65%, respectively. NCAME&PA subjects had both lower cortisone (p < 0.05) and lower PRA (p < 0.0001), higher FEK (p = 0.02) and higher MAC (p = 0.01) than EH or CTL. NCAME&PA subjects had also higher NGAL levels than CTL and PA (p < 0.05). Exosome miR-192, miR-133a and miR-21 expression decreased with phenotype severity and correlated with BP and PRA (p < 0.05). CONCLUSION: We identified adult subjects with a combined condition of NCAME and PA associated with higher BP, increased renal and endothelial damage markers than control and EH. Additionally, we observed a differential expression of a specific miRNAs, suggesting a potential role of these miRNAs associated to this novel combined phenotype.

Apparent mineralocorticoid excess: A diagnosis beyond classical causes of severe hypertension in a child.

A genetic defect of 11 ß-hydroxysteroid dehydrogenase causes apparent mineralocorticoid excess syndrome. Since 50 days of life, our patient was hospitalized several times for various reasons including hypokalemia. At the age of 3.3 years, she was diagnosed with severe hypertension (160/120 mmHg). She also had left ventricular hypertrophy and hypertensive retinopathy and referred to our center. Her renal function and electrolytes were normal except for hypokalemia. She was on captopril treatment; nifedipine and propranolol were added. Plasma renin and aldosterone concentrations were 1.13 pg/ml (1-8.2 pg/ml) and 12.2 ng/dl (35-300 ng/dl), respectively. Severe hypertension, hypokalemia, low renin and aldosterone levels pointed to the diagnosis of apparent mineralocorticoid excess syndrome. Strict salt-restricted diet and potassium citrate were ordered. Genetic analysis of the HSD11B2 gene showed c.623G>A (p.Arg208His). Spironolactone was initiated. On follow-up, amiloride was added and her blood pressure was controlled. In patients with severe HSD11B2 mutation, combination therapy of spironolactone with amiloride could be effective in controlling blood pressure.

Antifungal Therapy with Azoles Induced the Syndrome of Acquired Apparent Mineralocorticoid Excess: a Literature and Database Analysis.

We aimed to estimate the risk of varied antifungal therapy with azoles causing the syndrome of acquired apparent mineralocorticoid excess (AME) in real-world practice. First, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the signal differences of triazoles-related AME. Second, a systematic review was conducted, and clinical features of AME cases reported in clinical practice were described. In the FAERS database, we identified 27 cases of triazoles-AME, posaconazole [ROR = 865.37; 95%CI (464.14; 1613.45)], and itraconazole [ROR = 556.21; 95% (303.05; 1020.85)] significantly increased the risk of AME events, while fluconazole, voriconazole, and isavuconazole did not affect any of the mineralocorticoid excess targets. Eighteen studies with 39 cases raised evidence of AME following posaconazole and itraconazole treatment, and another 27 cases were identified by analysis of the description of clinical features in the FAERS database. The average age of 66 patients was 55.5 years (6-87 years). AME mainly occurs in patients with posaconazole concentrations above 3 µg/mL (mean = 4.4 µg/mL, range 1.8∼9.5 µg/mL), and is less likely to occur when levels are below 2 µg/mL (6%). The median time to event onset was 11.5 weeks, and 50% of the adverse events occurred within 3 months for posaconazole. The presented study supports very recent findings that posaconazole and itraconazole, but not the other three azole antifungals investigated, are associated with AME and that the effects are dose-dependent, which allows for a dose de-escalation strategy and for substitution with fluconazole, isavuconazole, or voriconazole to resolve the adverse effects.

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.

Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat.

We discovered high Na+ and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2-/- animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2-/- neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2-/- neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.

Species-specific differences in the inhibition of 11ß-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole.

11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) converts active 11ß-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11ß-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypokalemia, hypernatremia and hypertension. Recently, the azole antifungals itraconazole and posaconazole were identified to potently inhibit human 11ß-HSD2, and several case studies described patients with acquired AME. To begin to understand why this adverse drug effect was missed during preclinical investigations, the inhibitory potential of itraconazole, its main metabolite hydroxyitraconazole (OHI) and posaconazole against 11ß-HSD2 from human and three commonly used experimental animals was assessed. Whilst human 11ß-HSD2 was potently inhibited by all three compounds (IC50 values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC50 values compared to human), and mouse and zebrafish 11ß-HSD2 were very weakly inhibited (IC50 values above 7 µM). Sequence alignment and application of newly generated homology models for human and mouse 11ß-HSD2 revealed significant differences in the C-terminal region and the substrate binding pocket. Exchange of the C-terminus and substitution of residues Leu170,Ile172 in mouse 11ß-HSD2 by the corresponding residues His170,Glu172 of the human enzyme resulted in a gain of sensitivity to itraconazole and posaconazole, resembling human 11ß-HSD2. The results provide an explanation for the observed species-specific 11ß-HSD2 inhibition by the studied azole antifungals. The obtained structure-activity relationship information should facilitate future assessments of 11ß-HSD2 inhibitors and aid choosing adequate animal models for efficacy and safety studies.

Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia.

PURPOSE: Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations. METHODS: Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11ßHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted. RESULTS: Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02). CONCLUSIONS: We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.

Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.

CONTEXT: Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. EVIDENCE ACQUISITION: This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. EVIDENCE SYNTHESIS: The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11ßHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. CONCLUSION: NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.

Role of glucocorticoid- and monoamine-metabolizing enzymes in stress-related psychopathological processes.

Glucocorticoid signaling is fundamental in healthy stress coping and in the pathophysiology of stress-related diseases, such as post-traumatic stress disorder (PTSD). Glucocorticoids are metabolized by cytochrome P450 (CYP) as well as 11-ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) and 2 (11ßHSD2). Acute stress-induced increase in glucocorticoid concentrations stimulates the expression of several CYP sub-types. CYP is primarily responsible for glucocorticoid metabolism and its increased activity can result in decreased circulating glucocorticoids in response to repeated stress stimuli. In addition, repeated stress-induced glucocorticoid release can promote 11ßHSD1 activation and 11ßHSD2 inhibition, and the 11ßHSD2 suppression can lead to apparent mineralocorticoid excess. The activation of CYP and 11ßHSD1 and the suppression of 11ßHSD2 may at least partly contribute to development of the blunted glucocorticoid response to stressors characteristic in high trait anxiety, PTSD, and other stress-related disorders. Glucocorticoids and glucocorticoid-metabolizing enzymes interact closely with other biomolecules such as inflammatory cytokines, monoamines, and some monoamine-metabolizing enzymes, namely the monoamine oxidase type A (MAO-A) and B (MAO-B). Glucocorticoids boost MAO activity and this decreases monoamine levels and induces oxidative tissue damage which then activates inflammatory cytokines. The inflammatory cytokines suppress CYP expression and activity. This dynamic cross-talk between glucocorticoids, monoamines, and their metabolizing enzymes could be a critical factor in the pathophysiology of stress-related disorders.Lay summaryGlucocorticoids, which are produced and released under the control by brain regulatory centers, are fundamental in the stress response. This review emphasizes the importance of glucocorticoid metabolism and particularly the interaction between the brain and the liver as the major metabolic organ in the body. The activity of enzymes involved in glucocorticoid metabolism is proposed to play not only an important role in positive, healthy glucocorticoid effects, but also to contribute to the development and course of stress-related diseases.

Downregulation of exosomal miR-192-5p and miR-204-5p in subjects with nonclassic apparent mineralocorticoid excess.

BACKGROUND: The "nonclassic" apparent mineralocorticoid excess (NC-AME) has been identified in approximately 7% of general population. This phenotype is characterized by low plasma renin activity (PRA), high serum cortisol (F) to cortisone (E) ratio, low cortisone, high Fractional Excretion of potassium (FEK) and normal-elevated systolic blood pressure (SBP). An early detection and/or identification of novel biomarkers of this phenotype could avoid the progression or future complications leading to arterial hypertension. Isolation of extracellular vesicles, such as exosomes, in specific biofluids support the identification of tissue-specific RNA and miRNA, which may be useful as novel biomarkers. Our aim was to identify miRNAs within urinary exosomes associated to the NC-AME phenotype. METHODS: We perform a cross-sectional study in a primary care cohort of 127 Chilean subjects. We measured BP, serum cortisol, cortisone, aldosterone, PRA. According to the previous reported, a subgroup of subjects was classified as NC-AME (n = 10). Urinary exosomes were isolated and miRNA cargo was sequenced by Illumina-NextSeq-500. RESULTS: We found that NC-AME subjects had lower cortisone (p < 0.0001), higher F/E ratio (p < 0.0001), lower serum potassium (p = 0.009) and higher FEK 24 h (p = 0.03) than controls. We found miR-204-5p (fold-change = 0.115; p 0.001) and miR-192-5p (fold-change = 0.246; p 0.03) are both significantly downregulated in NC-AME. miR-192-5p expression was correlated with PRA (r = 0.45; p 0.028) and miR-204-5p expression with SBP (r = - 0.48, p 0.027) and F/E ratio (r = - 0.48; p 0.026). CONCLUSIONS: These findings could support a potential role of these miRNAs as regulators and novel biomarkers of the NC-AME phenotype.