Apparent mineralocorticoid excess syndrome

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Apparent mineralocorticoid excess syndrome
Other namesAME, 11-beta-hydroxysteroid dehydrogenase deficiency type 2, Ulick syndrome.
Autorecessive.svg
Apparent mineralocorticoid excess syndrome has an autosomal recessive pattern of inheritance
Specialty Medical genetics, endocrinology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity. [1]

Apparent mineralocorticoid excess is an autosomal recessive [2] disorder causing hypertension (high blood pressure), hypernatremia (increased blood sodium concentration) and hypokalemia (decreased blood potassium concentration). It results from mutations in the HSD11B2 gene, which encodes the kidney isozyme of 11β-hydroxysteroid dehydrogenase type 2. In an unaffected individual, this isozyme inactivates circulating cortisol to the less active metabolite cortisone. The inactivating mutation leads to elevated local concentrations of cortisol in the aldosterone sensitive tissues like the kidney. Cortisol at high concentrations can cross-react and activate the mineralocorticoid receptor due to the non-selectivity of the receptor, leading to aldosterone-like effects in the kidney. This is what causes the hypokalemia, hypertension, and hypernatremia associated with the syndrome. Patients often present with severe hypertension and end-organ changes associated with it like left ventricular hypertrophy, retinal, renal and neurological vascular changes along with growth retardation and failure to thrive. In serum both aldosterone and renin levels are low. [3]

Contents

Signs and symptoms

This disorder presents similarly to hyperaldosteronism, leading to feedback inhibition of aldosterone. Common symptoms include hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity. [1]

DOC excess syndrome is an excessive secretion of 21-hydroxyprogesterone also called 11-Deoxycorticosterone from adrenal glands and may cause mineralocorticoid hypertension. [4] [5] [6]

Genetics

AME is inherited in an autosomal recessive manner. [2] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. [7]

Diagnosis

Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. [8] Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. [9]

Treatment

The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases. [10] AME is exceedingly rare, with fewer than 100 cases recorded worldwide. [8]

History

Apparent mineralocorticoid excess is a rare form of monogenic hypertension that is transmitted as an autosomal recessive trait. The clinical symptoms of AME were first reported in 1974 by a Professor from Switzerland; Edmond A Werder in a 3-year-old girl with low birth weight, delayed growth, polydipsia, polyuria, and hypertension. In 1977, the US Professor Maria New identified patients with similar symptoms, characterized their biochemical profiles, and named the disease AME. Initially, it was speculated that HSD11B1 (encoding 11β-hydroxysteroid dehydrogenase type 1 [11β-HSD1]) was the causative gene but no mutation was detected in AME patients; thus, the focus was shifted to other candidate genes. In 1995, the US Professor Robert Wilson identified the first HSD11B2 mutation in several siblings with typical characteristics of AME from a consanguineous Iranian family, unraveling the genetic defects of AME. The molecular pathogenesis of AME primarily results from a deficiency in the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is involved in the peripheral metabolism of cortisol. In 1999, B. Scott Nunez; another US professor, summarized the AME genotype–phenotype correlation by studying 14 affected children and proposed that clinical and/or biochemical parameters and enzyme activity were closely related [11]

Liquorice effect

Liquorice consumption may also cause a temporary form of AME due to its ability to block 11β-hydroxysteroid dehydrogenase type 2, in turn causing increased levels of cortisol. [12] [13] Cessation of licorice consumption will reverse this form of AME. [14]

See also

Related Research Articles

<span class="mw-page-title-main">Aldosterone</span> Mineralocorticoid steroid hormone

Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a central role in the homeostatic regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. It does so primarily by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron. It influences the reabsorption of sodium and excretion of potassium (from and into the tubular fluids, respectively) of the kidney, thereby indirectly influencing water retention or loss, blood pressure, and blood volume. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and kidney disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

<span class="mw-page-title-main">Congenital adrenal hyperplasia</span> Medical condition

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. Most of these disorders involve excessive or deficient production of hormones such as glucocorticoids, mineralocorticoids, or sex steroids, and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. It is one of the most common autosomal recessive disorders in humans.

<span class="mw-page-title-main">Mineralocorticoid</span> Group of corticosteroids

Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances. The primary mineralocorticoid is aldosterone.

<span class="mw-page-title-main">Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency</span> Medical condition

Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is a form of congenital adrenal hyperplasia (CAH) which produces a higher than normal amount of androgen, resulting from a defect in the gene encoding the enzyme steroid 11β-hydroxylase (11β-OH) which mediates the final step of cortisol synthesis in the adrenal. 11β-OH CAH results in hypertension due to excessive mineralocorticoid effects. It also causes excessive androgen production both before and after birth and can virilize a genetically female fetus or a child of either sex.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene CYP17A1, which produces the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex hormones, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild cortisol deficiency, ambiguous genitalia in men or amenorrhea at puberty in women, and hypokalemic hypertension. However, partial (incomplete) deficiency often has inconsistent symptoms between patients, and affected women may be asymptomatic except for infertility.

<span class="mw-page-title-main">Enoxolone</span> Chemical compound

Enoxolone is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice.

11β-Hydroxysteroid dehydrogenase enzymes catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa, thus regulating the access of glucocorticoids to the steroid receptors.

Secondary hypertension is a type of hypertension which by definition is caused by an identifiable underlying primary cause. It is much less common than the other type, called essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">Corticosteroid 11-beta-dehydrogenase isozyme 2</span> Enzyme found in humans

Corticosteroid 11-β-dehydrogenase isozyme 2 also known as 11-β-hydroxysteroid dehydrogenase 2 is an enzyme that in humans is encoded by the HSD11B2 gene.

<span class="mw-page-title-main">11β-Hydroxysteroid dehydrogenase type 1</span> Mammalian protein found in Homo sapiens

11β-Hydroxysteroid dehydrogenase type 1, also known as cortisone reductase, is an NADPH-dependent enzyme highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system. In these tissues, HSD11B1 reduces cortisone to the active hormone cortisol that activates glucocorticoid receptors. It belongs to the family of short-chain dehydrogenases. It is encoded by the HSD11B1 gene.

Pseudohyperaldosteronism is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders, acquired conditions, metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma aldosterone concentration (PAC) which differentiates this group of conditions from other forms of secondary hypertension. Treatment is tailored to the specific cause and focuses on symptom control, blood pressure management, and avoidance of triggers.

<span class="mw-page-title-main">Pseudohypoaldosteronism</span> Medical condition

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.

<span class="mw-page-title-main">Mineralocorticoid receptor</span> Nuclear receptor that mediates the effects of the mineralocorticoid hormone Aldosterone

The mineralocorticoid receptor, also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.

<span class="mw-page-title-main">Aldosterone synthase</span> Protein-coding gene in the species Homo sapiens

Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme catalyzes sequential hydroxylations of the steroid angular methyl group at C18 after initial 11β-hydroxylation. It is encoded by the CYP11B2 gene in humans.

<span class="mw-page-title-main">11-Deoxycortisol</span> Chemical compound

11-Deoxycortisol, also known as cortodoxone (INN), cortexolone as well as 17α,21-dihydroxyprogesterone or 17α,21-dihydroxypregn-4-ene-3,20-dione, is an endogenous glucocorticoid steroid hormone, and a metabolic intermediate toward cortisol. It was first described by Tadeusz Reichstein in 1938 as Substance S, thus has also been referred to as Reichstein's Substance S or Compound S.

Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity, is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient.

<span class="mw-page-title-main">Cortisone reductase deficiency</span> Medical condition

Cortisone reductase deficiency is caused by dysregulation of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), otherwise known as cortisone reductase, a bi-directional enzyme, which catalyzes the interconversion of cortisone to cortisol in the presence of NADH as a co-factor. If levels of NADH are low, the enzyme catalyses the reverse reaction, from cortisol to cortisone, using NAD+ as a co-factor.
Cortisol is a glucocorticoid that plays a variety of roles in many different biochemical pathways, including, but not limited to: gluconeogenesis, suppressing immune system responses and carbohydrate metabolism.
One of the symptoms of cortisone reductase deficiency is hyperandrogenism, resulting from activation of the Hypothalamic–pituitary–adrenal axis. The deficiency has been known to exhibit symptoms of other disorders such as Polycystic Ovary Syndrome in women. Cortisone Reductase Deficiency alone has been reported in fewer than ten cases in total, all but one case were women. Elevated activity of 11β-HSD1 can lead to obesity or Type II Diabetes, because of the role of cortisol in carbohydrate metabolism and gluconeogenesis.

<span class="mw-page-title-main">11β-Hydroxyprogesterone</span> Chemical compound

11β-Hydroxyprogesterone (11β-OHP), also known as 21-deoxycorticosterone, as well as 11β-hydroxypregn-4-ene-3,20-dione, is a naturally occurring, endogenous steroid and derivative of progesterone. It is a potent mineralocorticoid. Syntheses of 11β-OHP from progesterone is catalyzed by the steroid 11β-hydroxylase (CYP11B1) enzyme, and, to a lesser extent, by the aldosterone synthase enzyme (CYP11B2).

<span class="mw-page-title-main">Generalized glucocorticoid resistance</span> Medical condition

Generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids.

References

  1. 1 2 Palermo, Mario; Quinkler, Marcus; Stewart, Paul M. (2004). "Apparent mineralocorticoid excess syndrome: an overview". Arquivos Brasileiros de Endocrinologia & Metabologia. FapUNIFESP (SciELO). 48 (5): 687–696. doi: 10.1590/s0004-27302004000500015 . ISSN   0004-2730. PMID   15761540.
  2. 1 2 Levtchenko, E. N.; Deinum, J.; Knoers, N. V. a. M.; Hermus, A. R.; Monnens, L. a. H.; Lenders, J. W. M. (2007). "Van gen naar ziekte; 'apparent mineralocorticoid excess'-syndroom, een syndroom met ogenschijnlijke overmaat aan mineralocorticoïden" [From gene to disease; 'apparent mineralocorticoid excess' syndrome, a syndrome with an apparent excess of mineral corticoids]. Nederlands Tijdschrift voor Geneeskunde (in Dutch). 151 (12): 692–694. hdl:11370/df94307a-2281-4450-93bf-a30c7bc2d0ab. PMID   17447595.
  3. ↑ Al-Harbi, Taiba; Al-Shaikh, Adnan (1 January 2012). "Apparent mineralocorticoid excess syndrome: report of one family with three affected children". Journal of Pediatric Endocrinology and Metabolism. 25 (11–12): 1083–8. doi:10.1515/jpem-2012-0113. PMID   23329753. S2CID   21281031.
  4. ↑ Marques, Pedro; Tufton, Nicola; Bhattacharya, Satya; Caulfield, Mark; Akker, Scott A (3 May 2019). "Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy". Endocrinology, Diabetes & Metabolism Case Reports. 2019. doi:10.1530/EDM-18-0164. PMC   6499913 . PMID   31051469.
  5. ↑ Gupta, Saurabh; Melendez, Jose; Khanna, Apurv (2010). "Deoxycorticosterone Producing Tumor as a Cause of Resistant Hypertension". Case Reports in Medicine. 2010: 372719. doi: 10.1155/2010/372719 . PMC   2909735 . PMID   20671982.
  6. ↑ Deoxycorticosterone (DOC) at eMedicine
  7. ↑ "Autosomal recessive: MedlinePlus Medical Encyclopedia". MedlinePlus. Retrieved November 10, 2023.
  8. 1 2 Palermo M, Quinkler M, Stewart PM (Oct 2004). "Apparent mineralocorticoid excess syndrome: an overview" (PDF). Arq Bras Endocrinol Metabol. 48 (5): 687–696. doi: 10.1590/S0004-27302004000500015 . PMID   15761540.
  9. ↑ DG, Warnock (2001). "Liddle's syndrome: genetics and mechanisms of Na+ channel defects". Contributions to Nephrology. Contrib Nephrol (136): 1–10. ISSN   0302-5144. PMID   11688373 . Retrieved November 10, 2023.
  10. ↑ Marshall, Ian; New, Maria I. (2003). "Mineralocorticoid Disorders, Genetic Basis of". Encyclopedia of Hormones. Elsevier. pp. 679–685. doi:10.1016/b0-12-341103-3/00105-4. ISBN   9780123411037.
  11. ↑ Zhang, Lu, Yt. (2022). "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics". Translational Medicine 2022. 20 (1): 500. doi: 10.1186/s12967-022-03698-9 . PMC   9632093 . PMID   36329487.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ "HSD11B2 Gene". GeneCards.
  13. ↑ Sontia, Bruno; Mooney, Jan; Gaudet, Lise; Touyz, Rhian M. (February 2008). "Pseudohyperaldosteronism, Liquorice, and Hypertension". The Journal of Clinical Hypertension. 10 (2): 153–157. doi:10.1111/j.1751-7176.2008.07470.x. PMC   8109973 . PMID   18256580. S2CID   20098685.
  14. ↑ Gallacher, Stuart Declan; Tsokolas, Georgios; Dimitropoulos, Ioannis (2017). "Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department". Clinical Medicine. Royal College of Physicians. 17 (1): 43–45. doi: 10.7861/clinmedicine.17-1-43 . ISSN   1470-2118. PMC   6297599 . PMID   28148579.
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