Genetic Steroid Di

C H A P T E R

6AApparent Mineralocorticoid Excess

Mabel Yau, Saroj NimkarnNew York-Presbyterian Hospital/Weill Cornell Medical College, New York, NY 10065

BACKGROUND

Steroid 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is one of the key enzymes in maintaining blood pressure homeostasis. It is the metabolic enzyme that confers specificity to the mineralocorticoid receptor. This relationship is evident in the syndrome of apparent mineralocorticoid excess. Steroid 11β-HSD2 is one of two distinct isozymes of 11β-hydroxysteroid dehydrogenases that catalyze the interconversion of hormonally active cortisol to inactive cortisone. Steroid 11β-HSD2 functions unidirectionally and selectively on cortisol. With the use of in situ hybridization and immunohistochemistry, it was found predominantly in mineralocorticoid respon-sive tissues: kidney, colon, and salivary gland. The type 1 enzyme (11β-HSD1) is more widely distributed, with the highest expression in the liver and adipose tissue, and functions to enhance organ-specific effects of cortisol. It functions bidirectionally and has a lower affinity for cortisol [1]. The two isoforms share only 20% sequence homology, suggesting that they belong to different gene families.

Apparent mineralocorticoid excess (AME) is the rare inherited form of hypertension caused by 11β-HSD2 deficiency. Clinical manifestations of AME mimic those of excessive mineralocorticoid states, but no elevation of known mineralocorticoids exists in these patients. Although Werder et al. described the clinical features of AME in 1974, the first biochemical and hormonal description of the disorder was made in 1977 by New et al. in a 3-year-old Native American girl with severe hypertension [2]. Endocrine evaluation of the patient did not reveal excessive secretion of known endogenous salt-retaining steroids in mineralocorticoid group. Ini-tially, it was thought that this condition was caused by an unknown mineralocorticoid. By measuring the release

sorders. http://dx.doi.org/10.1016/B978-0-12-416006-4.00017-X 23

of tritiated [11-3H] water after tritiated [11-3H] cortisol infusion, it was found that the metabolism of cortisol to biologically inactive cortisone was decreased and that the serum cortisol half-life was prolonged in these cases. This finding implicated diminished activity of 11β-HSD2, the enzyme responsible for converting cortisol to cor-tisone. The exploration and elucidation of this disease opened a new area in receptor biology as a result of the demonstration that the specificity of the mineralocorti-coid receptor function depends on a metabolic enzyme (11β-HSD2) rather than the receptor itself [3–7].

The natural ligand of mineralocorticoid receptor, aldosterone, is the primary mineralocorticoid respon-sible for regulating electrolyte excretion and intravascu-lar volume. Aldosterone stimulates increased resorption of sodium from the urine at the mineralocorticoid tar-get tissues, the cortical collecting duct in the kidneys. The mineralocorticoid receptor is non-selective in vitro and binds both aldosterone and cortisol, a glucocorti-coid, with similar affinity [8,9]. The 11β-HSD2 enzyme functions to protect the mineralocorticoid receptor by converting cortisol to its inactive metabolite, cortisone. This inactivation occurs through the conversion of the hydroxyl group at position C11 to a C11 oxo group. This is one of the pathways involved in cortisol metabolism. Other enzymatic pathways are shown in Figure 6A.1.

Both cortisol and cortisone metabolites are excreted through urine. Since cortisone is unable to bind the mineralocorticoid receptor, this enables aldosterone to selectively interact with the mineralocorticoid receptor in vivo [10,11]. Aldosterone, itself, is not metabolized by 11β-HSD2 because it forms a C11–C18 hemi-ketal group in aqueous solution.

Loss of function of the 11β-HSD2 enzyme allows cortisol to bind to the mineralocorticoid receptor and act as a mineralocorticoid. As cortisol is secreted in

Copyright © 2014 Published by Elsevier Inc.9

6A. APPARENT MINERALOCORTICOID EXCESS240

5α-dihydrocortisol

5β-dihydrocortisone

6β-hydroxylase5β-reductase

5β-reductase

20β-oxoreductase

Cortisone

Cortisol

6β-hydroxycortisone

6β-hydroxycortisol6β-hydroxylase/CYP3A

20β-dihydrocortisone

5β-dihydrocortisol

Tetrahydrocortisone

5β-tetrahydrocortisol

20β-dihydrocortisol20β-oxoreductase

5α-reductase

3α-hydroxysteroiddehydrogenase

3α-hydroxysteroiddehydrogenase

3α-hydroxysteroiddehydrogenase

11β-hydroxysteroiddehydrogenase

5α-tetrahydrocortisol

FIGURE 6A.1 Metabolization of cortisol. Cortisol is predominantly metabolized in the liver. The main pathway of cortisol inactivation oc-curs through the conversion of the hydroxyl group at position C11 to a C11 oxo group by the 11β-hydroxysteroid dehydrogenase type 2 enzyme. This functions to protect the mineralocorticoid receptor by converting cortisol to its inactive metabolite, cortisone. Other pathways of cortisol metabolism are shown. The majority of excreted cortisol appears in the urine as 5α-tetrahydrocortisol, 5β-tetrahydrocortisol, and tetrahydrocor-tisone. Adapted from Williams [14].

concentrations approximately 1000-fold higher than aldosterone, cortisol saturates the mineralocorticoid receptor in patients with 11β-HSD2 deficiency. This results in the clinical phenotype of excess mineralo-corticoid activity. Thus, AME illustrates an important “pre-receptor” pathway in the analysis of corticosteroid hormone action [12].

The role that 11β-HSD2 plays in mineralocorti-coid receptor specificity was also noted in the study of the effects of the licorice plant, Glycyrrhiza glabra, extracts, and its derived drug, carbenoxolone. Licorice and carbenoxolone are used in the treatment of gas-tric ulcers. Licorice ingestion in large amounts (greater than 50 g/day) can cause blood pressure elevation, sodium retention, and potassium wasting, similar to symptoms seen in AME. These symptoms tend to be milder than those of AME. Endocrine evaluation of patients with licorice ingestion also shows low plasma renin activity and low aldosterone concentrations. This effect was first documented in the 1940s [1]. The active components in licorice, glycyrrhizic acid and its hydrolytic product glycyrrhetinic acid, have a low affinity for the mineralocorticoid receptor. However, they act as potent competitive inhibitors of 11β-HSD2. This condition is reversible with discontinuation of licorice ingestion. In addition to licorice, glycyrrhizic acid can also be found in chewing gums and tobacco as a sweetening agent.

AME was thought to exist only in a severe form until 1998 when an unusual patient with a mild form of AME was reported by Wilson et al. [13]. The patient was a 12-year-old American girl with asymptomatic, mild, low

renin hypertension diagnosed during a sport physical. A moderately abnormal ratio of cortisol-to-cortisone metabolites and a mildly increased half-life of cortisol by measurement of tritiated water release after tritiated cor-tisol infusion led to the diagnosis. The findings of milder phenotype patients with partial functional 11β-HSD2 suggest the existence of a continuum between a caricatu-ral form of AME due to mutations drastically affecting the activity of the enzyme and more subtle genetic alter-ations resulting in milder phenotypes, which are labeled “essential hypertension”.

It has been speculated that a mild form of 11β-HSD2 defect may exist in a subgroup of individuals with essen-tial hypertension since a substantial percentage demon-strate low renin activity and/or are salt-sensitive. Indeed, several studies showed that reduced 11β-HSD2 activity might be a factor in a subset of patients diagnosed with essential hypertension.

MOLECULAR GENETICS

AME is an autosomal recessive monogenic disorder. The syndrome is caused by non-functional mutations in the HSD11B2 gene. The gene is located on the long arm of chromosome 16 (16q22) and is approximately 6 kb in length containing five exons. In 1995, the first muta-tion in the HSD11B2 gene was discovered in a consan-guineous Iranian family with three siblings suffering from AME [15]. Subsequently, more than 40 causative mutations in the HSD11B2 gene have been identified in patients affected with AME [16]. As seen in Figure 6A.2,

CliniCAl PREsEnTATion And diAgnosis 241

R74GP75,∆ 1nt

C-T, nt14A-G, nt1

771C>GL114,∆6nt

C1393T

1 2 3 4 5

A221VL170RS180FR186CR208C

R208H;R337H,∆3ntR213C

D223NY226NP227LY232C

Y232L,∆9ntA237VD244N

F246,+1ntL250RL250PL251SC771G

R279C∆299

N286∆1ntG305∆11nt

A328VV332,ins9nt

R337CR337H, ∆Y338

E356,∆1ntR359WR374XL376P

FIGURE 6A.2 Steroid 11β-HSD2 gene and its mutations. Mutations leading to AME in the HSD11B2 gene on the long arm of chromosome 16 are distributed in all five exons and also in the intron regions of the gene. Most mutations are located in exons 3,4, and 5. Modified from ref. [17].

the mutations are distributed in all five exons and also in the intron regions of the gene.

Correlations between the severity of the enzymatic defects and clinical presentation have been found [18,19]. Most of these mutations have been characterized by in vitro expression studies and have been shown to have varying degrees of enzyme activity. The mutations can be classified as “severe” or “mild,” as shown in Table 6A.1. Severe mutations have a very low enzyme activity, of broadly <10%. Two mild mutations were identified in patients with the clinical markers of AME (low aldoste-rone, hypertension, abnormal ratio of urinary free corti-sol [UFF]/urinary free cortisone [UFE]); in vitro studies demonstrated a very mild alteration in enzyme activity [4,20].

CLINICAL PRESENTATION AND DIAGNOSIS

AME typically presents early in life. In addition to hypertension, clinical features may include failure to thrive, poor growth, polydipsia, polyuria, and muscle weakness. Also, birthweights are significantly lower than those of their unaffected siblings [31]. Biochemical pro-files demonstrate metabolic alkalosis and severe hypo-kalemia. Insidious end-organ damage may arise at an early age because of chronic elevation of blood pressure and metabolic derangements, particularly hypokalemia. Renal, neurological, cardiovascular, and ocular systems

are particularly sensitive to damage. Left-ventricular hypertrophy is the most common cardiac abnormality seen. Renal manifestations include nephrocalcinosis, hypercalciuria, and renal insufficiency. Severe hypoka-lemia can lead to nephrogenic diabetes insipidus mani-festing as polydipsia and polyuria. Paralysis, respiratory failure, muscle weakness, and cardiac arrhythmias can also result from hypokalemia.

Pubertal delay is observed in all severe AME patients where data is available. Puberty is delayed secondary to poor weight gain, growth failure, and delayed bone age. The delayed puberty observed in patients with AME is unrelated to the genetic disorder, but is attributable to failure to thrive that is the result of the genetic disorder.

In evaluating a hypertensive child, it is important for clinicians to utilize proper tools to measure and inter-pret the blood pressure (BP) readings. The preferred method of BP measurement is auscultation using a mer-cury sphygmomanometer connected to the appropriate size cuff. Systolic blood pressure (SBP) is determined by the onset of the “tapping” Korotkoff sounds (K1) while diastolic blood pressure (DBP) is defined as the fifth Korotkoff sound (K5), or the disappearance of Korotkoff sounds. Use of automated devices can be used for BP measurement in newborns and young infants, in whom auscultation is difficult. An elevated BP reading obtained with an oscillometric device should be repeated with aus-cultation. To determine percentile of BP, values are com-pared to normal BP in children and adults adjusted for age, sex, and height. Hypertension is defined as average

6A. APPARENT MINERALOCORTICOID EXCESS242

TABLE 6A.1 Mutations in 11β-Hsd2 gene Classified as severe or Mild

Mutation

In vitro percentage activity conversion of cortisol to cortisone

Expression system Ref

SEVERE MUTATIONS AS DEFINED BY EXPRESSION STUDIES

E356-1 frameshift

0 CHO cell [21]

R337H, ΔY338 0 CHO cell [22]

R186C 0 CHO cell [21]

L250P, L251S

0 CHO cell [21,22]

R208C 7 CHO cell [22]

R337C 0 CHO cell [22,23]

Δ299 0 CHOP cell [24]

Y226N 2 HEK-293 cell [25]

L114, Δ6nt Near 0 HEK-293 cell lysate

[26]

L179R 0 CHO whole cell [19]

R208H 0 CHO whole cell [19]

S180F 1.8 CHO cell lysate [19]

A237V 3.1 CHO cell lysate [19]

A328V 0.6 CHO cell lysate [19]

R208H 0 HeLa cells and COS-1 cells

[27]

R213C <5 CHO cell [28]

A328V <5 CHO cell [28]

R208C 4 CHO cell [22]

R213C 7 CHO cell [22]

Y232C 1.5 HEK-293 [29]

R359W 5 HEK-293 [29]

L376P 9 HEK-293 [29]

SEVERE MUTATIONS AS BASED ON PREDICTION MODELS

R74G Predicted to generate stop codon leading to a truncated protein

ND [12]

R75Δ1nt Predicted to generate stop codon leading to a truncated protein

ND [12]

A221V Prediction of pre-mRNA splicing site interference

ND [12]

Ivs3+1G>A Destroy donor splice site sequence

ND [29]

Y232Δ9nt Completely inactive due to abolish catalytic site

ND [22]

SBP and/or DBP that is ≥95th percentile for gender, age, and height on three or more occasions. Elevated BP must be confirmed on repeated visits before characterizing a child as having hypertension.

All of the AME patients reported until 1998 had the characteristic signs of severe AME. In 1998 the first patient with a mild form of AME [32] associated with mutations that resulted in an 11β-HSD2 protein with attenuated activity was reported. Subsequently, addi-tional patients have been reported [29]. Table 6A.2 indi-cates the difference in phenotype in the mild and severe forms of AME. Only three clinical features of mild AME are the same as in severe AME: low renin activity, low aldosterone concentrations, and elevated ratio of tetra-hydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE).

In AME, low plasma renin activity (PRA) suggests a volume-expansion hypertension, which responds to dietary sodium restriction. All steroid concentrations, including aldosterone, are very low. The biochemical diagnosis of AME is made by indirectly measuring the ratio of cortisol to cortisone through the ratios of their uri-nary metabolites. As shown in Figure 6A.1, cortisol can be metabolized to tetrahydrocortisol and allotetrahydro-cortisol independent of 11β-HSD2 activity and excreted in urine. Cortisone is further metabolized to tetrahydro-cortisone by 5β-reductase and 3α-hydroxysteroid dehy-drogenase. The metabolite ratios are calculated, each reflecting a different aspect of enzyme function. The ratio of tetrahydrocortisol (THF) + allo-THF/tetrahy-drocortisone (THE) represents global function of HSD [33]. The ratio of urinary free cortisol (UFF)/urinary free cortisone (UFE) represents kidney HSD function [34].

Mutation

In vitro percentage activity conversion of cortisol to cortisone

Expression system Ref

771 C>G Aberrant splicing ND [29]

R374X Premature stop codon ND [30]

N286-1 frameshift

Extrapolated from E356-1 frameshift

ND [31]

D224N Algorithm developed by Chou and Fasman prediction

ND [31]

MILD MUTATIONS AS BASED ON EXPRESSION STUDIES

P227L Altered enzyme kinetics (Km increased by 5)

CHOP cell and homogenate

[15]

R279C Altered enzyme kinetics in homogenate (Vmax reduced by 33%)

CHOP homogenate

[20]

TABLE 6A.1 Mutations in 11β-Hsd2 gene Classified as severe or Mild — (cont’d)

ARy 243

suMM

Elevated ratios are consistent with 11β-HSD2 enzyme dysfunction or deficiency.

Originally, AME was described through the plasma half-life of tritiated [11-3H] cortisol which, when metabo-lized by 11β-HSD2, yields tritiated water and cortisone. The plasma cortisol half-life is prolonged at 120–190 min-utes compared to a half-life of 70–90 minutes in controls. This may have more accurately reflected renal 11β-HSD2 activity [35]. However, this diagnostic method, which required administration of radioisotopes, has been dis-continued in clinical practice.

TREATMENT

The treatment of AME is focussed on the correction of hypokalemia and hypertension. Spironolactone, a min-eralocorticoid receptor antagonist, is the medication of choice. Pharmacologically, it binds competitively and protects the receptors against any excess mineralocorti-coid activity. This competitive inhibition can be overcome by increased cortisol concentrations secreted in response to stress. Follow-up studies of AME patients treated with

TABLE 6A.2 Clinical Parameters Classifying severe Versus Mild Forms of AME

Clinical parameter Severe AME Mild AME

Birth weight (kg) Low (1.8–2.6) Normal (2.7–3.6)

Age at diagnosis (years)

1–14 12.6–36

Height and weight Less than the 3rd percentile for age

Normal growth parameters

Blood pressure (mmHg)

Very elevated (systolic155–250/ diastolic 90–180)

Slightly elevated (systolic 148–155/diastolic 80–92)

Kidney function Abnormal Normal

Puberty Delayed Normal

BIOCHEMICAL FEATURES

Serum potassium (mmol/L)

1.7–3.5 3.1–5.0

Urinary cortisol/cortisone metabolites [THF+5αTHF/THE]

Markedly elevated (6.7–33.0)

Moderately elevated (3.0–5.6)

Percentage conversion of F to E*

0–6.0 31–58.4

Renin Low renin (<0.12–7.9 ng/mL/h)

Low renin (0.14–0.7 ng/mL/h)

Aldosterone Low to absent aldosterone (undetectable –6 ng/dL)

Low to absent aldosterone (undetectable)

* Test no longer done.

spironolactone revealed significant improvement in clinical symptoms over a 13-year period. This suggests that early diagnosis and adequate treatment are impor-tant [4,31]. A reduction in dietary sodium and potassium supplementation has also been shown to be beneficial. Although other antihypertensive medications can be used, spironolactone and potassium supplement remain the main treatments for AME. In patients with hypercal-ciuria and/or nephrocalcinosis, a thiazide diuretic may be added. Loop diuretics should be used cautiously as they can aggravate hypokalemia and alkalosis.

Additional treatment may be required to address hypertensive end-organ damage. However, despite treatment that lowers blood pressure, some patients suf-fer severe consequences of AME, within years of diag-nosis. The mortality is more than 10%, due to stroke, cerebral hemorrhage, and infarction [33].

Dexamethasone has been used, but is not effective in all. Dexamethasone is a synthetic glucocorticoid similar to cortisol and therefore suppresses endogenous cortisol production by the adrenal glands. It lowers blood pres-sure to normal in 60% of patients. However, dexametha-sone has been shown to aggravate AME in some patients by worsening hypertension and potassium wasting.

Renal transplantation successfully reversed the clini-cal symptoms of AME and normalized cortisol metab-olism in two AME patient [36,37]. In 2013, a patient followed from birth through childhood with AME received a renal transplant from his wife at age 33. The patient was cured of AME with reduction in blood pres-sure, remission of hypokalemic alkalosis, and reversal of the ratio of cortisol/cortisone metabolites [37]. Although not considered standard of care, renal transplantation in early adolescence should be considered as a therapeutic strategy to prevent terminal renal failure.

SUMMARY

Steroid 11β-HSD2 is an important enzyme in blood pressure homeostasis. It is encoded by the HSD11B2 gene, located on chromosome 16 (16q22) and consisted of five exons spanning approximately 6.2 kb. This enzyme, which converts cortisol (F) to inactive cortisone (E), is typically expressed in tissues where the mineralo-corticoid receptor is present. Impairment in 11β-HSD2 enzymatic activity results in an inefficient conversion of F to E, triggering hypertension through cortisol activa-tion of mineralocorticoid receptor. Severe AME is a well described but rare syndrome. The hallmark of AME is a state of mineralocorticoid excess, in the absence of aldo-sterone and the presence of an abnormal urinary steroid profile with an increase in the F:E ratio.

Hypertension is a very common disease worldwide and is an important public health challenge. One of

Proc Natl Acad Sci,. USA 1998;95:10200–5.

6A. APPARENT MINERALO244

the main factors contributing to its development is the amount of salt intake. Nevertheless, not all individuals respond to a salt load in the same way; some develop hypertension while others do not, suggestive of genetic variation in salt sensitivity. AME is a form of salt- sensitive monogenic hypertension and a mild form has been described. Further, in view of the critical role of 11β-HSD2 in ensuring selectivity of the mineralocorticoid receptor in the distal nephron, it has been suggested that minor abnormalities of this enzyme may explain salt sensitivity and pathogenesis in essential hypertension.

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CORTICOID EXCESS

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