Electrolyte & Blood Pressure 5:34-41, 2007

Review article

Hypertensive Hypokalemic Disorders

Kyu Bok Choi, M.D.

Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea

Hypokalemia is a common clinical problem. The kidney is responsible for long term potassium homo-
eostasis, as well as the serum potassium concentration. The main nephron site where K secretion is
regulated is the cortical collecting duct, mainly via the effects of aldosterone. Aldosterone interacts
with the mineralocorticoid receptor to increase sodium reabsorption and potassium secretion; the
removal of cationic sodium makes the lumen relatively electronegative, thereby promoting passive
potassium secretion from the tubular cell into the lumen through apical potassium channels. As a
result, any condition that decreases the activity of renal potassium channels results in hyperkalemia
(for example, amiloride intake or aldosterone deficiency) whereas their increased activity results in
hypokalemia (for example, primary aldosteronism or Liddle's syndrome). The cause of hypokalemia
can usually be determined from the history. If there is no apparent cause, the initial step is to see if
hypokalemia is in associated with systemic hypertension or not. In the former group hypokalaemia is
associated with a high mineralocorticoid effect or hyperactive sodium channel as in Liddle's syndrome.
In hypertensive hypokalemic patients, measurement of the renin, aldosterone, and cortisol
concentrations would be of help in differential diagnosis.

Hypokalemia, Hyperaldosteronism, Hypertension, Liddle's syndrome

6)
is the major route of potassium excretion, accounting
Introduction
for 90% of potassium loss daily. The remaining 10%
is excreted through the gastrointestinal tract. The
Potassium is the most abundant cation in the body.
kidney is therefore responsible for long-term potas-
Although extracellular potassium accounts for only 2%
sium homoeostasis, as well as the serum potassium
of total body potassium, it has a major effect on the
concentration.
ratio of intracellular to extracellular potassium and on
The main nephron site where K secretion is re-
the resting membrane potential. As a result, serum
gulated is the cortical collecting duct (CCD), mainly via
potassium is normally regulated around the narrow
the effects of aldosterone. Transport studies in this
range of 3.5-5.0 mEq/L.
tubule segment have demonstrated that potassium
Hypokalemia is a common clinical problem. De-
secretion is accomplished via apical potassium channels
creased intake, increased translocation into the cells,
(ROMK: luminal, ATP-regulated, inwardly rectifying K
or increased losses in the urine (or gastrointestinal
channel). The secretion of potassium in this nephron
tract or sweat) all can lead to hypokalemia. The kidney
segment is indirectly but tightly coupled to sodium
reabsorption via the amiloride-sensitive sodium
Received March 10, 2007. Accepted May 4, 2007.
Corresponding author : Kyu Bok Choi, M.D. channel; increased sodium reabsorption increases
Department of Internal Medicine, Ewha Womans whereas decreased sodium reabsorption decreases
University Hospital, 911-1 Mok-dong, Yangcheon-gu,
158-710, Seoul, Korea potassium secretion. Aldosterone interacts with the
Tel :+82-2-2650-5375, Fax :+82-2655-0984
E-mail : [email protected] mineralocorticoid receptor (MR) to increase sodium
 KB Choi : Hypertensive Hypokalemic Disorders

reabsorption and potassium secretion; the removal of concentrations would be of help in differential diag-
cationic sodium makes the lumen relatively electrone- nosis.
gative, thereby promoting passive potassium secretion This review discusses the biology of aldosterone and
from the tubular cell into the lumen through apical cortisol followed by a discussion of several forms of
potassium channels (Fig. 1). As a result, any condition hypertensive hypokalemic disorder.
that decreases the activity of renal potassium channels
results in hyperkalemia (for example, amiloride intake Aldosterone and cortisol synthesis
or aldosterone deficiency) whereas their increased
activity results in hypokalemia (for example, primary Aldosterone is synthesized in the zona glomerulosa
1, 2)
aldosteronism or Liddle's syndrome) . Increased of the adrenal cortex. In the zona glomerulosa pro-
aldosterone, in addition, can cause metabolic alkalosis gesterone is hydroxylated at C21 by CYP21A2 to yield
by increasing bicarbonate reabsorption in the collecting deoxycorticosterone. The three final steps in the con-
duct. version of this intermediate to aldosterone (11-beta-
The cause of hypokalemia can usually be deter- hydroxylation, 18-hydroxylation, and 18-methyl
mined from the history. If there is no apparent cause, oxidation) are catalyzed by a single mitochondrial
the initial step is to see if hypokalaemia is in asso- P450 enzyme (aldosterone synthase, CYP11B2,
ciation with systemic hypertension or not. In the former P450c11as) encoded by the gene CYP11B2. A similar,
group hypokalaemia is associated with a high highly homologous enzyme, CYP11B1 (encoded by the
mineralocorticoid effect or hyperactive sodium channel gene CYP11B1), acts in parallel in the zona fasciculata
as in Liddle's syndrome. In normotensive patients, to convert 11-deoxycortisol to cortisol. The absence
hypokalaemia could be secondary to overt or occult of aldosterone synthase in the zona fasciculata prevents
gastrointestinal loss or due to renal potassium wasting aldosterone secretion from being regulated by ACTH.
(Table 1). In hypertensive hypokalemic patients, The human CYP11B2 is encoded by a gene closely
measurement of the renin, aldosterone, and cortisol related to CYP11B1, with over 90 percent homology at

Table 1 Work-up of Chronic Hypokalemia (more

than 24 hours of onset)
With normal blood pressure.
Increased potassium loss through gastrointestinal tract
diarrhea
laxatives
Increased potassium loss through kidney
diuretics,
hypomagnesaemia
renal tubular acidosis (proximal and distal)
genetic defects (for example, Bartter's syndrome,
Gitelman's syndrome)
With high blood pressure
Increased aldosterone
primary aldosteronism (low renin)
renal artery stenosis (high renin)
Cushing's disease (high renin)
Fig. 1. K+ transport at the principal cell of the cortical Normal or low aldosterone
collecting duct (CCD). MR, mineralocorticoid receptor; 11β hyperactive sodium channel (Liddle's syndrome)
-HSD, 11β-hydroxysteroid dehydrogenase; ENaC, epi- increased liquorice intake
thelial Na channel; ROMK, luminal ATP-regulated inwardly
rectifying K channel. [From Landau D : Cell Mol Life Sci [Modified from Rastergar A, Soleimani M : Postgrad Med J
77:759-764, 2001]
63:1962-1968, 2006]
 KB Choi : Hypertensive Hypokalemic Disorders

Cholesterol
17 α H
Pregnenolone 17-hydroxypregnenolone

17 α H
Progesterone 17-hydroxyprogesterone

21H 21H

Deoxycorticosterone 11-deoxycortisol

11 βH 11 βH CYP11B1
Corticosterone Cortisol
CYP11B2
18
Aldosterone

Zona Glomerulosa Zona Fasciculata

Fig. 2. Normal biosynthetic pathways for cortisol and aldosterone. 17α H, 17α–hydroxylase;
21H, 21-hydroxylase. 11 βH, 11-β hydroxylase; 18, 18-hydroxylase/oxidase. [From Freel
EM, Connel JNC : J Am Soc Nephrol 15:1993-2001, 2004]

the protein level. The CYP11B2 gene is located on has bi-directional activities, capable of carrying out
chromosome 8q24.3. both 11-oxoreductase (cortisone to cortisol) and
The last step in cortisol biosynthesis is the 11- dehydrogenase reactions (cortisol to cortisone). 11β-
beta-hydroxylation of 11-deoxycortisol, a reaction HSD2 is a unidirectional dehydrogenase inactivating
catalyzed by the mitochondrial enzyme CYP11B1. cortisol to cortisone. 11β- HSD2 exhibits a distinct
CYP11B1 is also encoded by a gene on chromosome tissue-specific expression in classical mineralocorti-
8q24.3, near the gene CYP11B2. The product of the coid target tissues, such as epithelial cells from the
CYP11B1 gene is a 51 kDa protein that is nearly distal nephron, colon and salivary glands, where it
identical to the CYP11B2 enzyme responsible for the serves to protect the MR from cortisol (Fig. 1). Thus,
terminal steps of aldosterone synthesis, except that it in vivo MR selectivity to aldosterone relies on the
lacks the ability to convert corticosterone to aldo- inactivation of cortisol to cortisone by 11β-HSD2 at
3)
sterone (Fig. 2) . the pre-receptor level. Aldosterone, in contrast to
cortisol, is not metabolised by 11β-HSD2.
Cortisol metabolism Following interconversion of cortisol and cortisone,
both steroids undergo A-ring reduction by 5α- and 5β
Circulating concentrations of cortisol are 100- -reductases and 3α-hydroxysteroid dehydrogenase
1000-fold higher than those of aldosterone. Further- (3α-HSD) to yield 5β-tetrahydrocortisol (THF), 5α-
more, cortisol has a high affinity for the MR. However, tetrahydrocortisol (allo-THF) and 5β-tetrahydrocor-
cortisol availability is modulated by two isoenzymes of tisone (THE). Overall 11β-HSD activity in the body
11β-hydroxysteroid dehydrogenase, 11β- HSD1 and is reflected by the ratio of total urinary cortisol and
11β-HSD2. Both enzymes control the interconversion cortisone metabolites: [THF+allo-THF]/THE (Fig.
4)
of biologically active cortisol to inactive cortisone. 11β 3A) .
-HSD1 is widely distributed but is most abundantly
expressed in liver and fat tissue. Principally the enzyme
 KB Choi : Hypertensive Hypokalemic Disorders

Fig. 3. A) Schematic depiction of the enzymatic activity involved in

glucocorticoid metabolism. In the liver, 5α- and 5β-reductases and 3α
-hydroxysteroid dehydrogenases (3α-HSDs) convert cortisol to 5α-
tetrahydrocortisol (allo-THF) and 5β-tetrahydrocortisol (THF) and
convert cortisone to tetrahydrocortisone (THE). B) In normal subjects,
urinary excretion of cortisol metabolites compared to the cortisone
metabolite is equivalent, resulting in a [THF+allo-THF]/THE ratio of 1.
Mutations that inactivate 11β-HSD2 in apparent mineralocorticoid excess
(AME) patients result in a grossly increased urinary excretion of THF and
allo-THF compounds, whereas THE is dramatically reduced, resulting in
a high [THF+allo-THF]/THE ratio. [From Hammer F, Stewart PM : Best
Pract Res Clin Endocrinol Metab 20:337-353, 2006]

Primary aldosteronism (PA) Table 2 Differential Diagnosis of Mineralocorticoid

Hypertension : Diagnosis Based on Response of
Mineralocorticoid

Mineralocorticoid hypertension is a potentially re- Aldosterone

Adrenal adenoma
versible cause of hypertension that is characterized by
Bilateral adrenal hyperplasia
the triad of hypertension, metabolic alkalosis, and Adrenal carcinoma
5, 6) GRA (glucorticoid-remediable hyperaldosteronism)
Cortisol via 11β-hydroxysteroid dehydrogenase
hypokalemia (Table 2) .
PA is the most common form of mineralocorticoid deficiency/inhibition
hypertension. The prevalence has varied from 0.5% to AME (apparent mineralocorticoid excess syndrome)
Licorice and carbenoxolone ingestion
10% of hypertensive patients. The two major subtypes Ectopic ACTH syndrome
are bilateral adrenal hyperplasia and adrenal adenoma. - Essential hypertension variant
- Pre-eclampsia
Familial forms of PA include familial hyperaldostero-
Deoxycorticosterone
nism type 1 (FH-1) or glucocorticoid-remediable Congenital adrenal hyperplasia (11β-hydroxylase
deficiency and 17-hydroxylase deficiency)
aldosteronism (GRA), and FH-2 (familial occurrence
Glucocorticoid receptor mutations
of bilateral adrenal hyperplasia, adrenal adenoma or Metyrapone, mifrestone ingestion
both).
[From Khosla N, Hogan D : Semin Nephrol 26:434-440, 2006]
Screening for PA is a challenging topic. An im-
portant point is that not all patients with PA present
 KB Choi : Hypertensive Hypokalemic Disorders

with hypokalemia. Any of the following clues may or unilateral hyperplasia. Patients with bilateral adrenal
prompt screening: (i) hypertension and unexplained hypereplasia, and those with adrenal adenoma or
persistent hypokalemia or diuretic-induced hypokale- unilateral hyperplasia who are not candidates for
mia; (ii) severe hypertension (i.e. Joint National Com- surgery or those who decline surgery, should receive
mittee 7 stage 2 hypertension, 160 mmHg systolic a mineralocorticoid receptor antagonist. Two drugs of
and/or 100 mmHg diastolic; (iii) patients with difficult- this class are currently available: spironolactone and
to-control hypertension requiring three or more drugs; eplerenone. Sprinolactone is more cost effective but
(iv) when hypertension manifests at a young age (e.g. has many unwanted antiandrogen and progesterone
<20 years); (v) when adrenal incidentaloma is present; side effects. Substitution of the 17- thioacetyl group
(vi) whenever an evaluation for secondary of spironolactone with a carbomethoxy group generates
hypertension is considered; and (vii) hypertensive eplerenone. The affinity of eplerenone for progestin
relatives of patients with PA. and androgen receptors is as much as 500-fold lower
The aldosterone renin ratio (ARR) has become the than that of spironolactone, thus nullifying the adverse
most widespread method of screening. Although there effects associated with progesterone agonism and
are no good data defining the optimal conditions and androgen antagonism.
cut-off values of the ARR, an ARR 20 ng/dL per ng/
mL per hour (554 pmol/L per ng/mL per hour) in Familial forms of PA
combination with a plasma aldosterone concentration 15
ng/dL (416 pmol/L) in a morning blood sample from an GRA (FH-1) first reported in 1966 is the most
ambulant patient with normokalemia is indicative of common monogenic cause of human hypertension. GRA
primary aldosteronism. is an autosomal-dominant form of low rennin hyper-
Once an abnormal ARR is seen then confirmatory test tension in which aldosterone excess is present under
should be performed. The most widely used con- the influence of ACTH rather than angiotensin II.
firmatory tests for PA are intravenous saline loading, Subjects with GRA have two normal copies of genes
oral sodium loading and the fludrocortisone suppres- encoding aldosterone synthase and 11β-hydroxylase,
sion test (FST). The captopril suppression test (CST) but they also have an abnormal gene duplication. This
has also been introduced as a potential confirmatory hybrid, or chimeric, gene combines the ACTH-
technique for primary aldosteronism. Because the CST responsive promoter sequence of the 11β-hydroxy-
did not depend on sodium intake, it could be performed lase gene fused to the more distal aldosterone-
in patients for whom salt loading is contraindicated synthase coding sequence. As a result, aldosterone
(such as those with cardiac failure) and is an efficient synthase is ectopically expressed in the cor-
7)
alternative test . As treatment options differ for tisol-producing zone of the adrenal cortex under the
different forms of primary aldosteronism, it is important regulation of ACTH. The chimerism also results in the
to determine the disease subtype. If biochemical production of the hybrid steroids 18-oxocortisol and
confirmation is documented, high resolution adrenal 18-hydroxycortisol that can be used as diagnostic
computed tomography and/or magnetic resonance aides8).
imaging should be performed. When the patient and GRA is usually characterized by severe hyperten-
clinician wish to pursue surgical treatment, adrenal vein sion, sodium retention and suppressed plasma renin
sampling should also be performed in most patients. activity. Unlike other mineralocorticoid-excess states,
Unilateral laparoscopic adrenalectomy is the optimal hypokalemia in the absence of diuretic treatment is
treatment for patients diagnosed with adrenal adenoma uncommon. The reason is unclear but may be related
 KB Choi : Hypertensive Hypokalemic Disorders

the influence of aldosterone on the circadian rhythms be normotension, and not normalization of biochemical
of ACTH release. A blunted aldosterone response to markers, such as urinary 18-oxosteroid or serum
dietary potassium in GRA subjects may also explain the aldosterone levels, since these remain elevated in the
9)
minimized potassium loss . An important clinical majority of patients whose blood pressure normalizes.
feature associated with GRA is early hemorrhagic The type I mineralocorticoid receptor antagonists,
stroke and ruptured aneurysm, occurring at a mean age eplerenone and spironolactone, are effective treatment
of 32 years and associated with high mortality (61%). alternatives. Amiloride and triamterene, sodium-epi-
As a result, screening with magnetic resonance imaging thelial channel antagonists, have also been used suc-
angiography, beginning at puberty and then every five cessfully.
years, has been recommended to detect asymptomatic In clinical practice, FH-2 is indistinguishable from
intra-cranial aneurysms. bilateral adrenal hyperplasia and adrenal adenoma, and
Diagnosis requires a high index of suspicion because the diagnosis can be made only by documenting primary
GRA patients can have mild hypertension and are aldosteronism in other family members and excluding
typically normokalemic; such patients are often GRA with genetic testing.
misdiagnosed as having 'essential' hypertension. Clues
pointing to a possible diagnosis of GRA include early Apparent mineralocorticoid excess syndrome
onset of hypertension in youth (before age 20 years), (AME)
a family history of early onset hypertension or early
cerebral hemorrhage (before age 30 years), preci- AME is an autosomal-recessive disorder charac-
pitation of hypokalemia when treated with potas- terized by clinical features suggesting excessive pro-
sium-wasting diuretics, and refractory hypertension duction of a mineralocorticoid-like substance with
refractory to standard treatments. hypertension, plasma volume expansion, hypokalemic
A confirmatory diagnosis can be made with either alkalosis, and a suppressed renin-angiotensin-aldo-
a dexamethasone-suppression test, measurement sterone system. AME is the outcome of defective 11β
12)
urinary 18/hydroxyl/oxy steroids, or direct genetic - HSD2 . In its full expression AME is rare, with
testing. In GRA the zona fasciculata ectopically fewer than 100 cases reported worldwide, but presen-
produces aldosterone under the regulation of ACTH. tation is dramatic. Usually patients are children with
As a result, when 0.5 mg of dexamethasone is given low birth weight, failure to thrive, short stature, and
every 6 hours for two days, suppression of aldo- severe, often fatal, hypertension with hypokalemic
sterone to undetectable levels (<4ng/dL) is seen in metabolic alkalosis and muscle weakness. Hypokale-
10)
GRA subjects . GRA patients excrete large amounts mic nephropathy sometimes causes nephrocalcinosis,
11)
of urinary 18-hydroxycortisol and 18-oxocortisol polycystic kidney, and nephrogenic diabetes insipidus
(socalled ‘hybrid’ steroids) reflecting the action of manifesting as thirst and polyuria. Renal insufficiency
aldosterone synthase on cortisol in the zona is not rare.
fasciculata. Biochemical abnormalities comprise suppressed
Treatment of GRA manipulates the dependency of PRA, undetectable serum aldosterone levels and hy-
aldosterone secretion on ACTH. Treatment with low pokalemia. The diagnosis is based on urinary cortisol
dose glucocorticoids is effective. The typical dose for metabolites, which show a greatly increased [THF+
adults ranges form 0.125 mg to 0.25 mg dexametha- allo-THF]/THE ratio of 8-80 (reference range 0.7-
sone, or 2.5 mg to 5 mg of prednisolone daily, usually 1.3) with very low or absent levels of THE clearly
administered at bedtime. The therapeutic goal should suggesting a defect in 11β-HSD2 activity (Fig. 3B)4).
 KB Choi : Hypertensive Hypokalemic Disorders

Interestingly, the excretion of 5α-cortisol metabolites kalemic alkalosis found in 95-100% of cases, in con-
exceeds that of 5β-cortisol metabolites, resulting in a trast to <10% in other forms of Cushing's syndrome.
high urinary allo-THF/THF ratio, which suggests an ACTH has no direct effect on 11β-HSD2, but the
additional defect in 5β-reductase activity. However, enzyme is saturated in ectopic ACTH syndrome by very
the [THF+allo-THF]/THE ratio provides only an high concentrations of ACTH-dependent 11β- HSD
overall index of 11β-HSD activity within the body. substrates such as cortisol and corticosterone. Both the
Thus, a high urinary free cortisol (UFF) to urinary free urinary ratio of THF+allo-THF/THE and UFF/UFE are
cortisone (UFE) ratio will be diagnostic, as it only elevated, not because of impaired 11β- HSD2 activity,
reflects 11β-HSD2 activity in the kidney, but not 11β but because of substrate saturation17).
14, 15)
-HSD1 activity in the liver . DNA analysis is
required to confirm the diagnosis. Liddle syndrome
Treatment involves blockade of the MR with a high
dose of spirinolactone or eperlenone and potassium Liddle syndrome is a rare form of an autosomal-
repletion. Patients have been successfully treated with dominant disorder. This syndrome results from con-
the potassium sparing diuretics triamterene and/or stitutive activation of the epithelial Na channel (ENaC),
amiloride. Suppression of cortisol with dexamethasone resulting in sodium retention and urinary potassium and
has had variable success. Thiazide diuretics are in- hydrogen ion wasting, causing hypokalaemic alkalosis
dicated when hypercalciuria and/or nephrocalcinosis with early onset severe hypertension and suppressed
are present. AME was reported “cured” in one patient renin and aldosterone (due to low renin plus
following kidney transplantation due to the normal 11β hypokalaemia)18).
-HSD2 activity of the transplanted kidney12). The amiloride-sensitive ENaC is comprised of three
An acquired form of AME can be seen with licorice subunit proteins (α, β and γ) having short cytosolic
ingestion. The active ingredient of licorice is termini, 2 transmembrane domains, and a large
glycyrrhizic acid, which is hydrolyzed into its aglicone extracellular loop. The α subunit appears to be re-
glycyrrhetinic acid in vivo. A number of commercial quired for the assembly or function of the whole
preparations containing licorice are available such as complex. Liddle syndrome is caused by missense or
herboristic and cosmetic; moreover some pre- frameshift mutations that delete or disrupt a proline-
parations are used as a cough remedy. A preparation rich motif (PPPxY) in the intracytoplasmic C-terminal
of the root of the licorice plant (carbenoxolone) was ‘tails’ of the β or γ subunits. These mutations increase
successfully used to treat patients with peptic ulcera- expression of the ENaC at the cell surface by disrupting
tion. Glycyrrhizic and glycyrrhetinic acids have a very its binding to Nedd4-2, a ubiquitin- protein ligase that
low affinity for the MR, but are very potent competitive targets the ENaC for degradation19).
inhibitors of 11β-HSD216). The condition should be suspected in patients (es-
pecially children) who present with hypertension and
Ectopic ACTH Syndrome hypokalaemic alkalosis. It can be distinguished from
hypertensive forms of congenital adrenal hyperplasia,
Cushing’s syndrome can also present signs with primary glucorticoid resistance and AME by normal
signs and symptoms of mineralocorticoid excess, levels of 17α-hydroxyprogesterone, 11β-deoxycor-
particularly in the sub-group caused by ectopic ACTH tisol and cortisol, normal ratios of free cortisol to
production. The ectopic ACTH syndrome is charac- cortisone (or metabolites) in urine and failure to
terized by mineralocorticoid excess, with hypo- respond to dexamethasone suppression of ACTH.
 KB Choi : Hypertensive Hypokalemic Disorders

Although mineralocorticoid antagonist (spironolac- 8) McMahon GT, Dluhy RG : Glucocorticoid-remedi-

able aldosteronism. Arq Bras Endocrinol Metabol
tone) is obsolete, K-sparing diuretics, specific ENaC
48:682-686, 2004
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Liddle’s syndrome. The use of amiloride and triam- aldosteronism (GRA): diagnosis, variability of
phenotype and regulation of potassium homeostasis.
terene are enhanced by dietary salt restriction.
Steroids 60:48-51, 1995
10) Litchfield WR, New MI, Coolidge C, Lifton RP,
Conclusion Dluhy RG : Evaluation of the dexamethasone sup-
pression test for the diagnosis of glucocorticoid-
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della C : Serum 18-hydroxycortisol in primary
unexplained hypokalemia, and metabolic alkalosis.
aldosteronism, hypertension, and normotensives.
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104-111, 2001
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antagonist to prevent the negative effects of aldo-
63:550-557, 1986
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