J Am Soc Nephrol 13: 191–196, 2002
Glycyrrhetinic Acid Decreases Plasma Potassium
Concentrations in Patients with Anuria
ANDREAS SERRA, DOMINIK E. UEHLINGER, PAOLO FERRARI,
BERNHARD DICK, BRIGITTE M. FREY, FELIX J. FREY, and BRUNO VOGT
University Hospital of Berne, Berne, Switzerland.
Abstract. Licorice-associated hypertension is thought to be due
to increased renal sodium retention. The active compound of
licorice, glycyrrhetinic acid (GA), inhibits renal 11␤-hydroxy-
steroid dehydrogenase type 2 (11␤-HSD2) and by that mech-
anism increases access of cortisol to the mineralocorticoid
receptor that causes renal sodium retention and potassium loss.
In addition, a direct vascular effect of 11␤-HSD activity has
recently been incriminated to promote hypertension, a conten-
tion based on in vitro observations. This investigation was
designed to establish whether this extrarenal effect of 11␤-
HSD is relevant for BP regulation and potassium concentra-
tions in plasma. In a prospective, double-blind, cross-over
study, seven patients with anuria on chronic hemodialysis were
randomly assigned after a baseline period of 2 wk to placebo or
The ingestion of licorice causes hypokalemic hypertension
with low renin and low aldosterone concentrations. The mech-
anism of this hypertension is the inhibition of the enzyme
11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2) by
glycyrrhetinic acid (GA), the active ingredient of licorice (1–
3). 11␤-HSD2 catalyzes the dehydrogenation of 11␤-hydroxy-
glucocorticoids, has a nanomolar Km for cortisol, uses NAD⫹
as cofactor, and is localized in the endoplasmic reticulum
membrane (4,5). The enzyme exhibits a cell-specific constitu-
tive expression in mineralocorticoid target tissues, such as
epithelial cells from the colon and the renal cortical collecting
tubule (4,6), where it regulates the intracellular localization of
the mineralocorticoid receptor (MR) and protects the MR from
promiscuous activation by 11␤-hydroxyglucocorticoids, in-
cluding cortisol (2,3,7,8). Loss of function mutation or inhibi-
tion of 11␤-HSD2 allows glucocorticoids to promote renal
sodium retention and potassium excretion in the cortical col-
lecting tubule, with subsequent volume expansion, hyperten-
sion, and suppression of renin and aldosterone (9 –11).
Recent evidence has suggested that the increase in BP as-
sociated with decreased 11␤-HSD2 activity is not only because
of enhanced renal sodium retention but also a direct vascular
Received June 12, 2001. Accepted June 23, 2001.
Correspondence to Dr. Bruno Vogt, Division of Nephrology and Hypertension,
Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland.
Phone: 4131-632-3144; Fax: 4131-632-9734; E-mail: bruno.vogt@insel.ch
1046-6673/1301-0191
Journal of the American Society of Nephrology
Copyright © 2001 by the American Society of Nephrology
GA (1 g/d) for 2 wk, separated by a washout phase of 3 wk.
The ratio of plasma cortisol/cortisone, determined by gas chro-
matography–mass spectrometry, increased in all patients after
GA intake (F ⫽ 9.705; P ⬍ 0.004), which indicates inhibition
of 11␤-HSD. Twenty-four– hour BP values did not change
throughout the study. The increase of the plasma cortisol/
cortisone ratio was paralleled by a decline in the plasma
potassium concentration in every patient. The mean ⫾ SD
plasma potassium concentration decreased from 5.5 ⫾ 0.6
mM/L at baseline to 4.9 ⫾ 0.7 and 4.5 ⫾ 0.8 mM/L after 1 and
2 wk on GA, respectively (F ⫽ 9.934, P ⬍ 0.003). Extrarenal
11␤-HSD activity influences serum potassium concentrations
but does not regulate BP independently of renal sodium
retention.
effect (12–14). Expression of 11␤-HSD2 is found in human
vascular smooth-muscle cells (15). In these cells, inhibition or
downregulation with an antisense DNA of 11␤-HSD2 in-
creased the glucocorticoid induced vascular angiotensin II
binding (15). In intact rat vascular rings, the contractile re-
sponse to angiotensin II and catecholamines was enhanced
when the dehydrogenase reaction of 11␤-HSD was inhibited
by licorice derivatives (12,13,15). Furthermore, skin vasocon-
striction of cortisol was shown to be potentiated by the 11␤-
HSD inhibitor GA in humans (16). Whether and to what extent
these extrarenal effects of 11␤-HSD2 are relevant for BP
regulation is unknown. To dissect the vascular from the renal
tubular effect of 11␤-HSD2, we studied the impact of inhibi-
tion of 11␤-HSD2 with GA on the BP in patients with anuria
on chronic hemodialysis.
Materials and Methods
Patients and Study Design
A prospective, placebo-controlled, double-blind, crossover study
approved by the local ethics committee was performed in 12 patients
with anuria on chronic hemodialysis. All patients gave written in-
formed consent. Three patients did not complete the study: one
received a kidney transplant, one was operated for hip fracture, and
one patient withdrew. Two patients were excluded from the study, one
because of progesterone medication and one because of ⬎10% dry
weight gain during the placebo period. The remaining seven patients,
three women and four men with a mean ⫾ SD age of 58 ⫾ 14 yr, had
a body-mass index of 24 ⫾ 6 and were dialysed three times weekly for
3.46 ⫾ 0.37 h by use of polysulfone filters and dialysate that con-
tained bicarbonate. Dialysis data are given in Table 1. The effective
Kt/V was calculated according to the method of Daugirdas et al.
192 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 191–196, 2002

Table 1. Dialysis data

Dialysate Composition
Blood Flow Effective Ultrafiltration (mM/I)
Patient Filter Time of HD (h) (ml/min) Kt/V (L; mean ⫾ SD)a
Na⫹ K⫹ Ca⫹⫹

DE HF 80S 3.5 400 1.24 2.17 ⫾ 0.49 140 1.5 1.75

AS HF 60S 3.5 270 1.17 1.42 ⫾ 0.35 140 2.0 1.25
ME HF 80S 3.0 400 1.19 2.09 ⫾ 0.41 140 2.0 1.75
PR HF 80S 3.5 500 1.05 2.59 ⫾ 0.6 140 1.5 1.75
GL HF 80S 3.75 380 1.09 1.51 ⫾ 0.46 140 2.0 1.25
ID HF 80S 3.0 400 1.02 1.0 ⫾ 0.34 140 1.5 1.25
LK HF 80S 4.0 400 1.19 2.72 ⫾ 0.49 140 1.5 1.25
a
Mean values for the entire study period.

(17,18). Dialysis prescriptions, dry body weight, and drug therapy
were not changed throughout the study. The patients were instructed
to avoid products with licorice.
After a run-in phase of 2 wk, patients were randomized to either
GA (500 mg) or placebo given twice daily for 14 d. After a washout
phase of 3 wk, the groups crossed over. Hard gelatin capsules (No.
000; Eli Lilly Co., Indianapolis, IN) that contained 250 mg of 18␤-GA
or saccharose (Fluka, Buchs, Switzerland) were manufactured by the
pharmacy at the University Hospital (19).
Blood samples were obtained at the end of the run-in and washout
phase as well as after 1 and 2 wk of placebo or GA intake. These blood
samples were collected before start of the hemodialysis session after 10
min supine rest. The hemodialysis sessions chosen for blood collection
were always those after the long hemodialysis interval of 3 d.
The 24-h ambulatory BP monitoring was performed with an auto-
matic oscillometer (Profilomat 2; Disentronic Burgdorf, Switzerland)
on the nonaccess arm at the end of the run-in, washout, and placebo
and GA phases. BP was recorded every 15 min during the hemodi-
alysis sessions, every 30 min during the daytime off dialysis, and
every 60 min from 10:00 p.m. to 6:00 a.m. the next day.
Analysis of Plasma Steroid Metabolites by Gas
Chromatography–Mass Spectrometry
To 1 ml of plasma, 2.5 ␮g of medroxyprogesterone was added as
a recovery standard, and the sample was extracted with 10 ml of
dichlormethane. After centrifugation, the phases were separated, and
the organic phase (containing the unconjugated steroids) was evapo-
rated under a stream of nitrogen at room temperature. A 2.5-␮g
volume of stigmasterol was added as an internal standard, and the
sample was derived to form the methyloxime-trimethylsilyl ethers.
To the water phase (containing the conjugated steroids), 2.5 ␮g of
medroxyprogesterone was added as a recovery standard. Plasma pro-
teins were precipitated with 5 ml of methanol. After centrifugation,
the supernatant was transferred into a new tube and evaporated under
a stream of nitrogen at 60°C. The sample was reconstituted in 0.1 M
acetate buffer, adjusted to pH 4.6, and hydrolyzed with powdered
Helix pomatia enzyme (12.5 mg, Sigma) and 12.5 ␮l of ␤-glucuron-
idase/arylsulfatase liquid enzyme (Boehringer Mannheim). The result-
ing free steroids were extracted on a SEP PAK C18 cartridge. To this
extract, 2.5 ␮g of stigmasterol was added as an internal standard, and
the sample was derived to form the methyloxim-trimethylsilyl ethers.
Fractions were analyzed by gas chromatography–mass spectrometry
by use of a Hewlett-Packard gas chromatograph 6890 with a mass-
selective detector 5973 by selective ion monitoring. One characteristic
ion was chosen for each compound being measured. Mass 605 was
monitored for cortisol and mass 531 for cortisone. A temperature-pro-
gramed run from 210°C to 265°C over 35 min was chosen. Calibration
lines were established over the range of 10 to 500 ng/ml. Correlation
coefficients were ⬎0.97. The results of cortisol and cortisone levels
represent concentrations found as unconjugated cortisol and cortisone.
Plasma renin and aldosterone were determined by RIA.
Statistical Analyses
Statistical analyses were performed with the statistical software
package SYSTAT 9.0 for Windows (SPSS Inc., Chicago, IL).
ANOVA was used to determine the effect of time and treatment with
GA on measured parameters. Paired comparisons were done with the
two-tailed t test.
Results
BP and Body Weight
The 24-h BP measurements did not differ among the run-in,
placebo, washout, and GA phases. To determine whether GA
intake affected BP during the hemodynamic stress of hemodi-
alysis, BP was measured during dialysis treatment. In Table 2,
the BP values obtained at the end of the placebo and GA phase,
as well as the percent change versus baseline, are given.
Twenty-four-hour ambulatory BP values did not change
throughout the study. The decline in BP at 2 and 3 h was
independent of intake of GA (Table 2). The predialytic and
postdialytic weight change were independent of GA (Table 3).
Laboratory Data
One and two weeks after daily ingestion of GA, the ratio of
plasma cortisol/cortisone increased from 9.6 ⫾ 2.2 to 14.7 ⫾
4.7 and 15.4 ⫾ 5.7, respectively (F ⫽ 9.705, P ⬍ 0.004)
(Figure 1). This increase was observed in every patient, inde-
pendent of whether the run-in, placebo, or washout phase was
considered as the baseline. In Table 3, the mean (⫾SD) values
before and at the end of the placebo and GA phase are given.
The increase in the cortisol/cortisone ratio was mainly due to a
decline in cortisone concentrations (Table 3). After 2 wk of
daily ingestion of GA, the mean (⫾SD) plasma aldosterone
concentration was 74 ⫾ 36, compared with 152 ⫾ 148 pmol/L
at the end of the placebo period (Table 3). This difference was
J Am Soc Nephrol 13: 191–196, 2002 Glycyrrhetinic Acid in Patients with Anuria 193

Table 2. Mean ⫾ SD BP (mm Hg) and heart rate (per min) of patients on hemodialysis with and without glycyrrhetinic acid
for 2 wk and percentage of change versus baseline
Placebo Glycyrrhetinic Acid
Parameter
Percentage of Change Percentage of Change
BP BP
versus Baseline versus Baseline

24-hour ambulatory BP
systolic pressure 121 ⫾ 24 0.8 ⫾ 13 124 ⫾ 24 4.5 ⫾ 8.9
diastolic pressure 76 ⫾ 16 ⫺2.6 ⫾ 10 78 ⫾ 17 6.8 ⫾ 10.8
heart rate 77 ⫾ 12 1.1 ⫾ 3 76 ⫾ 11 ⫺3.3 ⫾ 2.5
At start of hemodialysis session
systolic pressure 131 ⫾ 16 ⫺5 ⫾ 10 130 ⫾ 18 0.5 ⫾ 13
diastolic pressure 84 ⫾ 10 ⫺2.3 ⫾ 12 82 ⫾ 9 ⫺2.6 ⫾ 19
heart rate 75 ⫾ 12 4.1 ⫾ 11 75 ⫾ 10 0.1 ⫾ 17
2 h after start of hemodialysis session
systolic pressure 104 ⫾ 25a ⫺5.7 ⫾ 16 110 ⫾ 17 2.0 ⫾ 11
diastolic pressure 64 ⫾ 14a ⫺8.1 ⫾ 14 70 ⫾ 11a 11.3 ⫾ 18
heart rate 78 ⫾ 18 3.8 ⫾ 10 83 ⫾ 13 ⫺0.3 ⫾ 7.2
3 h after start of hemodialysis session
systolic pressure 114 ⫾ 30 ⫺10 ⫾ 18 112 ⫾ 23 ⫺0.3 ⫾ 14
diastolic pressure 69 ⫾ 18 ⫺12 ⫾ 10 74 ⫾ 16 11 ⫾ 21a
heart rate 78 ⫾ 15 ⫺2.6 ⫾ 11 79 ⫾ 16 ⫺2.3 ⫾ 9
a
P ⬍ 0.05 compared with the corresponding values at start of hemodialysis.

statistically NS (P ⫽ 0.16). The corresponding plasma renin
values were not affected by the intake of GA (Table 3).
A decrease in plasma potassium was observed in every
patient after 1 and 2 wk of GA, i.e., from mean ⫾ SD values
of 5.5 ⫾ 0.6 mM/L at baseline to 4.9 ⫾ 0.7 and 4.5 ⫾ 0.8
mM/L after 1 and 2 wk, respectively (F ⫽ 9.934; P ⬍ 0.003)
(Figure 2). This decrease was observed whether the run-in,
placebo, or washout phase was considered the baseline. The
decline in the plasma potassium concentration paralleled the
increase in the cortisol/cortisone ratio in each patient (Figure 1;
Table 3). A plot of the ratios of cortisol/cortisone versus the
plasma potassium concentrations revealed a significant corre-
lation when the values after 1 wk (R ⫽ 0.685; P ⬍ 0.05;
Pearson two-tailed) or after 2 wk (R ⫽ 0.803; P ⬍ 0.01) were
considered as a group. The other plasma and hematology
parameters were not influenced by GA (Table 3).
Discussion
The present investigation reveals that BP does not increase
when 11␤-HSD2 activity is significantly inhibited by GA in
patients with anuria on hemodialysis. Compliance with the
treatment regimen was demonstrated by the increased ratio of
cortisol/cortisone in all subjects while on GA. The absence of
an effect of GA on BP cannot be explained by changes in
dietary habits, because body weight did not change as a func-
tion of time during the various study periods. Although un-
likely, it is conceivable that an extrarenal effect of 11␤-HSD2
on BP was concealed by the uremic disease state in this study.
For methodological reasons, however, it is not possible to
investigate the relevance of extrarenal 11␤-HSD2 for BP con-
trol in subjects with a normal renal function. Thus, despite the
methodological caveat, the notion that extrarenal 11␤-HSD2 is
relevant for BP control (12,13,15) has to be reconsidered.
In patients with a loss of function mutation of 11␤-HSD2 or
in subjects with an inhibited activity of 11␤-HSD2 by endobi-
otics or xenobiotics, the increase in BP is associated with
activation of MR by cortisol (1,20 –22). The same receptors
can be activated by the mineralocorticoid fludrocortisone. This
drug has been investigated elsewhere in patients on hemodial-
ysis (23). In line with our observations, these patients did not
exhibit an increase in BP or body weight (23). Thus, activation
of MR is unlikely to increase BP independently of a function-
ing kidney. The two models, prescription of fludrocortisone
and inhibition of 11␤-HSD2, however, cannot a priori be
expected to yield the same biological effect, because inhibitors
of 11␤-HSD2 enzymes do not only modulate access of endog-
enous 11␤-hydroxyglucocorticoids to the mineralocorticoid re-
ceptor but also to the glucocorticoid receptor (24); therefore,
the absence of an impact of the MR agonist fludrocortisone
does not preclude an effect of 11␤-HSD2 inhibition on BP.
Indeed, the influence of the modulation of the activity of
11␤-HSD2 on the contractility of aortic preparations or on
binding of angiotensin II on vascular smooth-muscle cells
appeared to be mediated by both glucocorticoid and mineralo-
corticoid receptors (12–14).
The administration of GA reduced the plasma potassium
concentrations in all subjects. This decline in plasma potassium
concentrations was not explained by changes in dietary potas-
sium intake for the following reasons. First, predialytic and
postdialytic weight did not change during the study periods.
Second, predialytic urea, phosphate, and creatinine concentra-
tions were not affected by the intake of GA. Third, all patients
194 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 191–196, 2002

Table 3. Mean ⫾ SD laboratory data and body weight in patients on hemodialysis (HD) with and without glycyrrhetinic
acid
Placebo Glycyrrhetinic Acid
Parameter
Day 0 Day 14 Day 0 Day 14

Body weight
before HD (kg) 70.0 ⫾ 15.6 70.4 ⫾ 16.6 69.5 ⫾ 15.5 70.1 ⫾ 16.8
after HD (kg) 68.8 ⫾ 15.3 68.5 ⫾ 16.5 67.6 ⫾ 15.4 68.2 ⫾ 16.8
Plasma parameters
cortisol (ng/ml) 135 ⫾ 63 131 ⫾ 51 120 ⫾ 37 133 ⫾ 42
cortisone (ng/ml) 13 ⫾ 7 14 ⫾ 7 13 ⫾ 6 9⫾3
ratio cortisol/cortisone 10.9 ⫾ 5.4 9.8 ⫾ 2.9a 9.6 ⫾ 2.2b 15.4 ⫾ 5.7a,b
renin (ng/L) 8.0 ⫾ 9.5 11.1 ⫾ 14.8 8.9 ⫾ 10.4 8.9 ⫾ 10.5
aldosterone (pmol/L) 143 ⫾ 109 152 ⫾ 148 169 ⫾ 192 74 ⫾ 36
sodium (mM/L) 136 ⫾ 2 136 ⫾ 2 136 ⫾ 1.7 138 ⫾ 3
potassium (mM/L) 5.6 ⫾ 0.7 5.7 ⫾ 0.6c 5.5 ⫾ 0.6d 4.5 ⫾ 0.8c,d
calcium (mM/L) 2.36 ⫾ 0.23 2.37 ⫾ 0.23 2.33 ⫾ 0.23 2.35 ⫾ 0.13
chloride (mM/L) 95 ⫾ 3.2 96 ⫾ 2.2 95 ⫾ 3.2 97 ⫾ 2.8
phosphate (mM/L) 1.8 ⫾ 0.3 1.82 ⫾ 0.13 1.7 ⫾ 0.4 1.72 ⫾ 0.33
creatinine (␮M/L) 722 ⫾ 164 764 ⫾ 186 732 ⫾ 223 801 ⫾ 204
urea (mM/L) 22.7 ⫾ 4.8 24.9 ⫾ 4.0 24.5 ⫾ 6.0 27.3 ⫾ 4.7
Hematology
hematocrit 0.37 ⫾ 0.03 0.37 ⫾ 0.05 0.36 ⫾ 0.05 0.36 ⫾ 0.04
white blood cell count (⫻109/L) 6.6 ⫾ 1.5 7.1 ⫾ 1.0 6.9 ⫾ 1.8 7.6 ⫾ 2.1
platelet count (⫻109/L) 282 ⫾ 79 271 ⫾ 81 259 ⫾ 68 263 ⫾ 72
a
P ⬍ 0.004, glycyrrhetinic acid day 14 versus placebo day 14.
b
P ⬍ 0.004, glycyrrhetinic acid day 14 versus placebo day 0.
c
P ⬍ 0.001, glycyrrhetinic acid day 14 versus placebo day 14.
d
P ⬍ 0.003, glycyrrhetinic acid day 14 versus day 0.

Figure 1. Plasma cortisol/cortisone ratios at baseline and 1 and 2 wk

after the intake of glycyrrhetinic acid or placebo (mean ⫾ SEM). Figure 2. Plasma potassium concentrations at baseline and 1 and 2 wk
after the intake of glycyrrhetinic acid or placebo (mean ⫾ SEM).

were dialysed for many years, educated by dietitians, and

nutritionally compliant with constant predialysis plasma potas-
sium for several months before they entered the study. A
decline in plasma potassium of the same magnitude as that
observed in this study has been described elsewhere by Singhal
et al. (23) in patients undergoing hemodialysis who were given
fludrocortisone. Although some of the latter patients investi-
gated were not anuric, it is likely that their loss of potassium
was extrarenal (23). The bowel is probably a major source of
extrarenal potassium loss in patients with anuria (25). Potas-
sium secretion is a well-established mechanism of rectal and
colonic mucosa (26,27). This loss is regulated at least in part by
MR and is amiloride sensitive (28). The MR activated driving
J Am Soc Nephrol 13: 191–196, 2002
force is a Na,K-ATPase (26,29). The activation of the MR
by fludrocortisone enhances the rectal electrical potential
difference, an effect that is mimicked by inhibiting 11␤-
HSD2 in segments of normal rectal colon obtained from
humans (30).
Our observation of a decreased plasma potassium without
substantial sodium retention or increase in BP by GA might be
the basis for a potentially useful novel strategy to treat patients
undergoing hemodialysis who have a tendency toward in-
creased potassium concentrations. Before this strategy is ap-
plied in clinical practice, the effect of aldosterone receptor
activation in the heart has to be considered. Sato et al. (31)
observed an association between cardiac hypertrophy and al-
dosterone concentrations in patients undergoing hemodialysis,
an effect that is in line with the growth-promoting activity of
aldosterone in nonepithelial cells (32). The potential relevance
of aldosterone-induced myocardial fibrosis has been demon-
strated in the Randomized Aldactone Evaluation Study trial
(33). In that trial, the blockade of aldosterone receptors by
spironolactone reduced morbidity and mortality in patients
with heart failure. Thus, activation of MR by a strategy de-
signed to inhibit 11␤-HSD2 by GA in patients on hemodialysis
might be harmful for the heart. On the other hand, our obser-
vation that activation of MR decreases plasma potassium con-
centrations indicates that the administration of spironolactone
for the prevention of myocardial fibrosis and heart failure
might increase the risk of hyperkalemia in patients on
hemodialysis.
In conclusion, this investigation has demonstrated that a
decreased 11␤-HSD2 activity does not increase BP in patients
on hemodialysis. Furthermore, a pivotal role of extrarenal
potassium loss by MR activation is suggested, an observation
that might be relevant in a time when the nephrology commu-
nity is tempted to prescribe spironolactone to patients on
hemodialysis.
Acknowledgments
We thank Elisabeth Calame and Claude Jenni for excellent tech-
nical assistance. This work was supported by two grants from the
Swiss National Foundation for Scientific Research (32-57205.99 and
31-061505.00) and by a grant from the Novartis Foundation for
Clinical Research.
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