APRIL 2005, VOL. 63, NO. 4
A B S T R A C T
Glycyrrhetinic acid, the active constituent of liquorice,
inhibits renal 11?-hydroxysteroid dehydrogenase. This allows
cortisol to stimulate mineralocorticoid receptors, which
can result in hypertension and hypokalaemia. Treatment
options are based on pathophysiological understanding.
Liquorice, the root of the Glycyrrhiza glabra, has been used
throughout the millennia for its taste and for medical
purposes. Natural liquorice root was found in the 3000-
year-old Tomb of King Tut. Soldiers of Alexander the
Great’s army chewed the root as a thirst quencher. Early
Greek physicians as Hippocrates used natural liquorice
to heal wounds and sore throats, and liquorice is an
extremely important herb in Chinese medicine. In the
Middle Ages it was used for treatment of hypotension.
In 1946, the Dutch physician F.E. Revers demonstrated
that liquorice was the active ingredient in a domestic
medicine used in the Netherlands, and reported good
results in the treatment of stomach ulcers. He also
observed, however, that many patients developed
hypokalaemia and an increase in blood pressure.
Following this Borst et al. demonstrated that liquorice and
cortisone had a synergistic effect in Addison’s disease.1
Later investigations showed that aldosterone secretion
was suppressed in liquorice-induced hypertension, thus
the expression ‘pseudohyperaldosteronism’ was used.
The hypertension responds to spironolactone, a blocker
of mineralocorticoid receptors (MRs), but no steroids
stimulating the MRs could be identified.
The mechanism by which both liquorice and the apparent
mineralocorticoid excess (AME) syndrome cause hyper-
tension was not understood until the discovery of the
11?-hydroxysteroid dehydrogenase isozymes (11?-HSDs).2
These isozymes catalyse the interconversion of cortisol
and cortisone. 11?-HSD type 1 is most abundantly
expressed in liver and adipose tissue, where it mainly
functions as a reductase, converting inactive cortisone to
The second isozyme, 11?-HSD2, is highly expressed in
mineralocorticoid target tissues such as renal cortex5,6and
salivary glands.7This isozyme has mainly dehydrogenase
activity and is already active at very low cortisol concentra-
tions. 11?-HSD2 plays a key role in regulating mineralo-
corticoid activity of cortisol. In vivo MRs are protected
from exposure to cortisol by activity of 11?-HSD2. This
isozyme rapidly metabolises the active mineralocorticoid
cortisol to its inactive metabolite cortisone, thus preventing
stimulation of MRs by cortisol. Aldosterone is not meta-
bolised by 11?-HSD2 and can therefore bind to the MRs.
Liquorice contains glycyrrhizin, in the intestine this is
converted to glycyrrhetinic acid (GA) which is absorbed.
GA inhibits activity of 11?-HSD2, this allows cortisol to
bind to the MRs resulting in a hypermineralocorticoid state.
Two case reports in this issue of the Netherlands Journal
of Medicine demonstrate that liquorice-induced effects
can present in very different ways. The report by Van den
Bosch et al. reminds us that chronic liquorice intake can
result in very serious symptoms, including rhabdomyolysis
and paralyis.8The case report by Janse et al. demonstrates
that liquorice-induced hypertension can occur at any age,
and that a high level of suspicion is required to elucidate
liquorice abuse.9This is also illustrated by the story of a 42-
year-old female patient in Ontario, Canada. She developed
hypokalaemia and mild hypertension without apparent
cause. Only after several weeks it became clear that her
family in the Netherlands had sent her boxes of liquorice as
a Christmas present. As she enjoyed the taste she finished
the boxes within a few weeks, resulting in the clinical
situation described. It should be noted that GA can also
be ingested from a variety of other products, including
laxatives,10liquorice tea,11and Chinese medicines.12
When liquorice is suspected to be the cause of
hypokalaemia and/or hypertension, the diagnosis can be
confirmed by measuring plasma levels of GA,13or by
demonstrating an increased ratio of cortisol over cortisone
in plasma, saliva or urine.14In clinical practice, discon-
tinuation of liquorice intake will often be sufficient.
How much liquorice is required to develop symptoms?
This will depend on the amount of GA in the liquorice,
as there is a clear dose-response relation between GA
© 2005 Van Zuiden Communications B.V. All rights reserved.
E D I T O R I A L
Liquorice and hypertension
S.H. van Uum
Department of Medicine, University of Western Ontario, Canada,
and cortisol-cortisone ratio.15On average, 1 g of liquorice
contains about 2 mg GA, but the amount of GA varies
considerably, from 0.026 to 98 mg per gram liquorice.16
The effect on blood pressure is also dose related: in a
study in healthy volunteers, the increase in systolic blood
pressure was 3 mmHg following 75 mg GA, and 14 mmHg
following 540 mg GA a day.17
The sensitivity for the effect of liquorice varies between
individuals. A daily dose of 100 g liquorice, containing
150 mg GA, resulted in an increase in systolic blood pres-
sure of 15 mmHg in subjects with primary hypertension,
while the increase was only 3.5 mmHg in normotensive
subjects.18However, there was no difference in the urinary
cortisol-cortisone ratio between the groups, suggesting
that there was no difference in the inhibition of renal
11?-HSD2 activity by liquorice. It is not clear, therefore,
whether patients with hypertension are more sensitive to
the effect of liquorice on 11?-HSD2 activity, or that the
difference is located at or post mineralocorticoid receptor
level. Alternatively the effects could be located outside the
kidneys. Some studies have suggested that there is a relation
between 11?-HSD2 activity and salt sensitivity,19but other
studies could not confirm this.20Case reports have shown
that liquorice intake as low as 50 g a day has occasionally
resulted in clinical effects.21One wonders if these patients
had mutations in the 11?-HSD2 gene resulting in con-
genitally reduced activity of 11?-HSD2, rendering them
more susceptible to the inhibitory effects of liquorice.
The treatment of patients with liquorice-induced hyper-
tension and hypokalaemia is based on understanding the
pathophysiology. The first step is recognition of liquorice as
a cause, and discontinuation of its intake. Next steps may
be administration of potassium and blockade of the MRs.
In severe hypokalaemia, administration of dexamethasone
could be considered, as this will suppress the endogenous
production of cortisol, thus decreasing stimulation of
MRs by cortisol.
In conclusion, the story of liquorice and its effect on
blood pressure and potassium remains fascinating. It has
been a very useful tool in the discovery of the importance
of intracellular shuttling of cortisol and cortisone.
Liquorice-induced effects can be encountered in patients
of all ages and all over the world. In clinical practice, a
high level of suspicion remains warranted in patients
with unexplained hypokalaemia and/or hypertension.
R E F E R E N C E S
1. Borst JCG, ten Holt SP, de Vries LA, Molhuysen JA. Synergistic action of
liquorice and cortisone in Addison’s and Simmonds’s disease. Lancet
2. Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent
mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J Clin
3. Monder C, White PC. 11 beta-hydroxysteroid dehydrogenase. Vitam Horm
4. Walker BR, Campbell JC, Williams BC, Edwards CR. Tissue-specific
distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid
dehydrogenase. Endocrinology 1992;131:970-2.
5. Stewart PM, Murry BA, Mason JI. Human kidney 11 beta-hydroxysteroid
dehydrogenase is a high affinity nicotinamide adenine dinucleotide-
dependent enzyme and differs from the cloned type I isoform. J Clin
Endocrinol Metab 1994;79:480-4.
6. Agarwal AK, Tusie-Luna MT, Monder C, White PC. Expression of 11 beta-
hydroxysteroid dehydrogenase using recombinant vaccinia virus. Mol
7. Brown RW, Chapman KE, Kotelevtsev Y, et al. Cloning and production of
antisera to human placental 11beta- hydroxysteroid dehydrogenase type
2. Biochem J 1996;313:1007-17.
8. Van den Bosch AE, van der Klooster JM, Zuidgeest DMH, Ouwendijk RJTh,
Dees A. Severe hypokalaemic paralysis and rhabdomyolysis due to
ingestion of liquorice. Neth J Med 2005;63:146-8.
9. Janse A, van Iersel M, Hoefnagels WHL, Olde Rikkert M. The old lady who
liked liquorice: hypertension due to chronic intoxication in a memory-
impaired patient. Neth J Med 2005;63:149-50.
10. Scali M, Pratesi C, Zennaro MC, Zampollo V, Armanini D.
Pseudohyperaldosteronism from liquorice-containing laxatives.
J Endocrinol Invest 1990;13:847-8.
11. Brouwers AJ, van der Meulen J. [‘Licorice hypertension’ also caused by
liquorice tea]. Ned Tijdschr Geneeskd 2001;145:744-7.
12. Harada T, Ohtaki E, Misu K, Sumiyoshi T, Hosoda S. Congestive heart
failure caused by digitalis toxicity in an elderly man taking a licorice-
containing Chinese herbal laxative. Cardiology 2002;98:218.
13. Russel FGM, van Uum S, Tan Y, Smits P. Solid-phase extraction of
18beta-glycyrrhetinic acid from plasma and subsequent analysis by high-
performance liquid chromatography. J Chromatogr B: Biomed Sci Appl
14. Van Uum SH, Walker BR, Hermus AR, et al. Effect of glycyrrhetinic acid
on 11 beta-hydroxysteroid dehydrogenase activity in normotensive and
hypertensive subjects. Clin Sci (Lond) 2002;102:203-11.
15. Krahenbuhl S, Hasler F, Frey BM, Frey FJ, Brenneisen R, Krapf R. Kinetics
and dynamics of orally administered 18 beta-glycyrrhetinic acid in
humans. J Clin Endocrinol Metab 1994;78:581-5.
16. Spinks EA, Fenwick GR. The determination of glycyrrhizin in selected UK
liquorice products. Food Addit Contam 1990;7:769-78.
17. Sigurjonsdottir HA, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G,
Wallerstedt S. Liquorice-induced rise in blood pressure: a linear dose-
response relationship. J Hum Hypertens 2001;15:549-52.
18. Sigurjonsdottir HA, Manhem K, Axelson M, Wallerstedt S. Subjects with
essential hypertension are more sensitive to the inhibition of 11 beta-
HSD by liquorice. J Hum Hypertens 2003;17:125-31.
19. Ferrari P, Sansonnens A, Dick B, Frey FJ. In vivo 11beta-HSD-2 activity:
variability, salt-sensitivity, and effect of licorice. Hypertension
20. Melander O, Frandsen E, Groop L, Hulthen UL. No evidence of a relation
between 11beta-hydroxysteroid dehydrogenase type 2 activity and salt
sensitivity. Am J Hypertens 2003;16:729-33.
21. Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquorice-evalu-
ation of health hazard. Food Chem Toxicol 1993;31:303-12.
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Van Uum. Liquorice and hypertension.