Lesson of the week: hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum
BMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7082.731 (Published 08 March 1997) Cite this as: BMJ 1997;314:731
- Gerty J de Klerk, registrar in internal medicinea,
- Marietje G Nieuwenhuis, consultant in internal medicinea,
- Jaap J Beutler, consultant in nephrologya
- Department of Nephrology and Hypertension, Room F03.223, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands
- Correspondence to: Dr Beutler
- Accepted 28 January 1997
Introduction
Prolonged ingestion of substances containing glycyrrhizinic acid, such as liquorice, is a well known cause of exogenously induced hypermineralocorticoidism. This is characterised by sodium retention, hypokalaemia, hypertension, metabolic alkalosis, and suppression of the renin-aldosterone system.1 We describe two cases showing that hypokalaemia induced by glycyrrhizinic acid should be considered in patients with hypertension or oedema even if they have not eaten sweets that obviously contain liquorice.
Case reports
Case 1
A 21 year old woman presented to her general practitioner with a headache. She ate about 100 g of liquorice daily. She used an oral contraceptive. On earlier occasions her blood pressure had been 110/70 mm Hg. Clinical examination was unremarkable except that her blood pressure was 190/120 mm Hg. She was advised to stop eating liquorice and taking the oral contraceptive. Despite these measures, her blood pressure remained raised even after treatment with a combination of atenolol, lisinopril, hydrochlorothiazide, and amlodipine.
She was referred to our outpatient clinic. Two weeks after the drug treatment had been discontinued her blood pressure was 180/110 mm Hg and plasma concentrations of sodium, potassium, and bicarbonate were 143 mmol/1 (normal 136-146 mmol/1), 2.6 mmol/1 (3.8-5.0), and 35.9 mmol/1 (23-29), respectively. Plasma renin activity was 0.096 ng/(lxs) (normal 0.96-3.61), and plasma aldosterone concentration was 160 pmol/1 (normal 320-2000), both being inappropriately low as her 24 hour sodium excretion was 86 mmol.
The clinical picture was compatible with exogenously induced hypermineralocorticoidism, so a more thorough history was taken. This showed that she had replaced her liquorice intake by two packets of Stimorol Sugar Free R (Warner Lambert Confectionary) chewing gum a day. This chewing gum contains 585 mg liquorice in each 15 g packet, and 8-12% of the liquorice consists of glycyrrhizinic acid (manufacturer's information). Her daily intake of glycyrrhizinic acid was calculated to be about 120 mg. Three weeks after she stopped using the gum her blood pressure was 110/80 mm Hg and plasma potassium concentration 5.3 mmol/l.
Case 2
A 35 year old woman was referred to us with profound hypokalaemia of 2.2 mmol/1. She denied eating liquorice. She used an oral contraceptive. Because she had pretibial oedema she took chlorothiazide 500 mg twice daily. Clinical examination showed that her blood pressure was 140/80 mm Hg and that she had pitting oedema. Plasma potassium and bicarbonate concentrations were 2.2 mmol/1 and 30.8 mmol/l, respectively. One week after stopping chlorothiazide treatment and starting treatment with potassium chloride 600 mg three times a day her electrolyte concentrations were still abnormal: sodium was 146 mmol/1, potassium 2.0 mmol/1, and bicarbonate 37 mmol/1. Two weeks after discontinuation of the diuretic the concentrations had further deteriorated, sodium being 144 mmol/1, potassium 1.5 mmol/1, and bicarbonate 39 mmol/l. She was admitted to the hospital for further analysis and infusion of potassium chloride. Plasma renin activity was 0.036 ng/(lxs) and plasma aldosterone concentration 80 pmol/1 (normal 1.08-4.32 ng/(lxs) and 320-2000 pmol/l, respectively, for a daily sodium excretion of 57 mmol).
The clinical picture was suggestive of exogenous mineralocorticoid administration. She was noted to use chewing gum (BenBits Cool Mint R (Sorbits in Britain); Leaf United Kingdom). This gum is liquorice flavoured and contains 160 mg liquorice, of which 10% is glycyrrhizinic acid, in each 16 g packet. She used about three packets a day (50 mg glycyrrhizinic acid). She was advised to stop using the gum. Intravenous and oral potassium supplementation was able to be stopped after 2 and 15 days, respectively.
Three weeks after she stopped using the chewing gum her oedema had disappeared completely, her blood pressure had fallen to 110/80 mm Hg, and her plasma potassium had risen to 4.2 mmol/1 in association with normalisation of the other electrolyte concentrations.
Discussion
These two case histories show that low doses of glycyrrhizinic acid in liquorice flavoured chewing gum can raise renal cortisol concentrations, resulting in severe hypokalaemia and hypertension or oedema. Even in the Netherlands, where liquorice is popular and where the mineralocorticoid activity of the extract of Glycyrrhiza glabra root was described 50 years ago,2 the diagnosis was almost overlooked. The box lists products containing considerable amounts of glycyrrhizinic acid.3 4 5 6
Products containing considerable amounts of glycyrrhizinic acid
Confectionery:
Liquorice sticks, bricks, cakes, toffee, pipes, bars, balls, tubes, Catherine wheels, pastilles, and all sorts
Torpedos
Blackcurrant
Pomfret (Pontefract) cakes
Servez vous
Sorbits chewing gum
Stimorol chewing gum
Health products:
Liquirizia naturale
Liquorice flavoured diet gum
Throat pearls
Liquorice flavoured cough mixtures
Herbal cough mixtures
Antibron tablets
Liquorice tea
All types of liquorice root:
Russian, Iranian, Chinese, Turkish, Afghan, and unknown origin
Chewing tobacco
Alcoholic drinks:
Belgian beers
Pastis brands
Anisettes—raki, ouzo, Pernod
Glycyrrhizinic acid is hydrolysed into glycyrrhetenic acid, which is the active metabolite that inhibits renal 11β-hydroxysteroid dehydrogenase. This enzyme catalyses the inactivation of cortisol to cortisone.7 Cortisol, unlike cortisone, has the same affinity as mineralocorticoids for the mineralocorticoid receptors of the cells in the cortical collecting ducts.7 Given this equal receptor affinity and the much higher circulating concentrations of cortisol compared with aldosterone, inhibition of 11β-hydroxysteroid dehydrogenase increases the kidney's exposure to the mineralocorticoid effects of cortisol. A dose-response study of glycyrrhizinic acid in healthy volunteers showed that a significant fall in plasma potassium concentration from 4.3 mmol/l to 3.5 mmol/1 occurred at a dose of 800 mg or more a day.8 To our knowledge, only two similar cases of hypermineralocorticoidism associated with the use of chewing gum have been described.9 10 Why some people are susceptible to low doses of glycyrrhizinic acid remains to be elucidated. Oestrogens may react with the mineralocorticoid receptor or inhibit 11β-hydroxysteroid dehydrogenase activity,11 which may explain why female sex and the use of oral contraceptives can increase the susceptibility to glycyrrhizinic acid.8 Interestingly, both our patients were women using oral contraceptives, but other predisposing factors may be important as the association has been described in a man.9 The inhibition of 11β-hydroxysteroid dehydrogenase lasts for two weeks after glycyrrhizinic acid is removed, but suppression of the renin-angiotensin-aldosterone axis may persist for as long as two to four months,12 as happened in case 1.
In conclusion, the regular use of chewing gum containing small amounts of glycyrrhizinic acid should be considered in history taking, especially in women using oral contraceptives who present with hypokalaemia in combination with hypertension or oedema.
Acknowledgments
We thank Dr W H Boer for initially reviewing the manuscript.