[Adverse effects of licorice consumed as food: An update]. / Toxicités de l'exposition alimentaire à la réglisse : mise au point.

The word "licorice" refers to the plant, its root, and its aromatic extract. From a commercial point of view, Glycyrrhiza glabra is the most important species with a wide range of uses (herbal medicine, tobacco industry, cosmetics, food and pharmaceutical). Glycyrrhizin is one of the main constituents of licorice. Glycyrrhizin is hydrolyzed in the intestinal lumen by bacterial ß-glucuronidases to 3ß-monoglucuronyl-18ß-glycyrrhetinic acid (3MGA) and 18ß-glycyrrhetinic acid (GA), which are metabolized in the liver. Plasma clearance is slow due to enterohepatic cycling. 3MGA and GA can bind to mineralocorticoid receptors with very low affinity, and 3MGA induces apparent mineralocorticoid excess syndrome through dose-dependent inhibition of 11ß-hydroxysteroid dehydrogenase type 2 in renal tissue. The cases of apparent mineralocorticoid excess syndrome reported in the literature are numerous and sometimes severe, even fatal, most often in cases of chronic high dose consumption. Glycyrrhizin poisonings are characterized by hypertension, fluid retention, and hypokalemia with metabolic alkalosis and increased kaliuresis. Toxicity depends on the dose, the type of product consumed, the mode of consumption (acute or chronic) and a very large inter-individual variability. The diagnosis of glycyrrhizin-induced apparent mineralocorticoid excess syndrome is based on the history, clinical examination, and biochemical analysis. Management is primarily based on symptomatic care and stopping licorice consumption.

A life-threatening case of pseudo-aldosteronism secondary to excessive liquorice ingestion.

BACKGROUND: Liquorice is found in many food products, soft drinks, and herbal medicines. Liquorice ingestion is an uncommon cause of apparent mineralocorticoid excess or pseudo-aldosteronism. The mechanism involves the inhibition of 11-beta-hydroxysteroid dehydrogenase type-2 by the active ingredient called glycyrrhizin. This leads to the uninhibited activation of mineralocorticoid receptors by cortisol. Confectionary products that contain liquorice are readily available in many countries around the world. CASE PRESENTATION: We report a case of severe refractory hypokalaemia with hypertensive crisis and acute pulmonary oedema due to excessive liquorice consumption. A 79-year-old female presented to the emergency department following a road traffic accident. She described feeling weak and dizzy while driving before the collision. She attended her general practitioner (GP) several weeks earlier for fatigue and was being managed for hypokalaemia on oral potassium supplements. Investigations revealed hypertension (BP 180/69 mmHg), severe hypokalaemia (K 2.2 mmol/l), normal renal function, normal serum magnesium with metabolic alkalosis. Spot urinary potassium was 22 mmol/l. The patient denied taking medications including over-the-counter or herbal medication that can cause hypokalaemia. Hypokalaemia persisted despite aggressive intravenous (i.v.) and oral potassium replacement. She later developed a hypertensive crisis (BP 239/114 mmHg) with pulmonary oedema. She required admission to the intensive care unit and was managed with intravenous furosemide infusion and isosorbide dinitrate infusion. On further discussion, our patient admitted to struggling with nicotine cravings since quitting smoking two months earlier. She began eating an excessive amount of liquorice sweets to manage her cravings. Suppression of plasma renin and aldosterone supported the diagnosis of apparent mineralocorticoid excess secondary to excessive liquorice consumption. Her symptoms and hypokalaemia resolved after stopping liquorice intake. CONCLUSIONS: This case highlights the life-threatening and refractory nature of hypokalaemia secondary to excessive liquorice consumption. This case also emphasizes the importance of comprehensive history taking including dietary habits. Increased awareness among the public is required regarding the potential health hazards of excessive liquorice consumption.

Bitter experience with liquorice sweetening agent resulting in apparent mineralocorticoid excess with periodic paralysis.

Chronic liquorice ingestion is a rare cause of secondary hypertension and hypokalaemia with periodic paralysis. We report the case of a middle-aged Indian man who presented with hypertension and hypokalaemic alkalosis with recurrent bouts of periodic paralysis. Biochemical investigations revealed suppressed plasma renin and aldosterone concentrations with normal cortisol concentration. A detailed history revealed that he was addicted for the last 5 years to a form of chewing tobacco mixed with herbal preparations as a sweetening agent which on analysis revealed active principles of glycyrrhizin using the thin liquid chromatography method. The hypokalaemia resolved and hypertension control improved significantly after discontinuing liquorice consumption, and the patient was asymptomatic at 1-year follow-up. Long-term liquorice ingestion should be kept in mind as a reversible cause of hypokalaemic periodic paralysis, with a meticulous history and biochemical evaluation helping in identifying this recognisable and curable medical disorder.

[A Case of Perioperative Hypokalemia and Hypertension due to Concomitant Use of Multiple Herbal Medicines].

A 72-year-old woman underwent surgery for a distal radius fracture with lower jaw fracture under general anesthesia. Preoperative laboratory data showed hypokalemia (3.1 mEq · l(-1)), hypertension, and leg edema. The suspected cause of all of these symptoms was the licorice component of the multiple herbal medicines which she was taking. In addition, the ephedra and aconite tuber components of the Maobushisaishinto were suspected to be contributing to the hypertension. She was therefore taken off all of her herbal medicines. The patient underwent regular blood tests and her potassium levels were replenished perioperatively. Hypokalemia was alleviated within the few days following surgery. Given the identity of the crude contents of the multiple herbal medicines in addition to the postoperative plasma renin activity and aldosterone, pseudoaldosteronism was suspected. When administering multiple herbal medicines, knowledge of the precise contents is critical. Clarification of the doses of licorice and ephedra capable of inducing hypokalemia and hypertension would also be helpful.

A case of hyperemesis in bulimia nervosa.

Bulimia nervosa is an eating disorder defined by recurrent episodes of binge eating followed by compensatory behaviors, primarily self-induced vomiting. Most common complications are due to purge behaviors and are frequently responsible for hospitalization. These include electrolyte disturbances, dehydration, hypovolemia, stomatitis, esophageal diseases, and functional impairment of the colon. However, an obstruction-like syndrome has never been reported. We report the case of a middle-age woman suffering from bulimia nervosa and referring at the emergency department with a 7-day story of hyperemesis responsible for an acute renal failure. During hospitalization, after the most important and common medical causes of hyperemesis were excluded, an upper gastrointestinal endoscopy was performed. The endoscopist reported the presence of an impressive bezoar, which underwent to mechanical fragmentation and biopsy sampling, revealing it was made up exclusively of liquorice wheels. An endoscopy performed few days after showed the complete dissolution of the bezoar, and the patient was discharged without any further gastrointestinal complaint.

A randomized, double-blind comparison of licorice versus sugar-water gargle for prevention of postoperative sore throat and postextubation coughing.

BACKGROUND: One small study suggests that gargling with licorice before induction of anesthesia reduces the risk of postoperative sore throat. Double-lumen tubes are large and thus especially likely to provoke sore throats. We therefore tested the hypothesis that preoperative gargling with licorice solution prevents postoperative sore throat and postextubation coughing in patients intubated with double-lumen tubes. METHODS: We enrolled 236 patients having elective thoracic surgery who required intubation with a double-lumen endotracheal tube. Patients were randomly assigned to gargle 5 minutes before induction of anesthesia for 1 minute with: (1) Extractum Liquiritiae Fluidum (licorice 0.5 g); or (2) Sirupus Simplex (sugar 5 g); each diluted in 30 mL water. Sore throat and postextubation coughing were evaluated 30 minutes, 90 minutes, and 4 hours after arrival in the postanesthesia care unit, and the first postoperative morning using an 11-point Likert scale by an investigator blinded to treatment. RESULTS: The incidence of postoperative sore throat was significantly reduced in patients who gargled with licorice rather than sugar-water: 19% and 36% at 30 minutes, 10% and 35% at 1.5 hours, and 21% and 45% at 4 hours, respectively. The corresponding estimated treatment effects (relative risks) were 0.54 (95% CI, 0.30-0.99, licorice versus sugar-water; P = 0.005), 0.31 (0.14-0.68) (P < 0.001), and 0.48 (0.28-0.83) (P < 0.001). CONCLUSION: Licorice gargling halved the incidence of sore throat. Preinduction gargling with licorice appears to be a simple way to prevent a common and bothersome complication.

Drug-induced hypertension: an unappreciated cause of secondary hypertension.

A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Licorice consumption as a cause of posterior reversible encephalopathy syndrome: a case report.

INTRODUCTION: A 49-year-old woman was admitted to our hospital because of thunderclap headache and blurred vision. At the time of presentation, her blood pressure was 219/100 mmHg, her arterial pH was 7.64 and her potassium level was 2.7 mM/l. METHODS: The combination of sequential computed tomography (CT) and the triad of hypertension, hypokalemia and metabolic alkalosis in this patient suggested the diagnosis. Supplementary anamnesis and long-term follow-up confirmed it. RESULTS: Brain computed tomography imaging showed minor bleeding in the left Sylvian fissure and bilateral occipital edema, suggestive of posterior reversible encephalopathy syndrome (PRES). Repeated brain CT after 10 days showed a complete resolution of radiological signs. The patient informed us that she had quit smoking 2 weeks ago and had started consuming large amounts of licorice instead of smoking. After she abandoned licorice consumption, her blood pressure normalized. Her latest blood pressure reading was 106/60 mmHg without the use of any antihypertensive drugs. CONCLUSIONS: To the best of our knowledge, this is the first case report describing licorice consumption as a cause of PRES. Glycyrrhizic acid, a component of licorice, inhibits 11ß-hydroxysteroid dehydrogenase and subsequently causes mineralocorticoid excess. Mineralocorticoid excess in turn causes high blood pressure and ultimately gives rise to malignant hypertension. Physicians should remember that licorice use is a very easy-to-treat cause of hypertension, hypertensive encephalopathy and PRES.

Licorice - or more?

A 57 yr old man presented to endocrinology clinic with a six year history of poorly controlled hypertension which was treated with Metoprolol 200 mg/day and Enalapril 20 mg/day. He was asymptomatic but incidentally hypokalaemia was detected while having cholecystectomy, two years prior to his clinic appointment. He had never been on diuretics or laxatives. He was started on potassium supplements (120 mmol/d) and advised to increase dietary potassium by the surgical team. A detailed personal history revealed ingestion of 300-500 g licorice per day. Physical examination was unremarkable apart from increased blood pressure of 180/105 mmHg. Following the initial visit, his serum electrolyes (K+3.7 mmol/l) were normal with potassium supplementation and as were morning cortisol, ACTH, 11-deoxycortisol and plasma metanephrines. 17 OH-P, DHEAS and androstenedione were normal but testosterone was low. Morning ambulant aldosterone was slightly increased at 801 pmol/L and renin activity was undetectable. Urinary 24 h aldosterone excretion was significantly increased at 162 ng/24 h with normal cortisol and catecholamine excretion. Four weeks following advice to stop licorice, serum potassium decreased to 3.4 mmol/L despite continuous supplementation. Morning plasma aldosterone increased to 1 449 pmol/ml, renin activity remained undetectable but 24 h urine aldosterone excretion increased to 434 ng/24 h with a reduction in urinary cortisol excretion. Interestingly 17 OH-P and androstenedione levels, although within the reference range, were slightly higher compared to the levels whilst on licorice. Testosterone level had significantly increased to be within normal range. Abdominal imaging with US and MRI showed a 2.7 cmx2.2 cmx1.7 cm left adrenal mass. He underwent laparoscopic left adrenalectomy and histology confirmed aldosterone producing adrenal adenoma. Post-operatively his aldosterone and serum potassium levels normalized and he became normotensive without any antihypertensive medication.

Torsades de Pointes induced by a combination of garenoxacin and disopyramide and other cytochrome P450, family 3, subfamily A polypeptide-4-influencing drugs during hypokalemia due to licorice.

We report an 82-year-old man who developed ventricular tachycardia and Torsades de Pointes (TdP) after oral administration of garenoxacin, a novel quinolone antibiotic agent that differs from the third-generation quinolones, for pneumonia. He had hypokalemia (K 2.3 mmol/L) induced by licorice and also had received disopyramide for arrhythmia, bicalutamide for prostate cancer, and silodosin for prostate hypertrophy. After taking him off all drugs and administering spironolactone supplemented with potassium, his low serum potassium level was ameliorated. Therefore, although garenoxacin reportedly causes fewer adverse reactions for cardiac rhythms than third-generation quinolone antibiotics, one must be cautious of the interference of other drugs during hypokalemia in order to prevent TdP.

Licorice-induced hypokalemia.

Excessive intake of licorice can cause hypokalemia and hypertension and generally, the onset and severity of symptoms depend on the dose and duration of licorice intake, as well as individual susceptibility. We describe a patient with hypokalemia caused by long term consumption of natural licorice root after quitting smoking. The case emphasizes the importance of considering a detailed patients' history, which often may lead the treating physician to the correct clinical diagnosis.

Cortisol metabolism in hypertension.

Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension.

A hidden cause of hypokalemic paralysis in a patient with prostate cancer.

Hypokalemic paralysis is a medical emergency due to the risks of cardiac arrhythmia, respiratory failure, and rhabdomyolysis. Besides supplementing patients with KCl to hasten recovery, the astute physician must search for the underlying cause to avoid missing a treatable and curable disorder. We report on an elderly Korean man who presented with marked limb paralysis, myalgias, and mild hypertension. He had prostate cancer treated with orchiectomy and hormone therapy 2 years previously. The major biochemical abnormalities were hypokalemia (K+: 1.7 mmol/l) associated with high renal K+ wasting and metabolic alkalosis (HCO3-: 42.6 mmol/l). Low plasma renin activity, low aldosterone concentration, and normal cortisol concentration pointed to a state of pseudohyperaldosteronism. While reviewing his drug history, the patient revealed he had been consuming eight packs (100 ml/pack) of a Korean herbal tonic daily to treat his prostate cancer for the past 2 months. A significant amount of glycyrrhizic acid (0.23 mg/ml), an active ingredient of licorice, was detected in the tonic. Discontinuation of the herbal tonic along with KCl supplementation achieved recovery in 2 weeks. As many complementary/alternative medicines for cancer contain licorice, this must be kept in mind as a cause of hypokalemia in cancer patients.

[Licorice of 'shakuyaku kanzou tou' induced pseudoaldosteronism].

We report a case of pseudoaldosteronism induced by licorice in a kampo medication 'Shakuyaku Kanzou Tou' that was diagnosed after relief of urinary retention due to benign prostatic hypertrophy (BPH). A-71-year-old man was admitted to our hospital due to urinary retention. At admission, he had hypertension and leg edema, but serum potassium was in the normal range. One day after admission, hypokalemia was recognized. He was taking "Shakuyaku Kanzou Tou", a Chinese medicine that contains glycyrrhizin. So we suspected pseudoaldosteronism and had him stop taking it. Computed tomography did not reveal any adrenal tumor. Plasma rennin activity and aldosterone level were suppressed. Gradually, hypertension and leg edema improved and serum potassium became within the normal range. We diagnosed the case as pseudoaldosteronism induced by licorice of 'Shakuyaku Kanzou Tou'. Since we suspected BPH to be the cause of urinary retention, we performed transurethral resection of prostate. After surgery, he was able to void smoothly.

Licorice consumption causing severe hypokalemic paralysis.

Hypokalemic paralysis due to licorice consumption is extremely rare, with only 40 cases in the English literature describing paralysis secondary to exposure to licorice in candies, medications, chewing tobacco, and herbal preparations. We describe a patient who suffered life-threatening hypokalemic paralysis caused by consumption of licorice in the form of a tea sweetener superimposed on long-term consumption of licorice candy. Aggressive fluid and potassium replenishment produced complete and lasting recovery. To our knowledge, this is the first report of hypokalemic paralysis due to exposure to licorice as a tea sweetener, a common custom among the Arab population. The case emphasizes the importance of considering patients' cultural backgrounds and local customs, which often may lead the treating physician to the correct clinical diagnosis.