eMedicine Specialties > Emergency Medicine > Toxicology

Plant Poisoning, Licorice

Seth Schonwald, MD, FACEP, FACMT, Consulting Staff, Director of Toxicology, Department of Urgent Care, East Boston Neighborhood Health Center

Updated: Jul 6, 2009

Introduction

Background

Licorice (or liquorice) is a plant of ancient origin and steeped in history. Natural licorice is an extract from the root of Glycyrrhiza glabra, a 4- to 5-foot woody shrub that contains glycyrrhizic acid (GZA) and grows in subtropical climates in Europe, the Middle East, and Western Asia.
 
Licorice extracts and its principle component, glycyrrhizin, have extensive use in foods, tobacco products, and snuff, and in traditional and herbal medicine. As a result, there is a high level of use of licorice and glycyrrhizin in the US with an estimated consumption of 0.027-3.6 mg glycyrrhizin per kilograms per day.¹  Licorice extract (block, powder, or liquid) may be applied to cigarette tobacco at levels of about 1-4% to enhance and harmonize the flavor characteristics of smoke, improve moisture-holding characteristics of tobacco, and act as a surface active agent for ingredient application.²

Licorice flavor is found in a wide variety of licorice candies. Licorice is also found in some soft drinks (eg, root beer) and is in some herbal teas where it provides a sweet aftertaste. Licorice has also been used as a medicinal agent in a number of cultures,³ dating back to ancient Egypt and China. Medicinal uses have included cough suppression,⁴  gastric ulcer treatment,⁵ treatment of early Addison disease,^6,7 treatment of liver disease,^8,9 and as a laxative.

Pathophysiology

Natural licorice possesses both mineralocorticoid properties and glucocorticoid properties. Most licorice-flavored foods available in the United States do not contain GZA, and they do not produce the hypermineralocorticoid syndromes observed with the long-term consumption of moderate-to-significant amounts of natural licorice.

Large doses of GZA in licorice extract can lead to hypokalemia and serious hypertension, a syndrome known as hypermineralocorticoidism.^10,11 Biochemical studies indicate that glycyrrhizinates inhibit 11-beta-hydroxysteroid dehydrogenase (type 2), the enzyme responsible for inactivating cortisol. As a result, a continuous, high-level exposure to glycyrrhizin compounds can produce hypermineralocorticoid-like effects in both animals and humans. These effects are reversible upon withdrawal of licorice or glycyrrhizin.¹

In the kidney, cortisol activation of mineralocorticoid receptors alters renal tubular exchange of sodium (retained), potassium (excreted), and hydrogen ions (excreted); producing an increased extracellular volume (hypertension,¹²  edema), hypokalemia (weakness, muscle spasm),¹³  and metabolic alkalosis.¹⁴

Pseudoprimary aldosteronism of chronic licorice ingestion is characterized by low serum and urinary aldosterone levels and decreased serum renin activity. This differs from true primary hyperaldosteronism caused by aldosterone producing adenomas or primary adrenal hyperplasia; it is characterized by elevated urine and serum aldosterone levels.
 
Licorice can reduce serum testosterone level, probably by blocking 17-hydroxysteroid dehydrogenase, and 17,20 lyase.¹⁵  Licorice has therefore been considered an adjuvant therapy of hirsutism and polycystic ovary syndrome.¹⁶
 
The exact amount of ingested GZA that produces mineralocorticoid toxicity is unclear. Avoiding ingestion of natural licorice in the setting of hypertension, diuretic use, sexual dysfunction, or pregnancy is probably wise.

Frequency

United States

Licorice poisoning is rare in the United States.

International

The frequency is unknown.

Clinical

History

Most patients report chronic toxicity from daily excessive ingestion of natural licorice products (not artificial licorice flavoring); acute toxicity is not reported. Symptoms of licorice toxicity may include the following:

• Fatigue and muscle cramping
• Dark urine (myoglobinuria)
• Weakness (hypokalemia, myopathies)
• Polyuria/nocturia (increased extracellular volume)
• Edema (increased extracellular volume)
• Dyspnea (pulmonary edema)
• Headache (hypertension)
• Paresthesias/dysesthesias (eg, burning sensations of extremities)
• Impotence and diminished libido
• Amenorrhea

Physical

• Edema (peripheral, pulmonary), secondary to increased extracellular fluid from water retention, rales
• Licorice has been reported to cause high blood pressure,¹⁷ including dangerously high blood pressure with symptoms such as headache, nausea, vomiting, and hypertensive encephalopathy with stroke-like effects (eg, one-sided weakness).
• Spasms/tetany
• Hyporeflexia, muscle wasting, weakness, flaccid paralysis¹⁸
• Myoglobinuria/rhabdomyolysis¹⁹
• Trousseau and Chvostek signs (from hypokalemia with alkalosis)
• Cardiac arrest, dysrhythmias (rare) from hypokalemia

Differential Diagnoses

Other Problems to Be Considered

Other causes of hypokalemia

Aminoglycosides
Barium poisoning
Beta-adrenergic agonists
Diarrhea
Diuretics
Enemas or laxative use
Hyperaldosteronism
Ileal loop
Insulin
Leukemia
Magnesium depletion
Metabolic syndrome
Periodic hypokalemic paralysis
Renal tubular necrosis
Steroids
Theophylline 

Other causes of hyperaldosteronism

Adrenal adenoma
Bartter syndrome (ie, hyperaldosteronism, hyperreninism, hypokalemic acidosis)
Bilateral adrenal hyperplasia
Ectopic adrenocorticotropic hormone (ACTH) syndrome (eg, Wilms tumor) 
Hypertensive urgencies
Mineralocorticoid excess syndrome (eg, congenital adrenal hyperplasias)

Workup

Laboratory Studies

• Diagnosis is generally confirmed by combination of hypokalemia, increased urinary free cortisol, elevated cortisol-cortisone metabolite ratio, and low or absent urinary aldosterone.
• Low serum potassium level is the most helpful screening result for establishing mineralocorticoid excess in patients with hypertension.
• Elevated urinary potassium level may be present.
• Dilutional anemia may be present, and hematocrit may be depressed.
• Licorice poisoning can cause hypokalemic rhabdomyolysis with resultant myoglobinuria and elevated serum creatine kinase level.^20,21 Elevated creatine phosphokinase level can cause acute tubular necrosis.
• In so-called pseudo-primary hyperaldosteronism, plasma and urinary aldosterone levels are not elevated.

Imaging Studies

• Chest radiography: Assess for pulmonary edema if clinically indicated.
• Abdominal CT or MRI: If urine aldosterone levels are high in a patient with evidence of hypermineralocorticoidism (eg, hypertension, hypokalemia, suppression of renin-angiotensin system), causative tumors are more likely than chronic licorice toxicity, and imaging may be warranted.

Other Tests

• Electrocardiography: Evaluate for hypokalemic changes and evidence of arrhythmia, including torsades des pointes.
• Pulse oximetry and arterial blood gas (ABG) measurement: Evaluate for pulmonary edema and respiratory muscle weakness.
• Many tests are expensive and time-consuming. Consultation with an endocrinologist and toxicologist may be helpful for determining initial workup.
  • Measure serum GRA and GZA levels with enzyme-linked immunoabsorbent assay (ELISA) and high-performance liquid chromatography (HPLC).
  • Measure urinary GRA level with gas chromatography-mass spectrometry (GC-MS).
  • Ascertaining plasma renin activity and urine aldosterone level (24 h collections) may be helpful (both are typically low).
  • Determining urine cortisol levels (often elevated) and cortisol-cortisone metabolite ratios (often elevated) may be helpful. 

Treatment

Prehospital Care

Provide supportive treatment, including airway, breathing, and circulatory support (ABCs), as clinically indicated. Provide cardiac monitoring if clinically indicated.

Emergency Department Care

• Monitor electrolytes, especially potassium.
• Supplement potassium, as indicated.
• Consider potassium-sparing diuretics, as needed.
• Treat rhabdomyolysis, if present (eg, hydration, alkalinization of urine, mannitol).
• Monitor for and treat electrolyte-induced dysrhythmias.
• Monitor for and treat pulmonary edema and respiratory muscle weakness.

Consultations

Consultations with an endocrinologist and a toxicologist may be helpful.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Diuretics, potassium-sparing

These agents may be used to correct potassium deficiency or fluid/electrolyte imbalance.

Spironolactone (Aldactone)

Competes with aldosterone for receptor sites in distal renal tubules by increasing water excretion while retaining potassium and hydrogen ions.

Dosing

Adult

50-100 mg/d PO initial; typical dose is 100 mg/d, adjusted frequently as licorice toxicity resolves

Pediatric

0.5-1.5 mg/kg PO bid; not to exceed 200 mg/d

Interactions

May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone; lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of lithium toxicity; administer NSAIDs with caution (monitor serum potassium frequently); may attenuate positive inotropic effect of digoxin; may block tubular secretion of digoxin, reducing clearance and increasing levels; coadministration with ACE inhibitors may lead to hyperkalemia

Contraindications

Documented hypersensitivity; anuria, renal failure, or hyperkalemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal and hepatic impairment; adverse effects include nausea, vomiting, gastric ulcers, life-threatening hyperkalemia, metabolic acidosis (in patients with cirrhosis), gynecomastia, and impotence

Triamterene (Dyrenium)

Potassium-sparing diuretic with relatively weak natriuretic properties. Exerts diuretic effect on distal renal tubule to inhibit reabsorption of sodium in exchange for potassium and hydrogen. Increases sodium excretion and reduces excessive loss of potassium and hydrogen associated with hydrochlorothiazide. Not a competitive antagonist of mineralocorticoids; potassium-conserving effect is observed in patients with Addison disease (ie, without aldosterone).

Dosing

Adult

50-100 mg PO bid; adjust frequently as licorice toxicity resolves

Pediatric

1-2 mg/kg PO bid

Interactions

Coadministration with other potassium-conserving agents, such as spironolactone, amiloride HCl, or other formulations containing triamterene, may significantly increase serum potassium levels; lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of lithium toxicity; acute renal failure reported in patients receiving indomethacin and formulations containing triamterene; administer NSAIDs with caution (monitor serum potassium level frequently); may interfere with measurement of quinidine; may attenuate positive inotropic effect of digoxin; may block tubular secretion of digoxin, reducing clearance and increasing levels; coadministration with ACE inhibitors may lead to hyperkalemia

Contraindications

Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function (anuria, acute renal insufficiency, chronic renal insufficiency, significant renal impairment); diabetes

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in severe hepatic encephalopathy, diabetes, renal dysfunction, renal stones, and history of renal stones; adverse effects include hyperuricemia, renal stones, interstitial nephritis, photosensitization, glucose intolerance, and life-threatening hyperkalemia

Follow-up

Further Inpatient Care

• Consider admitting patients with the following:
  • Severe electrolyte abnormalities
  • Symptomatic hypokalemia
  • Severe or symptomatic hypertension
  • Progressive weakness or paralysis
  • Rhabdomyolysis
  • Pulmonary edema

Further Outpatient Care

• Frequent assessment of hypertension and hypokalemia, as well as the need for further potassium supplements and diuretics, may be included in outpatient care.

Inpatient & Outpatient Medications

• Potassium chloride (Use glucose-free solutions during intravenous administration to avoid worsening hypokalemia.)
• Potassium-sparing diuretics (eg, triamterene, spironolactone

Prognosis

• Patients generally fully recover with discontinued exposure.
  • After licorice exposure is discontinued, spontaneous correction of hypertension and hypokalemia generally occur within several weeks; however, months may pass before the renin-aldosterone system becomes active again.²²
  • Muscle weakness/paralysis may resolve within days of potassium replacement.

Patient Education

• Educate patients on the avoidance of natural licorice and GZA-containing products.

Miscellaneous

Medicolegal Pitfalls

• Failure to query regarding ingestion of natural licorice and use of herbal medicines, snuffs, and chewing tobaccos to ensure cessation of further exposure
• Failure to anticipate respiratory complications
• Failure to anticipate electrolyte-induced dysrhythmias
• Failure to ensure close outpatient follow-up

References

1. Isbrucker RA, Burdock GA. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol. Dec 2006;46(3):167-92. [Medline].

2. Carmines EL, Lemus R, Gaworski CL. Toxicologic evaluation of licorice extract as a cigarette ingredient. Food Chem Toxicol. Sep 2005;43(9):1303-22. [Medline].

3. Davis EA, Morris DJ. Medicinal uses of licorice through the millennia: the good and plenty of it. Mol Cell Endocrinol. Jun 1991;78(1-2):1-6. [Medline].

4. Anderson DM, Smith WG. The antitussive activity of glycyrrhetinic acid and its derivatives. J Pharm Pharmacol. Jul 1961;13:396-404. [Medline].

5. Krausse R, Bielenberg J, Blaschek W, Ullmann U. In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites. J Antimicrob Chemother. Jul 2004;54(1):243-6. [Medline].

6. Cooper H, Bhattacharya B, Verma V, McCulloch AJ, Smellie WS, Heald AH. Liquorice and soy sauce, a life-saving concoction in a patient with Addison's disease. Ann Clin Biochem. Jul 2007;44(Pt 4):397-9. [Medline].

7. Ross EJ. Liquorice and Addison's disease. Br Med J. Jun 20 1970;2(5711):733. [Medline].

8. Dhiman RK, Chawla YK. Herbal medicines for liver diseases. Dig Dis Sci. Oct 2005;50(10):1807-12. [Medline].

9. Kim YW, Kang HE, Lee MG, Hwang SJ, Kim SC, Lee CH, et al. Liquiritigenin, a flavonoid aglycone from licorice, has a choleretic effect and the ability to induce hepatic transporters and phase-II enzymes. Am J Physiol Gastrointest Liver Physiol. Feb 2009;296(2):G372-81. [Medline].

10. Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med. Oct 24 1991;325(17):1223-7. [Medline].

11. Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. Jun 1994;23(2):359-77. [Medline].

12. van Uum SH. Liquorice and hypertension. Neth J Med. Apr 2005;63(4):119-20. [Medline].

13. Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. Oct 2004;48(5):687-96. [Medline].

14. Khanna A, Kurtzman NA. Metabolic alkalosis. J Nephrol. Mar-Apr 2006;19 Suppl 9:S86-96. [Medline].

15. Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med. Oct 7 1999;341(15):1158. [Medline].

16. Armanini D, Mattarello MJ, Fiore C, Bonanni G, Scaroni C, Sartorato P. Licorice reduces serum testosterone in healthy women. Steroids. Oct-Nov 2004;69(11-12):763-6. [Medline].

17. Biglieri EG. Spectrum of mineralocorticoid hypertension. Hypertension. Feb 1991;17(2):251-61. [Medline].

18. Elinav E, Chajek-Shaul T. Licorice consumption causing severe hypokalemic paralysis. Mayo Clin Proc. Jun 2003;78(6):767-8. [Medline].

19. Barrella M, Lauria G, Quatrale R, Paolino E. Hypokaliemic rhabdomyolysis associated with liquorice ingestion: report of an atypical case. Ital J Neurol Sci. Aug 1997;18(4):217-20. [Medline].

20. van den Bosch AE, van der Klooster JM, Zuidgeest DM, Ouwendijk RJ, Dees A. Severe hypokalaemic paralysis and rhabdomyolysis due to ingestion of liquorice. Neth J Med. Apr 2005;63(4):146-8. [Medline].

21. Zenone T, Blanc Q. [Rhabdomyolysis with major hypokalemia secondary to chronic glycyrrhizic acid ingestion]. Rev Med Interne. Jan 2009;30(1):78-80. [Medline].

22. Epstein MT, Espiner EA, Donald RA, Hughes H. Liquorice toxicity and the renin-angiotensin-aldosterone axis in man. Br Med J. Jan 22 1977;1(6055):209-10. [Medline].

Keywords

licorice toxicity, natural licorice, liquorice, licorice extract, licorice root, chronic licorice ingestion, glycyrrhizic acid, GZA toxicology, Glycyrrhiza glabra, 18-beta-glycyrrhetinic acid, GRA, hypermineralocorticoid syndrome, hypermineralocorticoidism, glycyrrhizin

Contributor Information and Disclosures

Author

Seth Schonwald, MD, FACEP, FACMT, Consulting Staff, Director of Toxicology, Department of Urgent Care, East Boston Neighborhood Health Center
Seth Schonwald, MD, FACEP, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Massachusetts Medical Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

B Zane Horowitz, MD, FACMT, Professor, Fellowship Director, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System
B Zane Horowitz, MD, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare
Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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