Pathophysiology Epidemiology Frequency United States International History

Transcription

1 Alcaçuz - Licorice 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 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. Epidemiology Frequency United States Licorice poisoning is rare in the United States. International The frequency is unknown. History

2 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 paralysis[18] Myoglobinuria/rhabdomyolysis[19] Trousseau and Chvostek signs (from hypokalemia with alkalosis) Cardiac arrest, dysrhythmias (rare) from hypokalemia Differentials Acute Respiratory Distress Syndrome Congestive Heart Failure and Pulmonary Edema Encephalitis Hypernatremia

3 Hypertensive Emergencies Hypokalemia Myopathies Pediatrics, Respiratory Distress Syndrome Plant Poisoning, Herbs Respiratory Distress Syndrome, Adult Rhabdomyolysis 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. 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): Carmines EL, Lemus R, Gaworski CL. Toxicologic evaluation of licorice extract as a cigarette ingredient. Food Chem Toxicol. Sep 2005;43(9): 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): Anderson DM, Smith WG. The antitussive activity of glycyrrhetinic acid and its derivatives. J Pharm Pharmacol. Jul 1961;13:

4 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): 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): Ross EJ. Liquorice and Addison's disease. Br Med J. Jun ;2(5711): Dhiman RK, Chawla YK. Herbal medicines for liver diseases. Dig Dis Sci. Oct 2005;50(10): 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):G Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med. Oct ;325(17): Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. Jun 1994;23(2): van Uum SH. Liquorice and hypertension. Neth J Med. Apr 2005;63(4): Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. Oct 2004;48(5): Khanna A, Kurtzman NA. Metabolic alkalosis. J Nephrol. Mar-Apr 2006;19 Suppl 9:S Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med. Oct ;341(15): 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): Biglieri EG. Spectrum of mineralocorticoid hypertension. Hypertension. Feb 1991;17(2): Elinav E, Chajek-Shaul T. Licorice consumption causing severe hypokalemic paralysis. Mayo Clin Proc. Jun 2003;78(6): 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):

5 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): Zenone T, Blanc Q. [Rhabdomyolysis with major hypokalemia secondary to chronic glycyrrhizic acid ingestion]. Rev Med Interne. Jan 2009;30(1): Epstein MT, Espiner EA, Donald RA, Hughes H. Liquorice toxicity and the reninangiotensin-aldosterone axis in man. Br Med J. Jan ;1(6055):