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The Mechanism for Licorice (Glycyrrhiza glabra) Induced Swelling and Edema

Summary:

  • Licorice (Glycyrrhiza glabra) contains an ingredient called glycyrrhizin, also called glycyrrhizic acid, and has been used in the treatment of stomach ulcers, bronchitis, sore throat and even viral hepatitis.
  • Unfortunately, licorice ingestion can lead to excess mineralocorticoid activity that is manifested by suppressed renin levels, sodium retention, hypervolemia, hypokalemia, hypertension and edema.
  • Licorice is a known inhibitor of the type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2) and thus prevents to the inactivation of cortisol.
  • The increased cortisol is available to bind to the mineralocorticoid receptor in the kidney resulting in the reabsorption of sodium and water that leads to increases in intravascular volume and capillary hydrostatic pressures that contribute to edema formation.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015

Explanation

  • Licorice (Glycyrrhiza glabra) contains an ingredient called glycyrrhizin or glycyrrhizic acid and has been used in the treatment of stomach ulcers, bronchitis, sore throat and even viral hepatitis.1  It is available in a number of dosage forms that include powdered forms, capsules, tablets and liquid extracts.1  Unfortunately, licorice ingestion can lead to excess mineralocorticoid activity that is manifested by suppressed renin levels, sodium retention, hypokalemia, hypertension and edema.1-5  As it relates to edema, it can be caused one or more of the following: things known to influence vasculature oncotic pressures, vasomotor tone of the veins, permeability of the capillary membranes, lymphatic flow and/or intravascular volume.   Of these various biologic mechanisms, the change in intravascular volume appears to be the major contributor to the increased risk in patients developing swelling or edema when taking licorice supplements. 

    What is the mechanism by which the Glycyrrhiza glabra in licorice can increase the intravascular volume?
    The normal physiology for sodium-water retention is largely influenced by the expression of mineralocorticoids.  While aldosterone is regarded as the main hormone binding to mineralocorticoid receptors involved in the regulation of sodium reabsorption and potassium excretion in the distal renal tubules of the kidney, cortisol also binds to this receptor with the same binding affinity as aldosterone.  Interestingly, even though cortisol blood concentrations tend to be greater than aldosterone concentrations, the effect of aldosterone dominates in terms of regulating sodium and water reabsorption and blood volume.  

    If cortisol concentrations are greater than aldosterone and both have equal affinity for the mineralocorticoid receptor, why doesn't cortisol have a greater influence on the overall mineralocorticoid activity?
    The type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2) is normally involved in regulating corticosteroid specificity in the gastrointestinal tract, kidney and salivary glands (see figure 1).6  Cortisol (not aldosterone) is metabolized by 11 beta-HSD2 to cortisone, which does not bind to either the mineralocorticoid or glucocorticoid receptor.  Without this inactivation of cortisol, there would be mineralocorticoid excess.  In fact, there is an inherited disease called syndrome of apparent mineralocorticoid excess in which the mineralocorticoid receptor is overly activated thereby causing hypokalemia and hypervolemia due to the excessive reabsorption of sodium and water at the expense of potassium excretion.  This is the same effect created by licorice use. 

    Licorice is a known inhibitor of 11 beta-HSD2 and thus prevents the inactivation of cortisol, thereby causing a state of excess mineralocorticoid activity or pseudohyperaldosteronism.2-6  The increase in mineralocorticoid activity results in greater sodium and water reabsorption at the expense of potassium excretion. This will eventually manifest as an increase in hydrostatic and overall blood pressures thereby resulting in the development of edema. 

    The Details for Those Interested:

    • How does cortisol binding to the mineralocorticoid receptor in the distal renal tubule increase sodium and water reabsorption at the expense of potassium excretion?  The increased cortisol resulting from licorice use increases gene expression and availability of several enzymes.  The first of these is the Na+ ion permease enzyme, which allows for a greater number of sodium ions to cross from the lumen to the inside of the renal tubular cell.   Next is Na+/K+ATPase on the basal-lateral side of the renal tubular cell which acts to transfer the increased cytosolic Na+ into the peritubular fluid resulting in a lowering of the intracellular electronegativity.  Lastly, there is an increase in citrate synthase activity within the mitochondria for the purpose of increasing the number of ATP available to fuel the increase in Na+/K+ATPase activity on the basal-lateral side of the renal tubular cell.7-9

    Conclusion
    Excess mineralocorticoid activity and resulting increases in blood volume are clearly the main mechanisms by which licorice causes both edema and hypertension.  In fact, the increase in blood pressure and development of hypertension can be significant and last several weeks before returning to baseline despite the discontinuation of the licorice supplementation.2,4 Given the documented increases in edema and blood pressure, the use of licorice supplements should be taken into consideration for any patient with an unexplained increase in blood pressure, worsening of hypertension that is being adequately treated with antihypertensive medications and/or worsening of previously controlled heart failure. There is some evidence that spironolactone (Aldactone) may confer some benefit on blood pressure; however, stopping the licorice would be the preferred recommendation for patients.10


    References:
    1. National Institute of Health: National Center for Complimentary and Alternative Medicine.  Herbs at a glance: Licorice root.  June 2008. Last accessed on 6/1/09.  
    2. Wash LK, Bernard JD.  Licorice-induced pseudoaldosteronism.  Am J Hosp Pharm  1975;32:73-4.  
    3. Epstein MT, Espiner EA, Donald RA et al.  Liquorice toxicity and the renin-angiotensin-aldosterone axis in man.  Br Med J  1977;1:209-10.  
    4. Beretta-Piccoli C, Salvade G, Crivelli PL et al.  Body-sodium and blood volume in a patient with licorice-induced hypertension.  J Hypertens  1985;3:19-23.  
    5. Gomez-Sanchez EP, Gomez-Sanchez CE.  Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone.  Am J Physiol  1992;263:E1125-30. 
    6. Sandeep TC, Walker BR.  Pathophysiology of modulation of local glucocorticoid levels by 11beta-hydroxysteroid dehydrogenases.  Trends Endocrinol Metab  2001;12:446-53.  
    7. Garty H.  Mechanisms of aldosterone action in tight epithelia.  J Membr Biol  1986;90:193-205.  
    8. Verrey F, Schaerer E, Zoerkler P et al.  Regulation by aldosterone of Na+,K+-ATPase mRNAs, protein synthesis, and sodium transport in cultured kidney cells.  J Cell Biol  1987;104:1231-7.  
    9. Laplace JR, Husted RF, Stokes JB.  Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture.  Difference between glucocorticoid and mineralocorticoid hormones.  J Clin Invest  1992;90:1370-8.
    10. Salassa RM, Mattox VR, Rosevear JW.  Inhibition of the "mineralocorticoid" activity of licorice by spironolactone.  J Clin Endocrinol Metab  1962;22:1156-9.