How does excess licorice consumption cause hypertension and hypokalemia?

The active ingredient of licorice, glycyrrhizic acid or glycyrrhizin, is first converted to glycyrrhetinic acid (GRA) in the bowel which is then absorbed. Once in the circulation, GRA inhibits activation of 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD2), an enzyme in renal tissue that converts active cortisol to inactive cortisone. Without the full action of this enzyme, proper sodium and potassium homeostasis would be difficult because cortisol is just as effective in stimulating mineralocorticoid receptors as aldosterone but with 100-1000 times higher concentration than that of aldosterone! 1-3

Other ways that GRA may cause hypertension and hypokalemia include inhibition of 5 β-reductase in the liver, an enzyme that metabolizes aldosterone and direct stimulation of mineralocorticoid receptors, though overall these mechanisms may not be as important as the effect of GRA on cortisol metabolism in renal tissue.1,2

Besides causing fluid retention, licorice ingestion has also been found to increase systemic vascular resistance possibly by increasing vascular tone and remodeling of the vascular wall, potentiating the vasoconstrictor actions of angiotensin II and catecholamines in smooth muscle, and suppressing vasodilatory systems, including endothelial nitric oxide synthase and prostacyclin synthesis.

It’s no wonder that the FDA issued a statement in 2017: “If you’re 40 or older, eating 2 ounces of black licorice a day for a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.” 5

Bonus Pearl: Did you know that as early as 1951, extract of licorice was reported for treatment of Addison’s disease, a combination of licorice and soy sauce has been reported to be “life-saving” in a patient with Addison’s disease (2007), and GRA food supplementation may lower serum potassium in chronic hemodialysis patients (2009)? 6,7

 

References

  1. Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice and hypertension. J Clin Hypertens (Greenwich) 2008; 10:153-57. https://www.ncbi.nlm.nih.gov/pubmed/18256580
  2. Omar HR, Komarova I, El-Ghonemi M, et al. Licorice abuse: time to send a warning message. The Adv Endocrinol Metab 2012;3:125-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/
  3. Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: as systematic review and meta-analysis. Journal of Human Hypertension 2017;31:699-707. https://www.ncbi.nlm.nih.gov/pubmed/28660884
  4. Black licorice: trik or treat? https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm 277152.htm
  5. Hautaniemi EJ, Tahvanainen AM, Koskela JK, et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep 2017;7:10947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591274/
  6. Groen J, Pelser H, Willebrands AF, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-75. https://www.ncbi.nlm.nih.gov/pubmed/14806786
  7. Cooper H, Bhattacharya B, Verma V, et al. Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann Clin Biochem 2007;44:397-99. https://www.ncbi.nlm.nih.gov/pubmed/17594790
  8. Farese S, Kruse Anja, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney International 2009;76:877-84. https://www.ncbi.nlm.nih.gov/pubmed/19641483
How does excess licorice consumption cause hypertension and hypokalemia?

My patient is admitted with diabetic ketoacidosis (DKA) and is testing positive for cocaine. Can cocaine cause DKA?

Cocaine use has been generally linked to DKA but whether it’s through its antagonizing effect on insulin action or more indirectly through its association with non-compliance with insulin, or both, is not totally clear.

A retrospective study found cocaine users to account for 14% of all DKA admissions.1 Cocaine users were also less likely than controls to have an intercurrent illness identified as a precipitant for DKA, and more likely to have missed taking insulin prior to admission. Another study also reported active cocaine use to be associated with DKA, but found its effect to be independent of non-compliance. 2

Yet another retrospective study limited to patients admitted with hyperglycemia, found no significant association between active cocaine use and development of hyperglycemic crisis.

There are reasons to believe that cocaine may contribute to DKA. Cocaine has been proposed as a possible precipitant of DKA due to its ability to potentially enhance counterregulatory mechanisms designed to antagonize the effect of insulin by increasing catecholamine and cortisol levels. 1,3

So next time you have a patient with DKA, consider cocaine as a possible precipitant, particularly when the cause of DKA is unclear.

 

References

  1. Warner EA, Greene GS, Buchsbaum MS et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med 1998; 158:1799-802. https://www.ncbi.nlm.nih.gov/pubmed/9738609
  2. Nyenwe E, Loganathan R, Blum S, et al. Active use of cocaine: An independent risk factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract 2007;13:22-29. https://www.ncbi.nlm.nih.gov/pubmed/17360297
  3. Modzelewski KL, Rybin DV, Weinberg JM, et al. Active cocaine use does not increase the likelihood of hyperglycemic crisis. J Clin Transl Endocrinol 2017;9:1-7 http://www.jctejournal.com/article/S2214-6237(16)30056-4/pdf

 

Contributed in part by Quin L Sievers, Medical Student, Harvard Medical School

My patient is admitted with diabetic ketoacidosis (DKA) and is testing positive for cocaine. Can cocaine cause DKA?