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What increased consumption of licorice may reveal in anorexia nervosa
Nutrition 27 (2011) 853–854
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
What increased consumption of licorice may reveal in anorexia nervosa
Some nutritional deficiencies are known to trigger peculiar eating habits oriented to compensate for the missing food components. If no food is consumed, such behavior is also called pica; for example, potassium, zinc, or iron deficiency may be indicative in some subjects with geophagia, i.e., ingesting soils or clay [1]. When eating preferences are directed toward some foods or their components, the underlying biological cause that is not primarily related to the energy balance is not obvious. Licorice extract from the root of the plant Glycyrrhiza glabra is an ingredient in some candies, cookies, and cigarettes owing to its intense sweet taste and peculiar flavor. Its laxative and expectorant properties have been also used in traditional medicine. The active ingredient is glycyrrhizin, whose daily consumption should not be more that 100 mg. Glycyrrhizin inhibits 11-b-hydroxysteroid dehydrogenase (type 2), the enzyme that inactivates cortisol by forming cortisone (the cortisol-to-cortisone shuttle). The inhibition of 11-b-hydroxysteroid dehydrogenase may be caused by a metabolite of glycyrrhizin, namely 3-monoglucuronyl-glycyrrhetinic acid [2–4]. Although lower doses of glycyrrhizin are generally well tolerated, increased consumption of licorice may result in toxic effects, including increased blood pressure, pseudohyperaldosteronism with hypokalemia, cardiac arrhythmia, increased cortisol concentrations, and low serum and urinary aldosterone concentrations with decreased serum renin activity and hyperkaluria [5–8]. Furthermore, if hypokalemia is severe, it can result in hypokalemic paralysis, proximal myopathy, rhabdomyolysis, and flaccid quadriparesis. A case of licorice toxicity is reported in this issue of Nutrition in an elegant study by Støving et al. [9] showing licorice consumption-associated hypokalemia, low plasma aldosterone, and increased urinary cortisol. Although such symptoms are typical for glycyrrhizin overdose as discussed earlier, the peculiarity of the case is that these symptoms were observed at a relatively normal (70 mg/d) dose of glycyrrhizin in a patient with anorexia nervosa. The authors raise some important questions: Is increased glycyrrhizin sensitivity a common feature in anorexia nervosa? Is there a potential skin test that can detect such patients? Should licorice be avoided in this disease? Hence, follow-up research projects testing sensitivity to licorice in patients with anorexia nervosa will be justified. To identify the causative role of licorice in hypokalemia, several confounding factors should be eliminated [10]. As such, 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.05.004
psychogenic or surreptitious vomiting should also be considered in those with eating disorders in which dehydration, hypokalemia, hypochloremia, hypovolemia, and metabolic alkalosis can manifest. Clinical signs may consist of gastric reflux, esophagitis, dental erosion, enlarged salivary glands, and lesions on the backs of hands and fingers caused by trauma from the incisors [11]. Diuretic abuse with potassium-losing diuretics is seen in some patients with eating disorders and can present biochemically with severe hypokalemia, hyponatremia, and a metabolic alkalosis. If this is suspected, urine can be analyzed for the presence of diuretics to help confirm the diagnosis [12]. Similarly, purgative abuse should be considered; generally speaking, these can be caused by colonic stimulants or osmotic laxatives. Drug analysis of stools or urine for colonic stimulant laxatives or measurement of the stool osmolality gap, which is increased in the presence of osmotic laxatives, can facilitate the diagnosis [13]. For completeness, a drug screen for diuretic and laxative abuse might also have been useful and a urine chloride determination would be expected to be lower than 20 mmol/L in a saline-responsive metabolic alkalosis such as in chronic vomiting and equal to or higher than 20 mmol/L in mineralocorticoid excess syndromes such as Conn’s syndrome. In general, in the presence of hypokalemia, a urine spot potassium lower than or equal to 20 mmol/L is suggestive of poor potassium intake, gastrointestinal loss, or a transcellular potassium shift. A urine spot potassium higher than 20 mmol/L is indicative of renal potassium loss that occurs in the rare Bartter’s and Gitelman’s syndromes or mineralocorticoid excess disorders [14], although it should be stated that the interpretation of urine potassium concentration can be difficult in cases of chronic hypokalemia [15]. In eating disorders such as anorexia nervosa, the refeeding syndrome should also be considered, particularly if calories are reintroduced inappropriately and without correction of electrolyte imbalance; in such a case, hypokalemia, hypophosphatemia, hypomagnesemia, fluid imbalance, and thiamine deficiency can occur; the latter can be associated with Wernicke’s encephalopathy [16]. In anorexia nervosa, other vitamin deficiencies can result, albeit rarely, such as pellagra and deficiencies of trace metals such as zinc and selenium. Based on this clinical case, we may also ask if an increased eating preference for licorice in this patient is a coincidence or
854
Editorial / Nutrition 27 (2011) 853–854
if it reflects endocrine abnormalities that would help to shed light on the pathophysiology of anorexia nervosa. Although the amount of licorice taken daily by the patient did not exceed the highest recommended doses, in the frame of the generally restrictive feeding behavior in anorexia nervosa, such an amount of licorice extract-containing candies may be considered increased consumption versus subjects with normal food intake. In analogy to peculiar eating habits, what deficiency increased licorice consumption might compensate in anorexia nervosa? Because the main pharmacologic effect of glycyrrhizin is to inhibit activity of the specific 11-b-hydroxysteroid dehydrogenase enzyme responsible for conversion of cortisol to cortisone, resulting in increased plasma cortisol levels, we can speculate that licorice might be a substitution of a physiologic mechanism responsible for normal stimulation of cortisol secretion. Increased cortisol is in fact a common feature in patients with anorexia nervosa [17] and was increased in this clinical case. Spectacularly, it was decreased during licorice abstention. Although licorice cannot be responsible for all hypercortisolemic cases in anorexia nervosa, this clinical case suggests that the organism may sometime develop a preference for the substance that would increase cortisol secretion. It is noteworthy, however, that patients with eating disorders consume more artificial sweeteners than healthy controls [18], but the presence of glycyrrhizin in these sweeteners has not been specified. Another way to stimulate cortisol secretion is physical activity, and excessive exercise was indeed postulated as a behavioral strategy to increase cortisol in anorexia nervosa. If physiologic regulation of cortisol secretion is deficient in anorexia nervosa, it may underlie the altered activity of the hypothalamic-pituitaryadrenal axis [17] and in particular deficient corticotropin action. One possible reason for such deficiency may be corticotropin-reactive immunoglobulins detected in patients with eating disorders [19]. In addition to the primary role of cortisol to participate in the regulation of the metabolism, gene expression, and blood glucose level, its high concentrations display mineralocorticoid-like effects, i.e., increasing sodium and water reabsorption from the kidney. If this mineralocorticoid function were insufficient in anorexia nervosa, it might signify altered mechanisms to counteract dehydration [20]. Accordingly, patients with anorexia nervosa have been reported to have a hypersensitive aldosterone response to angiotensin II [21] electrolyte disturbances such as hypokalemia and dehydration [22]. In conclusion, hypokalemia should be looked for in patients with anorexia nervosa, particularly those at risk of refeeding syndrome. There are many causes of hypokalemia, among which licorice toxicity should be considered, particularly if hypertension, edema, and other features of mineralocorticoid excess are present. Conversely, increased licorice consumption may appear as a behavioral mechanism of adaptation to stress and may thus help to reveal the underlying metabolic and hormonal deficiencies.
References [1] Trivedi TH, Daga GL, Yeolekar ME. Geophagia leading to hypokalemic quadriparesis in a postpartum patient. J Assoc Phys India 2005;53: 205–7. [2] Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CR. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies. Endocrinology 1989;125:1046–53. [3] Edwards CR, Stewart PM. The cortisol-cortisone shuttle and the apparent specificity of glucocorticoid and mineralocorticoid receptors. J Steroid Biochem Mol Biol 1991;39:859–65. [4] Kato H, Kanaoka M, Yano S, Kobayashi M. 3-Monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin Endocrinol Metab 1995;80:1929–33. [5] Iida R, Otsuka Y, Matsumoto K, Kuriyama S, Hosoya T. Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of glycyrrhizin with angiotensin-converting enzyme inhibitor. Clin Exp Nephrol 2006;10:131–5. [6] Elinav E, Chajek-Shaul T. Licorice consumption causing severe hypokalemic paralysis. Mayo Clin Proc 2003;78:767–8. [7] Johns C. Glycyrrhizic acid toxicity caused by consumption of licorice candy cigars. Can J Emergency Med 2009;11:94–6. [8] Armanini D, Karbowiak I, Funder JW. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin Endocrinol (Oxf) 1983;19:609–12. [9] Støving RK, Lingqvist LE, Bonde RK, Andries A, Hansen MH, Andersen M, et al. Is glycyrrhizin sensitivity increased in anorexia nervosa and should licorice be avoided? Case report and review of the literature. Nutrition; 2011. In press. [10] Crook M. Clinical chemistry and metabolic medicine. 7th ed. London: Hodder Arnold; 2006. p. 82-93. [11] Richardson RM, Forbath N, Karanicolas S. Hypokalemic metabolic alkalosis caused by surreptitious vomiting: report of four cases. Can Med Assoc J 1983;129:142–6. [12] Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriced evaluation of health hazard. Food Chem Toxicol 1993;31:303–12. [13] Duncan A. Screening for surreptitious laxative abuse. Ann Clin Biochem 2000;37(Pt 1):1–8. [14] Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D. Bartter’s and Gitelman’s syndromes: from gene to clinic. Nephron Physiol 2004;96:65–78. [15] Reimann D, Gross P. Chronic, diagnosis-resistant hypokalaemia. Nephrol Dial Transplant 1999;14:2957–61. [16] Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001;17:632–7. [17] Stoving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa. J Psychiatr Res 1999;33:139–52. [18] Klein DA, Boudreau GS, Devlin MJ, Walsh BT. Artificial sweetener use among individuals with eating disorders. Int J Eat Disord 2006;39: 341–5. €ck E, Hulting AL, [19] Fetissov SO, Hallman J, Oreland L, af Klinteberg B, Grenba et al. Autoantibodies against a-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proc Natl Acad Sci U S A 2002;99:17155–60. [20] Thornton SN. Thirst and hydration: physiology and consequences of dysfunction. Physiol Behav 2010;100:15–21. [21] Mizuno O, Tamai H, Fujita M, Kobayashi N, Komaki G, Matsubayashi S, et al. Aldosterone responses to angiotensin II in anorexia nervosa. Acta Psychiatr Scand 1992;86:450–4. [22] Schneiter S, Berwert L, Bonny O, Teta D, Burnier M, Vogt B. Anorexia nervosa and the kidney. Rev Med Suisse 2009;5:440, 442–4.
Sergueï O. Fetissov, M.D., Ph.D. Digestive System and Nutrition Laboratory (ADEN EA4311) Rouen University, IFR23 Rouen, France Martin A. Crook, B.Sc., M.B.B.S., M.A., Ph.D. Department of Clinical Biochemistry and Metabolic Medicine University Hospital Lewisham London, United Kingdom
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
What increased consumption of licorice may reveal in anorexia nervosa
Some nutritional deficiencies are known to trigger peculiar eating habits oriented to compensate for the missing food components. If no food is consumed, such behavior is also called pica; for example, potassium, zinc, or iron deficiency may be indicative in some subjects with geophagia, i.e., ingesting soils or clay [1]. When eating preferences are directed toward some foods or their components, the underlying biological cause that is not primarily related to the energy balance is not obvious. Licorice extract from the root of the plant Glycyrrhiza glabra is an ingredient in some candies, cookies, and cigarettes owing to its intense sweet taste and peculiar flavor. Its laxative and expectorant properties have been also used in traditional medicine. The active ingredient is glycyrrhizin, whose daily consumption should not be more that 100 mg. Glycyrrhizin inhibits 11-b-hydroxysteroid dehydrogenase (type 2), the enzyme that inactivates cortisol by forming cortisone (the cortisol-to-cortisone shuttle). The inhibition of 11-b-hydroxysteroid dehydrogenase may be caused by a metabolite of glycyrrhizin, namely 3-monoglucuronyl-glycyrrhetinic acid [2–4]. Although lower doses of glycyrrhizin are generally well tolerated, increased consumption of licorice may result in toxic effects, including increased blood pressure, pseudohyperaldosteronism with hypokalemia, cardiac arrhythmia, increased cortisol concentrations, and low serum and urinary aldosterone concentrations with decreased serum renin activity and hyperkaluria [5–8]. Furthermore, if hypokalemia is severe, it can result in hypokalemic paralysis, proximal myopathy, rhabdomyolysis, and flaccid quadriparesis. A case of licorice toxicity is reported in this issue of Nutrition in an elegant study by Støving et al. [9] showing licorice consumption-associated hypokalemia, low plasma aldosterone, and increased urinary cortisol. Although such symptoms are typical for glycyrrhizin overdose as discussed earlier, the peculiarity of the case is that these symptoms were observed at a relatively normal (70 mg/d) dose of glycyrrhizin in a patient with anorexia nervosa. The authors raise some important questions: Is increased glycyrrhizin sensitivity a common feature in anorexia nervosa? Is there a potential skin test that can detect such patients? Should licorice be avoided in this disease? Hence, follow-up research projects testing sensitivity to licorice in patients with anorexia nervosa will be justified. To identify the causative role of licorice in hypokalemia, several confounding factors should be eliminated [10]. As such, 0899-9007/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2011.05.004
psychogenic or surreptitious vomiting should also be considered in those with eating disorders in which dehydration, hypokalemia, hypochloremia, hypovolemia, and metabolic alkalosis can manifest. Clinical signs may consist of gastric reflux, esophagitis, dental erosion, enlarged salivary glands, and lesions on the backs of hands and fingers caused by trauma from the incisors [11]. Diuretic abuse with potassium-losing diuretics is seen in some patients with eating disorders and can present biochemically with severe hypokalemia, hyponatremia, and a metabolic alkalosis. If this is suspected, urine can be analyzed for the presence of diuretics to help confirm the diagnosis [12]. Similarly, purgative abuse should be considered; generally speaking, these can be caused by colonic stimulants or osmotic laxatives. Drug analysis of stools or urine for colonic stimulant laxatives or measurement of the stool osmolality gap, which is increased in the presence of osmotic laxatives, can facilitate the diagnosis [13]. For completeness, a drug screen for diuretic and laxative abuse might also have been useful and a urine chloride determination would be expected to be lower than 20 mmol/L in a saline-responsive metabolic alkalosis such as in chronic vomiting and equal to or higher than 20 mmol/L in mineralocorticoid excess syndromes such as Conn’s syndrome. In general, in the presence of hypokalemia, a urine spot potassium lower than or equal to 20 mmol/L is suggestive of poor potassium intake, gastrointestinal loss, or a transcellular potassium shift. A urine spot potassium higher than 20 mmol/L is indicative of renal potassium loss that occurs in the rare Bartter’s and Gitelman’s syndromes or mineralocorticoid excess disorders [14], although it should be stated that the interpretation of urine potassium concentration can be difficult in cases of chronic hypokalemia [15]. In eating disorders such as anorexia nervosa, the refeeding syndrome should also be considered, particularly if calories are reintroduced inappropriately and without correction of electrolyte imbalance; in such a case, hypokalemia, hypophosphatemia, hypomagnesemia, fluid imbalance, and thiamine deficiency can occur; the latter can be associated with Wernicke’s encephalopathy [16]. In anorexia nervosa, other vitamin deficiencies can result, albeit rarely, such as pellagra and deficiencies of trace metals such as zinc and selenium. Based on this clinical case, we may also ask if an increased eating preference for licorice in this patient is a coincidence or
854
Editorial / Nutrition 27 (2011) 853–854
if it reflects endocrine abnormalities that would help to shed light on the pathophysiology of anorexia nervosa. Although the amount of licorice taken daily by the patient did not exceed the highest recommended doses, in the frame of the generally restrictive feeding behavior in anorexia nervosa, such an amount of licorice extract-containing candies may be considered increased consumption versus subjects with normal food intake. In analogy to peculiar eating habits, what deficiency increased licorice consumption might compensate in anorexia nervosa? Because the main pharmacologic effect of glycyrrhizin is to inhibit activity of the specific 11-b-hydroxysteroid dehydrogenase enzyme responsible for conversion of cortisol to cortisone, resulting in increased plasma cortisol levels, we can speculate that licorice might be a substitution of a physiologic mechanism responsible for normal stimulation of cortisol secretion. Increased cortisol is in fact a common feature in patients with anorexia nervosa [17] and was increased in this clinical case. Spectacularly, it was decreased during licorice abstention. Although licorice cannot be responsible for all hypercortisolemic cases in anorexia nervosa, this clinical case suggests that the organism may sometime develop a preference for the substance that would increase cortisol secretion. It is noteworthy, however, that patients with eating disorders consume more artificial sweeteners than healthy controls [18], but the presence of glycyrrhizin in these sweeteners has not been specified. Another way to stimulate cortisol secretion is physical activity, and excessive exercise was indeed postulated as a behavioral strategy to increase cortisol in anorexia nervosa. If physiologic regulation of cortisol secretion is deficient in anorexia nervosa, it may underlie the altered activity of the hypothalamic-pituitaryadrenal axis [17] and in particular deficient corticotropin action. One possible reason for such deficiency may be corticotropin-reactive immunoglobulins detected in patients with eating disorders [19]. In addition to the primary role of cortisol to participate in the regulation of the metabolism, gene expression, and blood glucose level, its high concentrations display mineralocorticoid-like effects, i.e., increasing sodium and water reabsorption from the kidney. If this mineralocorticoid function were insufficient in anorexia nervosa, it might signify altered mechanisms to counteract dehydration [20]. Accordingly, patients with anorexia nervosa have been reported to have a hypersensitive aldosterone response to angiotensin II [21] electrolyte disturbances such as hypokalemia and dehydration [22]. In conclusion, hypokalemia should be looked for in patients with anorexia nervosa, particularly those at risk of refeeding syndrome. There are many causes of hypokalemia, among which licorice toxicity should be considered, particularly if hypertension, edema, and other features of mineralocorticoid excess are present. Conversely, increased licorice consumption may appear as a behavioral mechanism of adaptation to stress and may thus help to reveal the underlying metabolic and hormonal deficiencies.
References [1] Trivedi TH, Daga GL, Yeolekar ME. Geophagia leading to hypokalemic quadriparesis in a postpartum patient. J Assoc Phys India 2005;53: 205–7. [2] Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CR. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies. Endocrinology 1989;125:1046–53. [3] Edwards CR, Stewart PM. The cortisol-cortisone shuttle and the apparent specificity of glucocorticoid and mineralocorticoid receptors. J Steroid Biochem Mol Biol 1991;39:859–65. [4] Kato H, Kanaoka M, Yano S, Kobayashi M. 3-Monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin Endocrinol Metab 1995;80:1929–33. [5] Iida R, Otsuka Y, Matsumoto K, Kuriyama S, Hosoya T. Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of glycyrrhizin with angiotensin-converting enzyme inhibitor. Clin Exp Nephrol 2006;10:131–5. [6] Elinav E, Chajek-Shaul T. Licorice consumption causing severe hypokalemic paralysis. Mayo Clin Proc 2003;78:767–8. [7] Johns C. Glycyrrhizic acid toxicity caused by consumption of licorice candy cigars. Can J Emergency Med 2009;11:94–6. [8] Armanini D, Karbowiak I, Funder JW. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin Endocrinol (Oxf) 1983;19:609–12. [9] Støving RK, Lingqvist LE, Bonde RK, Andries A, Hansen MH, Andersen M, et al. Is glycyrrhizin sensitivity increased in anorexia nervosa and should licorice be avoided? Case report and review of the literature. Nutrition; 2011. In press. [10] Crook M. Clinical chemistry and metabolic medicine. 7th ed. London: Hodder Arnold; 2006. p. 82-93. [11] Richardson RM, Forbath N, Karanicolas S. Hypokalemic metabolic alkalosis caused by surreptitious vomiting: report of four cases. Can Med Assoc J 1983;129:142–6. [12] Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriced evaluation of health hazard. Food Chem Toxicol 1993;31:303–12. [13] Duncan A. Screening for surreptitious laxative abuse. Ann Clin Biochem 2000;37(Pt 1):1–8. [14] Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D. Bartter’s and Gitelman’s syndromes: from gene to clinic. Nephron Physiol 2004;96:65–78. [15] Reimann D, Gross P. Chronic, diagnosis-resistant hypokalaemia. Nephrol Dial Transplant 1999;14:2957–61. [16] Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001;17:632–7. [17] Stoving RK, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa. J Psychiatr Res 1999;33:139–52. [18] Klein DA, Boudreau GS, Devlin MJ, Walsh BT. Artificial sweetener use among individuals with eating disorders. Int J Eat Disord 2006;39: 341–5. €ck E, Hulting AL, [19] Fetissov SO, Hallman J, Oreland L, af Klinteberg B, Grenba et al. Autoantibodies against a-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proc Natl Acad Sci U S A 2002;99:17155–60. [20] Thornton SN. Thirst and hydration: physiology and consequences of dysfunction. Physiol Behav 2010;100:15–21. [21] Mizuno O, Tamai H, Fujita M, Kobayashi N, Komaki G, Matsubayashi S, et al. Aldosterone responses to angiotensin II in anorexia nervosa. Acta Psychiatr Scand 1992;86:450–4. [22] Schneiter S, Berwert L, Bonny O, Teta D, Burnier M, Vogt B. Anorexia nervosa and the kidney. Rev Med Suisse 2009;5:440, 442–4.
Sergueï O. Fetissov, M.D., Ph.D. Digestive System and Nutrition Laboratory (ADEN EA4311) Rouen University, IFR23 Rouen, France Martin A. Crook, B.Sc., M.B.B.S., M.A., Ph.D. Department of Clinical Biochemistry and Metabolic Medicine University Hospital Lewisham London, United Kingdom