Pediatric Neurology 52 (2015) 457e459
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Posterior Reversible Encephalopathy Syndrome Associated With Licorice Consumption: A Case Report in a 10-Year-Old Boy Davide Tassinari MD a, *, Rosalba Bergamaschi MD a, Ilaria Corsini MD a, Susanna Landini MD a, Benedetta Romanin MD a, Elisa Ballarini MD a, Fabrizio De Ponti MD b, Filomena Carfagnini MD c, Francesco Toni MD c, Filippo Bernardi MD a a
Department of Pediatric Emergency, S. Orsola-Malpighi Hospital, University of Bologna, Italy Department of Medical and Surgical Sciences, Pharmacology Unit, University of Bologna, Italy c Department of Pediatric Radiology, S. Orsola-Malpighi Hospital of Bologna, Italy b
abstract BACKGROUND: Posterior reversible encephalopathy syndrome is characterized by a combination of clinical-
radiological findings and pathophysiologically by localized brain vasogenic edema. Many clinical illnesses may trigger the onset of posterior reversible encephalopathy syndrome and hypertension is present in about 80% of patients. METHODS: We describe a child with high consumption of licorice toffees who developed systemic hypertension followed by posterior reversible encephalopathy syndrome. RESULTS: This boy was hospitalized following a cluster of generalized tonic-clonic seizures. Monitoring his clinical parameters, we detected constant high blood pressure and a brain magnetic resonance scan showed a localized vasogenic edema; these symptoms suggested posterior reversible encephalopathy syndrome. He had been eating licorice toffees for a period of 4 months, consuming an estimated 72 mg of glycyrrhizic acid per day; this led to our assumption of the reason for his hypertension. CONCLUSION: There are several reported examples of posterior reversible encephalopathy syndromeeinduced licorice hypertension in adults, but none related to children. Our report examines a possible link between licorice consumption and hypertension/posterior reversible encephalopathy syndrome in children. Keywords: licorice, PRES, hypertension, 11b-hydroxysteroid dehydrogenase, children
Pediatr Neurol 2015; 52: 457-459 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Posterior reversible encephalopathy syndrome (PRES) is an association of acute neurological symptoms consequent to brain vasogenic edema and demonstrated by brain magnetic resonance imaging (MRI). Neurological symptoms are nonspecific, but tonic-clonic or focal seizures are often the initial manifestation.1 An acute rise in systemic blood pressure is the most common associated condition. PRES is also associated Article History: Received October 9, 2014; Accepted in final form December 3, 2014 * Communications should be addressed to: Dr. Tassinari; Department of Pediatric Emergency; S. Orsola-Malpighi Hospital; Via Massarenti 11; Bologna, 40126 Italy. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.12.001
with many other clinical conditions, with or without hypertension, which should be considered in differential diagnosis: acute or chronic renal failure, infections, sepsis or multiple organ dysfunction, autoimmune diseases, treatment with chemotherapeutic or immunosuppressant agents, and bone marrow or solid organ transplantation.1 Because the clinical findings associated with PRES are nonspecific, appropriate neuroimaging is essential to avoiding misdiagnosis, treatment delay, and permanent neurological injury. Brain MRI demonstrates the typical vasogenic edema involving focal cerebral districts, mostly and symmetrically localized in the parietal and occipital lobes.1 This edema usually decreases and disappears within days or weeks after prompt treatment of the originating cause of PRES.
458
D. Tassinari et al. / Pediatric Neurology 52 (2015) 457e459
Here we describe a boy whose excessive consumption of licorice toffees lead to the development of systemic hypertension followed by PRES. Patient Description A 10 year-old boy with no fever was admitted after a generalized and unexplained tonic-clonic seizure that lasted 2 minutes and resolved spontaneously. The general and neurological examinations were completely normal except for elevated blood pressure (135/88 mmHg). No previous critical episodes or seizures were reported. The admission laboratory tests were unremarkable, apart from blood potassium levels in the low normal range (3.5 mmol/L). In the next few hours, a cluster of another three generalized seizures occurred: one seizure that occurred during electroencephalography began in the right frontal lobe. His basal electroencephalography was normal after the seizure. Intravenous midazolam was administered continuously for the subsequent 24 hours. Cranial computed tomography was normal and excluded expansive brain masses, hemorrhage, and other cerebral abnormalities. When midazolam was stopped, he complained of a bad headache and his blood pressure was confirmed at 140/100 mmHg. A 24-hour blood pressure monitoring confirmed second-degree hypertension, with systolic/diastolic average values of 135/93 mmHg: the systolic and diastolic peaks were 144 and 102 mmHg, respectively (greater than the ninetyninth percentile). The association of seizures and persistent high blood pressure was suggestive of PRES; therefore, a brain MRI was performed. Neuroimaging documented vasogenic edema of the cortical and subcortical occipitoparietal regions bilaterally as well as in the right parasagittal frontal area. Neuroimages were hyperintense on T2 fluid-attenuated inversion recovery (Fig 1) with mild increase of the apparent diffusion coefficient in the right parieto-occipital region. Other major clinical conditions generating PRES were ruled out,1 and a normal blood pressure (100/64 mmHg) was achieved only with a combined administration of an angiotensin-converting enzyme inhibitor and amlodipine. Only the persistently high cortisol levels with normal circadian rhythm (cortisol at 8 am, 313 ng/mL; 8 pm 126 ng/mL; 12 pm, 37 ng/mL) suggested a possible association between hypertension and an endocrine disorder. Cortisoluria was also high (168.9 mg/24 hours), and blood potassium was persistently in the low-normal range. An endogenous adrenal disorder was excluded because both the adrenocorticotropic hormone values and all the remaining hormonal-adrenal markers were normal. A week after admission, during a daily medical examination, it was noticed that some of the patient’s teeth were black. The child told the doctors he had been eating at least 20 licorice sweets a day for the past 4 months. From the data on the packet, each sweet contained 120 mg of licorice, corresponding to 3.6 mg of glycyrrhizic acid, which amounted to a total daily consumption of 2400 mg of licorice and therefore 72 mg of glycyrrhizic acid. Considering the boy’s body weight, the total daily intake of glycyrrhizic acid was 2.88 mg/kg. This amount was well above the maximum safety range (2 mg/kg/day) suggested by the World Health Organization.2,3 We concluded that the licorice intake could explain the boy’s hypertension and we recommended he stop the excessive ingestion of licorice immediately. After he stopped eating licorice, the antihypertensive treatment was gradually reduced and then stopped. From the time he was admitted to hospital, the pharmacological therapy lasted a month. Two weeks later, a brain MRI showed a considerable decrease of the vasogenic edema (Fig 2). The clinical follow-up monitored regularly the patient’s blood pressure, which remained normal.
Discussion
Here we describe PRES associated with prolonged and severe licorice-induced hypertension; this is the first reported child with this condition.
FIGURE 1. Brain magnetic resonance imaging at admission. On T2 fluid-attenuated inversion recovery imaging, the arrows point to hyperintense signal of vasogenic edema in the cortical and subcortical occipito-parietal districts bilaterally, and the right lobe of the parasagittal frontal region.
The pathogenesis of PRES is not yet completely understood, but the primary pathophysiological mechanism is a vasogenic edema resulting from the extravasation of fluid and blood products into the brain interstitial space. In hypertensive patients, there are likely two main mechanisms generating PRES. 1) Severe hypertension produces hyperperfusion that leads to brain edema when it exceeds the limit of brain bloodstream autoregulation (150-160 mmHg). 2) Chronic mild to moderate hypertension leads to cerebral autoregulatory vasoconstriction with hypoperfusion, triggering hypoxia with endothelial arteriolar injury/ dysfunction, cytokine production, and finally vasogenic edema.4 Approximately 20%-30% of the individuals with PRES do not exhibit hypertension. In these patients, the vasogenic edema seems to be associated with high production of cytokines as a consequence of an endothelial-arteriolar injury/dysfunction.1,4 Out patient’s hypertension monitored by a 24-hour blood pressure monitoring and was linked to the excessive consumption of licorice. The biologically active component of licorice is glycyrrhizic acid. This acid inhibits 11b-hydroxysteroid dehydrogenase enzyme production and interrupts the conversion of circulating cortisol to the less active cortisone. This particular enzyme is produced mainly in the kidneys, liver, placenta, and brain tissue.5-9
D. Tassinari et al. / Pediatric Neurology 52 (2015) 457e459
459
cyrrhizic acid, which was much higher than the maximum recommended amount.2 The patients of Sigurjonsdottir and colleagues5 had reached a hypertensive status after being administered 50 g/day of licorice for 2 weeks. In the subsequent 2 weeks, the patients’ hypertension remained stable. Our patient had been consuming licorice for 4 months at a much lower dose and it was unknown exactly when he became hypertensive. If compared with Sjgurjonsdottir’s patients, it is possible that the hypertension set in rapidly and PRES manifested itself only after a period of 4 months. Subsequently, PRES was most probably associated with long-term brain hypoxic damage instead of a hypertension/ hyperperfusion mechanism. Besides the minimum daily licorice intake, the cumulative amount of licorice consumed over a long period should be taken into consideration in the PRES development. Finally, as a result of our research, we suggest that licorice sweet manufacturers indicate a recommended daily amount in relation to maximum safety limits on their packaging. This is particularly important for children with a low weight and body surface area.12,14 References
FIGURE 2. Brain magnetic resonance imaging 2 weeks after licorice suspension. On T2 fluid-attenuated inversion recovery imaging, the arrow points to the remaining area with a weakly altered signal in the right frontal lobe cortex.
As a result of this enzyme inhibition, cortisol blood levels increase because of prolongation of its plasma half-life and inappropriately occupies mineralocorticoid receptors of the renal distal tubules and collecting ducts. This condition is similar to the so-called “syndrome of apparent mineralocorticoid excess.”5,9,10 There have been several reports of hypertension in adult patients associated with abuse of licorice. However, the amount of licorice daily intake that makes hypertension a risk is not precisely known.5,6,11,12 Most articles include a calculation of the daily intake of glycyrrhizic acid, which demonstrate notable variation and susceptibility in individual patients. The recommended daily intake should be no more than 100 mg/day or about 2 mg/kg in an adult, but there is no information about children.2,3,6,11,13 To find a common conversion parameter to compare with adults, we based our calculations on total daily licorice assumption in relation to body surface area (mg/m2/day). Our patient had a body surface area of 0.94 m2, whereas the value of an adult at the 50th percentile is 1.84 m2 (Mosteller formula). This calculation suggests that the highest safety limit of glycyrrhizic acid intake (100 mg/day) should be converted to 54.3 mg/m2/day for an adult. Our patient had consumed 76.6 mg/m2/day of gly-
1. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. Am J Neuroradiol. 2008;29:1036-1042. Epub 2008 Mar 20. 2. World Health Organization. Evaluation of certain food additives. World Health Organ Tech Rep Ser. 2005;928:1-156. 3. Sontia B, Mooney J, Gaudet L, Touyz RM. Pseudohyperaldosteronism, Liquorice and Hypertension. J Clin Hypertens (Greenwich). 2008; 10:153-157. 4. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. Am J Neuroradiol. 2008;29:1043-1049. Epub 2008 Apr 10. 5. Sigurjónsdóttir HÁ, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedt S. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens. 2001;15: 549-552. 6. Russo S, Mastropasqua M, Mosetti MA, Persegani C, Paggi A. Low doses of liquorice can induce hypertension encephalopathy. Am J Nephrol. 2000;20:145-148. 7. Ferrari P, Lovati E, Frey FJ. The role of the 11 beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. 2000; 18:241-248. 8. Morgan RD, Chou SH, Stelfox HT. Posterior reversible encephalopathy syndrome in a patient following binge liquorice ingestion. J Neurol. 2011;258:1720-1722. 9. Makino T. 3-Monoglucuronyl Glycyrrhretinic Acid Is a Possible Marker Compound Related to Licorice-Induced Pseudoaldosteronis. Biol. Pharm. Bull. 2014;37:898-902. 10. White PC, Mune T, Agarwal AK. 11b-hydroxysteroid dehydrogenase and the syndrome of apparent mineralcorticoid excess. Endocr Rev. 1997;18:135-156. 11. Bernardi M, D’Intino PE, Trevisani F, et al. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 1994;55:863-872. 12. Kormann R, Languille E, Amiot HM, Hertig A. Dying for a cup of tea. BMJ Case Rep; 2012;. http://dx.doi.org/10.1136/bcr-2012-006805. 13. Stomer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriceavaluation of health hazard. Food Chem Toxicol. 1993;31:303-312. 14. 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.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Posterior Reversible Encephalopathy Syndrome Associated With Licorice Consumption: A Case Report in a 10-Year-Old Boy Davide Tassinari MD a, *, Rosalba Bergamaschi MD a, Ilaria Corsini MD a, Susanna Landini MD a, Benedetta Romanin MD a, Elisa Ballarini MD a, Fabrizio De Ponti MD b, Filomena Carfagnini MD c, Francesco Toni MD c, Filippo Bernardi MD a a
Department of Pediatric Emergency, S. Orsola-Malpighi Hospital, University of Bologna, Italy Department of Medical and Surgical Sciences, Pharmacology Unit, University of Bologna, Italy c Department of Pediatric Radiology, S. Orsola-Malpighi Hospital of Bologna, Italy b
abstract BACKGROUND: Posterior reversible encephalopathy syndrome is characterized by a combination of clinical-
radiological findings and pathophysiologically by localized brain vasogenic edema. Many clinical illnesses may trigger the onset of posterior reversible encephalopathy syndrome and hypertension is present in about 80% of patients. METHODS: We describe a child with high consumption of licorice toffees who developed systemic hypertension followed by posterior reversible encephalopathy syndrome. RESULTS: This boy was hospitalized following a cluster of generalized tonic-clonic seizures. Monitoring his clinical parameters, we detected constant high blood pressure and a brain magnetic resonance scan showed a localized vasogenic edema; these symptoms suggested posterior reversible encephalopathy syndrome. He had been eating licorice toffees for a period of 4 months, consuming an estimated 72 mg of glycyrrhizic acid per day; this led to our assumption of the reason for his hypertension. CONCLUSION: There are several reported examples of posterior reversible encephalopathy syndromeeinduced licorice hypertension in adults, but none related to children. Our report examines a possible link between licorice consumption and hypertension/posterior reversible encephalopathy syndrome in children. Keywords: licorice, PRES, hypertension, 11b-hydroxysteroid dehydrogenase, children
Pediatr Neurol 2015; 52: 457-459 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Posterior reversible encephalopathy syndrome (PRES) is an association of acute neurological symptoms consequent to brain vasogenic edema and demonstrated by brain magnetic resonance imaging (MRI). Neurological symptoms are nonspecific, but tonic-clonic or focal seizures are often the initial manifestation.1 An acute rise in systemic blood pressure is the most common associated condition. PRES is also associated Article History: Received October 9, 2014; Accepted in final form December 3, 2014 * Communications should be addressed to: Dr. Tassinari; Department of Pediatric Emergency; S. Orsola-Malpighi Hospital; Via Massarenti 11; Bologna, 40126 Italy. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.12.001
with many other clinical conditions, with or without hypertension, which should be considered in differential diagnosis: acute or chronic renal failure, infections, sepsis or multiple organ dysfunction, autoimmune diseases, treatment with chemotherapeutic or immunosuppressant agents, and bone marrow or solid organ transplantation.1 Because the clinical findings associated with PRES are nonspecific, appropriate neuroimaging is essential to avoiding misdiagnosis, treatment delay, and permanent neurological injury. Brain MRI demonstrates the typical vasogenic edema involving focal cerebral districts, mostly and symmetrically localized in the parietal and occipital lobes.1 This edema usually decreases and disappears within days or weeks after prompt treatment of the originating cause of PRES.
458
D. Tassinari et al. / Pediatric Neurology 52 (2015) 457e459
Here we describe a boy whose excessive consumption of licorice toffees lead to the development of systemic hypertension followed by PRES. Patient Description A 10 year-old boy with no fever was admitted after a generalized and unexplained tonic-clonic seizure that lasted 2 minutes and resolved spontaneously. The general and neurological examinations were completely normal except for elevated blood pressure (135/88 mmHg). No previous critical episodes or seizures were reported. The admission laboratory tests were unremarkable, apart from blood potassium levels in the low normal range (3.5 mmol/L). In the next few hours, a cluster of another three generalized seizures occurred: one seizure that occurred during electroencephalography began in the right frontal lobe. His basal electroencephalography was normal after the seizure. Intravenous midazolam was administered continuously for the subsequent 24 hours. Cranial computed tomography was normal and excluded expansive brain masses, hemorrhage, and other cerebral abnormalities. When midazolam was stopped, he complained of a bad headache and his blood pressure was confirmed at 140/100 mmHg. A 24-hour blood pressure monitoring confirmed second-degree hypertension, with systolic/diastolic average values of 135/93 mmHg: the systolic and diastolic peaks were 144 and 102 mmHg, respectively (greater than the ninetyninth percentile). The association of seizures and persistent high blood pressure was suggestive of PRES; therefore, a brain MRI was performed. Neuroimaging documented vasogenic edema of the cortical and subcortical occipitoparietal regions bilaterally as well as in the right parasagittal frontal area. Neuroimages were hyperintense on T2 fluid-attenuated inversion recovery (Fig 1) with mild increase of the apparent diffusion coefficient in the right parieto-occipital region. Other major clinical conditions generating PRES were ruled out,1 and a normal blood pressure (100/64 mmHg) was achieved only with a combined administration of an angiotensin-converting enzyme inhibitor and amlodipine. Only the persistently high cortisol levels with normal circadian rhythm (cortisol at 8 am, 313 ng/mL; 8 pm 126 ng/mL; 12 pm, 37 ng/mL) suggested a possible association between hypertension and an endocrine disorder. Cortisoluria was also high (168.9 mg/24 hours), and blood potassium was persistently in the low-normal range. An endogenous adrenal disorder was excluded because both the adrenocorticotropic hormone values and all the remaining hormonal-adrenal markers were normal. A week after admission, during a daily medical examination, it was noticed that some of the patient’s teeth were black. The child told the doctors he had been eating at least 20 licorice sweets a day for the past 4 months. From the data on the packet, each sweet contained 120 mg of licorice, corresponding to 3.6 mg of glycyrrhizic acid, which amounted to a total daily consumption of 2400 mg of licorice and therefore 72 mg of glycyrrhizic acid. Considering the boy’s body weight, the total daily intake of glycyrrhizic acid was 2.88 mg/kg. This amount was well above the maximum safety range (2 mg/kg/day) suggested by the World Health Organization.2,3 We concluded that the licorice intake could explain the boy’s hypertension and we recommended he stop the excessive ingestion of licorice immediately. After he stopped eating licorice, the antihypertensive treatment was gradually reduced and then stopped. From the time he was admitted to hospital, the pharmacological therapy lasted a month. Two weeks later, a brain MRI showed a considerable decrease of the vasogenic edema (Fig 2). The clinical follow-up monitored regularly the patient’s blood pressure, which remained normal.
Discussion
Here we describe PRES associated with prolonged and severe licorice-induced hypertension; this is the first reported child with this condition.
FIGURE 1. Brain magnetic resonance imaging at admission. On T2 fluid-attenuated inversion recovery imaging, the arrows point to hyperintense signal of vasogenic edema in the cortical and subcortical occipito-parietal districts bilaterally, and the right lobe of the parasagittal frontal region.
The pathogenesis of PRES is not yet completely understood, but the primary pathophysiological mechanism is a vasogenic edema resulting from the extravasation of fluid and blood products into the brain interstitial space. In hypertensive patients, there are likely two main mechanisms generating PRES. 1) Severe hypertension produces hyperperfusion that leads to brain edema when it exceeds the limit of brain bloodstream autoregulation (150-160 mmHg). 2) Chronic mild to moderate hypertension leads to cerebral autoregulatory vasoconstriction with hypoperfusion, triggering hypoxia with endothelial arteriolar injury/ dysfunction, cytokine production, and finally vasogenic edema.4 Approximately 20%-30% of the individuals with PRES do not exhibit hypertension. In these patients, the vasogenic edema seems to be associated with high production of cytokines as a consequence of an endothelial-arteriolar injury/dysfunction.1,4 Out patient’s hypertension monitored by a 24-hour blood pressure monitoring and was linked to the excessive consumption of licorice. The biologically active component of licorice is glycyrrhizic acid. This acid inhibits 11b-hydroxysteroid dehydrogenase enzyme production and interrupts the conversion of circulating cortisol to the less active cortisone. This particular enzyme is produced mainly in the kidneys, liver, placenta, and brain tissue.5-9
D. Tassinari et al. / Pediatric Neurology 52 (2015) 457e459
459
cyrrhizic acid, which was much higher than the maximum recommended amount.2 The patients of Sigurjonsdottir and colleagues5 had reached a hypertensive status after being administered 50 g/day of licorice for 2 weeks. In the subsequent 2 weeks, the patients’ hypertension remained stable. Our patient had been consuming licorice for 4 months at a much lower dose and it was unknown exactly when he became hypertensive. If compared with Sjgurjonsdottir’s patients, it is possible that the hypertension set in rapidly and PRES manifested itself only after a period of 4 months. Subsequently, PRES was most probably associated with long-term brain hypoxic damage instead of a hypertension/ hyperperfusion mechanism. Besides the minimum daily licorice intake, the cumulative amount of licorice consumed over a long period should be taken into consideration in the PRES development. Finally, as a result of our research, we suggest that licorice sweet manufacturers indicate a recommended daily amount in relation to maximum safety limits on their packaging. This is particularly important for children with a low weight and body surface area.12,14 References
FIGURE 2. Brain magnetic resonance imaging 2 weeks after licorice suspension. On T2 fluid-attenuated inversion recovery imaging, the arrow points to the remaining area with a weakly altered signal in the right frontal lobe cortex.
As a result of this enzyme inhibition, cortisol blood levels increase because of prolongation of its plasma half-life and inappropriately occupies mineralocorticoid receptors of the renal distal tubules and collecting ducts. This condition is similar to the so-called “syndrome of apparent mineralocorticoid excess.”5,9,10 There have been several reports of hypertension in adult patients associated with abuse of licorice. However, the amount of licorice daily intake that makes hypertension a risk is not precisely known.5,6,11,12 Most articles include a calculation of the daily intake of glycyrrhizic acid, which demonstrate notable variation and susceptibility in individual patients. The recommended daily intake should be no more than 100 mg/day or about 2 mg/kg in an adult, but there is no information about children.2,3,6,11,13 To find a common conversion parameter to compare with adults, we based our calculations on total daily licorice assumption in relation to body surface area (mg/m2/day). Our patient had a body surface area of 0.94 m2, whereas the value of an adult at the 50th percentile is 1.84 m2 (Mosteller formula). This calculation suggests that the highest safety limit of glycyrrhizic acid intake (100 mg/day) should be converted to 54.3 mg/m2/day for an adult. Our patient had consumed 76.6 mg/m2/day of gly-
1. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. Am J Neuroradiol. 2008;29:1036-1042. Epub 2008 Mar 20. 2. World Health Organization. Evaluation of certain food additives. World Health Organ Tech Rep Ser. 2005;928:1-156. 3. Sontia B, Mooney J, Gaudet L, Touyz RM. Pseudohyperaldosteronism, Liquorice and Hypertension. J Clin Hypertens (Greenwich). 2008; 10:153-157. 4. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. Am J Neuroradiol. 2008;29:1043-1049. Epub 2008 Apr 10. 5. Sigurjónsdóttir HÁ, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedt S. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens. 2001;15: 549-552. 6. Russo S, Mastropasqua M, Mosetti MA, Persegani C, Paggi A. Low doses of liquorice can induce hypertension encephalopathy. Am J Nephrol. 2000;20:145-148. 7. Ferrari P, Lovati E, Frey FJ. The role of the 11 beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. 2000; 18:241-248. 8. Morgan RD, Chou SH, Stelfox HT. Posterior reversible encephalopathy syndrome in a patient following binge liquorice ingestion. J Neurol. 2011;258:1720-1722. 9. Makino T. 3-Monoglucuronyl Glycyrrhretinic Acid Is a Possible Marker Compound Related to Licorice-Induced Pseudoaldosteronis. Biol. Pharm. Bull. 2014;37:898-902. 10. White PC, Mune T, Agarwal AK. 11b-hydroxysteroid dehydrogenase and the syndrome of apparent mineralcorticoid excess. Endocr Rev. 1997;18:135-156. 11. Bernardi M, D’Intino PE, Trevisani F, et al. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 1994;55:863-872. 12. Kormann R, Languille E, Amiot HM, Hertig A. Dying for a cup of tea. BMJ Case Rep; 2012;. http://dx.doi.org/10.1136/bcr-2012-006805. 13. Stomer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriceavaluation of health hazard. Food Chem Toxicol. 1993;31:303-312. 14. 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.
