Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme

Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11b-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11b-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis. Key words: adrenal hyperplasia, 11b-hydroxylase, hypertension, hypokalemia, mineralocorticoid excess, posaconazole Introduction and case report tomography of the abdomen, serum aldosterone and renin levels, serum chromogranin A and urine 5-hydroxyindoleacetic acid lev- A 15-year-old male adolescent presented to the hospital with els for carcinoid syndrome, as well as thyroid studies. All the hypertensive urgency (systolic readings up to 160 mmHg) and above studies were normal. Plasma renin and aldosterone levels hypokalemia [serum potassium 2.8 mmol/L (normal 3.3–4.9)]. were low/suppressed (renin 1.2 ng/mL/h, aldosterone<0.4 ng/dL), Due to combined immunodeficiency with hypogammaglobuli- supporting a hyporeninemic hypertension. nemia, he was on posaconazole therapy for fungal prophylaxis. Evaluation for pheochromocytoma was performed due to He was admitted to the general pediatric ward for further evalu- severe hypertension and episodic flushing. Plasma and urine ation and management. His blood pressure rose to >200 mmHg metanephrines were elevated: normetanephrine 2.7 nmol/L (nor- systolic and was associated with flushing and headache. He mal<0.9) and 1372 lg/24 h (normal<456), respectively. Plasma was transferred to the intensive care unit for management with and urine catecholamines were also elevated three times above intravenous antihypertensive infusions of nicardipine and the reference range. Because of the elevated metanephrines and esmolol to control blood pressure. catecholamines, he underwent positron emission tomography Evaluation for the cause of hypertension included an echocar- diogram, magnetic resonance imaging of the brain, abdominal (PET) nuclear imaging with DOTATATE peptide, which failed to ultrasound with Doppler wave analysis, computerized axial show a somatostatin receptor 2 expressing paraganglioma or Received: October 10, 2017. Editorial decision: December 12, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| K. Barton et al. Table 1. Hormone, electrolyte levels and blood pressure during and after posaconazole therapy Normal/therapeutic Test POSA POSA off range Deoxycorticosterone (ng/mL) 247 24 2–19 11-Deoxycortisol (ng/dL) 2445 167 12–158 Androstenedione (ng/dL) 194 75 33–192 17-Hydroxyprogesterone (ng/dL) 452 215 24–175 Cortisol (mcg/dL) 13 17 3–21 Serum potassium (mmol/L) 2.8 4.3 3.5–4.9 Plasma renin (ng/mL/h) 1.2 NA 1.2–2.4 Plasma aldosterone (ng/dL) <0.4 NA <21 Plasma normetanephrine (nmol/L) 2.7 0.28 <0.9 Posaconazole (ng/dL) 3000 NA >700 Blood pressure (mmHg) 176/72 102/64 <130/80 Average of three levels. Average of 1 week of measurements. NA, not available. pheochromocytoma, ruling out the diagnosis. With the Posaconazole is an antifungal agent that acts by inhibiting DOTATATE PET not identifying a normetanephrine-secreting fungal cell membrane synthesis by blocking steroidogenesis tumor, it was concluded that the elevated levels of metanephrine, and depletion of ergosterol in the cell membrane. Adrenal ste- normetanephrine and catecholamines were elevated due to inter- roid biosynthesis from cholesterol to aldosterone and cortisol is ference with the assay from esmolol and nicardipine [1]. mediated by multiple cytochrome P450 (CYP450) enzymes that The possibility of congenital adrenal hyperplasia (CAH) and/ include 11b-hydroxylase. Posaconazole has not previously been or the syndrome of apparent mineralocorticoid excess (AME) was reported to specifically inhibit the 11b-hydroxylase enzyme, but raised. A serum adrenal steroid laboratory panel was sent for it is an inhibitor of the CYP450 3A4 enzyme [4]. A similar anti- analysis. The patient and family did not reveal a history of fungal compound, ketoconazole, has a reported 98% inhibition chronic licorice (glycyrrhizic acid) ingestion. Licorice inhibits the rate of the 11b-hydroxylase enzyme at a concentration of 11b-hydroxysteroid dehydrogenase type 2 isoform (11b HSD2). In 1 mmol/L [5]. a review of the literature, it was found that posaconazole inhibits In light of animal studies showing that posaconazole stim- the same enzyme [2]. In this patient, the results of the adrenal ulates adrenal cells with an increased incidence of pheochro- steroid panel showed markedly elevated deoxycorticosterone mocytomas [4], our conclusion that metanephrine levels were and 11-deoxycortisol levels and androgens (Table 1)suggestive of elevated because of interference with the assay is question- a block at the level of 11b-hydroxylase and not AME from inhibi- able. Acetaminophen, amoxicillin and sulfa-based drugs tion of 11b-HSD2. are known to interfere with the assays, and he was on trime- Since he had no prior history of hypertension and no family thoprim with sulfamethoxazole [1, 6]. Beta-adrenergic block- history of CAH, 11b-hydroxylase deficiency CAH seemed ers (esmolol) and calcium channel blockers (nicardipine) unlikely. In addition, he previously had an extensive genetic increase levels of metanephrines and catecholamines, workup of the combined immunodeficiency including whole respectively [1]. Posaconazole likely induced adrenal hyper- exome sequencing, which did not identify mutations in either plasia (which would not be identified by PET imaging), with the CYP11B1 gene or the 11b-HSD2 gene. To evaluate the possi- increased metanephrine and catecholamine levels further bility of hypertension from 11b-hydroxylase inhibition, posaco- compounding hypertension. The return of normal plasma nazole was stopped. Within 3 weeks of stopping, blood pressure metanephrine levels after stopping posaconazole supports and serum potassium normalized. A repeat adrenal steroid this premise (Table 1). panel off posaconazole showed normal levels of deoxycorticos- In conclusion, clinical studies of posaconazole therapy have terone, 11-deoxycortisol and plasma metanephrines (Table 1). reported hypokalemia in up to 30% and incident hypertension in 18% of patients [7]. Evaluation of our pediatric patient Discussion for secondary hypertension and hypokalemia implicated posaconazole as a cause of mineralocorticoid excess due to This is the first case demonstrating that the mechanism of 11b-hydroxylase enzyme inhibition with adrenal hyperplasia. posaconazole-induced hypertension is inhibition of the We suggest that those receiving posaconazole therapy be 11b-hydroxylase enzyme. Previous cases of posaconazole- closely monitored for adverse effects. All patients on posacona- induced hypertension have been hypothesized to be a form of zole therapy should have screening for hypertension and hypo- acquired AME due to 11b-HSD2 inhibition [3]. However, the kalemia and, if detected, should undergo further endocrine testing in this patient shows a defect upstream in the adrenal evaluation accordingly. steroidogenesis pathway resulting in elevated deoxycorticoster- one and 11-deoxycortisol (Table 1). The supraphysiologic level of deoxycorticosterone activates the mineralocorticoid receptor. Acknowledgement This results in excessive activity of the epithelial sodium chan- The authors thank the family for giving permission to dis- nel in the distal tubule and collecting duct causing hypertension due to sodium and water retention as well as hypokalemia. cuss this case in the medical literature. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Posaconazole-induced hypertension and hypokalemia | 3 3. Thompson GR, Chang D, Wittenberg RR et al. In vivo Authors’ contributions 11b-hydroxysteroid dehydrogenase inhibition in K.B. and T.K.D. wrote the first draft of the manuscript. posaconazole-induced hypertension and hypokalemia. N.W., B.M. and A.E. provided critical revisions to the Antimicrob Agents Chemother 2017; 61: e00760 manuscript. 4. European Medicines Agency. Noxafil: EPAR-Scientific Discussion. London: European Medicines Agency, 2005. http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_ Conflict of interest statement Discussion/human/000610/WC500037781.pdf (16 November None declared. 2017, date last accessed) 5. Couch RM, Muller J, Perry YS et al. Kinetic analysis of inhibi- tion of human adrenal steroidogenesis by ketoconazole. J Clin References Endocrinol Metab 1987; 65: 551–554 1. Eisenhofer G, Peitzsch M. Laboratory evaluation of 6. Barco S, Alpigiani MG, Ghiggeri GM et al. Amoxicillin-associated pheochromocytoma and paraganglioma. Clin Chem 2014; 60: interference in an HPLC-EC assay for urinary fractionated 1486–1499 metanephrines: potential pitfall in pheochromocytoma bio- 2. Beck KR, Ba ¨ chler M, Vuorinen A et al. Inhibition of chemical diagnosis. Clin Biochem 2014; 47: 119–121 11b-hydroxysteroid dehydrogenase 2 by the fungicides itraco- 7. www.micromedexsolutions.com; search term: posaconazole nazole and posaconazole. Biochem Pharmacol 2017; 130: 93–103 (29 September 2017, date last accessed) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme

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European Renal Association - European Dialysis and Transplant Association
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.
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2048-8505
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2048-8513
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10.1093/ckj/sfx156
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Abstract

Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11b-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11b-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis. Key words: adrenal hyperplasia, 11b-hydroxylase, hypertension, hypokalemia, mineralocorticoid excess, posaconazole Introduction and case report tomography of the abdomen, serum aldosterone and renin levels, serum chromogranin A and urine 5-hydroxyindoleacetic acid lev- A 15-year-old male adolescent presented to the hospital with els for carcinoid syndrome, as well as thyroid studies. All the hypertensive urgency (systolic readings up to 160 mmHg) and above studies were normal. Plasma renin and aldosterone levels hypokalemia [serum potassium 2.8 mmol/L (normal 3.3–4.9)]. were low/suppressed (renin 1.2 ng/mL/h, aldosterone<0.4 ng/dL), Due to combined immunodeficiency with hypogammaglobuli- supporting a hyporeninemic hypertension. nemia, he was on posaconazole therapy for fungal prophylaxis. Evaluation for pheochromocytoma was performed due to He was admitted to the general pediatric ward for further evalu- severe hypertension and episodic flushing. Plasma and urine ation and management. His blood pressure rose to >200 mmHg metanephrines were elevated: normetanephrine 2.7 nmol/L (nor- systolic and was associated with flushing and headache. He mal<0.9) and 1372 lg/24 h (normal<456), respectively. Plasma was transferred to the intensive care unit for management with and urine catecholamines were also elevated three times above intravenous antihypertensive infusions of nicardipine and the reference range. Because of the elevated metanephrines and esmolol to control blood pressure. catecholamines, he underwent positron emission tomography Evaluation for the cause of hypertension included an echocar- diogram, magnetic resonance imaging of the brain, abdominal (PET) nuclear imaging with DOTATATE peptide, which failed to ultrasound with Doppler wave analysis, computerized axial show a somatostatin receptor 2 expressing paraganglioma or Received: October 10, 2017. Editorial decision: December 12, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| K. Barton et al. Table 1. Hormone, electrolyte levels and blood pressure during and after posaconazole therapy Normal/therapeutic Test POSA POSA off range Deoxycorticosterone (ng/mL) 247 24 2–19 11-Deoxycortisol (ng/dL) 2445 167 12–158 Androstenedione (ng/dL) 194 75 33–192 17-Hydroxyprogesterone (ng/dL) 452 215 24–175 Cortisol (mcg/dL) 13 17 3–21 Serum potassium (mmol/L) 2.8 4.3 3.5–4.9 Plasma renin (ng/mL/h) 1.2 NA 1.2–2.4 Plasma aldosterone (ng/dL) <0.4 NA <21 Plasma normetanephrine (nmol/L) 2.7 0.28 <0.9 Posaconazole (ng/dL) 3000 NA >700 Blood pressure (mmHg) 176/72 102/64 <130/80 Average of three levels. Average of 1 week of measurements. NA, not available. pheochromocytoma, ruling out the diagnosis. With the Posaconazole is an antifungal agent that acts by inhibiting DOTATATE PET not identifying a normetanephrine-secreting fungal cell membrane synthesis by blocking steroidogenesis tumor, it was concluded that the elevated levels of metanephrine, and depletion of ergosterol in the cell membrane. Adrenal ste- normetanephrine and catecholamines were elevated due to inter- roid biosynthesis from cholesterol to aldosterone and cortisol is ference with the assay from esmolol and nicardipine [1]. mediated by multiple cytochrome P450 (CYP450) enzymes that The possibility of congenital adrenal hyperplasia (CAH) and/ include 11b-hydroxylase. Posaconazole has not previously been or the syndrome of apparent mineralocorticoid excess (AME) was reported to specifically inhibit the 11b-hydroxylase enzyme, but raised. A serum adrenal steroid laboratory panel was sent for it is an inhibitor of the CYP450 3A4 enzyme [4]. A similar anti- analysis. The patient and family did not reveal a history of fungal compound, ketoconazole, has a reported 98% inhibition chronic licorice (glycyrrhizic acid) ingestion. Licorice inhibits the rate of the 11b-hydroxylase enzyme at a concentration of 11b-hydroxysteroid dehydrogenase type 2 isoform (11b HSD2). In 1 mmol/L [5]. a review of the literature, it was found that posaconazole inhibits In light of animal studies showing that posaconazole stim- the same enzyme [2]. In this patient, the results of the adrenal ulates adrenal cells with an increased incidence of pheochro- steroid panel showed markedly elevated deoxycorticosterone mocytomas [4], our conclusion that metanephrine levels were and 11-deoxycortisol levels and androgens (Table 1)suggestive of elevated because of interference with the assay is question- a block at the level of 11b-hydroxylase and not AME from inhibi- able. Acetaminophen, amoxicillin and sulfa-based drugs tion of 11b-HSD2. are known to interfere with the assays, and he was on trime- Since he had no prior history of hypertension and no family thoprim with sulfamethoxazole [1, 6]. Beta-adrenergic block- history of CAH, 11b-hydroxylase deficiency CAH seemed ers (esmolol) and calcium channel blockers (nicardipine) unlikely. In addition, he previously had an extensive genetic increase levels of metanephrines and catecholamines, workup of the combined immunodeficiency including whole respectively [1]. Posaconazole likely induced adrenal hyper- exome sequencing, which did not identify mutations in either plasia (which would not be identified by PET imaging), with the CYP11B1 gene or the 11b-HSD2 gene. To evaluate the possi- increased metanephrine and catecholamine levels further bility of hypertension from 11b-hydroxylase inhibition, posaco- compounding hypertension. The return of normal plasma nazole was stopped. Within 3 weeks of stopping, blood pressure metanephrine levels after stopping posaconazole supports and serum potassium normalized. A repeat adrenal steroid this premise (Table 1). panel off posaconazole showed normal levels of deoxycorticos- In conclusion, clinical studies of posaconazole therapy have terone, 11-deoxycortisol and plasma metanephrines (Table 1). reported hypokalemia in up to 30% and incident hypertension in 18% of patients [7]. Evaluation of our pediatric patient Discussion for secondary hypertension and hypokalemia implicated posaconazole as a cause of mineralocorticoid excess due to This is the first case demonstrating that the mechanism of 11b-hydroxylase enzyme inhibition with adrenal hyperplasia. posaconazole-induced hypertension is inhibition of the We suggest that those receiving posaconazole therapy be 11b-hydroxylase enzyme. Previous cases of posaconazole- closely monitored for adverse effects. All patients on posacona- induced hypertension have been hypothesized to be a form of zole therapy should have screening for hypertension and hypo- acquired AME due to 11b-HSD2 inhibition [3]. However, the kalemia and, if detected, should undergo further endocrine testing in this patient shows a defect upstream in the adrenal evaluation accordingly. steroidogenesis pathway resulting in elevated deoxycorticoster- one and 11-deoxycortisol (Table 1). The supraphysiologic level of deoxycorticosterone activates the mineralocorticoid receptor. Acknowledgement This results in excessive activity of the epithelial sodium chan- The authors thank the family for giving permission to dis- nel in the distal tubule and collecting duct causing hypertension due to sodium and water retention as well as hypokalemia. cuss this case in the medical literature. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Posaconazole-induced hypertension and hypokalemia | 3 3. Thompson GR, Chang D, Wittenberg RR et al. In vivo Authors’ contributions 11b-hydroxysteroid dehydrogenase inhibition in K.B. and T.K.D. wrote the first draft of the manuscript. posaconazole-induced hypertension and hypokalemia. N.W., B.M. and A.E. provided critical revisions to the Antimicrob Agents Chemother 2017; 61: e00760 manuscript. 4. European Medicines Agency. Noxafil: EPAR-Scientific Discussion. London: European Medicines Agency, 2005. http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_ Conflict of interest statement Discussion/human/000610/WC500037781.pdf (16 November None declared. 2017, date last accessed) 5. Couch RM, Muller J, Perry YS et al. Kinetic analysis of inhibi- tion of human adrenal steroidogenesis by ketoconazole. J Clin References Endocrinol Metab 1987; 65: 551–554 1. Eisenhofer G, Peitzsch M. Laboratory evaluation of 6. Barco S, Alpigiani MG, Ghiggeri GM et al. Amoxicillin-associated pheochromocytoma and paraganglioma. Clin Chem 2014; 60: interference in an HPLC-EC assay for urinary fractionated 1486–1499 metanephrines: potential pitfall in pheochromocytoma bio- 2. Beck KR, Ba ¨ chler M, Vuorinen A et al. Inhibition of chemical diagnosis. Clin Biochem 2014; 47: 119–121 11b-hydroxysteroid dehydrogenase 2 by the fungicides itraco- 7. www.micromedexsolutions.com; search term: posaconazole nazole and posaconazole. Biochem Pharmacol 2017; 130: 93–103 (29 September 2017, date last accessed) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx156/4830062 by Ed 'DeepDyve' Gillespie user on 12 July 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Jan 30, 2018

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