J Pediatr Endocr Met 2015; 28(3-4): 439–441
Patient report Raiz Ahmad Misgar*, Bashir Ahmad Laway, Sk Hammadur Rahaman, Arshad Iqbal Wani, Mir Iftikhar Bashir and Javeed Rasool Bhat
L-asparaginase induced hypoglycemia in a case of acute lymphoblastic leukemia: a patient report Abstract: L-asparaginase (L-Asp) is an essential component of acute lymphoblastic leukemia (ALL) treatment protocols and its use has been associated with many adverse effects. We report a case of a 15-year-old boy with ALL who developed L-Asp induced hypoglycemia. To the best of our knowledge, only one such case has been reported previously. Keywords: acute lymphoblastic leukemia; hypoglycemia; L-asparaginase. DOI 10.1515/jpem-2014-0227 Received June 1, 2014; accepted August 14, 2014; previously published online September 11, 2014
Introduction L-asparaginase (L-Asp) is an integral component of acute lymphoblastic leukemia (ALL) treatment protocols (1). Use of L-Asp has been associated with many adverse effects, such as acute pancreatitis, hepatotoxicity, hyperglycemia, allergic reaction, and coagulopathy (2, 3). We present a child diagnosed with ALL who developed L-Asp induced hypoglycemia.
Patient report
protocol includes prednisolone 60 mg/m2 day 1–day 28, vincristin and daunorubicin on days 8, 15, 22, and 29, and L-Asp 10,000 IU/m2 on days 12, 15, 18, 21, 24, 27, 30, and 33. As part of the protocol, he was started on prednisolone 90 mg/day. Three days after initiation of prednisolone, he developed glucocorticoid induced hyperglycemia (fasting plasma glucose 187 mg/dL and 191 mg/dL, and postprandial plasma glucose 220 mg/dL and 205 mg/dL). He was started on two doses of premixed insulin, six units before breakfast and four units before dinner. The patient was administered 10,000 IU/m2 L-Asp on days 12, 15, 18, 21, 24, 27, 30, and 33 of treatment. On day 13, he developed fasting hypoglycemia (glucose, 53 mg/dL) with severe hunger, palpitation, and sweating. Liver and kidney function tests were normal. Insulin treatment was withdrawn. The patient, however, continued with recurrent symptomatic fasting hypoglycemia (fasting plasma glucose ranged between 39 and 62 mg/dL from day 15 through 35). Supplemental snacks and intravenous glucose infusion were prescribed to prevent severe hypoglycemia. By day 4, following the last dose of L-Asp, fasting plasma glucose normalized and ranged from 82 to 91 mg/dL. Given the clear temporal relation between initiation of L-Asp treatment and occurrence of repeated hypoglycemia and between the (protocol determined) termination of L-Asp treatment and resolution of hypoglycemia, we strongly believe that hypoglycemia was due to L-Asp treatment.
A 15-year-old boy with ALL-L2 was treated with the induction therapy protocol of modified BFM-90 (4). This
Discussion
*Corresponding author: Raiz Ahmad Misgar, DM, Assistant professor, Sher-i-Kashmir Institute of Medical Sciences, Department of Endocrinology, Srinagar, Kashmir, India, Phone: +91-9419090026, E-mail: [email protected] Bashir Ahmad Laway, Sk Hammadur Rahaman, Arshad Iqbal Wani and Mir Iftikhar Bashir: Sher-i-Kashmir Institute of Medical Sciences, Department of Endocrinology, Srinagar, Kashmir, India Javeed Rasool Bhat: Sher-i-Kashmir Institute of Medical Sciences, Department of Clinical hematology, Srinagar, Kashmir, India
Asparagine was first isolated in 1806 from asparagus juice, becoming the first amino acid to be isolated. Asparagine is necessary for the synthesis of many proteins and is required for normal functioning in humans. As asparagine side chain can make efficient hydrogen bond interactions with the peptide backbone, asparagine residues are often found near the beginning and end of alpha-helices, and, in turn, motifs in beta sheets.
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440 Misgar et al.: L-asparaginase induced hypoglycemia Its role can be thought as “capping” the hydrogen bond interactions that would otherwise need to be satisfied by the polypeptide backbone (5). Asparagine also provides key sites for N-linked glycosylation, modification of the protein chain with the addition of carbohydrate chains. Asparagine plays an important role in the metabolism (disposal) of the toxic copound ammonia. The nervous system needs asparagine to maintain the equilibrium, as well as in amino acid transformation. L-Asp hydrolyses asparagine to form aspartate and ammonium (5). A transaminase converts the aspartate to oxaloacetate, which can then be metabolized in the citric acid cycle or gluconeogenesis. L-asparaginase depletes plasma of asparagine by hydrolyzing it into asparatic acid and ammonia. As leukemic cells possess insufficient asparagine synthetase activity, an intracellular deficiency of asparagine leads to inhibition of protein synthesis and subsequent cell death. This accounts for the therapeutic action of L-Asp and may account for its toxicity. Several metabolic complications have been associated with use of L-Asp. Hyperglycemia is a well-documented complication of L-Asp and the reported incidence of hyperglycemia ranges from 10% to 15% (6). The main risk factors for L-Asp induced hyperglycemia are older age, obesity, Down’s syndrome, and family history of diabetes mellitus (3). L-Asp induced hyperglycemia may present as mild glucose intolerance or severe hyperglycemia and is reversible. A number of pathogenic mechanisms have been proposed to explain L-Asp induced hyperglycemia. The main mechanism is hypoinsulinemia resulting from inhibition of insulin biosynthesis via depletion of L-asparagine (7). Additionally, L-Asp causes impairment of insulin secretion, reduction in insulin receptors, hyperglucagonemia, and pancreatic islet cell damage (3, 8, 9). Other metabolic complications associated with use of L-Asp are hyperlipidemia and hyperammonemia. The incidence of L-Asp induced hyperlipidemia has been reported as about 27% and L-Asp can cause significant elevations in triglyceride and cholesterol levels (10). A high incidence of symptomatic hyperammonemia in children with ALL receiving L-Asp has been reported (11). During ALL treatment, glucose levels are routinely monitored because many patients develop glucocorticoid and L-Asp induced hyperglycemia. Our patient initially developed glucocorticoid induced hyperglycemia, followed by repeated episodes of fasting hypoglycemia while on L-Asp. The literature search revealed a solitary case of L-Asp associated hypoglycemia in a patient with ALL (12). The demonstration of inappropriately normal
circulating insulin levels, normal free fatty acids, and low ketone bodies during severe hypoglycemia in the patient confirmed hyperinsulinism as the mechanism for L-Asp induced hypoglycemia. Whether it represents an insulin leak or genuine hypersecretion is unclear. Glucocorticoids are well known to induce hyperglycemia through insulin resistance and gluconeogenesis. Concomitant use of glucocorticoids during induction therapy for childhood ALL may mask the hypoglycemic effect of L-Asp. This may be the reason that hypoglycemia has not been commonly seen or reported with L-Asp. In conclusion, our patient with ALL had L-Asp induced hypoglycemia. Because L-Asp is widely used in the treatment of childhood ALL, and increasingly of adult ALL, this case report underscores the importance of carefully monitoring patients being treated with L-Asp for hypoglycemia in addition to its better known adverse effects. Conflict of interest statement: The authors have no conflicts of interest to disclose.
References 1. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010;24:265–84. 2. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010;32:554–63. 3. Pui CH, Burghen GA, Bowman WP, Aur RJ. Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone. J Pediatr 1981;99:46–50. 4. Schrappe M, Reiter A, Ludwig W, Harbott J, Zimmermann M, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000;95:3310–22. 5. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983). Pure Appl Chem 1984;56:595–624. 6. Roberson JR, Raju S, Shelso J, Pui CH, Howard SC. Diabetic ketoacidosis during therapy for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 2008;50:1207–12. 7. Gailani S, Nussbaum A, Ohnuma T, Freeman A. Diabetes in patients treated with asparaginase. Clin Pharmacol Ther 1971;12:487. 8. Gillette PC, Hill LL, Starling KA, Fernbach DJ. Transient diabetes mellitus secondary to L-asparaginase therapy in acute leukemia. J Pediatr 1972;81:109–11. 9. Iyer RS, Rao SR, Pai S, Advani SH, Magrath IT. L-asparaginase related hyperglycemia. Indian J Cancer 1993;30:72–6.
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Misgar et al.: L-asparaginase induced hypoglycemia 441 10. Nesheli HM, Tamaddoni A, Nesheli MM, Yahyai A, Khabiri F, et al. L-asparaginase induced hyperlipidaemia in acute lymphoblastic leukaemia. J Pak Med Assoc 2013;63:324–6. 11. Heitink-Polle KM, Prinsen BH, de Koning TJ, van Hasselt PM, Bierings MB. High incidence of symptomatic hyperammone-
mia in children with acute lymphoblastic leukemia receiving pegylated asparaginase. JIMD Rep 2013;7:103–8. 12. Tanaka R, Osumia T, Miharu M, Ishii T, Hasegawa T, et al. Hypoglycemia associated with L-asparaginase in acute lymphoblastic leukemia treatment: a case report. Exp Hematol Oncol 2012;1:8.
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Patient report Raiz Ahmad Misgar*, Bashir Ahmad Laway, Sk Hammadur Rahaman, Arshad Iqbal Wani, Mir Iftikhar Bashir and Javeed Rasool Bhat
L-asparaginase induced hypoglycemia in a case of acute lymphoblastic leukemia: a patient report Abstract: L-asparaginase (L-Asp) is an essential component of acute lymphoblastic leukemia (ALL) treatment protocols and its use has been associated with many adverse effects. We report a case of a 15-year-old boy with ALL who developed L-Asp induced hypoglycemia. To the best of our knowledge, only one such case has been reported previously. Keywords: acute lymphoblastic leukemia; hypoglycemia; L-asparaginase. DOI 10.1515/jpem-2014-0227 Received June 1, 2014; accepted August 14, 2014; previously published online September 11, 2014
Introduction L-asparaginase (L-Asp) is an integral component of acute lymphoblastic leukemia (ALL) treatment protocols (1). Use of L-Asp has been associated with many adverse effects, such as acute pancreatitis, hepatotoxicity, hyperglycemia, allergic reaction, and coagulopathy (2, 3). We present a child diagnosed with ALL who developed L-Asp induced hypoglycemia.
Patient report
protocol includes prednisolone 60 mg/m2 day 1–day 28, vincristin and daunorubicin on days 8, 15, 22, and 29, and L-Asp 10,000 IU/m2 on days 12, 15, 18, 21, 24, 27, 30, and 33. As part of the protocol, he was started on prednisolone 90 mg/day. Three days after initiation of prednisolone, he developed glucocorticoid induced hyperglycemia (fasting plasma glucose 187 mg/dL and 191 mg/dL, and postprandial plasma glucose 220 mg/dL and 205 mg/dL). He was started on two doses of premixed insulin, six units before breakfast and four units before dinner. The patient was administered 10,000 IU/m2 L-Asp on days 12, 15, 18, 21, 24, 27, 30, and 33 of treatment. On day 13, he developed fasting hypoglycemia (glucose, 53 mg/dL) with severe hunger, palpitation, and sweating. Liver and kidney function tests were normal. Insulin treatment was withdrawn. The patient, however, continued with recurrent symptomatic fasting hypoglycemia (fasting plasma glucose ranged between 39 and 62 mg/dL from day 15 through 35). Supplemental snacks and intravenous glucose infusion were prescribed to prevent severe hypoglycemia. By day 4, following the last dose of L-Asp, fasting plasma glucose normalized and ranged from 82 to 91 mg/dL. Given the clear temporal relation between initiation of L-Asp treatment and occurrence of repeated hypoglycemia and between the (protocol determined) termination of L-Asp treatment and resolution of hypoglycemia, we strongly believe that hypoglycemia was due to L-Asp treatment.
A 15-year-old boy with ALL-L2 was treated with the induction therapy protocol of modified BFM-90 (4). This
Discussion
*Corresponding author: Raiz Ahmad Misgar, DM, Assistant professor, Sher-i-Kashmir Institute of Medical Sciences, Department of Endocrinology, Srinagar, Kashmir, India, Phone: +91-9419090026, E-mail: [email protected] Bashir Ahmad Laway, Sk Hammadur Rahaman, Arshad Iqbal Wani and Mir Iftikhar Bashir: Sher-i-Kashmir Institute of Medical Sciences, Department of Endocrinology, Srinagar, Kashmir, India Javeed Rasool Bhat: Sher-i-Kashmir Institute of Medical Sciences, Department of Clinical hematology, Srinagar, Kashmir, India
Asparagine was first isolated in 1806 from asparagus juice, becoming the first amino acid to be isolated. Asparagine is necessary for the synthesis of many proteins and is required for normal functioning in humans. As asparagine side chain can make efficient hydrogen bond interactions with the peptide backbone, asparagine residues are often found near the beginning and end of alpha-helices, and, in turn, motifs in beta sheets.
Brought to you by | Florida International University Libraries Authenticated Download Date | 5/25/15 1:26 PM
440 Misgar et al.: L-asparaginase induced hypoglycemia Its role can be thought as “capping” the hydrogen bond interactions that would otherwise need to be satisfied by the polypeptide backbone (5). Asparagine also provides key sites for N-linked glycosylation, modification of the protein chain with the addition of carbohydrate chains. Asparagine plays an important role in the metabolism (disposal) of the toxic copound ammonia. The nervous system needs asparagine to maintain the equilibrium, as well as in amino acid transformation. L-Asp hydrolyses asparagine to form aspartate and ammonium (5). A transaminase converts the aspartate to oxaloacetate, which can then be metabolized in the citric acid cycle or gluconeogenesis. L-asparaginase depletes plasma of asparagine by hydrolyzing it into asparatic acid and ammonia. As leukemic cells possess insufficient asparagine synthetase activity, an intracellular deficiency of asparagine leads to inhibition of protein synthesis and subsequent cell death. This accounts for the therapeutic action of L-Asp and may account for its toxicity. Several metabolic complications have been associated with use of L-Asp. Hyperglycemia is a well-documented complication of L-Asp and the reported incidence of hyperglycemia ranges from 10% to 15% (6). The main risk factors for L-Asp induced hyperglycemia are older age, obesity, Down’s syndrome, and family history of diabetes mellitus (3). L-Asp induced hyperglycemia may present as mild glucose intolerance or severe hyperglycemia and is reversible. A number of pathogenic mechanisms have been proposed to explain L-Asp induced hyperglycemia. The main mechanism is hypoinsulinemia resulting from inhibition of insulin biosynthesis via depletion of L-asparagine (7). Additionally, L-Asp causes impairment of insulin secretion, reduction in insulin receptors, hyperglucagonemia, and pancreatic islet cell damage (3, 8, 9). Other metabolic complications associated with use of L-Asp are hyperlipidemia and hyperammonemia. The incidence of L-Asp induced hyperlipidemia has been reported as about 27% and L-Asp can cause significant elevations in triglyceride and cholesterol levels (10). A high incidence of symptomatic hyperammonemia in children with ALL receiving L-Asp has been reported (11). During ALL treatment, glucose levels are routinely monitored because many patients develop glucocorticoid and L-Asp induced hyperglycemia. Our patient initially developed glucocorticoid induced hyperglycemia, followed by repeated episodes of fasting hypoglycemia while on L-Asp. The literature search revealed a solitary case of L-Asp associated hypoglycemia in a patient with ALL (12). The demonstration of inappropriately normal
circulating insulin levels, normal free fatty acids, and low ketone bodies during severe hypoglycemia in the patient confirmed hyperinsulinism as the mechanism for L-Asp induced hypoglycemia. Whether it represents an insulin leak or genuine hypersecretion is unclear. Glucocorticoids are well known to induce hyperglycemia through insulin resistance and gluconeogenesis. Concomitant use of glucocorticoids during induction therapy for childhood ALL may mask the hypoglycemic effect of L-Asp. This may be the reason that hypoglycemia has not been commonly seen or reported with L-Asp. In conclusion, our patient with ALL had L-Asp induced hypoglycemia. Because L-Asp is widely used in the treatment of childhood ALL, and increasingly of adult ALL, this case report underscores the importance of carefully monitoring patients being treated with L-Asp for hypoglycemia in addition to its better known adverse effects. Conflict of interest statement: The authors have no conflicts of interest to disclose.
References 1. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010;24:265–84. 2. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010;32:554–63. 3. Pui CH, Burghen GA, Bowman WP, Aur RJ. Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone. J Pediatr 1981;99:46–50. 4. Schrappe M, Reiter A, Ludwig W, Harbott J, Zimmermann M, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000;95:3310–22. 5. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983). Pure Appl Chem 1984;56:595–624. 6. Roberson JR, Raju S, Shelso J, Pui CH, Howard SC. Diabetic ketoacidosis during therapy for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 2008;50:1207–12. 7. Gailani S, Nussbaum A, Ohnuma T, Freeman A. Diabetes in patients treated with asparaginase. Clin Pharmacol Ther 1971;12:487. 8. Gillette PC, Hill LL, Starling KA, Fernbach DJ. Transient diabetes mellitus secondary to L-asparaginase therapy in acute leukemia. J Pediatr 1972;81:109–11. 9. Iyer RS, Rao SR, Pai S, Advani SH, Magrath IT. L-asparaginase related hyperglycemia. Indian J Cancer 1993;30:72–6.
Brought to you by | Florida International University Libraries Authenticated Download Date | 5/25/15 1:26 PM
Misgar et al.: L-asparaginase induced hypoglycemia 441 10. Nesheli HM, Tamaddoni A, Nesheli MM, Yahyai A, Khabiri F, et al. L-asparaginase induced hyperlipidaemia in acute lymphoblastic leukaemia. J Pak Med Assoc 2013;63:324–6. 11. Heitink-Polle KM, Prinsen BH, de Koning TJ, van Hasselt PM, Bierings MB. High incidence of symptomatic hyperammone-
mia in children with acute lymphoblastic leukemia receiving pegylated asparaginase. JIMD Rep 2013;7:103–8. 12. Tanaka R, Osumia T, Miharu M, Ishii T, Hasegawa T, et al. Hypoglycemia associated with L-asparaginase in acute lymphoblastic leukemia treatment: a case report. Exp Hematol Oncol 2012;1:8.
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