Pediatr Transplantation 2015: 19: E104–E105
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12467
Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report Uygun V, Karasu G, Dalo glu H, Hazar V, Yesßilipek A. (2015) Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report. Pediatr Transplant, 19: E104–E105. DOI: 10.1111/petr.12467. Abstract: IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.
Vedat Uygun1, G€uls€un Karasu2, Hayriye Daloglu3, Volkan Hazar4 and Akif Yesßilipek1 1
Pediatric BMT Unit, Medical Park Antalya Hospital, Bahcßesßehir University, Antalya, Turkey, 2Pediatric BMT Unit, Medical Park G€oztepe Hospital, Bahcßesßehir University, _Istanbul, Turkey, 3Pediatric BMT Unit, Medical Park Antalya Hospital, Antalya, Turkey, 4Department of Pediatric Hematology and Oncology, Faculty of Medicine, Akdeniz University, Antalya, Turkey Key words: Fanconi anemia – hematopoietic stem cell transplantation – hyperammonemia Vedat Uygun, Pediatric BMT Unit, Medical Park Antalya Hospital, Bahcßesßehir University, Fener Mah. Tekelioglu Cad. No: 7 Lara Antalya, Antalya, Turkey Tel.: 00902423143434 Fax: 00902423143030 E-mail: [email protected] Accepted for publication 9 March 2015
IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT, especially in the neutropenic phase. Although there is no reported absolute association of IHA with any specific drug, cytarabine, daunomycin, cyclophosphamide, vincristine, amsacrine, etoposide, asparaginase, busulfan, methotrexate, vinorelbine, topotecan, melphalan, 5-fluorouracil, and cisplatin were used in the reported IHA cases (1–6). We describe a case of a patient with FA that developed acute IHA after the preparative regimen for HSCT.
Abbreviations: FA, Fanconi anemia; HSCT, hematopoietic stem cell transplantation; ICU, intensive care unit; IHA, Idiopathic hyperammonemia; VOD, veno-occlusive disease.
E104
Case
A 12-yr-old female was admitted to our unit for a bone marrow transplant because of FA with a progressive pancytopenia history. She received preparative regimen consisting of fludarabine 150 mg/m2 for five days, cyclophosphamide 40 mg/kg for four days, and antithymocyte globulin 60 mg/kg for three days. Cyclosporine A and methylprednisolone were given for GVHD prophylaxis. She was transplanted with bone marrow from a full-matched unrelated donor with a dose of total nucleated cells: 4.7 9 10-8/kg and CD 34: 4.1 9 10-6/kg. Her antimicrobial prophylaxis was performed with fluconazole, ciprofloxacin, trimethoprim–sulfamethoxazole, and acyclovir. The initial post-transplant course was unremarkable except for grade 2 mucositis, which necessitated total parenteral nutrition. On the fifth day of transplantation, the patient developed febrile neutropenia and piperacillin– tazobactam was administered, but because of unresponsiveness, the antibiotic was changed to
Idiopathic hyperammonemia after HSCT
meropenem. On the seventh day, mildly resistant thrombocytopenia decreased diuresis and weight gain developed. Prior to transplantation, the patient had been evaluated for frequent transfusion history, and we decided to start defibrotide in any suspicion of VOD that might be related with transfusional hemosiderosis; therefore, defibrotide was started. There was no increase either in liver enzymes or in coagulation tests, albumin was normal, and hepatomegaly was not present. VOD improved in a few days. On day 9, a mucous diarrhea began and metronidazole was started. On the 12th day, she was noted to be agitated in the morning and then experienced mental confusion which progressed to unresponsiveness developed till evening. She had mild isocoric myosis and hyperreflexia. MRI revealed no focal pathology. Because of suspected carbapenem neurotoxicity, meropenem was changed to cefoperazone–sulbactam. Screening for possible metabolic causes of encephalopathy was normal except that serum ammonia level was markedly elevated at 192 lg/dL (normal 19–87 lg/dL). Amino acid analyses were normal. There was no evidence of gastrointestinal bleeding. For the treatment of hyperammonemia, exogenous nitrogen loads were removed by L-ornithine L-aspartate, sodium benzoate, and lactulose. Despite this, ammonia levels elevated to 322 lg/ dL in a few hours and the neurological deterioration continued requiring ICU. On the follow-up in ICU, focal convulsions developed and phenytoin was started. Hemofiltration was commenced on day 14; however, ammonia levels did not respond and exceeded 3200 lg/dL despite continuous veno-venous hemofiltration. On day 16, because episodic convulsions were ongoing, a CT scan revealed marked cerebral edema with a left shift and a suspected frontal hemorrhage. Despite ongoing hemofiltration, ammonia levels did not decrease, cardiovascular insufficiency developed, and an asystolic arrest occurred on day 21 resulting in death. The family did not allow an autopsy. Discussion
The neurological complications in the preengraftment period, if imaging is normal, include organ failure, sepsis, and drug toxicity. Very often the etiology is multifactorial, and many episodes of post-transplant delirium may be transient. Besides these well-known conditions, IHA
is mostly overlooked and delayed for appropriate treatment. The underlying mechanism for the development of IHA following bone marrow transplantation remains uncertain, but an acquired defect in urea synthesis after chemotherapy remains a plausible explanation (2). Although children with IHA have rarely been reported (7), this is the first published report to our knowledge of IHA in a post-transplant child patient transplanted for FA. We did not assume this complication as a cause of hepatic dysfunction of FA, because it is not a prior symptom of FA, as liver disease in FA is generally a complication of treatment or hepatitis. Furthermore, the patient’s hepatic functions were well initially. Ammonia-induced oxidation and impairment in cellular responses to oxidative stress in FA may contribute to this rapid death. Neurological complications of HSCT are frequent. As the use of HSCT expands, these complications are expected to increase. Diagnosis of the neurological problems in this setting is difficult and requires the physician to be familiar with the neurological complications. In this context, a newly diagnosed mental confusion in HSCT patients should be suspected from IHA, and despite the unexpected level of insufficiency, hemofiltration should be started immediately. References 1. MITCHELL RB, WAGNER JE, KARP JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: Review of nine cases. Am J Med 1988: 85: 662–667. 2. NOTT L, PRICE TJ, PITTMAN K, PATTERSON K, FLETCHER J. Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 2007: 48: 1702–1711. 3. DEL ROSARIO M, WERLIN SL, LAUER SJ. Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate. J Clin Gastroenterol 1997: 25: 682–684. 4. HO AY, MIJOVIC A, PAGLIUCA A, MUFTI GJ. Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT). Bone Marrow Transplant 1997: 20: 1007–1008. 5. FRERE P, CANIVET JL, GENNIGENS C, REBEIX JP, FILLET G, BEGUIN Y. Hyperammonemia after high-dose chemotherapy and stem cell transplantation. Bone Marrow Transplant 2000: 26: 343–345. 6. CHEN YH, CHIOU TJ, HSU YN, LIU CY. Idiopathic hyperammonemia after chemotherapy with vinorelbine, topotecan, and cisplatin in a patient with acute lymphocytic leukemia. Hematology Oncol Stem Cell Ther 2010: 3: 199–202. 7. SNYDER MJ, BRADFORD WD, KISHNANI PS, HALE LP. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I. Pediatr Dev Pathol 2003: 6: 78–83.
E105
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12467
Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report Uygun V, Karasu G, Dalo glu H, Hazar V, Yesßilipek A. (2015) Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report. Pediatr Transplant, 19: E104–E105. DOI: 10.1111/petr.12467. Abstract: IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.
Vedat Uygun1, G€uls€un Karasu2, Hayriye Daloglu3, Volkan Hazar4 and Akif Yesßilipek1 1
Pediatric BMT Unit, Medical Park Antalya Hospital, Bahcßesßehir University, Antalya, Turkey, 2Pediatric BMT Unit, Medical Park G€oztepe Hospital, Bahcßesßehir University, _Istanbul, Turkey, 3Pediatric BMT Unit, Medical Park Antalya Hospital, Antalya, Turkey, 4Department of Pediatric Hematology and Oncology, Faculty of Medicine, Akdeniz University, Antalya, Turkey Key words: Fanconi anemia – hematopoietic stem cell transplantation – hyperammonemia Vedat Uygun, Pediatric BMT Unit, Medical Park Antalya Hospital, Bahcßesßehir University, Fener Mah. Tekelioglu Cad. No: 7 Lara Antalya, Antalya, Turkey Tel.: 00902423143434 Fax: 00902423143030 E-mail: [email protected] Accepted for publication 9 March 2015
IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT, especially in the neutropenic phase. Although there is no reported absolute association of IHA with any specific drug, cytarabine, daunomycin, cyclophosphamide, vincristine, amsacrine, etoposide, asparaginase, busulfan, methotrexate, vinorelbine, topotecan, melphalan, 5-fluorouracil, and cisplatin were used in the reported IHA cases (1–6). We describe a case of a patient with FA that developed acute IHA after the preparative regimen for HSCT.
Abbreviations: FA, Fanconi anemia; HSCT, hematopoietic stem cell transplantation; ICU, intensive care unit; IHA, Idiopathic hyperammonemia; VOD, veno-occlusive disease.
E104
Case
A 12-yr-old female was admitted to our unit for a bone marrow transplant because of FA with a progressive pancytopenia history. She received preparative regimen consisting of fludarabine 150 mg/m2 for five days, cyclophosphamide 40 mg/kg for four days, and antithymocyte globulin 60 mg/kg for three days. Cyclosporine A and methylprednisolone were given for GVHD prophylaxis. She was transplanted with bone marrow from a full-matched unrelated donor with a dose of total nucleated cells: 4.7 9 10-8/kg and CD 34: 4.1 9 10-6/kg. Her antimicrobial prophylaxis was performed with fluconazole, ciprofloxacin, trimethoprim–sulfamethoxazole, and acyclovir. The initial post-transplant course was unremarkable except for grade 2 mucositis, which necessitated total parenteral nutrition. On the fifth day of transplantation, the patient developed febrile neutropenia and piperacillin– tazobactam was administered, but because of unresponsiveness, the antibiotic was changed to
Idiopathic hyperammonemia after HSCT
meropenem. On the seventh day, mildly resistant thrombocytopenia decreased diuresis and weight gain developed. Prior to transplantation, the patient had been evaluated for frequent transfusion history, and we decided to start defibrotide in any suspicion of VOD that might be related with transfusional hemosiderosis; therefore, defibrotide was started. There was no increase either in liver enzymes or in coagulation tests, albumin was normal, and hepatomegaly was not present. VOD improved in a few days. On day 9, a mucous diarrhea began and metronidazole was started. On the 12th day, she was noted to be agitated in the morning and then experienced mental confusion which progressed to unresponsiveness developed till evening. She had mild isocoric myosis and hyperreflexia. MRI revealed no focal pathology. Because of suspected carbapenem neurotoxicity, meropenem was changed to cefoperazone–sulbactam. Screening for possible metabolic causes of encephalopathy was normal except that serum ammonia level was markedly elevated at 192 lg/dL (normal 19–87 lg/dL). Amino acid analyses were normal. There was no evidence of gastrointestinal bleeding. For the treatment of hyperammonemia, exogenous nitrogen loads were removed by L-ornithine L-aspartate, sodium benzoate, and lactulose. Despite this, ammonia levels elevated to 322 lg/ dL in a few hours and the neurological deterioration continued requiring ICU. On the follow-up in ICU, focal convulsions developed and phenytoin was started. Hemofiltration was commenced on day 14; however, ammonia levels did not respond and exceeded 3200 lg/dL despite continuous veno-venous hemofiltration. On day 16, because episodic convulsions were ongoing, a CT scan revealed marked cerebral edema with a left shift and a suspected frontal hemorrhage. Despite ongoing hemofiltration, ammonia levels did not decrease, cardiovascular insufficiency developed, and an asystolic arrest occurred on day 21 resulting in death. The family did not allow an autopsy. Discussion
The neurological complications in the preengraftment period, if imaging is normal, include organ failure, sepsis, and drug toxicity. Very often the etiology is multifactorial, and many episodes of post-transplant delirium may be transient. Besides these well-known conditions, IHA
is mostly overlooked and delayed for appropriate treatment. The underlying mechanism for the development of IHA following bone marrow transplantation remains uncertain, but an acquired defect in urea synthesis after chemotherapy remains a plausible explanation (2). Although children with IHA have rarely been reported (7), this is the first published report to our knowledge of IHA in a post-transplant child patient transplanted for FA. We did not assume this complication as a cause of hepatic dysfunction of FA, because it is not a prior symptom of FA, as liver disease in FA is generally a complication of treatment or hepatitis. Furthermore, the patient’s hepatic functions were well initially. Ammonia-induced oxidation and impairment in cellular responses to oxidative stress in FA may contribute to this rapid death. Neurological complications of HSCT are frequent. As the use of HSCT expands, these complications are expected to increase. Diagnosis of the neurological problems in this setting is difficult and requires the physician to be familiar with the neurological complications. In this context, a newly diagnosed mental confusion in HSCT patients should be suspected from IHA, and despite the unexpected level of insufficiency, hemofiltration should be started immediately. References 1. MITCHELL RB, WAGNER JE, KARP JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: Review of nine cases. Am J Med 1988: 85: 662–667. 2. NOTT L, PRICE TJ, PITTMAN K, PATTERSON K, FLETCHER J. Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leuk Lymphoma 2007: 48: 1702–1711. 3. DEL ROSARIO M, WERLIN SL, LAUER SJ. Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate. J Clin Gastroenterol 1997: 25: 682–684. 4. HO AY, MIJOVIC A, PAGLIUCA A, MUFTI GJ. Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT). Bone Marrow Transplant 1997: 20: 1007–1008. 5. FRERE P, CANIVET JL, GENNIGENS C, REBEIX JP, FILLET G, BEGUIN Y. Hyperammonemia after high-dose chemotherapy and stem cell transplantation. Bone Marrow Transplant 2000: 26: 343–345. 6. CHEN YH, CHIOU TJ, HSU YN, LIU CY. Idiopathic hyperammonemia after chemotherapy with vinorelbine, topotecan, and cisplatin in a patient with acute lymphocytic leukemia. Hematology Oncol Stem Cell Ther 2010: 3: 199–202. 7. SNYDER MJ, BRADFORD WD, KISHNANI PS, HALE LP. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I. Pediatr Dev Pathol 2003: 6: 78–83.
E105
