Bone Marrow Transplantation (2006) 37, 899 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00
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LETTER TO THE EDITOR
Idiopathic hyperammonemia following high-dose chemotherapy Bone Marrow Transplantation (2006) 37, 899. doi:10.1038/sj.bmt.1705346; published online 20 March 2006 The diagnosis of idiopathic hyperammonemia (IH) is made in the presence of elevated serum ammonia, neurological deterioration of no other obvious aetiology, normal liver function tests and normal amino-acid levels, which rule out enzymatic deficiencies of the urea cycle. Pathological features include presence of Alzheimer type II astrocytes in brain and centrilobular microvesicular steatosis. An acquired deficiency of glutamine synthetase of unknown origin has been suggested as a possible mechanism.1 Such deficiency would result in waste nitrogen circulating as ammonia and not being converted to glutamine. Immunosuppression and/or high-dose cytoreductive treatment might be responsible for the inactivation of glutamine synthetase. We report here the case of a 52-year-old woman with locally advanced HER2 þ breast cancer and extensive breast and axillary involvement after preoperative chemotherapy with anthracyclines and taxanes, who was enrolled onto a phase II study of a novel high-dose regimen of trastuzumab/docetaxel/melphalan/carboplatin. Her post transplant course was complicated with grade 4 colitis with multiorgan failure. After resolution of this toxicity, the patient remained obtunded. Her serum ammonia level was noticed to be high at 266 mg/dl, with normal serum GOT GPT, bilirubin and renal function parameters. No urease-producing bacteria were isolated in faeces. Amino-acid analyses (aspartic acid, glutamic acid, hydroxyproline, asparaginase, glycine, glutamine, taurine, histidine, citruline, threonine, alanine, arginine, proline, tyrosine, valine, methionine, cystine, isoleucine, leucine, phenylalanine, tryptophan, ornithine and lysine) were normal. Well-known iatrogenic causes of her hyperammonemia, such as valproic acid or asparaginase, were reasonably excluded. Lactulose enemas were unsuccessful, but ammonia-trapping treatment with intravenous and oral sodium benzoate resulted in gradual resolution of the neurological picture and normalization of the ammonia levels over the following 2 weeks. Following discharge, she received locoregional radiotherapy. She remains on maintenance triweekly trastuzumab treatment, free of disease and performance status 0 at last follow-up visit, 10 months after high-dose chemotherapy.
Few cases of post transplant IH have been previously described.2–7 Mitchell et al.2 described nine cases, eight after intensive cytoreductive therapy and the ninth, 2 months after an allogeneic BMT. Only three of them survived. The longest series was reported by Davies and colleagues, including 12 patients, 10 of whom died from this complication, despite dialysis and ammonia-trapping therapy. Idiopathic hyperammonemia is a highly lethal complication of BMT. Hyperammonemia needs to be ruled out in the presence of neurological deterioration of metabolic origin. Clinicians involved in the care of BMT patients need to be aware of this rare, albeit potentially fatal, diagnosis. J Espino´s, J Rifo´n, J Pe´rez-Calvo and Y Nieto Bone Marrow Transplant Program, Clinica University of Navarra, Pamplona, Navarra, Spain E-mail:
[email protected]
References 1 Berry GT, Bridges ND, Nathanson KL, Kaplan P, Clancy RR, Lichtenstein GR et al. Succesful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart–lung transplantation. Arch Neurol 1999; 56: 481–484. 2 Mitchell RB, Wagner JE, Karp JE, Watson AJ, Brusilow SW, Przepiorka D et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases. Am J Med 1988; 87: 249–250. 3 Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ. Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1119–1125. 4 Snyder MJ, Bradford WD, Kishnani PS, Hale LP. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I. Pediatr Dev Pathol 2002; 6: 78–83. 5 Tse N, Cederbaum S, Glaspy JA. Hyperammonemia following allogeneic bone marrow transplantation. Am J Hematol 1991; 38: 140–141. 6 Ho A, Mijovic A, Pagliuca A, Mufti GJ. Idiopathic hyperammonemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT). Bone Marrow Transplant 1997; 20: 1007–1008. 7 Watanabe R, Okamoto S, Asahi A, Mori T, Takayama N, Ikeda Y. Idiopathic hyperammonemia following allogeneic bone marrow transplantation for refractory lymphoma. Rinsho Ketsueki 2000; 41: 1285–1288.
