Laemmle Alexander, Hahn Dagmar, Hu Liyan, Rüfenacht Véronique, Gautschi Matthias, Leibundgut Kurt, Nuoffer Jean-Marc, Häberle Johannes
Division of Metabolism and Children's Research Center (CRC), University Children's Hospital, Zurich, Switzerland; Department of Pediatrics, University Children's Hospital, Bern, Switzerland.
University Institute of Clinical Chemistry, University of Bern, Switzerland.
Mol Genet Metab. 2015 Mar;114(3):438-44. doi: 10.1016/j.ymgme.2015.01.002. Epub 2015 Jan 24.
Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 μmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 μmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.
迄今为止，仅有少数患者被报道患有继发于血液系统恶性肿瘤化疗或骨髓移植后的致命性高氨血症。在这些患者中，高氨血症的发病机制仍不清楚，被认为是多因素的。我们观察到一名2岁男性患者出现严重高氨血症（最高达475μmol/L），该患者因IV期神经母细胞瘤接受了卡铂、依托泊苷和马法兰的大剂量化疗以及自体造血干细胞移植。尽管进行了重症监护治疗，但高氨血症仍持续存在，患者因脑水肿死亡。氨和谷氨酰胺升高（最高达1757μmol/L）的生化指标提示尿素循环功能障碍。在肝脏匀浆中，尿素循环酶氨甲酰磷酸合成酶1（CPS1）的酶活性和蛋白表达几乎缺失。然而，在肝脏CPS1 cDNA中未发现突变，且CPS1 mRNA表达仅略有下降。因此，我们推测高氨血症的急性发作是由于获得性化疗诱导的（转录后）CPS1缺乏所致。用卡铂和依托泊苷处理的HepG2细胞的体外实验显示CPS1蛋白表达呈剂量依赖性下降，这进一步支持了这一推测。由于严重高乳酸血症，我们分析了肝脏组织中的氧化磷酸化复合物，发现复合物I和V的活性降低，这提示存在更普遍的线粒体功能障碍。本研究增加了对化疗诱导的高氨血症的理解，因为提示其为药物诱导的CPS1缺乏。此外，我们强调了在未来化疗和干细胞移植期间患有高氨血症的患者中，需要针对可能的继发性尿素循环衰竭采取紧急诊断和治疗策略。
