应用左旋门冬酰胺酶致血氨升高和肝性脑病发生的原因分析

Analysis of L-asparaginase induced elevation of blood ammonia and hepatic encephalopathy

目的总结左旋门冬酰胺酶（L—Asp）临床应用中各种不良反应的发生率以及对3例患者引起肝性脑病的原因进行分析。方法收集2009年12月至2010年12月收治的有完整资料的23例患者，在L—Asp应用前、中、后检测血氨水平、转氨酶、血清白蛋白及凝血功能。结果①23例患者均出现血氨升高，血氨开始升高的中位时间为用药第2天，到达最高值的中位时间为用药第4天，血氨最高值中位数为300（194～446）μmol／L，在中位停药后5（3-7）d恢复至正常水平。其中3例（13．0％）发生肝性脑病。②23例患者均出现血浆纤维蛋白原（rIB）降低，其中仅FIB降低的10例（43．5％），伴APTT延长的13例（56．5％）；FIB水平的最低值均在用药1周后出现，14例（60．9％）血浆FIB轻度降低（1-2g／L），9例（39．1％）血浆FIB显著降低（0～1g／n）。③6例（26．1％）出现转氨酶轻度升高（〈2倍正常值），8例（34．8％）出现低白蛋白血症。结论L-Asp应用过程中血氨水平均升高，应密切监测血氨水平，警惕肝性脑病的发生，尤其是中老年患者、既往有肝脏疾病患者或长期大量饮酒者。L—Asp亦可引起低纤维蛋白血症、低自蛋白血症及转氨酶异常，需监测凝血功能及肝功能，必要时需输注血浆及护肝治疗。

Objective To summarize the incidence of various adverse reactions in the clinical application of L-asparaginase （L-Asp）, and to analyze the cause of hepatic encephalopathy in three cases. Methods The complete data of 23 patients in our department from December 2009 to December 2010 were collected. Their blood ammonia levels, transaminase, serum albumin and blood coagulation function before, during and after the L-Asp application were assayed. Results ① All patients had elevated blood ammonia level after the L-Asp application. This occurred 2 days after the beginning of treatment and the median time to reach peak level （ranged from 194 to 446 μmol/L, with a median value of 300 μmol/L） was 4 days. It returned to normal level after a median time of 5 days （ranged 3-7 days） with drug withdrawal. Of the 23 patients studied, 3 developed hepatic encephalopathy. ②All patients appeared lower blood fibrinogen, 10 cases （43.5%） with lower fibrinogen only, while 13 cases （56.5%） with both prolonged APTT and lower fibrinogen. The lowest level of fibrinogen was detected at 1 week after drug application. Of the 23 patients, 14 （60.9%） had mild lower blood fibrinogen （1-2 g/L）, and 9 （39.1%） had significantly lower fibrinogen （0-1 g/L）. ③Six cases （26.1%） had slightly elevated level of transaminase （ 〈2 times the upper limits of normal）, 8 （34.8%） appeared hypoalbuminemia. Conclusions As the incidence of elevated blood ammonia levels was high in the application of L-Asp, the level of blood ammonia should be closely monitored to avoid the occurrence of hepatic encephalopathy, especially in elderly patients and patients with previous liver disease or long-term heavy drinking. L-Asp can also lead to low fibrinogen level, hypoalbuminemia and abnormal transaminase. Monitoring the blood coagulation function and liver function is required and, if necessary, plasma infusion and liver protection therapy are required.