Parsons S K, Skapek S X, Neufeld E J, Kuhlman C, Young M L, Donnelly M, Brunzell J D, Otvos J D, Sallan S E, Rifai N
Department of Laboratory Medicine, Children's Hospital, Boston, MA 02115, USA.
Blood. 1997 Mar 15;89(6):1886-95.
To further elucidate the incidence and potential mechanism of asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia (ALL), we serially obtained fasting lipid and lipoprotein studies on 38 of the 43 consecutively diagnosed children with ALL before, during, and after asparaginase therapy. We also evaluated a second population of 30 long-term survivors of childhood ALL; a fasting lipid and lipoprotein profile was obtained once at study entry. The mean peak triglyceride level during asparaginase of 465 mg/dL (standard deviation [SD] 492) was significantly higher (P = .003) than the level of 108 mg/dL (SD 46) before the initiation of asparaginase therapy. Sixty-seven percent of the newly diagnosed patients had fasting triglyceride levels greater than 200 mg/dL during asparaginase therapy; 15 patients (42%) had levels greater than 400 mg/ dL, 7 with levels greater than 1,000 mg/dL. The incidence of hypertriglyceridemia did not vary by type of asparaginase or risk status of ALL (defined by white blood cell count and age). None of the 7 patients with triglyceride levels greater than 1,000 mg/dL developed pancreatitis. In contrast, 4 of the 13 patients without triglyceride elevation developed pancreatitis; 3 of the 4 patients had fasting studies at the height of their abdominal pain. Nuclear magnetic resonance analysis of lipid subclasses showed a significant increase in the smaller, denser forms of very low density lipoprotein (VLDL) and negligible chylomicron fraction in a subset of patients with marked triglyceride elevation. Lipoprotein lipase activity was consistently above normative values for all levels of triglyceride and could not be explained by obesity or hyperglycemia. Apolipoprotein B(100) levels increased during asparaginase therapy, although the mechanism of this remains unclear. LDL reciprocally decreased with increased VLDL during asparaginase therapy. After asparaginase therapy, triglyceride levels (mean, 73 mg/dL [SD 33]) were significantly lower than levels obtained during asparaginase therapy. Triglyceride levels for survivors did not differ from the normal range or postasparaginase levels in the newly diagnosed patients. These data show a striking temporal association between asparaginase therapy and hypertriglyceridemia. Changes in cholesterol, in contrast, were not temporally related to asparaginase treatment. Cholesterol levels were elevated (>200 mg/dL) in 20% of the patients after asparaginase, which may be due to continued treatment with corticosteroids. The mean cholesterol level of long-term survivors of 177 mg/dL was significantly higher than the norm (P = .045). High-density lipoprotein (HDL) levels were significantly lower than normal at all time periods and for both populations; 25% of survivors had HDL levels less than 35 mg/dL. We conclude that modifications in asparaginase therapy are not necessary. In cases of triglyceride elevation greater than 2,000 mg/dL when the risk of pancreatitis is increased, close clinical monitoring is imperative. Larger studies are needed to determine the incidence of dyslipidemia in long-term survivors of ALL as well as the relationship between lipid abnormalities and other late effects of treatment, notably obesity and cardiomyopathies.
为进一步阐明急性淋巴细胞白血病（ALL）患儿中天冬酰胺酶相关脂质异常的发生率及潜在机制，我们对43例连续确诊的ALL患儿中的38例在天冬酰胺酶治疗前、治疗期间及治疗后连续进行空腹血脂和脂蛋白研究。我们还评估了另一组30例儿童ALL长期存活者；在研究开始时获取一次空腹血脂和脂蛋白谱。天冬酰胺酶治疗期间甘油三酯平均峰值水平为465mg/dL（标准差[SD]492），显著高于天冬酰胺酶治疗开始前的108mg/dL（SD 46）水平（P = 0.003）。67%的新诊断患者在天冬酰胺酶治疗期间空腹甘油三酯水平高于200mg/dL；15例患者（42%）水平高于400mg/dL，7例高于1000mg/dL。高甘油三酯血症的发生率不因天冬酰胺酶类型或ALL的风险状态（由白细胞计数和年龄定义）而有所不同。7例甘油三酯水平高于1000mg/dL的患者均未发生胰腺炎。相比之下，13例甘油三酯未升高的患者中有4例发生了胰腺炎；4例患者中有3例在腹痛最严重时进行了空腹检查。脂质亚类的核磁共振分析显示，在一部分甘油三酯显著升高的患者中，较小、密度较高的极低密度脂蛋白（VLDL）形式显著增加，乳糜微粒部分可忽略不计。脂蛋白脂肪酶活性在所有甘油三酯水平均持续高于正常范围，且无法用肥胖或高血糖来解释。天冬酰胺酶治疗期间载脂蛋白B(100)水平升高，但其机制尚不清楚。天冬酰胺酶治疗期间，随着VLDL增加，低密度脂蛋白（LDL）相应降低。天冬酰胺酶治疗后，甘油三酯水平（平均73mg/dL[SD 33]）显著低于天冬酰胺酶治疗期间的水平。存活者的甘油三酯水平与新诊断患者的正常范围或天冬酰胺酶治疗后的水平无差异。这些数据显示天冬酰胺酶治疗与高甘油三酯血症之间存在显著的时间关联。相比之下，胆固醇的变化与天冬酰胺酶治疗在时间上无关联。天冬酰胺酶治疗后20%的患者胆固醇水平升高（>200mg/dL），这可能归因于持续使用皮质类固醇治疗。长期存活者的平均胆固醇水平为177mg/dL，显著高于正常水平（P = 样本045）。高密度脂蛋白（HDL）水平在所有时间段及两组人群中均显著低于正常；25%的存活者HDL水平低于35mg/dL。我们得出结论，天冬酰胺酶治疗无需调整。在甘油三酯升高超过2000mg/dL且胰腺炎风险增加的情况下，密切的临床监测至关重要。需要开展更大规模的研究以确定ALL长期存活者中血脂异常的发生率以及脂质异常与其他治疗后期效应（尤其是肥胖和心肌病）之间的关系。
