阿托伐他汀致肝损伤的机制

Mechanism of atorvastatin-induced liver injury

阿托伐他汀为3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶选择性抑制剂,是一种具有良好降血脂效果的降脂药。阿托伐他汀可引起剂量依赖性血清氨基转移酶升高,常伴有肝脏肿大、黄疸、直接胆红素升高、凝血酶原时间延长等。阿托伐他汀致肝损伤的类型有:细胞毒型、胆汁淤积型和混合型。阿托伐他汀致细胞毒型肝损伤的机制可能是通过竞争性抑制HMG-CoA还原酶,引起肝细胞染色体DNA断裂和细胞形态学变化,导致肝细胞凋亡所致。阿托伐他汀致胆汁淤积型肝损伤的机制可能是使肝细胞窦状隙膜或胆管侧膜上转运体表达减少或功能障碍,或通过抑制胆盐和胆汁酸排泄相关转运蛋白的活性所致。防治阿托伐他汀致肝损伤措施包括:应用阿托伐他汀前,应检测患者肝脏功能,了解病史、其他用药及饮酒习惯等;建议从小剂量开始应用。因服用阿托伐他汀致轻中度转氨酶升高者可减少用药剂量,服用保肝利胆等药物;严重肝损伤者应立即停药并对症治疗。

Atorvastatin,a 3-hydroxy-3methylglutaryl-coenzmye A（HMG-CoA） reductase inhibitor,is a lipid-lowering drug with good effects on plasma lipids.Atorvastatin can cause dose-dependent increase in serum aminotransferase accompanied by an enlarged liver,jaundice,an increased direct bilirubin level,and a prolonged prothrombin time.The types of atorvastatin-induced liver injury are cytotoxic,cholestatic,and mixed.The mechanism of atorvastatin-induced cytotoxic liver injury may be related to breakage of hepatocyte chromosome DNA and change in hepatocyte morphology by competitive inhibition of HMG-CoA and ultimately causes hepatocyte apoptosis.The mechanism of atorvastatin-induced cholestatic liver injury may be related to the decreased expression or dysfunction of transporter,which located in sinusoidal membrane of hepatocytes and bile duct membrane,or may be related to the inhibited activity of bile salt and bile acid excretion relative transporter protein.The measures of treatment and prevention for atorvastatin-induced liver injury include： before atorvastatin administration,patients＇liver function should be tested and the physician should be aware of patients＇medical history,other medications,and alcohol habit;it is suggested that atorvastatin should be started at a small dose;if atorvastatin-induced mild-to-moderate increase in aminotransferase occurs,the dosage should be reduced and the patient might receive liver-protective drug;once severe liver injury appears,the drug should be discontinued immediately and symptomatic treatment should be given.