【作者】 陈敏；

【导师】 诸葛宇征；

【作者基本信息】 南京大学 ， 临床医学（专业学位）， 2018， 硕士

【摘要】 背景与目的:门静脉高压(Portal hypertension,PHT)是肝硬化失代偿期主要临床表现之一,它所导致的食管胃静脉曲张破裂出血(esophageal gastric varices bleeding,EGVB)是门静脉高压患者死亡的主要原因。非选择性β受体阻滞剂(non-selective beta-blockers,NSBBs)是预防食管胃静脉曲张(esophageal gastric varices,EGV)患者首次出血及再次出血的主要治疗药物。NSBBs一方面可通过阻断β1肾上腺素受体降低心输出量,另一方面阻断β2肾上腺素受体,收缩内脏血管从而减少门静脉血流量,降低门静脉压力。肝静脉压力梯度(hepatic venous pressure gradient,HVPG)是诊断门静脉高压的“金标准”,患者应用NSBBs后,若HVPG较基线值下降20%或HVPG≤12mmHg,称为“应答者”,否则为“不应答者”。经典的NSBBs普萘洛尔广泛用于预防EGVB,既往大多数研究均根据心率下降滴定至可耐受的最高剂量,部分患者出现药物不耐受需要受减量甚至停药,有研究证实心率的下降与HVPG对普萘洛尔应答与否并无关联,因此,探索能使患者产生血流动力学应答且不良反应相对较少的应用剂量十分必要。大量研究证实NSBBs应答可降低肝硬化门静脉高压EGV患者出血风险,但只有部分患者对普萘洛尔有应答,既往研究表明普萘洛尔基因多态性可能影响普萘洛尔的血流动力学应答,但针对中国人普萘洛尔基因多态性的研究较少。故而,亟待在国人中开展普萘洛尔基因多态性相关的研究。本研究比较肝硬化门静脉EGV患者口服不同剂量普萘洛尔产生的门静脉血流动力学应答情况,及国人普萘洛尔基因多态性对血流动力学的影响及其意义。方法:收集2015年12月至2017年12月南京大学医学院附属鼓楼医院消化科的连续61例肝硬化EGV患者的临床资料,根据纳入和排除标准进行筛选。分别测量受试者基线HVPG及口服普萘洛尔40mg bid和口服60mg bid后的HVPG。HVPG等于肝静脉楔压(wedged hepatic venous pressure,WHVP)减去肝静脉游离压(free hepatic venous pressure,FHVP)。血流动力学应答被定义为药物干预后HVPG值较基线水平降低20%或绝对值降至12mmHg以下。所有患者均进行普萘洛尔基因检测。既往无出血史的应答者建议继续口服普萘洛尔预防出血,不应答者定期随访观察。对于既往有出血史的患者,应答者建议口服普萘洛尔联合规范的内镜治疗预防出血,不应答者建议序贯内镜治疗。对符合纳入及排除标准且成功完成基础HVPG及药物干预后HVPG测定的患者进行随访观察。本研究的主要终点是有临床意义的EGVB,次要终点为死亡。使用SPSS软件统计分析临床数据。结果:最终共52例患者成功进行40mg bid普萘洛尔干预并完成第二次HVPG测量,其中27例为应答者,应答率为51.9%(27/52)。25例不应答者中17例成功加量至60mg bid,加量后4例出现血流动力学应答,60mg bid总体应答率为59.6%(31/52),增加应答率为7.7%,差异无统计学意义(x2=0.624,P=0.43)。其中25例40mg bid普萘洛尔不应答患者中16%(4/25)出现药物不耐受无法加量至60mg bid。应答者和无应答者之间年龄、性别、肝硬化病因及肝功能等基线资料均无明显差异。平均随访时间为12.9±8.1个月,范围从0.3个月到27.7个月。短期口服普萘洛尔40mg bid或60mg bid,总体HVPG值、WHVP值、静息心率(heart rate,HR)、收缩压(systolic pressure,SP)和平均动脉血压(mean arterial pressure,MAP)均较基础值降低,药物干预后的总体FHVP值较基础值升高。应答者与不应答者用药前后HR的下降幅度分别为6.3±8.5次/分,6.4±7.3次/分,差异无统计学意义(t=-0.029,P=0.977),HR 下降百分比分别为 8.5±11.6%,8.7±10.0%,差异无统计学意义(t=-0.059,P=0.953)。应答者与不应答者SP及MAP下降幅度和下降百分比无明显差异。随访过程中,共14例患者发生EGVB,应答者和无应答者之间未发生出血的累积概率无明显差异(x2=0.736,P=0.391)。单因素回归分析提示CYP1A2基因、CYP2D6基因和β2-AR基因均不能预测血流动力学应答。结论:40mgbid的普萘洛尔即可使肝硬化门静脉高压患者获得较好的血流动力学应答。CYP1A2基因、CYP2D6基因和β2-AR基因均不能预测血流动力学应答。更多还原

【Abstract】 Background and Aims:Portal hypertension is one of the major clinical manifestations of decompensated cirrhosis.The bleeding caused by esophageal and gastric varices is the main cause of death in patients with portal hypertension.The non-selective beta-blockers(NSBBs)are the main drugs to prevent bleeding and rebleeding in patients with esophageal and gastric varices.NSBBs can blocking adrenaline receptor betal to decrease cardiac output and blocking beta2 adrenergic receptors to induce splanchnic vasoconstriction,reduce portal vein flow,thus decrease portal vein pressure.The hepatic venous pressure gradient(HVPG)is the "gold standard" for the diagnosis of portal hypertension.HVPG is reduced by 20%or HVPG less than 12 mmHg,and is called "responder",otherwise it is "non responder".The classic NSBBs such as propranolol,widely used to prevent gastroesophageal variceal bleeding,is always titrated to maximal tolerated dose.However,some patients still can not achieve hemodynamic response but suffer more intolerance and discontinuation.Some studys has been proved that the reduction in heart rate does not correlate with reduction in HVPG.Therefore,it is necessary to explore the dosage that can make the patients have hemodynamic response and less adverse reactions.Studies confirm that NSBBs responser can reduce the risk of bleeding in patients with cirrhosis esophageal and gastric varices.But only part of the patients responded to propranolol.Previous studies have shown that the polymorphism of propranolol metabolic enzyme gene may affect the hemodynamic response of propranolol.However,there are few studies on the polymorphism of propranolol metabolic enzyme gene in Chinese.Therefore,it is urgent to carry out related research on the metabolic enzymes of the propranolol in Chinese.This study compared the hemodynamic responses of EGV patients with cirrhosis to different doses of propranolol.And the effects of polymorphisms of propranolol metabolic enzyme gene on hemodynamics in Chinese population.Methods:Collect and analyze the clinical data of a prospective cohort of 61 consecutive liver cirrhosis patients with EGV from December 2015 and December 2017 in department of Gastroenterology,Drum Tower Hospital,Medical School of Nanjing University.Screening patients according to inclusion and exclusion criteria,Screening according to the inclusion and exclusion criteria.HVPG is equal to the wedged hepatic venous pressure(WHVP)minus the free hepatic vein pressure(FHVP).The hemodynamic response was defined as HVPG decrease by at least 20%or absolute value<12 mmHg.All patients underwent propranolol metabolic enzyme gene detection.Responders who had no history of bleeding were advised to continue oral propranolol to prevent bleeding,and those who did not respond regularly were followed up.Patients with previous history of bleeding,responders suggested oral propranolol combined with standard endoscopic therapy to prevent bleeding,and those who did not respond to the recommendations suggested that endoscopic therapy should be standardized.Follow up observation was carried out on patients who met the standard of HVPG and successfully completed the basic and drug intervention.The primary endpoint of this study was clinical significance of EGVB,and the secondary endpoint was death.The SPSS software was used to analyze the clinical data.Results:A total of 52 patients received 40mg bid propranolol intervention and second HVPG measurements,of which 27 were responders,and the response rate was 51.9%(27/52).In 25 non-responders,17 cases were successfully added to 60mg bid,and 4 cases had hemodynamic response.The total response rate of 60mg bid was 59.6%(31/52),and the increase of response rate was 7.7%.The difference was not statistically significant(x2=0.624,P=0.43).The probability of 60mg bid drug intervention intolerance was 16%in 25 non-responders.There was no significant difference in baseline datas,such as age,sex,liver cirrhosis and liver function between responders and non-responders.The mean follow-up time was 12.9±8.1 months,ranging from 0.3 months to 27.7 months.The average value of HVPG,WHVP,heart rate(HR),systolic pressure(SP)and mean arterial blood pressure(MAP)after taking medicine were lower than the basic values,and the FHVP was higher than that of the basic value.The decrease of HR in responders and non-responders before and after medication was 6.3±8.5 times/min,6.4±7.3 times/min,the difference was not statistically significant(t=-0.029,P=0.977).And there was no significant difference in SP and MAP between responders and non-responders.During the follow-up,14 patients had EGVB,and there was no significant difference in the cumulative probability of bleeding between responders and non-responders(x2=0.736,P=0.391).The CYP1A2 gene,CYP2D6 gene and beta 2-AR gene can not predict hemodynamic response.Conclusion:Application of 40mg bid propranolol can achieve considerable hemodynamic responses in cirrhotic patients with esophageal and gastric varices.The CYP1A2 gene,CYP2D6 gene and beta 2-AR gene can not predict hemodynamic response.更多还原