The Influence Of Different Doses Of Propranolol On Portal Venous Hemodynamic And Propranolol Gene Polymorphism In Cirrhotic Patients With Portal Hypertension

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.