Clinical Study On The Characteristics Of Patients With Recurrent Common Bile Duct Stones After ERCP And The Prevention Of Recurrence With The Gallbladder-removing And Stone-removing Mixtur

Research significance:Endoscopic retrograde cholangiopancreatography(ERCP)is a widely used treatment for common bile duct stones(CBDS).However,the recurrence rate remains high after patients undergo ERCP,resulting in serious psychological burden,health burden and economic burden to the majority of patients.Modern medicine is still relatively unavailable for the prevention of stone recurrence after ERCP.In this study,we explores the characteristics of patients with recurrent CBDS,starting from the risk factors of CBDS recurrence after ERCP and the characteristics of bile acid profile in patients with recurrent CBDS to observe the changes of TCM patterns,then considers the TCM disease cause and mechanisms of CBDS recurrence,and explores the mechanism of the "Li-Dan-Xiao-Shi mixture" for improving bile lithogenicity and preventing stone recurrence.Objective:1.To explore the risk factors for recurrence after ERCP in CBDS patients and the clinical characteristics of patients with multiple recurrences.2.To explore the bile acid profile characteristics of patients with recurrent CBDS after ERCP.3.To observe the changes of TCM patterns in patients with CBDS after ERCP,and to confirm the effectiveness of "Li-Dan-Xiao-Shi mixture" for preventing stone recurrence and elaborate its mechanism in bile composition improvement.Methods:Study 1:Patients undergoing ERCP due to CBDS were selected as study subjects,clinical data on whether or not stones recured after ERCP and the time of recurrence were collected,and the patients’ age,gender,past medical history,stone removal procedure,presence or absence of PAD,stone size and number,stone properties,and common bile duct diameter were recorded.Univariate and COX regression multifactor analyses were performed to screen the factors affecting recurrence.The clinical characteristics of patients with multiple recurrences were analyzed by contrasting the differences between patients with multiple recurrences and those with single recurrences.Study 2:Patients who underwent ERCP due to CBDS were selected as the study subjects.Bile from the nasal bile duct on the first day after surgery was collected,and the concentrations of 16 monomeric bile acids in the bile were detected.Then the patients were divided into primary and recurrence groups according to the frequency of patients’ illness for control analysis.Patients were divided into gallbladder stone group and no gallbladder stone group according to whether they had gallbladder stones in situ for control analysis.Patients were divided into PAD and no PAD groups according to the presence or absence of PAD for control analysis,to compare the bile acid profile differences between groups,and to analyze bile acid profile characteristics in patients with recurrent CBDS and in patients with gallbladder stones or PAD.Study 3:This study was a randomized controlled clinical study.Patients diagnosed with CBDS who underwent ERCP were selected as study subjects and randomly divided into the Chinese medicinals group and the control group.After ERCP,the Chinese medicinals group was given oral "Li-Dan-Xiao-Shi mixture" twice a day for 5 days a week,and the medication cycle was 6 months.The control group was not given oral medication.The bile flowing out of the nasobiliary ducts of the two groups of patients on postoperative days 1,3,and 5 was collected to detect the concentrations of UCB,Tbil,TBA,Cho,Ca,β-Gase and glycoproteins in the bile.The trends of each component changes and intergroup differences were compared.The changes of TCM patterns in postoperative patients were observed.Abdominal ultrasound was reviewed at 6 months and 1 year postoperatively to detect the recurrence of stones and to monitor changes in the common bile duct diameter.Results:Study 1:1.A total of 408 patients who underwent ERCP for stone removal due to the CBDS were included in the study,and the results showed that 52 patients experienced recurrence and 19 patients had two or more recurrences.The presence of PAD was an independent risk factor for recurrence of CBDS in patients with first-time CBDS(P<0.05).And in patients who have already had 1 or more CBDS episodes,the high number of previous ERCP is an independent risk factor for CBDS recurrence(P<0.05).2.There was a linear correlation between age and common bile duct diameter,with a correlation coefficient of r=0.225(P<0.001),and logistic regression analysis revealed that advanced age was an independent influencing factor of the presence of PAD(P<0.05).3.There were no statistically significant differences in age,common bile duct diameter,maximum diameter of bile duct stones or presence of PAD between patients with single recurrences and those with multiple recurrences,while patients with multiple recurrences were less likely than those with single recurrences to have gallbladder stones in situ,and the difference was statistically significant(P=0.01 8).Study 2:1 A total of 48 patients were collected for bile in this study on the first after ERCP,including 24 initial-onset patients and 24 recurrent patients.The Ca content in samples from the initial-onset group was significantly lower than that in the recurrence group(P=0.035),the UDCA content in samples from the initial-onset group was significantly lower than that in the recurrence group(P=0.01 7),the TCDCA content in samples from the initial-onset group was significantly higher than that in the recurrence group(P=0.003),and the TUDCA content in samples from the initial-onset group was significantly lower than that in the recurrence group(P=0.025).The differences above were all statistically significant.The CDCA content in the samples of the initial-onset group showed a higher trend than that of the recurrence group(P=0.053),and the GCDCA content in the samples of the initial onset group showed a lower trend than that of the recurrence group(P=0.050).The ratio of CDCA to CA in the initial-onset group was significantly higher than that in the recurrence group(P=0.004).The ratio of glycocholic acid to taurocholic acid(G/T)was significantly lower in the initial-onset group than in the recurrence group,and the difference was statistically significant(P=0.006).2.Among the 48 patients,13 were accompanied by gallbladder stones and 35 were not.The content of UDCA in the bile samples of the gallbladder stone group was significantly lower than that of the no gallbladder stone group(P=0.031),the content of TCDCA in the bile samples of the gallbladder stone group was significantly higher than that of the no gallbladder stone group(P=0.027),and the G/T in the bile samples of the gallbladder stone group was significantly lower than that of the no gallbladder stone group(P=0.018).The differences above were all statistically significant.3 Among the 48 patients,28 had PAD and 20 didn’t have.No statistically significant differences were observed in 16 bile acids content and FBA,CDCA/CA,and G/T between the two groups(P>0.05).Study 3:1.A total of 60 patients were included in this study,including 32 in the Chinese medicinals group and 28 in the control group.On the third day after ERCP,bile composition was contrasted between groups,and Tbil and Ca levels in bile of the Chinese medicinals group were significantly decreased compared with the control group(P<0.05)and the difference was statistically significant.There were no statistically significant differences in UCB,UCB%,β-gase,TBA,CHO,or glycoprotein levels.On the fifth day after ERCP,Chinese medicinals intervention significantly reduced the concentration of UCB and β-Gase in bile of recurrent patients,significantly reduced UCB%in bile of initial-onset patients,significantly reduced Tbil concentrations in bile of all patients with statistical significance(P<0.05).At the same time,Chinese medicinals interventions tended to promote the reduction Ca concentration in bile(P=0.068).There were no significant differences in TBA,Cho,or glycoprotein concentrations between the two groups.2 Liver and gallbladder damp-heat syndrome accounted for the most on the first day after operation,liver depression and spleen deficiency syndrome accounted for the most on the seventh day after operation,and liver depression and spleen deficiency syndrome accounted for the most at the postoperative 6 months.The distribution of syndrome types on the first day after operation was:3 cases(5.0%)of liver depression and qi stagnation syndrome,33(55.0%)cases of liver and gallbladder damp-heat syndrome,1 case(1.7%)of liver yin deficiency syndrome,2 cases(3.3%)of blood stasis block syndrome,0 cases of internal accumulation of heat toxin syndrome,12 cases(20.0%)of liver depression and spleen deficiency syndrome and 9 cases(15.0%)of internal obstruction of dampness turbidity syndrome.The distribution of syndrome types on the 7th day after operation was:3 cases(5.0%)of liver depression and qi stagnation syndrome,10 cases(16.7%)of liver and gallbladder damp-heat syndrome,4 cases(6.7%)of liver yin deficiency syndrome,2 cases(3.3%)of blood stasis block syndrome,0 cases of internal accumulation of heat toxin syndrome,30 cases(50.0%)of liver depression and spleen deficiency syndrome and 11 cases(18.3%)of internal obstruction of dampness turbidity syndrome.The distribution of syndrome types at the six months after operation was:2 cases(7.7%)of liver depression and qi stagnation syndrome,0 cases of liver and gallbladder damp-heat syndrome,0 cases of liver yin deficiency syndrome,2 cases(7.7%)of blood stasis block syndrome,0 cases of internal accumulation of heat toxin syndrome,19 cases(73.1%)of liver depression and spleen deficiency syndrome and 3 cases(11.5%)of internal obstruction of dampness turbidity syndrome.3 Among the two groups of patients who were followed up for more than 6 months,12 were in the Chinese medicinals group and 14 were in the control group.No patients recurred in the Chinese medicinals group,and 3 patients recurred in the control group with a recurrence rate of 21.4%.There was no statistical difference in the recurrence rate between the two groups(P=0.140).There was no significant difference in the common bile duct diameter between the two groups,while the common bile duct diameter of the Chinese medicinals group was smaller than that in the control group at 6 months after surgery,and the difference was statistically significant(P=0.025).Conclusions:1.The recurrence of CBDS has a habitual character,i.e.,the recurrence rate tends to further increase in patients who have already recurred.This result is due to the combination of the internal causes of abnormal metabolism of bile components and the external causes of surgical injury to the sphincter of Oddi.For recurrence prevention,it is important to both minimize surgical damage to the sphincter,enhance postoperative recovery of sphincter function and strengthen the power of bile excretion,and at the same time to improve the abnormal bile composition.2.After the first recurrence,patients with the recurrence are more likely to have gallbladder stone in situ compared with those who don’t recur.This suggests that recurrent CBDS is mostly primary,and the role of cholecystectomy for preventing the recurrence of CBDS still needs to be further discussed and should be used with caution in clinical decision-making.3.In the analysis of recurrence risk factors in patients with first-onset CBDS,the presence of PAD was an independent risk factor for recurrent events.Whereas multiple previous ERCP attempts were an independent risk factors for patients who already had one or more recurrences.4.Compared with the initial-onset patients,recurrent patients have lower TCDCA content in bile,higher CA,UDCA and TUDCA content,and lower CDCA/CA.Abnormalities in the related metabolic activities in the liver and alterations in the structure of the intestinal flora may be possible mechanisms for the above alterations in bile acid profiles.5.Compared with the initial-onset patients,recurrent patients have higher G/T in bile,which suggests that recurrent patients are mostly accompanied by relaxation of sphincter of Oddi and structural changes of biliary flora.This change of bile acid profile could precipitate UCB more easily in bile by affecting the solubility of UCB,which may be part of the mechanism of CBDS recurrence.6.Liver stagnation and spleen deficiency is the basis of the pathogenesis and recurrence mechanism of for CBDS.Manifestations of patients at 6 months after surgery are also mostly liver stagnation and spleen deficiency,with manifestations of dampness,qi stagnation,and blood stasis.7 The use of "Li-Dan-Xiao-Shi mixture",which can replenish qi and strengthen the spleen,soothe the liver and benefit gallbladder,can reduce the content of β-Gase,UCB and UCB%in a short time so as to reduce the lithiasis of bile and to strengthen the power of bile excretion.It has a good safety profile for long-term use,can promote the recovery of postoperative common bile duct dilatation,and its effectiveness in preventing stone recurrence has been initially confirmed.