Effect of rectal indomethacin on the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography for choledocholithiasis: a prospective randomized clinical trial.

BACKGROUND AND AIM: the aim of this study was to evaluate the efficacy and safety of rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients with common bile duct (CBD) stones. METHODS: a total of 167 patients undergoing ERCP between November 2019 and November 2022 for CBD stones in the First Affiliated Hospital of Dalian Medical University were prospectively analyzed. The patients were divided into an indomethacin group (n = 58) and a control group (n = 109). The primary endpoint was the percent of patients who experienced PEP. RESULTS: PEP was observed in a total of 26 patients (15.57 %); four patients (6.90 %) in the indomethacin group and 22 (20.18 %) in the control group (p = 0.042). Mild, moderate and severe PEP was observed in three (5.17 %), one (1.72 %) and zero patients, respectively, in the indomethacin group, and in eleven (10.09 %), nine (8.26 %) and two (1.83 %) patients, respectively, in the control group. There was one case (0.92 %) of death due to PEP in the control group. No cases of moderate or severe bleeding were observed in either group. CONCLUSIONS: rectal indomethacin is an effective and safe method to prevent PEP for patients with CBD stones undergoing ERCP.

Clinical and Microbiological Profile of Patients with Acute Cholangitis in a Tertiary Care Center.

INTRODUCTION: Acute cholangitis usually complicates biliary obstruction and antibiotic therapy plays a major role, as an adjunct to adequate biliary drainage in cholangitis. The knowledge of bacterial epidemiology in cholangitis will help to choose antibiotic wisely. The aim of the study was to analyze the clinical and bacteriological profile, in acute cholangitis. MATERIALS: We retrospectively analyzed the patients with acute cholangitis admitted under the Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar August 2020 and July 2022. RESULT: 100 patients with mean age of 53.79 ± 14.96 years (male:female = 48:52) were included in the study. Choledocholithiasis (54%), carcinoma gallbladder (16%) and periampullary carcinoma (13%) were the main cause of biliary obstruction. The most common presenting complaints were fever followed by jaundice, the classically described Charcot's triad was present in only 33 (33%) patients. Most of the patients had moderate cholangitis (52%), followed by mild cholangitis (27%) and severe cholangitis (21%); based on Tokyo 2018 guidelines. Biliary drainage was done by endoscopic retrograde stenting in 92% and percutaneous trans-hepatic drainage in 8% of patients. Bile culture were positive on 86% of patients; gram-negative isolates were in 82.5% (71/86), gram-positive isolates were in 15.2% (13/86) and candida species in 2.3% (2/86). The commonest gram negative organisms isolated were Escherichia coli (34/86) followed by Klebsiella pneumonia (26/86) and Enterococcus faecalis (6/86) being the commonest gram-positive organism. The overall mortality rate was 11%; all had severe cholangitis. CONCLUSION: Choledocholithiasis is the commonest cause of biliary obstruction in patients presenting with acute cholangitis. Escherichia coli and Klebsiella pneumonia are the major contributors to acute cholangitis. References Reiter FP, Obermeier W, Jung J, et al. Prevalence, resistance rates, and risk factors of pathogens in routine bile cultures obtained during endoscopic retrograde cholangiography. Dig Dis 2021;39(1):42-51. Kaya M, Bestas R, Bacalan F, et al. Microbial profile and antibiotic sensitivity pattern in bile cultures from endoscopic retrograde cholangiography patients. World J Gastroenterol 2012;18(27):3585-3589.

Roles of ursodeoxycholic acid in the bile biochemistry and metabolomics in patients with choledocholithiasis: a prospective study.

INTRODUCTION: Recurrence after the endoscopic treatment of common bile duct stones (CBDS) is related to bile metabolism and bile compositions. Ursodeoxycholic acid (UDCA) has been proved effective in reducing the recurrence of CBDS. However, the detailed effects of UDCA on bile metabolism are still not extensively explored. OBJECTIVES: This study aimed to analyze the role of UDCA in patients with choledocholithiasis (CDC) from the perspective of biochemistry and metabolomics. METHODS: A total of 89 patients with CDC who underwent endoscopic retrograde cholangiopancreatography were prospectively examined and randomly assigned to control and UDCA groups. The biochemical detections (cholesterol, bilirubin, and so on) were performed on the collected bile. Moreover, the metabolomics analysis was conducted based on bile from 20 patients in the UDCA group. RESULTS: The bile levels of cholesterol and endotoxins significantly decreased after UDCA treatment. Regarding bile metabolomics, the levels of 25 metabolites changed significantly after UDCA treatment. The pathway enrichment analysis showed that the UDCA addition evoked a common response related to phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; arachidonic acid metabolism; and terpenoid backbone biosynthesis. CONCLUSIONS: UDCA treatment within a short time interval (7 days) did not improve the circulating laboratory values in patients with CDC who had undergone endoscopy surgery. However, relevant decreases in the bile levels of cholesterol and endotoxin were observed. UDCA evoked a common response related to lipid metabolism and amino acid metabolism, which probably reduced the bile level of cholesterol, protected hepatocytes, and corrected the abnormality of lipid metabolism caused by CDC.

Familial low phospholipid-associated cholelithiasis resulting from an autosomal dominant ABCB4 mutation.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is characterized by early intrahepatic and symptomatic gallstones leading to cholangitis, acute pancreatitis and biliary colic. It has been associated with loss of function variants in the ABCB4 gene. ABCB4 encodes for a phospholipid translocator at the canalicular membrane of the hepatocyte, which "flops" phosphatidylcholine into bile. The autosomal recessive form is the most common, although autosomal dominant forms have also been described. We report the first family with autosomal dominant LPAC syndrome due to heterozygosity of the loss of function mutation c.2932T>C in ABCB4, identified by targeted next generation sequencing.

[IMPACT OF RONCOLEUKIN ON BALANCE OF CYTOKINS IN COMPLEX TREATMENT OF OBTURATION JAUNDICE OF NONTUMORAL GENESIS].

The results of surgical treatment of 137 patients, suffering obturation jaundice of non-tumoral etiology, were analyzed. In all the patients the cause of obturation jaundice was choledocholithiasis. Roncoleukin was infused intravenously additionally in a complex of therapy. A degree of hepatic dysfunction was determined, taking into account the cholestasis markers. In 23 patients purulent cholangitis have occurred on background of obturation jaundice. Concentration of cytokins TNF-α, IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10 in sera were determined, using immunoassay analysis. The cytokins dysbalance severity preoperatively and dynamics of its changes have depended upon the hepatic dysbalance degree and presence of purulent cholangitis; a dysbalance is deeper, when the hepatic dysfunction is higher. Application of pathogenetically substantiated purposeful cytokinotherapy, including roncoleukin, have promoted the cytokins dysbalance elimination and improvement of the patients treatment results.

[CLINIC-EXPERIMENTAL SUBSTANTIATION OF OZONOTHERAPY APPLICATION IN THE TREATMENT OF PURULENT CHOLANGITIS AND OBTURATION JAUNDICE].

Efficacy of the ozonotherapy application as an important component of complex treatment in purulent cholangitis (PCH) was studied. In choledocholithiasis (without infectioning of bile) ozonotherapy may be prescribed as additional component at complex treatment. In PCH ozonotherapy application have promoted the improvement of laboratory indices in 6.6 times, comparing with such, occurring after basic therapy.

Association between glucagon-like peptide-1 receptor agonists and biliary-related diseases in patients with type 2 diabetes: A nationwide cohort study.

STUDY OBJECTIVE: Clinical trials have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be associated with a higher risk of biliary-related diseases in patients with type 2 diabetes. Limited real-world studies have examined the comparative biliary safety of GLP-1RAs versus other antihyperglycemic drugs. We aimed to estimate the comparative risk of biliary-related diseases between GLP-1RAs and sodium glucose cotransporter 2 inhibitors (SGLT2is), which are indicated for patients with similar diabetes severity in Taiwan. DESIGN: Retrospective cohort study. DATA SOURCE: Taiwan National Health Insurance Database during 2011 to 2018. PATIENTS: Patients with type 2 diabetes who initiated GLP-1RAs or SGLT2is. INTERVENTION: GLP-1RAs versus SGLT2is. MEASUREMENTS AND MAIN RESULTS: We used an on-treatment approach to examine the effect of continuous use and an intention-to-treat approach to assess the effect of initiation of GLP-1RAs versus SGLT2is. We used Coxregression models to estimate the hazard ratios (HRs) and 95% confidenceintervals (CIs) for the composite hospitalized biliary-related diseases, including acute cholecystitis or cholecystectomy, choledocholithiasis, and acute cholangitis, after matching each GLP-1RA initiator to up to 10 SGLT2iinitiators using propensity scores (PSs). Among 78,253 PS-matched patients, GLP-1RA use was associated with a numerically higher risk of biliary-related diseases versus SGLT2i use in the on-treatment analysis, with an HR of 1.20 (95% CI, 0.93-1.56) for the composite outcome, an HR of 1.22 (95% CI, 0.92-1.62) for acute cholecystitis or cholecystectomy, an HR of 1.20 (95% CI, 0.69-2.07) for choledocholithiasis, and an HR of 1.14 (95% CI,0.82-2.42) for acute cholangitis. The HRs were more pronounced in theintention-to-treat analysis (1.27 [95% CI, 1.05-1.53] for the composite outcome, 1.29 [95% CI, 1.04-1.58] foracute cholecystitis or cholecystectomy, 1.74 [95% CI, 1.23-2.46] for choledocholithiasis, and 1.31 [95% CI, 0.89-1.94] for acute cholangitis). The increased risk of the composite outcome associated with GLP-1RAs was more evident in patients aged 〉60 years, women, and 120 days after treatment initiation. Liraglutide, but not dulaglutide, was associated with an elevated risk. CONCLUSIONS: GLP-1RAs might be associated with an elevated risk of biliary-related diseases compared to SGLT2is in Asian patients with type 2 diabetes.

Is the addition of choleretic agents in multiple double-pigtail biliary stents effective for difficult common bile duct stones in elderly patients? A prospective, multicenter study.

BACKGROUND: Temporary biliary stenting is both technically easy and feasible, and choleretic agents such as ursodeoxycholic acid (UDCA) and a terpene preparation may promote a reduction in stone size. However, there are few comparative data on the effectiveness of choleretic agents available. OBJECTIVE: To investigate the efficacy of multiple double-pigtail stents with or without UDCA and terpene on difficult common bile duct (CBD) stones. DESIGN: A prospective, multicenter study. SETTING: Four tertiary-care referral centers. PATIENTS: This study involved 51 patients. INTERVENTION: In total, 51 elderly patients with comorbidities who had difficult CBD stones refractory to conventional methods were randomized to receive either multiple 7F double-pigtail stents (group A) or stents in combination with UDCA and terpene (group B) for a period of 6 months. MAIN OUTCOME MEASUREMENTS: Stone size reduction, successful duct clearance, and complications. RESULTS: Complete endoscopic duct clearance was achieved in 14 patients (73.7%) in group A and 19 patients (86.4%) in group B (P = .826). The mean size of CBD stones (transverse/longitudinal diameter, mean ± SD) was 19.12 ± 4.48 mm/20.47 ± 3.86 mm in group A and 21.30 ± 7.08 mm/22.58 ± 7.61 mm in group B. Stone size decreased significantly to 12.04 ± 3.26 mm/13.31 ± 5.12 mm and 13.67 ± 5.40 mm/14.04 ± 6.12 mm, respectively (P < .01). However, there was no statistical difference in stone size reduction between the two groups (P = .685, P = .289). No serious complications related to the stent or endoscopic procedures were observed, except for cholangitis (n = 1, group A) and distal stent migration (n = 2, group B). LIMITATIONS: Small number of patients in East Asia. CONCLUSION: Temporary multiple double-pigtail biliary stenting was a safe and feasible method of treating difficult and large CBD stones in elderly patients and contributed to a reduction in stone size and successful duct clearance. However, the addition of choleretic agents did not result in a statistical difference in stone size or rate of successful duct clearance.

Efficacy of Lidan Tang on high-fat-diet induced hepatolithiasis in mice and possible mechanism.

OBJECTIVE: To investigate efficacy of Lidan Tang (LDT) on gallstone induced by high fat diet in mice, and to study its underlying mechanism. METHODS: Mice were fed with high fat diet every day and treated with LDT (9.01 times of human clinic dosage). Mice were randomly divided into 6 groups as control group, gallstone model group (high-fat diet), positive control ursodeoxycholic acid (UDCA) group (80 mg·kg-1·d-1, i.g.), LDT low dose group (6 kg/d, i.g.), LDT middle dose group (12 kg/d, i.g.), and LDT high dose group (24 kg/d, i.g.). The whole experiment was lasted for 4 weeks. The levels of ALT, AST, LDH, CHO, HDL-C and LDL-C in serum were measured, the pathological sections were observed by hematoxylin-eosin staining, the activities of antioxidant enzymes were measured by kits, and the proteins related to oxidative stress and lipid transport were detected by Western blot analysis. RESULTS: LDT could significantly reduce the contents of ALT and AST in serum and improve the pathological tissue of liver. LDT could significantly reduce the content of MDA and LPO, and increase the level of GSH and GSH-PX in liver tissue. The data of Western blot showed that LDT had antioxidant effect promoting Keap1/Nrf2 pathway and regulated the process of lipid transport, which was statistically significant. In addition, LDT treatment inhibited the expression of ATP-binding cassette transports ABCG5/8 in liver, and reduced cholesterol transport from the hepatocytes to the gallbladder. CONCLUSION: LDT has protective effect on gallstones induced by high fat diet in mice, which might be based on the protective effect on liver, including enhancing the antioxidant capacity of liver and reducing the production of lipid peroxides.

Ursodeoxycholic acid treatment for patients with postcholecystectomy pain and bile microlithiasis.

BACKGROUND: Microlithiasis has been identified as a cause of idiopathic acute pancreatitis in patients with an intact gallbladder. Microlithiasis has also been identified in the bile of some patients who have undergone cholecystectomy. However, it is unknown whether bile microlithiasis causes postcholecystectomy pain. OBJECTIVE: To identify bile microlithiasis in patients with postcholecystectomy pain and to investigate the therapeutic effect of ursodeoxycholic acid (urso) on such patients with microlithiasis in the bile. DESIGN: Prospective randomized trial. SETTING: Tertiary medical center. PATIENTS: Patients with postcholecystectomy pain and bile crystals. INTERVENTIONS: Urso treatment. MAIN OUTCOME MEASUREMENTS: The severity and frequency of right upper-quadrant abdominal pain were compared with and without urso treatment, and before and after urso treatment. RESULTS: A total of 118 patients with postcholecystectomy pain were screened for the study. Twelve patients (10%) were identified with bile crystals. In the first phase, 6 of these patients received urso treatment, whereas the other 6 patients did not receive urso treatment. In the second phase, the latter 6 patients were given the urso treatment. After using urso for a few months, their biliary-type abdominal pain significantly improved or resolved. In the control group, there was no improvement in symptoms. There was a significant difference between the 2 groups (P = .01). LIMITATIONS: Single-center, small number of patients. CONCLUSIONS: This study provided evidence that supports the hypothesis that bile microlithiasis is indeed a cause for postcholecystectomy pain. Patients with such postcholecystectomy pain may benefit from a microscopic examination of bile for crystals or microlithiasis, and urso treatment if bile crystals are identified.

Effect of Lidan Granule on bile lithogenesis in patients with choledocholithiasis combined with cholecystolithiasis.

OBJECTIVE: To observe the effect of Lidan Granule (, LDG) on bile lithogenic tendency and biliary 33.5 kd vesicular protein (VP) and to explore its mechanism. METHODS: Sixty patients with choledocholithiasis combined with cholecystolithiasis were randomly assigned to the LDG treated group, the sodium cholate treated group for positive control, and the untreated control group, 20 patients in each group. The 4 bile lithogenic trend indexes, including lithogenic index (LI), unconjugated bilirubin percent (UCB%), unconjugated bilirubin saturation index (BSI) and Z-value, were determined before and after treatment. The content of VP in bile was determined as well. RESULTS: Before treatment, the LI, UCB%, BSI and Z-value in the LDG treated group were 1.298+/- 0.265, 34.72+/-2.96, 0.353+/-0.093 and 0.556+/-0.499, respectively, which was decreased after the 2-week treatment to 0.926+/-0.208, 8.93+/-1.19, 0.154+/-0.056 and 0.257+/-0.211, respectively (all P<0.05). Meantime, the content of VP was also lowered from 0.050+/-0.005 g/L to 0.032+/-0.005 g/L. However, no significant change in any of the above-mentioned indexes was found in the other two groups. CONCLUSION: LDG could effectively suppress bile lithogenic trend and reduce 33.5 kd VP in bile.

Anisodamine accelerates spontaneous passage of single symptomatic bile duct stones ≤ 10 mm.

AIM: To investigate the rate of spontaneous passage of single and symptomatic common bile duct (CBD) stones ≤ 10 mm in diameter in 4 wk with or without a 2-wk course of anisodamine. METHODS: A multicenter, randomized, placebo-controlled trial was undertaken. A total of 197 patients who met the inclusion criteria were enrolled. Ninety-seven patients were assigned randomly to the control group and the other 100 to the anisodamine group. The anisodamine group received intravenous infusions of anisodamine (10 mg every 8 h) for 2 wk. The control group received the same volume of 0.9% isotonic saline for 2 wk. Patients underwent imaging studies and liver-function tests every week for 4 wk. The rate of spontaneous passage of CBD stones was analyzed. RESULTS: The rate of spontaneous passage of CBD stones was significantly higher in the anisodamine group than that in the control group (47.0% vs 22.7%). Most (87.2%, 41/47) stone passages in the anisodamine group occurred in the first 2 wk, and passages in the control group occurred at a comparable rate each week. Factors significantly increasing the possibility of spontaneous passage by univariate logistic regression analyses were stone diameter (< 5 mm vs ≥ 5 mm and ≤ 10 mm) and anisodamine therapy. Multivariate logistic regression analyses revealed that these two factors were significantly associated with spontaneous passage. CONCLUSION: Two weeks of anisodamine administration can safely accelerate spontaneous passage of single and symptomatic CBD stones ≤ 10 mm in diameter, especially for stones < 5 mm.

Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones.

BACKGROUND: When common bile duct (CBD) stones cannot be removed after conventional endoscopic techniques or mechanical lithotripsy, biliary stenting serves for further planned endoscopic attempt of stone removal or operation. The aim of our study was to investigate the effect of ursodeoxycholic acid (UDCA) or placebo plus endoprostheses on stones' fragmentation or size. METHODS: Forty-one patients with difficult to extract CBD stones were prospectively studied. They were randomised to receive either a 10 Fr straight plastic stent and oral 750 mg UDCA (group A, 21 patients) or placebo (group B, 20 patients) daily for 6 months. RESULTS: A total clearance of CBD was achieved in 16 patients (76.9%) of group A and 15 patients (75%) of group B. The stones remained unchanged in size in five patients (23.8%) of group A and five patients (25%) of group B. In seven patients (33%) of group A and five patients (25%) of group B a repeated ERCP demonstrated fragmentation of CBD stones that were easily extracted. A reduction in stones' size was observed in 8 patients (38%) of group A (1.61 +/- 0.32 cm before treatment vs. 1.21 +/- 0.24 cm after treatment, p = 0.002) and 10 patients (50%) of group B (1.61 +/- 0.35 cm before vs. 1.24+/-0.22 cm after treatment, p = 0.001). There was no statistically significant difference on stone size reduction (p = 0.602) and fragmentation (p=0.558) between the two groups. CONCLUSION: The results of this study suggest that UDCA does not seem to contribute to the reduction in stones' size or stones' fragmentation during the endoprosthetic procedure.

A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat.

Forty-eight rats with biliary obstruction induced by double ligation and section of the common bile duct were randomly and blindly assigned to receive subcutaneous injection of either conventional heparin sodium (1000IU kg(-1)), three already marketed low molecular weight heparin (LMWH) preparations: nadroparin (1000 anti-Xa IU kg(-1)), tinzaparin (1000 anti-Xa IU kg(-1)), enoxaparin (180 anti-Xa IU kg(-1)) or saline. Drugs were administered once a day, starting 7 days after surgery and continued for 3 weeks. At the end of the treatment period, rats were killed and analyzed for blood biochemistry and liver pathology. Liver fibrosis was assessed by image analysis. Data indicated that treatment with nadroparin decreased plasma total bilirubin, serum alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) levels by 80.3, 70.7 and 42%, compared with bile duct ligated (BDL) control values. The reduction in plasma total protein observed in BDL controls was prevented by nadroparin. Enoxaparin-treated rats showed significant reduction in plasma total bilirubin and alanine aminotransferase levels by 32.5 and 38.4% versus BDL controls. Liver necrosis evaluated histologically was significantly reduced in the nadroparin- and enoxaparin-treated rats. Morphometric analysis showed significant reduction in fibrosis on nadroparin and enoxaparin treatment: area of fibrosis: 1.66 +/- 0.17% and 14.03 +/- 1.1% versus 18.94 +/- 2.4% (P<0.05); nadroparin and enoxaparin versus BDL control. By contrast, neither conventional heparin nor tinzaparin prevented the bile duct ligation-induced liver damage as indicated by increased plasma aminotransferases, ALP and GGT concentrations and the histological evidence of necrosis. Total serum bilirubin was increased by 27.5% in rats treated with conventional heparin, while ALP and GGT levels were 38.6 and 31.4% higher after tinzaparin treatment versus BDL controls. Significant increase in the area of fibrosis was observed after tinzaparin treatment compared to BDL control group. Results suggest a beneficial effect for nadroparin and enoxaparin in the therapy of patients with obstructive jaundice or cholestatic liver disorders. The present data from bile duct ligated rats suggest an antifibrotic effect for nadroparin and enoxaparin.

Sludge ball, pseudolithiasis, cholelithiasis and choledocholithiasis from intrauterine life to 2 years: a 13-year follow-up.

OBJECTIVE: Evaluation and follow-up of infants with cholelithiasis and pseudolithiasis in a pediatric ward. PATIENTS & METHODS: Prospective study from April 1990 to October 2003 identified hospitalized infants younger than 2 years with ultrasonographic findings of cholelithiasis, choledocholithiasis or pseudolithiasis. Associated abnormalities or contributory factors were recorded and patients were followed for from 6 months to 13 years (mean, 4 years). RESULTS: Thirty-four patients were diagnosed between the age of 3 weeks and 24 months. Thirteen (38%) had been treated with third-generation cephalosporins. Other associated factors were dehydration in 10 (29%), urinary tract infection in two (6%) and one each for cholestatic liver disease, total parenteral nutrition, immunoglobulin A deficiency and prematurity. Six infants (17%) had no known risk factor. Six additional patients were diagnosed by antenatal ultrasound. CONCLUSIONS: Cholelithiasis in infants hospitalized for a variety of common pediatric conditions is not rare. Dehydration and treatment with third-generation cephalosporins are important associated factors. The classic risk factors of hemolysis and previous gastrointestinal surgery, were not found in our group. The overall prognosis was good. Pseudolithiasis disappeared in all infants. Of the 21 infants with cholelithiasis, only two developed cholecystitis. In nine infants, spontaneous resolution occurred. In the absence of other clinical or imaging evidence of biliary tract disease, conservative management is advised.