Increased risk of PLA after ES for choledocholithiasis thera | IDR



Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES) is widely applied as the standard management of bile duct stones.1,2 Although generally considered safe, ES still carries some risks of complications. The short-term complications include procedural bleeding, pancreatitis, cholangitis, and perforation, whose overall incidence ranges from 2.5– 13.1%.3–7 As for long-term complications, Oliveira-Cunha et al8 reported the incidence of cholangiocarcinoma varied from 0–3.1% between studies, the rate of recurrent choledocholithiasis from 3.2–22.3%, and low incidence of cholangitis in the absence of recurrent biliary stones.

Pyogenic liver abscess (PLA) is a potential life-threatening infectious disease. Recently, biliary tract diseases including choledocholithiasis, hepatobiliary malignancy, stricture, and congenital biliary anomalies become the predominant etiologies of PLA.9 Diabetes mellitus (DM), underlying hepatobiliary or pancreatic disease, and gastrointestinal cancers with biliary tract involvement are well-known risk factors for PLA.10–12 Prior ES procedure promotes duodenal-biliary reflux and may induce ascending bacterial colonization or even infection of the common bile duct (CBD).13,14 Theoretically, ES might be associated with development of PLA. To date, there has been a lack of comprehensive study associating the risk of PLA with ES.

Therefore, we conducted a population-based, cohort study from the Chang Gung Research Database to analyze the risk of PLA among patients undergoing an ES procedure, as well as other complications including pancreatitis, cholangitis, and recurrence of CBD stones.


Compliance with Ethical Requirements

The study protocol was approved by the Institutional Review Board and the Ethics Committee of Chang Gung Memorial Hospital at Taoyuan in Taiwan (permitted number 201900919B0C601). This study was performed in accordance with relevant guidelines and regulations. The Ethics Committee waived the requirement for informed consent for this study, and the data were analyzed anonymously. This study was performed in accordance with the Declaration of Helsinki.

Data Sources

We collected the patient data from the Chang Gung Research Database (CGRD), the largest hospital system in Taiwan. The CGRD is a de-identified database based on detailed medical records including outpatient and inpatient treatment, laboratory data, interventional procedures, and prescription of medication. The diseases are identified based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) for data before 2016 and ICD-10-CM for data thereafter. To protect the patients’ privacy, the data are encrypted and de-identified when entered into the CGRD and can be further decrypted for medical information if needed. According to a previous validation study,15 the CGRD contains more severe co-morbidities and higher prevalence of certain diseases than in the Taiwanese National Health Insurance Research Database. Therefore, the CGRD is more convincing in studying complicated or rare diseases.

Study Cohort, Inclusion, and Exclusion Criteria

The identifications of disease according to codes of ICD-9-CM or ICD-10-CM based on ≥1 claim of inpatients or ≥1 claims of outpatients in 1 year are shown in Supplementary Table S1. Those who had procedure codes including endoscopic sphincterotomy or endoscopic sphincterotomy with stone removal (56031B, 56033B, 56040B) were classified as endoscopic sphincterotomy (ES) group. Those who did not receive ES, but had other endoscopic retrograde cholangio-pancreatography (ERCP) procedures such as endoscopic papillary balloon dilation, endoscopic nasobiliary drainage or endoscopic retrograde biliary drainage and endoscopic retrograde pancreatic drainage (33033B, 33024B, 56032B, 56020B, 56021B) were classified as the other ERCP group. Those who had a combination of ES and other therapeutic procedures were classified as the ES group. Figure 1 showed a schematic flowchart of the study design. The cohort of patients with choledocholithiasis and received ERCP procedures was identified between January 1, 2001 and December 31, 2018. Those aged <18 years old, with a history of receiving ERCP procedure, pyogenic liver abscess, amebic liver abscess, alcoholism, history of surgery for hepato-pancreato-biliary system and malignancy including hepatocellular carcinoma (HCC), malignant neoplasm of gallbladder and extrahepatic bile ducts, malignant neoplasm of small intestine including duodenum and malignant neoplasm of pancreas were excluded before the index of choledocholithiasis. The eligible patients were then divided into the endoscopic sphincterotomy (ES) group (n=7,111) and other ERCP group (n=4,586) for further analysis.

Figure 1 Schematic flowchart of the study design.

Abbreviations: ERCP, endoscopic retrograde cholangio-pancreatography; ES, endoscopic sphincterotomy.

Study Outcomes

The definition of primary and secondary outcomes is shown in Supplementary Table. The primary outcome was the occurrence of liver abscess. All patients were followed from the index hospital admission to liver abscess, death, or end of following time on December 31, 2018, whichever came first. Besides, the complications related to liver abscess such as endophthalmitis, brain abscess, intra-spinal abscess, brain meningitis, lung abscess, osteomyelitis and prostate abscess were also collected for analysis. The complication of liver abscess was defined as occurrence of infectious events in the same hospitalization.

The secondary outcomes included the occurrence of acute pancreatitis, cholangitis, recurrence of common bile duct stones <180 days or ≧180 days and in-hospital mortality rates.

Confounder Assessment

As shown in Supplementary Table S1, patient’s underlying comorbidities were identified based on ≥1 claim of inpatients or ≥1 claims of outpatients in 1 year prior to the index hospitalization, which included liver cirrhosis, chronic kidney disease (CKD), diabetes mellitus (DM), disorders of lipoid, coronary artery disease (CAD), and hypertensive cardiovascular disease (HCVD).

The potential medications influencing the outcomes were collected according to Anatomical Therapeutic Chemical code and are shown in Supplementary Table S1, which included nonsteroidal anti-Inflammatory drugs (NSIADs)/Cyclooxygenase-2 (COX-2) inhibitors, aspirin, clopidogrel, warfarin, dipyridamole, cilostazol, systemic steroids, anti-hypertensives (diuretics, beta blocking agents, calcium channel blockers and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers(ARB)), ursodeoxycholic acid, statin (atorvastatin, fluvastatin, pitavastatin, rosuvastatin and simvastatin), and other Lipid lowering drugs (clofibrate, bezafibrate, gemfibrozil, fenofibrate, nicotinic acid, ezetimibe, bile acid sequestrants, nicotinic acid and derivatives and other lipid modifying agents).

Interventional procedures or diseases that occurred during the follow-up period possibly influencing the outcomes were also collected for further analysis, which included endoscopic retrograde biliary drainage (ERBD), endoscopic papillary balloon dilation (EPBD), surgery for hepato-pancreato-biliary system, cholecystectomy and hepatobiliary malignancy (HCC, malignant neoplasm of gallbladder and extrahepatic bile ducts, malignant neoplasm of small intestine including the duodenum and malignant neoplasm of the pancreas).

Statistical Analysis

The categorical data were presented as frequencies and percentages and analyzed by using Pearson’s Chi-square or Fisher’s exact 2-tailed tests. The continuous data were presented as means±standard deviation (SD) and analyzed using the t-test, where appropriate.

For accurate assessment of the competing risks on the impact of PLA, we applied a cause-specific approach of the Cox proportional hazard model to estimate the relative hazard ratio of outcome events between comparison groups. The regression model was made after adjustment of host factors, clinical conditions, and medication usage. Kaplan-Meier method with the Log rank test was used to compare cumulative incidence between comparison groups. Two-tailed p-values <0.05 were considered statistically significant. All statistical analyses were conducted using SAS version 9.4 (SAS Institute’s Inc., Cary, NC).


Patient Characteristics

Demographic data for the two groups are shown in Table 1. The gender was similar between the two groups. Patients with ES procedure were significantly older than those with other ERCP (64.70±16.28 vs 63.87±15.22, p=0.0051). As for comorbidities, the ES group had higher prevalence of DM (24.82% vs 23.11%, p=0.0352), disorders…


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