Recombinant Human Soluble Thrombomodulin Contributes to a Reduction In-Hospital Mortality of Acute Cholangitis with Disseminated Intravascular Coagulation: A Propensity Score Analyses of a Japanese Nationwide Database.

The anti-DIC biological agent, recombinant human soluble thrombomodulin (rhTM), is being used clinically for DIC treatment in Japan. Patients with acute cholangitis associated with DIC are severe and require improved treatment. In addition, although clinical efficacy of rhTM in patients with acute cholangitis and DIC is expected, its efficacy is controversial. Thus, it is useful to evaluate rhTM in patients with acute cholangitis with DIC. This study aimed to validate the hypothesis that rhTM use improves in-hospital mortality in patients with acute cholangitis with DIC. A propensity score-matching analysis using a nationwide administrative database, the Japanese Diagnosis Procedure Combination Inpatient Database from April 2012 to March 2018, was performed. This database includes administrative claims data for all inpatients discharged from more than 1,000 participating hospitals, covering 92% of all tertiary-care emergency hospitals in Japan. Eligible patients (n = 2,865) were categorized into the rhTM (n = 1,636) or control groups (n = 1,229). Propensity score-matching created a matched cohort of 910 pairs with and without rhTM. In-hospital mortality between the groups in the unmatched analysis showed no significant difference (rhTM vs. control; 10.8% vs. 12.2%; p = 0.227). However, in-hospital mortality between the groups in the propensity score-matched analysis showed a significant difference (rhTM vs. control; 9.5% vs. 12.9%; p = 0.021). These results demonstrated that the rhTM group had significantly lower in-hospital mortality for patients with acute cholangitis with DIC. We propose that rhTM should be used for the treatment of patients with acute cholangitis with DIC.

National trends and outcomes in timing of ERCP in patients with cholangitis.

INTRODUCTION: Guidelines recommend early endoscopic retrograde cholangiopancreatography for the management of acute cholangitis, but the definition of the term "early" remains debatable. This study analyzed national trends in the timing of endoscopic retrograde cholangiopancreatography and identified the ideal time to perform preoperative endoscopic retrograde cholangiopancreatography in patients with acute cholangitis. METHODS: The 2005 to 2016 National Inpatient Sample was used to identify patients undergoing cholecystectomy for acute cholangitis. Severity of cholangitis was defined using the 2013 Tokyo Grading Criteria, where Tokyo grade III patients were defined as having organ dysfunction and non-Tokyo grade III patients were defined as grades I and II. Multivariable regressions (accounting for patient and hospital characteristics) were used to identify the timing of preoperative endoscopic retrograde cholangiopancreatography associated with the least mortality risk. RESULTS: Of 91,051 patients undergoing cholecystectomy for cholangitis, 55% underwent preoperative endoscopic retrograde cholangiopancreatography: 24% of patients received endoscopic retrograde cholangiopancreatography on the day of admission, 41% on hospital day 2, and the use of endoscopic retrograde cholangiopancreatography decreased gradually thereafter. Mortality rates remained under 1% if endoscopic retrograde cholangiopancreatography was performed during the first 3 days and increased as endoscopic retrograde cholangiopancreatography was performed during days 4 to 7 (P < .001). On multivariable regression, endoscopic retrograde cholangiopancreatography performed >72 hours after admission was associated with increased mortality (adjusted odds ratio 1.80, P = .01). Receiving endoscopic retrograde cholangiopancreatography P > 72 hours increased risk of death among Tokyo grade III patients (adjusted odds ratio 1.88, P = .01). Overall, during the study period, the utilization of preoperative endoscopic retrograde cholangiopancreatography for all grades of acute cholangitis increased from 39% of patients in 2005 to 51% in 2016 (P < .001). CONCLUSION: There has been an increase in the use of endoscopic retrograde cholangiopancreatography for acute cholangitis. Although endoscopic retrograde cholangiopancreatography on the day of admission was not associated with a decrease in mortality in patients with Tokyo grade III disease, endoscopic retrograde cholangiopancreatography within 72 hours of hospitalization was associated with decreased in-hospital mortality.

Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

Microbiology and risk factors for gram-positive Cocci bacteremia in biliary infections.

BACKGROUND: The rapid antibiotics treatment targeted to a specific pathogen can improve clinical outcomes of septicemia. We aimed to evaluate the clinical characteristics and outcomes of biliary septicemia caused by cholangitis or cholecystitis according to causative organisms. METHODS: We performed a retrospective cohort study in 151 patients diagnosed with cholangitis or cholecystitis with bacterial septicemia from January 2013 to December 2015. All patients showed clinical evidence of biliary tract infection and had blood isolates that demonstrated septicemia. RESULTS: Gram-negative, gram-positive, and both types of bacteria caused 84.1% (127/151), 13.2% (20/151), and 2.6% (4/151) episodes of septicemia, respectively. The most common infecting organisms were Escherichia coli among gram-negative bacteria and Enterococcus species (Enterococcus casseliflavus and Enterococcus faecalis) among gram-positive bacteria. There were no differences in mortality, re-admission rate, and need for emergency decompression procedures between the gram-positive and gram-negative septicemia groups. In univariate analysis, previous gastrectomy history was associated with gram-positive bacteremia. Multivariate analysis also showed that previous gastrectomy history was strongly associated with gram-positive septicemia (Odds ratio = 5.47, 95% CI: 1.19-25.23; P = 0.029). CONCLUSIONS: Previous gastrectomy history was related to biliary septicemia induced by gram-positive organisms. This information would aid the choice of empirical antibiotics.

Timing of Performing Endoscopic Retrograde Cholangiopancreatography and Inpatient Mortality in Acute Cholangitis: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although early biliary drainage improves outcomes in patients with acute cholangitis, the optimal time to perform endoscopic retrograde cholangiopancreatography (ERCP) is controversial. Our aim was to evaluate the impact of timing of ERCP on mortality in hospitalized patients with acute cholangitis. METHODS: We searched PubMed, EMBASE, and The Cochrane Library (until February 2019) for studies evaluating the impact of timing of ERCP (<24, <48, and <72 hours from hospitalization) on outcomes in patients with acute cholangitis. The primary outcome was in-hospital mortality. RESULTS: Fourteen observational studies, including 84,063 patients (mean age = 66 ± 18), met the study criteria. The overall pooled in-hospital mortality with acute cholangitis was 1.9% (95% confidence interval [CI] 1.8%-7.6%), which increased to 4.3% (95% CI 1.8%-8.7%) when administrative database studies were excluded. In 9 studies, ERCP performed <24 compared with ≥24 hours decreased in-hospital mortality (odds ratio [OR] = 0.81, 95% CI 0.73-0.90; I = 0%). In 8 studies, ERCP performed <48 compared with ≥48 hours decreased in-hospital mortality (OR = 0.57, 95% CI 0.51-0.63; I = 0%). In 4 studies, ERCP performed <72 compared with ≥72 hours decreased in-hospital mortality (OR = 0.32, 95% CI 0.15-0.68; I = 0%). Furthermore, hospital stay was reduced in patients receiving ERCP <24 compared with ≥24 hours (mean difference [MD] = 3.2 days, 95% CI 2.3-4.1; I = 78%), <48 compared with ≥48 hours (MD = 3.6 days, 95% CI 2.1-5.1; I = 98%), and <72 compared with ≥72 hours (MD = 4.1 days, 95% CI 0.9-7.3; I = 63%). DISCUSSION: In observational studies, earlier ERCP performed in patients with acute cholangitis, even urgently performed <24 hours from presentation, was associated with reduced mortality. A randomized trial evaluating the impact of urgent ERCP on outcomes is needed.

Microbiology and clinical characteristics of acute cholangitis with their impact on mortality; a retrospective cross sectional study.

OBJECTIVE: To evaluate microbiological and clinical characteristics of acute cholangitis along with their impact on mortality, and to compare the role of early versus late biliary drainage in the management of cholangitis. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital Research Centre, Lahore, Pakistan, and comprised records of all patients presenting with acute cholangitis from June, 2012, to June, 2017. The risk factors, presence of bacteremia, resistance pattern of microbial pathogens and severity were assessed according to Tokyo guidelines in addition to associated mortality and recurrence at 3 months. Data was analysed using SPSS 20. RESULTS: Of the 230 patients, 137(59.6%) were male. The overall mean age was 56±13 years. The most common isolated organism was Escherichia coli 54(70.1%). Clinical severity (p=0.001), late biliary drainage (p=0.001) and use of multiple stents (p=0.03) were associated with increased mortality. However, in multivariable analysis, only high body mass index (p=0.01) and Tokyo severity grades II (p=0.04) and III (p=0.001) were significant factors associated with mortality. CONCLUSIONS: Early identification of risk factors, administration of appropriate antibiotics and establishing early biliary drainage were found to be the key management steps to reduce cholangitis-related mortality.

Antimicrobial therapy of 3 days or less is sufficient after successful ERCP for acute cholangitis.

BACKGROUND: Recommendations for the duration of antimicrobial therapy in cholangitis after successful endoscopic biliary drainage vary. The aim of this study was to compare the occurrence of local infectious complications in patients with acute cholangitis treated with antibiotics for 3 days or less compared with 4 days or more. METHODS: We performed a retrospective multicentre study in seven hospitals in the Netherlands. Patients who received a successful biliary drainage by endoscopic retrograde cholangio-pancreatography because of cholangitis due to common bile duct stones between 2012 and 2017 were included. The primary outcome was the occurrence of a local infectious complication within 3 months of endoscopic retrograde cholangio-pancreatography. Secondary outcomes included Clostridioides difficile infection, total length of hospital stay and all-cause mortality. RESULTS: A total of 426 patients with cholangitis were identified and 296 patients met all inclusion criteria. Therapy duration was ≤3 days in 137 patients (46.3%). During follow-up, 41 patients (13.9%) developed a local infectious complication. Occurrence of infectious complications did not differ between the two groups (p = 0.32). No patient developed Clostridioides difficile infection. Median hospital stay was 6 days (interquartile range 4-8 days) in the short antibiotic group compared with 7 days (interquartile range 5-9 days) in the long group (p = 0.03). Four (1.4%) patients died during follow-up, all were treated for ≥4 days (p = 0.13). CONCLUSIONS: Antimicrobial therapy of 3 days or less seems to be sufficient after successful biliary drainage in patients with acute cholangitis. Randomized trials should confirm our findings.

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis.

OBJECTIVES: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value. METHODS: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models. RESULTS: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively. DISCUSSION: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Prognostic Value of Noninvasive Fibrosis Scores in Primary Biliary Cholangitis.

OBJECTIVE: To explore the prognostic value of several widely used noninvasive fibrosis scores (NIFS) for the mortality due to liver-related events in Chinese primary biliary cholangitis (PBC) population. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China, from August 2008 to July 2018. METHODOLOGY: Patients were diagnosed as PBC when they fulfilled at least two of the following criteria: presence of antimitochondrial antibodies (AMA), or other PBC-specific autoantibodies; and/or biochemical evidence of cholestasis; and/or histological evidence of liver biopsy. Patients were excluded if they were just started UDCA administration within last year, followed up for less than a year, diagnosed as overlap syndrome, or suffered from other coexisting hepatic diseases. Clinical data were recorded and scores of 11 generally accepted NIFS were calculated. Cox proportional hazards model was performed to explore independent predictors of liver-related mortality. RESULTS: Sixty-five PBC patients were included in the current cohort. Five patients died due to liver-related events during a median of 35-month follow-up. The 5-year cumulative survival rate was 88.4%. Non-survival patients were characterised with lower platelet count (p=0.049), lower level of albumin (p=0.018), higher fibrosis index (p<0.001) and higher Doha score (p=0.006). Multivariate Cox regression analysis identified fibrosis index (HR 17.449, 95% CI 1.410-215.989, p=0.026) and Doha score (HR 1.782, 95% CI 1.146-2.771, p=0.010) as independent predictors for liver-related mortality of PBC patients. CONCLUSION: Fibrosis index and Doha score could serve as valuable prognostic factors for liver-related mortality in Chinese PBC population.

Timing of Cholecystectomy after Emergent Endoscopic Retrograde Cholangiopancreatography for Cholangitis.

Debate remains regarding the timing of laparoscopic cholecystectomy after emergent endoscopic retrograde cholangiopancreatography (ERCP) for acute cholangitis. We hypothesized that patients undergoing early laparoscopic cholecystectomy would have fewer operative complications and a lower conversion rate. This study is a retrospective review of an ERCP database from 2012 to 2016 of adults with a diagnosis of cholangitis secondary to choledocholithiasis who underwent ERCP followed by a laparoscopic cholecystectomy. Patient demographics, ERCP details, timing of operation (<72 hours vs >72 hours after ERCP), complications, and mortality were recorded. Analysis included chi-square, Fisher's exact, and Wilcoxon rank-sum tests, where appropriate. In the 127 patients (65 per cent male; median age, 67 years; 48 (38%) early surgery), there were no differences in demographics, BMI, vital signs, or laboratory values. Patients in the late surgery group were more likely to have a Charlson Comorbidity Index > 3 (P = 0.002), require pre-operative endoscopic sphincterotomy (P < 0.002), need pre-operative insertion of a ductal stent (P < 0.03), and had more postoperative complications (P = 0.04). Patients in the late laparoscopic cholecystectomy group had more comorbidities and suffered more complications.

[A retrospective analysis of clinical characteristics and mortality risks in elderly patients with acute cholecystitis and cholangitis].

Objective: To analyze the clinical characteristics and explore the risk predictors on mortality in elderly patients with acute cholecystitis and cholangitis. Methods: We conducted a retrospective analysis of elderly patients hospitalized in the Second Medical Center of General Liberation Army Hospital for acute cholecystitis and cholangitis during 2000 to 2018. Clinical data and risk predictors on mortality were assessed. The patients were stratified into three groups based on age:Ⅰ (65-74 years old),Ⅱ (75-84 years old), and Ⅲ (≥85 years old). Logistic regression analysis was used to identify the predictors of mortality. Results: A total of 574 patients were finally enrolled with the mean age 87.6 years including 191 in group Ⅰ, 167 in group Ⅱ, and 216 in group Ⅲ. The main cause of acute cholecystitis and cholangitis was gallstone (76.3%),and the main symptom was abdominal pain (62.9%),followed by chills(62.5%),fever(59.8%),jaundice (47.2%) and septic shock(26.3%). Cholecystitis was the most common diagnosis in groups Ⅰ and Ⅱ,whereas it was cholangitis in group Ⅲ. Percutaneous transhepatic biliary/gallbladder drainage (PTBD/PTGD) and endoscopic retrograde cholangiopancreatography (ERCP) were administrated more frequently in groups Ⅲ. A total of 35 patients (6.1%) died during follow-up. Senior in age (OR=11.1),the Charlson comorbidity index (OR=19.5),cancers (OR=9.6),blood stream infections (OR=7.4),severity of cholecystitis and cholangitis (OR=4.2) were risk factors associated with mortality. Conclusions: Even in the elderly patients with acute cholecystitis and cholangitis,comorbidity is one of the main factors affecting clinical outcomes. Due to the poor performance, this group of population presents more severe disease and undergoes conservative treatment strategies.

Unchanged mortality in patients with acute cholangitis despite an increase in malignant etiologies - a 25-year epidemiological study.

Background and aims: Acute cholangitis (AC) is a rare but serious condition, with an incidence of 7.0 per 10,000 people and mortality rates up to 10%. The aim of this study was to describe changes in obstruction etiology, comorbidities, clinical factors, and mortality among AC patients during a 25-year period. Methods: Using a database of 11,563 consecutive ERCP-procedures performed from 1990-2015 at Odense University Hospital, we identified all AC cases during that period. Clinical and epidemiological data were collected from the database and the Danish Patient Registry. Association with 30-day mortality was investigated using multiple logistic regression analysis with adjustment for confounding factors. Results: In total, 775 consecutive and individual cases of AC were included. Among cases, 42% (n = 326) were of malignant etiology, with an increasing incidence over time (regression coefficient [95% CI]: 0.03 [0.01-0.04] per year; p = .01). Mean Charlson Comorbidity Index was 1.4, with an increase over time (regression coefficient [95% CI]: 0.04 [0.03-0.05] per year; p < .01). Malignant obstruction etiology was associated with 30-day mortality (OR [95% CI]: 1.11 [1.04-1.18]; p < .01). Overall 30-day mortality was 12% (n = 91). After adjustment for confounding factors, no significant changes in 30-day mortality were observed over time (OR [95% CI]: 1 [1-1.00]; p = .91 per year). Conclusion: Significant increases in the incidence of malignant obstruction etiology and severity of comorbidities among AC patients were observed during the study period. Despite those findings, 30-day mortality remained unchanged, potentially reflecting a general improvement in the management of AC.

Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis.

BACKGROUND & AIMS: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. METHODS: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). RESULTS: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001). CONCLUSION: The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. LAY SUMMARY: In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.

Risk Factors for the Development of Stent-Associated Cholangitis Following Endoscopic Biliary Stent Placement.

BACKGROUND AND AIM: To elucidate the overall risk and risk factors for developing cholangitis following biliary stent placement by endoscopic retrograde cholangiopancreatography (ERCP) and to determine the clinical outcomes of these individuals. METHODS: We performed a retrospective review of 796 patients who had undergone 1127 ERCPs with biliary stent placement between 2007 and 2015 at a single tertiary care center. There were 91 episodes of stent-associated cholangitis (SAC) during the study period. Data obtained through the medical records included ERCP indication, patient factors (biliary anatomy, demographics, and comorbidities), stent characteristics (material, length, and design), change in serum bilirubin, stent indwelling time, rates and etiologies of bacteremia, and the mortality rate. RESULTS: Those with SAC were more likely to have an anatomic biliary stricture (13.1% vs. 2.3%, p < .0001), with hilar and multiple strictures having the highest risk (19.1% vs. 11.6%, p = .04). The ERCP indication of malignant biliary obstruction was associated with higher rates of SAC (15.6% vs. 3.4%, p = < .0001). Rates of SAC were higher in those who failed to normalize total bilirubin (16.9% vs. 7.8%, p = .0005), and these episodes occurred earlier compared to those who normalized total bilirubin (median 30.5 days vs. 140.5 days, p < .0001). CONCLUSIONS: Patients at increased risk of SAC include those with an anatomic stricture, malignant biliary obstruction, and those who fail to normalize total bilirubin after biliary stent placement. Future protocols should be designed to reduce the risk of cholangitis in these populations.

Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.

Upper gastrointestinal hemorrhage is associated with poor outcomes among patients with acute cholangitis: a nationwide analysis.

OBJECTIVE: Acute cholangitis (AC) and upper gastrointestinal hemorrhage (UGIH) are common emergencies encountered by gastroenterologists. We aimed to evaluate the impact of UGIH on in-hospital mortality, morbidity and resource utilization among patients with AC. PATIENTS AND METHODS: Adult admissions with a principal diagnosis of AC were selected from the National Inpatient Sample 2010-2014. The exposure of interest was significant UGIH (requiring red blood cell transfusion). The primary outcome was in-hospital mortality. Secondary outcomes were significant UGIH's incidence, morbidity (shock, prolonged mechanical ventilation and total parenteral nutrition), and resource utilization (length of hospital stay and total hospitalization charges and costs). Confounders were adjusted for using propensity matching and multivariate regression analysis. RESULTS: A total of 50 375 admissions were included in the analysis, 747 of whom developed significant UGIH. After adjusting for confounders, the adjusted odds ratio (aOR) of in-hospital mortality for patients who developed UGIH was 7.1 (95% confidence interval: 2.1-23.9, P<0.01) compared with those who did not. Significant UGIH was associated with substantial increase in morbidity [shock: aOR: 4.1 (2.1-9.3), P<0.01, prolonged mechanical ventilation: aOR: 5.8 (2.2-12.4), P<0.01, total parenteral nutrition: aOR: 4.7 (1.9-10.7), P<0.01], and resource utilization [mean adjusted difference in: length of hospital stay: 7.01 (4.72-9.29), P<0.01 and total hospitalization charges: $81 818 ($58 109-$105 527), P<0.01 and costs: $25 230 ($17 805-$32 653), P<0.01]. Similar results were obtained using multivariate regression analysis. CONCLUSION: Onset of significant UGIH among patients hospitalized with AC has a detrimental effect on in-hospital mortality, morbidity and resource utilization.

Effects of Age and Sex of Response to Ursodeoxycholic Acid and Transplant-free Survival in Patients With Primary Biliary Cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) predominantly affects middle-aged women; there are few data on disease phenotypes and outcomes of PBC in men and younger patients. We investigated whether differences in sex and/or age at the start of ursodeoxycholic acid (UDCA) treatment are associated with response to therapy, based on biochemical markers, or differences in transplant-free survival. METHODS: We performed a longitudinal retrospective study of 4355 adults in the Global PBC Study cohort, collected from 17 centers across Europe and North America. Patients received a diagnosis of PBC from 1961 through 2014. We evaluated the effects of sex and age on response to UDCA treatment (based on GLOBE score) and transplant-free survival using logistic regression and Cox regression analyses, respectively. RESULTS: Male patients were older at the start of treatment (58.3±12.1 years vs 54.3±11.6 years for women; P<.0001) and had higher levels of bilirubin and lower circulating platelet counts (P<.0001). Younger patients (45 years or younger) had increased serum levels of transaminases than older patients (older than 45 years). Patients older than 45 years at time of treatment initiation had increased odds of a biochemical response to UDCA therapy, based on GLOBE score, compared to younger patients. The greatest odds of response to UDCA were observed in patients older than 65 years (odds ratio compared to younger patients 45 years or younger, 5.48; 95% CI, 3.92-7.67; P<.0001). Risk of liver transplant or death (compared to a general population matched for age, sex, and birth year) decreased significantly with advancing age: hazard ratio for patients 35 years or younger, 14.59 (95% CI, 9.66-22.02) vs hazard ratio for patients older than 65 years, 1.39 (95% CI, 1.23-1.57) (P<.0001). On multivariable analysis, sex was not independently associated with response or transplant-free survival. CONCLUSION: In longitudinal analysis of 4355 adults in the Global PBC Study, we associated patient age, but not sex, with response to UDCA treatment and transplant-free survival. Younger age at time of treatment initiation is associated with increased risk of treatment failure, liver transplant, and death.

Biliary Atresia-associated Cholangitis: The Central Role and Effective Management of Bile Lakes.

OBJECTIVES: Cholangitis and bile lakes are incompletely understood complications after portoenterostomy (PE). We investigated relationships between recurrent cholangitis, bile lakes, and clinical outcomes as well as surgical management of bile lakes. METHODS: In this retrospective observational single institution study medical records and imaging studies of all patients who had undergone PE for biliary atresia during 1987 to 2016 (N = 61) were reviewed. We related occurrence of cholangitis episodes with the presence of intrahepatic bile lakes, patient characteristics, and PE outcomes. Risk factors for recurrent cholangitis and bile lakes, and management of bile lakes were analyzed. RESULTS: Despite routine antibiotic prophylaxis median of 3.0 cholangitis episodes (0.75 episodes/year) occurred in 48 (79%) patients. Intrahepatic bile lakes were discovered in 8 (13%) patients by 16 months after PE. Overall, 54% had survived with their native liver at median age of 7.3 years and 28 (46%) patients had ≥1 cholangitis episodes/year. Number and frequency of cholangitis episodes were >5 times higher among patients with bile lakes (P < 0.001). Six patients underwent Roux-en-Y bile lake-jejunostomy, resulting in regression/disappearance of bile lakes and normalization of serum bilirubin in 5 with reduction of median yearly cholangitis rate from 8.8 to 1.1 (P = 0.028) and native liver survival of 6.3 (range, 1.3-17) years after the operation. CONCLUSIONS: Bile lakes are a significant risk factor for recurrent cholangitis after PE and efficiently treated by operative intestinal drainage providing prolonged jaundice-free native liver survival. Bile lakes should be actively screened among patients presenting with recurrent cholangitis after PE.

[Timing of endoscopic retrograde cholangiopancreatography in patients with acute cholangitis].

The optimal timing for endoscopic retrograde cholangiopancreatography (ERCP) in patients with acute cholangitis (AC) remains unclear. The aim of this review is to clarify associations between timing of ERCP and clinical outcomes in patients with AC by discussing the current literature. Briefly, it is shown that ERCP before 72 and 48 hours of hospital admission is associated with reduced incidences of composite adverse outcomes and organ failure, respectively. ERCP before 24 hours seems to be associated with reduced 30-day mortality. Thus, performance of ERCP with biliary decompression within 24 hours from time of hospital admission is recommended in patients with AC.