Inflammation patterns in early post-operative cholangitis predict long-term outcomes in biliary atresia: a potential role of non-suppurative cholangitis.

PURPOSE: Frequent post-operative cholangitis in biliary atresia (BA) affects the long-term native liver survival. This study assessed the characteristics of early cholangitis and their influence on the prognosis. METHODS: Forty-three patients with BA who underwent surgery between 2000 and 2020 were analyzed for routine inflammatory markers. Early cholangitis characteristics were compared between native liver survivor (NLS) and living donor liver transplant (LDLT) patients. RESULTS: Among the 43 patients, 30 (69.8%) experienced 130 episodes of cholangitis. In the area under the receiver operating characteristics curve (AUROC) analysis, the cutoff value of the total cholangitis episodes was 3, with an area under the AUROC curve of 0.695 (95% confidence interval 0.522-0.868). Before 3 years old, 113 episodes (86.9%) of cholangitis were observed. The white blood cell, C-reactive protein, and alanine aminotransferase values at cholangitis onset did not markedly differ between the LDLT and NLS groups. Conversely, the neutrophil-to-lymphocyte ratio in the NLS group was significantly lower than in the LDLT group (0.85 vs. 1.63, p < 0.001). CONCLUSIONS: Cholangitis in the NLS group was lymphocyte-dominant and atypical in its pathogenesis. Lymphocyte-dominant cholangitis is non-suppurative, and future research should clarify its pathogenesis to improve the treatment and prognosis of BA.

Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA.

Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of polyinosinic-polycytidylic acid (poly I:C) for 24 weeks developed overt cholangitis with positive serum anti-mitochondria-M2 antibody, whereas male mice showed minimal pathological changes without induction in autoantibody. Poly I:C induced hepatic inflammatory cytokines and type-I interferons predominantly in females. Hepatic expression levels of toll-like receptor (TLR) 3 and melanoma differentiation-associated protein (MDA) 5 were equivalent in both genders; however, both mRNA and protein levels of retinoic acid-inducible gene (RIG)-I were nearly doubled in female livers. Following 4-week injections of poly I:C, not only hepatic RIG-I, but also TLR3 and MDA5 showed female-predominance. Moreover, hepatic RIG-I levels were 25% lower in ovariectomized mice, whereas supplementation of 17 ß-estradiol enhanced hepatic RIG-I expression, as well as cytokine induction. These results clearly indicate that hepatic RIG-I expression is potentiated by estrogen, and triggers gender-dependent hepatic innate immune response against double-stranded RNA, which most likely play a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.

Effects of Pristine C60 Fullerenes on Liver and Pancreas in α-Naphthylisothiocyanate-Induced Cholangitis.

BACKGROUND: A significant role in pathogenesis of cholangitis is attributed to excessive reactive oxygen species production and oxidative stress. Therefore, antioxidants could be promising therapeutics. AIMS: The effects of powerful free radical scavenger C60 fullerene on hepatic and pancreatic manifestations of acute and chronic cholangitis in rats were aimed to be discovered. METHODS: Acute (AC, 3 days) and chronic (CC, 28 days) cholangitis models were simulated by single (AC) and 4 weekly (CC) α-naphthylisothiocyanate per os administrations. Pristine C60 fullerene aqueous colloid solution (C60FAS, 0.15 mg/ml, size of aggregates 1.2-100 nm) was administered either per os or intraperitoneally at a dose of 0.5 mg/kg C60 fullerene daily (AC) and every other day (CC). Prednisolone was used as a reference. Liver and pancreas autopsies were analyzed, and blood serum biochemical markers were measured. Pan-cytokeratin expression in HepG2 cells was assessed after 48-h incubation with C60FAS. RESULTS: On AC, C60FAS normalized elevated bilirubin, alkaline phosphatase, and triglycerides, diminished fibrotic alterations in liver, and improved pancreas state when applied by both ways. Additionally, C60FAS per os significantly reduced the signs of inflammation in liver and pancreas. On CC, C60FAS also mitigated liver fibrosis and inflammation, improved pancreas state, and normalized alkaline phosphatase and triglycerides. The remedy effect of C60FAS was more expressed compared to that of prednisolone on both models. Furthermore, C60FAS inhibited pan-cytokeratin expression in HepG2 cells in a dose-dependent manner. CONCLUSION: Pristine C60 fullerene inhibits liver inflammation and fibrogenesis and partially improved liver and pancreas state under acute and chronic cholangitis.

Pembrolizumab-induced autoimmune haemolytic anaemia and cholangitis.

Increasing numbers of patients are now offered immunotherapy as part of their cancer treatment. These treatments, while often very effective, have a wide range of adverse effects that are distinct from those of traditional chemotherapy regimens. Thyroid disease, dermatological disease, colitis and pneumonitis are some of the most commonly reported immune side effects. We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab. An 81-year-old woman with metastatic melanoma completed a two-year course of pembrolizumab in August 2018 and six weeks later presented to hospital with jaundice. Admission haemoglobin (Hb) was 91 g/L, rapidly decreasing to 31 g/L, at which point she required admission to the intensive care unit. AIHA is a rare but potentially life-threatening complication of checkpoint inhibitors and should be considered in patients presenting with anaemia during or after immunotherapy treatment.

A Simple Method for Measuring Adenosine Triphosphate in Acute Cholangitis Patients to Determine the Need for Emergency Biliary Drainage.

Objective Acute cholangitis is occasionally life-threatening and requires immediate treatment. For the management of acute cases, globally accepted diagnostic criteria and the use of severity grading, as defined in the Tokyo Guidelines 2018 (TG18), are recommended. This study was performed to explore the association between acute cholangitis and the level of adenosine 5'-triphosphate (ATP) in blood as determined with a simple measurement method. Methods Twenty-three consecutive patients admitted for acute cholangitis and 14 healthy individuals were enrolled. Based on the TG18, the patients were categorized according to the degree of severity as Grade I, II, or III. We measured the amount of ATP in blood samples using a bioluminescence meter and evaluated the correlation with the degree of severity. Results The ATP/total hemoglobin (tHgb) level showed a significant decline in association with an increase in severity, as that in the healthy controls was 236.60 ± 8.10 and in the Grade I, II, and III groups was 238.56 ± 6.98, 186.88 ± 7.62, and 154.60 ± 11.01, respectively (p<0.01). While no significant difference was observed between the healthy controls and Grade I patients (p=0.649), there was a statistically significant difference between Grade I and Grade II (p<0.01) in the ATP/tHgb level. According to a receiver operating characteristic analysis, the area under the curve for ATP/tHgb, used as an index for predicting the need for emergency biliary drainage (Grade II, III cases), was the highest among various examined factors. Conclusion The present novel measurement method was found to be simple to perform and useful for detecting acute cholangitis patients with a low ATP level who may require emergency biliary drainage.

Endoscopic Retrograde Cholangio-Pancreatography-Obtained Bile Culture Can Guide Antibiotic Therapy in Acute Cholangitis.

BACKGROUND: Only a small proportion of patients with biliary tree infection grow microorganisms in blood cultures. Antibiotics chosen or tailored based on organisms identified on blood cultures have a potential for under-treatment and unfavorable outcomes, including recurrent infection and early stent occlusion. In our current practice, we collect bile for culture if an Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is performed in patients with suspected cholangitis. In this study, we compare the microbial yield of blood cultures and ERCP-obtained bile cultures in patients with ascending cholangitis. METHODS: We reviewed medical records of all the patients treated for ascending cholangitis who had blood cultures and ERCP-obtained bile cultures at a tertiary care center between 2010 and 2016. Bile was collected for culture before injecting contrast, via a catheter after discarding the initial 3 mL. RESULTS: Ninety-three patients were included with mean age of 71 (±15) years. Out of 93 patients, 11 (12%) had prior sphincterotomy, 29 (31%) had an indwelling biliary stent, and malignant obstruction was the most common etiology (34%). ERCP-obtained bile cultures were positive in 90 out of 93 (97%) patients with monomicrobial growth in 34 out of 93 (39%) patients. Mixed intestinal flora was noted in 3 patients. Blood cultures were positive in only 30 out of 93 patients (32%) and 24 out of 93 (26%) patients had monomicrobial growth. Totally 26 out of 30 patients (87%) grew the same organism as the bile culture, 3 grew an organism different from bile cultures, and one had no growth in the bile culture. On multivariable analysis, the presence of an indwelling biliary stent was the lone factor associated with polymicrobial growth, 83 vs. 52%, p = 0.007. CONCLUSION: ERCP-obtained bile cultures are a reliable and feasible mechanism to evaluate patients with suspected biliary tree infection. This technique has a significantly higher yield when compared to blood culture. Selection and tailoring of antibiotics based on bile culture in the management of ascending cholangitis are advised.

IgG4-related disease coexisting with autoimmune haemolytic anaemia.

An 85-year-old man presented with a pale appearance and generalised pruritic papules. Laboratory investigations disclosed eosinophilia, autoimmune haemolytic anaemia, mixed hyperbilirubinaemia, cholestasis and elevated serum IgG4 levels. Abdominal sonography and CT showed progressive dilatation of biliary trees, with diffuse pancreatic enlargement and a subtle capsule-like low-density rim around the pancreatic head and body. Endoscopic retrograde cholangiopancreatography found no stone-related biliary obstruction, while endoscopic transpapillary biopsy demonstrated chronic inflammation only. Nevertheless, the diagnosis of IgG4-related disease with coexisting autoimmune haemolytic anaemia was presumed. The clinical picture and laboratory abnormalities improved after administration of moderate dose of methylprednisolone.

Red blood cell distribution width to platelet ratio levels in assessment of histologic severity in patients with primary biliary cholangitis.

We aimed to investigate the relationship between the histologic severity and red blood cell distribution width to platelet ratio (RPR) in patients with primary biliary cholangitis (PBC). One hundred and seven consecutive patients with liver biopsy-proven and as yet treatment-naïve PBC were enrolled as the primary and validation cohort. The histologic stages were divided into early stage (Scheuer's stage 1 & 2) and late stage (Scheuer's stage 3 & 4). The overall patient demographics, clinical manifestations, hematological tests and biochemical profile were retrospectively collected from our database. Both groups were compared in terms of RPR, aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and AST/ALT ratio (AAR). Of the 77 patients in the primary cohort, a total of 24 (31.2%) had early stage PBC, whereas 53 (68.8%) represented late stage. Patients with late stage PBC showed significantly higher red blood cell distribution width (15.5 vs. 14.1%, p = .016), RPR (0.15 vs. 0.09, p < .001), direct bilirubin (32.4 vs. 12.9 µmol/L, p = .041), FIB-4 (3.41 vs. 6.34, p = .001) and significantly lower platelet (132.8 vs. 185.8 × 109/L, p = .002). The area under the curve, cut-off value, sensitivity, specificity, positive predictive value, negative predictive value for determining late stage were 0.74, 0.14, 49.1%, 95.8%, 96.3% and 46.0%, respectively. Additionally, high RPR may also serve as a prognostic indicator for 18-month mortality. In conclusion, RPR can be used as a non-invasive and effective predictor of histologic severity in patients with PBC.

Platelet count to spleen thickness ratio is related to histologic severity of primary biliary cholangitis.

The aim of this study was to evaluate the ability of noninvasive markers to identify the histological severity of primary biliary cholangitis (PBC).Fifty-eight treatment-naïve PBC patients who had undergone liver biopsy were enrolled in our study. The patients' histological stages were based on the classifications of Ludwig and Scheuer. Aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), red blood cell distribution width to platelet ratio (RPR), and platelet count to spleen thickness (PC/ST) ratio were calculated. Using the area under the receiver operating characteristic curve (AUROC) to evaluate the accuracy of different markers for predicting the histological severity.Among the 58 treatment-naïve PBC patients, the patients of Scheuer stage I/II/III/IV were 17/25/11/5, respectively. PC/ST ratio (AUROC = 0.807) was superior to RPR (AUROC = 0.717), APRI (AUROC = 0.726), FIB-4 (AUROC = 0.722), and mean platelet volume (MPV) (AUROC = 0.671) in discriminating between stage I and stage ≥II. The AUROC of PC/ST ratio, RPR, APRI, FIB-4, and MPV were 0.939, 0.872, 0.816, 0.831 and 0.572, respectively, for Scheuer stage ≥III; 0.968, 0.795, 0.744, and 0.723, respectively for stage IV. The sensitivity and specificity of PC/ST ratio were 73.4%,79.1%; 81%,100%;88.7%,100% for detection of Scheuer stage ≥ II, Scheuer stage ≥ III and Scheuer stage IV, respectively.Our study findings indicated that compared with previous noninvasive test PRP, APRI, FIB-4 and MPV, PC/ST ratio shows the most accurate for distinguish the histologic severity of PBC patients.

Primary biliary cholangitis is more severe in previous hepatitis B virus infection patients.

OBJECTIVES: The aim of this study was to evaluate the association between previous hepatitis B virus (HBV) infection and the severity of primary biliary cholangitis (PBC). PATIENTS AND METHODS: A total of 379 HBsAg-negative PBC patients were investigated between 2012 and 2017 in this study. Fifty-two of these patients underwent liver biopsy. The enrolled patients were divided into an anti-HBc-positive group and an anti-HBc-negative group; the patients with liver biopsy were further divided into early stage (stage I) and advanced stage (stages II, III, and IV) according to histological assessment. Liver fibrosis was also assessed by noninvasive prognosis scores including the Mayo Risk Score, the Newcastle model, the aspartate aminotransferase-to-platelet ratio index, the fibrosis index based on the four factors (FIB-4), and the albumin-bilirubin score. The difference in disease stage between the two groups was assessed by histological stage and noninvasive scores predicting fibrosis. RESULTS: The histology showed that more patients in the anti-HBc-positive group had advanced stage compared with anti-HBc-negative patients (P<0.05). Higher Mayo Risk Score, the Newcastle model, aminotransferase-to-platelet ratio index, and fibrosis index based on the four factors (all P<0.05) were obtained in all patients except for the albumin-bilirubin score (P=0.096). CONCLUSION: Previous HBV infection was associated with a worse histological stage and advanced fibrosis score of PBC. It appears that the previous HBV infection may have aggravated the PBC severity, potentially leading to poorer outcomes.

Performance of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

AIM: To investigate the performance of transient elastography (TE) for diagnosis of fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome. METHODS: A total of 70 patients with biopsy-proven AIH-PBC overlap syndrome were included. Spearman correlation test was used to analyze the correlation of liver stiffness measurement (LSM) and fibrosis stage. Independent samples Student's t-test or one-way analysis of variance was used to compare quantitative variables. Receiver operating characteristics (ROC) curve was used to calculate the optimal cut-off values of LSM for predicting individual fibrosis stages. A comparison on the diagnostic accuracy for severe fibrosis was made between LSM and other serological scores. RESULTS: Patients with AIH-PBC overlap syndrome had higher median LSM than healthy controls (11.3 ± 6.4 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM was significantly correlated with fibrosis stage (r = 0.756, P < 0.01). LSM values increased gradually with an increased fibrosis stage. The areas under the ROC curves of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.837 (95%CI: 0.729-0.914), 0.910 (0.817-0.965), and 0.966 (0.893-0.995), respectively. The optimal cut-off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.55, 10.50, and 14.45 kPa, respectively. LSM was significantly superior to fibrosis-4, glutaglumyl-transferase/platelet ratio, and aspartate aminotransferase-to-platelet ratio index scores in detecting severe fibrosis (F ≥ 3) (0.910 vs 0.715, P < 0.01; 0.910 vs 0.649, P < 0.01; 0.910 vs 0.616, P < 0.01, respectively). CONCLUSION: TE can accurately detect hepatic fibrosis as a non-invasive method in patients with AIH-PBC overlap syndrome.

Predictive factors of late cholangitis in patients undergoing pancreaticoduodenectomy.

BACKGROUND: Because the survival rate for patients experiencing late complications after pancreaticoduodenectomy (PD) is increasing, late complications should receive as much attention as early complications do. METHODS: Between April 2007 and August 2016, 133 patients underwent PD at our institution. We analyzed their cases to determine the predictors of late cholangitis after PD. RESULTS: Of the 133 patients, 28 (21.1%) were diagnosed with postoperative cholangitis. A multivariate analysis showed that abnormal postoperative values of alkaline phosphatase were independently associated with postoperative cholangitis (odds ratio, 3.81; 95% confidence interval, 1.519-9.553; P = 0.004). The optimal cut-off value for postoperative alkaline phosphatase calculated from the receiver operating characteristic curve was 410 IU/L (sensitivity, 76.2%; specificity, 67.9%; area under the curve, 0.73). A univariate analysis to identify risk factors showed that pneumobilia was significantly related to a postoperative alkaline phosphatase value ≥ 410 IU/L (P = 0.041). CONCLUSION: This study suggests that an alkaline phosphatase level ≥ 410 IU/L is a predictor of late postoperative cholangitis. In addition, pneumobilia is also related to the postoperative alkaline phosphatase level. Therefore, alkaline phosphatase levels should be carefully monitored in patients with postoperative pneumobilia in the late postoperative course.

Autoimmune Hepatitis Overlap Syndromes and Liver Pathology.

Autoimmune hepatitis (AIH) may have an atypical serum alkaline phosphatase elevation, antimitochondrial antibodies, histologic features of bile duct injury/loss, or cholangiographic findings of focal biliary strictures and dilations. These manifestations characterize the overlap syndromes. Patients can be classified as having AIH with features of primary biliary cholangitis, primary sclerosing cholangitis, or a cholestatic syndrome. The gold standard of diagnosis is clinical judgment. Histologic evaluation is a major diagnostic component. Treatment is based on algorithms; outcomes vary depending on the predominant disease component. Combination therapy has been the principal recommendation.

Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study.

AIM: To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics. METHODS: Nine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC. RESULTS: In total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation. CONCLUSION: AMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.

Carcinoembryonic Antigen Level in Primary Sclerosing Cholangitis Is Not Influenced by Dominant Strictures or Bacterial Cholangitis.

BACKGROUND: Carcinoembryonic antigen (CEA) can be used to screen for biliary tract cancer in patients with primary sclerosing cholangitis (PSC). AIM: To study the influence of benign dominant strictures (DS), superimposed bacterial cholangitis (SBC), smoking status, and inflammatory bowel disease on CEA serum levels. METHODS: A retrospective analysis of CEA values in cancer-free PSC patients was performed. We included the maximal CEA value obtained during follow-up and information on the presence of DS and SBC at that time, and we analyzed the CEA values in the presence and absence of DS and SBC. Results are reported as medians with the interquartile range (IQR). RESULTS: The median maximal CEA level, which was 1.8 ng/mL (IQR 1.2-2.9) in the final 270 PSC patients included in the study, was not influenced by the presence of either DS or SBC (P = 0.320). Moreover, in 49 patients, the first CEA value available at the time of DS (1.5 ng/mL; IQR 1.2-2.1) and that at a time without DS (1.6 ng/mL; IQR 1.1-2.3) did not differ significantly (P = 0.397). Lastly, in 24 patients, the median CEA values at a time without SBC (1.8 ng/mL; IQR 1.2-2.5) and at the time of SBC (1.8 ng/mL; IQR 1.0-3.0) were comparable (P = 0.305). Smoking did not influence CEA-based cancer screening. CONCLUSIONS: Serum CEA level is not influenced by the presence of DS or SBC and might therefore serve as a favorable parameter for improving cancer screening in PSC patients.

MiR-139-5p is associated with inflammatory regulation through c-FOS suppression, and contributes to the progression of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized pathologically by destruction of intrahepatic bile ducts. PBC is largely classified into three subtypes based on clinical course: (i) gradually progressive, (ii) portal hypertension, and (iii) hepatic failure. Previous studies have indicated that serum levels of the pro-inflammatory cytokine TNF-α, is elevated in PBC patients with fibrosis. Although the severity of cholangitis might also be related to the PBC subtype, its etiology has been unclear. Several studies have shown that microRNAs (miRNAs) demonstrate specific expression patterns in various diseases. In the present study, we evaluated miRNA expression patterns among the PBC subtypes using comprehensive deep sequencing. We also carried out histologic examination by laser capture microdissection and investigated how the identified miRNAs were involved in PBC clinical progression using the miRNA transfection method. On average, ~11 million 32-mer short RNA reads per sample were obtained, and we found that the expression levels of 97 miRNAs differed significantly among the four groups. Heat mapping demonstrated that the miRNA profiles from hepatic failure and portal hypertension type were clustered differently from those of the gradually progressive type and controls. Furthermore, we focused on miR-139-5p, which has an adequate number of total short reads. Quantitative reverse transcription PCR showed that miR-139-5p was significantly downregulated in clinically advanced PBC. Also, examination of liver tissues demonstrated that the expression of lymphocyte-derived miR-139-5p was significantly higher in hepatocytes. In vitro, the level of TNF-α was significantly elevated in supernatant of cells with upregulation of miR-139-5p. Furthermore, c-FOS gene transcription was repressed. Thus, we have demonstrated a novel inflammation-regulatory mechanism involving TNF-α and c-FOS transcription through miR-139-5p in the NF-κB signaling pathway. We conclude that the specific miRNA miR-139-5p might be involved in the pathogenesis of PBC, especially during clinical progression.

Association of Admission Laboratory Values and the Timing of Endoscopic Retrograde Cholangiopancreatography With Clinical Outcomes in Acute Cholangitis.

Importance: Acute cholangitis (AC), particularly severe AC, has historically required urgent endoscopic decompression, although the timing of decompression is controversial. We previously identified 2 admission risk factors for adverse outcomes in AC: total bilirubin level greater than 10 mg/dL and white blood cell count greater than 20 000 cells/µL. Objectives: To validate previously identified prognostic factors in AC, evaluate the effect of timing of endoscopic retrograde cholangiopancreatography on clinical outcomes, and compare recent experience with AC vs an historical cohort. Design, Setting, and Participants: A retrospective analysis (2008-2015) of patients with AC (validation cohort, n = 196) was conducted at 2 academic medical centers to validate predictors of adverse outcome. Timing of endoscopic retrograde cholangiopancreatography and outcome were stratified by severity using the Tokyo Guidelines for acute cholangitis diagnosis. Outcomes for the validation cohort were compared with the derivation cohort (1995-2005; n = 114). Data analysis was conducted from July 1, 2015, to September 9, 2015. Main Outcomes and Measures: Death and a composite outcome of death or organ failure. Results: The median age of patients in the derivation cohort was 54 years (interquartile range, 40-65 years) and in the validation cohort was 59 years (45-67 years). Multivariate logistic regression analysis of the validation cohort confirmed white blood cell count of more than 20 000 cells/µL (odds ratio, 3.4; 95% CI, 1.2-9.5; P = .02) and total bilirubin level of more than 10 mg/dL (odds ratio, 5.4; 95% CI, 1.8-16.4; P = .003) as independent risk factors for poor outcomes. In the validation cohort, timing of endoscopic retrograde cholangiopancreatography was not significantly different between those with and without an adverse outcome, even when stratified by AC severity (moderate: median, 0.6 hours [interquartile range (IQR), 0.5-0.9] vs 1.7 hours [IQR, 0.7-18.0] and severe: median, 10.6 hours [IQR, 1.2-35.1] vs 25.5 hours [IQR, 15.5-58.5] for those with and without adverse events, respectively). Patients in the validation cohort had a shorter hospital length of stay (median, 7 days [IQR, 4-10 days] vs 9 days [IQR, 5-16 days]) and lower rate of intensive care unit admission (26% vs 82%), despite a higher rate of severe cholangitis (n = 131 [67%] vs n = 29 [25%]). There were no significant differences in the composite outcome between the validation and derivation cohorts (22 [18.6%] vs 44 [22.4%]; P = .47). Adjusted analysis demonstrated decreased mortality in the validation cohort (odds ratio, 0.3; 95% CI, 0.1-0.7; P = .01). Conclusions and Relevance: White blood cell count greater than 20 000 cells/µL and total bilirubin level greater than 10 mg/dL are independent prognostic factors for adverse outcomes in AC. Consideration should be given to include these criteria in the Tokyo Guidelines severity assessment. Timing of endoscopic retrograde cholangiopancreatography does not appear to affect clinical outcomes in these patients. Management of AC has improved with time, with an overall shorter hospital length of stay, lower rate of intensive care unit admission, and a decreased adjusted mortality, demonstrating improvements in care efficiency and delivery.

[Serum and bile cytokines dynamics in patients with non-tumoral obstructive jaundice and suppurative cholangitis]. / Dinamika tsitokinov v syvorotke krovi i zhelchi u patsientov s mekhanicheskoi zheltukhoi i gnoinym kholangitom neopukholevogo geneza.

AIM: To study serum and bile cytokines dynamics in patients with non-tumoral obstructive jaundice and suppurative cholangitis. MATERIAL AND METHODS: Comparative study of serum and bile cytokines in 49 operated patients with biliary pathology was performed. Patients were divided into 3 groups. The first group included 24 patients with acute calculous cholecystitis (ACCh), the second group consisted of 12 patients with chronic calculous cholecystitis (CCCh) and the third group included 13 patients with choledocholithiasis complicated by obstructive jaundice and suppurative cholangitis. RESULTS AND DISCUSSION: All patients had increased level of TNF-α, IL-4 и IL-6. There was augmentation of biliary cytokines in patients with obstructive jaundice compared with those with acute and chronic calculous cholecystitis. In patients with obstructive jaundice and suppurative cholangitis the highest levels of cytokines were observed. Patients with obstructive jaundice (OJ), suppurative cholangitis (SCh) and chronic calculous cholecystitis had higher levels of cytokines in both blood and bile than in those with OJ, SCh and acute calculous cholecystitis that is explained by development of purulent inflammation on background of previous cytokines imbalance and chronic inflammation. In general, patients with acute calculous cholecystitis had higher levels of TNF-α and IL-6 in blood serum and IL-4 in bile. Patients with chronic calculous cholecystitis had higher concentration of TNF-α and IL-4 in bile and IL-6 - in blood serum. CONCLUSION: Both forms of cholecystitis and their complications are associated with increased cytokines in serum and bile. The level of augmentation depends on the type of inflammation and complications. Comparative study of cytokines can be the most informative criterion to monitor the postoperative period.

A scoring system for the prediction of choledocholithiasis: a prospective cohort study.

BACKGROUND: Techniques for diagnosing choledocholithiasis pose significant morbidity and mortality risks. OBJECTIVES: We aimed to develop and validate a clinical scoring system for predicting choledocholithiasis. DESIGN: Data from a prospectively maintained database of all patients with gallstones. SETTING: Patients were admitted to the general surgery department of a military hospital. PATIENTS AND METHODS: We enrolled consecutive patients with symptomatic gallstones, biliary pancreatitis, obstructive jaundice, or cholangitis, who subsequently underwent biochemical testing and ultrasonography. A predictive model was developed from a scoring system using their imaging and laboratory data. Endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative cholangiography were used for confirmatory diagnoses. The predictive efficacy of the scoring system was validated using a retrospective cohort of 272 patients. MAIN OUTCOME MEASURES: Predictive accuracy of the scoring system. RESULTS: We enrolled 155 patients in the development group. The common bile duct diameter, alkaline phosphatase of >=200 IU, elevated bilirubin levels, alanine transaminase of >=220 IU, and male age of >=50 years were significantly associated with choledocholithiasis and were included in the scoring system. Ninety-six patients (35%) had scores of >=8 (high risk), 86 patients (32%) had scores of 4-7 (intermediate risk), and 27 patients (10%) had scores of 1-3 (low risk). In the validation cohort, the positive predictive value for a score of >=8 was 91.7%, and the scoring system had an area under the curve of 0.896. CONCLUSION: Scores of >=8 were strongly correlated with choledocholithiasis in the developmental and validation groups, which indicates that our scoring system may be useful for predicting the need for therapeutic ERCP. However, prospective validation in a large multicenter cohort is needed to fully understand the benefits of the system. LIMITATIONS: The retrospective validation cohort might have introduced selection and observational biases. The study may have been underpowered because of the sample size of the developmental cohort. The delay between admission and the time of ERCP theoretically may have increased the number of negative ERCP results, but our false negative rate for ERCP was consistent with the previously reported rates.