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Biliary atresia is a rare liver disease of unknown etiology affecting approximately 1 in 10,000 children. This disease initially presents as inflammatory obstruction of bile ducts leading to cholestasis and eventually fibrosis of hepatic tissue. Affected patients are ideally treated early with portoenterostomy (Kasai procedure) as age at surgery is an important prognostic factor for native liver survival and need for liver transplant. This study aimed to evaluate the age at which patients in the United States are receiving this procedure. The American College of Surgeons National Surgical Quality Improvement Program Pediatric database was used to identify patients between 2012 and 2021 who underwent a primary procedure of portoenterostomy. The age at time of surgery and perioperative analysis was performed. The data underwent simple descriptive statistics. Eight hundred twenty four patients were identified who underwent Kasai procedure. Four hundred seventy four (58.2%) were female with the predominant race being White (49.5%). The median age at surgery was 57 d old (interquartile range 41-71). Readmission and reoperation rates within 30 d were 30% and 15.2%, respectively. There were no deaths within 30 d. Within the National Surgical Quality Improvement Program database, the median age of pediatric patients undergoing Kasai procedure for biliary atresia in the United States exceeds the goal of 45 d. Further studies are needed to investigate factors that may affect time to diagnosis and time to Kasai procedure. [ABSTRACT FROM AUTHOR]

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes. We applied unsupervised clustering algorithms to unbiasedly classify the recovered mutants into three classes. Further computational analysis revealed that each of the recovered mutations in these three classes has a unique phenotype on node-subtype composition and distribution within the intrahepatic biliary network. In addition, we found most of the recovered mutations are viable. In those mutant fish, which are already good animal models to study chronic cholestatic liver diseases, the biliary network phenotypes persist into adulthood. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases. [Display omitted] • 24 zebrafish mutants with intrahepatic biliary network defects were identified. • Unsupervised classification algorithms sorted the mutants into subgroups. • Computational analysis revealed the detailed network structures in the mutants. • This work provides computational and biological toolsets for biliary system biology. [ABSTRACT FROM AUTHOR]

Reports of liver transplantation (LT) after Kasai portoenterostomy (KPE) in adult patients with biliary atresia are scarce. The aim of this study was to evaluate the outcomes and investigate the risk factors of LT after KPE in both pediatric and adult patients. We retrospectively reviewed a prospective database of patients with biliary atresia who underwent LT after KPE. Eighty-nine consecutive patients were included, and risk factors for in-hospital mortality after LT were assessed. The median age of the patients was 2 y (range, 0-45 y). Forty-six patients (51.7%) had a history of upper abdominal surgery after KPE. The in-hospital mortality rate was 5.6% (5 patients). Of these, 80% of patients with mortality were aged ≥17 y, and all patients with mortality had a history of two or more upper abdominal surgeries. In the univariate and receiver operating characteristic curve analyses, age ≥17 y and the number of previous upper abdominal surgeries ≥2 were identified as possible risk factors. Our study suggests that older age and multiple previous upper abdominal surgeries are important risk factors for mortality after LT following KPE. We believe that these findings will serve as indications for safe LT in future patients. [ABSTRACT FROM AUTHOR]

In many resource-limited settings, patients with biliary atresia present too late for surgical correction to be offered, and the diagnosis is fatal. As pediatric surgical and anesthesia capabilities have improved, patients in Rwanda have been offered surgical exploration. This study explores initial outcomes. Patients presenting with direct hyperbilirubinemia and clinical suspicion of biliary atresia were identified at the main university teaching hospital in Kigali, Rwanda, from January 2016 to June 2019. Patient demographics, referral history, geographic location, preoperative imaging, preoperative laboratory studies, operative details, postoperative laboratory studies, in-hospital complications, length of stay, and survival were abstracted from retrospective chart review. Descriptive analysis was performed, and univariate analysis evaluated survival and complications. Seventeen patients were identified with biliary atresia, and thirteen were offered surgery. The median age of admission was 77 d (interquartile range [IQR] 63-92 d), with the median time wait for the operation being 19 d (IQR 9-27 d). The median age at operation was 93 d (IQR 76-123 d). In-hospital postoperative mortality was 15.4% (n = 2) and postoperative complications occurred in 46.2% (n = 6). Eleven patients survived to hospital discharge (84.6%), with a median length of stay of 8 d (IQR 6-13 d). While future studies are needed to evaluate the long-term outcomes, this series shows that surgical treatment of biliary atresia can be safely performed in Rwanda. Early referral of direct hyperbilirubinemia is essential, particularly as limited resources and personnel may impact the time from diagnosis to operation. • A preliminary report on the profile and outcome of biliary atresia in Rwanda. • Surgical treatment was found to be safe, with 85% survival to discharge. • Locally driven, quality-improvement initiatives are being made. • When led by local leadership, complex procedures can be safely introduced in low-resource settings. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is an inflammatory pediatric cholangiopathy with only surgical means for treatment. Many contributors to bile acid synthesis and transport have previously been reported to be downregulated in patients with BA; yet, the driving factors of the abnormal bile acid synthesis and transport in regard to BA have not been previously studied. Wild type or Ig-α-/- mice were injected with salt solution (control) or rotavirus on day of life 0, and analyses were performed on day of life 14. The mRNA levels of bile acid transporters/nuclear receptors and liver microRNAs (miRNAs) were compared between groups. A mouse hepatocyte cell line was used to examine the effects of innate cytokines on miRNA levels and bile acid transporter/nuclear receptor expression and miRNAs on bile acid transporter/nuclear receptor expression. BA mice had significantly increased mRNA expression of innate cytokines and miRNAs known to bind bile acid transporters/nuclear receptors (miRNAs -22-5p, -34a-5p, and -222-3p) and decreased mRNA expression of bile acid transporters and nuclear receptors. In vitro , TNF-α and IL-1β decreased BSEP and CYP7A1 while increasing miRNA-34a-5p and miRNA 222-3p. LXR, SHP , CYP7A1 , NTCP , and MRP2 were decreased by miRNA-34a-5p, whereas miRNA-222-3p decreased NTCP and MRP4. TNF-α and IL-1β increased expression of miRNAs 34a-5p and 222-3p and these miRNAs then decrease expression of multiple bile acid transporters and nuclear receptors. Loss of bile acid transporters increases hepatotoxicity via bile acid retention. Therapeutic agents that increase bile acid transport or nuclear receptor functioning should be investigated in BA. [ABSTRACT FROM AUTHOR]

Kasai portoenterostomy (KPE) remains the first-line operation for patients with biliary atresia (BA), but ultimately fails in up to 60% of cases. This study sought to identify factors contributing to hospital readmission and early liver transplant. The Nationwide Readmissions Database from 2010 to 2014 was used to identify patients with BA who underwent KPE on index admission. Patient factors, hospital characteristics, and complications of BA were compared by readmission rates and rate of liver transplant within 1 y. The results were weighted for national estimates. Nine hundred and sixty three patients were identified. The readmission rate within 30-d was 36% (n = 346) and within 1-y was 67% (n = 647). Only 9% (n = 90) received a liver transplant within a year. The most common complications after KPE were cholangitis in 58%, decompensated cirrhosis in 54%, and recurrent jaundice in 34%. Male patients (OR 1.5, P = 0.02) with comorbid gastrointestinal anomalies (OR 2.1, P < 0.01) from lower income households (OR 4.6, P < 0.01) and early development of cirrhosis (OR 3.0, P < 0.01) were more likely to be readmitted. Liver transplant was more common in men (OR 4.0, P < 0.01) and those from lower income households (OR 5.2, P < 0.01) with decompensated cirrhosis (OR 8.6, P < 0.01), cholangitis (OR 5.0, P < 0.01), or sepsis (OR 5.7, P < 0.01) on index admission. This is the first nationwide study to evaluate readmissions in patients with BA undergoing KPE. Although KPE is a lifesaving procedure, hospital readmission rates are high and complications are common. Cholangitis, early progression of cirrhosis, and infections are highly associated with readmission and failure of KPE. [ABSTRACT FROM AUTHOR]

To explore the distribution of biliary ductules in biliary remnants of patients with biliary atresia and to investigate the relationship between the ductules and the prognosis after Kasai portoenterostomy. From October 01, 2015 to September 30, 2017, 46 patients who were diagnosed as type 3 biliary atresia were enrolled in this study. Continuous sections of biliary remnants were stained with cytokerantin 19 antibody. The number, area, and distribution of micro-biliary ductules of each section were recorded. According to the number of ductules in the most proximal section (n ≥ 20 or n < 20), patients were divided into two groups (A or B) and followed up for 1-3 y, including cholangitis, jaundice clearance, and survival with native liver. Four patients had no micro-biliary ductules. In 17 patients with ductules, the numbers at bilateral parts were similar (P > 0.05), while the ductules in the middle part were significantly less than bilateral parts (P < 0.05). Starting from 2 mm from the proximal end of remnants, the number of ductules significantly and gradually decreased (P < 0.05). The total area of ductules in Group A was significantly increased compared to that in Group B (P < 0.05). Patients in Group A had significantly higher jaundice clearance rate and better survival rate with native liver than patients in Group B (both, P < 0.05). Patients had significantly higher incidence of cholangitis in Group A compared to Group B (P < 0.05). The number/area of ductules yielded by technical precision is closely related to effective bile drainage, jaundice clearance, and first onset of cholangitis in patients after Kasai procedure. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a rare obstructive cholangiopathy that presents in early infancy. The Kasai portoenterostomy (PE) improves survival with the native liver. Epidural analgesia is an appealing option to control pain in this fragile patient population, yet its safety, efficacy, and potential benefits remain unproven. Patients undergoing PE for BA between 2001 and 2016 at a single institution were identified by ICD codes. Preoperative laboratories, procedure details, and recovery outcomes were reviewed retrospectively. Outcomes of interest were need for postoperative mechanical ventilation, pain scores, normalized opioid administration, return of bowel function, and length of hospital stay after PE. Of 47 infants undergoing PE for BA, 25 received epidural analgesia, and 22 did not. Infants with epidurals received less systemic opioids over the first 96 h postoperatively than those without (P < 0.001). Epidurals were associated with lower pain scores between 6 and 30 h postoperatively (P = 0.01 to 0.04), during which the highest median 6-h interval pain score was 0.2 (IQR 0-1.3) for patients with epidurals yet 2.1 (IQR 1.2-3.3) for patients without. Patients with epidurals (88%, n = 22) were more commonly extubated before leaving the operating room than those without (59%, n = 13; P = 0.02). No significant difference was observed in time to first bowel movement (P = 0.48) or first oral feed (P = 0.81). However, infants with epidurals had shorter hospital stays after PE than those without (6 d [IQR 5-7] versus 8 d [IQR 6.3-11], P = 0.01). No major complications were associated with epidural catheters. Epidural analgesia in patients undergoing PE for BA appears safe and effectively controls pain while minimizing the need for systemic opioids. Reduced need for mechanical ventilation postoperatively and shortened hospital stays serve as further evidence for using epidurals to enhance recovery after PE. [ABSTRACT FROM AUTHOR]

Open Kasai portoenterostomy (KPE) remains the mainstay of treatment for biliary atresia (BA) even in the era of minimally invasive surgery and is generally considered to be technically challenging. This study describes the learning curve (LC) of open KPE and its effect on outcomes. In our center, the caseload of BA was relatively low with average annual caseload below five in the past, and open KPE was started in the early 2000s. This study retrospectively enrolled the first 35 consecutive children undergoing open KPE for BA by the same surgeon in our center between June 2003 and April 2014. The LC was evaluated using the cumulative sum (CUSUM) method for operative time (OT). The CUSUM LC of OT, which peaked at the 23rd case, was best modeled as a second-order polynomial with equation CUSUM (min) = −0.8851 × case number2 + 33.54 × case number −45.978 (R2 = 0.7287). The LC consisted of two distinct phases: phase 1 (the initial 23 cases), representing the initial learning phase and phase 2 (the remaining 12 cases), representing acquisition of technical competency. Preoperative parameters were comparable between the two phases (each P > 0.05). Of note, OT and estimated blood loss significantly decreased in phase 2 compared with phase 1 (P < 0.001; P < 0.001, respectively). Furthermore, the rates of early jaundice clearance and 2-y native liver survival significantly increased in phase 2 (P = 0.032; P = 0.034, respectively). The two phases identified by CUSUM analysis of OT represents characteristic stages of LC for open KPE of the surgeon in our center. It is possible for surgeons to achieve competency of this demanding technique in centers with relatively low caseload of BA and late start of KPE. [ABSTRACT FROM AUTHOR]

Abstract Background Inflammation-based prognostic scores are associated with tumor recurrence and survival in various cancers. The aim of this study was to identify the significance of inflammation-based prognostic scores and to detect the most useful score in patients with distal extrahepatic bile duct cancer after pancreaticoduodenectomy. Methods Between 2000 and 2015, 121 patients were enrolled in this retrospective study. The relationship between clinicopathological variables including various prognostic scores and disease-free (DFS) as well as overall (OS) survival was investigated by univariate analysis. The area under the receiver operating characteristics curve was calculated to compare the predictive ability of each scoring system. Multivariate analysis was performed to identify the clinicopathological variables associated. Results In univariate analysis, Glasgow prognostic score (GPS), mGPS, C-reactive protein/Alb ratio score, prognostic index, and preoperative monocyte count were significant risk factors for both DFS and OS. The area under the receiver operating characteristics curve of GPS is consistently larger in comparison with other four scores in both DFS as well as OS. In multivariate analysis, GPS was an independent risk factor of both tumor recurrence and poor prognosis. Conclusions GPS score is an independent tumor recurrence and prognostic factor in patients with distal extrahepatic bile duct cancer and is superior to the other prognostic scores. [ABSTRACT FROM AUTHOR]

Highlights • Twenty-five Th17-associated cytokine were tested. • Our result indicated a different Th-17 associated cytokines profile in BA patients. • MIP3a is of potential value in the diagnosis of BA patients. • The results were further validated by in a partnering institution. Abstract Background & aims Biliary atresia (BA) is a neonatal obliterative cholangiopathy with high prevalence in south China. Accurate identification of BA among infants with obstructive jaundice is still difficult by noninvasive diagnostic tools. Th17 cells have been reported closely related with the development of BA, which suggest that Th17-associated cytokines were potential biomarkers for the diagnosis of BA patients. Methods In the training study, 76 infants who were divided into 2 groups, including BA group (n = 31) and non-BA jaundice group (n = 45). Clinical and routine laboratory data were collected from all subjects. Totally 25 Th17-associated cytokines were tested and compared between groups. The diagnostic value of each differential cytokine was evaluated by the area under the receiver operating characteristic curve (AUC). The best potential diagnostic biomarker was further validated in a cohort including 68 jaundice infants from our partnering institution in a blinded fashion. Results Data from the training study showed that gamma-glutamyl transferase (GGT) and clay stool would be helpful in the identification of BA patients in jaundice subjects. Th17-associated cytokines assay indicated that IL-17F, IL-10, macrophage inflammatory protein-3alpha (MIP3a), IL-22, IL-13, IL-33, IL-6, IL-17E, IL-27, IL-31, TNF-a and TNF-b were differentially expressed in BA patients, and the AUC of MIP3a was higher than other markers. MIP3a alone or combined with other laboratory data would significantly increase the diagnostic accuracy of BA. The diagnostic value of MIP3a was further confirmed in our validation study. Conclusion MIP3a alone or combined with other laboratory data would significantly increase the diagnostic accuracy of BA. [ABSTRACT FROM AUTHOR]

Abstract Background Laparoscopic Kasai portoenterostomy (LKPE) is generally regarded to have a poorer outcome for surgical treatment of uncorrectable biliary atresia. We herein described our initial experience of some modifications to make LKPE easier in the treatment of type III biliary atresia (BA). Methods During the period July 2012-October 2016, a total of 25 infants with type III BA were treated with a modified LKPE technique. A percutaneous suture was introduced just below the xiphoid process to snare the round ligament and retract the liver; other percutaneous stay sutures were then introduced to the fundus and neck of the gallbladder to elevate the liver and expose the porta hepatis. In 15 cases, part of the hepatic lobus quadratus was removed laparoscopically to expose the porta hepatis. The two elastic rubber bands were put around the portal vein and hepatic artery, and the porta hepatis was exposed by stretching the two rubber bands laterally to facilitate laparoscopic portoenterostomy. Results Patients were divided into two groups according to their ages at operation: group I: age between 30 and 75 days (n = 18), and group II: age between 76 and 85 days (n = 8). There were no operative deaths, but two patients died of repeated cholangitis and liver failure. Blood loss during operation was minimal and no blood transfusions were required. Operating times varied from 210 to 270 min (mean 232.4 ± 19.0 min). Among the two groups, there were no differences in blood loss (P > 0.05), but there were differences in operating time (P < 0.05). All patients survived the surgery without any intraoperative complications, and the median follow-up time was 25.3 months. Total bilirubin dropped to normal in 18 patients with an additional 5 patients showing a significant overall drop after surgery. Conclusions With the original concepts of Kasai portoenterostomy, perfect laparoscopic skills and some key modifications to expose the porta hepatis, our LKPE can be performed safely and successfully with improved outcome for infants with type III BA. [ABSTRACT FROM AUTHOR]

Abstract Background A 30-40 cm Roux loop is widely accepted in Kasai portoenterostomy in infants with Ohi Type III biliary atresia (BA), regardless of patient's size, to avoid reflux cholangitis. However, the redundant length of the jejunal limb may lead to complications; hence, we compared the outcome of a shorter Roux loop with the standard loop length in Kasai portoenterostomy in infants with Ohi Type III BA. Methods There were 166 patients with Ohi Type III BA who underwent the Kasai procedure and were prospectively randomized into two groups: (1) the long Roux loop group (LRLG) contained 91 patients, where a standard 30-40 cm Roux loop was used regardless of the child's size and (2) the short Roux loop group (SRLG) included 75 patients in which the Roux loop length was based on the distance between hepatic hilum and umbilicus. The follow-up periods were 3 to 50 mo. Contrast-enhanced ultrasonography of the upper gastrointestinal tract was studied, and laboratory tests were included during the follow-up period. Result The mean Roux loop length of SRLG was 17.42 ± 3.91 cm (13-20 cm); it was significantly shorter than that of the LRLG (32.87 ± 3.91 cm [30-40 cm], P = 0.00). There were no significant differences between the LRLG and SRLG in terms of age, body weight at time of the operation, length of operation, blood loss during the operation, and length of postoperative hospital stay (64.50 ± 20.41 d versus 68.34 ± 17.59 d, 4.3 ± 0.8 kg versus 4.1 ± 1.2 kg, 187.6 ± 35.7 min versus 172.3 ± 20.4 min, 21.71 ± 9.41 mL versus 25.32 ± 10.82 mL, 9.01 ± 3.97 d versus 8.16 ± 2.40 d; P = 0.63, 0.47, 0.09, 0.89, and 0.61, respectively). Six months after the operation, the clearance of jaundice rate in the LRLG was 45.1% (41/91), while the rate was 50.7% (38/75) in the SRLG; there was no statistically significant difference (P = 0.47). The incidence of cholangitis in the LRLG was 42.9% (39/91), which was similar to that of the SRLG (46.7%, 35/75) (P = 0.62). The incidence of overall complications (such as intestinal obstruction, gastrointestinal bleeding, bile leak, and anastomotic stenosis) in the SRLG was lower than that of the LRLG, but the difference did not reach statistical significance (4/91, 4.4% versus 5/75, 6.7%; P = 0.76). According to the Kaplan–Meier survival analysis and log rank test, the native liver survival rate in the LRLG and the SRLG also showed no significant difference (P = 0.964, log rank test). Grade I reflux was detected in three patients in the LRLG and two patients in the SRLG (P = 0.54). However, the reflux subsided 6 months later in all five patients. Conclusions A shorter Roux-loop length in Kasai portoenterostomy reconstruction had a similar efficacy as the conventional Roux-loop length. [ABSTRACT FROM AUTHOR]

Highlights • 22 immunomodulatory mediators detectable in liver and sera of biliary atresia infants. • No correlation of inflammatory mediators and Kasai-procedure outcome. • Immunomodulatory mediators are unsuitable predictors for biliary atresia course. Abstract Purpose Biliary atresia (BA) is a rare disease of unknown pathogenesis in infants characterized by an inflammatory, progressive destruction of the biliary system and deterioration of liver function. The standard treatment for BA is a Kasai-hepatoportoenterostomy (KPE). However, liver transplantation (LTX) becomes necessary in about 50–80% of cases. Therefore, some authors advocate for primary LTX in BA, but this would require early markers to predict which children would benefit from KPE or to show rapid progression to liver cirrhosis (RLC) instead. Methods Snap-frozen liver biopsies and sera samples of 57 infants with BA were collected during KPE. Clinical and follow-up data were assessed via the biliary atresia and related diseases registry (BARD-online.com). Protein-levels of 25 pro- and anti-inflammatory mediators of 49 infants were assessed via multiplex protein-immunoassay and analyzed by t -test as well as multidimensional principal component analysis. Results 22 different immunomodulatory mediators were detectable in livers of children with BA, while serum protein levels were very low to undetectable. Following KPE, 33 BA patients showed RLC that required early LTX, while 24 had favorable course of disease with long-term survival with native liver (SNL). There were no significant differences between RLC and SNL in terms of local (from liver samples) nor systemic (from sera) immunomodulatory mediators. Protein levels were much lower in sera than in livers without statistical correlation. Conclusion Our data suggest that local or systemic immunomodulatory mediators are unsuitable for predicting the disease course of BA. Thus, no deduction for optimal treatment strategy can be drawn. Collectively, we conclude that in BA, the degree of inflammation and protein microenvironment in the liver at the time-point of KPE are dismissible factors for the future course of disease. [ABSTRACT FROM AUTHOR]

Purpose To identify genes potentially involved in the pathogenesis of bile duct obstruction in biliary atresia (BA). Methods We used rhesus rotavirus (RRV) Balb/c mouse BA model to study BA. Liver and serum samples were harvested from BA and normal control (NC) groups at 1, 3, 5, 7, 10 and 14 days postinoculation. Serum total bilirubin (STB) and conjugated bilirubin (CB) were measured. Livers of each group at day 7 were used for a genome-wide expression analysis. Expression of TLR7 signaling pathway in liver was measured by immunohistochemical staining and western blotting, including expression of TLR7, activation of phosphorylated IRF7 and secretion of IFN-β, IL-1α and IL-6. Cell viability and survival rate after RRV infection were measured by using TLR7 knockdown human cholangiocarcinoma cell RBE. Results STB was significantly elevated from day 5 postinoculation and CB was from day 7 postinoculation, while CK19 (the biomarker of biliary epithelial cells) expression by western blotting was decreased. By microarray analysis of liver tissues at day 7 postinoculation, TLR7 signaling pathway was up-regulated in BA mice. Based on the results of microarray analysis, the protein expression of TLR7 in the liver tissues of BA groups were found to be up-regulated from day 5 comparing to respective NC groups, although it was increased as pups aged in NC groups. And the level of p-IRF7 and secretion of cytokines were also statistically significant in BA groups. In vitro, TLR7 knockdown cell line showed less cellular proliferation and more susceptible to RRV infection. Conclusion By in vivo study, TLR7 signal pathway was up-regulated in BA group; by additional in vitro study, intact TLR7 signal pathway might have some protective abilities in BA pathogenesis. [ABSTRACT FROM AUTHOR]

Background With the advent of minimally invasive techniques, laparoscopic Ladd's procedure is increasingly used to treat children with malrotation, yet evidence regarding its safety and efficacy is lacking. We hypothesize that operative and postoperative outcomes with the open technique are superior to the laparoscopic Ladd's procedure. Methods We conducted a 5-y retrospective chart review of all patients who underwent Ladd's procedure at our institution from 2010-2015. Exclusion of patients included those with concomitant conditions, such as poor gut perfusion, significant reflux, tracheoesophageal fistula, failure to thrive requiring concomitant gastrostomy, and biliary atresia. Kruskal–Wallis and Mann–Whitney tests were used where appropriate. Results Between 2010 and 2015, of 130 patients who underwent Ladd's procedure, 77 met inclusion criteria. Sixty-two patients underwent initial open surgery, 15 patients underwent laparoscopy, seven of which were converted to open. Patients undergoing open surgery were younger compared to the laparoscopic groups. Thirty-three of the 77 malrotation patients (43%) presented with volvulus, 27 underwent open surgery, four had laparoscopic converted to open procedures, and two patients underwent laparoscopic Ladd's without incident. Laparoscopy resulted in increased operative time and clinic visits. Patients undergoing laparoscopic to open surgery had longer operative times, time to resume diet, and length of hospital stay. No difference was noted in complications among the groups. Conclusions Although minimally invasive approaches are becoming increasingly used, no evidence supports laparoscopic superiority over open Ladd's procedure. We found that open surgery was associated with shorter operating times and fewer clinic visits. Furthermore, laparotomy remains the favored procedure for patients presenting with volvulus. [ABSTRACT FROM AUTHOR]

Background Biliary atresia (BA) is difficult to distinguish from other causes of cholestasis. We evaluated the use of liquid chromatography–mass spectroscopy (LC-MS) and bile acid profiles in the rapid, noninvasive diagnosis of BA. Materials and methods Following Institutional Animal Care and Use Committee and Institutional Review Board approval, we used LC-MS to measure 26 bile acids in serum and stool samples from experimental models of BA and in urine, stool, and serum samples from non-cholestatic and cholestatic human infants. Results We first evaluated the utility of LC-MS to distinguish bile acid profiles between sham, bile duct ligation, and 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse models of BA. Serum bile acids were significantly higher and stool bile acids were significantly lower in experimental BA. Next, we evaluated samples from non-cholestatic, cholestatic non-BA, and BA infants. There was no significant difference between cholestatic non-BA and BA stool and urine samples. However, primary bile acids were significantly higher in BA versus cholestatic non-BA samples (128.1 ± 14.2 versus 61.2 ± 20.5 μM). In addition, the primary, conjugated bile acids glycochenodeoxycholic acid and taurochenodeoxycholic acid were significantly elevated in BA compared with cholestatic non-BA serum samples. Using a receiver operating characteristic curve, we found that a serum glycochenodeoxycholic acid concentration of 30 μM had a sensitivity of 100%, specificity of 83.3%, positive predictive value of 88.9%, and negative predictive value of 100% in the diagnosis of BA. Conclusions Our data indicate that bile acid patterns can be used to distinguish experimental and human BA from non-cholestatic and, more importantly, cholestatic disease. This suggests that LC-MS may be useful in the accurate, rapid, and non-invasive diagnosis of BA. [ABSTRACT FROM AUTHOR]

Background Biliary atresia (BA) is a congenital, progressive, fibro-obliterative disease of the extrahepatic biliary tree and the most common cause of end-stage liver disease in children. BA is characterized by extensive intrahepatic proliferating ductular reactions that may contribute to biliary fibrosis. Lineage tracing during experimental cholestasis indicates that cells within ductular reactions derive from PROM1-expressing hepatic progenitor cells. Given the role of Notch signaling in normal biliary development, we hypothesize that activated Notch signaling promotes the formation of ductular reactions in BA. Methods Liver samples collected from BA infants at Kasai portoenterostomy and age-matched controls, as well as from wild-type and Prom1 knockout mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholestasis were analyzed histologically using immunofluorescence and by quantitative polymerase chain reaction. Results Increased expression of genes encoding Notch ligand JAG1 and its receptor NOTCH2 was observed in BA livers compared with control by quantitative polymerase chain reaction analyses. Livers of DDC-treated mice, which exhibit cytokeratin-19–positive ductular reactions typical of BA livers, demonstrated significant increases in the expression level of the gene encoding Notch2 , as well as downstream Notch target gene Hes1 compared with control. Prom1 knockout mice exhibit diminished ductular reactions and decreased levels of Jag1 and Hes1 compared with littermate controls. Conclusions Human BA and cholestasis induced by DDC are associated with Notch signaling activation. Null mutation of Prom1 is associated with decreased ductular reactions and decreased Notch signaling activation during DDC treatment. These data are consistent with Notch signaling promoting ductular reactions of Prom1 expressing progenitor cells in BA. [ABSTRACT FROM AUTHOR]

The Rhesus rotavirus (RRV) induced murine model of biliary atresia (BA) is a useful tool in studying the pathogenesis of this neonatal biliary obstructive disease. In this model, the mitogen associated protein kinase pathway is involved in RRV infection of biliary epithelial cells (cholangiocytes). We hypothesized that extracellular signal-related kinase (ERK) phosphorylation is integral to calcium influx, allowing for viral replication within the cholangiocyte. Utilizing ERK and calcium inhibitors in immortalized cholangiocytes and BALB/c pups, we determined that ERK inhibition resulted in reduced viral yield and subsequent decreased symptomatology in mice. In vitro , the RRV VP6 protein induced ERK phosphorylation, leading to cellular calcium influx. Pre-treatment with an ERK inhibitor or Verapamil resulted in lower viral yields. We conclude that the pathogenesis of RRV-induced murine BA is dependent on the VP6 protein causing ERK phosphorylation and triggering calcium influx allowing replication in cholangiocytes. [ABSTRACT FROM AUTHOR]

Biliary atresia presents as an obliterative cholangiopathy with neonatal jaundice and pale stools. The disease exhibits aetiological heterogeneity with a multiplicity of potential causative factors, both developmental and environmental. A number of clinical variants making up a minority of all cases can be defined relatively precisely which match suggested aetiology better although in most it still remains speculative. These include the syndromic form (BASM), the cystic form and those associated with CMV IgM antibodies. We review not only the clinical evidence for a developmental or an immune-mediated aetiology perhaps triggered by perinatal viral exposure but also several other recently suggested concepts such as microchimerism, gene susceptibility and environmental toxins. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 is a critical circulating adipokine involving in metabolic disorders and various liver diseases. This study was performed to investigate whether FGF21 is also associated with the pathophysiology of biliary atresia. Serum FGF21 levels were measured in 57 BA patients and 20 age matched healthy controls. We also examined hepatic FGF21 mRNA expression and FGF21 protein levels in liver tissues obtained from 15 BA patients undergoing liver transplantation and 5 cases of pediatric donation after cardiac death donor without liver diseases by RT-PCR and Western blotting. Patients with BA showed significantly higher serum FGF21 levels than those without BA (554.7 pg/mL [83–2300] vs. 124.5 pg/mL [66–270], P < 0.05). Patients with BA also had significantly higher FGF21 mRNA and protein levels in hepatic tissues than control subjects. Serum FGF21 expression increased corresponding to the severity of liver fibrosis. Furthermore, serum FGF21 levels dropped significantly in BA patients within 6 months after liver transplantation and approached baseline in healthy controls (P > 0.05). In vivo, FXR knockout could significantly abrogate cholestasis induced FGF21 expression. FGF21 levels in serum and liver tissue increased significantly in BA patients. In vivo, cholestasis could induce FGF21 expression in FXR dependent manner. [ABSTRACT FROM AUTHOR]

Highlights: [•] The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. [•] miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. [•] miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. [•] miR-222 might represent a potential target for improving biliary atresia prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Biliary atresia (BA) is a unique neonatal disease resulting from inflammatory and fibrosing obstruction of the extrahepatic biliary tree. Previous studies have demonstrated the critical role of innate immunity and the Th1 response to activated inflammatory cells and overexpressed cytokines in the pathogenesis of BA. Myeloid differentiation factor 88 (MyD88) is a critical adaptor molecule that has been shown to play a crucial role in immunity. We investigated the role of MyD88 in the inflammatory response and development of cholangiopathy in murine BA. Methods: MyD88 knockout (MyD88−/−) and wild-type (WT) BALB/c pups were injected with Rhesus rotavirus or saline on day 1 of life. The mice were monitored for clinical symptoms of BA, including jaundice, acholic stools, bilirubinuria, and death. The liver and extrahepatic bile ducts were harvested for histologic evaluation and the quantification of viral content, determination of cytokine expression, and detection of inflammatory cells. Results: Rhesus rotavirus infection produced symptoms in 100% of both MyD88−/− and WT pups, with survival of 18% of WT and 0% of MyD88−/− mice. Histologic analysis demonstrated bile duct obstruction in both MyD88−/− and WT mice. Viral titers obtained 7 d after infection and expression of interferon-γ and tumor necrosis factor-α at day 3, 5, 8, and 12 after infection revealed no significant differences between the WT and MyD88−/− mice. Flow cytometry demonstrated similar levels of activated CD8+ T cells and natural killer cells. Conclusions: The pathogenesis of murine BA is independent of the MyD88 signaling inflammatory pathway, suggesting alternative mechanisms are crucial in the induction of the model. [Copyright &y& Elsevier]

Abstract: Interleukin-33 (IL-33) plays a crucial role in inflammation. However, it is not clear whether IL-33 levels are of clinical significance for patients with biliary atresia (BA). The purpose of this study was to determine correlations between serum IL-33 levels and the clinicopathologic features of BA. Serum samples were collected from 18 BA infants, 12 nonicteric choledochal cyst (CC) infants with normal liver function, and 10 healthy controls (HCs). Serum IL-33 levels were measured with an enzyme-linked immunosorbent assay (ELISA). Routine liver function tests were performed on the serum samples. qRT-PCR and Western blot analysis were used to detect IL-33 expression in BA liver biopsy tissues. Hepatic lobule localization of IL-33 expression in the hepatic lobule was conducted by immunohistochemistry (IHC). IL-33 levels in serum collected from BA infants were significantly elevated in comparison with CC and HC patients. Furthermore, the elevated serum levels of IL-33 in BA infants were correlated with gamma-glutamyl transferase (GGT) levels. The expression of IL-33 mRNA and protein levels were up-regulated in BA liver biopsy tissues in comparison with CC patients. IHC analysis revealed increased positive immunostaining for IL-33 in BA liver tissues as compared to that in CC tissues. These results suggest that IL-33 may play an important role in the pathogenesis of BA. In addition, the correlation of serum IL-33 levels with GGT levels may provide a novel marker for the diagnosis of BA. [Copyright &y& Elsevier]

Abstract: Introduction: Biliary atresia (BA) is the leading indication for liver transplantation in the pediatric population. The murine model of BA supports a viral etiology, because infection of neonatal mice with rhesus rotavirus (RRV) results in biliary obstruction. Viral infection targets the biliary epithelium and development of the model is viral strain dependent. No study has yet determined whether human cholangiocytes are also susceptible to rotaviral infection. We established an in vitro human model using an immortalized human cholangiocyte cell line and primary human cholangiocytes obtained from explanted livers to determine human cholangiocyte susceptibility to rotavirus infection. Methods: Replication and binding assays were performed on immortalized mouse (mCL) and human (H69) cells using six different strains of rotavirus. Primary human cholangiocytes were isolated from cadaveric livers, characterized in culture, and infected with RRV, which causes BA in mice, and another simian strain, TUCH, which does not cause BA in mice. Results: Immortalized mouse and human cholangiocytes demonstrated similar patterns of infectivity and binding with different strains of rotavirus. Both cell lines produced a significantly higher viral yield with RRV infection than with the other strains tested. In primary human cholangiocytes, which maintained their epithelial characteristics, as demonstrated by cytokeratin staining, RRV replicated to a yield 1000-fold higher than TUCH. Conclusions: Both immortalized and primary human cholangiocytes are susceptible to RRV infection in a fashion similar to murine cholangiocytes. These novel findings suggest rotavirus infection could have a potential role in the pathogenesis of human BA. [Copyright &y& Elsevier]

Abstract: Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that leads to biliary cirrhosis and is the most common cause of liver transplantation in children. A still undetermined hepatobiliary viral infection may elicit an uncontrollable autoimmune response against the biliary epithelial cells in genetically predisposed children and culminates in atresia of the biliary trees. Interleukin 4 (IL4) is crucial for the differentiation of naive T helper cells into the T helper 2 effector cells that promote humoral immunity. This study aims to investigate whether polymorphisms of the IL4 gene are associated with susceptibility to BA. Genomic DNA was extracted from whole blood samples of 53 Taiwanese children with BA and 904 ethnically-matched healthy controls. The IL4 –590 C/T, –33 C/T, and 8375 A/G polymorphisms were genotyped using the Pre-Developed TaqMan Allelic Discrimination Assay in a real-time polymerase chain reaction system. No significant difference between children with BA and healthy controls were found when comparing genotype, allele, carrier, and haplotype frequencies of these IL4 gene variants. These results suggest that the tested polymorphisms of IL4 gene are unlikely to contribute significantly to BA susceptibility in Taiwanese children. [Copyright &y& Elsevier]

Abstract: Recent evidence indicates that alterations to epigenetic DNA methylation patterns contribute to many autoimmune diseases. Biliary atresia (BA) is a virus-induced autoimmune disease characterized by impaired T cells, which may be due to aberrant DNA methylation. CD11a, a subunit of the β2-integrin LFA-1 (CD11a/CD18) with costimulatory functions, is overexpressed due to hypomethylation of its promoter regulatory elements in CD4+ T cells from patients with many autoimmune diseases. However, it is unknown whether aberrant expression and methylation of CD11a occur in T cells from infants with BA. We aimed to compare the CD11a expression level and the methylation status of the CD11a promoter region in CD4+ T cells from BA infants and healthy controls (HC). We used real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to examine CD11a mRNA levels in CD4+ T cells from BA and HC infants. Bisulfite sequencing was used to determine the methylation status of the CD11a promoter and flanking regions in CD4+ T cells from BA and HC infants, and in CD4+ T cells with DNA methylation inhibitors. We found that CD11a expression is significantly decreased in BA CD4+ T cells (P =0.007). This was associated with hypermethylation of the CD11a promoter region in CD4+ T cells from infants with BA. Treatment with a DNA methylation inhibitor decreased CD11a promoter methylation and increased CD11a mRNA. Therefore, DNA hypermethylation at the CD11a locus contributes to the lowered expression of CD11a in BA CD4+ T cells. [Copyright &y& Elsevier]

Abstract: Biliary atresia (BA) is a progressive fibro-inflammatory pediatric liver disease in which osteopontin (OPN), a glycoprotein with inflammatory and fibrogenic activity, may play a pathogenic role. The current studies were conducted in a mouse model of rotavirus-induced BA to test the hypotheses that live but not inactivated rotavirus causes antigenemia, upregulation of hepatic OPN expression, and induction of BA and fibrosis; and that OPN is necessary for development of BA. Prolonged or transient antigenemia developed in mice inoculated with live or inactivated virus, respectively, but only live virus upregulated hepatic OPN and caused BA and fibrosis. OPN was expressed in intra- and extrahepatic bile ducts in healthy mice and in mice with BA. OPN-deficient mice, similar to WT mice, developed BA. Together, these data show that live but not inactivated rotavirus causes upregulation of hepatic OPN expression and BA but that OPN is not necessary for development of BA. [Copyright &y& Elsevier]

Background: Chronic inflammatory conditions of the biliary tree strongly predispose patients to biliary carcinoma. The aim of this study was to evaluate the role of interleukin-6 (IL-6) expression during biliary carcinogenesis in bilioenterostomized hamsters. Materials and Methods: Syrian hamsters were subjected to either a choledochoduodenostomy (CD, n =11) or a simple laparotomy (SL, n =10) and then received N-nitrosobis(2-oxopropyl)amine (BOP) treatment. The animals were sacrificed 20 wk after surgery and the development of biliary carcinoma, the presence and degree of cholangitis, and IL-6 expression on the biliary epithelia were examined histologically. Results: In the CD group, eight hamsters (73%) demonstrated persistent cholangitis and six (55%) of them developed intrahepatic biliary carcinoma, while no hamster without cholangitis showed any biliary carcinoma. In the SL group, cholangitis was recognized in four hamsters (40%) and no development of biliary carcinoma was identified. A significantly high incidence of tumor development (P =0.024) and a close correlation between the presence of cholangitis and the occurrence of biliary carcinoma (P =0.013) were thus evident in the CD group. Moreover, the degree of cholangitis was significantly higher in the CD hamsters (P =0.041) and an IL-6 overexpression was identified in five hamsters that had undergone a CD, with a scattered expression on the intra- and extrahepatic biliary epithelia. Despite the fact that the induced biliary carcinomas showed a multicentric occurrence in the liver, these tumors originated from within the restricted area where IL-6 was expressed. Conclusions: A deregulated IL-6 overexpression on the biliary epithelia may therefore be involved in inflammation-associated biliary carcinogenesis in hamsters that have undergone a bilioenterostomy. [Copyright &y& Elsevier]

Background: Hepatic fibrosis leading to cirrhosis is the major morbidity in patients with biliary atresia (BA). This fibrosis is due to an imbalance in extracellular matrix (ECM) breakdown and deposition. We have previously demonstrated increased mRNA expression for inhibitors of ECM breakdown without increased expression for mediators of ECM deposition in our animal model of BA by d 14. However, only a mild degree of hepatic fibrosis was seen at this time. We hypothesized that expression patterns for these proteins may change once more significant fibrosis had been established, and added resuscitation to the model to improve survival. Interestingly, we found that some mice spontaneously recovered at later time points with resuscitation, and thus compared expression for inhibitors of ECM breakdown and deposition in sick and recovered mice to determine the differences. Methods: Newborn Balb/c mice received an intraperitoneal injection 1.0 × 106 fluorescence forming units of rhesus rotavirus 24h after birth. Mice were monitored daily for weight gain, development of jaundice, acholic stools, and bilirubinuria. Fifty μL/g of 5% dextrose in normal saline were subcutaneously injected daily to each mouse starting on d 7 until sacrifice. Mice that survived past d 14 were sacrificed at d 21 after saline or RRV infection. Livers were then harvested post-injection d 21 for histologic and immunohistochemical analysis. RNA expression of known mediators of fibrosis was evaluated using quantitative real-time PCR. Protein expression was assessed using ELISA. Weights and normally distributed data were compared using Student''s t test. Histologic findings were compared using Fisher''s exact test. Comparisons of gene expression and skewed data were performed by the Mann-Whitney U test. Statistical significance was assigned to any P value less than 0.05. Results: Daily resuscitation resulted in a 35% (24/68) survival rate to d 21 in our model. Mice that recovered were significantly heavier than those that remained ill on d 14 (6.15 ± 1.16 versus 4.94 ± 0.82, P = 0.02) and 21 (7.31 ± 1.41 versus 4.14 ± 0.53, P < 0.001) despite the fact that there was no difference between the groups with respect to weight on d 7 (4.29 ± 0.90 versus 3.89 ± 0.81, P = 0.32). We found that all (10/10) animals that displayed clinical signs of biliary atresia on d 21 had moderate or severe histologic findings, while only one (1/9) of the recovered animals had liver abnormalities at sacrifice (P < 0.001 versus sick group). We also found that the sick mice had statistically significant median fold-increases of mRNA expression for TIMP-1 (31.9 versus 9.1, P = 0.041), TIMP-4 (88.1 versus 1.8, P = 0.022), and MMP-7 (51.8 versus 11.9, P = 0.006) compared with those that recovered. There was a trend toward decreased mRNA expression for PAI-1, which did not reach statistical significance (median 27.7 versus 2.19, P = 0.066). Increased protein expression for TIMP-1 and PAI-1 were also found in the sick group. The mRNA expression for the fibrillar collagens, fibronectin-1, connective tissue growth factor, snail-1, TIMP-2 and -3, and MMP-2 and MMP-9 was not different in the sick and recovered groups 21 d after RRV infection, and was not elevated from baseline gene expression. Conclusions: With resuscitation added to the animal model of BA, some mice spontaneously recover while others progress to more significant hepatic fibrosis. Mice with hepatic fibrosis have a continued increase in mRNA expression of TIMP-1, TIMP-4, and MMP-7, with a trend toward increased mRNA expression of PAI-1 on d 21. Protein levels for TIMP-1 and PAI-1 were also increased in the sick mice. Recovered mice display mild to no hepatic parenchymal disease and a normal pattern of mRNA expression for the mediators of fibrosis tested. No increase in mRNA expression for the mediators of ECM deposition was found in either group. These data further support the notion that inhibition of ECM breakdown alone is sufficient to induce hepatic fibrosis. Modulation of this process may be a putative target for preventing liver injury in patients with BA. [Copyright &y& Elsevier]

Background: Biliary atresia is characterized by extrahepatic bile duct obliteration along with persistent intrahepatic portal inflammation. Steroids are standard in the treatment of cholangitis following the Kasai portoenterostomy, and were advocated for continued suppression of the ongoing immunologic attack against intrahepatic ducts. Recent reports, however, have failed to demonstrate an improved patient outcome or difference in the need for liver transplant in postoperative patients treated with a variety of steroid regimes compared with historic controls. In the wake of progressive liver disease despite biliary decompression, steroids are hypothesized to suppress inflammation and promote bile flow without any supporting data regarding their effect on the emerging cellular and molecular mechanisms of liver repair. We have previously shown in a reversible model of cholestatic injury that repair is mediated by macrophages, neutrophils, and specific matrix metalloproteinase activity (MMP8); we questioned whether steroids would alter these intrinsic mechanisms. Methods: Rats underwent biliary ductal suspension for 7 d, followed by decompression. Rats were treated with IV dexamethasone or saline at the time of decompression. Liver tissue obtained at the time of decompression or after 2 d of repair was processed for morphometric analysis, immunohistochemistry, and quantitative RT-PCR. Results: There was a dramatic effect of dexamethasone on the inflammatory component with the initiation of repair. Immunohistochemistry revealed a reduction of both ED1+ hepatic macrophages and ED2+Kupffer cells in repair compared with saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by day 2. TNF-α expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (day 2) whereas IL-6, IL-10, and CINC-1 remained unchanged compared with saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by day 2, whereas MMP9, 13, and 14 were unchanged compared with sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups Conclusion: Dexamethasone has clear effects on both the hepatic macrophage populations and infiltrating neutrophils following biliary decompression. Altered MMP and TIMP gene expression might suggest that steroids have the potential to modify matrix metabolism during repair. Nevertheless, successful resorption of collagen fibrosis proceeded presumably through other MMP activating mechanisms. We conclude that steroids do not impede the rapid intrinsic repair mechanisms of matrix degradation required for successful repair. [Copyright &y& Elsevier]

Introduction: Biliary atresia (BA) is a progressive obliteration of the extrahepatic bile ducts resulting in hepatic fibrosis. The underlying mechanisms have not been defined. We used an animal model of BA to evaluate mediators of extracellular matrix (ECM) processing to determine which factors may be involved. Methods: Newborn BALB/c mice received an intraperitoneal injection with rhesus rotavirus or saline within 24 h of birth. Livers were harvested on days 7 and 14 for histology and immunohistochemistry (IHC). RNA expression was determined using quantitative real-time PCR. Human liver from patients with BA and those having a resection for nonfibrosing diseases was also evaluated. Results: In experimental mice, mRNA expression for tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-7 was increased 18-fold and 69-fold, respectively on day 7, with further increases on day 14. On day 14, mRNA expression for plasminogen activator inhibitor (PAI)-1 (38-fold), TIMP-4 (9.5-fold), and MMP-9 (5.5-fold) mRNA was also observed. Furthermore, integrin αv β6 mRNA expression was increased on days 7 (11-fold) and 14 (6-fold). Presence of integrin αv β6 protein was confirmed by IHC in both mouse and human specimens in the proliferating biliary epithelium. Conclusions: Our data suggest experimental BA is associated with increased mRNA expression of ECM degradation inhibitors, TIMP-1, PAI-1, and TIMP-4. MMP-7 and MMP-9 expression is also elevated in this model. Furthermore, increased gene expression of integrin αvβ6 was demonstrated and IHC confirmed protein expression. Integrin αvβ6 or the inhibitors of ECM breakdown may be attractive targets for future treatment strategies. [Copyright &y& Elsevier]

Introduction: In the new era of resident work hour restrictions and an emphasis on minimally invasive surgery, experience in performing open biliary surgery is diminishing. We sought to review our resident operative experience to determine if it appears adequate for a well-trained general surgeon. Methods: The case logs of the General Surgery, Oncology, and Trauma/Emergency General Surgery (EGS) services were reviewed for a 1-year period. All biliary procedures that included the potential for gallbladder or bile duct surgery were reviewed. Results: We performed 745 laparoscopic cholecystectomies last year on our General Surgery, Oncology, and Trauma/EGS services. Conversion to open procedure was 4.5% (16/364) on our elective services and 6% (23/381) on our Trauma/EGS services. Effective clearance of common bile duct stones performed retrograde by endoscopy and transhepatically by interventional radiology limited our residents’ experience performing common bile duct surgery for stones to 13 performed laparoscopically and 10 performed open. Other operations that included open cholecystectomies and common bile duct procedures were pancreatico-duodenectomy (87), biliary bypass (22), biliary resection/reconstruction (20), hepatic lobectomy (48), sphincteroplasty and ampullectomy (6). Conclusions: The small number of conversions from laparoscopic to open cholecystectomies and the few common bile duct explorations performed for stone disease would be inadequate to train our six categorical surgical residents to perform open cholecystectomies and common bile duct procedures without a training program that augments this by providing a strong hepato-biliary-pancreatic experience. Programs without a strong hepato-biliary-pancreatic program should review their residents’ operative experience. [Copyright &y& Elsevier]

Background: The purpose of the study was to compare the intraoperative blood glucose changes and the dosage of glucose infused between biliary atresia and glycogen storage disease (GSD) patients undergoing living donor liver transplantation (LDLT). Patients and methods: The anesthesia records of biliary atresia and GSD patients undergoing LDLT were reviewed retrospectively. The levels of intraoperative blood glucose before operation, after induction of anesthesia, in the dissection, anhepatic, 10 min after reperfusion, and at the end of operation, as well as the dosage glucose infused, were compared between groups. The Mann-Whitney U test was used for statistical analysis; P &#60; 0.05 was regarded as significant. Results: Seventy-two biliary atresia patients were grouped into group I (GI) and 8 GSD patients into group II (GII). The blood glucose levels of both groups increased after operation and remained hyperglycemic, around 100–300 mg/dl, until the end of the operation. The mean glucose amounts infused were 2.7 ± 1.9 and 2.5 ± 1.15 mg/kg/min for GI and GII, respectively. Conclusion: No significant difference was found in the anesthetic management between groups. The only difference was that the GSD patients required continuous glucose supply the night before the operation, while biliary atresia patients did not. [Copyright &y& Elsevier]

Abstract: Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4+ T cells producing IFN-γ and in macrophages producing TNF-α. The intrahepatic pattern of inflammation evolved rapidly from an initial predominant CD4+ Th1 cellular response to a subsequent influx of activated macrophages producing TNF-α and iNOS. This immune response persisted despite viral clearance and was representative of the hepatic immune profile present in human BA. Utilization of the murine model of BA yielded mechanistic data that can provide much needed insight into the role played by different arms of the immune system related to the pathogenesis of human BA. [Copyright &y& Elsevier]

Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis. Our findings revealed that the serum levels and hepatic expression of Slit2 were significantly increased in patients with primary biliary cirrhosis (PBC). Additionally, Slit2-Tg mice were much more vulnerable to BDL-induced liver injury and fibrosis compared to WT control. Slit2 up-regulation by Slit2 recombinant protein induced proliferation, and inhibited apoptosis of human HSCs cell line LX-2 via p38 and ERK signaling pathway, resulting in the activation of HSCs. In contrast, Slit2 down-regulation by siRNA silencing inhibit the activation of HSCs. In conclusion, Slit2 is involved in the activation of HSCs and liver fibrogenesis, highlighting Slit2 as a potential therapeutic target for liver fibrosis. • Liver fibrosis is related with high Slit2 expression in both liver biliary atresia (PBC) patients and BDL-induced mice. • Slit2 up-regulation promoted the activation and proliferation, whereas inhibited the apoptosis of human HSCs cell line LX-2. • Slit2 promoted the activation, survival and proliferation of HSCs likely via up-regulating ERK1/2 and p38 signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Background: In our institutional experience treating pediatric choledochal cysts over the past 12 y, we noted that seven of 32 patients (21.9%) had comorbid congenital cardiac anomalies. This association has not been previously described other than in isolated case reports. We aimed to quantify this association on a national level. Materials and methods: We queried the 2009 Healthcare Cost and Utilization Project Kids'' Inpatient Database. We identified patients with a diagnosis of choledochal cyst (ICD-9-CM 75169, 75162, and 75160) or biliary atresia (75161). We defined cardiac anomalies using the Clinical Classification Software code (CCS 213). Comorbid choledochal cysts or biliary atresia and congenital cardiac anomalies were quantified in both infant (<12 mo) and child (1–18 y) subpopulations. Results: Of 1646 estimated discharges for patients with choledochal cysts, 506 (30.7%) were for patients who also had congenital cardiac anomalies, compared with 2.6% in the general hospitalized population (χ2; P < 0.001). The frequency of congenital cardiac anomalies was lower in 1973 hospitalizations for biliary atresia (13.8%) than in those for patients with choledochal cysts (χ2; P < 0.001). We detected cardiac anomalies in 44.9% of choledochal cyst hospitalizations for infants <12 mo (versus 3.44% general hospitalized population; χ2; P < 0.001), but in 6.9% of children ages 1–18 y (versus 1.3% general hospitalized population; χ2; P < 0.001). Conclusions: We observed a strong association between pediatric choledochal cysts and congenital cardiac anomalies that commonly manifests in infancy. When choledochal cysts are diagnosed either prenatally or in infancy, we suggest echocardiographic screening for cardiac anomalies, which may affect the timing of surgery and anesthetic planning. [Copyright &y& Elsevier]